Profitability, uncertainty and multi-product firm product proliferation: The Spanish car industry

This article studies how product introduction decisions relate to profitability and uncertainty in the context of multi-product firms and product differentiation. These two features, common to many modern industries, have not received much attention in the literature as compared to the classical problem of firm entry, even if the determinants of firm and product entry are quite different. The theoretical predictions about the sign of the impact of uncertainty on product entry are not conclusive. Therefore, an econometric model relating firms’ product introduction decisions with profitability and profit uncertainty is proposed. Firm’s estimated profits are obtained from a structural model of product demand and supply, and uncertainty is proxied by profits’ variance. The empirical analysis is carried out using data on the Spanish car industry for the period 1990-2000. The results show a positive relationship between product introduction and profitability, and a negative one with respect to profit variability. Interestingly, the degree of uncertainty appears to be a driving force of entry stronger than profitability, suggesting that the product proliferation process in the Spanish car market may have been mainly a consequence of lower uncertainty rather than the result of having a more profitable market. Keywords: Product introduction, entry, uncertainty, multiproduct firms, automobile JEL codes: L11, L13

Phenotypic and molecular characterization of proliferating and differentiated GnRH-expressing GnV-3 cells.

GnRH neurons provide the primary driving force upon the neuroendocrine reproductive axis. Here we used GnV-3 cells, a model of conditionally immortalized GnRH-expressing neurons, to perform an analysis of cell cycle and compare the gene expression profile of proliferating cells with differentiated cells. In the proliferation medium, 45 ± 1.5% of GnV-3 cells are in S-phase by FACS analysis. In the differentiation medium, only 9 ± 0.9% of them are in S-phase, and they acquire the characteristic bipolar shape displayed by preoptic GnRH neurons in vivo. In addition, GnV-3 cells in the differentiated state exhibit electrophysiological properties characteristic of neurons. Transcriptomic analysis identified up-regulation of 1931 genes and down-regulation of 1270 genes in cells grown in the differentiation medium compared to cells in the proliferation medium. Subsequent gene ontology study indicated that genes over-expressed in proliferating GnV-3 cells were mainly involved in cell cycle regulations, whereas genes over-expressed in differentiated cells were mainly involved in processes of differentiation, neurogenesis and neuronal morphogenesis. Taken together, these data demonstrate the occurrence of morphological and physiological changes in GnV-3 cells between the proliferating and the differentiated state. Moreover, the genes differentially regulated between these two different states are providing novel pathways potentially important for a better understanding of the physiology of mature GnRH neurons.

Middle and Late Jurassic carbon stable-isotope stratigraphy and radiolarite sedimentation of the Umbria-Marche basin (Central Italy)

A continuous carbon isotope curve from Middle-Upper Jurassic pelagic carbonate rocks was acquired from two sections in the southern part of the Umbria-Marche Apennines in central Italy. At the Colle Bertone section (Terni) and the Terminilletto section (Rieti), the Upper Toarcian to Bajocian Calcari e Marne a Posidonia Formation and the Aalenian to Kimmeridgian Calcari e Marne a Posidonia and Calcari Diasprigni formations were sampled, respectively. Biostratigraphy in both sections is based on rich assemblages of calcareous nannofossils and radiolarians, as well as some ammonites found in the upper Toarcian-Bajocian interval. Both sections revealed a relative minimum of delta(13)C(PDB) close to + 2 parts per thousand in the Aalenian and a maximum around 3.5 parts per thousand in early Bajocian, associated with an increase in visible chert. In basinal sections in Umbria-Marche, this interval includes the very cherry base of the Calcari Diasprigni Formation (e.g. at Valdorbia) or the chert-rich uppermost portion of the Calcari a Posidonia (e.g at Bosso). In the Terminilletto section, the Bajocian-early Barthonian interval shows a gradual decrease in delta(13)C(PDB) values and a low around 2.3 parts per thousand. This part of the section is characterised by more than 40 m of almost chart-free limestones and correlates with a recurrence of limestone-rich facies in basinal sections at Valdorbia. A double peak with values of delta(13)C(PDB) around + 3 parts per thousand was observed in the Callovian and Oxfordian, constrained by well preserved radiolarian faunas. The maxima lie in the Callovian and the middle Oxfordian, and the minimum between the two peaks should be near the Callovian/Oxfordian boundary. In the Terminilletto section, visible chert increases together with delta(13)C(PDB) values from the middle Bathonian and reaches peak values in the Callovian-Oxfordian. In basinal sections in Umbria-Marche, a sharp increase in visible chert is observed at this level within the Calcari Diasprigni. A drop of delta(13)C values towards + 2 parts per thousand occurs in the Kimmeridgian and coincides with a decrease of visible chert in outcrop. The observed delta(13)C positive anomalies during the early Bajocian and the Callovian-Oxfordian may record changes in global climate towards warmer, more humid periods characterised by increased nutrient mobilisation and increased carbon burial. High biosiliceous (radiolarians, siliceous sponges) productivity and preservation appear to coincide with the delta(13)C positive anomalies, when the production of platform carbonates was subdued and ceased in many areas, with a drastic reduction of periplatform ooze input in many Tethyan basins. The carbon and silica cycles appear to be linked through global warming and increased continental weathering. Hydrothermal events related to extensive rifting and/or accelerated oceanic spreading may be the endogenic driving force that created a perturbation of the exogenic system (excess CO2 into the atmosphere and greenhouse conditions) reflected by the positive delta(13)C shifts and biosiliceous episodes.

Melt topology and chemistry during partial melting in contact aureoles : an experimental study and field example

This study was initiated to investigate partial melting within the high-grade metamorphic rocks beneath the Little Cottonwood contact aureole (Utah, USA), in order to understand the melt generation, melt migration, and geometry of initial melt distribution on grain scale during crustal anatexis. The emplacement of the Little Cottonwood stock produced a contact aureole in the pelitic host rocks of the Big Cottonwood formation (BC). Metamorphic isogrades in pelitic rocks range form biotite to 2nd sillimanite grade as a function of distance from the contact. Migmatites are restricted to the highest grade and resulted form partial melting of the BC formation rocks. First melt was produced by a combined muscovite/biotite dehydration reaction in the sillimanite + k-feldspar stability field. Melt extraction from the pelites resulted in restites (magnetite + cordierite + alumosilicate ± biotite) surrounded by feldspar enriched quartzite zones. This texture is the result of gradual infiltration of partial melts into the quartzite. Larger, discrete melt accumulation occurred in extensional or transpressional domains such as boudin necks, veins, and ductile shear zones. Melt composition are Si02- rich, crystallized as pegmatites, and apparently were very mobile. They were able to infiltrate the quartzite pervaisivly. These melts are similar in composition to first melts produced in the hydrothermal partial melt experiments at 2kbar between 700 - 800°C on fine grained high metamorphic rocks (andalusite-cordierited-biotite-zone) of the BC formation. The experimental melts are water rich and in disequilibrium with the melting rock. Initial melt composition is heterogeneous for short run duration, reflective a lack of chemical equilibrium between individual melt pools. Rock core scale heterogeneity decreased with time indicating partial homogenization of melt compositions. A simultaneous shift of melt composition to higher silica content with time was observed. The silica content of the melt increased due to local melt/mineral reactions. Melt textures indicate that reactive melt transport is most efficient along grain boundaries rimmed by dissimilar grains. Melt heterogeneity resulted in chemical potential gradients which are major driving forces for initial melt migration and govern melt distribution during initial melting. An additional subject of the thesis is the crystal size distributions of opaque minerals in a fine-grained, high-grade meta-pelite of the Big Cottonwood which were obtained from 3D X-ray tomography (uCT) and 2D thin section analysis. µCT delivers accurate size distributions within a restricted range (~ a factor of 20 in size in a single 3D image), while the absolute number of crystals is difficult to obtain from these sparsely distributed, small crystals on the basis of 2D images. Crystal size distributions obtained from both methods are otherwise similar. - Ce travail de recherche a été entrepris dans le but d'étudier les processus de fusion partielle dans les roches fortement métamorphiques de l'auréole de contact de Little Cottonwood (Utah, USA) et ceci afin de comprendre la génération de liquide de fusion, la migration de ces liquides et la géométrie de la distribution initiale des liquides de fusion à l'échelle du grain durant l'anatexie de la croûte. L'emplacement du petit massif intrusif de Little Cottonwood a produit une auréole de contact dans les roches pélitiques encaissantes appartenant à la Foimation du Big Cottonwood (BC). Les isogrades métamorphiques dans les roches pélitiques varient de l'isograde de la biotite à la deuxième isograde de la sillimanite en fonction de la distance par rapport au massif intrusif. Les migmatites sont restreintes aux zones montrant le plus haut degré métamorphique et résultent de la fusion partielle des roches de la Formation de BC. Le premier liquide de fusion a été produit par la réaction de déshydratation combinée de la muscovite et de la biotite dans le champ de stabilité du feldspath potassique Pt de la sillimanite. L'extraction du liquide de fusion des pélites forme des restites (magnétites + cordiérite + aluminosilicate ± biotite) entourées par des zones de quartzites enrichies en feldspath. Cette texture est le résultat de l'infiltration graduelle du liquide de fusion partielle dans les quartzites. Des accumulations distinctes et plus larges de liquide de fusion ont lieu dans des domaines d'extension ou de transpression tels que les boudins, les veines, et les zones de cisaillement ductile. La composition des liquides de fusion est similaire à celle des liquides pegmatoïdes, et ces liquides sont apparemment très mobiles et capables d'infiltrer les quartzites. Ces liquides de fusion ont la même composition que les premiers liquides produits dans les expériences hydrotheunales de fusion partielle à 2kbar et entre 700-800° C sur les roches finement grenues et hautement métamorphiques (andalousite-cordiérite-biotite zone) de la Formation de BC. Les liquides de fusion obtenus expérimentalement sont riches en eau et sont en déséquilibre avec la roche en fusion. La composition initiale des liquides de fusion est hétérogène pour les expériences de courte durée et reflète l'absence d'équilibre chimique entre les différentes zones d'accumulation des liquides de fusion. L'hétérogénéité à l'échelle du noyau s'estompe avec le temps et témoigne de l'homogénéisation de la composition des liquides de fusion. Par ailleurs, on observe parallèlement un décalage de la composition des liquides vers des compositions plus riches en silice au cours du temps. Le contenu en silice des liquides de fusion évolue vers un liquide pegmatitique en raison des réactions liquides/minéraux. Les textures des liquides de fusion indiquent que le transport des liquides est plus efficace le long des bordures de grains bordés par des grains différents. Aucun changement apparent du volume total n'est visible. L'hétérogénéité des liquides s'accompagne d'un gradient de potentiel chimique qui sert de moteur principal à la migration des liquides et à la distribution des liquides durant la fusion. Un sujet complémentaire de ce travail de thèse réside dans l'étude de la distribution de la taille des cristaux opaques dans les pélites finement grenues et fortement métamorphiques de la Formation de Big Cottonwood. Les distributions de taille ont été obtenues suite à l'analyse d'images 3D acquise par tomographie ainsi que par analyse de lames minces. La microtomographie par rayon X fournit une distribution de taille précise sur une marge restreinte (- un facteur de taille 20 dans une seule image 3D), alors que le nombre absolu de cristaux est difficile à obtenir sur la base d'image 2D en raison de la petite taille et de la faible abondance de ces cristaux. Les distributions de taille obtenues par les deux méthodes sont sinon similaire. Abstact: Chemical differentiation of the primitive Earth was due to melting and separation of melts. Today, melt generation and emplacement is still the dominant process for the growth of the crust. Most granite formation is due to partial melting of the lower crust, followed by transport of magma through the crust to the shallow crust where it is emplaced. Partial melting and melt segregation are essential steps before such a granitic magma can ascent through the crust. The chemistry and physics of partial melting and segregation is complex. Hence detailed studies, in which field observations yield critical information that can be compared to experimental observations, are crucial to the understanding of these fundamental processes that lead and are leading to the chemical stratification of the Earth. The research presented in this thesis is a combined field and experimental study of partial melting of high-grade meta-pelitic rocks of the Little Cottonwood contact aureole (Utah, USA). Contact metamorphic rocks are ideal for textural studies of melt generation, since the relatively short times of the metamorphic event prevents much of the recrystallization which plagues textural studies of lower crustal rocks. The purpose of the study is to characterize melt generation, identify melting reactions, and to constrain melt formation, segregation and migration mechanisms. In parallel an experimental study was undertaken to investigate melt in the high grade meta pelitic rocks, to confirm melt composition, and to compare textures of the partial molten rock cores in the absence of deformation. Results show that a pegmatoidal melt is produced by partial melting of the pelitic rocks. This melt is highly mobile. It is capable of pervasive infiltration of the adjacent quartzite. Infiltration results in rounded quartz grains bordered by a thin feldspar rim. Using computed micro X-ray tomography these melt networks can be imaged. The infiltrated melt leads to rheological weakening and to a decompaction of the solid quartzite. Such decompaction can explain the recent discovery of abundant xenocrysts in many magmas, since it favors the isolation of mineral grains. Pervasive infiltration is apparently strongly influenced by melt viscosity and melt-crystal wetting behavior, both of which depend on the water content of melt and the temperature. In all experiments the first melt is produced on grain boundaries, dominantly by the local minerals. Grain scale heterogeneity of a melting rock leads thus to chemical concentration gradients in the melt, which are the driving force for initial melt migration. Pervasive melt films along grain boundaries leading to an interconnected network are immediately established. The initial chemical heterogeneities in the melt diminish with time. Résumé large public: La différenciation chimique de la Terre primitive est la conséquence de la fusion des roches et de la séparation des liquides qui en résultent. Aujourd'hui, la production de liquide magmatique est toujours le mécanisme dominant pour la croissance de la croûte terrestre. Ainsi la formation de la plupart des granites est un processus qui implique la production de magma par fusion partielle de la croûte inférieure, la migration de ces magmas à travers la croûte et finalement son emplacement dans les niveaux superficielle de la croûte terrestre. Au cours de cette évolution, les processus de fusion partielle et de ségrégation sont des étapes indispensables à l'ascension des granites à travers la croûte. Les conditions physico-chimiques nécessaires à la fusion partielle et à l'extraction de ces liquides sont complexes. C'est pourquoi des études détaillées des processus de fusion partielle sont cruciales pour la compréhension de ces mécanismes fondamentaux responsables de la stratification chimique de la Terre. Parmi ces études, les observations de terrain apportent notamment des informations déterminantes qui peuvent être comparées aux données expérimentales. Le travail de recherche présenté dans ce mémoire de thèse associe études de terrain et données expérimentales sur la fusion partielle des roches pélitiques de haut degré métamorphiques provenant de l'auréole de contact de Little Cottonwood (Utah, USA). Les roches du métamorphisme de contact sont idéales pour l'étude de la folination de liquide de fusion. En effet, la durée relativement courte de ce type d'événement métamorphique prévient en grande partie la recristallisation qui perturbe les études de texture des roches dans la croûte inférieure. Le but de cette étude est de caractériser la génération des liquides de fusion, d'identifier les réactions responsables de la fusion de ces roches et de contraindre la formation de ces liquides et leur mécanisme de ségrégation et de migration. Parallèlement, des travaux expérimentaux ont été entrepris pour reproduire la fusion partielle de ces roches en laboratoire. Cette étude a été effectuée dans le but de confirmer la composition chimique des liquides, et de comparer les textures obtenues en l'absence de déformation. Les résultats montrent qu'un liquide de fusion pegmatoïde est produit par fusion partielle des roches pélitiques. La grande mobilité de ce liquide permet une infiltration pénétrative dans les quarzites. Ces infiltrations se manifestent par des grains de quartz arrondis entourés par une fine bordure de feldspath. L'utilisation de la tomography à rayons X a permis d'obtenir des images de ce réseau de liquide de fusion. L'infiltration de liquide de fusion entraîne un affaiblissement de la rhéologie de la roche ainsi qu'une décompaction des quartzites massifs. Une telle décompaction peut expliquer la découverte récente d'abondants xénocristaux dans beaucoup de magmas, puisque elle favorise l'isolation des minéraux. L'infiltration pénétrative est apparemment fortement influencée par la viscosité du fluide de fusion et le comportement de la tension superficielle entre les cristaux et le liquide, les deux étant dépendant du contenu en eau dans le liquide de fusion et de la température. Dans toutes les expériences, le premier liquide est produit sur les bordures de grains, principalement par les minéraux locaux. L'hétérogénéité à l'échelle des grains d'une roche en fusion conduit donc à un gradient de concentration chimique dans le liquide, qui sert de moteur à l'initiation de la migration du liquide. Des fines couches de liquide de fusion le long de bordures de grains formant un réseau enchevêtré s'établit immédiatement. Les hétérogénéités chimiques initiales dans le liquide s'estompent avec le temps.

Nanopartícul·les core-shell estabilitzades en polímer amb propietats calítiques i bactericides medioambientalment segure

Aquest projecte de doctorat és un treball interdisciplinari adreçat a l’obtenció de nous nanocompòsits (NCs) funcionals sintetitzats a partir de materials polimèrics bescanviadors d’ions que són modificats amb nanopartícules metàl•liques (NPMs) de diferent composició. Els materials desenvolupats s’avaluen en funció de dues possibles aplicacions: 1) com a catalitzadors de reaccions orgàniques d’interès actual (NCs basats en pal•ladi) i, 2) la seva dedicació a aplicacions bactericides en el tractament d’aigües domèstiques o industrials (NCs basats en plata). El desenvolupament de nanomaterials és de gran interès a l’actualitat donades les seves especials propietats, l’aprofitament de les quals és la força impulsora per a la fabricació de nous NCs. Les nanopartícules metàl•liques estabilitzades en polímer (Polymer Stabilized Metal Nanoparticles, PSNPM) s’han preparat mitjançant la tècnica in-situ de síntesi intermatricial (Inter-matrix synthesis, IMS) que consisteix en la càrrega seqüencial dels grups funcionals de les matrius polimèriques amb ions metàl•lics, i la seva posterior reducció química dins de la matriu polimèrica de bescanvi iònic. L’estabilització en matrius polimèriques evita l’agregació entre elles (self-aggreagtion), un dels principals problemes coneguts de les NPs. Pel desenvolupament d’aquesta metodologia, s’han emprat diferents tipus de matrius polimèriques de bescanvi iònic: membrana Sulfonated PolyEtherEtherKetone, SPEEK, així com fibres sintètiques basades en polypropilè amb diferents tipus de grups funcionals, que ens permeten el seu ús com a filtres en la desinfecció de solucions aquoses o com a material catalitzador. Durant el projecte s’ha anat avançant en l’optimització del material nanocomposite final per a les aplicacions d’interès, en quant activitat i funcionalitat de les nanopartícules i estabilitat del nanocomposite. Així, s’ha optimitzat la síntesi de NPs estabilitzades en resines de bescanvi iònic, realitzant un screening de diferents tipus de resines i la seva avaluació en aplicacions industrials d’interès.

Distinct population structure for co-occurring Anopheles goeldii and Anopheles triannulatus in Amazonian Brazil

To evaluate whether environmental heterogeneity contributes to the genetic heterogeneity in Anopheles triannulatus, larval habitat characteristics across the Brazilian states of Roraima and Pará and genetic sequences were examined. A comparison with Anopheles goeldii was utilised to determine whether high genetic diversity was unique to An. triannulatus. Student t test and analysis of variance found no differences in habitat characteristics between the species. Analysis of population structure of An. triannulatus and An. goeldii revealed distinct demographic histories in a largely overlapping geographic range. Cytochrome oxidase I sequence parsimony networks found geographic clustering for both species; however nuclear marker networks depicted An. triannulatus with a more complex history of fragmentation, secondary contact and recent divergence. Evidence of Pleistocene expansions suggests both species are more likely to be genetically structured by geographic and ecological barriers than demography. We hypothesise that niche partitioning is a driving force for diversity, particularly in An. triannulatus.

Profitability, uncertainty and multi-product firm product proliferation: The Spanish car industry

This article studies how product introduction decisions relate to profitability and uncertainty in the context of multi-product firms and product differentiation. These two features, common to many modern industries, have not received much attention in the literature as compared to the classical problem of firm entry, even if the determinants of firm and product entry are quite different. The theoretical predictions about the sign of the impact of uncertainty on product entry are not conclusive. Therefore, an econometric model relating firms’ product introduction decisions with profitability and profit uncertainty is proposed. Firm’s estimated profits are obtained from a structural model of product demand and supply, and uncertainty is proxied by profits’ variance. The empirical analysis is carried out using data on the Spanish car industry for the period 1990-2000. The results show a positive relationship between product introduction and profitability, and a negative one with respect to profit variability. Interestingly, the degree of uncertainty appears to be a driving force of entry stronger than profitability, suggesting that the product proliferation process in the Spanish car market may have been mainly a consequence of lower uncertainty rather than the result of having a more profitable market

Social and commercial entrepreneurship: same, different, or both?

Entrepreneurship has been the engine propelling much of the growth of the business sector as well as a driving force behind the rapid expansion of the social sector. This article offers a comparative analysis of commercial and social entrepreneurship using a prevailing analytical model from commercial entrepreneurship. The analysis highlights key similarities and differences between these two forms of entrepreneurship and presents a framework on how to approach the social entrepreneurial process more systematically and effectively. We explore the implications of this analysis of social entrepreneurship for both practitioners and researchers.

Education and male-female differences in later-life cognition: international evidence from latin america and the Caribbean.

This study explores the role of early-life education for differences in cognitive functioning between men and women aged 60 and older from seven major urban areas in Latin America and the Caribbean. After documenting statistically significant differences in cognitive functioning between men and women for six of the seven study sites, I assess the extent to which these differences can be explained by prevailing male-female differences in education. I decompose predicted male-female differences in cognitive functioning based on various statistical models for later-life cognition and find robust evidence that male-female differences in education are a major driving force behind cognitive functioning differences between older men and women. This study therefore suggests that early-life differences in educational attainment between boys and girls during childhood have a lasting impact on gender inequity in cognitive functioning at older ages. Increases in educational attainment and the closing of the gender gap in education in many countries in Latin America and the Caribbean may thus result in both higher levels and a more gender-equitable distribution of later-life cognition among the future elderly in those countries.

Experimental plant communities develop phylogenetically overdispersed abundance distributions during assembly

The importance of competition between similar species in driving community assembly is much debated. Recently, phylogenetic patterns in species composition have been investigated to help resolve this question: phylogenetic clustering is taken to imply environmental filtering, and phylogenetic overdispersion to indicate limiting similarity between species. We used experimental plant communities with random species compositions and initially even abundance distributions to examine the development of phylogenetic pattern in species abundance distributions. Where composition was held constant by weeding, abundance distributions became overdispersed through time, but only in communities that contained distantly related clades, some with several species (i.e., a mix of closely and distantly related species). Phylogenetic pattern in composition therefore constrained the development of overdispersed abundance distributions, and this might indicate limiting similarity between close relatives and facilitation/complementarity between distant relatives. Comparing the phylogenetic patterns in these communities with those expected from the monoculture abundances of the constituent species revealed that interspecific competition caused the phylogenetic patterns. Opening experimental communities to colonization by all species in the species pool led to convergence in phylogenetic diversity. At convergence, communities were composed of several distantly related but species-rich clades and had overdispersed abundance distributions. This suggests that limiting similarity processes determine which species dominate a community but not which species occur in a community. Crucially, as our study was carried out in experimental communities, we could rule out local evolutionary or dispersal explanations for the patterns and identify ecological processes as the driving force, underlining the advantages of studying these processes in experimental communities. Our results show that phylogenetic relations between species provide a good guide to understanding community structure and add a new perspective to the evidence that niche complementarity is critical in driving community assembly.

The histone deactylase SIRT6 is a novel tumor suppressor that regulates cancer metabolism.

Report for the scientific sojourn carried out at the University of Aarhus, Denmark, from 2010 to 2012. Reprogramming of cellular metabolism is a key process during tumorigenesis. This metabolic adaptation is required in order to sustain the energetic and anabolic demands of highly proliferative cancer cells. Despite known for decades (Warburg effect), the precise molecular mechanisms regulating this switch remained unexplored. We have identify SIRT6 as a novel tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of this sirtuin in non-transformed cells leads to tumor formation without activation of known oncogenes, indicating that SIRT6 functions as a first-hit tumor suppressor. Furthermore, transformed SIRT6-deficient cells display increased glycolysis and tumor growth in vivo, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. We provide data demonstrating that the glycolytic switch towards aerobic glycolysis is the main driving force for tumorigenesis in SIRT6-deficient cells, since inhibition of glycolysis in these cells abrogates their tumorigenic potential. By using a conditional SIRT6-targeted allele, we show that deletion of SIRT6 in vivo increases the number, size and aggressiveness of tumors, thereby confirming a role of SIRT6 as a tumor suppressor in vivo. In addition, we describe a new role for SIRT6 as a regulator of ribosome biogenesis by co-repressing MYC transcriptional activity. Therefore, by repressing glycolysis and ribosomal gene expression, SIRT6 inhibits tumor establishment and progression. Further validating these data, SIRT6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict both prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our results provide a potential Achilles’ hill to tackle cancer metabolism.

T-Cell Receptors Binding Orientation over Peptide/MHC Class I Is Driven by Long-Range Interactions.

Crystallographic data about T-Cell Receptor - peptide - major histocompatibility complex class I (TCRpMHC) interaction have revealed extremely diverse TCR binding modes triggering antigen recognition. Understanding the molecular basis that governs TCR orientation over pMHC is still a considerable challenge. We present a simplified rigid approach applied on all non-redundant TCRpMHC crystal structures available. The CHARMM force field in combination with the FACTS implicit solvation model is used to study the role of long-distance interactions between the TCR and pMHC. We demonstrate that the sum of the coulomb interactions and the electrostatic solvation energies is sufficient to identify two orientations corresponding to energetic minima at 0° and 180° from the native orientation. Interestingly, these results are shown to be robust upon small structural variations of the TCR such as changes induced by Molecular Dynamics simulations, suggesting that shape complementarity is not required to obtain a reliable signal. Accurate energy minima are also identified by confronting unbound TCR crystal structures to pMHC. Furthermore, we decompose the electrostatic energy into residue contributions to estimate their role in the overall orientation. Results show that most of the driving force leading to the formation of the complex is defined by CDR1,2/MHC interactions. This long-distance contribution appears to be independent from the binding process itself, since it is reliably identified without considering neither short-range energy terms nor CDR induced fit upon binding. Ultimately, we present an attempt to predict the TCR/pMHC binding mode for a TCR structure obtained by homology modeling. The simplicity of the approach and the absence of any fitted parameters make it also easily applicable to other types of macromolecular protein complexes.

Neuronal adaptation effects in decision making

Recently, there has been an increased interest on the neural mechanisms underlying perceptual decision making. However, the effect of neuronal adaptation in this context has not yet been studied. We begin our study by investigating how adaptation can bias perceptual decisions. We considered behavioral data from an experiment on high-level adaptation-related aftereffects in a perceptual decision task with ambiguous stimuli on humans. To understand the driving force behind the perceptual decision process, a biologically inspired cortical network model was used. Two theoretical scenarios arose for explaining the perceptual switch from the category of the adaptor stimulus to the opposite, nonadapted one. One is noise-driven transition due to the probabilistic spike times of neurons and the other is adaptation-driven transition due to afterhyperpolarization currents. With increasing levels of neural adaptation, the system shifts from a noise-driven to an adaptation-driven modus. The behavioral results show that the underlying model is not just a bistable model, as usual in the decision-making modeling literature, but that neuronal adaptation is high and therefore the working point of the model is in the oscillatory regime. Using the same model parameters, we studied the effect of neural adaptation in a perceptual decision-making task where the same ambiguous stimulus was presented with and without a preceding adaptor stimulus. We find that for different levels of sensory evidence favoring one of the two interpretations of the ambiguous stimulus, higher levels of neural adaptation lead to quicker decisions contributing to a speed–accuracy trade off.

Healthy Iowans 2010 Mid-Course Revision, July 2005

In the past century, public health has been credited with adding 25 years to life expectancy by contributing to the decline in illness and injury. Progress has been made, for example, in smoking reduction, infectious disease, and motor vehicle and workplace injuries. Besides its focus on traditional concerns such as clean water and safe food, public health is adapting to meet emerging health problems. Particular troublesome are health threats to youth: teenage pregnancies, violence, substance abuse, sexually transmitted diseases, and other conditions associated with high-risk behaviors. These threats add to burgeoning health care costs. A conservative estimate of $69 billion in medical spending could be averted through the impact of public health strategies aimed at heart disease, stroke, fatal and nonfatal occupational injuries, motor vehicle-related injuries, low birth weight, and violence. These strategies require the collaboration of many groups in the public and private sectors. Collaboration is the bedrock of public health and Healthy Iowans planning. At the core of Healthy Iowans 2000 and its successor, Healthy Iowans 2010, is the idea that all Iowans benefit when stakeholders decide on disease prevention and health promotion strategies and agree to work together on them. These strategies can improve the quality of life and hold down health care costs. The payoff for health promotion and disease prevention is not immediate, but it has long-lasting benefits. The Iowa plan is a companion to the national plan, Healthy People 2010. An initiative to improve the health of Americans, the national plan is the driving force for federal resource allocation for disease prevention and health promotion. The state plan is used in the same way. Both plans have received broad support from Republican and Democratic administrations. Community planners are using the state plan to help assess health needs and craft health improvement plans. Healthy Iowans 2010 was written at an unusual point in history – a new decade, a new century, a new millennium. The introduction was optimistic. “The 21st century,” it says, “promises to add life as well as years through improved health habits coupled with medical advances. Scientists have suggested that if these changes occur, the definition of adulthood will also change. An extraordinary number of people will live fuller, more active lives beyond that expected in the late 20th century.” At the same time, the country has spawned a new generation of health hazards. According to Dr. William Dietz of the Centers for Disease Control and Prevention (CDC), it has replaced “the diseases of deficiency with diseases of excess” (Newsweek, August 2, 1999). New threats, such as childhood overweight, can reverse progress made in the last century. This demands concerted action.

Spatially-resolved eigenmode decomposition of red blood cells membrane fluctuations questions the role of ATP in flickering.

Red blood cells (RBCs) present unique reversible shape deformability, essential for both function and survival, resulting notably in cell membrane fluctuations (CMF). These CMF have been subject of many studies in order to obtain a better understanding of these remarkable biomechanical membrane properties altered in some pathological states including blood diseases. In particular the discussion over the thermal or metabolic origin of the CMF has led in the past to a large number of investigations and modeling. However, the origin of the CMF is still debated. In this article, we present an analysis of the CMF of RBCs by combining digital holographic microscopy (DHM) with an orthogonal subspace decomposition of the imaging data. These subspace components can be reliably identified and quantified as the eigenmode basis of CMF that minimizes the deformation energy of the RBC structure. By fitting the observed fluctuation modes with a theoretical dynamic model, we find that the CMF are mainly governed by the bending elasticity of the membrane and that shear and tension elasticities have only a marginal influence on the membrane fluctations of the discocyte RBC. Further, our experiments show that the role of ATP as a driving force of CMF is questionable. ATP, however, seems to be required to maintain the unique biomechanical properties of the RBC membrane that lead to thermally excited CMF.