Uniform pricing and social welfare

We re-examine the case for uniform pricing in a monopolistic third-degree price-discrimination setting by introducing differentiated costs. A profit-maximizing monopolist could then use price differentiation to reduce the production of the more costly goods, thereby decreasing average cost and increasing welfare. Indeed, monopolistic price differentiation can improve welfare and also aggregate consumer surplus even if, as in the benchmark linear case, total output does not increase. Accordingly, the welfare criterion based on total output fails and should be replaced by the computation of well-defined price indexes. These results possibly pave the way for a more optimistic assessment of monopolistic pricing.uniform pricing; third-degree price discrimination; welfare bounds; price and quantity indexes

A note on the Exclusion Principle

According to the so-called Exclusion Principle (introduced by Baye et alii, 1993), it might be profitable for the seller to reduce the number of fully-informed potential bidders in an all-pay auction. We show that it does not apply if the seller regards the bidders’ private valuations as belonging to the class of identical and independent distributions with a monotonic hazard rate.all-pay auctions; Exclusion Principle; monotonic hazard rate; economic theory of lobbying

On the reserve price in all-pay auctions with complete information and lobbying games

We show that the seller’s optimal reserve price in an all-pay auction with complete information is higher than in a standard auction. We use our results to re-consider some findings of the literature that models lobbying games as all-pay auctions. In particular, we show that the so-called Exclusion Principle appears to rely crucially on the implicit assumption of a “weak” (in terms of bargaining power) seller, and does not hold if she regards bidders’ valuations as iid according to a monotonic hazard rate. Our preliminary results for the case of independent but asymmetric bidders make it even more suspicious.all-pay auctions; reserve price; economic theory of lobbying

On Marginal Returns and Inferior Inputs

A necessary and sufficient condition for an input to be inferior is that, taking into account the input adjustment, an increase of its price raises the marginal productivity of all inputs. Contrary to a widespread opinion, it is not necessary that (some) inputs are “rivals” (i.e., that some marginal productivity cross derivative is negative). We discuss these facts and illustrate them by introducing a few simple functional forms for the production function. Our results suggest that the existence of inferior inputs is naturally associate to the presence of increasing returns, and possibly make the case for inferiority considerably stronger.inferior and normal inputs, marginal productivity, homotheticity.

Structural Characterization of 17β-Hydroxysteroid Dehydrogenase Type 14 and Inhibitor Optimization Using Crystallography and Computational Techniques

17β-Hydroxysteroid dehydrogenase type 14 (17β-HSD14) is the latest identified subtype of 17β HSDs. In vivo this enzyme oxidizes the hydroxyl group at position 17 of estradiol (E2) and 5 androstenediol (5-diol) in the presence of NAD+ as cofactor. Two isoforms of this cytosolic protein exist that differ only in sequence position 205: S205 and T205. So far, the protein has not been thoroughly investigated in detail and its physiological role remains unknown. Prior to this thesis, the 17β-HSD14 apoenzyme (S205) had already been crystallized. The determined structure revealed a very broad and open active site and the conserved catalytic triad and the Rossmann fold motif. However, all C-terminal tails and for some chains also amino acids in the flexible loop (189-212) were not defined in the electron density. Moreover, it is impossible to derive information regarding a potential substrate from this apo structure. Therefore, the renewed structural determination of the 17β-HSD14 apo protein as well as in complex with its cofactor and substrate was of utmost importance. After successful establishment of the expression and purification protocols for 17β HSD14 protein, the two enzyme isoforms (S205 and T205) were characterized biochemically. The structures of the S205 apoenzyme and the binary complexes with NAD+ of both isoforms were determined. In these complex structures the flexible loop adopts a unique closed conformation differing from the apo structure. Binding of the cofactor is accompanied by a shift of the flexible loop and of the C-terminal Tyr253’ of the adjacent monomer, thereby reducing the size of the active site. The ternary complex of the enzyme with estrone (E1) and NAD+ was also determined. E1 binds to the active site in an atypical fashion, in so far as its A-ring and not the enzymatically modified position 17 close to the nicotinamide moiety of NAD+. Enzyme inhibitors are useful tools to study the consequences of enzyme inhibition in vivo. This allows to clarify whether this enzyme may be interesting as a new drug target for a certain disease. In addition, potent and selective 17β HSD14 inhibitors may help understand the selectivity issue with other 17β HSDs. As no 17β HSD14 inhibitor was known prior to this study, the goal was to identify and optimize nonsteroidal 17β-HSD14 inhibitors. To that, a library of 17β-HSD1 and 17β HSD2 inhibitors was screened against 17β-HSD14. The most promising hit was taken as the starting point for further chemical modification applying a ligand based approach. Newly designed compounds were synthesized and subsequently tested for their 17β HSD14 inhibitory activity. Prior to this thesis, no human 17β HSD structure in complex with a nonsteroidal ligand was published. The crystal structures confirmed that the inhibitors bind to the substrate binding site and allowed to rationalize the strong affinity of these inhibitors. Subsequently, two different structure-based strategies were pursued for inhibitor design. The first structure based modifications of the initial pyridine-based scaffold led to a ten-fold more potent inhibitor. The goal of the second structure based optimization strategy was to extend the central pyridine core to interact with the empty binding pocket adjacent to the steroid A and B-ring. The predicted binding mode was verified by co-crystal structures and the low nanomolar potency was confirmed by biophysical characterization. The new crystal structures revealed how small changes of the inhibitors affect the adopted binding mode. The characterization of the most promising 17β HSD14 inhibitors against 17β HSD1, 17β-HSD2, and 17β HSD10 revealed varying degrees of selectivity. In addition, some of these inhibitors showed very low cytotoxicity and did not interact with the multi-drug resistance protein Pgp, indicating these compounds might not be effluxed from the brain and that the risk of potential side effects is reduced. This suggests these inhibitors as tool compounds for further investigation in vivo. To explain the selectivity profiles of the ligands towards 17β HSD14 and other 17β HSDs we conducted a structural comparison. The typical V-like shape of the binding pocket of 17β HSD14 is determined by His93 and Gln148, which are not present in 17β HSD1, 17β HSD8 and 17β HSD10. In addition, the latter three enzymes have a rather flat binding pocket. This suggests that matching the characteristic three-dimensional requirements of 17β-HSD14 and optionally addressing His93 and/or Gln148 will increase the selectivity toward this target. Such inhibitors were predicted by docking a library of about 400 17β-HSD1 and 17β-HSD2 inhibitors with GOLD followed by in vitro screening of docking hits and related compounds. Remarkably, predicted binding modes were in poor agreement with the subsequently determined crystal structures due to the adaptability of the binding pocket caused by the flexible loop. Finally, a large fragment screening campaign by X-ray crystallography with the aim to discover new inhibitor scaffolds bound to 17β HSD14 was performed. This resulted in two fragments that could be clearly identified in the electron density. However, these fragments did not significantly inhibit 17β HSD14. In order to enhance affinity, fragment growing and fragment linking strategies were applied, resulting in two new inhibitors with better affinity than the starting fragments. In summary, both isoforms of 17β-HSD14, S205 and T205, were characterized biochemically and structurally resulting in four new crystal structures. The first two classes of inhibitor for this enzyme were discovered and the ligands were thoroughly profiled. In addition, the structures of 12 nonsteroidal inhibitors in complex with the protein were elucidated for the first time for this protein family. The fragment screening by determining 96 fragment-soaked structures, resulted in two fragment hits that were successfully optimize culminating in two inhibitors more active than their precursor fragments

Reconstitution of hepatitis B virus (HBV)-specific T cell responses with treatment of human immunodeficiency virus/HBV coinfection

Liver-related mortality is an increasing problem in human immunodeficiency virus (HIV)/hepatitis B virus (HBV)-coinfected patients receiving highly active antiretroviral therapy (HAART). In HIV-negative patients, HBV chronicity is associated with a reduction in specific T cell responses that can be partially restored by treatment with lamivudine. We studied 5 HIV/HBV-coinfected patients treated with HAART, either with or without addition of a drug with specific anti-HBV activity. Our data show that reconstitution of some HBV-specific T cell responses can also occur in HIV-positive patients after a reduction in HBV load. This potential to recover T cell responses, which has been thought to be critical for HBV control, provides support for the addition of anti-HBV therapy in the treatment of HIV/HBV-coinfected patients

Esquizofrenia y vitamina D, la relación desconocida

La esquizofrenia es una enfermedad mental grave crónica perteneciente al grupo de las psicosis. Posee una etiología multifactorial con un componente genético demostrado pero impreciso. El diagnóstico se realiza siguiendo la pauta de cuestionarios y guías clínicas especializadas basadas en alteraciones de los patrones de pensamiento, percepción y afectividad. Aparte de la sintomatología propia de la enfermedad, en algunos casos pueden estar presentes distintas comorbilidades biológicas como son, entre otras, la inflamación cerebral, la oxidación y el síndrome metabólico. La vitamina D, que se ha demostrado deficiente en estos pacientes, tiene propiedades antioxidantes y desinflamatorias, lo cuál podría ser relevante en esta enfermedad. Esta revisión tiene como objetivo determinar si existe una relación entre el déficit en vitamina D y la manifestación o gravedad clínica de la esquizofrenia. Se ha realizado una revisión sistemática de aquellos trabajos que estudian la relación entre los valores séricos de vitamina D presentes en estos pacientes y la sintomatología clínica. Para llevarlo a cabo se han utilizado artículos publicados en los últimos diez años. La mayoría de los artículos revisados encuentran un déficit significativo en los niveles de vitamina D en la esquizofrenia. En cuanto a la posible relación entre sintomatología clínica y los distintos niveles de vitamina D, no se han obtenido resultados concluyentes ya que casi el 60% de los artículos revisados muestran una relación significativa, mientras que el otro 40% apunta en la dirección contraria. Como conclusión, el déficit en vitamina D parece estar presente en la esquizofrenia. Sin embargo, los estudios disponibles hasta la fecha no han encontrado una relación entre este déficit y la gravedad de su manifestación clínica. Algunos factores como la heterogeneidad de la muestra de pacientes y su tratamiento farmacológico podrían ser responsables de la variabilidad de resultados. No obstante, son necesarias más investigaciones para poder establecer resultados concluyentes.Grado en Nutrición Humana y Dietétic

El fenómeno de la corrupción en el contrato de concesión del aeropuerto el Dorado

En este trabajo podemos encontrar la problemática actual de la corrupción en la contratación estatal en general, pero más exactamente en el contrato de concesión del Aeropuerto Internacional El Dorado ya que han surgido una serie de diferencias, omisiones y tardanzas por parte del consorcio encargado de realizar la obra. Para ello haré de manera sucinta un recorrido por lo que se considera corrupción desde la perspectiva de varios autores nacionales y extranjeros, pasando por la definición de lo que en nuestra legislación se concibe como contrato de concesión así como su finalidad y características básicas, para así concluir con la situación fáctica y jurídica que se presentó en el contrato de concesión para la modernización del Aeropuerto Internacional El Dorado, el cual infortunamente está afectado por vicios de corrupció

Outcomes in the emergency endovascular repair of blunt thoracic aortic injuries

Abstract Thoracic aorta blunt injury (BAI) is a highly lethal lesion. A large number of victims die before obtaining emergency care. Thoracic endovascular aneurysm repair (TEVAR) is a less invasive method compared with open surgery and may change protocols for BAI treatment. This retrospective study was developed to evaluate the potential issues about thoracic endografting in the management of these patients. Twenty-seven patients with a BAI underwent aortic stent grafting. Intervention was preceded by the treatment of more urgent associated lesions in nine cases. In-hospital mortality was 7.4%. No paraplegia or ischemic complications developed because of the coverage of the left subclavian artery. In one case (3.2%), a type I endoleak was detected, proximal endograft infolding in two cases (7.4%) and endograft distal migration in further two cases were detected during follow-up (6-110 months). Thoracic endovascular aneurysm repair of BAI showed encouraging results in terms of perioperative mortality and morbidity. Concerns still remain about the potential mid- and long-term complications in younger patients

Immune Therapeutic Strategies in Chronic Hepatitis B Virus Infection: Virus or Inflammation Control?

10.1371/journal.ppat.1003784PLoS Pathogens9121-