Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed α-helix

The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas' disease. It is functionally involved in host cell invasion. We have determined the three-dimensional crystal structure of TcMIP at 1.7 Å resolution. The monomeric protein displays a peptidyl-prolyl cis-trans isomerase (PPlase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted β-sheet of the core is extended by an extra β-strand, preceded by a long, exposed N-terminal α-helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N-terminal α-helix, can substitute for TcMIP. An additional exposed α-helix, this one unique to TcMIP, is located in the C-terminus of the protein. The high-resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis.This work was supported by grants from Ministerio de Educación y Cultura (PB98-1631 and 2FD97-0518), CSIC and Generalitat de Catalunya (CERBA and 1999SGR188) to M.C., grant PB98-0479 to A.G. and by grant BIO2000-1659 to F.X.G.-R. P.J.B.P. and S.M.-R. acknowledge postdoctoral fellowships from FCT (Portugal). Data collection at DESY was supported by EC grants ERBFMGECT980134 and HPRI-CT-1999-00017 to EMBL-HamburgPeer Reviewe

Effect of sex in systemic psoriasis therapy: Differences in prescription, effectiveness and safety in the BIOBADADERM prospective cohort

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be pre-scribed biologics. There were no differences between men and women in effectiveness of therapy, measur-ed in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness.The BIOBADADERM project is promoted by the Fundación Piel Sana Academia Española de Dermatología y Venereología, which receives financial support from the Spanish Medicines and Health Products Agency (Agencia Española de Medicamentos y Productos Sanitarios) and from pharmaceutical companies (Abbott/Abbvie, Pfizer, MSD, Novartis, Lilly, Janssen and Almirall)

Evaluación y clasificación de las técnicas utilizadas por las organizaciones, en las últimas décadas, para seleccionar proyectos // Evaluation and classification of the techniques used by organizations in the last decades to select projects

La metodología empleada por las organizaciones empresariales para distribuir su presupuesto y seleccionar qué proyectos, entre todos los posibles candidatos, deben ser ejecutados para cubrir sus necesidades ha evolucionado mucho desde que dichas organizaciones empezaron a apoyar sus decisiones de selección en algún modelo matemático. El propósito de este trabajo es realizar un análisis descriptivo y comparativo de las diferentes técnicas empleadas a lo largo del tiempo, incorporando un pequeño ejemplo que clarifique su funcionamiento y poniendo de manifiesto tanto sus ventajas como sus inconvenientes. En alguna medida, estos inconvenientes fueron motivando su evolución hacia técnicas cada vez más complejas y completas hasta llegar a nuestros días. Nuestro estudio ha permitido observar, por un lado, que la evolución de las organizaciones ha llevado a que cambie sustancialmente el problema de selección, pasando de seleccionarse proyectos a seleccionarse y planificar carteras de proyectos y, por otro lado, que el problema aún no está solucionado, ya que es necesario lograr un modelo global que resuelva cualquier problema de selección y planificación temporal de cartera de proyectos.-----------------------------------The methodology used by business organizations to distribute their budget and select which projects –among all potential candidates– must be carried out to satisfy their needs has changed considerably since the organizations started to support their selection decisions in a mathematical model. The purpose of this paper is to provide a descriptive and comparative analysis of the different techniques used over time; we also present a small example to clarify their function, and thereby we show both its advantages and disadvantages. These drawbacks were the principal cause of their evolution towards more completed and sophisticated techniques. This study highlights two aspects: first, the evolution of the organizations has changed the problem of selection from project selection to portfolio selection and scheduling, and secondly, the problem is not solved yet, and we need a global model to resolve whatever problem of project portfolio scheduling and selection

Evaluación y clasificación de las técnicas utilizadas por las organizaciones, en las últimas décadas, para seleccionar proyectos = Evaluation and classification of the techniques used by organizations in the last decades to select projects

La metodología empleada por las organizaciones empresariales para distribuir su presupuesto y seleccionar qué proyectos, entre todos los posibles candidatos, deben ser ejecutados para cubrir sus necesidades ha evolucionado mucho desde que dichas organizaciones empezaron a apoyar sus decisiones de selección en algún modelo matemático. El propósito de este trabajo es realizar un análisis descriptivo y comparativo de las diferentes técnicas empleadas a lo largo del tiempo, incorporando un pequeño ejemplo que clarifique su funcionamiento y poniendo de manifiesto tanto sus ventajas como sus inconvenientes. En alguna medida, estos inconvenientes fueron motivando su evolución hacia técnicas cada vez m´as complejas y completas hasta llegar a nuestros días. Nuestro estudio ha permitido observar, por un lado, que la evolución de las organizaciones ha llevado a que cambie sustancialmente el problema de selección, pasando de seleccionarse proyectos a seleccionarse y planificar carteras de proyectos y, por otro lado, que el problema aún no está solucionado, ya que es necesario lograr un modelo global que resuelva cualquier problema de selección y planificación temporal de cartera de proyectos. = The methodology used by business organizations to distribute their budget and select which projects –among all potential candidates– must be carried out to satisfy their needs has changed considerably since the organizations started to support their selection decisions in a mathematical model. The purpose of this paper is to provide a descriptive and comparative analysis of the different techniques used over time; we also present a small example to clarify their function, and thereby we show both its advantages and disadvantages. These drawbacks were the principal cause of their evolution towards more completed and sophisticated techniques. This study highlights two aspects: first, the evolution of the organizations has changed the problem of selection from project selection to portfolio selection and scheduling, and secondly, the problem is not solved yet, and we need a global model to resolve whatever problem of project portfolio scheduling and selection.cartera de proyectos; selección de proyectos; técnicas de clasificación. = portfolio; project selection; classification techniques.

Selección de cartera de proyectos: Formalización de un modelo genérico

Las organizaciones se enfrentan fundamentalmente al problema de cómo invertir sus recursos escasos entre un conjunto de alternativas o proyectos candidatos. Para ayudar a dar respuesta a este problema presentamos el siguiente estudio en el que lo que se persigue es seleccionar, en función de un conjunto de criterios y recursos existentes, una cartera de proyectos en la que los proyectos que la compongan estén distribuidos en el tiempo de la manera más eficiente posible teniendo en cuenta aspectos como las interacciones entre proyectos y la existencia de múltiples criterios en los que debemos hacer hincapié para que dicha selección sea la adecuada. Hay muchos y muy diferentes métodos para la evaluación y selección de una cartera de proyectos, cada una con sus ventajas e inconvenientes, sin embargo, no existen (a conocimiento de los autores) modelos que de manera integrada agreguen todos aquellos aspectos que tradicionalmente han sido considerados fundamentales. En esta investigación presentamos un modelo global que integre todos estos aspectos y que pretende dar una respuesta universal al problema de la selección y programación de cartera de proyectos

La diversité cyanobactérienne pour une estimation des impacts anthropogéniques dans la région des Montagnes Sor Rondane, Antarctique

ANTAR-IMPAC

Stadsplanering utifrån ett äldreperspektiv. : En studie om hur sociala konsekvensanalyser kan tillämpas för att utveckla goda livsmiljöer för äldre.

A partir de datos de consumo alimentario de España se han realizado las transformaciones y agrupaciones necesarias para establecer los contenidos nutricionales por toma, en forma de porcentajes, respecto a la ingesta total diaria de cada individuo encuestado (n = 3000). Así mismo, se ha comprobado el efecto de los factores de clasificación (sexo, edad y localidad) sobre la distribución de dichos porcentajes. El resultado del estudio estadístico indica que se deben considerar como grupos diferentes los individuos por debajo de 25 años respecto a los que superan esa edad y que el efecto localidad (entendido como aleatorio y no como fijo) ocasiona diferencias en la distribución de nutrientes entre las tomas de alimentos del día. En cambio, el factor sexo no resultó relevante al encontrarse en tomas anecdóticas las diferencias estadísticamente significativas. Se propone una distribución porcentual de nutrientes concretos entre las diferentes tomas de alimentos.Based on the raw data from the Spanish intake, have made the necessary changes and groupings to establish nutritional content per serving as percentages, regarding the total daily intake of each individual surveyed (n = 3000). Also, it was found the effect of the rating factors (sex, age and location) on the distribution of these percentages. The result indicates that individuals below 25 year should be considered as different groups, front those above that age; and locality effect (treated as random factor rather than fixed) causes differences in the distribution of nutrients between food daily intakes. However, the sex was was not relevant to the anecdotal footage found in statistically significant differences. Percentage distribution of individual nutrients between different food outlets is proposed

Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed α-helix

The macrophage infectivity potentiator protein from Trypanosoma cruzi (TcMIP) is a major virulence factor secreted by the etiological agent of Chagas’ disease. It is functionally involved in host cell invasion. We have determined the three-dimensional crystal structure of TcMIP at 1.7 Å resolution. The monomeric protein displays a peptidyl-prolyl cis–trans isomerase (PPIase) core, encompassing the characteristic rotamase hydrophobic active site, thus explaining the strong inhibition of TcMIP by the immunosuppressant FK506 and related drugs. In TcMIP, the twisted β-sheet of the core is extended by an extra β-strand, preceded by a long, exposed N-terminal α-helix, which might be a target recognition element. An invasion assay shows that the MIP protein from Legionella pneumophila (LpMIP), which has an equivalent N-terminal α-helix, can substitute for TcMIP. An additional exposed α-helix, this one unique to TcMIP, is located in the C-terminus of the protein. The high-resolution structure reported here opens the possibility for the design of new inhibitory drugs that might be useful for the clinical treatment of American trypanosomiasis

Long-term safety of nine systemic medications for psoriasis: A cohort study using the Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases (BIOBADADERM) Registry.

Registry studies broadly describing the safety of systemic drugs in psoriasis are needed. To describe the safety findings of the systemic drugs acitretin, adalimumab, apremilast, cyclosporine, etanercept, infliximab, methotrexate, secukinumab, and ustekinumab used for the treatment of moderate to severe psoriasis in patients included in the Spanish Registry of Adverse Events for Biological Therapy in Dermatological Diseases (BIOBADADERM) Registry. The incidence rate ratio (IRR) and adjusted IRR (including propensity scores) of identified adverse events for each drug, using methotrexate as reference, were determined by means of a prospective cohort. Our study included 2845 patients (8954 treatment cycles; 9642 patient-years). Ustekinumab and secukinumab had the lowest rate of adverse events for several of the system organ classes, with a statistically significant decreased rate ratio (IRR of Observational study, drug allocation not randomized, depletion of susceptibles, and prescribed doses not registered. Our data provide comparative safety information in the real-life setting that could help clinicians selecting between available products

Effect of Sex in Systemic Psoriasis Therapy: Differences in Prescription, Effectiveness and Safety in the BIOBADADERM Prospective Cohort.

The effect of sex on systemic therapy for psoriasis has not been well studied. The aim of this study was to analyse a large multicentre Spanish cohort of 2,881 patients with psoriasis (58.3% males), followed from January 2008 to November 2018, to determine whether sex influences prescription, effectiveness of therapy, and the risk of adverse events. The results show that women are more likely than men to be prescribed biologics. There were no differences between men and women in effectiveness of therapy, measured in terms of drug survival. Women were more likely to develop adverse events, but the difference in risk was small and does not justify different management. Study limitations include residual confounding and the use of drug survival as a proxy for effectiveness