Learning-by-employing: the value of commitment

We analyze a dynamic principal–agent model where an infinitely-lived principal faces asequence of finitely-lived agents who differ in their ability to produce output. The ability of anagent is initially unknown to both him and the principal. An agent’s effort affects the informationon ability that is conveyed by performance. We characterize the equilibrium contracts andshow that they display short–term commitment to employment when the impact of effort onoutput is persistent but delayed. By providing insurance against early termination, commitmentencourages agents to exert effort, and thus improves on the principal’s ability to identify theirtalent. We argue that this helps explain the use of probationary appointments in environmentsin which there exists uncertainty about individual ability.Keywords: dynamic principal–agent model, learning, commitment.

Baseline and postoperative C-reactive protein levels predict mortality in operable lung cancer.

Background Higher blood levels of C-reactive protein (CRP) have been associated with shorter survival in patients with cardiovascular, chronic obstructive pulmonary disease and cancer. We investigated the impact of baseline and postoperative CRP levels on survival of patients with operable lung cancer (LC). Patients and methods CRP values at baseline (CRP0) and 3 days after surgery (CRP3) were measured in a consecutive series of 1750 LC patients who underwent complete resection between 2003 and 2015. Patients were classified as having 0 (N = 593), 1 (N = 658) or 2 (N = 553) risk factors: CRP0 and/or CRP3 values above the respective median value. The effect of higher CRP was evaluated by Kaplan–Meier mortality curves and adjusted hazard ratio (HR) with 95% confidence interval (CI), by fitting Cox proportional hazards models. Results Cumulative proportions of 5-year survival were 67% for 0 risk factors, 58% for 1 risk factor and 41% for 2 risk factors (P < 0.0001). The overall 5-year mortality risk was significantly higher in patients with 1 risk factor (adjusted hazard ratio [aHR] 1.43 [95% CI 1.14–1.79]), or 2 risk factors (aHR 2.49 [95% CI 1.99–3.11]). A significant impact on survival was observed in each tumour-node-metastasis stage group, and in the subset of non-smokers. Postoperative 30-day mortality was significantly higher in patients with 2 risk factors only (aHR 2.2% versus 0.6%, p < 0.0475). Conclusions Baseline and postoperative CRP levels predict immediate and long-term mortality in all stages of operable lung cancer. Patients with higher CRP levels could be candidate to randomised adjuvant trials with anti-inflammatory agents

Restauración del bosque quemado del cerro Otto, Bariloche : un compromiso de hoy con las generaciones futuras

El aumento de la densidad poblacional y de las condiciones ambientales predisponentes debido al cambio climático, determina la ocurrencia cada vez más frecuente y catastrófica de incendios forestales en toda la Patagonia andina. Está en nuestras manos el legado que dejaremos a nuestros hijos: un entorno degradado y lleno de pasivos ambientales, o una naturaleza en camino a recuperar los valores y funciones que está disfrutando nuestra generación.Estación Experimental Agropecuaria Bariloche. Área ForestalFil: Pastorino, Mario Juan. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Área Sistemas Forestales. Unidad de Genética Ecológica y Mejoramiento Forestal; ArgentinaFil: Aparicio, Alejandro Gabriel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estacion Experimental Agropecuaria Bariloche. Área Sistemas Forestales. Grupo de Genética Ecológica y Mejoramiento Forestal; ArgentinaFil: Azpilicueta, María Marta. Instituto Nacional de Tecnología Agropecuaria (INTA). Estacion Experimental Agropecuaria Bariloche. Área Sistemas Forestales. Grupo de Genética Ecológica y Mejoramiento Forestal; ArgentinaFil: Rusch, Verónica Elena. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Bariloche. Área Sistemas Forestales. Grupo de Ecología Forestal; Argentin

Journey on VX-809-Based Hybrid Derivatives towards Drug-like F508del-CFTR Correctors: From Molecular Modeling to Chemical Synthesis and Biological Assays

open12Cystic fibrosis (CF) is a genetic disease affecting the lungs and pancreas and causing progressive damage. CF is caused by mutations abolishing the function of CFTR, a protein whose role is chloride's mobilization in the epithelial cells of various organs. Recently a therapy focused on small molecules has been chosen as a main approach to contrast CF, designing and synthesizing compounds acting as misfolding (correctors) or defective channel gating (potentiators). Multi-drug therapies have been tested with different combinations of the two series of compounds. Previously, we designed and characterized two series of correctors, namely, hybrids, which were conceived including the aminoarylthiazole (AAT) core, merged with the benzodioxole carboxamide moiety featured by VX-809. In this paper, we herein proceeded with molecular modeling studies guiding the design of a new third series of hybrids, featuring structural variations at the thiazole moiety and modifications on position 4. These derivatives were tested in different assays including a YFP functional assay on models F508del-CFTR CFBE41o-cells, alone and in combination with VX-445, and by using electrophysiological techniques on human primary bronchial epithelia to demonstrate their F508del-CFTR corrector ability. This study is aimed (i) at identifying three molecules (9b, 9g, and 9j), useful as novel CFTR correctors with a good efficacy in rescuing the defect of F508del-CFTR; and (ii) at providing useful information to complete the structure-activity study within all the three series of hybrids as possible CFTR correctors, supporting the development of pharmacophore modelling studies, taking into account all the three series of hybrids. Finally, in silico evaluation of the hybrids pharmacokinetic (PK) properties contributed to highlight hybrid developability as drug-like correctors.openParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, EnricoParodi, Alice; Righetti, Giada; Pesce, Emanuela; Salis, Annalisa; Tomati, Valeria; Pastorino, Cristina; Tasso, Bruno; Benvenuti, Mirko; Damonte, Gianluca; Pedemonte, Nicoletta; Cichero, Elena; Millo, Enric

Improved Prognostic Prediction in Never-Smoker Lung Cancer Patients by Integration of a Systemic Inflammation Marker with Tumor Immune Contexture Analysis

Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyte antigens (HLA-DR and HLA-I), CD8, CD4, CD3, CD33, CD163, and CD68 were evaluated by immunohistochemistry on surgical samples given TIC evaluation. The classification model based on TIC scores was generated by Classification and Regression Tree analysis. Tumor mutational burden was evaluated by targeted next-generation sequencing. Exclusively high CRP (H-CRP) subset showed PD-L1 expression in 35% of LC as well as lower HLA-I and HLA-DR in their stromal cells. CD3, CD4, CD8, HLA-I, HLA-DR tumor cells staining were associated with a "low inflammatory profile" subset. CRP and LC immune profiles drive clinical outcome: 5-year survival 88% against 8% was associated with low and high-risk profiles (p&lt; 0.0001). Clinical outcome prediction in never-smoker LC patients may be improved by both CRP and tumor immune contexture evaluation

chitosan biopolymer alternative adhesion factor and scaffold matrix for 2d and 3d neuronal cultures

The increase of different types of cell cultures, which can be used for the in vitro studies of physiological and/or pathological processes, has introduced the need to improve culture techniques through the use of materials and culture media that promote growth, recreating a cellular micro-environment that can be asserted in in vivo condition. The standard methods for the functionalization of supports used for cell cultures are based on the use of synthetic or natural biopolymers, which generally have high costs, such as poly-lysine and polyornithine. The aim of this work is to demonstrate the alternative use of the polysaccharide chitosan as adhesion factor and structural component for 2D/3D neuronal cultures. Thanks to its versatility, it could be easily functionalized for the fabrication of personalized of in vitro model

Effects of Pin1 Loss in Hdh(Q111) Knock-in Mice

Huntington's disease (HD) is a fatal, dominantly inherited, neurodegenerative disorder due to a pathological expansion of the CAG repeat in the coding region of the HTT gene. In the quest for understanding the molecular basis of neurodegeneration, we have previously demonstrated that the prolyl isomerase Pin1 plays a crucial role in mediating p53-dependent apoptosis triggered by mutant huntingtin (mHtt) in vitro. To assess the effects of the lack of Pin1 in vivo, we have bred Pin1 knock-out mice with Hdh(Q111) knock-in mice, a genetically precise model of HD. We show that Pin1 genetic ablation modifies a portion of Hdh(Q111) phenotypes in a time-dependent fashion. As an early event, Pin1 activity reduces the DNA damage response (DDR). In midlife mice, by taking advantage of next-generation sequencing technology, we show that Pin1 activity modulates a portion of the alterations triggered by mHtt, extending the role of Pin1 to two additional Hdh(Q111) phenotypes: the unbalance in the "synthesis/concentration of hormones", as well as the alteration of "Wnt/\u3b2-catenin signaling". In aging animals, Pin1 significantly increases the number of mHtt-positive nuclear inclusions while it reduces gliosis. In summary, this work provides further support for a role of Pin1 in HD pathogenesis. \ua9 2016 Agostoni, Michelazzi, Maurutto, Carnemolla, Ciani, Vatta, Roncaglia, Zucchelli, Leanza, Mantovani, Gustincich, Santoro, Piazza, Del Sal and Persichetti