Biased agonism in drug discovery: is it too soon to choose a path?

A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists stabilize receptor conformations preferentially stimulating one of these pathways, and therefore allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased µ opioid receptor agonist oliceridine. However, leveraging the theoretical potential of biased agonism for drug discovery faces several challenges. Some of these challenges are technical, such as techniques for quantitative analysis of bias and development of suitable screening assays; others are more fundamental, such as the need to robustly identify in a very early phase which cell type harbors the cellular target of the drug candidate, which signaling pathway leads to the desired therapeutic effect, and how these pathways may be modulated in the disease to be treated. We conclude that biased agonism has potential mainly in the treatment of conditions with a well-understood pathophysiology; in contrast, it may increase effort and commercial risk under circumstances where the pathophysiology has been less well defined, as is the case with many highly innovative treatments

Characterization of the resistance to Botrytis fabae and Ascochyta fabae in faba bean lines

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Investigating a new simple screening method for Ascochyta blight (Mycosphaerella pinodes) resistance applicable in field pea (Pisum sativum L.) breeding nurseries

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Variation of the Si/Al ratio in nanosized zeolite Beta crystals

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Impact of crop successions including legumes species on the durability of Aphanomyces euteiches partial resistance on pea

Impact of crop successions including legumes species on the durability of Aphanomyces euteiches partial resistance on pe

Analysis of the French insurance market exposure to floods: a stochastic model combining river overflow and surface runoff

The analysis of flood exposure at a national scale for the French insurance market must combine the generation of a probabilistic event set of all possible (but which have not yet occurred) flood situations with hazard and damage modeling. In this study, hazard and damage models are calibrated on a 1995–2010 historical event set, both for hazard results (river flow, flooded areas) and loss estimations. Thus, uncertainties in the deterministic estimation of a single event loss are known before simulating a probabilistic event set. To take into account at least 90 % of the insured flood losses, the probabilistic event set must combine the river overflow (small and large catchments) with the surface runoff, due to heavy rainfall, on the slopes of the watershed. Indeed, internal studies of the CCR (Caisse Centrale de Reassurance) claim database have shown that approximately 45 % of the insured flood losses are located inside the floodplains and 45 % outside. Another 10 % is due to sea surge floods and groundwater rise. In this approach, two independent probabilistic methods are combined to create a single flood loss distribution: a generation of fictive river flows based on the historical records of the river gauge network and a generation of fictive rain fields on small catchments, calibrated on the 1958–2010 Météo-France rain database SAFRAN. All the events in the probabilistic event sets are simulated with the deterministic model. This hazard and damage distribution is used to simulate the flood losses at the national scale for an insurance company (Macif) and to generate flood areas associated with hazard return periods. The flood maps concern river overflow and surface water runoff. Validation of these maps is conducted by comparison with the address located claim data on a small catchment (downstream Argens)

Cation Migration and Structural Deformations upon Dehydration of Nickel-Exchanged NaY Zeolite: A Combined Neutron Diffraction and Monte Carlo Study

International audienceCombining neutron diffraction and classical molecular simulations, we describe the cation migration and associated structural changes taking place in a Ni-exchanged NaY faujasite zeolite upon stepwise dehydration from room temperature up to 400 °C. The cation redistribution between sites and the related framework deformations taking place upon water removal are identified and quantified. Neutron diffraction allows monitoring the zeolite structure, the average cation location and the water content, whereas molecular modeling provides insights into the correlations between the positions of cations and water molecules. Importantly, we demonstrate that the migration of Ni2+ toward highly confined sites upon dehydration is the driving force behind deformation of the hexagonal prisms. The present work illustrates the relevance of combining these two experimental and theoretical approaches to clarify the complex interplay between cation hydration, cation location, and framework deformation. It also underlines the importance to capture the flexibility of the framework in molecular simulation of hydrated zeolite in particular when multivalent ions are involved

Evaluation of plan-of-the-day selection in adaptive radiation therapy of cervical cancer

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