Magnetic resonance imaging and ultrasound elastography in the context of preclinical pharmacological research: significance for the 3R principles

The 3Rs principles—reduction, refinement, replacement—are at the core of preclinical research within drug discovery, which still relies to a great extent on the availability of models of disease in animals. Minimizing their distress, reducing their number as well as searching for means to replace them in experimental studies are constant objectives in this area. Due to its non-invasive character in vivo imaging supports these efforts by enabling repeated longitudinal assessments in each animal which serves as its own control, thereby enabling to reduce considerably the animal utilization in the experiments. The repetitive monitoring of pathology progression and the effects of therapy becomes feasible by assessment of quantitative biomarkers. Moreover, imaging has translational prospects by facilitating the comparison of studies performed in small rodents and humans. Also, learnings from the clinic may be potentially back-translated to preclinical settings and therefore contribute to refining animal investigations. By concentrating on activities around the application of magnetic resonance imaging (MRI) and ultrasound elastography to small rodent models of disease, we aim to illustrate how in vivo imaging contributes primarily to reduction and refinement in the context of pharmacological research

The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size

LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration

Editorial: In vivo imaging in pharmacological research

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Magnetic Resonance Imaging in Drug Discovery: Opportunities and Challenges

The better and earlier a disease can be diagnosed and characterized, the higher the chance to be able to interfere in this process with a chemical entity. This is the rationale for the use of imaging techniques in the drug discovery and development process. One of the principal imaging modalities is magnetic resonance imaging (MRI). Its multiparametric nature enables anatomical, functional, metabolic, and to a certain extent, also target-related information to be obtained non-invasively at high spatial resolution. This favors the characterization of a disease state and the corresponding drug intervention. The non-invasiveness of MRI strengthens the link between pre-clinical and clinical pharmaceutical research

Editorial for “Echo Time-Dependence of Observed Lung T1 in Patients With Cystic Fibrosis and Correlation With Clinical Metrics”

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Editorial for "MRI Fat-Saturated T2-Weighted Radiomics Model for Predicting the Ki-67 Index of Soft Tissue Sarcomas”

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Neste trabalho são abordadas duas técnicas de geração de imagens por ressonância magnética nuclear, a retroprojeção e o método da transformada direta. Estas técnicas baseiam-se na aquisição de sinais de RMN cujas fases e componentes de freqüência são espacialmente codificadas por aplicação de gradientes de campo magnético. A construção de bobinas de gradiente é discutida no caso particular de uma geometria apropriada para um ímã com peças polares e \"gap\" de ar. Analisa-se também a obtenção de contraste pelos tempos de relaxação T1 e T2 em imagens reconstruídas a partir de sinais gerados empregando seqüências como a de spin-eco, inversão-recuperação e eco estimulado. Sob forma de apêndice, apresenta-se o formalismo matemático que fornece uma solução matricial para as equações de BLOCH, permitindo a determinação da evolução de um sinal em presença de gradientes de campo e pulsos de radiofreqüência, e da dependência de sua magnitude com os tempos de relaxação da amostra.This work treats two techniquesfor the generation of images by nuclear magnetic resonance, the method of the direct transform. These techniques are based on the acquisition of NMR signals whose phases and frequency components gradients. The construction of gradient coils is discussed for the particular geometry appropriate for a magnet with pole caps and air gap. It contains also an analysis of the obtention of contrast by the relaxation times T1 and T2 in images reconstructed from signals generated employing sequences such as spin-echo, inversion-recovery and stimulated echo. In form of an appendix, a mathematical formalism is presented, that furnishes a matrix solution for the BLOCH equations, allowing the determination of the evolution of a signal in presence of gradients and radiofrequency pulses, and the dependence of its magnitude with relaxation times of the sample

The fragmentation of a discipline: how diversity elevates and undermines Ir’s normative potential

International Relations (ir) has transformed from a relatively state-centric discipline that was primarily concerned about international security and the behavior of great powers into a highly diverse intellectual playing field. The present article assesses the implications of this transformation in relation to ir’s norma­tive potential, defined in terms of knowledge production and critical thinking. Although the field’s growing diversity helps addressing the multiple challenges and crises the world is currently facing, it is also evident that the spe­cialized knowledge and jargon that is needed to engage in a specific subfield prevents ir scholars from understanding one another. This development not only undermines the liveliness of the field, but also obstructs our capacity to interact with political actors and engage with the public. Furthermore, inward-looking scholarly communities curtail critical thinking. Although there is no panacea that can reverse this trend, the article claims that cultivating networks of dialogue may assuage its worst effects by facilitating mutual learn­ing and improving our communicative skills.Las relaciones internacionales (RR.II.) se han ido transformando de una disciplina relativa­mente Estado-céntrica, que principalmente se preocupa por la seguridad internacional y el comportamiento de las grandes potencias, en un campo de juego intelectual mucho más diverso. El presente artículo evalúa las impli­caciones de esta transformación en relación con el potencial normativo de las RR.II., el cual es definido en términos de producción de conocimiento y pensamiento crítico. Aunque la creciente diversidad ayuda a abordar los múltiples desafíos y crisis a los que se enfrenta la humanidad, también es evidente que el co­nocimiento y la jerga especializados, que son necesarios para participar en un subcampo particular, impiden que los académicos de las RR.II. se entiendan entre ellos. Este desarrollo no solo socava la vitalidad de nuestro campo de estudio, sino que también obstruye nuestra capacidad de interactuar con actores políticos y relacionarnos con el público. Además, comuni­dades académicas que solo miran hacia adentro minimizan el pensamiento crítico. Aunque no existe una panacea para revertir esta tendencia, el artículo afirma que el cultivo de redes de diálogo puede mitigar sus peores efectos al fa­cilitar el aprendizaje mutuo y mejorar nuestras habilidades comunicativas