Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC)

The thiazide-sensitive NaCl cotransporter (NCC) plays key roles in renal electrolyte transport and blood pressure maintenance. Regulation of this cotransporter has received increased attention recently, prompted by the discovery that mutations in the with-no-lysine (WNK) kinases are the molecular explanation for pseudohypoaldosteronism type II (PHAII). Studies suggest that WNK4 regulates NCC via two distinct pathways, depending on its state of activation. Furthermore, an intact STE20-related proline–alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4 PHAII mutation to increase NCC phosphorylation and blood pressure in mice. The mouse protein 25α is a novel regulator of the SPAK/OSR1 kinase family, which greatly increases their activity. The phosphorylation status of NCC and the WNK is regulated by the serum- and glucocorticoid-inducible kinase 1, suggesting novel mechanisms whereby aldosterone modulates NCC activity. Dephosphorylation of NCC by protein phosphatase 4 strongly influences the activity of the cotransporter, confirming an important role for NCC phosphorylation. Finally, γ-adducin increases NCC activity. This stimulatory effect is dependent on the phosphorylation status of the cotransporter. γ-Adducin only binds the dephosphorylated cotransporter, suggesting that phosphorylation of NCC causes the dissociation of γ-adducin. Since γ-adducin is not a kinase, it is tempting to speculate that the protein exerts its function by acting as a scaffold between the dephosphorylated cotransporter and the regulatory kinase. As more molecular regulators of NCC are identified, the system-controlling NCC activity is becoming increasingly complex. This intricacy confers an ability to integrate a variety of stimuli, thereby regulating NCC transport activity and ultimately blood pressure

Dialogue sur le mariage, dialogue dans le mariage. Sur le troisième livre de la Civil Conversatione de Stefano Guazzo

The starting point for this study of the marriage according to Guazzo is the notion of conversation in its original meaning, as living together. The treaty of Guazzo (1574) develops the concept of « civil conversazione » in which men exchange their opinions, but especially support each other and show mutual respect and amiability, which avoids conflicts. The study shows the analogies between such ideal of communication and Guazzo’s vision of the marriage – both envisaged in the humanistic and Christian perspectives: as foundations of society and means of mutual edification. Guazzo’s discourse concerning conversation of the spouses oscillates between the necessity of accomodation to the spouse (related to concealment) and sincerity. Given the complexity of codes that characterize other types of communication, « marital conversazione » is presented as the closest to the ideal of transparency.The starting point for this study of the marriage according to Guazzo is the notion of conversation in its original meaning, as living together. The treaty of Guazzo (1574) develops the concept of « civil conversazione » in which men exchange their opinions, but especially support each other and show mutual respect and amiability, which avoids conflicts. The study shows the analogies between such ideal of communication and Guazzo’s vision of the marriage – both envisaged in the humanistic and Christian perspectives: as foundations of society and means of mutual edification. Guazzo’s discourse concerning conversation of the spouses oscillates between the necessity of accomodation to the spouse (related to concealment) and sincerity. Given the complexity of codes that characterize other types of communication, « marital conversazione » is presented as the closest to the ideal of transparency

La discorde concordia dell’animo nella riflessione antropologica e nell’epica di Tasso

The article reconstructs the conception of the soul that emerges from the writings of Torquato Tasso. The analysis of the Allegory of Jerusalem Delivered, of the correspondence which arose from the revision of the poem and of some fragments of other works, centres on the relationship between reason and passions. It shows that Tasso’s concept of the harmony of the soul is analogous to his concept of the epos. Both are founded on two principles: that of unity composed of opposites and that of the functional indispensability of all constitutive parts. There is a relationship of subordination and a relationship of interdependence between reason and the irrational part of the soul. Tasso has a positive view of the intense affetti, as drivers of magnificent actions and as foundations on which a person can develop his/her virtues.The article reconstructs the conception of the soul that emerges from the writings of Torquato Tasso. The analysis of the Allegory of Jerusalem Delivered, of the correspondence which arose from the revision of the poem and of some fragments of other works, centres on the relationship between reason and passions. It shows that Tasso’s concept of the harmony of the soul is analogous to his concept of the epos. Both are founded on two principles: that of unity composed of opposites and that of the functional indispensability of all constitutive parts. There is a relationship of subordination and a relationship of interdependence between reason and the irrational part of the soul. Tasso has a positive view of the intense affetti, as drivers of magnificent actions and as foundations on which a person can develop his/her virtues

Biophysical model to predict lung delivery from a dual bronchodilator dry-powder inhaler

A biophysical lung model was designed to predict inhaled drug deposition in patients with obstructive airway disease, and quantitatively investigate sources of deposition variability. Different mouth-throat anatomies at varying simulated inhalation flows were used to calculate the lung dose of indacaterol/glycopyrronium [IND/GLY] 110/50 µg (QVA149) from the dry-powder inhaler Breezhaler®. Sources of variability in lung dose were studied using computational fluid dynamics, supported by aerosol particle sizing measurements, particle image velocimetry and computed tomography. Anatomical differences in mouth-throat geometries were identified as a major source of inter-subject variability in lung deposition. Lung dose was similar across inhalation flows of 30–120 L/min with a slight drop in calculated delivery at high inspiratory flows. Delivery was relatively unaffected by inhaler inclination angle. The delivered lung dose of the fixed-dose combination IND/GLY matched well with corresponding monotherapy doses. This biophysical model indicates low extra-thoracic drug loss and consistent lung delivery of IND/GLY, independent of inhalation flows. This is an important finding for patients across various ages and lung disease severities. The model provides a quantitative, mechanistic simulation of inhaled therapies that could provide a test system for estimating drug delivery to the lung and complement traditional clinical studies

Understanding pharmacokinetics using realistic computational models of fluid dynamics: biosimulation of drug distribution within the CSF space for intrathecal drugs

We introduce how biophysical modeling in pharmaceutical research and development, combining physiological observations at the tissue, organ and system level with selected drug physiochemical properties, may contribute to a greater and non-intuitive understanding of drug pharmacokinetics and therapeutic design. Based on rich first-principle knowledge combined with experimental data at both conception and calibration stages, and leveraging our insights on disease processes and drug pharmacology, biophysical modeling may provide a novel and unique opportunity to interactively characterize detailed drug transport, distribution, and subsequent therapeutic effects. This innovative approach is exemplified through a three-dimensional (3D) computational fluid dynamics model of the spinal canal motivated by questions arising during pharmaceutical development of one molecular therapy for spinal cord injury. The model was based on actual geometry reconstructed from magnetic resonance imaging data subsequently transformed in a parametric 3D geometry and a corresponding finite-volume representation. With dynamics controlled by transient Navier–Stokes equations, the model was implemented in a commercial multi-physics software environment established in the automotive and aerospace industries. While predictions were performed in silico, the underlying biophysical models relied on multiple sources of experimental data and knowledge from scientific literature. The results have provided insights into the primary factors that can influence the intrathecal distribution of drug after lumbar administration. This example illustrates how the approach connects the causal chain underlying drug distribution, starting with the technical aspect of drug delivery systems, through physiology-driven drug transport, then eventually linking to tissue penetration, binding, residence, and ultimately clearance. Currently supporting our drug development projects with an improved understanding of systems physiology, biophysical models are being increasingly used to characterize drug transport and distribution in human tissues where pharmacokinetic measurements are difficult or impossible to perform. Importantly, biophysical models can describe emergent properties of a system, i.e. properties not identifiable through the study of the system’s components taken in isolation

Localization and function of the renal calcium-sensing receptor

The ability to monitor changes in the ionic composition of the extracellular environment is a crucial feature that has evolved in all living organisms. The cloning and characterization of the extracellular calcium-sensing receptor (CaSR) from the mammalian parathyroid gland in the early 1990s provided the first description of a cellular, ion-sensing mechanism. This finding demonstrated how cells can detect small, physiological variations in free ionized calcium (Ca 2+) in the extracellular fluid and subsequently evoke an appropriate biological response by altering the secretion of parathyroid hormone (PTH) that acts on PTH receptors expressed in target tissues, including the kidney, intestine, and bone. Aberrant Ca 2+ sensing by the parathyroid glands, as a result of altered CaSR expression or function, is associated with impaired divalent cation homeostasis. CaSR activators that mimic the effects of Ca 2+ (calcimimetics) have been designed to treat hyperparathyroidism, and CaSR antagonists (calcilytics) are in development for the treatment of hypercalciuric disorders. The kidney expresses a CaSR that might directly contribute to the regulation of many aspects of renal function in a PTH-independent manner. This Review discusses the roles of the renal CaSR and the potential impact of pharmacological modulation of the CaSR on renal function

What is damaging the kidney in lupus nephritis?

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy i