Délégation Paris Michel-Ange

Pseudohypoaldosteronism type II (PHAII) is a genetic disease characterized by association of hyperkalemia, hyperchloremic metabolic acidosis, hypertension, low renin, and high sensitivity to thiazide diuretics. It is caused by mutations in the WNK1, WNK4, KLHL3 or CUL3 gene. There is strong evidence that excessive sodium chloride reabsorption by the sodium chloride cotransporter NCC in the distal convoluted tubule is involved. WNK4 is expressed not only in distal convoluted tubule cells but also in β-intercalated cells of the cortical collecting duct. These latter cells exchange intracellular bicarbonate for external chloride through pendrin, and therefore, account for renal base excretion. However, these cells can also mediate thiazide-sensitive sodium chloride absorption when the pendrin-dependent apical chloride influx is coupled to apical sodium influx by the sodium-driven chloride/bicarbonate exchanger. Here we determine whether this system is involved in the pathogenesis of PHAII. Renal pendrin activity was markedly increased in a mouse model carrying a WNK4 missense mutation (Q562E) previously identified in patients with PHAII. The upregulation of pendrin led to an increase in thiazide-sensitive sodium chloride absorption by the cortical collecting duct, and it caused metabolic acidosis. The function of apical potassium channels was altered in this model, and hyperkalemia was fully corrected by pendrin genetic ablation. Thus, we demonstrate an important contribution of pendrin in renal regulation of sodium chloride, potassium and acid-base homeostasis and in the pathophysiology of PHAII. Furthermore, we identify renal distal bicarbonate secretion as a novel mechanism of renal tubular acidosis.

Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known. To determine if CAII was required for urinary concentration, we studied water handling in CAII-deficient mice. CAII-deficient mice demonstrate polyuria and polydipsia as well as an alkaline urine and bicarbonaturia, consistent with a type III renal tubular acidosis. Natriuresis and hypercalciuria cause polyuria, however, CAII-deficient mice did not have increased urinary sodium nor calcium excretion. Further examination revealed dilute urine in the CAII-deficient mice. Urinary concentration remained reduced in CAII-deficient mice relative to wild-type animals even after water deprivation. The renal expression and localization by light microscopy of NKCC2 and aquaporin-2 was not altered. However, CAII-deficient mice had increased renal AQP1 expression. CAII associates with and increases water flux through aquaporin-1. Water flux through aquaporin-1 in the TDL of the loop of Henle is essential to the concentration of urine, as this is required to generate a concentrated medullary interstitium. We therefore measured cortical and medullary interstitial concentration in wild-type and CAII-deficient mice. Mice lacking CAII had equivalent cortical interstitial osmolarity to wild-type mice: however, they had reduced medullary interstitial osmolarity. We propose therefore that reduced water flux through aquaporin-1 in the TDL in the absence of CAII prevents the generation of a maximally concentrated medullary interstitium. This, in turn, limits urinary concentration in CAII deficient mice.

Abstract This paper stresses a new channel through which global financial linkages contribute to the co‐movement in economic activity across countries. We show in a two‐country setting with borrowing constraints that international credit markets are subject to self‐fulfilling variations in the world real interest rate. Those expectation‐driven changes in the borrowing cost in turn act as global shocks that induce strong cross‐country co‐movements in both financial and real variables (such as asset prices, gross domestic product, consumption, investment, and employment). When firms around the world benefit from unexpectedly low debt repayments, they borrow and invest more, which leads to excessive supply of collateral and of loanable funds at a low interest rate, thus fueling a boom both at home and abroad. As a consequence, business cycles are synchronized internationally. Such a stylized model thus offers one way to rationalize both the existence of a world business‐cycle component, documented by recent empirical studies through dynamic factor analysis, and the factor's intimate link to global financial markets.

This paper stresses a new channel through which global financial linkages contribute to the co-movement in economic activity across countries.We show in a two-country setting with borrowing constraints that international credit markets are subject to self-fulfilling variations in the world real interest rate.Those expectation-driven changes in the borrowing cost in turn act as global shocks that induce strong cross-country co-movements in both financial and real variables (such as asset prices, GDP, consumption, investment and employment).When firms around the world benefit from unexpectedly low debt repayments, they borrow and invest more, which leads to excessive supply of collateral and of loanable funds at a low interest rate, thus fueling a boom in both home and abroad.As a consequence, business cycles are synchronized internationally.Such a stylized model thus offers one way to rationalize both the existence of a world business-cycle component, documented by recent empirical studies through dynamic factor analysis, and the factor's intimate link to global financial markets.

The poxvirus Modified Vaccinia virus Ankara (MVA) is a safe and versatile licensed vaccine and viral vector, yet its immunogenicity remains improvable, as it often requires multiple doses for optimal protection and also induces waning of antibody responses. To enable more rational optimization of MVA-based vaccines, we developed a mechanistic and executable systems vaccinology framework based on Boolean modeling to capture the dynamics of vaccine-induced immune responses. We constructed and calibrated a Boolean network of the MVA-induced immune response by integrating literature-derived mechanisms with longitudinal in vivo experimental data. The model accurately reproduced immune dynamics with high fidelity and, importantly, was validated against independent datasets of genetically modified MVA vaccines, demonstrating strong predictive capacity. Using this framework, we performed in silico perturbations to evaluate novel genetically modified MVA mutants derived from expert knowledge. To further guide rational design, we built two other vaccine-induced response Boolean networks: one describing the MVA response in a broader fashion, the other modeling the YF-17D yellow fever vaccine response that represents a reference for durable protection after single-dose immunization. Comparative analysis of network topology and dynamics revealed shared and divergent features that informed strategies to enhance MVA-induced responses by reorienting them toward YF-17D-like immune signatures, and allowed us to design and test virtually two new genetically modified MVA deletion mutants. Throughout this work, we exploited the executable nature of the models of response to MVA to simulate perturbations, identifying potential targets to boost immunogenicity. Together, this work establishes executable Boolean modeling as a valuable predictive tool for systems vaccinology and provides a generalizable framework for the rational design and optimization of next-generation MVA-based vaccines.

The poxvirus Modified Vaccinia virus Ankara (MVA) is a safe and versatile licensed vaccine and viral vector, yet its immunogenicity remains improvable, as it often requires multiple doses for optimal protection and also induces waning of antibody responses. To enable more rational optimization of MVA-based vaccines, we developed a mechanistic and executable systems vaccinology framework based on Boolean modeling to capture the dynamics of vaccine-induced immune responses. We constructed and calibrated a Boolean network of the MVA-induced immune response by integrating literature-derived mechanisms with longitudinal in vivo experimental data. The model accurately reproduced immune dynamics with high fidelity and, importantly, was validated against independent datasets of genetically modified MVA vaccines, demonstrating strong predictive capacity. Using this framework, we performed in silico perturbations to evaluate novel genetically modified MVA mutants derived from expert knowledge. To further guide rational design, we built two other vaccine-induced response Boolean networks: one describing the MVA response in a broader fashion, the other modeling the YF-17D yellow fever vaccine response that represents a reference for durable protection after single-dose immunization. Comparative analysis of network topology and dynamics revealed shared and divergent features that informed strategies to enhance MVA-induced responses by reorienting them toward YF-17D-like immune signatures, and allowed us to design and test virtually two new genetically modified MVA deletion mutants. Throughout this work, we exploited the executable nature of the models of response to MVA to simulate perturbations, identifying potential targets to boost immunogenicity. Together, this work establishes executable Boolean modeling as a valuable predictive tool for systems vaccinology and provides a generalizable framework for the rational design and optimization of next-generation MVA-based vaccines.

The poxvirus Modified Vaccinia virus Ankara (MVA) is a safe and versatile licensed vaccine and viral vector, yet its immunogenicity remains improvable, as it often requires multiple doses for optimal protection and also induces waning of antibody responses. To enable more rational optimization of MVA-based vaccines, we developed a mechanistic and executable systems vaccinology framework based on Boolean modeling to capture the dynamics of vaccine-induced immune responses. We constructed and calibrated a Boolean network of the MVA-induced immune response by integrating literature-derived mechanisms with longitudinal in vivo experimental data. The model accurately reproduced immune dynamics with high fidelity and, importantly, was validated against independent datasets of genetically modified MVA vaccines, demonstrating strong predictive capacity. Using this framework, we performed in silico perturbations to evaluate novel genetically modified MVA mutants derived from expert knowledge. To further guide rational design, we built two other vaccine-induced response Boolean networks: one describing the MVA response in a broader fashion, the other modeling the YF-17D yellow fever vaccine response that represents a reference for durable protection after single-dose immunization. Comparative analysis of network topology and dynamics revealed shared and divergent features that informed strategies to enhance MVA-induced responses by reorienting them toward YF-17D-like immune signatures, and allowed us to design and test virtually two new genetically modified MVA deletion mutants. Throughout this work, we exploited the executable nature of the models of response to MVA to simulate perturbations, identifying potential targets to boost immunogenicity. Together, this work establishes executable Boolean modeling as a valuable predictive tool for systems vaccinology and provides a generalizable framework for the rational design and optimization of next-generation MVA-based vaccines.