Reversed polarized delivery of an aquaporin-2 mutant causes dominant nephrogenic diabetes insipidus

Vasopressin regulates body water conservation by redistributing aquaporin-2 (AQP2) water channels from intracellular vesicles to the apical surface of renal collecting ducts, resulting in water reabsorption from urine. Mutations in AQP2 cause autosomal nephrogenic diabetes insipidus (NDI), a disease characterized by the inability to concentrate urine. Here, we report a frame-shift mutation in AQP2 causing dominant NDI. This AQP2 mutant is a functional water channel when expressed in Xenopus oocytes. However, expressed in polarized renal cells, it is misrouted to the basolateral instead of apical plasma membrane. Additionally, this mutant forms heterotetramers with wild-type AQP2 and redirects this complex to the basolateral surface. The frame shift induces a change in the COOH terminus of AQP2, creating both a leucine- and a tyrosine-based motif, which cause the reversed sorting of AQP2. Our data reveal a novel cellular phenotype in dominant NDI and show that dominance of basolateral sorting motifs in a mutant subunit can be the molecular basis for disease

Indentation of the Pamirs with respect to the northern margin of Tibet: constraints from the Tarim basin sedimentary record

The Pamirs represent the indented westward continuation of the northern margin of the Tibetan Plateau, dividing the Tarim and Tajik basins. Their evolution may be a key factor influencing aridification of the Asian interior, yet the tectonics of the Pamir Salient are poorly understood. We present a provenance study of the Aertashi section, a Paleogene to late Neogene clastic succession deposited in the Tarim basin to the north of the NW margin of Tibet (the West Kunlun) and to the east of the Pamirs. Our detrital zircon U-Pb ages coupled with zircon fission track, bulk rock Sm-Nd, and petrography data document changes in contributing source terranes during the Oligocene to Miocene, which can be correlated to regional tectonics. We propose a model for the evolution of the Pamir and West Kunlun (WKL), in which the WKL formed topography since at least ~200 Ma. By ~25 Ma, movement along the Pamir-bounding faults such as the Kashgar-Yecheng Transfer System had commenced, marking the onset of Pamir indentation into the Tarim-Tajik basin. This is coincident with basinward expansion of the northern WKL margin, which changed the palaeodrainage pattern within the Kunlun, progressively cutting off the more southerly WKL sources from the Tarim basin. An abrupt change in the provenance and facies of sediments at Aertashi has a maximum age of 14 Ma; this change records when the Pamir indenter had propagated sufficiently far north that the North Pamir was now located proximal to the Aertashi region

Revised age and stratigraphy of the classic Homo erectus-bearing succession at Trinil (Java, Indonesia)

Obtaining accurate age control for fossils found on Java (Indonesia) has been and remains challenging due to geochronologic and stratigraphic uncertainties. In the 1890s, Dubois excavated numerous faunal fossils—including the first remains of Homo erectus—in sediments exposed along the Solo River at Trinil. Since then, various, and often contradictory age estimates have been proposed for the Trinil site and its fossils. However, the age of the fossil-bearing layers and the fossil assemblage remains inconclusive. This study constructs a chronostratigraphic framework for the Trinil site by documenting new stratigraphic sections and test pits, and by applying 40Ar/39Ar, paleomagnetic, and luminescence (pIRIR290) dating methods. Our study identifies two distinct, highly fossiliferous channel fills at the Trinil site. The stratigraphically lower Bone-Bearing Channel 1 (BBC-1) dates to 830–773 ka, while Bone-Bearing Channel 2 (BBC-2) is substantially younger with a maximum age of 450 ± 110 ka and an inferred minimum age of 430 ± 50 ka. Furthermore, significantly younger T2 terrace deposits are present at similar low elevations as BBC-1 and BBC-2. Our results demonstrate the presence of Early and Middle Pleistocene, and potentially even late Middle to Late Pleistocene fossiliferous sediments within the historical excavation area, suggesting that Dubois excavated fossils from at least three highly fossiliferous units with different ages. Moreover, evidence for reworking suggests that material found in the fossil-rich strata may originate from older deposits, introducing an additional source of temporal heterogeneity in the Trinil fossil assemblage. This challenges the current assumption that the Trinil H.K. fauna –which includes Homo erectus-is a homogeneous biostratigraphic unit. Furthermore, this scenario might explain why the Trinil skullcap collected by Dubois is tentatively grouped with Homo erectus fossils from Early Pleistocene sediments at Sangiran, while Trinil Femur I shares affinities with hominin fossils of Late Pleistocene age

Propriétés régulatrices des cellules dendritiques humaines traitées par l'acide mycophénolique

En transplantation d organes, la réponse immunitaire de l hôte contre son donneur reste une cause très importante de perte de greffons. Ainsi, un meilleur contrôle de la réponse par induction d une tolérance spécifique reste une priorité en transplantation humaine. Dans ce travail, nous avons exploré les effets de l acide mycophénolique (MPA, immunosuppresseur couramment utilisé en transplantation) sur les cellules dendritiques (DC) humaines. Nous avons mis en évidence que le MPA diminue la capacité des DC à activer des lymphocytes T CD8+ cytotoxiques allogéniques en diminuant la synthèse d interféron gamma dans les DC. Par ailleurs, les DC traitées par MPA sont capables d induire des lymphocytes T CD4+ régulateurs antigène-spécifiques (iTreg) qui peuvent reprogrammer des DC matures en DC aux propriétés tolérogènes. Enfin, ces iTreg entraînent une réduction de la sécrétion d IFN-g par les cellules T CD8+ et une inhibition de leur fonction cytotoxique en réponse à une stimulation allogénique. L ensemble de ces résultats obtenus in vitro suggèrent que les DC-MPA humaines pourraient être potentiellement utilisés en thérapie cellulaire afin de promouvoir une tolérance d allogreffe.In organ transplantation, host immune response against donor still remains a major cause of graft loss. A better control of allogeneic response through the induction of specific tolerance is a major goal in human transplantation. In this work, we explored the effects of mycophenolic acid (MPA, an immunosuppressive drug currently used in transplantation) on dendritic cell (DC) functions. We demonstrated that MPA inhibits DC ability to induce allogeneic cytotoxic CD8+ T cells through inhibition of interferon gamma synthesis in DC. Moreover, mycophenolic acid-treated dendritic cells (MPA-DC) are able to induce antigen-specific regulatory CD4+ T lymphocytes (iTreg) which can convert fully mature DC into tolerogenic DC. These iTreg decrease the expression of proteins associated with cytotoxic function (perforin and granzymes A and B), reduce IFN-g production by CD8+ T cells and inhibit their cytotoxic function in response to allogeneic stimulation. These results taken together suggest that human MPA-DC could be use in cellular therapy in order to promote allograft tolerance.TOURS-Bibl.électronique (372610011) / SudocSudocFranceF

L' ischémie rénale d'effort (à propos de trois cas)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Left atrial shape is independent predictor of arrhythmia recurrence after catheter ablation for atrial fibrillation: A shape statistics study

International audienceBACKGROUND Markers of left atrial (LA) shape may improve the prediction of postablation outcomes in atrial fibrillation (AF). Correlations to LA volume and AF persistence limit their incremental value over current clinical predictors. OBJECTIVE To develop a shape score independent from AF persistence and LA volume using shape-based statistics, and to test its ability to predict postablation outcome. METHODS Preablation computed tomography (CT) images from 141 patients with paroxysmal (57%) or persistent (43%) AF were segmented. Deformation of an average LA shape into each patient encoded patient-specific shape. Local analysis investigates regional differences between patient groups. Linear regression was used to remove shape variations related to LA volume and AF persistence, and to build a shape score to predict postablation outcome. Cross-validation was performed to evaluate its accuracy. RESULTS Ablation failure rate was 23% over a median 12-month follow-up. Regions associated with ablation failure mostly consisted of a large area on posteroinferior LA, mitral isthmus, and left inferior vein. On univariate analysis, strongest predictors were AF persistence (P 5 .005), LA indexed volume (P 5 .02), and the proposed shape score (P 5 .001). On multivariate analysis, all 3 were independent predictors of ablation failure, with the LA shape score showing the highest predictive value (odds ratio [OR] 5 6.2 [2.5-15.8], P , .001), followed by LA indexed volume (OR 5 3.1 [1.2-7.9], P 5 .019) and AF persistence (OR 5 2.9 [1.2-7.6], P 5 .022). CONCLUSION Posteroinferior LA, mitral isthmus, and left inferior vein are the regions whose shape have the highest impact on outcome. LA shape predicts AF ablation failure independently from, and more accurately than, atrial volume and AF persistence

Mycophenolate mofetil in patients with systemic lupus erythematosus: a prospective pharmacokinetic study

International audienc

High-Resolution Late Gadolinium Enhancement Magnetic Resonance for the Diagnosis of Myocardial Infarction With Nonobstructed Coronary Arteries

International audienceObjectives: The aim of this study was to assess the diagnostic yield of cardiac magnetic resonance (CMR) including high-resolution (HR) late gadolinium enhancement (LGE) imaging using a 3-dimensional respiratory-navigated method in patients with myocardial infarction with nonobstructed coronary arteries (MINOCA).Background: CMR plays a pivotal role for the diagnosis of patients with MINOCA. However, the diagnosis remains inconclusive in a significant number of patients, the results of CMR being either negative or uncertain (i.e., compatible with multiple diagnoses).Methods: Consecutive patients categorized as having MINOCA after blood testing, electrocardiography, coronary angiography, and echocardiography underwent conventional CMR, including cine, T2-weighted, first-pass perfusion, and conventional breath-held LGE imaging. HR LGE imaging using a free-breathing method allowing improved spatial resolution (voxel size 1.25 × 1.25 × 2.5 mm) was added to the protocol when the results of conventional CMR were inconclusive and was optional otherwise. Diagnoses retained after reviewing conventional CMR were compared with those retained after the addition of HR LGE imaging.Results: From 2013 to 2016, 229 patients were included (mean age 56 ± 17 years, 45% women). HR LGE imaging was performed in 172 patients (75%). In this subpopulation, definite diagnoses were retained after conventional CMR in 86 patients (50%): infarction in 39 (23%), myocarditis in 32 (19%), takotsubo cardiomyopathy in 13 (8%), and other diagnoses in 2 (1%). In the remaining 86 patients (50%), results of CMR were inconclusive: negative in 54 (31%) and consistent with multiple diagnoses in 32 (19%). HR LGE imaging led to changes in final diagnosis in 45 patients (26%) and to a lower rate of inconclusive final diagnosis (29%) (p < 0.001). In particular, HR LGE imaging could reveal or ascertain the diagnosis of infarction in 14% and rule out the diagnosis of infarction in 12%. HR LGE imaging was particularly useful when the results of transthoracic echocardiography, ventriculography, and conventional CMR were negative, with a 48% rate of modified diagnosis in this subpopulation.Conclusions: HR LGE imaging has high diagnostic value in patients with MINOCA and inconclusive findings on conventional CMR. This has major diagnostic, prognostic, and therapeutic implications