Tumor necrosis factor stimulates prostaglandin production and cyclic AMP levels in rat cultured mesangial cells

AbstractHuman recombinant tumor necrosis factor-α (TNF) was found to stimulate the production of prostaglandins (PG) by cultured rat mesangial cells. This effect was demonstrable from 6 h, was dose dependent and affected the synthesis of PGE2, PGF2α, and 6-keto-PGF1α. It required both RNA and protein synthesis but was not associated with a modification of cell proliferation. TNF also stimulated adenosine 3′–5′ cyclic monophosphate (cAMP) levels in the mesangial cell culture medium. Indomethacin suppressed the effect of TNF on PGs but only reduced that on cAMP, indicating that PG production partly mediates the increase in cAMP. These findings demonstrate that mesangial cells can be a target for TNF and that the mechanism of TNF action includes stimulation of both PG production and cAMP levels

On the ill/well-posedness and nonlinear instability of the magneto-geostrophic equations

We consider an active scalar equation that is motivated by a model for magneto-geostrophic dynamics and the geodynamo. We prove that the non-diffusive equation is ill-posed in the sense of Hadamard in Sobolev spaces. In contrast, the critically diffusive equation is well-posed. In this case we give an example of a steady state that is nonlinearly unstable, and hence produces a dynamo effect in the sense of an exponentially growing magnetic field.Comment: We have modified the definition of Lipschitz well-posedness, in order to allow for a possible loss in regularity of the solution ma

Update on vitamin D and evaluation of vitamin D status.

Knowledge about vitamin D has greatly improved during the last few years. Vitamin D cannot any more be considered as exclusively necessary to prevent ricket/osteomalacia. Its role in the prevention of some osteoporotic fractures in the elderly (in association with calcium nutrition) is now well demonstrated and many epidemiologic and laboratory data argue for a role in the prevention of several diseases or anomalies (cancer, auto-immune diseases, cardiovascular events, sarcopenia...). A few intervention studies confirming some of these effects also exist. Vitamin D status can easily be assessed by measuring serum 25 hydroxy vitamin D (25OHD) level. However, many experts have claimed that the population-based reference values for 25OHD are too low and that the cut-off value below which vitamin D insufficiency can be present is somewhere between 20 and 40ng/mL with a clear tendency to target values above 30ng/mL (75nmol/L). The main consequences are that vitamin D insufficiency is highly frequent whereas the currently recommended supplementation doses are not sufficient

A New Human NHERF1 Mutation Decreases Renal Phosphate Transporter NPT2a Expression by a PTH-Independent Mechanism

Background: The sodium-hydrogen exchanger regulatory factor 1 (NHERF1) binds to the main renal phosphate transporter NPT2a and to the parathyroid hormone (PTH) receptor. We have recently identified mutations in NHERF1 that decrease renal phosphate reabsorption by increasing PTH-induced cAMP production in the renal proximal tubule. Methods: We compared relevant parameters of phosphate homeostasis in a patient with a previously undescribed mutation in NHERF1 and in control subjects. We expressed the mutant NHERF1 protein in Xenopus Oocytes and in cultured cells to study its effects on phosphate transport and PTH-induced cAMP production. Results: We identified in a patient with inappropriate renal phosphate reabsorption a previously unidentified mutation (E68A) located in the PDZ1 domain of NHERF1.We report the consequences of this mutation on NHERF1 function. E68A mutation did not modify cAMP production in the patient. PTH-induced cAMP synthesis and PKC activity were not altered by E68A mutation in renal cells in culture. In contrast to wild-type NHERF1, expression of the E68A mutant in Xenopus oocytes and in human cells failed to increase phosphate transport. Pull down experiments showed that E68A mutant did not interact with NPT2a, which robustly interacted with wild type NHERF1 and previously identified mutants. Biotinylation studies revealed that E68A mutant was unable to increase cell surface expression of NPT2a. Conclusions: Our results indicate that the PDZ1 domain is critical for NHERF1- NPT2a interaction in humans and for th

The Phosphate Transporter PiT1 (Slc20a1) Revealed As a New Essential Gene for Mouse Liver Development

BACKGROUND: PiT1 (or SLC20a1) encodes a widely expressed plasma membrane protein functioning as a high-affinity Na(+)-phosphate (Pi) cotransporter. As such, PiT1 is often considered as a ubiquitous supplier of Pi for cellular needs regardless of the lack of experimental data. Although the importance of PiT1 in mineralizing processes have been demonstrated in vitro in osteoblasts, chondrocytes and vascular smooth muscle cells, in vivo evidence is missing. METHODOLOGY/PRINCIPAL FINDINGS: To determine the in vivo function of PiT1, we generated an allelic series of PiT1 mutations in mice by combination of wild-type, hypomorphic and null PiT1 alleles expressing from 100% to 0% of PiT1. In this report we show that complete deletion of PiT1 results in embryonic lethality at E12.5. PiT1-deficient embryos display severely hypoplastic fetal livers and subsequent reduced hematopoiesis resulting in embryonic death from anemia. We show that the anemia is not due to placental, yolk sac or vascular defects and that hematopoietic progenitors have no cell-autonomous defects in proliferation and differentiation. In contrast, mutant fetal livers display decreased proliferation and massive apoptosis. Animals carrying two copies of hypomorphic PiT1 alleles (resulting in 15% PiT1 expression comparing to wild-type animals) survive at birth but are growth-retarded and anemic. The combination of both hypomorphic and null alleles in heterozygous compounds results in late embryonic lethality (E14.5-E16.5) with phenotypic features intermediate between null and hypomorphic mice. In the three mouse lines generated we could not evidence defects in early skeleton formation. CONCLUSION/SIGNIFICANCE: This work is the first to illustrate a specific in vivo role for PiT1 by uncovering it as being a critical gene for normal developmental liver growth

Carboxy-terminal fragment of fibroblast growth factor 23 induces heart hypertrophy in sickle cell disease

International audienc

Quantum ergodicity for graphs related to interval maps

We prove quantum ergodicity for a family of graphs that are obtained from ergodic one-dimensional maps of an interval using a procedure introduced by Pakonski et al (J. Phys. A, v. 34, 9303-9317 (2001)). As observables we take the L^2 functions on the interval. The proof is based on the periodic orbit expansion of a majorant of the quantum variance. Specifically, given a one-dimensional, Lebesgue-measure-preserving map of an interval, we consider an increasingly refined sequence of partitions of the interval. To this sequence we associate a sequence of graphs, whose directed edges correspond to elements of the partitions and on which the classical dynamics approximates the Perron-Frobenius operator corresponding to the map. We show that, except possibly for subsequences of density 0, the eigenstates of the quantum graphs equidistribute in the limit of large graphs. For a smaller class of observables we also show that the Egorov property, a correspondence between classical and quantum evolution in the semiclassical limit, holds for the quantum graphs in question.Comment: 20 pages, 1 figur