Field-temperature phase diagram of the enigmatic Nd2(Zr1−xTix)2O7 pyrochlore magnets

By combining neutron scattering and magnetization measurements down to 80 mK, we determine the (H, T ) phase diagram of the Nd2(Zr1−xTix )2O7 pyrochlore magnet compounds. In those samples, Zr is partially substituted by Ti, hence tuning the exchange parameters and testing the robustness of the various phases. In all samples, the ground state remains all in/all out, while the field induces phase transitions toward new states characterized by two in–two out or one out–three in/one in–three out configurations. These transitions manifest as metamagnetic singularities in the magnetization versus field measurements. Strikingly, it is found that moderate substitution reinforces the stability of the all in/all out phase: the Néel temperature, the metamagnetic fields along with the ordered magnetic moment, are higher in substituted samples with x < 10%

Expressed sequence tag analysis of khat (Catha edulis) provides a putative molecular biochemical basis for the biosynthesis of phenylpropylamino alkaloids

Khat (Catha edulis Forsk.) is a flowering perennial shrub cultivated for its neurostimulant properties resulting mainly from the occurrence of (S)-cathinone in young leaves. The biosynthesis of (S)-cathinone and the related phenylpropylamino alkaloids (1S,2S)-cathine and (1R,2S)-norephedrine is not well characterized in plants. We prepared a cDNA library from young khat leaves and sequenced 4,896 random clones, generating an expressed sequence tag (EST) library of 3,293 unigenes. Putative functions were assigned to > 98% of the ESTs, providing a key resource for gene discovery. Candidates potentially involved at various stages of phenylpropylamino alkaloid biosynthesis from L-phenylalanine to (1S,2S)-cathine were identified

Protection of Human Pancreatic Islets from Lipotoxicity by Modulation of the Translocon

International audienceType 2 diabetes is characterized by peripheral insulin resistance and pancreatic beta cell dysfunction. Elevated free fatty acids (FFAs) may impair beta cell function and mass (lipotoxicity). Altered calcium homeostasis may be involved in defective insulin release. The endoplasmic reticulum (ER) is the major intracellular calcium store. Lipotoxicity induces ER stress and in parallel an ER calcium depletion through unknown ER calcium leak channels. The main purposes of this study is first to identify one of these channels and secondly, to check the opportunity to restore beta cells function (i.e., insulin secretion) after pharmacological inhibition of ER calcium store depletion. We investigated the functionality of translocon, an ER calcium leak channel and its involvement on FFAs-induced alterations in MIN6B1 cells and in human pancreatic islets. We evidenced that translocon acts as a functional ER calcium leak channel in human beta cells using anisomycin and puromycin (antibiotics), respectively blocker and opener of this channel. Puromycin induced a significant ER calcium release, inhibited by anisomycin pretreatment. Palmitate treatment was used as FFA model to induce a mild lipotoxic effect: ER calcium content was reduced, ER stress but not apoptosis were induced and glucose induced insulin secretion was decreased in our beta cells. Interestingly, translocon inhibition by chronic anisomycin treatment prevented dysfunctions induced by palmitate, avoiding reticular calcium depletion, ER stress and restoring insulin secretion. Our results provide for the first time compelling evidence that translocon actively participates to the palmitate-induced ER calcium leak and insulin secretion decrease in beta cells. Its inhibition reduces these lipotoxic effects. Taken together, our data indicate that TLC may be a new potential target for the treatment of type 2 diabetes

Translocon inhibition partially modulates palmitate-induced ER stress.

<p>ER stress mRNA expression markers were measured after 48h BSA (white bar) + anisomycin (grey bars) or palmitate (black bar) + anisomycin (hatched bars) treatment in 5 different human islet preparations. ***p<0.001;**p<0.01;*p<0.05.</p

Translocon inhibition partially prevents palmitate-induced reticular calcium depletion.

<p>Quantification of fluorescence ratio (F340/F380) of resting calcium (<b>a</b>) and of reticular calcium release induced by 1 μM thapsigargin (<b>b</b>) in 4 different human islets preparations (11 cells per preparation) under 48h BSA (white bar) + anisomycin (grey bars and palmitate (black bar) conditions + anisomycin (hatched bars). *p<0.05, **p<0.01.</p

Anisomycin restores GSIS in palmitate condition in human islets.

<p>GSIS were measured after 48h BSA (white bar) + anisomycin (200 nM; grey bars) or palmitate (black bar) treatment + anisomycin (200 nM; hatched bars) in 6 human islet different preparations. *p<0.05.</p

Puromycin and anisomycin acute effects on calcium homeostasis in human islets.

<p>Puromycin and anisomcyin effects were evaluated in 4 different human islets preparation (44 different cells) (<b>a</b>-<b>e</b>). Typical cytosolic calcium traces in response to 200 μM thapsigargin (<b>a</b>) or to 1 μM puromycin (<b>b</b>) under control conditions and after 30 min incubation with 200 μM anisomycin. Cumulative data of peak cytosolic calcium increases evoked by puromycin responses under control conditions and with anisomycin 200 μM (<b>c</b>). Cumulative data of peak cytosolic calcium increases evoked by thapsigargin responses (<b>d</b>) and (<b>e</b>) resting fluorescence (F340/F380) under control conditions ± puromycin or anisomycin pretreatment. *p<0.05, **p<0.01. Measures were assessed in a calcium-free medium. Preparations were done in duplicate.</p

Characteristics of human islet donors.

<p>Characteristics of human islet donors.</p

Model of translocon implication in pancreatic beta cells.

<p>Chronic palmitate causes ER calcium depletion due to a greater ER calcium leak through the translocon, triggering ER stress and decreased glucose-stimulated insulin release, indicating an altered metabolism-secretion coupling. Addition of anisomycin reduced ER stress and ER calcium leak from translocon, leading to restored insulin secretion.</p