MATH/BTB CRL3 receptors target the homeodomain-leucine zipper ATHB6 to modulate abscisic acid signaling.

Being sessile organisms, plants need rapid and finely tuned signaling pathways to adapt their growth and survival over their immediate and often adverse environment. Abscisic acid (ABA) is a plant hormone crucial for both biotic and abiotic stress responses. In this study, we highlight a function of six Arabidopsis MATH-BTB proteins in ABA signaling. MATH-BTB proteins act as substrate-binding adaptors for the Cullin3-based ubiquitin E3 ligase. Our genetic and biochemical experiments demonstrate that the MATH-BTB proteins directly interact with and target for proteasomal degradation the class I homeobox-leucine zipper (HD-ZIP) transcription factor ATHB6, which was previously identified as a negative regulator of ABA responses. Reducing CUL3(BPM) function leads to higher ATHB6 protein accumulation, reducing plant growth and fertility, and affects stomatal behavior and responses to ABA. We further demonstrate that ABA negatively regulates ATHB6 protein turnover, a situation reminiscent to ABI5, another transcription factor involved in ABA signaling.

Diagnostics hardening for harsh environment in Laser Megajoule (invited).

The diagnostic designs for the Laser Megajoule (LMJ) will require components to operate in environments far more severe than those encountered in present facilities. This harsh environment will be induced by fluxes of neutrons, gamma rays, energetic ions, electromagnetic radiations, and, in some cases, debris and shrapnel, at levels several orders of magnitude higher than those experienced today on existing facilities. The lessons learned about the vulnerabilities of present diagnostic parts fielded mainly on OMEGA for many years, have been very useful guide for the design of future LMJ diagnostics. The present and future LMJ diagnostic designs including this vulnerability approach and their main mitigation techniques will be presented together with the main characteristics of the LMJ facility that provide for diagnostic protection.

Activation analysis and first occupational dose rates estimates for the Laser Megajoule facility.

A three-dimensional neutronic modelling of the LMJ facility has been performed. The Monte Carlo transport code TRIPOLI is used to obtain the neutron spectra required for the inventory code FISPACT. Nodal activation responses and time-dependent decay gamma spectra are produced and used as source terms for further treatment by TRIPOLI for a range of engineering and safety assessments. It is shown that three-dimensional neutronic and nodal activation can be performed in a convenient way and the results obtained by this procedure will serve as a data-base for design and S&E analysis.

Hyperprolinemia is a risk factor for schizoaffective disorder.

DNA sequence variations within the 22q11 DiGeorge chromosomal region are likely to confer susceptibility to psychotic disorders. In a previous report, we identified several heterozygous alterations, including a complete deletion, of the proline dehydrogenase (PRODH) gene, which were associated with moderate hyperprolinemia in a subset of DSM III schizophrenic patients. Our objective was (i) to determine whether hyperprolinemia is associated with increased susceptibility for any of three psychiatric conditions (schizophrenia, schizoaffective disorder and bipolar disorder) and (ii) to establish a correlation between hyperprolinemia and PRODH genotypes. We have conducted a case-control study including 114 control subjects, 188 patients with schizophrenia, 63 with schizoaffective disorder and 69 with bipolar disorder. We report that, taking into account a confounding effect due to valproate treatment, hyperprolinemia is a risk factor for DSM IIIR schizoaffective disorder (P=0.02, Odds ratio=4.6, 95% confidence interval 1.3-16.3). We did not detect 22q11 interstitial deletions associated with the DiGeorge syndrome among the 320 patients of our sample and we found no association between common PRODH polymorphisms and any of the psychotic disorders. In contrast, we found that five rare PRODH alterations (including a complete PRODH deletion and four missense substitutions) were associated with hyperprolinemia. In several cases, two variations were present simultaneously, either in cis or trans in the same subject. A total of 11 from 30 hyperprolinemic subjects bore at least one genetic variation associated with hyperprolinemia. This study demonstrates that moderate hyperprolinemia is an intermediate phenotype associated with certain forms of psychosis.

The molecular basis of the specificity of action of K(ATP) channel openers.

K(ATP) channels incorporate a regulatory subunit of the ATP-binding cassette (ABC) transporter family, the sulfonylurea receptor (SUR), which defines their pharmacology. The therapeutically important K(+) channel openers (e.g. pinacidil, cromakalim, nicorandil) act specifically on the SUR2 muscle isoforms but, except for diazoxide, remain ineffective on the SUR1 neuronal/pancreatic isoform. This SUR1/2 dichotomy underpinned a chimeric strategy designed to identify the structural determinants of opener action, which led to a minimal set of two residues within the last transmembrane helix of SUR. Transfer of either residue from SUR2A to SUR1 conferred opener sensitivity to SUR1, while the reverse operation abolished SUR2A sensitivity. It is therefore likely that these residues form part of the site of interaction of openers with the channel. Thus, openers would target a region that, in other ABC transporters, is known to be tightly involved with the binding of substrates and other ligands. This first glimpse of the site of action of pharmacological openers should permit rapid progress towards understanding the structural determinants of their affinity and specificity.

Pharmacological plasticity of cardiac ATP-sensitive potassium channels toward diazoxide revealed by ADP.

The pharmacological phenotype of ATP-sensitive potassium (K(ATP)) channels is defined by their tissue-specific regulatory subunit, the sulfonylurea receptor (SUR), which associates with the pore-forming channel core, Kir6.2. The potassium channel opener diazoxide has hyperglycemic and hypotensive properties that stem from its ability to open K(ATP) channels in pancreas and smooth muscle. Diazoxide is believed not to have any significant action on cardiac sarcolemmal K(ATP) channels. Yet, diazoxide can be cardioprotective in ischemia and has been found to bind to the presumed cardiac sarcolemmal K(ATP) channel-regulatory subunit, SUR2A. Here, in excised patches, diazoxide (300 microM) activated pancreatic SUR1/Kir6.2 currents and had little effect on native or recombinant cardiac SUR2A/Kir6.2 currents. However, in the presence of cytoplasmic ADP (100 microM), SUR2A/Kir6.2 channels became as sensitive to diazoxide as SUR1/Kir6. 2 channels. This effect involved specific interactions between MgADP and SUR, as it required Mg(2+), but not ATP, and was abolished by point mutations in the second nucleotide-binding domain of SUR, which impaired channel activation by MgADP. At the whole-cell level, in cardiomyocytes treated with oligomycin to block mitochondrial function, diazoxide could also activate K(ATP) currents only after cytosolic ADP had been raised by a creatine kinase inhibitor. Thus, ADP serves as a cofactor to define the responsiveness of cardiac K(ATP) channels toward diazoxide. The present demonstration of a pharmacological plasticity of K(ATP) channels identifies a mechanism for the control of channel activity in cardiac cells depending on the cellular ADP levels, which are elevated under ischemia.

A transmembrane domain of the sulfonylurea receptor mediates activation of ATP-sensitive K(+) channels by K(+) channel openers.

ATP-sensitive K(+) (K(ATP)) channels are a complex of an ATP-binding cassette transporter, the sulfonylurea receptor (SUR), and an inward rectifier K(+) channel subunit, Kir6.2. The diverse pharmacological responsiveness of K(ATP) channels from various tissues are thought to arise from distinct SUR isoforms. Thus, when assembled with Kir6. 2, the pancreatic beta cell isoform SUR1 is activated by the hyperglycemic drug diazoxide but not by hypotensive drugs like cromakalim, whereas the cardiac muscle isoform SUR2A is activated by cromakalim and not by diazoxide. We exploited these differences between SUR1 and SUR2A to pursue a chimeric approach designed to identify the structural determinants of SUR involved in the pharmacological activation of K(ATP) channels. Wild-type and chimeric SUR were coexpressed with Kir6.2 in Xenopus oocytes, and we studied the resulting channels with the patch-clamp technique in the excised inside-out configuration. The third transmembrane domain of SUR is found to be an important determinant of the response to cromakalim, which possibly harbors at least part of its binding site. Contrary to expectations, diazoxide sensitivity could not be linked specifically to the carboxyl-terminal end (nucleotide-binding domain 2) of SUR but appeared to involve complex allosteric interactions between transmembrane and nucleotide-binding domains. In addition to providing direct evidence for the structure-function relationship governing K(ATP) channel activation by potassium channel-opening drugs, a family of drugs of the highest therapeutic interest, these findings delineate the determinants of ligand specificity within the modular ATP-binding cassette-transporter architecture of SUR.

A relation between automorphic forms on GL(2) and GL(3).

Let rho(n) denote the standard n-dimensional representation of GL(n,C) and rho(n) (2) its symmetric square. For each automorphic cuspidal representation pi of GL(2,A) we introduce an Euler product L(s,pi,rho(2) (2)) of degree 3 which we prove is entire. We also prove that there exists an automorphic representation II of GL(3)-"the lift of pi"-with the property that L(s,II,rho(3)) = L(s,pi,rho(2) (2)). Our results confirm conjectures described in a more general context by R. P. Langlands [(1970) Lecture Notes in Mathematics, no. 170 (Springer-Verlag, Berlin-Heidelberg-New York)].