Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex

Proteins of the death domain (DD) superfamily mediate assembly of oligomeric signaling complexes for the activation of caspases and kinases via unknown mechanisms. Here we report the crystal structure of the PIDD DD and RAIDD DD complex, which forms the core of the caspase-2-activating complex PIDDosome. Although RAIDD DD and PIDD DD are monomers, they assemble into a complex that comprises seven RAIDD DDs and five PIDD DDs. Despite the use of an asymmetric assembly mechanism, all DDs in the complex are in quasi-equivalent environments. The structure provided eight unique asymmetric interfaces, which can be classified into three types. These three types of interactions together cover a majority of the DD surface. Mutagenesis on almost all interfaces leads to disruption of the assembly, resulting in defective caspase-2 activation. The three types of interactions may represent most, if not all, modes of interactions in the DD superfamily for assembling complexes of different stoichiometry

Risk prediction of developing venous thrombosis in combined oral contraceptive users.

Venous thromboembolism (VTE) is a complex multifactorial disease influenced by genetic and environmental risk factors. An example for the latter is the regular use of combined oral contraceptives (CC), which increases the risk to develop VTE by 3 to 7 fold, depending on estrogen dosage and the type of progestin present in the pill. One out of 1'000 women using CC develops thrombosis, often with life-long consequences; a risk assessment is therefore necessary prior to such treatment. Currently known clinical risk factors associated with VTE development in general are routinely checked by medical doctors, however they are far from being sufficient for risk prediction, even when combined with genetic tests for Factor V Leiden and Factor II G20210A variants. Thus, clinical and notably genetic risk factors specific to the development of thrombosis associated with the use of CC in particular should be identified. Step-wise (logistic) model selection was applied to a population of 1622 women using CC, half of whom (794) had developed a thromboembolic event while using contraceptives. 46 polymorphisms and clinical parameters were tested in the model selection and a specific combination of 4 clinical risk factors and 9 polymorphisms were identified. Among the 9 polymorphisms, there are two novel genetic polymorphisms (rs1799853 and rs4379368) that had not been previously associated with the development of thromboembolic event. This new prediction model outperforms (AUC 0.71, 95% CI 0.69-0.74) previously published models for general thromboembolic events in a cross-validation setting. Further validation in independent populations should be envisaged. We identified two new genetic variants associated to VTE development, as well as a robust prediction model to assess the risk of thrombosis for women using combined oral contraceptives. This model outperforms current medical practice as well as previously published models and is the first model specific to CC use

PROCESSEUR HYBRIDE PROGRAMMABLE POUR LE TRAITEMENT NUMÉRIQUE RÉCURSIF ET ITÉRATIF DU SIGNAL

An hybrid acousto-optic processor, limited to iterative signal processing (transversal filtering), has been first studied in our laboratory. An extension to recursive filtering is now reported. As a benefit from the needed modifications, the computation cycles of the system are now fully programmable (like for bit-slice processors) and optimized in order to preserve the high speed rate capability of the acousto-optic interaction.The various stages in the design, the realization using erasable programmable logic devices, together with applications to infinite impulse response filtering are presented. The performances of the new system discussed.Un premier processeur acousto-optique hybride a été développé dans notre laboratoire mais celui-ci était limité au traitement itératif du signal (filtrage transversal). Nous présentons maintenant son extension au filtrage récursif pour lequel il a été nécessaire d'adapter et de rendre complètement programmable chaque cycle de calcul du système tout en préservant les capacités de traitement, en vitesse, de la première version. Nous terminons cette présentation par les performances de ce nouveau système de traitement

Système de traitement acousto-optique de signaux numériques

The transversal filter is a fundamental device in numerical signal processing. Among all available techniques, the acousto-optic convolution is very well matched to this function. Some penalties occur however, for very long input signals, owing to the physical configuration of the convolver and to the propagation of acoustic waves in its bulk. This calls for the study of a convenient computation algorithm taking all the constraints into account. The realization of an hybrid processor enabled us to evaluate its main characteristics using experiments like autoconvolution, F.I.R. filtering, Golay's and Barker's codes or matrix multiplication. Since the built system is actually a prototype, a number of extensions and improvements are presented, which may lead to the optimization of the processing speed.L'élément fondamental du traitement numérique du signal est le filtre transversal. Parmi les techniques utilisables, la convolution acousto-optique est particulièrement bien adaptée à cette fonction. Les difficultés de cette opération, pour le traitement d'un signal d'entrée relativement long, proviennent de la configuration propre du convoluteur et du phénomène de propagation. Celles-ci vont nécessiter l'étude d'un algorithme de calcul respectant certaines contraintes. La réalisation du processeur hybride nous a permis d'en évaluer les caractéristiques à partir des résultats expérimentaux tels que : autoconvolutions, filtrage F.I.R., corrélations, codes de Golay, codes de Barker et multiplication matricielle. Le fait même de la nature prototype du système réalisé nous amène à présenter un grand nombre d'extensions et d'améliorations qui permettent d'optimiser fortement la vitesse de traitement

Système de traitement acousto-optique de signaux numériques

The transversal filter is a fundamental device in numerical signal processing. Among all available techniques, the acousto-optic convolution is very well matched to this function. Some penalties occur however, for very long input signals, owing to the physical configuration of the convolver and to the propagation of acoustic waves in its bulk. This calls for the study of a convenient computation algorithm taking all the constraints into account. The realization of an hybrid processor enabled us to evaluate its main characteristics using experiments like autoconvolution, F.I.R. filtering, Golay's and Barker's codes or matrix multiplication. Since the built system is actually a prototype, a number of extensions and improvements are presented, which may lead to the optimization of the processing speed

Traitement numerique du signal par processeur hybride : Acousto-optique et numerique

Les filtres acousto-optiques transversaux et leurs applications sont maintenant bien connus. Parmi ceux-ci, le convoluteur acousto-optique a été l'objet d'un intérêt particulier. Le travail a porté sur la conception d'algorithmes et la réalisation d'un système digital de pilotage adapté à la structure de ce composant en vue de traitements numériques du signal

Topoisomerase I and II inhibitors control caspase-2 pre-messenger RNA splicing in human cells

We have recently shown that the topoisomerase II inhibitor, etoposide (VP16), could trigger caspase-2 pre-mRNA splicing in human leukemic cell lines. This leads to increased inclusion of exon 9, which is specifically inserted into the short caspase-2S isoform mRNA and absent from the long caspase-2L isoform mRNA. One of the consequences of this alternative splicing is a decrease in the total amount of the mature form of caspase-2L mRNA and protein. In this study, we analyzed the effects of several representative molecules of various classes of cytotoxic agents on caspase-2 pre-mRNA splicing in both U937 leukemic cells and in HeLa cervix carcinoma cells. Very strikingly, both topoisomerase I (camptothecin and homocamptothecin derivatives) and II (VP16, amsacrine, doxorubicin, mitoxantrone) inhibitors induced exon 9 inclusion. DNA intercalating glycosyl indolocarbazole derivatives as well as DNA alkylating agents, such as cisplatin and melphalan, antimetabolites like 5-fluorouracil, and mitotic spindle poisons like vinblastine had no effect. Therefore, both classes of DNA topoisomerases can control pre-mRNA splicing of the caspase-2 transcript. In addition, the splicing reaction brought about by camptothecin was hampered in human CEM/C2 and in murine P388-45R leukemic deficient in topoisomerase I activity. Conversely, VP16 did not trigger caspase-2 alternative splicing in human HL60/MX2 leukemic cells harboring a mutant topoisomerase II. Minigene transfection analysis revealed that topoisomerase inhibitors did not change the splicing profile when cis-acting elements in intron-9, reported to control exon 9 inclusion independently of drug treatment, were removed. Rather, our experiments suggest that exon 9 inclusion induced by topoisomerase inhibitors reflects the activity exerted by topoisomerase I or II on proteins that control splicing reactions, or their direct involvement in pre-mRNA splicing