HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

Evaluation of type-B RR dimerization in poplar: A mechanism to preserve signaling specificity?

Plants possess specific signaling pathways, such as the MultiStep Phosphorelay (MSP), which is involved in cytokinin and ethylene sensing, and light, drought or osmotic stress sensing. These MSP comprise histidine-aspartate kinases (HKs) as receptors, histidine phosphotransfer (HPts) proteins acting as phosphorelay proteins, and response regulators (RRs), some of which act as transcription factors (type-B RRs). In previous studies, we identified partners of the poplar osmosensing signaling pathway, composed of two HKs, three main HPts, and six type-B RRs. To date, it is unresolved as to how cytokinin or osmotic stress signal specificity is achieved in the MSP in order to generate specific responses. Here, we present a large-scale interaction study of poplar type-B RR dimerization. Using the two-hybrid assay, we were able to show the homodimerization of type-B RRs, the heterodimerization of duplicated type-B RRs, and surprisingly, a lack of interaction between some type-B RRs belonging to different duplicates. The lack of interaction of the duplicates RR12-14 and RR18-19, which are involved in the osmosensing pathway has been confirmed by BiFC experiments. This study reveals, for the first time, an overview of type-B RR dimerization in poplar and makes way for the hypothesis that signal specificity for cytokinin or osmotic stress could be in part due to the fact that it is impossible for specific type-B RRs to heterodimerize.

Drag forces in statistically stationary and homogeneous submerged granular flows.

The paper deals with the interaction forces between the two phases of a granular flow immersed in water, analyzing in detail the effects on the drag of the concentration of the solid phase and of the interactions between velocities of the two phases and particle concentration. According to the system of equations, the relations between these variables are strongly nonlinear. In particular, this article addresses two issues: how the drag force varies as a function of the concentration only, and whether it is proper to determine the averaged drag force only as a function of the time-averaged values of velocities and concentration. We demonstrate, in fact, that by separating the average and the fluctuating part of each quantity, new terms arise representing a residual drag. To better understand the role of the interphases forces, we performed a series of tests on a two-phase flow (spherical particles in water) through a vertical column in a statistically stationary and homogeneous condition.

Highlighting type A RRs as potential regulators of the dkHK1 multi-step phosphorelay pathway in Populus.

In previous studies, we highlighted a multistep phosphorelay (MSP) system in poplars composed of two hybrid-type Histidine aspartate Kinases, dkHK1a and dkHK1b, which interact with three Histidine Phosphotransfer proteins, dkHPt2, 7, and 9, which in turn interact with six type B Response Regulators. These interactions correspond to the dkHK1a-b/dkHPts/dkRRBs MSP. This MSP is putatively involved in an osmosensing pathway, as dkHK1a-b are orthologous to the Arabidopsis osmosensor AHK1, and able to complement a mutant yeast deleted for its osmosensors. Since type A RRs have been characterized as negative regulators in cytokinin MSP signaling due to their interaction with HPt proteins, we decided in this study to characterize poplar type A RRs and their implication in the MSP. For a global view of this MSP, we isolated 10 poplar type A RR cDNAs, and determined their subcellular localization to check the in silico prediction experimentally. For most of them, the in planta subcellular localization was as predicted, except for three RRAs, for which this experimental approach gave a more precise localization. Interaction studies using yeast two-hybrid and in planta BiFC assays, together with transcript expression analysis in poplar organs led to eight dkRRAs being singled out as partners which could interfere the dkHK1a-b/dkHPts/dkRRBs MSP identified in previous studies. Consequently, the results obtained in this study now provide an exhaustive view of dkHK1a-b partners belonging to a poplar MSP.

Observation of subdiffusion in a disordered interacting system.

We study the transport dynamics of matter-waves in the presence of disorder and nonlinearity. An atomic Bose-Einstein condensate that is localized in a quasiperiodic lattice in the absence of atom-atom interaction shows instead a slow expansion with a subdiffusive behavior when a controlled repulsive interaction is added. The measured features of the subdiffusion are compared to numerical simulations and a heuristic model. The observations confirm the nature of subdiffusion as interaction-assisted hopping between localized states and highlight a role of the spatial correlation of the disorder.

[Retrospective study--pregnancy after assisted medical reproduction from 2001 to 2009 at the Central Hospital of Luxembourg (first section)]. / Etude retrospective--suivis de grossesses après Procréation Médicalement Assistée (PMA) de 2001 à 2009 au Centre Hospitalier de Luxembourg (1re partie).

Retrospective study on a nine year ART practice focusing on pregnancy outcomes and multiple pregnancies, their complications, the gestational duration, delivery options, the new born weights and health statements til the age of two. Post ART pregnancies seem to have an increased complication rate; multiple births are more frequent than with spontaneous conception. The first chapter deals with the entire group. The second chapter analyses several sub-groups according to the ART method employed. The results are compared to publications in PubMed and Medline.

[Retrospective studies of pregnancies after assisted medical reproduction from 2001-2009 and Central Hospital in Luxembourg (part 2)]. / Etude rétrospective--suivis de grossesses après Procréation Médicalement Assistée (PMA) de 2001 à 2009 au Centre Hospitalier de Luxembourg (2e partie).

The first chapter analyses the ART methods of the Centre Hospitalier of Luxembourg, in the department of reproductive medicine between 2001 and 2009. The second chapter examines the techniques individually, their influence on pregnancy outcomes, the complications on offsprings and their health. The results coincide with literature in that risks are acceptable as long as good medical and biological conditions are maintained. Multiple pregnancies remain the most frequent complication, particularly once out of IVF. These are analysed separately as well as the pregnancies after egg and semen donation.

Risk assessment of the fatality due to explosion in land mass transport infrastructure by fast transient dynamic analysis.

Terrorist attacks in New York have shocked the world community showing clearly the vulnerability of air transport in such events. However, the terrorist attacks in Madrid and London showed that land mass transport infrastructure is equally vulnerable in case of similar attacks. The fact that there has not been substantial investment in the domain of risk analysis and evaluation of the possible effects due to such events in land mass transportation infrastructure leaves large room for new developments that could eventually fill this gap. In the present work using the finite element code EUROPLEXUS there has been a large effort to perform a complete study of the land mass infrastructure in case of explosion events. This study includes a train station, a metro station and a metro carriage providing thus valuable simulation data for a variety of different situations. For the analysis of these structures it has been necessary to apply a laser scanning method for the acquisition of geometrical data, to improve the simulation capabilities of EUROPLEXUS by adding failure capabilities for specific finite elements, to implement new material models (e.g. glass), and to add new modules that achieve data post-processing for the calculation of fatal and non-fatal injuries risk. The aforementioned improvements are explained in the present work with emphasis in the newly developed risk analysis features of EUROPLEXUS.

Comparison of two techniques for diagnosis of giardiasis in dogs.

Giardiasis is an intestinal parasitosis affecting dogs and able to infect human beings. Its diagnosis can not be done with the only clinical signs, the main of which is non characteristic diarrhoea. It implicates to perform further tests to detect the parasite. The zinc sulfate concentration technique (ZSCT) is the more effective one if performed on two or three successive days. Fecal ELISA kits have been developed to detect Giardia in humans and were found to be less sensitive than the ZSCT in dogs. In this study, we used 30 infected Beagles to compare the sensitivity of one, two or three fecal examinations following ZSCT and one or two ELISA tests. We conclude that if a single ZSCT is insufficient, two or three ZSCT and one or two ELISA using the commercial kit ProSpecT Giardia have almost the same sensitivity.

Early modifications of Brassica napus root system architecture induced by a plant growth-promoting Phyllobacterium strain.

• Plant growth-promoting bacteria (PGPB) have been reported to stimulate root morphogenesis. To improve our knowledge of the PGPB effect, the early modifications of Brassica napus root system architecture induced by the PGPB Phyllobacterium sp. (29-15) were analysed. • Plants were grown in Petri dishes on a vertical medium supplemented with variable doses of Phyllobacterium sp. in gnotobiotic conditions. Root system elementary variables were measured in a nondestructive manner and the distribution of the bacteria throughout the primary root was quantified. • Phyllobacterium sp. in doses from 3 × 107 to 3 × 108 colony-forming units ml-1 significantly promoted B. napus total root length up to 50% by increasing both lateral root density throughout the primary root and growth rate of mature lateral roots. The primary root was progressively colonized by the bacteria from the tip to the base and the number of colonizing cells was positively correlated with the inoculum density. • Relationships between inoculum density, root colonization and root system architecture emphasized the relevance of this approach to specify PGPB effects on plants.

Illegitimate transcription: its use for studying genetic abnormalities in lymphoblastoid cells from patients with Glanzmann thrombasthenia.

Glanzmann thrombasthenia is the most common inherited disorder of platelets that may induce severe bleeding complications. Molecular biology techniques have offered the possibility to assess the basis of this chronic haemorrhagic disease at the molecular level. However, the accessibility of mRNA in platelets is limited by the availability of the patient's blood samples and the relatively weak amount of this material in these cells. Taking advantage of the genetic phenomenon of illegitimate transcription, we have demonstrated that glycoprotein IIb and glycoprotein IIIa mRNA could be detected in lymphoblastoid cell lines issued from normal EBV-transformed lymphoblasts. We further analysed the sequences of the two glycoprotein transcripts in lymphoblastoid cell lines from two previously characterized patients presenting with Glanzmann thrombasthenia. The results showed that illegitimate transcripts presented similar molecular abnormalities to those found in platelets. These data demonstrated that the nucleotide sequences of illegitimate transcripts were identical to tissue-specific mRNA found in platelets. We applied this methodology to screen for the genetic defect in a new thrombasthenic patient, and found a homozygous nonsense mutation GCA-->TGA converting Arg8 to stop in the glycoprotein IIIa gene. This immortalized source of genetic material is therefore particularly useful for molecular genetic studies in inherited platelet disorders, avoiding repetitive and large blood samplings in frequently anaemic patients.

[Cardiac insufficiency caused by iatrogenic arteriovenous fistula]. / Scompenso cardiaco da fistola artero-venosa iatrogena.

Two cases of iatrogenic arterio-venous fistula complicated by heart failure are described. A 50 year-old woman was admitted to the hospital with congestive heart failure and a questionable diagnosis of congestive cardiomyopathy. A continuous murmur heard over the lumbar spine close to a surgical scar from an intervention on the L4-L5 disc that the patient had undergone six months before, led to the diagnosis of an arterio-venous fistula. Angiography demonstrated a direct communication between the right iliac artery and the right iliac vein. After surgical closure of the fistula normal cardiac function was restored. The second patient (a sixty-year-old woman) had undergone surgical mitral valve replacement with a Hancock bioprosthesis 18 months before the current admission. In the post-operative period the percutaneous insertion of an intravenous line through the left jugular vein had been unsuccessfully attempted. She had mild heart failure which was ascribed to incompetence of the bioprosthetic valve. A continuous murmur in the left supraclavear area suggested the presence of an arterio-venous fistula. Angiography showed a direct communication between the supraclavear branch of the left subclavian artery and the left subclavian vein. The fistula was successfully closed. Both cases confirm the potential harmfulness for the vascular bed of certain surgical interventions and intravascular monitoring techniques. When heart failure of uncertain etiology appears in patients previously submitted to the one of the above mentioned procedures, a careful clinical examination can lead to a correct diagnosis of iatrogenic arterio-venous fistula, whose surgical correction is usually followed by the restoration of a normal cardiac function.