Search

Neuroblastoma is a tumor of the peripheral sympathetic nervous system, derived from multipotent neural crest cells (NCCs). To define core regulatory circuitries (CRCs) controlling the gene expression program of neuroblastoma, we established and analyzed the neuroblastoma super-enhancer landscape. We discovered three types of identity in neuroblastoma cell lines: a sympathetic noradrenergic identity, defined by a CRC module including the PHOX2B, HAND2 and GATA3 transcription factors (TFs); an NCC-like identity, driven by a CRC module containing AP-1 TFs; and a mixed type, further deconvoluted at the single-cell level. Treatment of the mixed type with chemotherapeutic agents resulted in enrichment of NCC-like cells. The noradrenergic module was validated by ChIP-seq. Functional studies demonstrated dependency of neuroblastoma with noradrenergic identity on PHOX2B, evocative of lineage addiction. Most neuroblastoma primary tumors express TFs from the noradrenergic and NCC-like modules. Our data demonstrate a previously unknown aspect of tumor heterogeneity relevant for neuroblastoma treatment strategies.

AbstractThis article examines the transmission of voicing – the use of voice during the execution of a song – in Gwoka music. Considered at the time of French colonization as mizik a vié nèg (‘vagrants’ music’) this traditional music from Guadeloupe recently underwent a rehabilitation process that led to the idea that it reflected the ‘roots’ and the ‘authenticity’ of the Guadeloupean people. Gwoka music has since then become an important part of Guadeloupe’s cultural heritage, to the point that it is now listed on the UNESCO World Heritage List. The present work explores the relation between voicing in Gwoka and the questions of identity and memory. We suggest that traditional singers are chroniclers of their time, and memory smugglers who educate the audience by evoking values through their lyrics and voice. Gwoka music is strongly attached to political movements of resistance since its emergence. Previous generations of singers have not only transmitted vocal practice and lyrics, but also Creole language. Finally, we relate voicing to the preservation of Guadeloupean identity and to resistance in the face of Western domination.

The importance of DNA structures in medicine has motivated researchers to develop sequencing methods with low costs and high speeds. The potential use of nanofluidics for the analysis of the translocation of polynucleotides through a nanopore is a very interesting solution. Herein, we demonstrate both by experiments and by explicit solvent molecular dynamics simulations that the translocation of polyadenylic acid and polycytidylic acid can significantly affect the ionic flux behavior. In particular, the nanochannel enhances the velocity difference between polynucleotides during the translocation process. Our results revealed the important role of the strand structures during their translocation, as already observed in biochannels. The folding/unfolding process leads to stronger interactions with the nanopore wall that decrease the velocity of the strands. This behavior could lead to the detection of different polynucleotides in a mixture.

Normal human erythroid cell maturation requests the transcription factor GATA-1 and a transient activation of caspase-3, with GATA-1 being protected from caspase-3–mediated cleavage by interaction with the chaperone heat shock protein 70 (Hsp70) in the nucleus. Erythroid cell dysplasia observed in early myelodysplastic syndromes (MDS) involves impairment of differentiation and excess of apoptosis with a burst of caspase activation. Analysis of gene expression in MDS erythroblasts obtained by ex vivo cultures demonstrates the down-regulation of a set of GATA-1 transcriptional target genes, including GYPA that encodes glycophorin A (GPA), and the up-regulation of members of the HSP70 family. GATA-1 protein expression is decreased in MDS erythroblasts, but restores in the presence of a pan-caspase inhibitor. Expression of a mutated GATA-1 that cannot be cleaved by caspase-3 rescues the transcription of GATA-1 targets, and the erythroid differentiation, but does not improve survival. Hsp70 fails to protect GATA-1 from caspases because the protein does not accumulate in the nucleus with active caspase-3. Expression of a nucleus-targeted mutant of Hsp70 protects GATA-1 and rescues MDS erythroid cell differentiation. Alteration of Hsp70 cytosolic-nuclear shuttling is a major feature of MDS that favors GATA-1 cleavage and differentiation impairment, but not apoptosis, in dysplastic erythroblasts.

We report 2 cases of nephrogenic adenoma several years after successful cadaver kidney transplantation. In 1 case the lesion had cytomegalovirus inclusions, and we observed a marked and sustained reduction in the extension of the lesion with cessation of azathioprine. Surgical trauma and cytomegalovirus infections are discussed as etiologic factors. Conservative treatment seemed appropriate.

No relevant conflicts of interest to declare.

No relevant conflicts of interest to declare.

Structural and composition properties of HfO2-based layers fabricated by RF magnetron sputtering were studied by means of X-ray diffraction and transmission electron microscopy, Energy dispersive spectroscopy and ATR-FTIR techniques versus the deposition parameters and post-deposition annealing treatment. It was observed that the temperature at which amorphous-crystalline transformation of pure HfO2layers occurs depends on deposition conditions. It was found that silicon incorporation in HfO2matrix plays main role in the stability of the layers and allows to increase the temperature of layer crystallization up to 900-1100{degree sign}C.

Atomic Layer Deposition (ALD) has gained increasing attention for the sub-nm growth of high permittivity (k) rare earth oxide films. State of the art device operation heavily depends on the oxide/semiconductor interface properties. In this work, we address mainly through HRTEM-EELS experiments interface issues for ALD-grown Lu2O3/Si and La2O3/Si interfaces. Complementary results from GIXRD and electrical measurements on selective samples are presented. We show that, after exposure to air, Lu2O3 films capped with an Al2O3 layer are essentially free of interfacial layer formation, even if the starting Si surface is chemically oxidized. We also demonstrate that the La2O3 film reactivity with Si can be controlled up to a certain extent by appropriately choosing the ALD precursor combination. In particular, the La(Cp)3+O3 scheme favours over the La(Cp3)+H2O one in terms of a (i) smaller low-k interfacial layer thickness and interface trap density and (ii) stabilization of the high-k hexagonal La2O3 phase.

Background Recently, direct thrombin inhibitors such as Hirudin, Bivalirudin, Melagatran and Argatroban have been introduced in the armamentarium of an antithrombotic drugs. Danaparoid, an anti-Xa - anti IIa agent is also used especially in Heparin induced thrombocytopenia. Objective Thrombin generation test (TGT) has been recently automated and could be useful for the evaluation of the inhibitory activity of these drugs and the measurement of their anticoagulant effects at established therapeutic concentrations. Moreover, TGT can elucidate some information about their mechanism of action. The aim was to compare Hirudin, Argatroban, Melagatran and Danaparoid while Bivalirudin was not available. Methods and results Pools of normal human plasma were spiked with increasing concentrations of the four studied drugs and TGT was determined by studying the lag time (LT) and time to peak TTP as well as the peak (P), the endogenous thrombin potential (ETP) and the mean rate of thrombin generation (velocity TG) and its inhibition once a maximal concentration has been reached (velocity TI). The mechanism of action on TGT was heterogeneous. At therapeutic concentrations, Hirudin delays dramatically thrombin generation without affecting significantly its velocity and the amount of thrombin formed. Argatroban and Melagatran induce a far less marked prolongation of LT and TTP than hirudin but they both reduce the velocity of the reaction and the amount of thrombin generated in this in vitro study. Melagatran was found more active than Argatroban but the patterns of the thrombograms were similar. Danaparoid exerts a minimal effect on LT and TTP which is associated with a very significant influence on the parameters related to the reaction of thrombin formation (velocity index, peak and ETP). In total ETP generally considered as the most informative parameter of the thrombogram was not found as relevant as predicted. Schematically, 3 different patterns for the thrombogram have been observed indicating different mechanisms of anticoagulation, all of them, clearly associated with an antithrombotic activity in vivo. Conclusion The mechanism of action of hirudin on thrombin generation is clearly different from that of Argatroban, Melagatran and Danaparoid. This work demonstrates that antithrombotic activity is associated with different alterations of TGT. The results could help to determine the blood concentrations required for an effective anticoagulation or reciprocally the alterations of the thrombogram which are associated with therapeutic efficacy. Moreover they could be useful when laboratory monitoring of the treatment with these different drugs is considered.