Université Paris-Saclay

About: Université Paris-Saclay is a education organization based out in Gif-sur-Yvette, France. It is known for research contribution in the topics: Population & Context (language use). The organization has 29307 authors who have published 43183 publications receiving 867404 citations.

A magnetic synapse: multilevel spin-torque memristor with perpendicular anisotropy.

Abstract: Memristors are non-volatile nano-resistors which resistance can be tuned by applied currents or voltages and set to a large number of levels. Thanks to these properties, memristors are ideal building blocks for a number of applications such as multilevel non-volatile memories and artificial nano-synapses, which are the focus of this work. A key point towards the development of large scale memristive neuromorphic hardware is to build these neural networks with a memristor technology compatible with the best candidates for the future mainstream non-volatile memories. Here we show the first experimental achievement of a multilevel memristor compatible with spin-torque magnetic random access memories. The resistive switching in our spin-torque memristor is linked to the displacement of a magnetic domain wall by spin-torques in a perpendicularly magnetized magnetic tunnel junction. We demonstrate that our magnetic synapse has a large number of intermediate resistance states, sufficient for neural computation. Moreover, we show that engineering the device geometry allows leveraging the most efficient spin torque to displace the magnetic domain wall at low current densities and thus to minimize the energy cost of our memristor. Our results pave the way for spin-torque based analog magnetic neural computation.

Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound ALK Mutations in ALK-Positive Lung Cancer

Abstract: The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4-ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4-ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714-29. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

The tubulin code at a glance.

Abstract: Microtubules are key cytoskeletal elements of all eukaryotic cells and are assembled of evolutionarily conserved α-tubulin–β-tubulin heterodimers. Despite their uniform structure, microtubules fulfill a large diversity of functions. A regulatory mechanism to control the specialization of the microtubule cytoskeleton is the ‘tubulin code’, which is generated by (i) expression of different α- and β-tubulin isotypes, and by (ii) post-translational modifications of tubulin. In this Cell Science at a Glance article and the accompanying poster, we provide a comprehensive overview of the molecular components of the tubulin code, and discuss the mechanisms by which these components contribute to the generation of functionally specialized microtubules.

Pervasive chromosomal instability and karyotype order in tumour evolution.

Abstract: Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes1,2. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution1,3,4. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2+ breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.