Direction de la Recherche Fondamentale

Systemic anticancer chemotherapy is immunosuppressive and mostly induces nonimmunogenic tumor cell death. Here, we show that even in the absence of any adjuvant, tumor cells dying in response to anthracyclins can elicit an effective antitumor immune response that suppresses the growth of inoculated tumors or leads to the regression of established neoplasia. Although both antracyclins and mitomycin C induced apoptosis with caspase activation, only anthracyclin-induced immunogenic cell death was immunogenic. Caspase inhibition by Z-VAD-fmk or transfection with the baculovirus inhibitor p35 did not inhibit doxorubicin (DX)-induced cell death, yet suppressed the immunogenicity of dying tumor cells in several rodent models of neoplasia. Depletion of dendritic cells (DCs) or CD8+T cells abolished the immune response against DX-treated apoptotic tumor cells in vivo. Caspase inhibition suppressed the capacity of DX-killed cells to be phagocytosed by DCs, yet had no effect on their capacity to elicit DC maturation. Freshly excised tumors became immunogenic upon DX treatment in vitro, and intratumoral inoculation of DX could trigger the regression of established tumors in immunocompetent mice. These results delineate a procedure for the generation of cancer vaccines and the stimulation of anti-neoplastic immune responses in vivo.

We point out a natural mechanism for quenching of star formation in early-type galaxies. It automatically links the color of a galaxy with its morphology and does not require gas consumption, removal or termination of gas supply. Given that star formation takes place in gravitationally unstable gas disks, it can be quenched when a disk becomes stable against fragmentation to bound clumps. This can result from the growth of a stellar spheroid, for instance by mergers. We present the concept of morphological quenching (MQ) using standard disk instability analysis, and demonstrate its natural occurrence in a cosmological simulation using an efficient zoom-in technique. We show that the transition from a stellar disk to a spheroid can be sufficient to stabilize the gas disk, quench star formation, and turn an early-type galaxy red and dead while gas accretion continues. The turbulence necessary for disk stability can be stirred up by sheared perturbations within the disk in the absence of bound star-forming clumps. While gas stripping processes are limited to dense groups and clusters, and other quenching mechanisms like AGN feedback, virial shock heating and gravitational heating, are limited to halos more massive than ∼ 10 12 M⊙, the MQ can explain the appearance of red ellipticals even in less massive halos and in the field. The dense gas disks observed in some of today’s red ellipticals may be the relics of this mechanism, whereas red galaxies with quenched gas disks are expected to be more frequent at high redshift.

Abstract Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry 1,2 . Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated ( P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis 3 , and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN ) and variants (such as at GRK5 and NOS3 ). Using a three-pronged approach 4 , we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry 5 . Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Carbon‐oxide and carbon‐sulfide nanocomposites have attracted tremendous interest as the anode materials for Li and Na ion batteries. Such composites are fascinating as they often show synergistic effect compared to their singular components. Carbon nanomaterials are often used as the matrix due to their high conductivity, tensile strength, and chemical stability under the battery condition. Metal oxides and sulfides are often used as active material fillers because of their large capacity. Numerous works have shown that by taking one step further into fabricating nanocomposites with rational structure design, much better performance can be achieved. The present review aims to present and discuss the development of carbon‐based nanocomposite anodes in both Li ion batteries and Na ion batteries. The authors introduce the individual components in the composites, i.e., carbon matrices (e.g., carbon nanotube, graphene) and metal oxides/sulfides; followed by evaluating how advanced nanostructures benefit from the synergistic effect when put together. Particular attention is placed on strategies employed in fabricating such composites, with examples such as yolk–shell structure, layered‐by‐layered structure, and composite comprising one or more carbon matrices. Lastly, the authors conclude by highlighting challenges that still persist and their perspective on how to further develop the technologies.

ea (Pisum sativum L., 2n = 14) is the second most important grain legume in the world after common bean and is an important green vegetable with 14.3 t of dry pea and 19.9 t of green pea produced in 2016 (http://www.fao.org/faostat/). Pea belongs to the Leguminosae (or Fabaceae), which includes cool season grain legumes from the Galegoid clade, such as pea, lentil (Lens culinaris Medik.), chickpea (Cicer arietinum L.), faba bean (Vicia faba L.) and tropical grain legumes from the Milletoid clade, such as common bean (Phaseolus vulgaris L.), cowpea (Vigna unguiculata (L.) Walp.) and mungbean (Vigna radiata (L.) R. Wilczek). It provides significant ecosystem services: it is a valuable source of dietary proteins, mineral nutrients, complex starch and fibers with demonstrated health benefits 1-4 and its symbiosis with N-fixing soil bacteria reduces the need for applied N fertilizers so mitigating greenhouse gas emissions Pea was domesticated ~10,000 years ago by Neolithic farmers of the Fertile Crescent, along with cereals and other grain legumes 8 . The large reservoir of genetic diversity in Pisum has facilitated its spread throughout Asia, Europe, Africa, the Americas and Oceania where it has adapted to diverse environments and culinary practices (https://iyp2016.org/). Due to its large genome size (1 C ~ 4.45 gigabases, Gb 9 ), pea genomics has lagged behind that of legumes with smaller genomes, such as Medicago truncatula Gaertn. 10 , Lotus japonicus L. 11 or soybean (Glycine max (L.) Merr) 12 . Yet, pea has been studied as a genetic model since the eighteenth century; the analysis of the inheritance of different pea morphotypes led Gregor Mendel to uncover the laws of genetics 13 . Several pea developmental mutations have since been characterized 14 and chromosomal regions controlling agronomic traits identified 15 , but tools exploiting pea diversity for plant breeding, identifying favorable alleles underlying phenotypic variations and accelerating

Memristive nanodevices can feature a compact multilevel nonvolatile memory function, but are prone to device variability. We propose a novel neural network-based computing paradigm, which exploits their specific physics, and which has virtual immunity to their variability. Memristive devices are used as synapses in a spiking neural network performing unsupervised learning. They learn using a simplified and customized “spike timing dependent plasticity” rule. In the network, neurons' threshold is adjusted following a homeostasis-type rule. We perform system level simulations with an experimentally verified model of the memristive devices' behavior. They show, on the textbook case of character recognition, that performance can compare with traditional supervised networks of similar complexity. They also show that the system can retain functionality with extreme variations of various memristive devices' parameters (a relative standard dispersion of more than 50% is tolerated on all device parameters), thanks to the robustness of the scheme, its unsupervised nature, and the capability of homeostasis. Additionally the network can adjust to stimuli presented with different coding schemes, is particularly robust to read disturb effects and does not require unrealistic control on the devices' conductance. These results open the way for a novel design approach for ultraadaptive electronic systems.

Human longevity is heritable, but genome-wide association (GWA) studies have had limited success. Here, we perform two meta-analyses of GWA studies of a rigorous longevity phenotype definition including 11,262/3484 cases surviving at or beyond the age corresponding to the 90th/99th survival percentile, respectively, and 25,483 controls whose age at death or at last contact was at or below the age corresponding to the 60th survival percentile. Consistent with previous reports, rs429358 (apolipoprotein E (ApoE) ε4) is associated with lower odds of surviving to the 90th and 99th percentile age, while rs7412 (ApoE ε2) shows the opposite. Moreover, rs7676745, located near GPR78, associates with lower odds of surviving to the 90th percentile age. Gene-level association analysis reveals a role for tissue-specific expression of multiple genes in longevity. Finally, genetic correlation of the longevity GWA results with that of several disease-related phenotypes points to a shared genetic architecture between health and longevity.

Ferromagnetic resonance measurements in Co films of 11.3, 20, and 80 A\r{} thickness sandwiched by Au have been made as a function of the dc magnetic field orientation in a plane perpendicular to the film. These polycrystalline films were measured to have the hcp structure with the c axis perpendicular to the film plane within a few degrees. The experimental results are well explained by a theoretical model where an axial magnetic anisotropy up to the second-order term is included.

In most mammalian species, a key process of placenta development is the fusion of trophoblast cells into a highly specialized, multinucleated syncytiotrophoblast layer, through which most of the maternofetal exchanges take place. Little is known about this process, despite the recent identification of 2 pairs of envelope genes of retroviral origin, independently acquired by the human (syncytin-1 and syncytin-2) and mouse (syncytin-A and syncytin-B) genomes, specifically expressed in the placenta, and with in vitro cell-cell fusion activity. By generating knockout mice, we show here that homozygous syncytin-A null mouse embryos die in utero between 11.5 and 13.5 days of gestation. Refined cellular and subcellular analyses of the syncytin-A-deficient placentae disclose specific disruption of the architecture of the syncytiotrophoblast-containing labyrinth, with the trophoblast cells failing to fuse into an interhemal syncytial layer. Lack of syncytin-A-mediated trophoblast cell fusion is associated with cell overexpansion at the expense of fetal blood vessel spaces and with apoptosis, adding to the observed maternofetal interface structural defects to provoke decreased vascularization, inhibition of placental transport, and fetal growth retardation, ultimately resulting in death of the embryo. These results demonstrate that syncytin-A is essential for trophoblast cell differentiation and syncytiotrophoblast morphogenesis during placenta development, and they provide evidence that genes captured from ancestral retroviruses have been pivotal in the acquisition of new, important functions in mammalian evolution.

Intracellular inclusions rich in alpha-synuclein are a hallmark of several neuropathological diseases including Parkinson's disease (PD). Previously, we reported the structure of alpha-synuclein fibrils (residues 1-121), composed of two protofibrils that are connected via a densely-packed interface formed by residues 50-57 (Guerrero-Ferreira, eLife 218;7:e36402). We here report two new polymorphic atomic structures of alpha-synuclein fibrils termed polymorphs 2a and 2b, at 3.0 Å and 3.4 Å resolution, respectively. These polymorphs show a radically different structure compared to previously reported polymorphs. The new structures have a 10 nm fibril diameter and are composed of two protofilaments which interact via intermolecular salt-bridges between amino acids K45, E57 (polymorph 2a) or E46 (polymorph 2b). The non-amyloid component (NAC) region of alpha-synuclein is fully buried by previously non-described interactions with the N-terminus. A hydrophobic cleft, the location of familial PD mutation sites, and the nature of the protofilament interface now invite to formulate hypotheses about fibril formation, growth and stability.

Microglia are the CNS resident immune cells that react to misfolded proteins through pattern recognition receptor ligation and activation of inflammatory pathways. Here, we studied how microglia handle and cope with α-synuclein (α-syn) fibrils and their clearance. We found that microglia exposed to α-syn establish a cellular network through the formation of F-actin-dependent intercellular connections, which transfer α-syn from overloaded microglia to neighboring naive microglia where the α-syn cargo got rapidly and effectively degraded. Lowering the α-syn burden attenuated the inflammatory profile of microglia and improved their survival. This degradation strategy was compromised in cells carrying the LRRK2 G2019S mutation. We confirmed the intercellular transfer of α-syn assemblies in microglia using organotypic slice cultures, 2-photon microscopy, and neuropathology of patients. Together, these data identify a mechanism by which microglia create an "on-demand" functional network in order to improve pathogenic α-syn clearance.

Two variants of the human N-formylpeptide chemoattractant receptor have been isolated from a CDM8 expression library prepared from mRNA of human myeloid HL-60 cells differentiated to the granulocyte phenotype with Bt2cAMP. Both recombinant receptors, fMLP-R26 and fMLP-R98, are 350 amino acids long (Mr 38,420); they differ from each other by two residue changes at positions 101 and 346 and by significant differences in the 5' and 3' untranslated regions. Both clones were able to transfer to COS-7 cells the capacity to specifically bind a new and highly efficient hydrophilic derivative of N-formyl-Met-Leu-Phe-Lys, referred to as fMLPK-Pep12. Photolabeling experiments revealed that the glycosylated form of the fMLP receptor in COS cells has a molecular weight (Mr 50,000-70,000) similar to that observed for the native receptor in differentiated HL-60 cells. Northern blot analysis revealed a major transcript of 1.6-1.7 kb and two minor hybridization signals of 2.3 and 3.1 kb, suggesting a related family of receptors. The complex hybridization pattern obtained with restricted genomic DNA was consistent with either two genes encoding fMLP receptor isoforms or a single gene with at least one intron in the coding sequence. Sequence comparison established that the fMLP receptor belongs to the G-protein-coupled receptor superfamily. The structural similarities observed with RDC1, a receptor isolated from a dog thyroid cDNA library, which shares weak homologies with other members of the family, suggests that the fMLP receptor is representative of a new subfamily.

Depression is the leading cause of disability worldwide. Recent observations have revealed an association between mood disorders and alterations of the intestinal microbiota. Here, using unpredictable chronic mild stress (UCMS) as a mouse model of depression, we show that UCMS mice display phenotypic alterations, which could be transferred from UCMS donors to naïve recipient mice by fecal microbiota transplantation. The cellular and behavioral alterations observed in recipient mice were accompanied by a decrease in the endocannabinoid (eCB) signaling due to lower peripheral levels of fatty acid precursors of eCB ligands. The adverse effects of UCMS-transferred microbiota were alleviated by selectively enhancing the central eCB or by complementation with a strain of the Lactobacilli genus. Our findings provide a mechanistic scenario for how chronic stress, diet and gut microbiota generate a pathological feed-forward loop that contributes to despair behavior via the central eCB system.

This review article provides an overview of the different species that α-synuclein aggregates can populate. It also attempts to reconcile conflicting views regarding the cytotoxic roles of oligomers versus fibrils. α-synuclein, while highly dynamic in the monomeric state, can access a large number of different assembly states. Depending on assembly conditions, these states can interconvert over different timescales. The fibrillar state is the most thermodynamically favored due to the many stabilizing interactions formed between each monomeric unit, but different fibrillar types form at different rates. The end distribution is likely to reflect kinetic partitioning as much as thermodynamic equilibra. In addition, metastable oligomeric species, some of which are on-pathway and others off-pathway, can be populated for remarkably long periods of time. Chemical modifications (phosphorylation, oxidation, covalent links to ligands, etc.) perturb these physical interconversions and invariably destabilize the fibrillar state, leading to small prefibrillar assemblies which can coalesce into amorphous states. Both oligomeric and fibrillar species have been shown to be cytotoxic although firm conclusions require very careful evaluation of particle concentrations and is complicated by the great variety and heterogeneity of different experimentally observed states. The mechanistic relationship between oligomers and fibrils remains to be clarified, both in terms of assembly of oligomers into fibrils and potential dissolution of fibrils into oligomers. While oligomers are possibly implicated in the collapse of neuronal homeostasis, the fibrillar state(s) appears to be the most efficient at propagating itself both in vitro and in vivo, pointing to critical roles for multiple different aggregate species in the progression of Parkinson's disease (https://onlinelibrary.wiley.com/page/journal/14714159/homepage/virtual_issues.htm). This article is part of the Special Issue "Synuclein".

Synucleinopathies, such as Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), are defined by the presence of α-synuclein (αSYN) aggregates throughout the nervous system but diverge from one another with regard to their clinical and pathological phenotype. The recent generation of pure fibrillar αSYN polymorphs with noticeable differences in structural and phenotypic traits has led to the hypothesis that different αSYN strains may be in part responsible for the heterogeneous nature of synucleinopathies. To further characterize distinct αSYN strains in the human brain, and establish a structure-pathology relationship, we pursued a detailed comparison of αSYN assemblies derived from well-stratified patients with distinct synucleinopathies. We exploited the capacity of αSYN aggregates found in the brain of patients suffering from PD, MSA or DLB to seed and template monomeric human αSYN in vitro via a protein misfolding cyclic amplification assay. A careful comparison of the properties of total brain homogenates and pure in vitro amplified αSYN fibrillar assemblies upon inoculation in cells and in the rat brain demonstrates that the intrinsic structure of αSYN fibrils dictates synucleinopathies characteristics. We report that MSA strains show several similarities with PD strains, but are significantly more potent in inducing motor deficits, nigrostriatal neurodegeneration, αSYN pathology, spreading, and inflammation, reflecting the aggressive nature of this disease. In contrast, DLB strains display no or only very modest neuropathological features under our experimental conditions. Collectively, our data demonstrate a specific signature for PD, MSA, and DLB-derived strains that differs from previously described recombinant strains, with MSA strains provoking the most aggressive phenotype and more similarities with PD compared to DLB strains.

A spin-glass model with two-dimensional, isotropic spins (XY model) is studied. The model exhibits two-level systems (TLS) which are related to the sense of rotation of the spin direction. The two-dimensional version of the model is equivalent at low temperature to an Ising model with Coulomb interactions (which are logarithmic in two dimensions). However, this long-range effective interaction between TLS may be a special feature of two-dimensional spins. The model depends on a continuous parameter x and can reproduce, in particular, the 'Edwards-Anderson model', the 'Mattis model', and the 'odd model'.

Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer's disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer's disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer's disease.

Transcriptional repression at the silent mating-type loci in yeast requires the targeting of silent information regulator (Sir) proteins through specific interactions formed at cis-acting silencer elements. We show here that a reporter gene flanked by two functional silencers is not repressed when integrated at >200 kb from a telomere. Repression is restored by creation of a new telomere 13 kb from the integrated reporter or by elevated expression of SIR1, SIR3, and/or SIR4. Coupled expression represses in an additive manner, suggesting that all three factors are in limiting concentrations. When overexpressed, Sir3 and Sir4 are dispersed throughout the nucleoplasm, in contrast to wild-type cells where they are clustered in a limited number of foci together with telomeres. Efficient silencer function thus seems to require either proximity to a pool of concentrated Sir proteins, that is, proximity to telomeres, or delocalization of the silencing factors.

Abstract The Alzheimer’s Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10 −7 ), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10 −7 ), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10 −6 ). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.

Among cerium pnictides, the compound CeSb exhibits the most complex behavior. The magnetic structures of the numerous observed phases have been determined. The magnetic field has been applied along a fourfold axis of the rock salt structure. For all the phases the order consists of square-wave structures characterized by a propagation vector $\stackrel{\ensuremath{\rightarrow}}{\mathrm{k}}=(0, 0, k)$ of value commensurate with the crystallographic cell and by a strong anisotropy confining the moments along the $k$ vector. All the structures can be generated by a periodic stacking of zero magnetized planes $P$ and ferromagnetic planes with a magnetization parallel $M\ensuremath{\uparrow}$ or antiparallel ${M}_{\ensuremath{\downarrow}}$ to the applied field. Three types of structures can be distinguished: (a) at low temperature only $M\ensuremath{\uparrow}$ and ${M}_{\ensuremath{\downarrow}}$ planes exist, the structures $k=\frac{4}{7} (++\ensuremath{-}\ensuremath{-}++\ensuremath{-})$, $k=\frac{2}{3} (++\ensuremath{-})$, and $k=0$ are successively observed when the field is increased. (b) at high temperature and low field $M\ensuremath{\uparrow}$, ${M}_{\ensuremath{\downarrow}}$, and $P$ planes coexist leading to an "antiferroparamagnetic order." (c) at high temperature and high field only $M\ensuremath{\uparrow}$ and $P$ planes exists defining a ferroparamagnetic order. The phase diagram feature can be understood by a simple thermodynamic analysis considering an entropy ${S}_{0}=k\mathrm{ln}2$ for paramagnetic planes and a moment of 2.1 ${\mathrm{\ensuremath{\mu}}}_{\mathrm{B}}$/Ce atom for magnetized planes.