French Institute of Health and Medical Research

About: French Institute of Health and Medical Research is a government organization based out in Paris, France. It is known for research contribution in the topics: Population & Receptor. The organization has 109367 authors who have published 174236 publications receiving 8365503 citations.

Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice

Abstract: The regulation of mitochondrial DNA (mtDNA) expression is crucial for mitochondrial biogenesis during development and differentiation. We have disrupted the mouse gene for mitochondrial transcription factor A (Tfam; formerly known as m-mtTFA) by gene targetting of loxP-sites followed by cre-mediated excision in vivo. Heterozygous knockout mice exhibit reduced mtDNA copy number and respiratory chain deficiency in heart. Homozygous knockout embryos exhibit a severe mtDNA depletion with abolished oxidative phosphorylation. Mutant embryos proceed through implantation and gastrulation, but die prior to embryonic day (E)10.5. Thus, Tfam is the first mammalian protein demonstrated to regulate mtDNA copy number in vivo and is essential for mitochondrial biogenesis and embryonic development.

PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation

Abstract: Tumor-infiltrating myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) form an important component of the hypoxic tumor microenvironment. Here, we investigated the influence of hypoxia on immune checkpoint receptors (programmed death [PD]-1 and CTLA-4) and their respective ligands (PD-1 ligand 1 [PD-L1], PD-L2, CD80, and CD86) on MDSCs. We demonstrate that MDSCs at the tumor site show a differential expression of PD-L1 as compared with MDSCs from peripheral lymphoid organ (spleen). Hypoxia caused a rapid, dramatic, and selective up-regulation of PD-L1 on splenic MDSCs in tumor-bearing mice. This was not limited to MDSCs, as hypoxia also significantly increased the expression of PD-L1 on macrophages, dendritic cells, and tumor cells. Furthermore, PD-L1 up-regulation under hypoxia was dependent on hypoxia-inducible factor-1α (HIF-1α) but not HIF-2α. Chromatin immunoprecipitation and luciferase reporter assay revealed direct binding of HIF-1α to a transcriptionally active hypoxia-response element (HRE) in the PD-L1 proximal promoter. Blockade of PD-L1 under hypoxia enhanced MDSC-mediated T cell activation and was accompanied by the down-regulation of MDSCs IL-6 and IL-10. Finally, neutralizing antibodies against IL-10 under hypoxia significantly abrogated the suppressive activity of MDSCs. Simultaneous blockade of PD-L1 along with inhibition of HIF-1α may thus represent a novel approach for cancer immunotherapy.

Stimulus Specificity of Phase-Locked and Non-Phase-Locked 40 Hz Visual Responses in Human

Abstract: Considerable interest has been raised by non-phase-locked episodes of synchronization in the gamma-band (30-60 Hz). One of their putative roles in the visual modality is feature-binding. We tested the stimulus specificity of high-frequency oscillations in humans using three types of visual stimuli: two coherent stimuli (a Kanizsa and a real triangle) and a noncoherent stimulus ("no-triangle stimulus"). The task of the subject was to count the occurrences of a curved illusory triangle. A time-frequency analysis of single-trial EEG data recorded from eight human subjects was performed to characterize phase-locked as well as non-phase-locked high-frequency activities. We found in early phase-locked 40 Hz component, maximal at electrodes Cz-C4, which does not vary with stimulation type. We describe a second 40 Hz component, appearing around 280 msec, that is not phase-locked to stimulus onset. This component is stronger in response to a coherent triangle, whether real or illusory: it could reflect, therefore, a mechanism of feature binding based on high-frequency synchronization. Because both the illusory and the real triangle are more target-like, it could also correspond to an oscillatory mechanism for testing the match between stimulus and target. At the same latencies, the low-frequency evoked response components phase-locked to stimulus onset behave differently, suggesting that low- and high-frequency activities have different functional roles.

Pelvic incidence: a fundamental pelvic parameter for three-dimensional regulation of spinal sagittal curves

Abstract: This paper proposes an anatomical parameter, the pelvic incidence, as the key factor for managing the spinal balance. Pelvic and spinal sagittal parameters were investigated for normal and scoliotic adult subjects. The relation between pelvic orientation, and spinal sagittal balance was examined by statistical analysis. A close relationship was observed, for both normal and scoliotic subjects, between the anatomical parameter of pelvic incidence and the sacral slope, which strongly determines lumbar lordosis. Taking into account the Cobb angle and the apical vertebral rotation confers a three-dimensional aspect to this chain of relations between pelvis and spine. A predictive equation of lordosis is postulated. The pelvic incidence appears to be the main axis of the sagittal balance of the spine. It controls spinal curves in accordance with the adaptability of the other parameters.

Targeting mitochondria for cancer therapy

Abstract: Mitochondria are the cells' powerhouse, but also their suicidal weapon store. Dozens of lethal signal transduction pathways converge on mitochondria to cause the permeabilization of the mitochondrial outer membrane, leading to the cytosolic release of pro-apoptotic proteins and to the impairment of the bioenergetic functions of mitochondria. The mitochondrial metabolism of cancer cells is deregulated owing to the use of glycolytic intermediates, which are normally destined for oxidative phosphorylation, in anabolic reactions. Activation of the cell death machinery in cancer cells by inhibiting tumour-specific alterations of the mitochondrial metabolism or by stimulating mitochondrial membrane permeabilization could therefore be promising therapeutic approaches.