巴黎第七大学

Inflammatory bowel diseases present with elevated levels of intestinal epithelial cell (IEC) death, which compromises the gut barrier, activating immune cells and triggering more IEC death. The endogenous signals that prevent IEC death and break this vicious cycle, allowing resolution of intestinal inflammation, remain largely unknown. Here we show that prostaglandin E2 signalling via the E-type prostanoid receptor 4 (EP4) on IECs represses epithelial necroptosis and induces resolution of colitis. We found that EP4 expression correlates with an improved IBD outcome and that EP4 activation induces a transcriptional signature consistent with resolution of intestinal inflammation. We further show that dysregulated necroptosis prevents resolution, and EP4 agonism suppresses necroptosis in human and mouse IECs. Mechanistically, EP4 signalling on IECs converges on receptor-interacting protein kinase 1 to suppress tumour necrosis factor-induced activation and membrane translocation of the necroptosis effector mixed-lineage kinase domain-like pseudokinase. In summary, our study indicates that EP4 promotes the resolution of colitis by suppressing IEC necroptosis.

Collisionless shocks convert bulk flow energy into heat, electromagnetic fields, and non-thermal particle populations. Recent studies suggest that downstream magnetic oscillations could play an important role in ion-scale energy dissipation at low-Mach-number shocks; however, the specific shock and plasma parameters involved remain poorly understood. Interplanetary (IP) shocks, often characterized by low Mach numbers, provide an excellent opportunity for investigating these kinetic dissipation mechanisms. We demonstrate, using observations of an IP shock from the Magnetospheric Multiscale (MMS) and Solar Orbiter (SolO) missions, supported by test-particle simulations, that gyrating protons generate the downstream magnetic oscillations. We found bursts of ion-acoustic waves at the troughs and crests of the magnetic oscillations, suggesting their energy source is related to proton gyration. Comparing MMS and SolO observations, we conclude that the upstream flow speed to ion thermal speed ratio and magnetic compression ratio are key parameters controlling the ion kinetic behavior that produces downstream magnetic oscillations.

Context. In situ measurements of space plasma are necessary to explore heliospheric and planetary ionized environments. Mutual impedance experiments are an active plasma diagnostic technique used to measure the properties of space plasmas, including the plasma density and the electron temperature. Although various models have been developed for unmagnetized space plasmas, they fail to describe the instrument behavior in magnetized plasmas, such as the ionosphere and magnetosphere of magnetized planets and moons. A quantitative instrument model of the mutual impedance experiment is required, however, for current and future space missions, including ESA/JAXA BepiColombo and ESA JUICE, which will both conduct mutual impedance experiments (PWI/AM2P and RPWI/MIME, respectively). Aims. We develop an instrument model for exploring and quantitatively characterizing mutual impedance experiment measurements performed in planetary plasmas, with the goal of providing in situ diagnostics of the plasma density and electron temperature. Methods. To reach this goal, we combined numerical investigation and laboratory experiments. We investigated the experimental regime of high magnetization for the first time, where the electron gyrofrequency is higher than the plasma frequency, both experimentally and numerically. On the experimental side, we built a setup composed of a plasma chamber, a mutual impedance experiment, and a Langmuir probe. With this, we achieved a controlled plasma environment representative of magnetized space plasmas, which we diagnosed with two independent plasma instruments. On the numerical side, we developed a model for magnetized mutual impedance experiments that took the geometry of the mutual impedance antennas and the plasma chamber into account and that employed a kinetic linear description of the plasma electrons. Results. First, we characterized the plasma environment generated in the plasma chamber: the achievable plasma parameters, the stability, and the repeatability of the plasma conditions. Second, we validated the instrument model by comparing the numerical model predictions to the measurements obtained in the plasma chamber. Third, we extracted the plasma density and temperature from in situ mutual impedance measurements using our new numerical instrument model, and we validated them using the independent in situ measurements from the Langmuir probe. Conclusions. This work (i) proves that mutual impedance experiments are able to provide robust plasma diagnostics in a magnetized space plasma environment, and (ii) develops a methodological framework that will be used for the planetary space missions BepiColombo and JUICE to perform both the in-flight calibration and the exploitation of the measurements from PWI/AM2P and RPWI/MIME, respectively, in the magnetospheres of Mercury, Jupiter, and Ganymede.

Promyelomonocytic leukemia (PML) is a prominent oncosuppressor whose inactivation is involved in the pathogenesis of hematological and epithelial cancers. Here, we report that PML aggregated in nuclear bodies in syncytia elicited by the envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) in vitro. PML aggregation occurred after the fusion of nuclei (karyogamy) within syncytia but before the apoptotic program was activated. The aggregation of PML was detectable in syncytia present in the brain or lymph nodes from patients with HIV-1 infection, as well as in a fraction of blood leukocytes, correlating with viral status. Using a range of specific inhibitors of PML (the oncogenic PML/RARα fusion product or specific small interfering RNAs), we demonstrated that, in Env-elicited syncytia, PML was required for activating phosphorylation of ataxia telangiectasia mutated (ATM), which colocalized with PML in nuclear bodies, in a molecular complex that also involved topoisomerase IIβ-binding protein 1. PML knockdown thus inhibited the ATM-dependent DNA damage response that culminates in the activation of p53, p53-dependent transcription of pro-apoptotic genes and cell death. Infection of CD4-expressing cells with HIV-1 also induced syncytial apoptosis, which could be suppressed by inhibiting PML. Altogether, these data indicate that PML activation is a critical early event that participates in the apoptotic demise of HIV-1-elicited syncytia.

AIM:This study aimed to identify what young adults with type 1 diabetes (T1D) do to make diabetes care fit in their lives and the impact of diabetes and diabetes care on living. METHODS:Dutch young adults with T1D (18-30 years old) submitted photographed real-life situations of efforts to make care fit and of the impact of care on their lives. Participants organised their photos in themes, which guided the focus group discussions. We added a reflective questionnaire, semi-structured interview and iterative validation to identify participant-defined themes and summarise the data. RESULTS:Participants (N = 18) submitted 240 photographs in total, showing a broad range of situations and emotions. Participants identified 16 themes, grouped into four overarching categories describing their experiences with diabetes: (1) My diabetes: glucose levels, workload, 24/7 present; (2) My life: flow of (daily) life, special and irregular circumstances, life changes, body and health; (3) Support: devices and technology, social network, clinical (diabetes) care; (4) Mental aspects: emotional processes, perspective, being a patient. In the overlap of My diabetes and My life, they identified eating and counting carbohydrates, activity and exercise, recreational substances. CONCLUSION:Young adults with T1D face the complex challenge of fitting their care into their ever-changing lives. While support systems, such as devices, healthcare professionals and social networks can help, they can also create burdens. Participants emphasised the importance of mental health in their lives with T1D. This study highlights the need for diabetes care that acknowledges the emotional, social and practical realities of young adults' lives.