Prediction of disease activity in models of multiple sclerosis by molecular magnetic resonance imaging of P-selectin.

New strategies for detecting disease activity in multiple sclerosis are being investigated to ameliorate diagnosis and follow-up of patients. Today, although magnetic resonance imaging (MRI) is widely used to diagnose and monitor multiple sclerosis, no imaging tools exist to predict the evolution of disease and the efficacy of therapeutic strategies. Here, we show that molecular MRI targeting the endothelial adhesion molecule P-selectin unmasks the pathological events that take place in the spinal cord of mice subjected to chronic or relapsing experimental autoimmune encephalomyelitis. This approach provides a quantitative spatiotemporal follow-up of disease course in relation to clinical manifestations. Moreover, it predicts relapse in asymptomatic mice and remission in symptomatic animals. Future molecular MRI targeting P-selectin may be used to improve diagnosis, follow-up of treatment, and management of relapse/remission cycles in multiple sclerosis patients by providing information currently inaccessible through conventional MRI techniques.

NOMAD spectrometer on the ExoMars trace gas orbiter mission: part 2-design, manufacturing, and testing of the ultraviolet and visible channel.

NOMAD is a spectrometer suite on board the ESA/Roscosmos ExoMars Trace Gas Orbiter, which launched in March 2016. NOMAD consists of two infrared channels and one ultraviolet and visible channel, allowing the instrument to perform observations quasi-constantly, by taking nadir measurements at the day- and night-side, and during solar occultations. Here, in part 2 of a linked study, we describe the design, manufacturing, and testing of the ultraviolet and visible spectrometer channel called UVIS. We focus upon the optical design and working principle where two telescopes are coupled to a single grating spectrometer using a selector mechanism.

Optical and radiometric models of the NOMAD instrument part I: the UVIS channel.

The NOMAD instrument has been designed to best fulfil the science objectives of the ExoMars Trace Gas Orbiter mission that will be launched in 2016. The instrument is a combination of three channels that cover the UV, visible and IR spectral ranges and can perform solar occultation, nadir and limb observations. In this series of two papers, we present the optical models representing the three channels of the instrument and use them to determine signal to noise levels for different observation modes and Martian conditions. In this first part, we focus on the UVIS channel, which will sound the Martian atmosphere using nadir and solar occultation viewing modes, covering the 200-650nm spectral range. High SNR levels (>1000) can easily be reached for wavelengths higher than 300nm both in solar occultation and nadir modes when considering binning. Below 300nm SNR are lower primarily because of the lower signal and the impact of atmospheric absorption.

Central nervous system-associated macrophages modulate the immune response following stroke in aged mice.

Age is a major nonmodifiable risk factor for ischemic stroke. Central nervous system-associated macrophages (CAMs) are resident immune cells located along the brain vasculature at the interface between the blood circulation and the parenchyma. By using a clinically relevant thromboembolic stroke model in young and aged male mice and corresponding human tissue samples, we show that during aging, CAMs acquire a central role in orchestrating immune cell trafficking after stroke through the specific modulation of adhesion molecules by endothelial cells. The absence of CAMs provokes increased leukocyte infiltration (neutrophils and CD4+ and CD8+ T lymphocytes) and neurological dysfunction after stroke exclusively in aged mice. Major histocompatibility complex class II, overexpressed by CAMs during aging, plays a significant role in the modulation of immune responses to stroke. We demonstrate that during aging, CAMs become central coordinators of the neuroimmune response that ensure a long-term fine-tuning of the immune responses triggered by stroke.

Synchronized Fabry-Perot cavity used for enhanced sensitivity electro-optic measurements of electric fields in the microwave range.

An electro-optic (EO) sensing system for measuring free-space electric fields in the microwave range has been developed. The system is based on a phase modulation heterodyning technique using a Mach-Zehnder interferometer. In one of the arms of the interferometer, an acousto-optic frequency shifter is used to downconvert the frequency of the detected signal in order to discriminate it from parasites emitted at the external electric field frequency. The sensing part is a LiTaO3 crystal placed in a Fabry-Perot cavity. The cavity aims at enhancing the sensitivity of the measurements. Cavity-based EO setups already used in the literature propose this sensitivity enhancement at the expense of the frequency bandwidth, whereas our setup allows this without a major impact on the frequency bandwidth. Electric fields are measured at both 15 kHz and 2.4 GHz with cavities of two different finesses; the best EO phase retardation gains obtained with the cavity are 34 and 60, respectively. The minimum detectable electric field is 0.003 V⋅m-1⋅Hz-1/2.

Immuno-MRI for Stroke Diagnosis and Prognosis.

Following a stroke, an inflammatory response occurs, characterized by an increased blood-brain barrier permeability, expression of endothelial trafficking molecules, and infiltration of immune cells. Adhesion molecules expressed on activated brain endothelial cells are potential biomarkers of intraparenchymal inflammation. However, in current clinical practice, it is not possible to measure endothelial activation using clinically available imaging. Using targeted micro-sized particles of iron oxide (MPIO), immuno-MRI enables the detection of endothelial adhesion molecules at high resolution and, consequently, facilitates the detection of stroke-induced brain inflammation. In this review, we highlight the most recent studies that used immuno-MRI in models of neurovascular disorders, including transient ischemic attack, ischemic stroke, intracranial hemorrhage, and subarachnoid hemorrhage. We also discuss the potential of immuno-MRI in clinical practice and the necessary next steps for its implementation in patients.

Single-Cell Transcriptomics Identifies Brain Endothelium Inflammatory Networks in Experimental Autoimmune Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by infiltration of immune cells in multifocal areas of the CNS. The specific molecular processes allowing autoreactive immune cells to enter the CNS compartment through the blood-brain barrier remain elusive. METHODS: Using endothelial cell (EC) enrichment and single-cell RNA sequencing, we characterized the cells implicated in the neuroinflammatory processes in experimental autoimmune encephalomyelitis, an animal model of MS. Validations on human MS brain sections of the most differentially expressed genes in venous ECs were performed using immunohistochemistry and confocal microscopy. RESULTS: We found an upregulation of genes associated with antigen presentation and interferon in most populations of CNS-resident cells, including ECs. Interestingly, instead of transcriptionally distinct profiles, a continuous gradient of gene expression separated the arteriovenous zonation of the brain vasculature. However, differential gene expression analysis presented more transcriptomic alterations on the venous side of the axis, suggesting a prominent role of venous ECs in neuroinflammation. Furthermore, analysis of ligand-receptor interactions identified important potential molecular communications between venous ECs and infiltrated immune populations. To confirm the relevance of our observation in the context of human disease, we validated the protein expression of the most upregulated genes (Ackr1 and Lcn2) in MS lesions. DISCUSSION: In this study, we provide a landscape of the cellular heterogeneity associated with neuroinflammation. We also present important molecular insights for further exploration of specific cell processes that promote infiltration of immune cells inside the brain of experimental autoimmune encephalomyelitis mice.

CLMP Promotes Leukocyte Migration Across Brain Barriers in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: In multiple sclerosis (MS), peripheral immune cells use various cell trafficking molecules to infiltrate the CNS where they cause damage.The objective of this study was to investigate the involvement of coxsackie and adenovirus receptor-like membrane protein (CLMP) in the migration of immune cells into the CNS of patients with MS. METHODS: Expression of CLMP was measured in primary cultures of human brain endothelial cells (HBECs) and human meningeal endothelial cells (HMECs), postmortem brain samples, and peripheral blood mononuclear cells (PBMCs) from patients with MS and controls by RNA sequencing, quantitative PCR, immunohistochemistry, and flow cytometry. In vitro migration assays using HBECs and HMECs were performed to evaluate the function of CLMP. RESULTS: Using bulk RNA sequencing of primary cultures of human brain and meningeal endothelial cells (ECs), we have identified CLMP as a new potential cell trafficking molecule upregulated in inflammatory conditions. We first confirmed the upregulation of CLMP at the protein level on TNFα-activated and IFNγ-activated primary cultures of human brain and meningeal ECs. In autopsy brain specimens from patients with MS, we demonstrated an overexpression of endothelial CLMP in active MS lesions when compared with normal control brain tissue. Flow cytometry of human PBMCs demonstrated an increased frequency of CLMP+ B lymphocytes and monocytes in patients with MS, when compared with that in healthy controls. The use of a blocking antibody against CLMP reduced the migration of immune cells across the human brain and meningeal ECs in vitro. Finally, we found CLMP+ immune cell infiltrates in the perivascular area of parenchymal lesions and in the meninges of patients with MS. DISCUSSION: Collectively, our data demonstrate that CLMP is an adhesion molecule used by immune cells to access the CNS during neuroinflammatory disorders such as MS. CLMP could represent a target for a new treatment of neuroinflammatory conditions.

Identification of SARS-CoV-2-specific immune alterations in acutely ill patients.

Dysregulated immune profiles have been described in symptomatic patients infected with SARS-CoV-2. Whether the reported immune alterations are specific to SARS-CoV-2 infection or also triggered by other acute illnesses remains unclear. We performed flow cytometry analysis on fresh peripheral blood from a consecutive cohort of (a) patients hospitalized with acute SARS-CoV-2 infection, (b) patients of comparable age and sex hospitalized for another acute disease (SARS-CoV-2 negative), and (c) healthy controls. Using both data-driven and hypothesis-driven analyses, we found several dysregulations in immune cell subsets (e.g., decreased proportion of T cells) that were similarly associated with acute SARS-CoV-2 infection and non-COVID-19-related acute illnesses. In contrast, we identified specific differences in myeloid and lymphocyte subsets that were associated with SARS-CoV-2 status (e.g., elevated proportion of ICAM-1+ mature/activated neutrophils, ALCAM+ monocytes, and CD38+CD8+ T cells). A subset of SARS-CoV-2-specific immune alterations correlated with disease severity, disease outcome at 30 days, and mortality. Our data provide an understanding of the immune dysregulation specifically associated with SARS-CoV-2 infection among acute care hospitalized patients. Our study lays the foundation for the development of specific biomarkers to stratify SARS-CoV-2-positive patients at risk of unfavorable outcomes and to uncover candidate molecules to investigate from a therapeutic perspective.

Optical deflection tomography with the phase-shifting schlieren.

We present a new optical deflection tomography method that takes advantage of the phase-shifting schlieren. The reconstruction algorithm is based on filtered backprojection. The instrument is well adapted for three-dimensional imaging of spatially sparse objects exhibiting large refractive index variations. It achieves a 35 µm resolution with a 3 mm depth of field. Its performance is illustrated with a bundle of fibers immersed in a matching index solution.

Environmental enrichment alleviates the deleterious effects of stress in experimental autoimmune encephalomyelitis.

BACKGROUND: Clinical observations support the hypothesis that stressful events increase relapse occurrence in multiple sclerosis patients, while stress-reduction strategies can modulate this effect. However, a direct cause-effect relationship between stress level and relapse cannot be firmly established from these data. OBJECTIVES: The purpose of this work was to address whether modulation of stress could interfere with symptom relapse in an animal model of multiple sclerosis with relapsing-remitting course. METHODS: Mice bred in standard or enriched environment were subjected to repeated acute stress during the remission phase of relapsing-remitting PLP-induced experimental autoimmune encephalomyelitis. RESULTS: We report that repeated acute stress induced a twofold increase in relapse incidence in experimental autoimmune encephalomyelitis. On the other hand, environmental enrichment reduced relapse incidence and severity, and reversed the effects of repeated acute stress. CONCLUSION: These data provide the platform for further studies on the biological processes that link stress and multiple sclerosis relapses in a suitable animal model.