Metabolism regulates exposure of pancreatic islets to circulating molecules in vivo.

International audiencePancreatic β-cells modulate insulin secretion through rapid sensing of blood glucose and integration of gut-derived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass and leads to gestational diabetes mellitus and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory β-cell expansion may be key to developing novel antidiabetic therapies. Here, using two-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high-fat-diet feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of β-cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping β-cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules

A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Cytotoxic CD8⁺ T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 <sup>+</sup> T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 <sup>+</sup> T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 <sup>+</sup> T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 <sup>+</sup> T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) <sup>G93A</sup> mutant decreased spinal motoneuron loss. Using motoneuron-CD8 <sup>+</sup> T cell coculture systems, we found that mutant SOD1-expressing CD8 <sup>+</sup> T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 <sup> G93A </sup> CD8 <sup>+</sup> T cells. Activated mutant SOD1 CD8 <sup>+</sup> T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 <sup>+</sup> T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS

The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease

Background\ud In order to identify novel loci associated with Alzheimer's disease (AD), we conducted a genome-wide association study (GWAS) in the Spanish population.\ud \ud Methods\ud We genotyped 1,128 individuals using the Affymetrix Nsp I 250K chip. A sample of 327 sporadic AD patients and 801 controls with unknown cognitive status from the Spanish general population were included in our initial study. To increase the power of the study, we combined our results with those of four other public GWAS datasets by applying identical quality control filters and the same imputation methods, which were then analyzed with a global meta-GWAS. A replication sample with 2,200 sporadic AD patients and 2,301 controls was genotyped to confirm our GWAS findings.\ud \ud Results\ud Meta-analysis of our data and independent replication datasets allowed us to confirm a novel genome-wide significant association of AD with the membrane-spanning 4-domains subfamily A (MS4A) gene cluster (rs1562990, P = 4.40E-11, odds ratio = 0.88, 95% confidence interval 0.85 to 0.91, n = 10,181 cases and 14,341 controls).\ud \ud Conclusions\ud Our results underscore the importance of international efforts combining GWAS datasets to isolate genetic loci for complex diseases

ATP5H/KCTD2 locus is associated with Alzheimer's disease risk

To identify loci associated with Alzheimer disease, we conducted a three-stage analysis using existing genome-wide association studies (GWAS) and genotyping in a new sample. In Stage I, all suggestive single-nucleotide polymorphisms (at P<0.001) in a previously reported GWAS of seven independent studies (8082 Alzheimer's disease (AD) cases; 12 040 controls) were selected, and in Stage II these were examined in an in silico analysis within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium GWAS (1367 cases and 12904 controls). Six novel signals reaching P<5 × 10-6 were genotyped in an independent Stage III sample (the Fundació ACE data set) of 2200 sporadic AD patients and 2301 controls. We identified a novel association with AD in the adenosine triphosphate (ATP) synthase, H+ transporting, mitochondrial F0 (ATP5H)/Potassium channel tetramerization domain-containing protein 2 (KCTD2) locus, which reached genome-wide significance in the combined discovery and genotyping sample (rs11870474, odds ratio (OR)=1.58, P=2.6 × 10 -7 in discovery and OR=1.43, P=0.004 in Fundació ACE data set; combined OR=1.53, P=4.7 × 10 -9). This ATP5H/KCTD2 locus has an important function in mitochondrial energy production and neuronal hyperpolarization during cellular stress conditions, such as hypoxia or glucose deprivation

First year of energetic particle measurements in the inner heliosphere with Solar Orbiter's Energetic Particle Detector

Context. Solar Orbiter strives to unveil how the Sun controls and shapes the heliosphere and fills it with energetic particle radiation. To this end, its Energetic Particle Detector (EPD) has now been in operation, providing excellent data, for just over a year. Aims. EPD measures suprathermal and energetic particles in the energy range from a few keV up to (near-) relativistic energies (few MeV for electrons and about 500 MeV nuc−1 for ions). We present an overview of the initial results from the first year of operations and we provide a first assessment of issues and limitations. In addition, we present areas where EPD excels and provides opportunities for significant scientific progress in understanding how our Sun shapes the heliosphere. Methods. We used the solar particle events observed by Solar Orbiter on 21 July and between 10 and 11 December 2020 to discuss the capabilities, along with updates and open issues related to EPD on Solar Orbiter. We also give some words of caution and caveats related to the use of EPD-derived data. Results. During this first year of operations of the Solar Orbiter mission, EPD has recorded several particle events at distances between 0.5 and 1 au from the Sun. We present dynamic and time-averaged energy spectra for ions that were measured with a combination of all four EPD sensors, namely: the SupraThermal Electron and Proton sensor (STEP), the Electron Proton Telescope (EPT), the Suprathermal Ion Spectrograph (SIS), and the High-Energy Telescope (HET) as well as the associated energy spectra for electrons measured with STEP and EPT. We illustrate the capabilities of the EPD suite using the 10 and 11 December 2020 solar particle event. This event showed an enrichment of heavy ions as well as 3He, for which we also present dynamic spectra measured with SIS. The high anisotropy of electrons at the onset of the event and its temporal evolution is also shown using data from these sensors. We discuss the ongoing in-flight calibration and a few open instrumental issues using data from the 21 July and the 10 and 11 December 2020 events and give guidelines and examples for the usage of the EPD data. We explain how spacecraft operations may affect EPD data and we present a list of such time periods in the appendix. A list of the most significant particle enhancements as observed by EPT during this first year is also provided.Ministerio de Economía y CompetitividadAgencia Estatal de Investigació

Diazoxide attenuates autoimmune encephalomyelitis and modulates lymphocyte proliferation and dendritic cell functionality

Activation of mitochondrial ATP-sensitive potassium (KATP) channels is postulated as an effective mechanism to confer cardio and neuroprotection, especially in situations associated to oxidative stress. Pharmacological activation of these channels inhibits glia-mediated neuroinflammation. In this way, diazoxide, an old-known mitochondrial KATP channel opener, has been proposed as an effective and safe treatment for different neurodegenerative diseases, demonstrating efficacy in different animal models, including the experimental autoimmune encephalomyelitis (EAE), an animal model for Multiple Sclerosis. Although neuroprotection and modulation of glial reactivity could alone explain the positive effects of diazoxide administration in EAE mice, little is known of its effects on the immune system and the autoimmune reaction that triggers the EAE pathology. The aim of the present work was to study the effects of diazoxide in autoimmune key processes related with EAE, such as antigen presentation and lymphocyte activation and proliferation. Results show that, although diazoxide treatment inhibited in vitro and ex-vivo lymphocyte proliferation from whole splenocytes it had no effect in isolated CD4(+) T cells. In any case, treatment had no impact in lymphocyte activation. Diazoxide can also slightly decrease CD83, CD80, CD86 and major histocompatibility complex class II expression in cultured dendritic cells, demonstrating a possible role in modulating antigen presentation. Taken together, our results indicate that diazoxide treatment attenuates autoimmune encephalomyelitis pathology without immunosuppressive effect

Image perception and interpretation of abnormalities; can we believe our eyes? Can we do something about it?

The radiologist’s visual impression of images is transmitted, via non-visual means (the report), to the clinician. There are several complex steps from the perception of the images by the radiologist to the understanding of the impression by the clinician. With a process as complex as this, it is no wonder that errors in perception, cognition, interpretation, transmission and understanding are very common. This paper reviews the processes of perception and error generation and possible strategies for minimising them

MEGARA, the new intermediate-resolution optical IFU and MOS for GTC: getting ready for the telescope

MEGARA (Multi-Espectrógrafo en GTC de Alta Resolución para Astronomía) is an optical Integral-Field Unit (IFU) and Multi-Object Spectrograph (MOS) designed for the GTC 10.4m telescope in La Palma that is being built by a Consortium led by UCM (Spain) that also includes INAOE (Mexico), IAA-CSIC (Spain), and UPM (Spain). The instrument is currently finishing AIV and will be sent to GTC on November 2016 for its on-sky commissioning on April 2017. The MEGARA IFU fiber bundle (LCB) covers 12.5x11.3 arcsec2 with a spaxel size of 0.62 arcsec while the MEGARA MOS mode allows observing up to 92 objects in a region of 3.5x3.5 arcmin2 around the IFU. The IFU and MOS modes of MEGARA will provide identical intermediate-to-high spectral resolutions (RFWHM~6,000, 12,000 and 18,700, respectively for the low-, mid- and high-resolution Volume Phase Holographic gratings) in the range 3700-9800ÅÅ. An x-y mechanism placed at the pseudo-slit position allows (1) exchanging between the two observing modes and (2) focusing the spectrograph for each VPH setup. The spectrograph is a collimator-camera system that has a total of 11 VPHs simultaneously available (out of the 18 VPHs designed and being built) that are placed in the pupil by means of a wheel and an insertion mechanism. The custom-made cryostat hosts a 4kx4k 15-μm CCD. The unique characteristics of MEGARA in terms of throughput and versatility and the unsurpassed collecting are of GTC make of this instrument the most efficient tool to date to analyze astrophysical objects at intermediate spectral resolutions. In these proceedings we present a summary of the instrument characteristics and the results from the AIV phase. All subsystems have been successfully integrated and the system-level AIV phase is progressing as expected