General control non-derepressible 2 (GCN2) in T cells controls disease progression of autoimmune neuroinflammation

Relapsing-remitting multiple sclerosis (MS)(2) is characterized by phases of acute neuroinflammation followed by spontaneous remission. Termination of inflammation is accompanied by an influx of regulatory T cells (Tregs).(3) The molecular mechanisms responsible for directing Tregs into the inflamed CNS tissue, however, are incompletely understood. In an MS mouse model we show that the stress kinase general control non-derepressible 2 (GCN2),(4) expressed in T cells, contributes to the resolution of autoimmune neuroinflammation. Failure to recover from acute inflammation was associated with reduced frequencies of CNS-infiltrating Tregs. GCN2 deficient Tregs displayed impaired migration to a CCL2 gradient. These data suggest an important contribution of the T cell stress response to the resolution of autoimmune neuroinflammation

Test system for the Service Hybrid of the 2S Module for the CMS Phase-2 Outer Tracker Upgrade

Alongside the High-Luminosity LHC upgrade, the silicon tracker of the CMS detector will be replaced within the scope of the so-called Phase-2 Upgrade. The new tracker will consist of an inner part (Inner Tracker with pixelated modules) and at larger radii the Outer Tracker with two different module types (PS and 2S modules). One hybrid type used on these modules is the 2S service hybrid. It provides the optical link connection of a 2S module via the Low Power Giga Bit Transceiver (lpGBT) and a Versatile Transceiver Plus module (VTRx+). It is also responsible for the module power distribution. The different responsibilities of the hybrid require a complete testing, which is performed by a dedicated custom made test card. After a hybrid has been installed on the test card, all signal connections can be tested and verified. The test system is designed to handle a high throughput during mass production. The requirements and the design for the 2S service hybrid test card are presented together with testing results of the first final 2S service hybrid prototypes

Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan - from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation

Peroxisome-mitochondria interplay and disease

Copyright © Springer International Publishing AG, Part of Springer Science+Business MediaPeroxisomes and mitochondria are ubiquitous, highly dynamic organelles with an oxidative type of metabolism in eukaryotic cells. Over the years, substantial evidence has been provided that peroxisomes and mitochondria exhibit a close functional interplay which impacts on human health and development. The so-called "peroxisome-mitochondria connection" includes metabolic cooperation in the degradation of fatty acids, a redox-sensitive relationship, an overlap in key components of the membrane fission machineries and cooperation in anti-viral signalling and defence. Furthermore, combined peroxisome-mitochondria disorders with defects in organelle division have been revealed. In this review, we present the latest progress in the emerging field of peroxisomal and mitochondrial interplay in mammals with a particular emphasis on cooperative fatty acid β-oxidation, redox interplay, organelle dynamics, cooperation in anti-viral signalling and the resulting implications for disease.BBSRCPortuguese Foundation for Science and Technology (FCT)FEDER/COMPETEMarie Curie

Evaluation of planar silicon pixel sensors with the RD53A readout chip for the Phase-2 Upgrade of the CMS Inner Tracker

The Large Hadron Collider (LHC) at CERN will undergo an upgrade in order to increase its luminosity to $7.5 \times 10^{34}$ cm$^{-2}$s$^{-1}$. The increased luminosity during this High-Luminosity running phase\\ (HL-LHC), starting around 2029, means a higher rate of proton-proton interactions, hence a larger ionizing dose and particle fluence for the detectors. The current tracking system of the CMS experiment will be fully replaced in order to cope with the new operating conditions. Prototype planar pixel sensors for the CMS Inner Tracker with square $50 \mu$m $\times \; 50 \mu$m and rectangular $100 \mu$m $\times \; 25 \mu$m pixels read out by the RD53A chip were characterized in the lab and at the DESY-II testbeam facility in order to identify designs that meet the requirements of CMS at the HL-LHC. A spatial resolution of approximately 3.4$\mu$m (2$\mu$m) is obtained using the modules with $50 \mu$m $\times \; 50 \mu$m ($100 \mu$m $\times \; 25 \mu$m) pixels at the optimal angle of incidence before irradiation. After irradiation to a 1 MeV neutron equivalent fluence of $\Phi_{\rm eq} = 5.3 \times 10^{15}$ cm$^{-2}$, a resolution of 9.4$\mu$m is achieved at a bias voltage of 800 V using a module with $50 \mu$m $\times \; 50 \mu$m pixel size. All modules retain a hit efficiency in excess of 99\% after irradiation to fluences up to $2.1 \times 10^{16}$ cm$^{-2}$. Further studies of the electrical properties of the modules, especially crosstalk, are also presented in this paper.The Large Hadron Collider at CERN will undergo an upgrade inorder to increase its luminosity to7.5 × 10$^{34}$ cm$^{-2}$s$^{-1}$. The increased luminosityduring this High-Luminosity running phase, starting around 2029,means a higher rate of proton-proton interactions, hence a largerionizing dose and particle fluence for the detectors. The currenttracking system of the CMS experiment will be fully replaced inorder to cope with the new operating conditions. Prototype planarpixel sensors for the CMS Inner Tracker with square50 μm × 50 μm and rectangular100 μm × 25 μm pixels read out by theRD53A chip were characterized in the lab and at the DESY-II testbeamfacility in order to identify designs that meet the requirements ofCMS during the High-Luminosity running phase. A spatial resolutionof approximately 3.4 μm (2 μm) is obtained using themodules with 50 μm × 50 μm(100 μm × 25 μm) pixels at the optimalangle of incidence before irradiation. After irradiation to a 1 MeVneutron equivalent fluence ofΦ$_{eq}$ = 5.3 × 10$^{15}$ cm$^{-2}$, a resolution of9.4 μm is achieved at a bias voltage of 800 V using a modulewith 50 μm × 50 μm pixel size. All modulesretain a hit efficiency in excess of 99% after irradiation tofluences up to 2.1 × 10$^{16}$ cm$^{-2}$. Further studies ofthe electrical properties of the modules, especially crosstalk, arealso presented in this paper.The Large Hadron Collider (LHC) at CERN will undergo an upgrade in order to increase its luminosity to $7.5 \times 10^{34}$ cm$^{-2}$s$^{-1}$. The increased luminosity during this High-Luminosity running phase (HL-LHC), starting around 2029, means a higher rate of proton-proton interactions, hence a larger ionizing dose and particle fluence for the detectors. The current tracking system of the CMS experiment will be fully replaced in order to cope with the new operating conditions. Prototype planar pixel sensors for the CMS Inner Tracker with square $50 \mu$m $\times \; 50 \mu$m and rectangular $100 \mu$m $\times \; 25 \mu$m pixels read out by the RD53A chip were characterized in the lab and at the DESY-II testbeam facility in order to identify designs that meet the requirements of CMS at the HL-LHC. A spatial resolution of approximately 3.4$\mu$m (2$\mu$m) is obtained using the modules with $50 \mu$m $\times \; 50 \mu$m ($100 \mu$m $\times \; 25 \mu$m) pixels at the optimal angle of incidence before irradiation. After irradiation to a 1 MeV neutron equivalent fluence of $\Phi_{\rm eq} = 5.3 \times 10^{15}$ cm$^{-2}$, a resolution of 9.4$\mu$m is achieved at a bias voltage of 800 V using a module with $50 \mu$m $\times \; 50 \mu$m pixel size. All modules retain a hit efficiency in excess of 99% after irradiation to fluences up to $2.1 \times 10^{16}$ cm$^{-2}$. Further studies of the electrical properties of the modules, especially crosstalk, are also presented in this paper