IL-6, IL-12, and IL-23 STAT-Pathway Genetic Risk and Responsiveness of Lymphocytes in Patients with Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated demyelinating disease characterized by central nervous system (CNS) lymphocyte infiltration, abundant production of pro-inflammatory cytokines, and inappropriate activation of Th1 and Th17 cells, B cells, and innate immune cells. The etiology of MS is complex, and genetic factors contribute to disease susceptibility. Genome-wide association studies (GWAS) have revealed numerous MS-risk alleles in the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways implicated in the differentiation of Th1 and Th17 cells. In this study, we investigated the signaling properties of these pathways in T, B, and NK cells from patients with relapsing-remitting MS (RRMS) and healthy controls, and assessed the genetic contribution to the activity of the pathways. This revealed a great variability in the level of STAT-pathway molecules and STAT activation between the cell types investigated. We also found a strong donor variation in IL-6, IL-12, and IL-23 responsiveness of primed CD4+ T cells. This variation could not be explained by a single MS-risk variant in a pathway component, or by an accumulation of multiple STAT-pathway MS-risk SNPs. The data of this study suggests that other factors in cohesion with the genetic background contribute to the responsiveness of the IL-6/STAT3, IL-12/STAT4, and IL-23/STAT3-pathways

Tess data for asteroseismology: Timing verification

The Transiting Exoplanet Survey Satellite (TESS) is NASA´s latest space telescope dedicated to the discovery of transiting exoplanets around nearby stars. Besides the main goal of the mission, asteroseismology is an important secondary goal and very relevant for the high-quality time series that TESS will make during its two-year all-sky survey. Using TESS for asteroseismology introduces strong timing requirements, especially for coherent oscillators. Although the internal clock on board TESS is precise in its own time, it might have a constant drift. Thus, it will need calibration, or else offsets might inadvertently be introduced. Here, we present simultaneous ground- and space-based observations of primary eclipses of several binary systems in the Southern ecliptic hemisphere, used to verify the reliability of the TESS timestamps. From 12 contemporaneous TESS/ground observations, we determined a time offset equal to 5.8 ± 2.5 s, in the sense that the barycentric time measured by TESS is ahead of real time. The offset is consistent with zero at the 2.3σ level. In addition, we used 405 individually measured mid-eclipse times of 26 eclipsing binary stars observed solely by TESS in order to test the existence of a potential drift with a monotonic growth (or decay) affecting the observations of all stars. We find a drift corresponding to σ drift = 0.009 ± 0.015 s day-1. We find that the measured offset is of a size that will not become an issue for comparing ground-based and space data for coherent oscillations for most of the targets observed with TESS.Fil: Essen, Carolina von. University Aarhus; DinamarcaFil: Lund, Mikkel N.. University Aarhus; DinamarcaFil: Handberg, Rasmus. University Aarhus; DinamarcaFil: Sosa, Marina Soledad. University Aarhus; Dinamarca. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Astrofísica La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Instituto de Astrofísica La Plata; ArgentinaFil: Gadeberg, Julie Thiim. University Aarhus; DinamarcaFil: Kjeldsen, Hans. University Aarhus; DinamarcaFil: Vanderspek, Roland K.. Massachusetts Institute of Technology; Estados UnidosFil: Mortensen, Dina S.. University Aarhus; DinamarcaFil: Mallonn, M.. Leibniz Institute for Astrophysics Potsdam; AlemaniaFil: Mammana, Luis Antonio. Universidad Nacional de La Plata; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Juan. Complejo Astronómico "El Leoncito". Universidad Nacional de Córdoba. Complejo Astronómico "El Leoncito". Universidad Nacional de la Plata. Complejo Astronómico "El Leoncito". Universidad Nacional de San Juan. Complejo Astronómico "El Leoncito"; ArgentinaFil: Morgan, Edward H.. Massachusetts Institute of Technology; Estados UnidosFil: Villaseñor, Jesus Noel S.. Massachusetts Institute of Technology; Estados UnidosFil: Fausnaugh, Michael M.. Massachusetts Institute of Technology; Estados UnidosFil: Ricker, George R.. Massachusetts Institute of Technology; Estados Unido

Frequency of fatigue and its changes in the first 6 months after traumatic brain injury: results from the CENTER-TBI study

Background: Fatigue is one of the most commonly reported subjective symptoms following traumatic brain injury (TBI). The aims were to assess frequency of fatigue over the first 6 months after TBI, and examine whether fatigue changes could be predicted by demographic characteristics, injury severity and comorbidities. Methods: Patients with acute TBI admitted to 65 trauma centers were enrolled in the study Collaborative European NeuroTrauma Effectiveness Research in TBI (CENTER-TBI). Subj

TCR down-regulation boosts T cell-mediated cytotoxicity and protection against poxvirus infections

Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3γLLAA mice. We found that Tc cells from CD3γLLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3γLLAA mice with a mortality rate almost as high as in granzyme B knock-out mice. Finally, we found that TCR signaling in CD3γLLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c-Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c-Cbl. Thus, our work demonstrates that TCR down-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection