Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy

USP18 lack in microglia causes destructive interferonopathy of the mouse brain

Microglia are tissue macrophages of the central nervous system (CNS) that control tissue homeostasis. Microglia dysregulation is thought to be causal for a group of neuropsychiatric, neurodegenerative and neuroinflammatory diseases, called "microgliopathies". However, how the intracellular stimulation machinery in microglia is controlled is poorly understood. Here, we identified the ubiquitin-specific protease (Usp) 18 in white matter microglia that essentially contributes to microglial quiescence. We further found that microglial Usp18 negatively regulates the activation of Stat1 and concomitant induction of interferon-induced genes, thereby terminating IFN signaling. The Usp18-mediated control was independent from its catalytic activity but instead required the interaction with Ifnar2. Additionally, the absence of Ifnar1 restored microglial activation, indicating a tonic IFN signal which needs to be negatively controlled by Usp18 under non-diseased conditions. These results identify Usp18 as a critical negative regulator of microglia activation and demonstrate a protective role of Usp18 for microglia function by regulating the Ifnar pathway. The findings establish Usp18 as a new molecule preventing destructive microgliopathy

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

\u3cp\u3eAfter completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3 10\u3csup\u3e19\u3c/sup\u3e m\u3csup\u3e-3\u3c/sup\u3e, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.\u3c/p\u3

Major results from the first plasma campaign of the Wendelstein 7-X stellarator

After completing the main construction phase of Wendelstein 7-X (W7-X) and successfully commissioning the device, first plasma operation started at the end of 2015. Integral commissioning of plasma start-up and operation using electron cyclotron resonance heating (ECRH) and an extensive set of plasma diagnostics have been completed, allowing initial physics studies during the first operational campaign. Both in helium and hydrogen, plasma breakdown was easily achieved. Gaining experience with plasma vessel conditioning, discharge lengths could be extended gradually. Eventually, discharges lasted up to 6 s, reaching an injected energy of 4 MJ, which is twice the limit originally agreed for the limiter configuration employed during the first operational campaign. At power levels of 4 MW central electron densities reached 3 1019 m-3, central electron temperatures reached values of 7 keV and ion temperatures reached just above 2 keV. Important physics studies during this first operational phase include a first assessment of power balance and energy confinement, ECRH power deposition experiments, 2nd harmonic O-mode ECRH using multi-pass absorption, and current drive experiments using electron cyclotron current drive. As in many plasma discharges the electron temperature exceeds the ion temperature significantly, these plasmas are governed by core electron root confinement showing a strong positive electric field in the plasma centre.Peer reviewe