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The antiviral protein IFIT1 is upregulated substantially in the cytoplasm of virus-infected cells. Superti-Furga and colleagues show that IFIT1 is part of a virus-recognition pathway that sequesters specific viral RNA. Antiviral innate immunity relies on the recognition of microbial structures. One such structure is viral RNA that carries a triphosphate group on its 5′ terminus (PPP-RNA). By an affinity proteomics approach with PPP-RNA as the 'bait', we found that the antiviral protein IFIT1 (interferon-induced protein with tetratricopeptide repeats 1) mediated binding of a larger protein complex containing other IFIT family members. IFIT1 bound PPP-RNA with nanomolar affinity and required the arginine at position 187 in a highly charged carboxy-terminal groove of the protein. In the absence of IFIT1, the growth and pathogenicity of viruses containing PPP-RNA was much greater. In contrast, IFIT proteins were dispensable for the clearance of pathogens that did not generate PPP-RNA. On the basis of this specificity and the great abundance of IFIT proteins after infection, we propose that the IFIT complex antagonizes viruses by sequestering specific viral nucleic acids.

Cells maintain the balance between homeostasis and inflammation by adapting and integrating the activity of intracellular signaling cascades, including the JAK-STAT pathway. Our understanding of how a tailored switch from homeostasis to a strong receptor-dependent response is coordinated remains limited. Here, we use an integrated transcriptomic and proteomic approach to analyze transcription-factor binding, gene expression and in vivo proximity-dependent labelling of proteins in living cells under homeostatic and interferon (IFN)-induced conditions. We show that interferons (IFN) switch murine macrophages from resting-state to induced gene expression by alternating subunits of transcription factor ISGF3. Whereas preformed STAT2-IRF9 complexes control basal expression of IFN-induced genes (ISG), both type I IFN and IFN-γ cause promoter binding of a complete ISGF3 complex containing STAT1, STAT2 and IRF9. In contrast to the dogmatic view of ISGF3 formation in the cytoplasm, our results suggest a model wherein the assembly of the ISGF3 complex occurs on DNA. A rapid cellular response to interferons (IFNs) is critical for establishing antimicrobial immunity, but how cells switch from from homeostasis to IFN signaling is not fully understood. Here, the authors provide evidence that IFNs induce gene expression by alternating subunits of transcription factor ISGF3.

Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signal transduction mediates cytokine responses. Canonical signaling is based on STAT tyrosine phosphorylation by activated JAKs. Downstream of interferon (IFN) receptors, activated JAKs cause the formation of the transcription factors IFN-stimulated gene factor 3 (ISGF3), a heterotrimer of STAT1, STAT2 and interferon regulatory factor 9 (IRF9) subunits, and gamma interferon-activated factor (GAF), a STAT1 homodimer. In recent years, several deviations from this paradigm were reported. These include kinase-independent JAK functions as well as extra- and intranuclear activities of U-STATs without phosphotyrosines. Additionally, transcriptional control by STAT complexes resembling neither GAF nor ISGF3 contributes to transcriptome changes in IFN-treated cells. Our review summarizes the contribution of non-canonical JAK-STAT signaling to the innate antimicrobial immunity imparted by IFN. Moreover, we touch upon functions of IFN pathway proteins beyond the IFN response. These include metabolic functions of IRF9 as well as the regulation of natural killer cell activity by kinase-dead TYK2 and different phosphorylation isoforms of STAT1.

STAT3 and STAT5 proteins are oncogenic downstream mediators of the JAK–STAT pathway. Deregulated STAT3 and STAT5 signaling promotes cancer cell proliferation and survival in conjunction with other core cancer pathways. Nuclear phosphorylated STAT3 and STAT5 regulate cell-type-specific transcription profiles via binding to promoter elements and exert more complex functions involving interaction with various transcriptional coactivators or corepressors and chromatin remodeling proteins. The JAK–STAT pathway can rapidly reshape the chromatin landscape upon cytokine, hormone, or growth factor stimulation and unphosphorylated STAT proteins also appear to be functional with respect to regulating chromatin accessibility. Notably, cancer genome landscape studies have implicated mutations in various epigenetic modifiers as well as the JAK–STAT pathway as underlying causes of many cancers, particularly acute leukemia and lymphomas. However, it is incompletely understood how mutations within these pathways can interact and synergize to promote cancer. We summarize the current knowledge of oncogenic STAT3 and STAT5 functions downstream of cytokine signaling and provide details on prerequisites for DNA binding and gene transcription. We also discuss key interactions of STAT3 and STAT5 with chromatin remodeling factors such as DNA methyltransferases, histone modifiers, cofactors, corepressors, and other transcription factors.

The electrification of the mobility and heating sectors will significantly change the electrical behavior of households in the future. To investigate this behavior, it is important to include the heating and mobility sectors in load profile models. Existing models do not sufficiently consider these sectors. Therefore, this work aims to develop an integrated, consistent model for the electrical and thermal load of private households and their mobility behavior. The model needs to generate regionally distinct profiles depending on the building, household and resident type and should be valid for Germany. Based on a bottom-up approach, a model consisting of four components is developed. In an activity model based on a modified Markov chain process, persons are assigned to activities. The activities are then allocated to devices in the electrical and thermal models. A mobility model assigns distances to the journey activities. The results of the simulation to validate the model shows an average annual energy consumption per household of 2751 kWh and a shape of the average load profile, both in good agreement with the reference. Furthermore, the temporal distribution of the vehicles to the locations is in accordance with the reference but the annual mileage is slightly underestimated with 10,730 km.

There continues to be difficulties when it comes to replication of studies in the field of Psychology. In part, this may be caused by insufficiently standardized analysis methods that may be subject to state dependent variations in performance. In this work, we show how to easily adapt the two-layer feedforward neural network architecture provided by Huang 1 to a behavioral classification problem as well as a physiological classification problem which would not be solvable in a standardized way using classical regression or “simple rule” approaches. In addition, we provide an example for a new research paradigm along with this standardized analysis method. This paradigm as well as the analysis method can be adjusted to any necessary modification or applied to other paradigms or research questions. Hence, we wanted to show that two-layer feedforward neural networks can be used to increase standardization as well as replicability and illustrate this with examples based on a virtual T-maze paradigm 2–5 including free virtual movement via joystick and advanced physiological data signal processing.

Key Points Type I interferons (IFNs), a family of around 20 members, were originally described as antiviral cytokines. Research in recent years has shown that type I IFNs also affect immune responses to bacteria. IFNs are produced in response to bacterial infection when Toll-like receptor 4 (TLR4) or TLR9 are stimulated, or from within the cytoplasm when bacteria enter a cell. Induction of type I IFN genes by bacteria and their products requires activation of IFN regulatory factor 3 (IRF3) and/or IRF7. Most cells in the body must increase the amounts of IRF7 before transcribing the majority of type I IFN genes in response to infection. This occurs through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signalling by the type I IFN receptor (IFNAR), which is stimulated by low amounts of type I IFNs produced at the onset of infection. Specialized cells known as IFN-producing cells (IPCs) constitutively express IRF7 and immediately produce large amounts of type I IFNs in response to bacterial signals. These cells rapidly activate IRF7 after TLR signalling. Type I IFNs increase immunity to some Gram-negative bacteria by stimulating IFN-γ production. Some studies suggest that type I IFNs inhibit the invasion of epithelial cells and that this activity limits the ability of enteric bacteria to cross the intestinal epithelium. Type I IFNs influence maturation, activation, migration and survival of dendritic cells (DCs). By regulating DC activity, they can indirectly enhance both T cell and B cell-mediated adaptive immunity to bacteria. Type I IFNs exert adverse effects during infection with at least some intracellular bacteria ( Listeria monocytogenes and under some circumstances also Mycobacterium tuberculosis ). This activity can be attributed to a sensitization of effector cells to bacteria-induced death. Interferons (IFNs) are cytokines that are important for immune responses, particularly to intracellular pathogens. They are divided into two structurally and functionally distinct types that interact with different cell-surface receptors. Classically, type I IFNs are potent antiviral immunoregulators, whereas the type II IFN enhances antibacterial immunity. However, as outlined here, type I IFNs are also produced in response to infection with other pathogens, and an increasing body of work shows that type I IFNs have an important role in the host response to bacterial infection. Strikingly, their activity can be either favourable or detrimental, and can influence various immune effector mechanisms.

Macrophages are critical for granuloma formation, but the cell-intrinsic mechanisms remain unknown. Weichhart and colleagues demonstrate that chronic mTOR activity leads to macrophage-dependent granuloma formation, which may have relevance to sarcoidosis. The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 ( Tsc2 ) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo . TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.

The shift toward electric mobility in Germany is a major component of the German climate protection program. In this context, public charging is growing in importance, especially in high-density urban areas, which causes an additional load on the distribution grid. In order to evaluate this impact and prevent possible overloads, realistic models are required. Methods for implementing such models and their application in the context of grid load are research topics that are only minorly addressed in the literature. This paper aims to demonstrate the entire process chain from the selection of a modelling method to the implementation and application of the model within a case study. Applying a stochastic approach, charging points are modelled via probabilities to determine the start of charging, plug-in duration, and charged energy. Subsequently, load profiles are calculated, integrated into an energy system model and applied in order to analyze the effects of a high density of public charging points on the urban distribution grid. The case study highlights a possible application of the implemented probabilistic load profile model, but also reveals its limitations. The primary results of this paper are the identification and evaluation of relevant criteria for modelling the load profiles of public charging points as well as the demonstration of the model and its comparison to real charging processes. By publishing the determined probabilities and the model for calculating the charging load profiles, a comprehensive tool is provided.

Acrophobia is characterized by intense fear in height situations. Virtual reality (VR) can be used to trigger such phobic fear, and VR exposure therapy (VRET) has proven effective for treatment of phobias, although it remains important to further elucidate factors that modulate and mediate the fear responses triggered in VR. The present study assessed verbal and behavioral fear responses triggered by a height simulation in a 5-sided cave automatic virtual environment (CAVE) with visual and acoustic simulation and further investigated how fear responses are modulated by immersion, i.e., an additional wind simulation, and presence, i.e., the feeling to be present in the VE. Results revealed a high validity for the CAVE and VE in provoking height related self-reported fear and avoidance behavior in accordance with a trait measure of acrophobic fear. Increasing immersion significantly increased fear responses in high height anxious (HHA) participants, but did not affect presence. Nevertheless, presence was found to be an important predictor of fear responses. We conclude that a CAVE system can be used to elicit valid fear responses, which might be further enhanced by immersion manipulations independent from presence. These results may help to improve VRET efficacy and its transfer to real situations.