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.
Frontal asymmetry has been investigated over the past 30 years, and several theories have been developed about its meaning. The original theory of Davidson and its diversification by Harmon‐Jones & ...Allen allocated approach motivation to relative left frontal brain activity and withdrawal motivation to relative right frontal brain activity. Hewig and colleagues extended this theory by adding bilateral frontal activation representing a biological correlate of the behavioral activation system if actual behavior is shown. Wacker and colleagues formulated a theory related to the revised reinforcement sensitivity theory by Gray & McNaughton. Here, relative left frontal brain activation represents the revised behavioral activation system and behavior, while relative right frontal brain activation represents the revised behavioral inhibition system, representing the experience of conflict. These theories were investigated with a newly developed paradigm where participants were able to move around freely in a virtual T maze via joystick while having their EEG recorded. Analyzing the influence of frontal brain activation during this virtual reality task on observable behavior for 30 participants, we found more relative left frontal brain activation during approach behavior and more relative right brain activation for withdrawal behavior of any kind. Additionally, there was more bilateral frontal brain activation when participants were engaged in behavior compared to doing nothing. Hence, this study provides evidence for the idea that frontal asymmetry stands for behavioral approach or avoidance motivation, and bilateral frontal activation stands for behavior. Additionally, observable behavior is not only determined by frontal asymmetry, but also by relevant traits.
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.
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.
Abstract
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.
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.
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.
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.
The qualitative results of SARS-CoV-2 specific real-time reverse transcription (RT) PCR are used for initial diagnosis and follow-up of Covid-19 patients and asymptomatic virus carriers. However, ...clinical decision-making and health management policies often are based additionally on cycle threshold (C
) values (i.e., quantitative results) to guide patient care, segregation and discharge management of individuals testing positive. Therefore, an analysis of inter-protocol variability is needed to assess the comparability of the quantitative results.
C
values reported in a SARS-CoV-2 virus genome detection external quality assessment challenge were analyzed. Three positive and two negative samples were distributed to participating test laboratories. Qualitative results (positive/negative) and quantitative results (C
values) were assessed.
A total of 66 laboratories participated, contributing results from 101 distinct test systems and reporting C
values for a total of 92 different protocols. In all three positive samples, the means of the C
values for the
-,
-,
-,
-, and
-genes varied by less than two cycles. However, 7.7% of reported results deviated by more than ±4.0 (maximum 18.0) cycles from the respective individual means. These larger deviations appear to be systematic errors.
In an attempt to use PCR diagnostics beyond the identification of infected individuals, laboratories are frequently requested to report C
values along with a qualitative result. This study highlights the limitations of interpreting C
values from the various SARS-CoV genome detection protocols and suggests that standardization is necessary in the reporting of C
values with respect to the target gene.
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.
PDF
