Regulation of IFN signaling is critical in host recognition and response to pathogens while its dysregulation underlies the pathogenesis of several chronic diseases. STimulator of IFN Genes (STING) has been identified as a critical mediator of IFN inducing innate immune pathways, but little is known about direct coregulators of this protein. We report here that TMEM203, a conserved putative transmembrane protein, is an intracellular regulator of STING-mediated signaling. We show that TMEM203 interacts, functionally cooperates, and comigrates with STING following cell stimulation, which in turn leads to the activation of the kinase TBK1, and the IRF3 transcription factor. This induces target genes in macrophages, including IFN-β. Using Tmem203 knockout bone marrow-derived macrophages and transient knockdown of TMEM203 in human monocyte-derived macrophages, we show that TMEM203 protein is required for cGAMP-induced STING activation. Unlike STING, TMEM203 mRNA levels are elevated in T cells from patients with systemic lupus erythematosus, a disease characterized by the overexpression of type I interferons. Moreover, TMEM203 mRNA levels are associated with disease activity, as assessed by serum levels of the complement protein C3. Identification of TMEM203 sheds light into the control of STING-mediated innate immune responses, providing a potential novel mechanism for therapeutic interventions in STING-associated inflammatory diseases.
Our aim was to explore insights from clinical practice that may inform efforts to understand and account for factors that predict spoken language outcomes for children with ASD who use minimal verbal language. We used a qualitative design involving three focus groups with 14 speech pathologists to explore their views and experiences. Using the Framework Method of analysis, we identified 9 themes accounting for 183 different participant references to potential factors. Participants highlighted the relevance of clusters of fine-grained social, communication, and learning behaviours, including novel insights into prelinguistic vocal behaviours. The participants suggested the potential value of dynamic assessment in predicting spoken language outcomes. The findings can inform efforts to developing clinically relevant methods for predicting children's communication outcomes.
We assessed the spoken language of 73 preschool aged children on the autism spectrum receiving community-based early intervention at two time points, approximately 7 months apart. Using the Spoken Language Benchmarks, there was a small non-significant change in the proportion of children transitioning from below, to at or above, Phase 3 (word combinations). Using binomial regression, a model comprising seven of nine clinician-proposed child-related predictors explained 64% of the variance. None of the predictors were individually significant, although a large effect size (OR = 16.71) was observed for children’s baseline rate of communicative acts. The findings point to substantial unmet clinical need in children with minimal verbal language, but also the relevance of clinician-proposed predictors of their spoken language outcomes.
Background In many countries, children who are diagnosed with autism during the first 5 years of life are offered a range of early intervention options. These options vary considerably in the theoretical approaches and techniques applied, their intensity and duration, settings, the person/s delivering supports and the training they require. Early interventions are a significant contributor to total autism-related costs in Western countries, but only in the last 10–20 years has there been adequate outcome data to enable the comparison of different interventions’ cost-effectiveness. This protocol describes a scoping review to better understand what economic evaluations have been completed in this field, and the methods used to date. Methods We will systematically search the following databases from their inception to 2021 for eligible studies: MEDLINE, EMBASE, PsycINFO, Econlit, PEDE, NHS EED and HTA. Full economic evaluations of any types of early intervention for children with autism prior to school entry will be included. Two reviewers will screen the studies, extract the data and assess the study quality using established checklists. The risk of bias will be assessed using the extended CHEC-list for all studies and, additionally, the Philips checklist for modelled studies. Quality of reporting will be assessed using the CHEERS checklist. A narrative synthesis will be completed to collate the findings, describe the methods used and identify which interventions have been researched from an economic perspective. Discussion This review will provide researchers, policymakers and service providers with current information about the economic evidence for early interventions for young children with autism and point to priorities for further research. It will inform future economic evaluations by highlighting the gaps or inconsistencies in the methods used to date. Limitations of the review will be acknowledged and discussed. Systematic review registration Open Science Framework: https://osf.io/sj7kt
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