A systematic comparison of FOSL1, FOSL2 and BATF-mediated transcriptional regulation during early human Th17 differentiation.

Th17 cells are essential for protection against extracellular pathogens, but their aberrant activity can cause autoimmunity. Molecular mechanisms that dictate Th17 cell-differentiation have been extensively studied using mouse models. However, species-specific differences underscore the need to validate these findings in human. Here, we characterized the human-specific roles of three AP-1 transcription factors, FOSL1, FOSL2 and BATF, during early stages of Th17 differentiation. Our results demonstrate that FOSL1 and FOSL2 co-repress Th17 fate-specification, whereas BATF promotes the Th17 lineage. Strikingly, FOSL1 was found to play different roles in human and mouse. Genome-wide binding analysis indicated that FOSL1, FOSL2 and BATF share occupancy over regulatory regions of genes involved in Th17 lineage commitment. These AP-1 factors also share their protein interacting partners, which suggests mechanisms for their functional interplay. Our study further reveals that the genomic binding sites of FOSL1, FOSL2 and BATF harbour hundreds of autoimmune disease-linked SNPs. We show that many of these SNPs alter the ability of these transcription factors to bind DNA. Our findings thus provide critical insights into AP-1-mediated regulation of human Th17-fate and associated pathologies.

Economic burden on caregivers or parents with Down syndrome children-a systematic review protocol.

BACKGROUND: Financial burden is a common phenomenon, often noticed in the caregivers of children with Down syndrome. It echoes adverse effects on the caregiver's mental and physical health. The economic burden covers direct healthcare costs, direct non-health-care costs, and indirect costs and is substantial for the family of a person with Down syndrome, as well as for society. Evidence, in this area, is necessary to reduce mental stress and promote financial well-being among caregivers. METHODS: In this review, quantitative studies that assess the economic burden on caregivers of children with Down syndrome will be considered. We will perform a systematic literature search conducted from the year 2000 to 2022 on electronic databases CINAHL, EBSCO, EMBASE, PubMed, Scopus, Web of Science, and EconLit. An additional gray literature search will be carried out. Two researchers will independently conduct the screening and data extraction and assess the risk of bias. DISCUSSIONS: The review attempts to methodically analyze the economic burden among caregivers of children with Down syndrome from the societal perspective and individual perspectives. The current study will provide an evidence base to researchers, academicians, and society in identifying need-based learning to caregivers, and the selection of appropriate therapies for children suffering from Down syndrome. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021265312.

PIM kinases regulate early human Th17 cell differentiation.

The serine/threonine-specific Moloney murine leukemia virus (PIM) kinase family (i.e., PIM1, PIM2, and PIM3) has been extensively studied in tumorigenesis. PIM kinases are downstream of several cytokine signaling pathways that drive immune-mediated diseases. Uncontrolled T helper 17 (Th17) cell activation has been associated with the pathogenesis of autoimmunity. However, the detailed molecular function of PIMs in human Th17 cell regulation has yet to be studied. In the present study, we comprehensively investigated how the three PIMs simultaneously alter transcriptional gene regulation during early human Th17 cell differentiation. By combining PIM triple knockdown with bulk and scRNA-seq approaches, we found that PIM deficiency promotes the early expression of key Th17-related genes while suppressing Th1-lineage genes. Further, PIMs modulate Th cell signaling, potentially via STAT1 and STAT3. Overall, our study highlights the inhibitory role of PIMs in human Th17 cell differentiation, thereby suggesting their association with autoimmune phenotypes.

Effectiveness of mindfulness-based interventions on well-being and work-related stress in the financial sector: a systematic review and meta-analysis protocol.

BACKGROUND: Work-related stress is a common phenomenon, often noticed in the employees of the finance sector. It mirrors counter effects on the wellness of employees, their mental well-being, and physical health. Mindfulness-based interventions (MBIs) raise awareness and attention to the present moment experiences by adopting coping skills. It is necessary to promote employee well-being and reduce work-related stress; hence, the need arises to associate between the level of mindfulness, employee well-being, and work-related stress. A systematic review on the effectiveness of MBIs in the finance sector is necessary to facilitate evidence for the future utility to reduce work-related stress and promote employee well-being. METHODS: In this review, randomized controlled trials, non-randomized control trials, cohort, and cross-sectional and case-control studies that assess the effectiveness of MBIs on the employees in the finance sector will be considered. We propose to perform a literature search which will be conducted from the years 2000 to 2021 on CINAHL, Cochrane Library, ProQuest, PubMed, Scopus, and Web of Science. The search terms will include controlled and accessible terms such as mindfulness-based interventions, mindfulness training, workplace, employees, workers, well-being, employee wellness, occupational health, and finance sector. The outcomes will include the effect on employee well-being and reduction in work-related stress. Two researchers will independently conduct the screening and data extraction and assess the risk of bias. Based on the availability of data, a meta-analysis will also be performed. This protocol follows the Preferred Reporting Items for Systematic reviews and Meta-Analysis-Protocol (PRISMA-P) guidelines. "Assessing the Methodological Quality of Systematic Reviews" will be used to assess the quality of this review. DISCUSSION: The review attempts to methodically analyse the effectiveness of MBIs among finance sector employees. It will foster to facilitate a detailed description and evidence-based overview of the effectiveness of MBIs on improving work-related stress, mindful awareness, and employee wellness and well-being in employees in the finance sector. The current study will provide an evidence base to researchers, academicians, and practitioners in the selection of mindfulness-based therapies for employees in the finance sector. SYSTEMATIC REVIEW REGISTRATION: PROSPERO 2021 CRD42021249782.

Interactome Networks of FOSL1 and FOSL2 in Human Th17 Cells.

Dysregulated function of Th17 cells has implications in immunodeficiencies and autoimmune disorders. Th17 cell differentiation is orchestrated by a complex network of transcription factors, including several members of the activator protein (AP-1) family. Among the latter, FOSL1 and FOSL2 modulate the effector functions of Th17 cells. However, the molecular mechanisms underlying these effects are unclear, owing to the poorly characterized protein interaction networks of FOSL factors. Here, we establish the first interactomes of FOSL1 and FOSL2 in human Th17 cells, using affinity purification-mass spectrometry analysis. In addition to the known JUN proteins, we identified several novel binding partners of FOSL1 and FOSL2. Gene ontology analysis found a significant fraction of these interactors to be associated with RNA-binding activity, which suggests new mechanistic links. Intriguingly, 29 proteins were found to share interactions with FOSL1 and FOSL2, and these included key regulators of Th17 fate. We further validated the binding partners identified in this study by using parallel reaction monitoring targeted mass spectrometry and other methods. Our study provides key insights into the interaction-based signaling mechanisms of FOSL proteins that potentially govern Th17 cell differentiation and associated pathologies.

NF-κB Signaling and IL-4 Signaling Regulate SATB1 Expression via Alternative Promoter Usage During Th2 Differentiation.

SATB1 is a genome organizer protein that is expressed in a lineage specific manner in CD4+ T-cells. SATB1 plays a crucial role in expression of multiple genes throughout the thymic development and peripheral differentiation of T cells. Although SATB1 function has been subjected to intense investigation, regulation of SATB1 gene expression remains poorly understood. Analysis of RNA-seq data revealed multiple transcription start sites at the upstream regulatory region of SATB1. We further demonstrated that SATB1 gene is expressed via alternative promoters during T-helper (Th) cell differentiation. The proximal promoter "P1" is used more by the naïve and activated CD4+ T-cells whereas the middle "P2" and the distal "P3" promoters are used at a significantly higher level by polarized T-helper cells. Cytokine and TCR signaling play crucial roles toward SATB1 alternative promoter usage. Under Th2 polarization conditions, transcription factor STAT6, which operates downstream of the cytokine signaling binds to the P2 and P3 promoters. Genetic perturbation by knockout and chemical inhibition of STAT6 activation resulted in the loss of P2 and P3 promoter activity. Moreover, chemical inhibition of activation of NF-κB, a transcription factor that operates downstream of the TCR signaling, also resulted in reduced P2 and P3 promoter usage. Furthermore, usage of the P1 promoter correlated with lower SATB1 protein expression whereas P2 and P3 promoter usage correlated with higher SATB1 protein expression. Thus, the promoter switch might play a crucial role in fine-tuning of SATB1 protein expression in a cell type specific manner.

Quantitative Proteomics Reveals the Dynamic Protein Landscape during Initiation of Human Th17 Cell Polarization.

Th17 cells contribute to the pathogenesis of inflammatory and autoimmune diseases and cancer. To reveal the Th17 cell-specific proteomic signature regulating Th17 cell differentiation and function in humans, we used a label-free mass spectrometry-based approach. Furthermore, a comprehensive analysis of the proteome and transcriptome of cells during human Th17 differentiation revealed a high degree of overlap between the datasets. However, when compared with corresponding published mouse data, we found very limited overlap between the proteins differentially regulated in response to Th17 differentiation. Validations were made for a panel of selected proteins with known and unknown functions. Finally, using RNA interference, we showed that SATB1 negatively regulates human Th17 cell differentiation. Overall, the current study illustrates a comprehensive picture of the global protein landscape during early human Th17 cell differentiation. Poor overlap with mouse data underlines the importance of human studies for translational research.