Latent profile analysis of depression in US adults with obstructive sleep apnea hypopnea syndrome.

Objective: This study used latent profile analysis to explore the level of depression among US adults with obstructive sleep apnea hypopnea syndrome (OSAHS) symptoms and to identify different latent categories of depression to gain insight into the characteristic differences between these categories. Methods: The data of this study were obtained from the National Health and Nutrition Examination Survey (NHANES) database, and the subjects with OSAHS symptoms were aged 18 years and older. The latent profile analysis (LPA) method was used to fit the latent depression categories in subjects with OSAHS symptoms. The chi-square test, rank sum test, and binary logistic regression were used to analyze the influencing factors of depression subgroups in subjects with OSAHS symptoms. Results: Three latent profiles were identified: low-level (83.7%), moderate-level (14.5%) and high-level (1.8%) depression. The scores of 9 items in the high-level depression group were higher than those in the other two groups. Among them, item 4 "feeling tired or lack of energy" had the highest score in all categories. Conclusion: Depression in subjects with OSAHS symptoms can be divided into low-level, moderate-level and high-level depression. There are significant differences among different levels of depression in gender, marital status, PIR, BMI, smoking, general health condition, sleep duration and OSAHS symptom severity.

Translation and validation of the Chinese version of the Self-awareness Scale for Nurses.

Background: Levels of self-awareness may affect the decision-making ability of clinical nurses and may also be related to mental health. Therefore, it is crucial to develop tools to identify nurses' level of self-awareness. The purpose of this study was to investigate the reliability and validity of a short scale among Chinese nurses and to explore the factors associated with nurses' self-awareness. Methods: A total of 957 participants were recruited, 549 participants were used for reliability tests and 408 subjects were used for impact factor studies. They completed the General Information Questionnaire, the Self-Awareness Scale for Nurses, and the Psychological Distress Scale. Exploratory factor analysis, confirmatory factor analysis, Cronbach's alpha, and retest reliability were used to investigate the psychometric properties of the Self-Awareness Scale for Nurses. Multiple regression analyses were used in this study to investigate the relationship between nurses' self-awareness and the independent variables. Results: A 4-factor model of the Chinese version of the Self-Awareness Scale for Nurses was validated. The overall Cronbach's alpha value for the Chinese version of the Self-Awareness Scale for Nurses was 0.873. Cronbach's alpha values for each subscale ranged from 0.808 to 0.979. Significant predictors of each dimension of the Self-awareness and the total score of the scale were age and work experience. Conclusion: The Chinese version of the Self-Awareness Scale for Nurses is a valid and reliable scale.

Cat-E: A comprehensive web tool for exploring cancer targeting strategies.

Identifying potential cancer-associated genes and drug targets from omics data is challenging due to its diverse sources and analyses, requiring advanced skills and large amounts of time. To facilitate such analysis, we developed Cat-E (Cancer Target Explorer), a novel R/Shiny web tool designed for comprehensive analysis with evaluation according to cancer-related omics data. Cat-E is accessible at https://cat-e.bioinfo-wuerz.eu/. Cat-E compiles information on oncolytic viruses, cell lines, gene markers, and clinical studies by integrating molecular datasets from key databases such as OvirusTB, TCGA, DrugBANK, and PubChem. Users can use all datasets and upload their data to perform multiple analyses, such as differential gene expression analysis, metabolic pathway exploration, metabolic flux analysis, GO and KEGG enrichment analysis, survival analysis, immune signature analysis, single nucleotide variation analysis, dynamic analysis of gene expression changes and gene regulatory network changes, and protein structure prediction. Cancer target evaluation by Cat-E is demonstrated here on lung adenocarcinoma (LUAD) datasets. By offering a user-friendly interface and detailed user manual, Cat-E eliminates the need for advanced computational expertise, making it accessible to experimental biologists, undergraduate and graduate students, and oncology clinicians. It serves as a valuable tool for investigating genetic variations across diverse cancer types, facilitating the identification of novel diagnostic markers and potential therapeutic targets.

Reliability and validity evaluation of the Chinese version of the gender misconceptions of men in nursing (GEMINI) scale among nursing students.

BACKGROUND: Misconceptions about male nurses not only exacerbate the gender imbalance in the nursing profession but also negatively impact male nurses embarking on their careers. Currently, no tool exists to measure the gender biases toward males in nursing among nursing students in China. Consequently, the primary objective of this study is to assess the validity and reliability of the Chinese translation of the Gender Misconceptions of Men in Nursing (GEMINI) scale among nursing students. METHODS: This cross-sectional study involved 1,102 nursing students from China who participated online. We utilized the Brislin translation technique with a forward-backward approach. To determine the factor structure within the Men in Nursing Gender Misconceptions Scale's Chinese version, both exploratory (EFA) and confirmatory factor analysis (CFA) were applied. The scale's internal consistency was measured through the Cronbach's alpha coefficient, corrected item-total correlation, and a retest reliability assessment. RESULTS: The scale showed a content validity index of 0.938 and a retest reliability of 0.844. EFA indicated a two-factor structure for the translated instrument. CFA revealed a chi-square/degree of freedom of 3.837, an incremental fit index (IFI) of 0.952, a goodness-of-fit index (GFI) of 0.910, a comparative fit index (CFI) of 0.952, and an RMSEA of 0.073, all of which were within acceptable limits. The scale's Cronbach's α was 0.953, and the corrected item-total correlations ranged between 0.539 and 0.838. Gender-based misconceptions about men in nursing among students appeared to be influenced by their gender and whether they considered a nursing program as their first choice when applying for a major. Misconceptions about male nurses are greater among men and those who do not consider nursing programs as their first choice when applying for a major. CONCLUSIONS: The Chinese adaptation of the GEMINI scale showcased high reliability and validity. It stands as a potential instrument to gauge gender misconceptions concerning male nurses among Chinese nursing students.

Relationship between social support and self-perceived burden in patients with obstructive sleep apnea: an analysis of chain-mediated effects.

OBJECTIVE: To estigate the relationship between social support, self-efficacy, coping style, and self-perceived burden and the mechanisms that underlie the action in Chinese OSA patients. METHODS: Between October 2022 and June 2023,316 OSA patients from two hospitals were surveyed. Data were collected using the General Demographic Characteristics Questionnaire, Social Support Rating Scale (SSRS), Self-Efficacy for Chronic Disease Scale (SECD6), and Simple Coping Style Questionnaire (SCSQ). Correlation analysis was performed using Pearson correlation. Regression analysis was performed using multiple linear regression analysis. The mediation effect analysis was performed using the Process macro (version 3.4.1) in SPSS. RESULTS: (1)This study confirmed that social support, self-efficacy, and coping styles had significant negative predictions regarding self-perceived burden. (2)The influence of social support on self-perceived burden in OSA patients is mainly through three indirect effects: single mediation effect of self-efficacy and coping style and interlocking mediation effect of self-efficacy→coping style. CONCLUSION: Social support can indirectly predict self-efficacy in OSA patients through the single mediation effect of self-efficacy and coping style and indirectly predict the self-perception burden in OSA patients through the linked mediation effects of self-efficacy and coping style.

ATF3 characterizes aggressive drug-tolerant persister cells in HGSOC.

High-grade serous ovarian cancer (HGSOC) represents the most common and lethal subtype of ovarian cancer. Despite initial response to platinum-based standard therapy, patients commonly suffer from relapse that likely originates from drug-tolerant persister (DTP) cells. We generated isogenic clones of treatment-naïve and cisplatin-tolerant persister HGSOC cells. In addition, single-cell RNA sequencing of barcoded cells was performed in a xenograft model with HGSOC cell lines after platinum-based therapy. Published single-cell RNA-sequencing data from neo-adjuvant and non-treated HGSOC patients and patient data from TCGA were analyzed. DTP-derived cells exhibited morphological alterations and upregulation of epithelial-mesenchymal transition (EMT) markers. An aggressive subpopulation of DTP-derived cells showed high expression of the stress marker ATF3. Knockdown of ATF3 enhanced the sensitivity of aggressive DTP-derived cells to cisplatin-induced cell death, implying a role for ATF3 stress response in promoting a drug tolerant persister cell state. Furthermore, single cell lineage tracing to detect transcriptional changes in a HGSOC cell line-derived xenograft relapse model showed that cells derived from relapsed solid tumors express increased levels of EMT and multiple endoplasmic reticulum (ER) stress markers, including ATF3. Single cell RNA sequencing of epithelial cells from four HGSOC patients also identified a small cell population resembling DTP cells in all samples. Moreover, analysis of TCGA data from 259 HGSOC patients revealed a significant progression-free survival advantage for patients with low expression of the ATF3-associated partial EMT genes. These findings suggest that increased ATF3 expression together with partial EMT promote the development of aggressive DTP, and thereby relapse in HGSOC patients.

Attenuation of fibroblast activation and fibrosis by adropin in systemic sclerosis.

Fibrotic diseases impose a major socioeconomic challenge on modern societies and have limited treatment options. Adropin, a peptide hormone encoded by the energy homeostasis-associated (ENHO) gene, is implicated in metabolism and vascular homeostasis, but its role in the pathogenesis of fibrosis remains enigmatic. Here, we used machine learning approaches in combination with functional in vitro and in vivo experiments to characterize adropin as a potential regulator involved in fibroblast activation and tissue fibrosis in systemic sclerosis (SSc). We demonstrated consistent down-regulation of adropin/ENHO in skin across multiple cohorts of patients with SSc. The prototypical profibrotic cytokine TGFß reduced adropin/ENHO expression in a JNK-dependent manner. Restoration of adropin signaling by therapeutic application of bioactive adropin34-76 peptides in turn inhibited TGFß-induced fibroblast activation and fibrotic tissue remodeling in primary human dermal fibroblasts, three-dimensional full-thickness skin equivalents, mouse models of bleomycin-induced pulmonary fibrosis and sclerodermatous chronic graft-versus-host-disease (sclGvHD), and precision-cut human skin slices. Knockdown of GPR19, an adropin receptor, abrogated the antifibrotic effects of adropin in fibroblasts. RNA-seq demonstrated that the antifibrotic effects of adropin34-76 were functionally linked to deactivation of GLI1-dependent profibrotic transcriptional networks, which was experimentally confirmed in vitro, in vivo, and ex vivo using cultured human dermal fibroblasts, a sclGvHD mouse model, and precision-cut human skin slices. ChIP-seq confirmed adropin34-76-induced changes in TGFß/GLI1 signaling. Our study characterizes the TGFß-induced down-regulation of adropin/ENHO expression as a potential pathomechanism of SSc as a prototypical systemic fibrotic disease that unleashes uncontrolled activation of profibrotic GLI1 signaling.

Psychometric evaluation of the Chinese version of the Scale of Effects of Social Media on Eating Behaviour and research of its influencing factors.

BACKGROUND: Social media has become an indispensable part of contemporary young people's lives, and the influence of social media on college students' eating and other health-related behaviors has become increasingly prominent. However, there is no assessment tool to determine the effects of social media on Chinese college students' eating behavior. This study aims to translate the Scale of Effects of Social Media on Eating Behaviour (SESMEB) into Chinese. Its applicability to Chinese college students was examined through reliability and validity indexes, and the influencing factors of SESMEB were explored. METHODS: The questionnaire survey included 2374 Chinese college students. The Brislin translation model was used to translate the original scale into Chinese. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to test the construct validity of the scale, and the content validity of the scale was assessed through the content validity index. The internal consistency of the scale was assessed by calculating Cronbach's alpha coefficient, McDonald's Omega coefficient, split-half reliability, and test-retest reliability. Multiple stepwise linear regression analysis was performed to identify potential influences on the effects of social media on eating behavior. RESULTS: EFA supported the one-factor structure, and the factor loadings of each item on this dimension were higher than 0.40. CFA showed good model fitness indexes. The content validity index of the scale was 0.94. The Cronbach's alpha coefficient and McDonald's Omega coefficient for the scale were 0.964, the split-half reliability coefficient was 0.953, and the test-retest reliability was 0.849. Gender, education, major, frequency of social media use, online sexual objectification experiences, fear of negative evaluations, and physical appearance perfectionism explained 73.8% of the variance in the effects of social media on eating behavior. CONCLUSIONS: The Chinese version of the SESMEB has good psychometric properties and is a valid measurement tool for assessing the effects of social media on college students' eating behavior. Subjects who were female, highly educated, non-medical, had frequent social media use, online sexual objectification experiences, fear of negative evaluations, and physical appearance perfectionism used social media to have a higher impact on eating behavior.

Tissue niche occupancy determines the contribution of fetal- versus bone-marrow-derived macrophages to IgG effector functions.

Understanding the mechanisms underlying cytotoxic immunoglobulin G (IgG) activity is critical for improving therapeutic antibody activity and inhibiting autoantibody-mediated tissue pathology. While prior research highlights the important role of the mononuclear phagocytic system for removing opsonized target cells, it remains unclear which monocyte or macrophage subsets stemming from fetal or post-natal bone-marrow (BM)-associated definitive hematopoiesis are involved in target cell depletion. By using a titrated irradiation approach as well as Kupffer-cell-specific deletion of activated Fcγ receptor signaling, we establish conditions under which the contribution of BM-derived monocytes versus yolk-sac-derived liver-resident macrophages to cytotoxic IgG activity can be studied. Our results demonstrate that liver-resident macrophages originating from either fetal or adult hematopoiesis play a central role in IgG-mediated depletion of opsonized target cells from the peripheral blood under steady-state conditions, highlighting the impact of the tissue niche and not macrophage origin for cytotoxic antibody activity.

L-arginine metabolism inhibits arthritis and inflammatory bone loss.

OBJECTIVES: To investigate the effect of the L-arginine metabolism on arthritis and inflammation-mediated bone loss. METHODS: L-arginine was applied to three arthritis models (collagen-induced arthritis, serum-induced arthritis and human TNF transgenic mice). Inflammation was assessed clinically and histologically, while bone changes were quantified by µCT and histomorphometry. In vitro, effects of L-arginine on osteoclast differentiation were analysed by RNA-seq and mass spectrometry (MS). Seahorse, Single Cell ENergetIc metabolism by profilIng Translation inHibition and transmission electron microscopy were used for detecting metabolic changes in osteoclasts. Moreover, arginine-associated metabolites were measured in the serum of rheumatoid arthritis (RA) and pre-RA patients. RESULTS: L-arginine inhibited arthritis and bone loss in all three models and directly blocked TNFα-induced murine and human osteoclastogenesis. RNA-seq and MS analyses indicated that L-arginine switched glycolysis to oxidative phosphorylation in inflammatory osteoclasts leading to increased ATP production, purine metabolism and elevated inosine and hypoxanthine levels. Adenosine deaminase inhibitors blocking inosine and hypoxanthine production abolished the inhibition of L-arginine on osteoclastogenesis in vitro and in vivo. Altered arginine levels were also found in RA and pre-RA patients. CONCLUSION: Our study demonstrated that L-arginine ameliorates arthritis and bone erosion through metabolic reprogramming and perturbation of purine metabolism in osteoclasts.

The mediating role of coping styles in illness perception and self-management in patients with obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has become a chronic disease that threatens human health. Self-management in patients with OSA can influence their quality of life, and illness perception and coping styles are relevant facilitators of self-management, but this specific relationship has not been adequately studied. The purpose of this study was to investigate the current status and relationship between illness perception, coping styles, and self-management behaviors in patients with OSA, and how coping styles mediate this relationship. METHODS: This is a cross-sectional study. Conducted between September 2022 and March 2023, the study involved patients aged ≥18 years old in two hospitals who were diagnosed with OSA. The survey was conducted using the demographic characteristics questionnaire, the Brief Illness Perception Questionnaire, the Simple Coping Style Questionnaire, and the Self-management Behavior Questionnaire of patients with obstructive sleep apnea. Spearman's correlation analysis was used for correlation analysis and multiple linear regression and structural equation models were used for mediation effect testing. RESULTS: There were 282 valid questionnaires, with a 94 % valid response rate. Higher levels of self-management behaviors were associated with low negative illness perceptions, high positive coping, and low negative coping. The study also demonstrated that the mediating effect accounted for 25.65 % (-0.049/-0.191) of the overall effect. CONCLUSION: Illness perceptions in OSA patients were negatively related to positive coping styles, positively related to negative coping styles, and negatively related to self-management. This study suggests that coping styles of OSA patients mediate illness perception and self-management.

Validation of the Chinese version of the Sleep Regularity Questionnaire (SRQ) and analysis of influencing factors.

BACKGROUND: Currently, there is no instrument to measure sleep regularity in China. In this study, the Sleep Regularity Questionnaire（SRQ） was translated into Chinese, tested for reliability and validity, and analyzed for factors affecting sleep regularity. METHODS: The English version of the SRQ was translated into Chinese, and a total of 3642 individuals were included in this research. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to examine the underlying factor structure of the Chinese version of the SRQ and to measure its reliability and validity. In addition, the correlations between sleep regularity and general information, personal habits, self-control, stress, anxiety, and depression were explored. RESULTS: The Cronbach's α of the Chinese SRQ was 0.858, supporting the two-factor structure. Sleep regularity was statistically different between gender and ethnicity (p < 0.05), and personal habits (exercise, continued eating after dinner, smoking and drinking) had an effect on sleep regularity. Sleep regularity was positively associated with individual self-control and negatively associated with stress, anxiety, and depression. CONCLUSIONS: The Chinese version of the SRQ has excellent reliability and validity. There are two dimensions, namely circadian regularity and sleep continuity regularity, which can be used to assess the sleep regularity of Chinese adults. The results of this study showed that males and Han Chinese having better sleep regularity. And people with good lifestyle habits and greater self-control sleep more regularly, while stress, anxiety and depression can affect individuals' sleep regularity.

The relationship between living alone or not and depressive symptoms in older adults: a parallel mediation effect of sleep quality and anxiety.

BACKGROUND: With modernization and ageing in China, the population of older adults living alone is increasing. Living alone may be a potential risk factor for depressive symptoms. However, no parallel mediation model analysis has investigated the mediating factors for living alone or not (living arrangements) and depressive symptoms. METHODS: This cross-sectional study included a total number of 10,980 participants from the Chinese Longitudinal Healthy Longevity Survey (CLHLS), 1699 of whom lived alone and 9281 of whom did not live alone. Binary logistic regression and parallel mediation effect model were used to explore the relationship between living alone or not and depressive symptoms and possible mediation effects. Bootstrap analysis was used to examine the mediation effect of living alone or not on depressive symptoms. RESULTS: Compared to the participants who were not living alone, the living alone group had a higher rate of depressive symptoms. The binary logistic regression showed that after adjusting for other covariates, the risk of depressive symptoms was approximately 0.21 times higher for living alone compared to not living alone (OR = 1.21, 95% CI: 1.06, 1.37). Further, the results of the bootstrap analysis supported the partial mediating role of sleep quality and anxiety. Mediation analysis revealed that sleep quality and anxiety partially mediate the relationship between living alone and depressive symptoms (ß = 0.008, 95% CI [0.003, 0.014]; ß = 0.015, 95% CI [0.008, 0.024], respectively). CONCLUSIONS: Sleep quality and anxiety were identified as partially parallel mediators between living alone or not and depressive symptoms. Older adults living alone with poorer sleep quality and more pronounced anxiety were positively associated with higher levels of depressive symptoms. Older adults living alone should be encouraged to engage in social activities that may improve sleep quality, relieve anxiety, and improve feelings of loneliness caused by living alone. Meanwhile, older adults living alone should receive attention and support to alleviate their depressive symptoms.

XCR1 expression distinguishes human conventional dendritic cell type 1 with full effector functions from their immediate precursors.

Dendritic cells (DCs) are major regulators of innate and adaptive immune responses. DCs can be classified into plasmacytoid DCs and conventional DCs (cDCs) type 1 and 2. Murine and human cDC1 share the mRNA expression of XCR1. Murine studies indicated a specific role of the XCR1-XCL1 axis in the induction of immune responses. Here, we describe that human cDC1 can be distinguished into XCR1- and XCR1+ cDC1 in lymphoid as well as nonlymphoid tissues. Steady-state XCR1+ cDC1 display a preactivated phenotype compared to XCR1- cDC1. Upon stimulation, XCR1+ cDC1, but not XCR1- cDC1, secreted high levels of inflammatory cytokines as well as chemokines. This was associated with enhanced activation of NK cells mediated by XCR1+ cDC1. Moreover, XCR1+ cDC1 excelled in inhibiting replication of Influenza A virus. Further, under DC differentiation conditions, XCR1- cDC1 developed into XCR1+ cDC1. After acquisition of XCR1 expression, XCR1- cDC1 secreted comparable level of inflammatory cytokines. Thus, XCR1 is a marker of terminally differentiated cDC1 that licenses the antiviral effector functions of human cDC1, while XCR1- cDC1 seem to represent a late immediate precursor of cDC1.

PRO-Simat: Protein network simulation and design tool.

PRO-Simat is a simulation tool for analysing protein interaction networks, their dynamic change and pathway engineering. It provides GO enrichment, KEGG pathway analyses, and network visualisation from an integrated database of more than 8 million protein-protein interactions across 32 model organisms and the human proteome. We integrated dynamical network simulation using the Jimena framework, which quickly and efficiently simulates Boolean genetic regulatory networks. It enables simulation outputs with in-depth analysis of the type, strength, duration and pathway of the protein interactions on the website. Furthermore, the user can efficiently edit and analyse the effect of network modifications and engineering experiments. In case studies, applications of PRO-Simat are demonstrated: (i) understanding mutually exclusive differentiation pathways in Bacillus subtilis, (ii) making Vaccinia virus oncolytic by switching on its viral replication mainly in cancer cells and triggering cancer cell apoptosis and (iii) optogenetic control of nucleotide processing protein networks to operate DNA storage. Multilevel communication between components is critical for efficient network switching, as demonstrated by a general census on prokaryotic and eukaryotic networks and comparing design with synthetic networks using PRO-Simat. The tool is available at https://prosimat.heinzelab.de/ as a web-based query server.

Reliability and validity evaluation of the chinese revision of the attitude towards adult vaccination scale.

BACKGROUND: Although vaccination is one of the critical interventions to address global health issues, inadequate vaccination rates has become an international challenge. Vaccine hesitancy is the key to affecting inadequate vaccination rates. According to the WHO SAGE working group's definition, vaccine hesitancy refers to delaying or refusing vaccination and has been ranked as one of the top 10 health threats. There has yet to be a scale that evaluates vaccination attitudes among Chinese adults. However, an attitude quantity, the adult vaccination attitude scale, has been developed to assess adult vaccination attitudes and reasons for vaccine hesitancy. OBJECTIVE: The Adult Attitudes to Vaccination Scale (ATAVAC) was initially developed by Professor Zoi Tsimtsiou et al. This study aimed to analyze the structure of the Chinese version of the ATAVAC and explore the relationship between adult vaccination attitudes, e-health literacy, and medical distrust. METHODS: After obtaining author permission for the initial scales, the study was translated using the Brislin back-translation method. 693 adults were enrolled to the study. To validate this hypothesis, participants finished the socio-demographic questionnaire, the Chinese version of the ATAVAC, the electronic Health Literacy Scale (e-HEALS) and the Medical Mistrust Index (MMI). The exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were used to examine the underlying structure of the factors of the Chinese version of the Adult Vaccination Attitude Scale and to measure its reliability and validity. RESULTS: The Cronbach's alpha coefficient for the Chinese version of the ATAVAC was 0.885, with Cronbach's alpha coefficients ranging from 0.850 to 0.958 for each dimension. The content validity index was 0.90, and the retest reliability was 0.943. The exploratory factor analysis (EFA) supported the 3-factor structure of the translation instrument, and the scale had good discriminant validity. The confirmatory factor analysis (CFA) revealed a degree of freedom of 1.219, a model fit index (GFI) of 0.979, a normative fit index (NFI) of 0.991, a Tucker-Lewis index (TLI) of 0.998, a comparability index (CFI) of 0.998 and a root mean square error of approximation (RMSEA) of 0.026. CONCLUSION: The results show that the Chinese version of the ATAVAC has demonstrated good reliability and validity. Hence, it can be used as an effective tool to assess vaccination attitudes among Chinese adults.

Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1.

Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.

Perfusion Air Culture of Precision-Cut Tumor Slices: An Ex Vivo System to Evaluate Individual Drug Response under Controlled Culture Conditions.

Precision-cut tumor slices (PCTS) maintain tissue heterogeneity concerning different cell types and preserve the tumor microenvironment (TME). Typically, PCTS are cultured statically on a filter support at an air-liquid interface, which gives rise to intra-slice gradients during culture. To overcome this problem, we developed a perfusion air culture (PAC) system that can provide a continuous and controlled oxygen medium, and drug supply. This makes it an adaptable ex vivo system for evaluating drug responses in a tissue-specific microenvironment. PCTS from mouse xenografts (MCF-7, H1437) and primary human ovarian tumors (primary OV) cultured in the PAC system maintained the morphology, proliferation, and TME for more than 7 days, and no intra-slice gradients were observed. Cultured PCTS were analyzed for DNA damage, apoptosis, and transcriptional biomarkers for the cellular stress response. For the primary OV slices, cisplatin treatment induced a diverse increase in the cleavage of caspase-3 and PD-L1 expression, indicating a heterogeneous response to drug treatment between patients. Immune cells were preserved throughout the culturing period, indicating that immune therapy can be analyzed. The novel PAC system is suitable for assessing individual drug responses and can thus be used as a preclinical model to predict in vivo therapy responses.

Pepstatin-Based Probes for Photoaffinity Labeling of Aspartic Proteases and Application to Target Identification.

Aspartic proteases are a small class of proteases implicated in a wide variety of human diseases. Covalent chemical probes for photoaffinity labeling (PAL) of these proteases are underdeveloped. We here report a full on-resin synthesis of clickable PAL probes based on the natural product inhibitor pepstatin incorporating a minimal diazirine reactive group. The position of this group in the inhibitor determines the labeling efficiency. The most effective probes sensitively detect cathepsin D, a biomarker for breast cancer, in cell lysates. Moreover, through chemical proteomics experiments and deep learning algorithms, we identified sequestosome-1, an important player in autophagy, as a direct interaction partner and substrate of cathepsin D.

Software JimenaE allows efficient dynamic simulations of Boolean networks, centrality and system state analysis.

The signal modelling framework JimenaE simulates dynamically Boolean networks. In contrast to SQUAD, there is systematic and not just heuristic calculation of all system states. These specific features are not present in CellNetAnalyzer and BoolNet. JimenaE is an expert extension of Jimena, with new optimized code, network conversion into different formats, rapid convergence both for system state calculation as well as for all three network centralities. It allows higher accuracy in determining network states and allows to dissect networks and identification of network control type and amount for each protein with high accuracy. Biological examples demonstrate this: (i) High plasticity of mesenchymal stromal cells for differentiation into chondrocytes, osteoblasts and adipocytes and differentiation-specific network control focusses on wnt-, TGF-beta and PPAR-gamma signaling. JimenaE allows to study individual proteins, removal or adding interactions (or autocrine loops) and accurately quantifies effects as well as number of system states. (ii) Dynamical modelling of cell-cell interactions of plant Arapidopsis thaliana against Pseudomonas syringae DC3000: We analyze for the first time the pathogen perspective and its interaction with the host. We next provide a detailed analysis on how plant hormonal regulation stimulates specific proteins and who and which protein has which type and amount of network control including a detailed heatmap of the A.thaliana response distinguishing between two states of the immune response. (iii) In an immune response network of dendritic cells confronted with Aspergillus fumigatus, JimenaE calculates now accurately the specific values for centralities and protein-specific network control including chemokine and pattern recognition receptors.