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RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells
Get PDFConventional dendritic cells (cDCs) are potent antigen-presenting cells (APCs) that integrate signals from their environment allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination, autoimmunity, and cancer. Here, we use fate mapping, functional analyses, and comparative cross-species transcriptomics to show that RORγt+ DCs are a conserved, functionally versatile, and transcriptionally distinct type of DCs. RORγt+ DCs entail various populations described in different contexts including Janus cells/RORγt-expressing extrathymic Aire-expressing cells (eTACs), subtypes of Thetis cells, RORγt+-DC (R-DC) like cells, cDC2C and ACY3+ DCs. We show that in response to inflammatory triggers, RORγt+ DCs can migrate to lymph nodes and in the spleen can activate naïve CD4+ T cells. These findings expand the functional repertoire of RORγt+ DCs beyond the known role of eTACs and Thetis cells in inducing T cell tolerance to self-antigens and intestinal microbes in mice. We further show that RORγt+ DCs with proinflammatory features accumulate in autoimmune neuroinflammation in mice and men. Thus, our work establishes RORγt+ DCs as immune sentinel cells that exhibit a broad functional spectrum ranging from inducing peripheral T cell tolerance to T cell activation depending on signals they integrate from their environment
Dropout from trauma-focused treatment for PTSD in a naturalistic setting
Get PDFBackground: Although evidence-based interventions for posttraumatic stress disorder (PTSD) are highly effective, on average about 20% of patients drop out of treatment. Despite considerable research investigating PTSD treatment dropout in randomized controlled trials (RCTs), findings in naturalistic settings remain sparse.
Objective: Therefore, the present study investigated the frequency and predictors of dropout in trauma-focused interventions for PTSD in routine clinical care.
Method: The sample included n = 195 adults with diagnosed PTSD, receiving trauma-focused, cognitive behavioral therapy in routine clinical care in three outpatient centers. We conducted a multiple logistic regression analysis with the following candidate predictors of dropout: patient variables (e.g., basic sociodemographic status and specific clinical variables) as well as therapist’s experience level and gender match between therapist and patient.
Results: Results showed a dropout rate of 15.38%. Age (higher dropout probability in younger patients) and living situation (living with parents predicted lower dropout probability compared to living alone) were significant predictors of dropout. Dropout was not significantly associated with the therapist’s experience level and gender match.
Conclusions: In conclusion, routinely assessed baseline patient variables are associated with dropout. Ultimately, this may help to identify patients who need additional attention to keep them in therapy
The Dice Trails Test: A modified Trail Making Test for children and adults with Down Syndrome
Get PDFBackground: Psychometrically sound instruments to assess cognitive flexibility in people with Down Syndrome (DS) are lacking. The Trail Making Test (TMT) is well-established but requires reading letters and numerals, limiting its applicability for people with DS.
Aims: To evaluate the psychometric properties and developmental sensitivity of a newly developed TMT adaptation without letters and numerals – the Dice Trails Test (DTT).
Methods: The DTT was administered to 39 children (8–14 years, 46 % female) and 57 adults (18–57 years, 47 % female) with DS. We evaluated feasibility (proportion of participants completing the task), distributional properties, construct validity, developmental sensitivity, and split-half reliability. Nineteen individuals were reassessed for test-retest reliability. Individuals with DS were compared to typically developing (TD) groups matched on chronological and mental age.
Results: The DTT showed adequate feasibility (≥ 80 %) for individuals with DS and mild intellectual disability (ID), no relevant floor effects, acceptable construct validity, developmental sensitivity, good split-half reliability, and preliminary evidence for good test-retest reliability in DS. DTT performance differed between DS and TD individuals matched on chronological age, but not when matched on mental age.
Conclusions: Although limited in applicability for individuals with DS and moderate ID, the DTT shows potential as a direct measure of cognitive flexibility in DS across a broad age range
Exploratory analysis of the proteomic profile in plasma in adults with Down syndrome in the context of Alzheimer's disease
Get PDFIntroduction: Adults with Down syndrome (DS) show increased risk for Alzheimer's disease (AD) due to the triplication of chromosome 21 encoding the amyloid precursor protein gene. Further, this triplication possibly contributes to dysregulation of the immune system, furthering AD pathophysiology.
Methods: Using Olink Explore 3072, we measured ∼3000 proteins in plasma from 73 adults with DS and 15 euploid, healthy controls (HC). Analyses for differentially expressed proteins (DEP) were carried out, and pathway and protein network enrichment using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes (KEGG), and STRING database was investigated. Within DS, the LASSO (least absolute shrinkage and selection operator) feature selection was applied.
Results: We identified 253 DEP between DS and HC and 142 DEP between symptomatic and asymptomatic DS. Several pathways regarding inflammatory and neurodevelopmental processes were dysregulated in both analyses. LASSO feature selection within DS returned 15 proteins as potential blood markers.
Discussion: This exploratory proteomic analysis found potential new blood biomarkers for diagnosing DS-AD in need of further investigation
Analysis of chicken LGALSL (galectin-related protein) gene’s proximal promoter and its control by Krüppel-like factors 3 and 7
Get PDFThe Galectin-Related Protein (GRP), encoded by the LGALSL gene, assigned to the protein family of β-galactoside-binding Galectins, has lost carbohydrate-binding abilities. Its chicken homolog (C-GRP) occurs in the bursa of Fabricius’ epithelial and B cells. Our study investigates the unknown regulatory mechanisms controlling its expression by analyzing the promoter region of the chicken (C-)LGALSL gene in chicken cells. We aimed to identify the sequence elements of the C-LGALSL gene promoter responsible for maximum activity and transcription factors (TFs) that can modulate this activity. Using luciferase reporter assays, we investigated deletion variants of the 5′ region (−2480 bp to +26 bp). Through in silico analyses and site-directed mutagenesis, we explored potential transcription factor binding sites, identified crucial transcription factors through transient overexpression and tested its direct binding by ChIP. Our findings highlight that the region from −274 to −75 bp, conserved among bird species, is crucial for promoter regulation. Among other tested factors, only the chicken (ch) Krüppel-like factors, chKLF3 and chKLF7, modulate the promoter’s activity. The TFs chKLF3 acts as a repressor, and chKLF7 as an activator, although direct binding could not be confirmed. In conclusion, chKLF3 and chKLF7 contribute, in contrast to other factors with binding sites in the region from −274 to −75 bp, to C-LGALSL gene promoter regulation with a balanced impact on activity
Sex dimorphism in kidney health and disease: mechanistic insights and clinical implication
Get PDFSex is a key variable in the regulation of human physiology and pathology. Many diseases disproportionately affect one sex: autoimmune diseases, such as systemic lupus erythematosus, are more common in women but more severe in men, whereas the incidence of other disorders such as gouty arthritis and malignant cancers is higher in men. Besides the pathophysiology, sex may also influence the efficacy of therapeutics; participants in clinical trials are still predominately men, and the side effects of drugs are more common in women than in men. Sex dimorphism is a prominent feature of kidney physiology and function, and consequently affects the predisposition to many adult kidney diseases. These differences subsequently influence the response to immune stimuli, hormones, and therapies. It is highly likely that these responses differ between the sexes. Therefore, it becomes imperative to consider sex differences in translational science from basic science to preclinical research to clinical research and trials. Under-representation of one sex in preclinical animal studies or clinical trials remains an issue and key reported outcomes of such studies ought to be presented separately. Without this, it remains difficult to tailor the management of kidney disease appropriately and effectively. In this review, we provide mechanistic insights into sex differences in rodents and humans, both in kidney health and disease, highlight the importance of considering sex differences in the design of any preclinical animal or clinical study, and propose guidance on how to optimal design and conduct preclinical animal studies in future research
Progress of Angiographic Cardiac Allograft Vasculopathy in Patients With Long-Term Transplantation: Longitudinal Evaluation of Its Association With Dyslipidemia Patterns
Get PDFCardiac allograft vasculopathy (CAV) is a progressive disease with limited options for secondary prevention. Ways to manage lipid parameters and dyslipidemia patterns in care after transplantation remain unclear. In this longitudinal study, we included 32 patients with long-term heart transplantations (median interval after transplant 13.8 years) with angiographic manifest CAV. In 299 matched nonstented segments at 3 distinct time points ([TPs] 0 to 2, with median intervals of 2 years, respectively), progress of diameter stenosis (Δ%DS) defined CAV progress. Values above the median of maximal Δ%DS defined substantial CAV progress. Category of left ventricular ejection fraction was evaluated at TP0 and TP3 (2 years after TP2). Findings were correlated with dyslipidemia patterns at TP0, and lipid variations at follow-up (TP1 to TP3). Analyses included routine lipid assessment, and triglycerides/high-density lipoprotein-cholesterol ratio (TG/HDL-c) and atherogenic index of plasma (AIP). At TP1 and TP2, patients with increase of TG/HDL-c ≥0.1 (p = 0.02, respectively) and with increase of AIP (p = 0.01 and p = 0.049, respectively) presented a greater maximal Δ%DS. Dyslipidemia patterns at TP0 did not show a relevant association with CAV progress. At TP2, increase of TGs, TG/HDL-c, and AIP were associated with substantial CAV progress (odds ratio [OR] 5.0, p = 0.046, and OR 9.2, p = 0.01, OR 6.6, p = 0.02, respectively). At TP3, patients with CAV-related worsening of left ventricular ejection fraction category presented with a greater increase of TG/HDL-c (p = 0.03). Although findings at TP0 did not affect CAV progress, an increase of TG/HDL-c could define patients at greater risk of CAV progress and CAV-related deterioration of graft function
Selection for altruistic defense in structured populations
Get PDFWe model natural selection for or against an anti-parasite (or anti-predator) defense allele in a host (or prey) population that is structured into many demes. The defense behavior has a fitness cost for the actor compared to non defenders (“cheaters”) in the same deme and locally reduces parasite growth rates. Hutzenthaler et al. (2022) have analytically derived a criterion for fixation or extinction of defenders in the limit of large populations, many demes, weak selection and slow migration. Here, we use both individual-based and diffusion-based simulation approaches to analyze related models. We find that the criterion still leads to accurate predictions for settings with finitely many demes and with various migration patterns.
A key mechanism of providing a benefit of the defense trait is genetic drift due to randomness of reproduction and death events leading to between-deme differences in defense allele frequencies and host population sizes. We discuss an inclusive-fitness interpretation of this mechanism and present in-silico evidence that under these conditions a defense trait can be altruistic and still spread in a structured population
Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice
Get PDFBackground and Purpose:
Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo.
Experimental Approach:
Gpr55−/− and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg−1 min−1) or vehicle infusion. In isolated adult Gpr55−/− and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046.
Key Results:
Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55−/− myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation.
Conclusions and Implications:
Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females
A systematic assessment of robustness in CNS safety pharmacology
Get PDFBackground and Purpose:
Irwin tests are key preclinical study elements for characterising drug-induced neurological side effects. This multicentre study aimed to assess the robustness of Irwin tests across multinational sites during three stages of protocol harmonisation. The projects were part of the Enhanced Quality in Preclinical Data framework, aiming to increase success rates in transition from preclinical testing to clinical application.
Experimental Approach:
Female and male NMRI mice were assigned to one of three groups (vehicle, MK-801 0.1 and 0.3 mg kg−1). Irwin scores were assessed at baseline and multiple times following intraperitoneal injection of MK-801 using local protocols (Stage 1), shared protocols with harmonised environmental design (Stage 2) and fully harmonised Irwin scoring protocols (Stage 3).
Key Results:
The analysis based on the four functional domains (motor, autonomic, sedation and excitation) revealed substantial data variability in Stages 1 and 2. Although there was still marked overall heterogeneity between sites in Stage 3 after complete harmonisation of the Irwin scoring scheme, heterogeneity was only moderate within functional domains. When comparing treatment groups versus vehicle, we found large effect sizes in the motor domain and subtle to moderate effects in the excitation-related and autonomic domains.
Conclusion and Implications:
The pronounced interlaboratory variability in Irwin datasets for the CNS-active compound MK-801 needs to be carefully considered when making decisions during drug development. While environmental and general study design had a minor impact, the study suggests that harmonisation of parameters and their scoring can limit variability and increase robustness