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Background & Aims: The role of hepatocytes in producing chemokines and triggering liver inflammation and damage in chronic hepatitis D (CHD) is not fully understood. Herein, we investigated the contribution of primary human hepatocytes (PHHs) infected with HDV in triggering inflammation by producing the chemokines CXCL9–11. Methods: We performed quantitative PCR, RNA in situ hybridisation, activation-induced marker (AIM) assays, and FACS analysis to investigate the CXCR3/CXCL9–11 receptor/ligand axis of T cells in peripheral blood and livers from patients with chronic hepatitis B (n = 27 and 18, respectively) and CHD (n = 20 and 18, respectively). Chemokine expression was investigated in cultured HDV-infected PHHs and in livers of HBV- or HBV/HDV-infected humanised mice in the presence or absence of adoptively transferred human immune cells (n = 35 in total). Results: In patient and chimeric mouse livers, higher expression levels of CXCL9–11 were found in an HBV/HDV-coinfected vs. HBV-mono-infected setting. Similarly, high levels of CXCL9–11 were observed in HDV-infected PHHs in vitro. Analysis by RNA in situ hybridisation on patient livers revealed that HDV-infected hepatocytes were a significant contributor to the chemokine expression. The corresponding chemokine receptor CXCR3 was found upregulated specifically on peripheral bulk CD4 T cells of patients with CHD. CXCR3 upregulation was unspecific and was not detected on HDAg- or HBsAg-specific CD4 T cells by activation-induced marker assay. Lastly, adoptive transfer of human T cells in humanised mice led to recruitment of non-HBV/HDV-specific CD4+ T cells only in the setting of HBV/HDV coinfection, but not in HBV-mono-infected mice. Conclusions: HDV infection upregulated the intrahepatic expression of the CXCL9–11/CXCR3 receptor/ligand axis. Higher amounts of HBV/HDV-unspecific CD4 T cells expressing CXCR3 may contribute to the aggravated liver inflammation frequently observed in patients with CHD. Impact and implications: Chronic hepatitis D (CHD) causes the most severe form of viral hepatitis, and treatment options are still limited; therefore, a more precise understanding of CHD immunopathology is needed. In this study, we demonstrated that HDV infection triggers CXCL9–11 expression in hepatocytes and liver infiltration of CXCR3-expressing CD4 T cells in preclinical models as well as patient biopsies. Because recruitment of Th1-polarised CD4 T cells to the liver has been also described for other severe liver diseases, such as autoimmune hepatitis, it may represent an important mechanism of aggravating liver diseases. The data of this study set hereby the basis for future studies analysing phenotype and function of intrahepatic T cells in CHD.

The COVID-19 pandemic has caused a rise in stress, mental health concerns, and externalizing behaviors in children and their caregivers across the globe and illuminated the need to reduce stress levels and support self-regulation skills in even the youngest of children. The goal of this literature review is to describe what research has shown about the use of mindfulness-based interventions (MBIs) to support young children's self-regulation in early childhood settings. A total of 18 research studies conducted between 2010 and 2021 were identified. The main purposes of the studies reviewed were to examine the effects of MBIs on the development of emotional, behavioral, and cognitive self-regulation. Results showed that teachers generally found mindfulness practices feasible, acceptable, and effective in their classrooms. Although MBIs were found to have mixed effects on self-regulation in young children, positive effects on self-regulation were significantly greater for children in need of additional support, including those with difficulties or delays in developing self-regulation skills. The current review found a wide variety of MBIs used in early childhood settings globally. The results of this review suggest that teaching mindfulness practices to young children and their caregivers can both support the development of self-regulation of young children and foster socially and emotionally healthy environments in which this development can occur.

Postmodernism’s claim against absolute truth has been problematic for preaching. If the primary purpose for preaching is disseminating truth, and there is no absolute truth, then what is preaching’s principal purpose? Many preachers feel the pressure of navigating a context in which truth and authority are under fire, and questioners are leaving the evangelical church in the US in increasing numbers. Homiletic responses to postmodernism include ignoring or vocally opposing it, with few preachers accepting postmodernism as a worthy conversation partner. However, postmodernism has given way to a new cultural era identified as metamodernism, and the postmodern truth dismissal has shifted, allowing room for the possibility of truth. Metamodernism maintains postmodernism’s cynicism toward truth, but is fused with modern optimism for the possibility that truth exists. This provides a unique opportunity for preaching through a metamodern lens and accepting the challenges of preaching that deconstructs toward that which is “undeconstructible.”

During the Mauritian period of Dutch Brazil (1637‑1644), a great deal of information about the biota of northeastern Brazil was obtained, consisting of both written records and paintings. Among them is an eel-like fish, depicted in two paintings labeled “Caramurû” and “Caramuru”, whose taxonomic identity is controversial. One of them, attributed to Albert Eckhout, is part of the Theatrum Rerum Naturalium Brasiliae collection, stored at the Jagiellonian University Library, in Poland. This painting was possibly a model for the second “Caramuru”, of unknown authorship, which is deposited at the Archive of the Russian Academy of Sciences. These paintings are doubtfully identified as the snake eel Echiophis intertinctus (Ophichthidae, Anguilliformes), a proposal likely induced by the vulgar name “caramuru”, which is applied to muraenids and ophichthids in Brazil. After careful examination of these two paintings regarding the anatomical details depicted, we concluded that the fish corresponds, with great certainty, to Gobioides broussonnetii (Gobiidae, Gobiiformes), popularly known as “aimoré” and “tajasica”. Furthermore, we suggest the possibility that the written counterpart of these paintings is the description associated with the woodcut of the fish labeled as “Tajasica” in the Historia Naturalis Brasiliae (Marggraf in de Laet, 1648). The confusion probably stems from mismatches between Georg Marggraf’s descriptions and the images of organisms produced at the time, perhaps before the return of Johan Maurits van Nassau-Siegen’s entourage to Europe. In an attempt to support our conclusions about the identity of that fish, as well as for historical purposes, we also discuss the vernacular names applied to G. broussonnetii and the authorship of the notes made on those paintings.

Phelan-McDermid syndrome (PMS) is a syndromic form of Autism Spectrum Disorders (ASD) classified as a rare genetic neurodevelopmental disorder featuring global developmental delay, absent or delayed speech, ASD-like behaviour and neonatal skeletal muscle hypotonia. PMS is caused by a heterozygous deletion of the distal end of chromosome 22q13.3 or SHANK3 mutations. We analyzed striated muscles of newborn Shank3Δ11(−/−) animals and found a significant enlargement of the sarcoplasmic reticulum as previously seen in adult Shank3Δ11(−/−) mice, indicative of a Shank3-dependent and not compensatory mechanism for this structural alteration. We analyzed transcriptional differences by RNA-sequencing of muscle tissue of neonatal Shank3Δ11(−/−) mice and compared those to Shank3(+/+) controls. We found significant differences in gene expression of ion channels crucial for muscle contraction and for molecules involved in calcium ion regulation. In addition, calcium storage- [i.e., Calsequestrin (CSQ)], calcium secretion- and calcium-related signaling-proteins were found to be affected. By immunostainings and Western blot analyses we could confirm these findings both in Shank3Δ11(−/−) mice and PMS patient muscle tissue. Moreover, alterations could be induced in vitro by the selective downregulation of Shank3 in C2C12 myotubes. Our results emphasize that SHANK3 levels directly or indirectly regulate calcium homeostasis in a cell autonomous manner that might contribute to muscular hypotonia especially seen in the newborn.

Objectives This study aimed to determine the genetic and environmental contributions to phenotypic variations of palatal morphology during development. Methods Longitudinal three-dimensional digital maxillary dental casts of 228 twin pairs (104 monozygotic and 124 dizygotic) at primary, mixed, and permanent dentition stages were included in this study. Landmarks were placed on the casts along the midpoints of the dento-gingival junction on the palatal side of each tooth and the mid-palatine raphe using MeshLab. Palatal widths, depths, length, area, and volume were measured using those landmarks. Univariate genetic structural equation modelling was performed on twin data at each stage of dental development. Results Except for anterior depth, all palatal dimensions increased significantly from the primary to permanent dentition stages. The phenotypic variance for most of the palatal dimensions during development was best explained by a model, including additive genetic and non-shared environment variance components. Variance in volume and area in the primary dentition stage was best explained by a model including additive genetic, shared environment, and non-shared environment variance components. For posterior palatal depth and width, narrow-sense heritability estimates were above 0.8 for all dental developmental stages. In contrast, heritability estimates for other palatal traits fluctuated during development. Limitation This study was limited to twins of European ancestry. Conclusions Additive genetic and non-shared environmental factors primarily influenced palatal morphology during development. While the genetic influence on different aspects of the palate varied throughout development, it was particularly strong in the posterior region of the palate and during the permanent dentition stage. [ABSTRACT FROM AUTHOR]

Infections with hepatotropic viruses are associated with various immune phenomena. Hepatitis D virus (HDV) causes the most severe form of viral hepatitis. However, few recent data are available on non-disease-specific and non-organ-specific antibody (NOSA) titers and immunoglobulin G (IgG) levels in chronic hepatitis D (CHD) patients. Here, we examined the NOSA titers and IgG levels of 40 patients with CHD and different disease courses and compared them to 70 patients with chronic hepatitis B (CHB) infection. 43% of CHD patients had previously undergone treatment with pegylated interferon-α (IFN-α). The antibody display of 46 untreated patients diagnosed with autoimmune hepatitis (AIH) was used as a reference. The frequency of elevated NOSA titers (CHD 69% vs. CHB 43%, p

Background & Aims: Pegylated interferon alpha (pegIFNα) is commonly used for the treatment of people infected with HDV. However, its mode of action in HDV-infected cells remains elusive and only a minority of people respond to pegIFNα therapy. Herein, we aimed to assess the responsiveness of three different cloned HDV strains to pegIFNα. We used a previously cloned HDV genotype 1 strain (dubbed HDV-1a) that appeared insensitive to interferon-α in vitro, a new HDV strain (HDV-1p) we isolated from an individual achieving later sustained response to IFNα therapy, and one phylogenetically distant genotype 3 strain (HDV-3). Methods: PegIFNα was administered to human liver chimeric mice infected with HBV and the different HDV strains or to HBV/HDV infected human hepatocytes isolated from chimeric mice. Virological parameters and host responses were analysed by qPCR, sequencing, immunoblotting, RNA in situ hybridisation and immunofluorescence staining. Results: PegIFNα treatment efficiently reduced HDV RNA viraemia (∼2-log) and intrahepatic HDV markers both in mice infected with HBV/HDV-1p and HBV/HDV-3. In contrast, HDV parameters remained unaffected by pegIFNα treatment both in mice (up to 9 weeks) and in isolated cells infected with HBV/HDV-1a. Notably, HBV viraemia was efficiently lowered (∼2-log) and human interferon-stimulated genes similarly induced in all three HBV/HDV-infected mouse groups receiving pegIFNα. Genome sequencing revealed highly conserved ribozyme and L-hepatitis D antigen post-translational modification sites among all three isolates. Conclusions: Our comparative study indicates the ability of pegIFNα to lower HDV loads in stably infected human hepatocytes in vivo and the existence of complex virus-specific determinants of IFNα responsiveness. Impact and implications: Understanding factors counteracting HDV infections is paramount to develop curative therapies. We compared the responsiveness of three different cloned HDV strains to pegylated interferon alpha in chronically infected mice. The different responsiveness of these HDV isolates to treatment highlights a previously underestimated heterogeneity among HDV strains.

ABSTRACT Mutations of the postsynaptic scaffold protein Shank2 lead to autism spectrum disorders (ASD). These patients frequently suffer from higher fracture risk. Here, we investigated whether Shank2 directly regulates bone mass. We show that Shank2 is expressed in bone and that Shank2 levels are increased during osteoblastogenesis. Knockdown of Shank2 by siRNA targeting the encoding regions for PDZ and SAM domain inhibits osteoblastogenesis of primary murine calvarial osteoblasts. Shank2 knockout mice (Shank2−/−) have a decreased bone mass due to reduced osteoblastogenesis and bone formation, whereas bone resorption remains unaffected. Induced pluripotent stem cells (iPSCs)‐derived osteoblasts from a loss‐of‐function Shank2 mutation in a patient showed a significantly reduced osteoblast differentiation potential. Moreover, silencing of known Shank2 interacting proteins revealed that a majority of them promote osteoblast differentiation. From this we conclude that Shank2 and interacting proteins known from the central nervous system are decisive regulators in osteoblast differentiation. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Individuals with a SHANK3-related neurodevelopmental disorder, also termed Phelan-McDermid syndrome or abbreviated as PMS, exhibit significant global developmental delay, language impairment, and muscular hypotonia. Also common are repetitive behaviors and altered social interactions, in line with a diagnosis of autism spectrum disorders. This study investigated the developmental aspect of autism-related behaviors and other phenotypes in a Shank3-transgenic mouse model. The animals underwent two sets of identical behavioral experiments, spanning motor skills, social and repetitive behavior, and cognition: baseline began at 5 weeks of age, corresponding to human adolescence, and the follow-up was initiated when aged 13 weeks, resembling early adulthood in humans. Interestingly, the animals displayed relatively stable phenotypes. Moreover, motor coordination and endurance were impaired, while muscle strength was unchanged. Surprisingly, the animals displayed only minor impairments in social behavior, but pronounced stereotypic and repetitive behaviors. Some behavioral tests indicated increased avoidance and anxiety. While spatial learning and memory were unchanged, knockout animals displayed slightly impaired cognitive flexibility. Female animals had similar abnormalities as males in the paradigms testing avoidance, anxiety, and cognition, but were less pathological in motor function and repetitive behavior. In all test paradigms, heterozygous Shank3 knockout animals had either no abnormal or a milder phenotype. Accurate characterization of animal models for genetic diseases is a prerequisite for understanding the pathophysiology. This is subsequently the basis for finding suitable and, ideally, translational biomarkers for therapeutic approaches and, thereby reducing the number of animals needed for preclinical trials.