Basal MET phosphorylation is an indicator of hepatocyte dysregulation in liver disease.

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, metabolic dysfunction-associated steatotic liver disease (MASLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in MASLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) an increased basal MET phosphorylation and a strong downregulation of the PI3K-AKT pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.

Thy-1 restricts steatosis and liver fibrosis in steatotic liver disease.

BACKGROUND AND AIMS: Steatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction-associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy-1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation. METHODS: The impact of Thy-1 on the development of SLD and progression to fibrosis was investigated in high-fat diet (HFD)-induced SLD wild-type and Thy-1-deficient mice. In addition, the serum soluble Thy-1 (sThy-1) concentration was analysed in patients with metabolic dysfunction-associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers. RESULTS: We demonstrated that Thy-1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD-induced SLD mice. Mechanistically, Thy-1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy-1 prevents palmitic acid-mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy-1-deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy-1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score. CONCLUSION: Our data strongly suggest that Thy-1 may function as a fibrosis-protective factor in mouse and human SLD.

Past attachment experiences, the potential link of mentalization and the transmission of behavior to the child by mothers with mental health problems: cross-sectional analysis of a clinical sample.

Maternal capacity to mentalize (= reflective functioning, RF), secure attachment and emotionally available parenting has an impact on the child's development. The transmission of mothers' past attachment experiences gained with both her caregivers in her own childhood and the impact on current mother-child interaction is part of the 'transmission gap.' This study explores the transgenerational transmission mechanisms and the potential moderating effect of RF in a clinical sample of 113 mother-child dyads suffering from mental health problems. In a cross-sectional study, the associations between maternal attachment experiences, RF (coded based on Adult Attachment Interviews) and current mother-child interaction (Emotional Availability Scales) were examined with univariate correlation, moderator analyses, and structural equation models. We found relationships between attachment experiences and mother-child interaction, but RF had no moderating effect. Past loving experiences and perceived neglection, particularly with the own father in childhood, were predictors for the present mother-child interaction. There seems to be an intergenerational transmission of attachment experiences to the ongoing generation. Particularly past adverse childhood experiences with the own father seem to explain currently disruptive interactions with the child.Trial registration: DRKS00017008 and DRKS00016353.

Efficacy of parent-infant psychotherapy compared to care as usual in children with regulatory disorders in clinical and outpatient settings: study protocol of a randomised controlled trial as part of the SKKIPPI project.

BACKGROUND: The first years of life are a significant period for child development, when children are particularly sensitive and prone to crises. This early phase lays the foundation for healthy growth. Clinical assessment of psychological symptoms in early infancy and adequate treatment are both important in improving the diagnostic outcome and preventing later long-term developmental consequences. The most common psychological problems in the first 3 years of life are regulatory disorders. The aim of this trial is to investigate the efficacy of Parent-Infant Psychotherapy (PIP) for infants and young children (aged 0-36 months, diagnosed with at least one regulatory disorder) and their mothers, compared to care as usual (CAU). METHODS: In this open multicentre randomised controlled trial, 160 mother-infant dyads are randomised to receive PIP or CAU for 6 weeks of intervention in clinical or outpatient (including home treatment) settings. The primary outcome is the maternal sensitivity (sensitivity scale of the Emotional Availability Scales (EAS)) after 6 weeks. Secondary outcomes include assessment of interaction, mental health problems, attachment, development, psychological factors, treatment adherence, health care system utilisation, and costs, after 6 weeks and 12 months. DISCUSSION: This study will evaluate whether a manualised focus-based short-term psychodynamic psychotherapeutic intervention in mother-child dyads improves the care situation for families of children diagnosed with regulatory disorders, and helps prevent long-term psychopathologies. Assessment of the intervention in different settings will support the development of more tailored interventions for affected infants and their mothers. TRIAL REGISTRATION: German Clinical Trial Register, ID: DRKS00017008 . Registered 03/20/2019.

Sex-dependent dynamics of metabolism in primary mouse hepatocytes.

The liver is one of the most sexually dimorphic organs. The hepatic metabolic pathways that are subject to sexual dimorphism include xenobiotic, amino acid and lipid metabolism. Non-alcoholic fatty liver disease and hepatocellular carcinoma are among diseases with sex-dependent prevalence, progression and outcome. Although male and female livers differ in their abilities to metabolize foreign compounds, including drugs, sex-dependent treatment and pharmacological dynamics are rarely applied in all relevant cases. Therefore, it is important to consider hepatic sexual dimorphism when developing new treatment strategies and to understand the underlying mechanisms in model systems. We isolated primary hepatocytes from male and female C57BL6/N mice and examined the sex-dependent transcriptome, proteome and extracellular metabolome parameters in the course of culturing them for 96 h. The sex-specific gene expression of the general xenobiotic pathway altered and the female-specific expression of Cyp2b13 and Cyp2b9 was significantly reduced during culture. Sex-dependent differences of several signaling pathways increased, including genes related to serotonin and melatonin degradation. Furthermore, the ratios of male and female gene expression were inversed for other pathways, such as amino acid degradation, beta-oxidation, androgen signaling and hepatic steatosis. Because the primary hepatocytes were cultivated without the influence of known regulators of sexual dimorphism, these results suggest currently unknown modulatory mechanisms of sexual dimorphism in vitro. The large sex-dependent differences in the regulation and dynamics of drug metabolism observed during cultivation can have an immense influence on the evaluation of pharmacodynamic processes when conducting initial preclinical trials to investigate potential new drugs.

[Postpartum mental health problems: healthcare service situation and effectiveness of parent-infant psychotherapy. Presentation of the SKKIPPI project funded by the German Innovationsfonds]. / Postpartale psychische Erkrankungen: Versorgungslage und Wirksamkeit der Eltern-Säugling-Kleinkind-Psychotherapie. Vorstellung des Innovationsfondprojektes SKKIPPI.

After the birth of a child, parents may experience episodes of stress and psychological strain. Some infants show psychological or somatic stress in the form of early regulatory disorders. While the close connection between parental psychological stress, early regulatory disorders, and the development of the parent-child relationship is well documented, current data on effective treatment options are lacking. Previous care services mostly operate on a preventive basis; evidence-based psychotherapeutic services with a special focus on the parent-child relationship are rare.SKKIPPI is a multicenter research project (Berlin, Flensburg, Hamburg, Leipzig) and consists of several study parts with a mixed methods approach: an epidemiological cohort study, two randomized controlled intervention studies (RCTs), and a qualitative study. A population-based cohort study records the occurrence and determinants of psychosocial stress and mental health disorders, as well as the use of health and social services by parents and their children within the first two years of life, using online questionnaires and telephone interviews. The aim of the two RCTs is to evaluate the efficacy of a focused, dyadic parent-infant psychotherapy (Eltern-Säugling-Kleinkind-Psychotherapie, ESKP) compared to routine treatment in inpatient and outpatient settings. The focus of these RCTs is on the improvement of maternal sensitivity and on mother-child attachment, as well as child development and the reduction of mother-child psychopathological symptoms. The qualitative study intends to reconstruct the perspectives of parents on the assistance system and to explore reasons for underuse. The results are expected to help develop preventive as well as therapeutic strategies in the German health system.

Assessment of Psychosocial Stress and Mental Health Disorders in Parents and Their Children in Early Childhood: Cross-Sectional Results from the SKKIPPI Cohort Study.

BACKGROUND/OBJECTIVES: Early childhood can be a stressful period for families with a significant impact on parents' mental health, the child's healthy development, and the development of a secure mother-child attachment. The goal of the cross-sectional study part of SKKIPPI was to assess the occurrence of psychosocial stress and mental health disorders in parents as well as in their offspring in early childhood in three German regions. METHODS: Based on random samples from three residents' registration offices, parents with infants aged up to 12 months were invited to participate. An online screening questionnaire was developed in four languages to assess common psychosocial stressors and mental health problems of parents with small children. RESULTS: The study enrolled 4984 mothers and 962 fathers. The most common potential psychosocial stressors were professional problems (mothers 22%, fathers 33%), lack of social support (20%, 14%), and severe, negative experiences in childhood (22%, 16%). Obsessive-compulsive thoughts (21%, 16%) and depressive (9%, 9%) and anxiety symptoms (11%, 7%) were the most frequently reported mental health problems by both parents. Regulatory problems of the child were reported by between 1.5% and 5.1% of parents. CONCLUSIONS: The study showed that a substantial proportion of parents are burdened by psychosocial problems and suffer from mental health problems in the first years after the birth of their children. Early preventive and low-threshold support measures should be available in the health and social care system. Low-threshold questionnaires, which cover a wide range of possible stress factors, should be further developed for the practical healthcare of this group of people.

Cell atlas of the regenerating human liver after portal vein embolization.

The liver has the remarkable capacity to regenerate. In the clinic, regeneration is induced by portal vein embolization, which redirects portal blood flow, resulting in liver hypertrophy in locations with increased blood supply, and atrophy of embolized segments. Here, we apply single-cell and single-nucleus transcriptomics on healthy, hypertrophied, and atrophied patient-derived liver samples to explore cell states in the regenerating liver. Our data unveils pervasive upregulation of genes associated with developmental processes, cellular adhesion, and inflammation in post-portal vein embolization liver, disrupted portal-central hepatocyte zonation, and altered cell subtype composition of endothelial and immune cells. Interlineage crosstalk analysis reveals mesenchymal cells as an interaction hub between immune and endothelial cells, and highlights the importance of extracellular matrix proteins in liver regeneration. Moreover, we establish tissue-scale iterative indirect immunofluorescence imaging for high-dimensional spatial analysis of perivascular microenvironments, uncovering changes to tissue architecture in regenerating liver lobules. Altogether, our data is a rich resource revealing cellular and histological changes in human liver regeneration.

Being an Infant in a Pandemic: Influences of the COVID-19 Pandemic on Infants, Toddlers and Their Mothers in a Clinical Population.

The COVID-19 pandemic and the ongoing lockdowns might have had a strong impact on mental health of mothers and their infants/toddlers. For example, families had to deal with health issues and social isolation, which might have affected mental health and parent-child interactions. The aim of this study is to evaluate differences in (1) infantile regulatory disorders, (2) maternal mental health, (3) the impact of maternal mental health on infantile regulatory disorders, and (4) alterations in the mother-child interaction for participants recruited before versus after the onset of the first German lockdown. For this reason, mother-child dyads have been divided into two groups and were compared by analyzing clinical interviews on psychopathology of mother and child (M.I.N.I. & DC:05) and mother-child-interactions (Emotional Availability Scales). Results showed that (1) differences in infantile sleeping disorders emerged (phi = 0.243; p = 0.016) compared to the pre-lockdown group, while (2) the occurrence of maternal panic and anxiety increased in the post-lockdown group (phi = 0.229; p = 0.022). Moreover, there was (3) an association for maternal panic and child's sleep disorder, and (4) specific associations with maternal non-hostility in the mother-child-interaction. In conclusion, the present study highlights the differences of maternal mental health occurrences and infants' regulatory problems, as well as the possible effects of the COVID-19 pandemic for infants. In the pre-lockdown group, maternal non-hostility might have acted as a promotive factor against regulatory disorders, while this mechanism was mitigated in the post-lockdown group.

Hepatic Hedgehog Signaling Participates in the Crosstalk between Liver and Adipose Tissue in Mice by Regulating FGF21.

The Hedgehog signaling pathway regulates many processes during embryogenesis and the homeostasis of adult organs. Recent data suggest that central metabolic processes and signaling cascades in the liver are controlled by the Hedgehog pathway and that changes in hepatic Hedgehog activity also affect peripheral tissues, such as the reproductive organs in females. Here, we show that hepatocyte-specific deletion of the Hedgehog pathway is associated with the dramatic expansion of adipose tissue in mice, the overall phenotype of which does not correspond to the classical outcome of insulin resistance-associated diabetes type 2 obesity. Rather, we show that alterations in the Hedgehog signaling pathway in the liver lead to a metabolic phenotype that is resembling metabolically healthy obesity. Mechanistically, we identified an indirect influence on the hepatic secretion of the fibroblast growth factor 21, which is regulated by a series of signaling cascades that are directly transcriptionally linked to the activity of the Hedgehog transcription factor GLI1. The results of this study impressively show that the metabolic balance of the entire organism is maintained via the activity of morphogenic signaling pathways, such as the Hedgehog cascade. Obviously, several pathways are orchestrated to facilitate liver metabolic status to peripheral organs, such as adipose tissue.