👤 Andreas Ritter

Exposure to a Western diet during gestation and lactation adversely impacts offspring mood, learning, and memory. We determined if high dose maternal methyl donor nutrient (MDN) supplementation ameliorated the effects of a high fat/high sucrose (HFS) diet during gestation and lactation on the behavior of young, adult offspring. Rat dams consumed the following diets through gestation and lactation: [1] AIN93G control (CON) diet, [2] 45% fat diet with sucrose (HFS), [3] CON diet supplemented with folic acid, B MDN supplementation increased depression-related behavior regardless of maternal base diet (P = 0.003). Learning under stress was reduced in offspring of MDN supplemented dams evidenced by fewer SBET escapes (P = 0.042) and increased escape latency in FR1 trials (P = 0.037). MDNs did not alter novelty reactivity, anxiety-related behavior, or working memory but improved reference memory (P = 0.023). MDNs did not affect corticosterone, reduced BDNF when dams consumed the HFS diet (P = 0.025), and tended to increase DNA methylation (P = 0.065). Maternal MDN supplementation increased depression-related behavior and decreased learning under stress, indicating high dose MDN supplementation may not be warranted. Show less

Cardiac damage predicts poor outcomes in polytrauma (PT). In older patients, cardiovascular risk factors may predispose to post-traumatic cardiac dysfunction. This study examined whether cardiovascular risk correlates with cardiac damage and influences clinical outcomes in PT. This study at a German Level 1 Trauma Centre enrolled 59 polytrauma patients upon ER admission. Blood samples were taken at ER, 24h, 48h, 72h, 96h & 10d to assess cardiac damage via Troponin T & NT-proBNP. Transthoracic echocardiography (TTE) was performed at 24h/48h. Cardiovascular risk was evaluated using the SCORE2 algorithm. Subgroup analysis compared cardiac damage in patients with high (SCORE2 >7.5%) vs low risk, & assessed the additional impact of chest trauma. Arrhythmias were observed in 39% of patients, whereas acute repolarization disorder occurred in nearly 19%. TTE revealed wall motion abnormalities in 12%, diastolic dysfunction in 10% & right ventricular dysfunction in 5%. SCORE2 and Lp(a) significantly correlated with serum levels of TnT & NT-proBNP. SCORE2 values were associated with non-survival, wall motion disorders, diastolic dysfunction and relaxation disorders (p<0.05). A higher incidence of arrhythmias, diastolic dysfunction and relaxation disorders was observed in the subgroup of high-risk patients with chest trauma. Patients in the high-risk group without chest trauma showed higher non-survival rates (50%), which may be strongly influenced by a history of myocardial infarction. Cardiovascular risk was significantly associated with cardiac damage markers, TTE abnormalities & increased mortality. A history of myocardial infarction was associated with higher mortality in PT-patients with an elevated SCORE2 risk. Show less

Adipose tissue-derived mesenchymal stromal/stem cells (ASCs) possess regenerative potential. Obesity induces a pro-inflammatory environment that compromises their function. Here we investigate how obesity affects ASC biology, focusing on primary cilia. Our data show that obesity alters ASC gene expression, particularly in pathways related to the extracellular matrix, transforming growth factor-β (TGFβ) signaling, cell motility, and differentiation. The gene levels of regulatory factor X2 (RFX2) and adenylate cyclase 3 (ADCY3), important for ciliary biogenesis, are downregulated in obese ASCs. TGFβ treatment significantly decreases the expression of RFX2 and ADCY3 in lean ASCs. Knockdown of ADCY3 reduces primary cilium length, whereas pharmacological activation restores it and improves cell motility. These results suggest that obesity impairs ASC ciliary function, contributing to defective adipogenesis and reduced regenerative capacity. Restoring ADCY3 activity partially rescues ciliary integrity and cellular function, highlighting the role of primary cilia in ASC dysfunction and offering potential therapeutic targets for obesity-related disorders. Show less

Various adverse mental health outcomes (e.g., burnout) have been reported and shown to impact the longevity of veterinarians' careers, especially during the early career. Both compassion fatigue (CF) and compassion satisfaction (CS) are significant predictors of burnout. Increasing attention is being paid to positive psychology, including psychological wellbeing (PWB) and resilience, as they have the potential to enhance wellbeing in the profession. The objectives of this research were to measure various psychological outcomes of newly graduated veterinarians in Canada and identify underlying profiles based on empirical data. An online questionnaire with validated psychometric scales was distributed to graduates of all five Canadian veterinary schools in 2022 and 2023. Latent profile analysis (LPA) (n = 189) revealed two profiles, interpreted as follows: thriving (n = 116; high PWB, CS and resilience, and low burnout and CF) and surviving (n = 73; low PWB, CS and resilience, and high burnout and CF). The sample size was smaller than typically recommended for LPA. Our findings revealed that 61% (116/191) of newly graduated veterinarians were considered to have good mental wellbeing or were 'thriving'. Our study amplifies the need for more research on positive wellbeing outcomes and interventions to strengthen veterinary students' and veterinarians' wellbeing. Show less

The diagnosis of Sjögren's disease (SjD) in patients without autoantibodies against Ro/SSA is a major challenge. We aimed to identify novel autoantibodies in SjD that may facilitate the diagnostic procedure for Ro/SSA negative SjD. IgG and IgA autoantibody reactivity of 94 potential candidate autoantigens for SjD, selected from a discovery screen of 1,629 human antigens coupled to Luminex beads and prior knowledge about potential biological relevance, were examined in serum of SjD patients (n=347) using Luminex and ELISA technology. Healthy (HC, n=118) and non-Sjögren's sicca syndrome (NSS, n=44) individuals served as controls. To assess disease specificity, the novel autoantibodies were also measured in serum of patients with Rheumatoid Arthritis (RA, n=50), Systemic Lupus Erythematosus (SLE, n=49), and Systemic Sclerosis (SSc, n=37). 45 novel autoantibodies were significantly (p ≤ 0.05) more prevalent in SjD than in HC and were detected in up to 19% of the SjD cohort. The most common autoantibodies were against CCL4, M5, TMPO and OAS3. Some of the novel autoantibodies were associated with extraglandular disease manifestations, such as anti-TONSL or anti-IL6 with pulmonary involvement. We have developed a three and five marker panel for the detection of Ro/SSA negative patients, consisting of anti-FNBP4, anti-SNRPC, anti-CCL4, anti-M3 and anti-KDM6B, which had a sensitivity of up to 46% with a specificity of 95% (SjD vs. HC). Both panels discriminate these patients from HC, whereas the three-marker more effectively differentiates between Ro/SSA negative patients and NSS. Novel autoantibodies will facilitate the diagnosis of Ro/SSA negative patients with SjD, in particular our predictive panel will be useful in the diagnosis and differentiation of these patients from healthy and NSS individuals in a clinical context. In addition, the autoantibodies may also be useful for risk stratification of extraglandular manifestations. Show less

In adult organisms, a number of receptors have been identified which modulate metabolic processes related to peptides derived from the intestinal tract. These receptors play significant roles in glucose homeostasis, food intake and energy balance. Here we assess these classical metabolic receptors and their expression as well as their potential role in early development of hypothalamic neuronal circuits. Chow-fed C57BL6/N female mice were mated and hypothalamic tissue was collected from offspring across postnatal development (postnatal day 7-21). Subsequent qPCR and Western Blot analyses were used to determine mRNA and protein changes in gut-derived peptide hormone receptors. Correlations to body weight, blood glucose and circulating leptin levels were analyzed. We describe the gene expression and dynamic protein regulation of key gut-derived peptide hormone receptors in the early postnatal period of the mouse brain. Specifically, we show changes to Gastric inhibitory polypeptide receptor (GIPR), glucagon-like peptide 1 receptor (GLP1R), and cholecystokinin receptor 2 (CCK2R) in the developing hypothalamus. The changes to GIPR and InsR seem to be strongly negatively correlated with body weight. This comprehensive analysis underscores the need to understand the roles of maternal-derived circulating gut hormones and their direct effect on offspring brain development. Show less

The brain renin-angiotensin system (RAS) is implicated in control of blood pressure (BP), fluid intake, and energy expenditure (EE). Angiotensin II (ANG II) within the arcuate nucleus of the hypothalamus contributes to control of resting metabolic rate (RMR) and thereby EE through its actions on Agouti-related peptide (AgRP) neurons, which also contribute to EE control by leptin. First, we determined that although leptin stimulates EE in control littermates, mice with transgenic activation of the brain RAS (sRA) exhibit increased EE and leptin has no additive effect to exaggerate EE in these mice. These findings led us to hypothesize that leptin and ANG II in the brain stimulate EE through a shared mechanism. Because AgRP signaling to the melanocortin MC Show less

In tuberculosis (TB), protective inflammatory immune responses and the pathological sequelae of chronic inflammation significantly depend on a timely balance of cytokine expression. In contrast to other anti-inflammatory cytokines, interleukin (IL)-27 has fundamental effects in experimental Show less

Effective targeting of metastasis is considered the main problem in cancer therapy. The development of herbal alkaloid Berberine (Ber)-based anticancer drugs is limited due to Ber' low effective concentration, poor membrane permeability, and short plasma half-life. To overcome these limitations, we used Ber noncovalently bound to C Show less

Neonatal heart failure is a rare, poorly-understood presentation of familial dilated cardiomyopathy (DCM). Exome sequencing in a neonate with severe DCM revealed a homozygous nonsense variant in leiomodin 2 ( Show less

Despite abundant evidence for pathogenicity of large copy number variants (CNVs) in neurodevelopmental disorders (NDDs), the individual significance of genome-wide rare CNVs <500 kb has not been well elucidated in a clinical context. By high-resolution chromosomal microarray analysis, we investigated the clinical significance of all rare non-polymorphic exonic CNVs sizing 1-500 kb in a cohort of 714 patients with undiagnosed NDDs. We detected 96 rare CNVs <500 kb affecting coding regions, of which 58 (60.4%) were confirmed. 6 of 14 confirmed de novo, one of two homozygous and four heterozygous inherited CNVs affected the known microdeletion regions 17q21.31, 16p11.2 and 2p21 or OMIM morbid genes (CASK, CREBBP, PAFAH1B1, SATB2; AUTS2, NRXN3, GRM8). Two further de novo CNVs affecting single genes (MED13L, CTNND2) were instrumental in delineating novel recurrent conditions. For the first time, we here report exonic deletions of CTNND2 causing low normal IQ with learning difficulties with or without autism spectrum disorder. Additionally, we discovered a homozygous out-of-frame deletion of ACOT7 associated with features comparable to the published mouse model. In total, 24.1% of the confirmed small CNVs were categorised as pathogenic or likely pathogenic (median size 130 kb), 17.2% as likely benign, 3.4% represented incidental findings and 55.2% remained unclear. These results verify the diagnostic relevance of genome-wide rare CNVs <500 kb, which were found pathogenic in ∼2% (14/714) of cases (1.1% de novo, 0.3% homozygous, 0.6% inherited) and highlight their inherent potential for discovery of new conditions. Show less

Apolipoprotein A-IV (apoA-IV), an intestinally and cerebrally synthesized satiety factor and anti-atherogenic plasma apolipoprotein, was recently identified as an anti-inflammatory protein. In order to elucidate whether intestinal apoA-IV exerts similar repair function as its hepatic homologue apolipoprotein A-V (apoA-V), apoA-IV-interactive proteins were searched and in vitro functional studies were performed with apoA-IV overexpressing cells. ApoA-IV was also analyzed in the intestinal mucosa of patients with inflammatory bowel diseases (IBD), together with other genes involved in epithelial junctional integrity. A yeast-two-hybrid screening was used to identify apoA-IV-interactors. ApoA-IV was overexpressed in Caco-2 and HT-29 mucosal cells for colocalization and in vitro epithelial permeability studies. Mucosal biopsies from quiescent regions of colon transversum and terminal ileum were subjected to DNA-microarray analysis and pathway-related data mining. Four proteins interacting with apoA-IV were identified, including apolipoprotein B-100, alpha1-antichymotrypsin, cyclin C, and the cytosolic adaptor alpha-catenin, thus linking apoA-IV to adherens junctions. Overexpression of apoA-IV was paralleled with a differentiated phenotype of intestinal epithelial cells, upregulation of junctional proteins, and decreased paracellular permeability. Colocalization between alpha-catenin and apoA-IV occurred exclusively in junctional complexes. ApoA-IV was downregulated in quiescent mucosal tissues from patients suffering from IBD. In parallel, only a distinct set of junctional genes was dysregulated in non-inflamed regions of IBD gut. ApoA-IV may act as a stabilizer of adherens junctions interacting with alpha-catenin, and is likely involved in the maintenance of junctional integrity. ApoA-IV expression is significantly impaired in IBD mucosa, even in non-inflamed regions. Show less