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Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients
Fontanes Medien
(2023)
Theodor Fontane war, im durchaus modernen Sinne, ein Medienarbeiter: Als Presse-Agent in London lernte er die innovativste Presselandschaft seiner Zeit kennen; als Redakteur in Berlin leistete er journalistische Kärrnerarbeit; er schrieb Kritiken über das Theater, die bildende Kunst und die Literatur – und auch seine Romane wie seine Reisebücher sind stets Medienprodukte, als Serien in in Zeitungen und Zeitschriften platziert, bevor sie auf dem Buchmarkt erschienen.
Der vorliegende Band dokumentiert die Ergebnisse eines internationalen Kongresses, veranstaltet 2019 vom Theodor-Fontane-Archiv in Potsdam. Die ebenso rasante wie umfassende Medialisierung und Vernetzung der Gesellschaft im Laufe des 19. Jahrhunderts wird dabei als produktive Voraussetzung der schriftstellerischen Tätigkeit Fontanes begriffen. Eingebettet in ein weit verzweigtes Netz der Korrespondenz und der postalischen Textzirkulation, vertraut mit den Routinen und Publika der periodischen Massenpresse, für die er sein Leben lang schrieb, und auf vielfältige Weise geprägt von der visuellen Kultur seiner Zeit wird Theodor Fontane als gleichermaßen journalistisch versierter wie ästhetisch sensibler Grenzgänger erkennbar.
The poly(A) tail at 3’ ends of eukaryotic mRNAs promotes their nuclear export, stability and translational efficiency, and changes in its length can strongly impact gene expression. The Arabidopsis thaliana genome encodes three canonical nuclear poly(A) polymerases, PAPS1, PAPS2 and PAPS4. As shown by their different mutant phenotypes, these three isoforms are functionally specialized, with PAPS1 modifying organ growth and suppressing a constitutive immune response. However, the molecular basis of this specialization is largely unknown. Here, we have estimated poly(A)-tail lengths on a transcriptome-wide scale in wild-type and paps1 mutants. This identified categories of genes as particularly strongly affected in paps1 mutants, including genes encoding ribosomal proteins, cell-division factors and major carbohydrate-metabolic proteins. We experimentally verified two novel functions of PAPS1 in ribosome biogenesis and redox homoeostasis that were predicted based on the analysis of poly(A)-tail length changes in paps1 mutants. When overlaying the PAPS1-dependent effects observed here with coexpression analysis based on independent microarray data, the two clusters of transcripts that are most closely coexpressed with PAPS1 show the strongest change in poly(A)-tail length and transcript abundance in paps1 mutants in our analysis. This suggests that their coexpression reflects at least partly the preferential polyadenylation of these transcripts by PAPS1 versus the other two poly(A)-polymerase isoforms. Thus, transcriptome-wide analysis of poly(A)-tail lengths identifies novel biological functions and likely target transcripts for polyadenylation by PAPS1. Data integration with large-scale co-expression data suggests that changes in the relative activities of the isoforms are used as an endogenous mechanism to co-ordinately modulate plant gene expression.
This longitudinal study of N = 1,566 adolescents investigated the protective role of optimism in adjustment to parental separation, focusing on two salient challenges faced by adolescents, namely academic achievement and self-esteem. Based on latent change models, the results indicated associations between parental separation and short-term declines in academic achievement as well as short-term and longer term declines in self-esteem. Although optimism in general showed positive associations with academic achievement and self-esteem, its role as a protective factor proved to be particularly important for academic achievement in adjustment following parental separation.
Background: Functional abdominal pain (FAP) is not only a highly prevalent disease but also poses a considerable burden on children and their families. Untreated, FAP is highly persistent until adulthood, also leading to an increased risk of psychiatric disorders. Intervention studies underscore the efficacy of cognitive behavioral treatment approaches but are limited in terms of sample size, long-term follow-up data, controls and inclusion of psychosocial outcome data.
Methods/Design: In a multicenter randomized controlled trial, 112 children aged 7 to 12 years who fulfill the Rome III criteria for FAP will be allocated to an established cognitive behavioral training program for children with FAP (n = 56) or to an active control group (focusing on age-appropriate information delivery; n = 56). Randomization occurs centrally, blockwise and is stratified by center. This study is performed in five pediatric gastroenterology outpatient departments. Observer-blind assessments of outcome variables take place four times: pre-, post-, 3- and 12-months post-treatment. Primary outcome is the course of pain intensity and frequency. Secondary endpoints are health-related quality of life, pain-related coping and cognitions, as well as selfefficacy.
Discussion: This confirmatory randomized controlled clinical trial evaluates the efficacy of a cognitive behavioral intervention for children with FAP. By applying an active control group, time and attention processes can be controlled, and long-term follow-up data over the course of one year can be explored.