BMP Signaling Modulates Hepcidin Expression in Zebrafish Embryos Independent of Hemojuvelin

Hemojuvelin (Hjv), a member of the repulsive-guidance molecule (RGM) family, upregulates transcription of the iron regulatory hormone hepcidin by activating the bone morphogenetic protein (BMP) signaling pathway in mammalian cells. Mammalian models have identified furin, neogenin, and matriptase-2 as modifiers of Hjv's function. Using the zebrafish model, we evaluated the effects of hjv and its interacting proteins on hepcidin expression during embryonic development. We found that hjv is strongly expressed in the notochord and somites of the zebrafish embryo and that morpholino knockdown of hjv impaired the development of these structures. Knockdown of hjv or other hjv-related genes, including zebrafish orthologs of furin or neogenin, however, failed to decrease hepcidin expression relative to liver size. In contrast, overexpression of bmp2b or knockdown of matriptase-2 enhanced the intensity and extent of hepcidin expression in zebrafish embryos, but this occurred in an hjv-independent manner. Furthermore, we demonstrated that zebrafish hjv can activate the human hepcidin promoter and enhance BMP responsive gene expression in vitro, but is expressed at low levels in the zebrafish embryonic liver. Taken together, these data support an alternative mechanism for hepcidin regulation during zebrafish embryonic development, which is independent of hjv

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Phagocyte localization and function during organismal apoptosis and regeneration in botryllus schlosseri

Programmed cell death (PCD) is an important part in the development and maintenance of homeostasis in multicellular animals. We utilized the colonial marine urochordate Botryllus Schlosseri as a model system to investigate this process because it is an organism whose adult generation (zooids) cyclically undergoes massive PCD in all of its organs every 5 days at 21oC. Specialized blood phagocytes have previously been shown to play a major role in the clearance of apoptotic cell corpses during this death phase. Here, using fluorescence stereomicroscopy and laser-scanning confocal microscopy, we investigated phagocyte localization and function during colony homeostasis in Botryllus colonies via intravascular microinjection of fluorescent bioparticles and liposomes containing the phagocidal drug clodronate. Our findings indicate that both bioparticles and liposomes were rapidly targeted and engulfed within phagocytic cells localized within ventral islands of adult zooids. Knockdown of phagocyte function using clodronate liposomes further revealed that phagocytes were important throughout the blastogenic cycle of this animal, but most notably during the PCD phase. Clodronate colonies showed abnormalities consistent with phagocyte disruption. Using co-microinjection of liposomes and bioParticles, phagocyte populations were also observed to engulf foreign particles with different levels of specificity. The stationary endothelial cells only engulfed bioParticles, while migratory blood phagocytes ingested both types of particles. Collectively, our observations indicate that blood phagocytes are critical effectors in colony regeneration and homeostasis. Finally, in order to characterize molecular markers expressed in Botryllus phagocytic cell populations, a 180bp segment of a putative scavenger receptor homolog was also successfully isolated and amplified

6. Folge: Making us Matter

Ein Leader muss sich als Teil der Gruppe sehen und der Gruppe eine Identität anbieten, mit der sich die Follower gerne identifizieren. Um als ein solcher Leader aufzutreten, ist eine passend eingesetzte Rhetorik des Leaders von zentraler Bedeutung. Darüber hinaus ist die Realisierung der aufgebauten Identität wichtig dafür, als Leader auch langfristig anerkannt zu bleiben und zu beweisen, dass man am besten als der Leader geeignet ist, der die Gruppe an ihr Ziel führt

PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury

Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N-acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage.Dana-Farber Cancer InstituteHarvard Digestive Disease CenterMount Desert Island Biological Laboratory (Junior Investigator Award)American Cancer SocietyHarvard Stem Cell InstituteNational Institutes of Health (U.S.)National Institute of Diabetes and Digestive and Kidney Diseases (U.S.)National Cancer Institute (U.S.) (CA26731)Massachusetts Institute of Technology. Center for Environmental Health SciencesHoward Hughes Medical Institut

DATA FACT SHEETS of the Data Steward Service Center (DSSC) from the NFDI consortium FAIRagro

These data fact sheets introduce data types and provide an overview about typically used data in the agrosystem research community. Specifics regarding to research data management and where data can be found and published are elaborated for soil data, field data in general, genetic data ("omics-data"), phenotyping data, field robotics & sensor data and big geodata. We also lay out the legal framework for data use with specifics to our domain. FAIRagro is the agrosystem science consortium within the German National Research Data Infrastructure (NFDI), offering a helpdesk for any stages of the data life cycle

Genetic and functional analyses implicate microRNA 499A in bipolar disorder development

Bipolar disorder (BD) is a complex mood disorder with a strong genetic component. Recent studies suggest that microRNAs contribute to psychiatric disorder development. In BD, specific candidate microRNAs have been implicated, in particular miR-137, miR-499a, miR-708, miR-1908 and miR-2113. The aim of the present study was to determine the contribution of these five microRNAs to BD development. For this purpose, we performed: (i) gene-based tests of the five microRNA coding genes, using data from a large genome-wide association study of BD; (ii) gene-set analyses of predicted, brain-expressed target genes of the five microRNAs; (iii) resequencing of the five microRNA coding genes in 960 BD patients and 960 controls and (iv) in silico and functional studies for selected variants. Gene-based tests revealed a significant association with BD for MIR499A, MIR708, MIR1908 and MIR2113. Gene-set analyses revealed a significant enrichment of BD associations in the brain-expressed target genes of miR-137 and miR-499a-5p. Resequencing identified 32 distinct rare variants (minor allele frequency < 1%), all of which showed a non-significant numerical overrepresentation in BD patients compared to controls (p = 0.214). Seven rare variants were identified in the predicted stem-loop sequences of MIR499A and MIR2113. These included rs142927919 in MIR2113 (p(nom) = 0.331) and rs140486571 in MIR499A (p(nom) = 0.297). In silico analyses predicted that rs140486571 might alter the miR-499a secondary structure. Functional analyses showed that rs140486571 significantly affects miR-499a processing and expression. Our results suggest that MIR499A dysregulation might contribute to BD development. Further research is warranted to elucidate the contribution of the MIR499A regulated network to BD susceptibility.ISSN:2158-318