Effect of flosulide, a selective cyclooxygenase 2 inhibitor, on passive Heymann nephritis in the rat

Effect of flosulide, a selective cyclooxygenase 2 inhibitor, on passive Heymann nephritis in the rat.BackgroundNonsteroidal anti-inflammatory drugs (NSAIDs) induce an inhibition of cyclooxygenase (COX), an enzyme that makes prostaglandins. Two isoforms of COX exist: COX-1 represents the constitutively expressed enzyme, whereas COX-2 is the inducible isoform. This study investigated the role of COX-2 in the inflammatory processes of the kidneys of rats with passive Heymann nephritis (PHN), and focused of the effect of a selective COX-2 inhibitor, flosulide. COX-2–selective inhibitors are thought to represent potent anti-inflammatory agents without major renal side effects.MethodsPHN was induced by injecting heterologous Fx1A antiserum into female Wistar rats. Two treatment groups, each consisting of 12 rats with PHN, received either 3 or 9 mg of flosulide/kg body wt/day and were compared with untreated controls. After four weeks, the generation of thromboxane B2 (TxB2) and 6-keto-PGF1α were determined in renal tissue and in urine. COX-2 protein expression was investigated by Western blotting using a selective antibody.ResultsRats with PHN exhibited a marked proteinuria of 71 ± 8 mg/24 hr as compared with 2.0 ± 0.3 mg/24 hr in healthy controls (P < 0.01). Treatment with flosulide reduced the proteinuria to 26.1 ± 9 mg/24 hr at 3 mg flosulide/kg body wt/day and 35.5 ± 6 mg/24 hr at 9 mg/kg body wt/day, which was equivalent to a reduction of proteinuria by a maximum of 65% (P < 0.05). This was accompanied by an increase in glomerular TxB2 from 3073 ± 355 to 5255 ± 1041 pg/mg glomerular protein and 6-keto-PGF1α from 1702 ± 161 to 2724 ± 770 pg/mg glomerular protein in rats with PHN. COX-2 protein expression was also highly elevated in comparison to healthy controls. Low-dose flosulide treatment had no effect on COX protein expression and renal prostaglandin formation. High-dose flosulide treatment reduced renal prostaglandin production and caused a marked decline in COX-1 and COX-2 protein expression. Urine prostanoid excretion remained unchanged in all therapeutic groups. There was a small though significant reduction in renal creatinine clearance from 0.86 ml ± 0.2/min in untreated controls to 0.6 ml ± 0.1/min in flosulide-treated rats with PHN (P < 0.01) after four weeks.ConclusionsUnder the influence of flosulide, a highly COX-2–selective inhibitor, we observed an antiproteinuric drug effect. The inflammation in PHN induced COX-2 protein expression that was not affected by low-dose flosulide. COX-1 and COX-2 protein expression was affected by high-dose flosulide, which therefore might lose its selectivity. High-dose flosulide induced a decrease in glomerular prostanoid production possibly because of COX-1 inhibition. Our results suggest that the therapeutic use of flosulide in proteinuria seems advantageous and deserves further studies because the basal prostaglandin levels remain unchanged in the low-dose–treated group, indicating that the compensatory capacity of prostaglandin production, which is essential for the regulation of renal hemodynamics, is maintained

The role of clathrin in post-golgi trafficking in toxoplasma gondii

Apicomplexan parasites are single eukaryotic cells with a highly polarised secretory system that contains unique secretory organelles (micronemes and rhoptries) that are required for host cell invasion. In contrast, the role of the endosomal system is poorly understood in these parasites. With many typical endocytic factors missing, we speculated that endocytosis depends exclusively on a clathrin-mediated mechanism. Intriguingly, in Toxoplasma gondii we were only able to observe the endogenous clathrin heavy chain 1 (CHC1) at the Golgi, but not at the parasite surface. For the functional characterisation of Toxoplasma gondii CHC1 we generated parasite mutants conditionally expressing the dominant negative clathrin Hub fragment and demonstrate that CHC1 is essential for vesicle formation at the trans-Golgi network. Consequently, the functional ablation of CHC1 results in Golgi aberrations, a block in the biogenesis of the unique secretory microneme and rhoptry organelles, and of the pellicle. However, we found no morphological evidence for clathrin mediating endocytosis in these parasites and speculate that they remodelled their vesicular trafficking system to adapt to an intracellular lifestyle

COSMOS-Europe : a European network of cosmic-ray neutron soil moisture sensors

We thank TERENO (Terrestrial Environmental Observatories), funded by the Helmholtz-Gemeinschaft for the financing and maintenance of CRNS stations. We acknowledge financial support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) of the research unit FOR 2694 Cosmic Sense (grant no. 357874777) and by the German Federal Ministry of Education of the Research BioökonomieREVIER, Digitales Geosystem – Rheinisches Revier project (grant no. 031B0918A). COSMOS-UK has been supported financially by the UK’s Natural Environment Research Council (grant no. NE/R016429/1). The Olocau experimental watershed is partially supported by the Spanish Ministry of Science and Innovation through the research project TETISCHANGE (grant no. RTI2018-093717-BI00). The Calderona experimental site is partially supported by the Spanish Ministry of Science and Innovation through the research projects CEHYRFO-MED (grant no. CGL2017-86839- C3-2-R) and SILVADAPT.NET (grant no. RED2018-102719-T) and the LIFE project RESILIENT FORESTS (grant no. LIFE17 CCA/ES/000063). The University of Bristol’s Sheepdrove sites have been supported by the UK’s Natural Environment Research Council through a number of projects (grant nos. NE/M003086/1, NE/R004897/1, and NE/T005645/1) and by the International Atomic Energy Agency of the United Nations (grant no. CRP D12014). Acknowledgements. We thank Peter Strauss and Gerhab Rab from the Institute for Land and Water Management Research, Federal Agency for Water Management Austria, Petzenkirchen, Austria. We thank Trenton Franz from the School of Natural Resources, University of Nebraska–Lincoln, Lincoln, NE, United States. We also thank Carmen Zengerle, Mandy Kasner, Felix Pohl, and Solveig Landmark, UFZ Leipzig, for supporting field calibration, lab analysis, and data processing. We furthermore thank Daniel Dolfus, Marius Schmidt, Ansgar Weuthen, and Bernd Schilling, Forschungszentrum Jülich, Germany. The COSMOS-UK project team is thanked for making its data available to COSMOS-Europe. Luca Stevanato is thanked for the technical details about the Finapp sensor. The stations at Cunnersdorf, Lindenberg, and Harzgerode have been supported by Falk Böttcher, Frank Beyrich, and Petra Fude, German Weather Service (DWD). The Zerbst site has been supported by Getec Green Energy GmbH and Jörg Kachelmann (Meteologix AG). The CESBIO sites have been supported by the CNES TOSCA program. The ERA5-Land data are provided by ECMWF (Muñoz Sabater, 2021). The Jena dataset was retrieved at the site of The Jena Experiment, operated by DFG research unit FOR 1451.Peer reviewedPublisher PD

Traces of trauma – a multivariate pattern analysis of childhood trauma, brain structure and clinical phenotypes

Background: Childhood trauma (CT) is a major yet elusive psychiatric risk factor, whose multidimensional conceptualization and heterogeneous effects on brain morphology might demand advanced mathematical modeling. Therefore, we present an unsupervised machine learning approach to characterize the clinical and neuroanatomical complexity of CT in a larger, transdiagnostic context. Methods: We used a multicenter European cohort of 1076 female and male individuals (discovery: n = 649; replication: n = 427) comprising young, minimally medicated patients with clinical high-risk states for psychosis; patients with recent-onset depression or psychosis; and healthy volunteers. We employed multivariate sparse partial least squares analysis to detect parsimonious associations between combinations of items from the Childhood Trauma Questionnaire and gray matter volume and tested their generalizability via nested cross-validation as well as via external validation. We investigated the associations of these CT signatures with state (functioning, depressivity, quality of life), trait (personality), and sociodemographic levels. Results: We discovered signatures of age-dependent sexual abuse and sex-dependent physical and sexual abuse, as well as emotional trauma, which projected onto gray matter volume patterns in prefronto-cerebellar, limbic, and sensory networks. These signatures were associated with predominantly impaired clinical state- and trait-level phenotypes, while pointing toward an interaction between sexual abuse, age, urbanicity, and education. We validated the clinical profiles for all three CT signatures in the replication sample. Conclusions: Our results suggest distinct multilayered associations between partially age- and sex-dependent patterns of CT, distributed neuroanatomical networks, and clinical profiles. Hence, our study highlights how machine learning approaches can shape future, more fine-grained CT research