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Seit den letzten Jahrzehnten rückte die chemische Gruppe der PFAS (Per- und Polyfluorierte Alkylsubstanzen) in den Fokus der Wissenschaft. PFAS gelangen durch Industrieprozesse, unsachgemäße Handhabung und Produktverwendungen in die Umwelt und stellen dort eine Gefahr für die Gesundheit von Lebewesen dar. Die Erforschung des Verhaltens von PFAS im Boden und deren Modellierung ist erforderlich, um Langzeitrisiken abschätzen zu können. In vergangenen Modellierungsstudien wurde bereits festgestellt, dass neben den bekannten reversiblen Sorptionsprozessen weitere Bindungsvorgänge im Boden (irreversible Adsorption, Sorption an Grenzflächen), stattfinden müssen. Die irreversible Sorption wird innerhalb von PROSPeCT in diePFAS-Modellierung integriert.

An increase in pulmonary artery pressure is a common observation in adult mammals exposed to global alveolar hypoxia. It is considered a maladaptive response that places an increased workload on the right ventricle. The mechanisms initiating and maintaining the elevated pressure are of considerable interest in understanding pulmonary vascular homeostasis. There is an expectation that identifying the key molecules in the integrated vascular response to hypoxia will inform potential drug targets. One strategy is to take advantage of experiments of nature, specifically, to understand the genetic basis for the inter-individual variation in the pulmonary vascular response to acute and chronic hypoxia. To date, detailed phenotyping of highlanders has focused on haematocrit and oxygen saturation rather than cardiovascular phenotypes. This review explores what we can learn from those studies with respect to the pulmonary circulation.

Fragile X syndrome is one of the most common genetic causes of mental retardation, yet the mechanisms controlling expression of the fragile X mental retardation gene FMR1 are poorly understood. To identify sequences regulating FMR1 transcription, transgenic mouse lines were established using a fusion gene consisting of an E.coli β-galactosidase reporter gene (lacZ) linked to a 2.8 kb fragment spanning the 5′-region of FMR1. Five transgenic mouse lines showed lacZ expression in brain, in particular in neurons of the hippocampus and the granular layer of the cerebellum. Expression of the reporter gene was also detected in Leydig cells and spermatogonia in the testis, in many epithelia of adult mice, and in the two other steroidogenic cell types, adrenal cortex cells and ovarian follicle cells. Embryonic tissues which showed strong activity of the reporter gene included the telencephalon, the genital ridge, and the notochord. This expression pattern closely resembles the endogenous one, indicating that the 5′ FMR1 gene promoter region used in this study contains most cis-acting elements regulating FMR1 transcription

Louise Ostergaard,1,2,* Alain Rudiger,3,* Sven Wellmann,2,4,5 Elena Gammella,6 Beatrice Beck-Schimmer,2,3 Joachim Struck,7 Marco Maggiorini,2,8 Max Gassmann,1,2,9 1Institute of Veterinary Physiology, Vetsuisse Faculty, University of Zürich, 2Zürich Center for Integrative Human Physiology, 3Institute of Anesthesiology, 4Division of Neonatology, University Hospital Zürich, Zürich, 5Department of Neonatology, University Children's Hospital Basel, Basel, Switzerland; 6Department of Human Morphology and Biomedical Science, University of Milan, Milan, Italy; 7Research Department, B•R•A•H•M•S Biomarkers, Thermo Fisher Scientific, Hennigsdorf, Germany; 8Medical Intensive Care Unit, University Hospital Zürich, Zürich, Switzerland; 9Universidad Peruana Cayetano Heredia, Lima, Peru *These authors contributed equally to this work and share first authorship Background: A reduced oxygen supply puts patients at risk of tissue hypoxia, organ damage, and even death. In response, several changes are activated that allow for at least partial adaptation, thereby increasing the chances of survival. We aimed to investigate whether the arginine vasopressin marker, copeptin, can be used as a marker of the degree of acclimatization/adaptation in rats exposed to hypoxia. Methods: Sprague-Dawley rats were exposed to 10% oxygen for up to 48 hours. Arterial and right ventricular pressures were measured, and blood gas analysis was performed at set time points. Pulmonary changes were investigated by bronchoalveolar lavage, wet and dry weight measurements, and lung histology. Using a newly developed specific rat copeptin luminescence immunoassay, the regulation of vasopressin in response to hypoxia was studied, as was atrial natriuretic peptide (ANP) by detecting mid-regional proANP. Results: With a decreasing oxygen supply, the rats rapidly became cyanotic and inactive. Despite continued exposure to 10% oxygen, all animals recuperated within 16 hours and ultimately survived. Their systemic blood pressure fell with acute (5 minutes) hypoxia but was partially recovered over time. In contrast, right ventricular pressures increased with acute (5 minutes) hypoxia and normalized after 16 hours. No signs of pulmonary inflammation or edema were found despite prolonged hypoxia. Whereas copeptin levels increased significantly after acute (5 minutes) hypoxia and then returned to near baseline after 16 hours, mid-regional proANP levels were even further increased after 16 hours of exposure to hypoxia. Conclusion: Plasma copeptin is a sensitive marker of acute (5 minutes) exposure to severe hypoxia, and subsequent regulation can indicate recovery. Copeptin levels can therefore reflect clinical and physiological changes in response to hypoxia and indicate recovery from ongoing hypoxic exposure. Keywords: vasoactive peptides, hypoxia, copeptin, atrial natriuretic peptide, acclimatization, adaptation, critical illness

PURPOSE: To identify the mutation responsible for an abnormal electroretinogram (ERG) in a transgenic mouse line (tg21) overexpressing erythropoietin (Epo). The tg21 line was generated on a mixed (C3H; C57BL/6) background and lacked the b-wave component of the ERG. This no-b-wave (nob) ERG is seen in other mouse models with depolarizing bipolar cell (DBC) dysfunction and in patients with the complete form of congenital stationary night blindness (cCSNB). We determined the basis for the nob ERG phenotype and screened C3H mice for the mutation to evaluate whether this finding is important for the vision research community. METHODS: ERGs were used to examine retinal function. The retinal structure of the transgenic mice was investigated using histology and immunohistochemistry. Inverse PCR was performed to identify the insertion site of the Epo transgene in the mouse genome. Affected mice were backcrossed to follow the inheritance pattern of the nob ERG phenotype. Quantitative real-time PCR (qRT PCR), Sanger sequencing, and immunohistochemistry were used to identify the mutation causing the defect. Additional C3H sublines were screened for the detected mutation. RESULTS: Retinal histology and blood vessel structure were not disturbed, and no loss of DBCs was observed in the tg21 nob mice. The mutation causing the nob ERG phenotype is inherited independently of the tg21 transgene. The qRT PCR experiments revealed that the nob ERG phenotype reflected a mutation in Gpr179, a gene involved in DBC signal transduction. PCR analysis confirmed the presence of the Gpr179(nob5) insertional mutation in intron 1 of Gpr179. Screening for mutations in other C3H-derived lines revealed that C3H.Pde6b(+) mice carry the Gpr179 (nob5) allele whereas C3H/HeH mice do not. CONCLUSIONS: We identified the presence of the Gpr179(nob5) mutation causing DBC dysfunction in a C3H-derived transgenic mouse line. The nob phenotype is not related to the presence of the transgene. The Gpr179(nob5) allele can be added to the list of background alleles that impact retinal function in commonly used mouse lines. By providing primers to distinguish between Gpr179 mutant and wild-type alleles, this study allows investigators to monitor for the presence of the Gpr179(nob5) mutation in other mouse lines derived from C3H.

holecystokinin expressing interneurons (CCK INs) mediate behavior state dependent inhibition in cortical circuits and themselves receive strong GABAergic input. However it remains unclear to what extent GABABreceptors (GABABRs) contribute to their inhibitory control. Using immunoelectron microscopy we found that CCK INs in the rat hippocampus possessed high levels of dendritic GABABRs and KCTD12 auxiliary proteins whereas postsynaptic effector Kir3 channels were present at lower levels. Consistently whole cell recordings revealed slow GABABR mediated inhibitory postsynaptic currents (IPSCs) in most CCK INs. In spite of the higher surface density of GABABRs in CCK INs than in CA1 principal cells the amplitudes of IPSCs were comparable suggesting that the expression of Kir3 channels is the limiting factor for the GABABR currents in these INs. Morphological analysis showed that CCK INs were diverse comprising perisomatic targeting basket cells (BCs) as well as dendrite targeting (DT) interneurons including a previously undescribed DT type. GABABR mediated IPSCs in CCK INs were large in BCs but small in DT subtypes. In response to prolonged activation GABABR mediated currents displayed strong desensitization which was absent in KCTD12 deficient mice. This study highlights that GABABRs differentially control CCK IN subtypes and the kinetics and desensitization of GABABR mediated currents are modulated by KCTD12 proteins.

Gamma aminobutyric acid (GABA) the major inhibitory neurotransmitter in the brain is fundamental to brain function and implicated in the pathophysiology of several neuropsychiatric disorders. GABA activates G protein coupled GABAB receptors comprising principal GABAB1 and GABAB2 subunits as well as auxiliary KCTD8 12 12b and 16 subunits. The KCTD12 gene has been associated with bipolar disorder major depressive disorder and schizophrenia. Here we compare Kctd12 null mutant (Kctd12-/-) and heterozygous (Kctd12+/-) with wild type (WT) littermate mice to determine whether lack of or reduced KCTD12 expression leads to phenotypes that extrapolating to human could constitute endophenotypes for neuropsychiatric disorders with which KCTD12 is associated. Kctd12-/- mice exhibited increased fear learning but not increased memory of a discrete auditory conditioned stimulus. Kctd12+/- mice showed increased activity during the inactive (light) phase of the circadian cycle relative to WT and Kctd12-/- mice. Electrophysiological recordings from hippocampal slices a region of high Kctd12 expression revealed an increased intrinsic excitability of pyramidal neurons in Kctd12-/- and Kctd12+/- mice. This is the first direct evidence for involvement of KCTD12 in determining phenotypes of emotionality behavioral activity and neuronal excitability. This study provides empirical support for the polymorphism and expression evidence that KCTD12 confers risk for and is associated with neuropsychiatric disorders.