The Zebrafish (Danio rerio) Is a Relevant Model for Studying Sex-Specific Effects of 17β-Estradiol in the Adult Heart

Cardiovascular diseases are a major cause of morbidity and mortality, and there are significant sex differences therein. However, the underlying mechanisms are poorly understood. The steroid hormone 17β-estradiol (E2) is thought to play a major role in cardiovascular sex differences and to be protective, but this may not hold true for males. We aimed at assessing whether the zebrafish is an appropriate model for the study of E2 effects in the heart. We hypothesized that E2 regulates the cardiac contractility of adult zebrafish in a sex-specific manner. Male and female zebrafish were treated with vehicle (control) or E2 and the cardiac contractility was measured 0, 4, 7 and 14 days after treatment initiation using echocardiography. There was no significant effect on the heart rate by E2. Notably, there was a significant decrease in the ejection fraction of male zebrafish treated with E2 compared with controls. By contrast, there was no major difference in the ejection fraction between the two female groups. The dramatic effect in male zebrafish occurred as early as 4 days post treatment initiation. Although there was no significant difference in stroke volume and cardiac output between the two male groups, these were significantly higher in female zebrafish treated with E2 compared with controls. Gene expression analysis revealed that the levels of estrogen receptors were comparable among all groups. In conclusion, our data demonstrate that the adult zebrafish heart robustly responds to E2 and this occurs in a sex-specific manner. Given the benefits of using zebrafish as a model, new targets may be identified for the development of novel cardiovascular therapies for male and female patients. This would contribute towards the realization of personalized medicine

Orai1 deficiency leads to heart failure and skeletal myopathy in zebrafish.

Mutations in the store-operated Ca²⁺ entry pore protein ORAI1 have been reported to cause myopathies in human patients but the mechanism involved is not known. Cardiomyocytes express ORAI1 but its role in heart function is also unknown. Using reverse genetics in zebrafish, we demonstrated that inactivation of the highly conserved zebrafish orthologue of ORAI1 resulted in severe heart failure, reduced ventricular systolic function, bradycardia and skeletal muscle weakness. Electron microscopy of Orai1-deficient myocytes revealed progressive skeletal muscle instability with loss of myofiber integrity and ultrastructural abnormalities of the z-disc in both skeletal and cardiac muscle. Isolated Orai1-deficient cardiomyocytes showed loss of the calcineurin-associated protein calsarcin from the z-discs. Furthermore, we found mechanosignal transduction was affected in Orai1-depleted hearts, indicating an essential role for ORAI1 in establishing the cardiac signaling transduction machinery at the z-disc. Our findings identify ORAI1 as an important regulator of cardiac and skeletal muscle function and provide evidence linking ORAI1-mediated calcium signaling to sarcomere integrity and cardiomyocyte function

Southern Germany’s innovation clusters: regional growth coalitions in the knowledge economy

This paper examines Germany’s distinctive path toward the knowledge economy, emphasizing the role of regional innovation dynamics and governance, with a focus on Southern Germany’s high-innovation clusters. Unlike other advanced economies that pivoted toward high-tech services, Germany has prioritized digital advancements within its manufacturing base, creating a model driven by smart manufacturing and Industry 4.0. We argue that regional growth coalitions, formed by firms, social partners, and local governments, foster institutional configurations supporting knowledge-based and innovation-focused competition. This regionalized governance has enabled Southern Germany to capitalize on Germany’s innovation agenda, a success that other regions have struggled to replicate. By analysing multi-scalar dynamics—interactions across regional, national, and EU levels—our study expands evolutionary economic geography (EEG) and political economy literature, challenging traditional, nation-centric frameworks. Our findings highlight that cohesive regional governance can enhance national and supranational innovation strategies, underscoring the importance of regional institutions in advancing and sustaining knowledge economy innovation

Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram

BACKGROUND: Sympathetic nerve activity is important to cardiac arrhythmogenesis. OBJECTIVE: The purpose of this study was to develop a method for simultaneous noninvasive recording of skin sympathetic nerve activity (SKNA) and electrocardiogram (ECG) using conventional ECG electrodes. This method (neuECG) can be used to adequately estimate sympathetic tone. METHODS: We recorded neuECG signals from the skin of 56 human subjects. The signals were low-pass filtered to show the ECG and high-pass filtered to show nerve activity. Protocol 1 included 12 healthy volunteers who underwent cold water pressor test and Valsalva maneuver. Protocol 2 included 19 inpatients with epilepsy but without known heart diseases monitored for 24 hours. Protocol 3 included 22 patients admitted with electrical storm and monitored for 39.0 ± 28.2 hours. Protocol 4 included 3 patients who underwent bilateral stellate ganglion blockade with lidocaine injection. RESULTS: In patients without heart diseases, spontaneous nerve discharges were frequently observed at baseline and were associated with heart rate acceleration. SKNA recorded from chest leads (V1-V6) during cold water pressor test and Valsalva maneuver (protocol 1) was invariably higher than during baseline and recovery periods (P < .001). In protocol 2, the average SKNA correlated with heart rate acceleration (r = 0.73 ± 0.14, P < .05) and shortening of QT interval (P < .001). Among 146 spontaneous ventricular tachycardia episodes recorded in 9 patients of protocol 3, 106 episodes (73%) were preceded by SKNA within 30 seconds of onset. Protocol 4 showed that bilateral stellate ganglia blockade by lidocaine inhibited SKNA. CONCLUSION: SKNA is detectable using conventional ECG electrodes in humans and may be useful in estimating sympathetic tone

Left Cervical Vagal Nerve Stimulation Reduces Skin Sympathetic Nerve Activity in Patients with Drug Resistant Epilepsy

Background We recently reported that skin sympathetic nerve activity (SKNA) can be used to estimate sympathetic tone in humans. In animal models, vagal nerve stimulation (VNS) can damage the stellate ganglion, reduce stellate ganglion nerve activity, and suppress cardiac arrhythmia. Whether VNS can suppress sympathetic tone in humans remains unclear. Objective The purpose of this study was to test the hypothesis that VNS suppresses SKNA in patients with drug-resistant epilepsy. Methods ECG patch electrodes were used to continuously record SKNA in 26 patients with drug-resistant epilepsy who were admitted for video electroencephalographic monitoring. Among them, 6 (2 men, age 40 ± 11 years) were previously treated with VNS and 20 (7 men, age 37 ± 8 years) were not. The signals from ECG leads I and II were filtered to detect SKNA. Results VNS had an on-time of 30 seconds and off-time of 158 ± 72 seconds, with output of 1.92 ± 0.42 mA at 24.17 ± 2.01 Hz. Average SKNA during VNS off-time was 1.06 μV (95% confidence interval [CI] 0.93–1.18) in lead I and 1.13 μV (95% CI 0.99–1.27) in lead II, which was significantly lower than 1.38 μV (95% CI 1.01–1.75; P = .036) and 1.38 μV (95% CI 0.98–1.78; P = .035) in the control group, respectively. Heart rate was 65 bpm (95% CI 59–71) in the VNS group, which was significantly lower than 77 bpm (95% CI 71–83) in the control group. Conclusion Patients with VNS had significantly lower SKNA than those without VNS

How does microclimate affect the growth of the rare liverwort Scapania nimbosa?

Vegetative growth of bryophytes is dependent on water and will stop as soon as the plants dry out. The growth rate depends on the quality of the micro-habitat. Clonal growth and dispersal of plant fragments are important parameters to understand local distribution of bryophytes lacking spore and gemmae production. Species of the mixed northern hepatic mat mainly rely on plant fragments and vegetative growth to disperse and maintain local populations. Understanding a species’ means for population maintenance and dispersal potential is important for a successful management. This study aims to investigate the micro-scale climatic requirements and growth rate of the mixed northern hepatic mat species Scapania nimbosa through measuring its growth in situ in Norway, and through comparison of micro-climate between presence localities and seemingly suitable absence localities. The results show that S. nimbosa grows approximately 4.38-2.78 mm during one growing season. No difference in micro-climate was found between the presence and absence localities, suggesting that S. nimbosa is limited by dispersal, not by suitable habitats. The availability of suitable habitat, and the ability to identify these, opens up the possibility to expand its range through transplantation of plant fragments.publishedVersion© 2017 The Authors. This is an Open Access article. This work is licensed under the terms of a Creative Commons Attribution 4.0 International License (CC-BY) . The license permits use, distribution and reproduction in any medium, provided the original work is properly cited

Typification of Jungermannia pinguis L. (Marchantiophyta, Aneuraceae)

publishedVersio

What lies beneath: Hydra provides cnidarian perspectives into the evolution of FGFR docking proteins

Across the Bilateria, FGF/FGFR signaling is critical for normal development, and in both Drosophila and vertebrates, docking proteins are required to connect activated FGFRs with downstream pathways. While vertebrates use Frs2 to dock FGFR to the RAS/MAPK or PI3K pathways, the unrelated protein, downstream of FGFR (Dof/stumps/heartbroken), fulfills the corresponding function in Drosophila. To better understand the evolution of the signaling pathway downstream of FGFR, the available sequence databases were screened to identify Frs2, Dof, and other key pathway components in phyla that diverged early in animal evolution. While Frs2 homologues were detected only in members of the Bilateria, canonical Dof sequences (containing Dof, ankyrin, and SH2/SH3 domains) were present in cnidarians as well as bilaterians (but not in other animals or holozoans), correlating with the appearance of FGFR. Although these data suggested that Dof coupling might be ancestral, gene expression analysis in the cnidarian Hydra revealed that Dof is not upregulated in the zone of strong FGFRa and FGFRb expression at the bud base, where FGFR signaling controls detachment. In contrast, transcripts encoding other, known elements of FGFR signaling in Bilateria, namely the FGFR adaptors Grb2 and Crkl, which are acting downstream of Dof (and Frs2), as well as the guanyl nucleotide exchange factor Sos, and the tyrosine phosphatase Csw/Shp2, were strongly upregulated at the bud base. Our expression analysis, thus, identified transcriptional upregulation of known elements of FGFR signaling at the Hydra bud base indicating a highly conserved toolkit. Lack of transcriptional Dof upregulation raises the interesting question, whether Hydra FGFR signaling requires either of the docking proteins known from Bilateria

Is interspecific gene flow and speciation in peatmosses (Sphagnum) constrained by phylogenetic relationship and life-history traits?

Peatmosses are interesting for studies of speciation processes not only because of their frequent hybridization and recent diversification, but also their phenotypic diversity, ecological importance and ancient history. Diverse and widespread hybridization has been widely documented in the genus, but little is known about what factors underlie this phenomenon. We hypothesize that these factors include phylogenetic distance and variation in life-history traits of parental species. We summarize current knowledge about the occurrence of hybridization in peatmosses and explore how it is associated with phylogenetic distance and life-history trait variation of parental species. Possibly as much as one out of five (or more) peatmoss species hybridize, mostly producing allopolyploid hybrids. Parents of admixed haploids are more closely related to each other than parents of allopolyploids. Hybridization seems to be most frequent in 1) monoicous and polyoicous species exhibiting 2) relatively high sporulation frequency, 3) producing relatively small spores, as well as 4) growing in poor habitats. Surprisingly, neither phylogenetic proximity nor life-history trait variation explain patterns of hybridization in peatmosses, and other likely explanations for patterns observed are discussed.publishedVersion© 2018 The Authors. This work is licensed under the terms of a Creative Commons Attribution 4.0 International License (CC-BY