Cross-Sectional Associations between Homoarginine, Intermediate Phenotypes, and Atrial Fibrillation in the CommunityThe Gutenberg Health Study

Homoarginine has come into the focus of interest as a biomarker for cardiovascular disease. Atrial fibrillation (AF) causes a substantial increase in morbidity and mortality. Whether circulating homoarginine is associated with occurrence or persistence of AF and may serve as a new predictive biomarker remains unknown. We measured plasma levels of homoarginine in the population-based Gutenberg health study (3761 patients included, of them 51.7% males), mean age 55.6 +/- 10.9 years-old. Associations between homoarginine and intermediate electrocardiographic and echocardiographic phenotypes and manifest AF were examined. Patients with AF (124 patients, of them 73.4% males) had a mean age 64.8 +/- 8.6 years-old compared to a mean age of 55.3 +/- 10.9 in the population without AF (p-value < 0.001) and showed a less beneficial risk factor profile. The median homoarginine levels in individuals with and without AF were 1.9 mol/L (interquartile range (IQR) 1.5-2.5) and 2.0 mol/L (IQR 1.5-2.5), respectively, p = 0.56. In multivariable-adjusted regression analyses homoarginine was not statistically significantly related to electrocardiographic variables. Among echocardiographic variables beta per standard deviation increase was -0.12 (95% confidence interval (CI) -0.23-(-0.02);p = 0.024) for left atrial area and -0.01 (95% CI -0.02-(-0.003);p = 0.013) for E/A ratio. The odds ratio between homoarginine and AF was 0.91 (95% CI 0.70-1.16;p = 0.45). In our large, population-based cross-sectional study, we did not find statistically significant correlations between lower homoarginine levels and occurrence or persistence of AF or most standard electrocardiographic phenotypes, but some moderate inverse associations with echocardiographic left atrial size and E/A. Homoarginine may not represent a strong biomarker to identify individuals at increased risk for AF. Further investigations will be needed to elucidate the role of homoarginine and cardiac function

Efficacy and safety of baricitinib or ravulizumab in adult patients with severe COVID-19 (TACTIC-R): a randomised, parallel-arm, open-label, phase 4 trial

Background From early in the COVID-19 pandemic, evidence suggested a role for cytokine dysregulation and complement activation in severe disease. In the TACTIC-R trial, we evaluated the efficacy and safety of baricitinib, an inhibitor of Janus kinase 1 (JAK1) and JAK2, and ravulizumab, a monoclonal inhibitor of complement C5 activation, as an adjunct to standard of care for the treatment of adult patients hospitalised with COVID-19. Methods TACTIC-R was a phase 4, randomised, parallel-arm, open-label platform trial that was undertaken in the UK with urgent public health designation to assess the potential of repurposing immunosuppressants for the treatment of severe COVID-19, stratified by a risk score. Adult participants (aged ≥18 years) were enrolled from 22 hospitals across the UK. Patients with a risk score indicating a 40% risk of admission to an intensive care unit or death were randomly assigned 1:1:1 to standard of care alone, standard of care with baricitinib, or standard of care with ravulizumab. The composite primary outcome was the time from randomisation to incidence (up to and including day 14) of the first event of death, invasive mechanical ventilation, extracorporeal membrane oxygenation, cardiovascular organ support, or renal failure. The primary interim analysis was triggered when 125 patient datasets were available up to day 14 in each study group and we included in the analysis all participants who were randomly assigned. The trial was registered on ClinicalTrials.gov (NCT04390464). Findings Between May 8, 2020, and May 7, 2021, 417 participants were recruited and randomly assigned to standard of care alone (145 patients), baricitinib (137 patients), or ravulizumab (135 patients). Only 54 (39%) of 137 patients in the baricitinib group received the maximum 14-day course, whereas 132 (98%) of 135 patients in the ravulizumab group received the intended dose. The trial was stopped after the primary interim analysis on grounds of futility. The estimated hazard ratio (HR) for reaching the composite primary endpoint was 1·11 (95% CI 0·62–1·99) for patients on baricitinib compared with standard of care alone, and 1·53 (0·88–2·67) for ravulizumab compared with standard of care alone. 45 serious adverse events (21 deaths) were reported in the standard-of-care group, 57 (24 deaths) in the baricitinib group, and 60 (18 deaths) in the ravulizumab group. Interpretation Neither baricitinib nor ravulizumab, as administered in this study, was effective in reducing disease severity in patients selected for severe COVID-19. Safety was similar between treatments and standard of care. The short period of dosing with baricitinib might explain the discrepancy between our findings and those of other trials. The therapeutic potential of targeting complement C5 activation product C5a, rather than the cleavage of C5, warrants further evaluation

Strukturelle und funktionelle Untersuchungen am Herztroponin in Abhängigkeit des Herztroponin I-Phosphorylierungszustandes

Das heterotrimere Herztroponin (cTnT, cTnI, cTnC) moduliert den Kontraktionsprozess im Herzen durch Bisphosphorylierung von zwei Serinresten in dem flexiblen N-terminalen Arm des cTnI. Die Ca$^{2+}$-Affinität des cTnC wird dadurch erniedrigt, was mit einer erhöhten Relaxationsrate von Myofibrillen korreliert. $^{31}$P-NMR und Peptidarrays zeigten, dass die Phosphorylierungsregion, wenn sie bisphosphoryliert vorliegt, nicht mit cTnT und cTnC, aber wenn sie dephosphoryliert vorliegt mit cTnC interagiert. In dem putativen Interaktionsbereich wurde in einem Patienten mit HKM ein Leucin-Glutamin-Austausch an Position 29 im cTnC (L29Q) festgestellt. Die Bestimmung der Aktomyosin-S1-ATPase-Aktivität und der $\textit {in vitro}$-Gleitgeschwindigkeit von rekonstituierten dünnen Filamenten mit TnC- Wildtyp bzw. -L29Q zeigten, dass der L29Q-Austausch die Auswirkung der cTnI-Phosphorylierung auf die Ca$^{2+}$-Sensitivität aufhebt. Leucin-29 ist also essentiell für die Weiterleitung des Phosphorylierungssignals

Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia-7

Red) at pericentric heterochromatin (thin arrow), H3K9(green) remained associated with centromeric domains in the chromosomes of neonatal spermatogonia. Importantly, H3K9is also preferentially associated with one of the unmethylated chromosomes on each spread analyzed (bold arrow). In contrast, H3K4(green) remains associated with entire chromatids in the majority of chromosomes (thin arrow). However, one of the unmethylated chromosomes was consistently found to be completely devoid of H3K4(bold arrow). Notably, the chromatin remodeling protein ATRX (green) remains associated with pericentric heterochromatin and consistently marks a single unmethylated chromosome on each metaphase spread analyzed. Scale bar = 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia"</p><p>http://www.biomedcentral.com/1471-2199/9/29</p><p>BMC Molecular Biology 2008;9():29-29.</p><p>Published online 13 Mar 2008</p><p>PMCID:PMC2275742.</p><p></p

Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia-2

N; ) consistently associate with pericentric heterochromatin domains in autosomes (thin arrows). In addition to their centromeric localization, ATRX as well as H3K9preferentially associate with both arms of the Y chromosome (red; bold arrows). In contrast, a transcriptionally permissive histone modification such as H3K4(green) exhibited an inverted chromosomal distribution whereby constitutive heterochromatin (i.e. pericentric heterochromatin and the Y chromosome; red) are completely devoid of H3K4. The Y chromosome in neonatal spermatogonia occupies a transcriptionally quiescent nuclear domain during interphase. Transcription run-on assays after incorporation of Br-UTP (green) in permeabilized interphase nuclei of somatic and neonatal spermatogonia revealed that global transcriptional activity is undetectable in the nuclear domain occupied by the Y chromosome (red; see inset) in both somatic cell and germ cell nuclei. Neonatal spermatogonial cell nuclei were identified by their unique global DNA methylation patterns (5-mC; green). Scale bar = 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia"</p><p>http://www.biomedcentral.com/1471-2199/9/29</p><p>BMC Molecular Biology 2008;9():29-29.</p><p>Published online 13 Mar 2008</p><p>PMCID:PMC2275742.</p><p></p

Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia-0

Ethylated autosomal centromeric domains (thin arrow) as determined by 5-methyl cytosine (5-mC) staining (red). Chromosomes in neonatal spermatogonia lack global DNA methylation at pericentric heterochromatin, while 5-mC (red) decorates entire chromatids in the majority of autosomes (thin arrow). Two chromosomes on each metaphase spread consistently exhibit lack of 5-mC staining (bold arrow and arrowhead). These patterns are reproducible after using two standard chromosome fixation protocols using either paraformaldehyde (PFA) or methanol/acetic acid (MeOH/AA) as shown in . Fluorescent in situ hybridization (FISH) and subsequent determination of DNA methylation patterns (5-mC; red) confirms that the two hypo-methylated chromosomes observed on each spread correspond to the X chromosome (green; arrow head) and the Y chromosome (red; Inset and bold arrow in K-L). Note the lack of 5-mC staining on the Y chromosome and the low levels of global methylation on the X chromosome compared to autosomes (thin arrows) in germ cell metaphases. DNA was counterstained with HOECHST 33258 (blue). Scale bars = 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia"</p><p>http://www.biomedcentral.com/1471-2199/9/29</p><p>BMC Molecular Biology 2008;9():29-29.</p><p>Published online 13 Mar 2008</p><p>PMCID:PMC2275742.</p><p></p

Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia-4

Uno-FISH. The sub-chromosomal localization of ATRX, H3K9, H3K4and 5-mC were correlated with the position of the Y chromosome (red). The patterns of ATRX and H3K9localization to centromeric domains (thin arrows) and the Y chromosome (bold arrow) in cells lacking LSH protein were undistinguishable compared to the patterns observed in heterozygous littermate controls. Neonatal spermatogonial cell nuclei were identified by their unique global DNA methylation patterns (5-mC; green) on the same metaphase spread. Scale bar = 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia"</p><p>http://www.biomedcentral.com/1471-2199/9/29</p><p>BMC Molecular Biology 2008;9():29-29.</p><p>Published online 13 Mar 2008</p><p>PMCID:PMC2275742.</p><p></p

Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia-6

Ethylated autosomal centromeric domains (thin arrow) as determined by 5-methyl cytosine (5-mC) staining (red). Chromosomes in neonatal spermatogonia lack global DNA methylation at pericentric heterochromatin, while 5-mC (red) decorates entire chromatids in the majority of autosomes (thin arrow). Two chromosomes on each metaphase spread consistently exhibit lack of 5-mC staining (bold arrow and arrowhead). These patterns are reproducible after using two standard chromosome fixation protocols using either paraformaldehyde (PFA) or methanol/acetic acid (MeOH/AA) as shown in . Fluorescent in situ hybridization (FISH) and subsequent determination of DNA methylation patterns (5-mC; red) confirms that the two hypo-methylated chromosomes observed on each spread correspond to the X chromosome (green; arrow head) and the Y chromosome (red; Inset and bold arrow in K-L). Note the lack of 5-mC staining on the Y chromosome and the low levels of global methylation on the X chromosome compared to autosomes (thin arrows) in germ cell metaphases. DNA was counterstained with HOECHST 33258 (blue). Scale bars = 10 μm.<p><b>Copyright information:</b></p><p>Taken from "Association of ATRX with pericentric heterochromatin and the Y chromosome of neonatal mouse spermatogonia"</p><p>http://www.biomedcentral.com/1471-2199/9/29</p><p>BMC Molecular Biology 2008;9():29-29.</p><p>Published online 13 Mar 2008</p><p>PMCID:PMC2275742.</p><p></p