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Background Asymmetric dimethylarginine (ADMA) acts as an endogenous inhibitor of NO-synthase. In the last years ADMA has emerged as a cardiovascular risk factor. The aim of this study was to determine a reference value for ADMA. Methods Plasma samples of 500 healthy subjects in the 19–75 year age group were analyzed. Exclusion criteria from this study were smoking, any known significant disease, body-mass-index (BMI) above 30 kg m−2, elevated plasma lipid levels, impaired renal function, hypertension, and intake of any medication. The ADMA levels were determined by ELISA, (DLD Diagnostics, Hamburg, Germany). Results Mean ADMA plasma concentration of the total population was 0·69 µmol L−1 (SD 0·20) and 95% of the measured values were in the range from 0·36 µmol L−1 to 1·17 µmol L−1. Women below 50 years of age had lower ADMA levels than men below 50 years of age [0·62 (0·17) µmol L−1 vs. 0·69 (0·19) µmol L−1; P = 0·001] and woman above 50 years of age had higher ADMA levels than men above 50 years of age [0·80 (0·22) µmol L−1 vs. 0·73 (0·20) µmol L−1; P = 0·036]. A regression analysis of ADMA levels and age was performed for each sex. The regression factor was r = 0·444 for women in a squared regression model ( P < 0·001) and r = 0·212 for men in a linear regression model ( P < 0·001). Conclusion The study was able to define a reference value for ADMA plasma levels with 0·36–1·17 µmol L−1 and found sex dependent correlations between ADMA and age. Women showed a significant increase in ADMA plasma levels with onset of menopause. [ABSTRACT FROM AUTHOR]

Within the virion, adenovirus DNA associates with the virus-encoded, protamine-like structural protein pVII. Whether this association is organized, and how genome packaging changes during infection and subsequent transcriptional activation is currently unclear. Here, we combined RNA-seq, MNase-seq, ChIP-seq, and single genome imaging during early adenovirus infection to unveil the structure- and time-resolved dynamics of viral chromatin changes as well as their correlation with gene transcription. Our MNase mapping data indicates that the adenoviral genome is arranged in precisely positioned nucleoprotein particles with nucleosome-like characteristics, that we term adenosomes. We identified 238 adenosomes that are positioned by a DNA sequence code and protect about 60-70 bp of DNA. The incoming adenoviral genome is more accessible at early gene loci that undergo additional chromatin de-condensation upon infection. Histone H3.3 containing nucleosomes specifically replaces pVII at distinct genomic sites and at the transcription start sites of early genes. Acetylation of H3.3 is predominant at the transcription start sites and precedes transcriptional activation. Based on our results, we propose a central role for the viral pVII nucleoprotein architecture, which is required for the dynamic structural changes during early infection, including the regulation of nucleosome assembly prior to transcription initiation. Our study thus may aid the rational development of recombinant adenoviral vectors exhibiting sustained expression in gene therapy., (© 2023 The Authors. Published under the terms of the CC BY NC ND 4.0 license.)

Chromatin-associated non-coding RNAs modulate the epigenetic landscape and its associated gene expression program. The formation of triple helices is one mechanism of sequence-specific targeting of RNA to chromatin. With this study, we show an important role of the nucleosome and its relative positioning to the triplex targeting site (TTS) in stabilizing RNA-DNA triplexes in vitro and in vivo. Triplex stabilization depends on the histone H3 tail and the location of the TTS close to the nucleosomal DNA entry-exit site. Genome-wide analysis of TTS-nucleosome arrangements revealed a defined chromatin organization with an enrichment of arrangements that allow triplex formation at active regulatory sites and accessible chromatin. We further developed a method to monitor nucleosome-RNA triplexes in vivo (TRIP-seq), revealing RNA binding to TTS sites adjacent to nucleosomes. Our data strongly support an activating role for RNA triplex-nucleosome complexes, pinpointing triplex-mediated epigenetic regulation in vivo., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The packaging and organization of genomic DNA into chromatin represents an additional regulatory layer of gene expression, with specific nucleosome positions that restrict the accessibility of regulatory DNA elements. The mechanisms that position nucleosomes in vivo are thought to depend on the biophysical properties of the histones, sequence patterns, like phased di-nucleotide repeats and the architecture of the histone octamer that folds DNA in 1.65 tight turns. Comparative studies of human and P. falciparum histones reveal that the latter have a strongly reduced ability to recognize internal sequence dependent nucleosome positioning signals. In contrast, the nucleosomes are positioned by AT-repeat sequences flanking nucleosomes in vivo and in vitro. Further, the strong sequence variations in the plasmodium histones, compared to other mammalian histones, do not present adaptations to its AT-rich genome. Human and parasite histones bind with higher affinity to GC-rich DNA and with lower affinity to AT-rich DNA. However, the plasmodium nucleosomes are overall less stable, with increased temperature induced mobility, decreased salt stability of the histones H2A and H2B and considerable reduced binding affinity to GC-rich DNA, as compared with the human nucleosomes. In addition, we show that plasmodium histone octamers form the shortest known nucleosome repeat length (155bp) in vitro and in vivo. Our data suggest that the biochemical properties of the parasite histones are distinct from the typical characteristics of other eukaryotic histones and these properties reflect the increased accessibility of the P. falciparum genome., Competing Interests: The authors have declared that no competing interests exist.

Recent studies have shown that in response to vascular damage or ischemia, bone marrow-derived endothelial progenitor cells (EPCs) are recruited into the circulation. To investigate whether antihypertensive treatment has an influence on the number of circulating EPCs, patients with essential hypertension were treated either with the angiotensin receptor antagonist telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks. At baseline and after 3 and 6 weeks of treatment, EPCs were identified and quantified by fluorescence-activated cell sorting (FACS) analysis and by their capacity to generate colony-forming units of the endothelial lineage (CFU-EC) in a methylcellulose-based assay. During treatment, patients in the nisoldipine groups, but not in the telmisartan group, showed a significant mobilization of EPCs, which in part had the capacity to generate large-sized colonies comprising more than 1,000 cells. Moreover, a remarkable correlation between the number of CFU-EC and the number of circulating CD133(+)/CD34(+)/CD146(+) cells was observed, thereby providing strong evidence that cells with this phenotype represent functional EPCs. No correlation was found between the numbers of CFU-EC and the blood pressure levels at any time point during the treatment. Hence, nisoldipine-induced mobilization of EPCs might represent a novel mechanism by which this antihypertensive compound independently of its blood pressure-lowering effect contributes to vasoprotection in patients with essential hypertension.

Hypertension is a cardiovascular risk factor commonly associated with insulin resistance, the metabolic syndrome, and type 2 diabetes mellitus. Recent in vitro data indicate that certain angiotensin receptor antagonists, for example, telmisartan, activate peroxisome proliferator-activated receptor gamma (PPAR-gamma) and increase adiponectin protein content in adipocytes. By this means, they may improve insulin sensitivity in vivo. To investigate the effect of antihypertensive treatment on insulin sensitivity and fasting adiponectin serum levels, 37 nondiabetic patients with essential hypertension were randomized to receive telmisartan, the calcium channel blocker nisoldipine, or their combination for 6 weeks in a prospective, parallel group study. Fasting serum glucose, insulin, and adiponectin were evaluated before, 3 weeks (low dose), and 6 weeks (high dose) after initiation of treatment. Furthermore, the effect of telmisartan on PPAR-gamma receptor activity was investigated in vitro using a PPAR-gamma reporter gene assay. As reported previously, telmisartan significantly enhanced PPAR-gamma receptor activity in vitro. At baseline, a positive correlation between insulin serum levels and body mass index of investigated subjects was observed, whereas body mass index and serum adiponectin levels were negatively associated. High-dose treatment with telmisartan but not with nisoldipine reduced serum insulin levels as well as the homeostasis model assessment of insulin resistance, but did not affect serum adiponectin levels. In conclusion, in our study cohort of nondiabetic patients with essential hypertension, telmisartan improved insulin sensitivity by mechanisms apparently not involving adiponectin induction. Future studies will demonstrate whether these telmisartan-induced effects may contribute to a blood pressure-independent reduction in cardiovascular morbidity.

In order to estimate the proportion which may enter the aquatic environment and characterize exposure potential, the environmental fate properties of two polycarboxylate polymers in activated sludge were determined. The polycarboxylates studied were a polymer emulsion (PE), a high-molecular-weight polymer (MW 50,000-60,000), and a resin polymer (RP), a low-molecular-weight polymer (MW 4500 to 9000). Both polymers exhibited a high degree of sorption to sludge solids in a series of sorption/ desorption studies, indicating a high potential for removal during wastewater treatment. In isotherm tests, the adsorption coefficient, Koc, was 1060 and 2730 for the RP and the PE, respectively. The biodegradation of the two polymers was measured under aerobic conditions in a 60-day semicontinuous activated sludge test and in a 60-day modified Sturm test using 14C-labeled compounds. In both studies, polymers accumulated in sludge solids over time and there was no evidence of significant biodegradation, although small amounts of radiolabeled CO2 were produced, suggesting the potential for biodegradation. Testing confirmed that the lack of biodegradation was not due to inhibition of microbial respiration by the polymers. High removals of PE and RP during wastewater treatment were confirmed in a field study at a facility receiving polymer inputs from households and manufacturing plants.

The toxicity of octamethylcyclotetrasiloxane (OMCTS) to the midge Chironomus tentans was examined in a series of aqueous and sediment exposures. Midge larvae were exposed for 14 days to five concentrations of radiolabeled [14C]OMCTS in each of three sediments (low, medium, and high organic carbon content). Additional tests were conducted with a water-only exposure. Results indicate the lowest 14-day no observed effect concentrations (NOEC) to be 65, 120, and 54 mg/kg for the low, medium, and high organic carbon sediments, respectively. For the water-only exposure, the 14-day NOEC was > 15 micrograms/liter. These results were used in the preparation of a risk assessment for OMCTS which took into consideration the physicochemical and environmental fate properties of the compound, as well as actual field monitoring and worst-case modeling results for assessment of exposure. Available evidence suggests that sediment concentrations of OMCTS do not present a risk to sediment-associated organisms. For 95% of sediment samples, data indicate that the margins of safety would be greater than 400 and potentially over 1000. Worst-case margins of safety were greater than 150.

Polychlorinated biphenyls (PCBs) and polybrominated biphenyls (PBBs) are compounds whose physical/chemical properties led to their widespread commercial use. Although their production has been banned or severely limited in most countries since the 1970s, the persistence and stability of these compounds have resulted in a worldwide distribution, especially of PCBs. PBB contamination is limited principally to the state of Michigan, where a series of tragic errors eventually resulted in the accumulation of residues in livestock and the general human population. Long-term exposure to PCBs and PBBs in animals has been associated with the induction of neoplastic nodules in the liver and in some cases hepatocellular carcinoma. This review discusses the role of PCBs and PBBs in the process of carcinogenesis. The mutagenicity/genotoxicity of these compounds, as well as their initiation/promotion potential is discussed. The epidemiology of PCB and PBB exposure is reported along with an estimation of the risk of cancer to humans. Finally, possible molecular mechanisms of action are suggested for polyhalogenated biphenyls in cancer development.