The suitability of iodinated Angiotensin-(1-7) peptides as pharmacological tools

INTRODUCTION: The heptapeptide Angiotensin-(1-7) [(Ang-(1-7)] is a biologically active component of the Renin-Angiotensin System. Pharmacological studies often involve Ang-(1-7) radioactively labelled with (125)I. Given the small size of the original peptide, we investigated whether introduction of a rather bulky iodine label interferes with the biological activity of Ang-(1-7). METHODS: Ang-(1-7) was labelled with nonradioactive iodine with the chloramine-T method. The reaction products were separated on HPLC and analysed with mass spectrometry. The products were tested for biological activity in two ways: The ability of labelled Ang-(1-7) to block Ang II-induced contraction in rat aortic rings was tested in an organ bath setup. The affinity of labelled angiotensin for ACE in rat plasma was examined in vitro. RESULTS: Iodination of Angiotensin-(1-7) resulted in two main products: monoiodinated and diiodinated Ang-(1-7) that could be easily separated on HPLC. In an organ bath experiment, monoiodinated Ang-(1-7) blocked Ang II responses identical to the native compound, whereas diiodinated Ang-(1-7) had lost its ability to block Ang II responses. Likewise, monoiodinated Ang-(1-7) had retained its affinity for ACE, while the affinity of diiodinated Ang-(1-7) was greatly reduced. DISCUSSION: Monoiodinated Ang-(1-7) has a biological activity identical to the native compound, whereas this is lost in diiodinated Ang-(1-7). Therefore, only the monoiodinated radioactive form seems suited for pharmacological studies

Building an alliance to map global supply networks

The global economy consists of more than 300 million firms, connected through an estimated 13 billion supply links [see supplementary materials (SM)], that produce most goods and services. It has long been unthinkable to analyze the world economy at the firm level, even less so its intricate network of supply chain linkages. This blind spot has left us ill-prepared to make fast and well-informed decisions, begetting, for example, prolonged shortages in raw materials and critical medical supplies during the COVID-19 pandemic. Now, the availability of new data and recent methodological advances allow us to reconstruct a large share of the global firm-level supply network. Because mapping this network is likely to continue to improve, it is essential to initiate a discussion about responsible management and effective use of these data for the global public good. This requires new collaborative efforts between nations, their public institutions, international organizations, the private sector, and scientists

The High-redshift Clusters Occupied by Bent Radio AGN (COBRA) Survey: Investigating the Role of Environment on Bent Radio AGNs Using LOFAR

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Bent radio active galactic nucleus (AGN) morphology depends on the density of the surrounding gas. However, bent sources are found inside and outside clusters, raising the question of how environment impacts bent AGN morphology. We analyze new LOw-Frequency Array the LOFAR Two-metre Sky Survey (LoTSS) Data Release II observations of 20 bent AGNs in clusters and 15 not in clusters from the high-z Clusters Occupied by Bent Radio AGN (COBRA) survey (0.35 1.2 Mpc) or bent AGNs in weaker groups rather than the field.Peer reviewe

Homozygous whole body Cbs knockout in adult mice features minimal pathology during ageing despite severe homocysteinemia

Deficiencies in Cystathionine-β-synthase (CBS) lead to hyperhomocysteinemia (HHCy), which is considered a risk factor for cardiovascular, bone and neurological disease. Moreover, CBS is important for the production of cysteine, hydrogen sulfide (H2 S) and glutathione. Studying the biological role of CBS in adult mice has been severely hampered by embryological disturbances and perinatal mortality. To overcome these issues and assess the effects of whole-body CBS deficiency in adult mice, we engineered and characterized a Cre-inducible Cbs knockout model during ageing. No perinatal mortality occurred before Cbs-/- induction at 10 weeks of age. Mice were followed until 90 weeks of age and ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy was observed in Cbs-/- (289 ± 58 µM) but not in Cbs+/- or control mice (<10 µM). Cbs-/- showed impaired growth, facial alopecia, endothelial dysfunction in absence of increased mortality, and signs of liver or kidney damage. CBS expression in skin localized to sebaceous glands and epidermis, suggesting local effects of Cbs-/- on alopecia. Cbs-/- showed increased markers of oxidative stress and senescence but expression of other H2 S producing enzymes (CSE and 3-MST) was not affected. CBS deficiency severely impaired H2 S production capacity in liver, but not in brain or kidney. In summary, Cbs-/- mice presented a mild phenotype without mortality despite severe HHCy. The findings demonstrate that HHCy is not directly linked to development of end organ damage

Abdominal aortic calcification on a plain X-ray and the relation with significant coronary artery disease in asymptomatic chronic dialysis patients

BACKGROUND: Coronary artery disease (CAD) is common in asymptomatic chronic dialysis patients and plays an important role in their poor survival. Early identification of these high-risk patients could improve treatment and reduce mortality. Abdominal aortic calcification (AAC) has previously been associated with CAD in autopsy studies. Since the AAC can be quantified easily using a lateral lumbar X-ray we hypothesized that the extent of AAC as assessed on a lateral lumbar X-ray might be predictive of the presence of significant CAD in dialysis patients. METHODS: All patients currently enrolled in the ICD2 trial without a history of CABG or a PCI with stent implantation were included in this study. All patients underwent CT-angiography (CTA) and a lateral X-ray of the abdomen. AAC on X-ray was quantified using a previously validated scoring system whereupon the association between AAC and the presence of significant CAD was assessed. RESULTS: A total of 90 patients were included in this study (71% male, 67 ± 7 years old). Forty-six patients were found to have significant CAD. AAC-score was significantly higher in patients with CAD (10.1 ± 4.9 vs 6.3 ± 4.6 (p < 0.05). Multivariate regression analysis revealed that AAC score is an independent predictor for the presence of CAD with a 1,2 fold higher risk per point increase (p < 0.01). The AAC score has a sensitivity of 85% and a specificity of 57% for the presence of significant CAD. CONCLUSION: This study shows that abdominal aortic calcification as assessed on a lateral lumbar X-ray is predictive for the presence of significant coronary artery disease in asymptomatic dialysis patients. This simple, non-invasive and cheap screening method could contribute to early identification of patients eligible for further screening of CAD. TRIAL REGISTRATION: NTR948, registered 10-4-2007 ; ISRCTN20479861, registered 2-5-200

Prediction of All-Cause Mortality Following Percutaneous Coronary Intervention in Bifurcation Lesions Using Machine Learning Algorithms

Stratifying prognosis following coronary bifurcation percutaneous coronary intervention (PCI) is an unmet clinical need that may be fulfilled through the adoption of machine learning (ML) algorithms to refine outcome predictions. We sought to develop an ML-based risk stratification model built on clinical, anatomical, and procedural features to predict all-cause mortality following contemporary bifurcation PCI. Multiple ML models to predict all-cause mortality were tested on a cohort of 2393 patients (training, n = 1795; internal validation, n = 598) undergoing bifurcation PCI with contemporary stents from the real-world RAIN registry. Twenty-five commonly available patient-/lesion-related features were selected to train ML models. The best model was validated in an external cohort of 1701 patients undergoing bifurcation PCI from the DUTCH PEERS and BIO-RESORT trial cohorts. At ROC curves, the AUC for the prediction of 2-year mortality was 0.79 (0.74–0.83) in the overall population, 0.74 (0.62–0.85) at internal validation and 0.71 (0.62–0.79) at external validation. Performance at risk ranking analysis, k-center cross-validation, and continual learning confirmed the generalizability of the models, also available as an online interface. The RAIN-ML prediction model represents the first tool combining clinical, anatomical, and procedural features to predict all-cause mortality among patients undergoing contemporary bifurcation PCI with reliable performance