The aim of the present study was to investigate the coronary effects of Ang-(1-7) angiotensin-(1-7) in hypertrophic rat hearts. Heart hypertrophy was induced by abdominal aorta CoA (coarctation). ...Ang-(1-7) and AVE 0991, a non-peptide Mas-receptor agonist, at picomolar concentration, induced a significant vasodilation in hearts from sham-operated rats. These effects were blocked by the Mas receptor antagonist A-779. Pre-treatment with L-NAME (N(G)-nitro-L-arginine methyl ester) or ODQ (1H-1,2,4oxadiazolo4,3-aquinozalin-1-one) NOS (NO synthase) and soluble guanylate cyclase inhibitors respectively also abolished the effect of Ang-(1-7) in control hearts. The coronary vasodilation produced by Ang-(1-7) and AVE 0991 was completely blunted in hypertrophic hearts. Chronic oral administration of losartan in CoA rats restored the coronary vasodilation effect of Ang-(1-7). This effect was blocked by A-779 and AT2 receptor (angiotensin II type 2 receptor) antagonist PD123319. Acute pre-incubation with losartan also restored the Ang-(1-7)-induced, but not BK (bradykinin)-induced, coronary vasodilation in hypertrophic hearts. This effect was inhibited by A-779, PD123319 and L-NAME. Chronic treatment with losartan did not change the protein expression of Mas and AT2 receptor and ACE (angiotensin-converting enzyme) and ACE2 in coronary arteries from CoA rats, but induced a slight increase in AT2 receptor in aorta of these animals. Ang-(1-7)-induced relaxation in aortas from sham-operated rats was absent in aortas from CoA rats. In vitro pre-treatment with losartan restored the Ang-(1-7)-induced relaxation in aortic rings of CoA rats, which was blocked by the Mas antagonist A-779 and L-NAME. These data demonstrate that Mas is strongly involved in coronary vasodilation and that AT1 receptor (angiotensin II type 1 receptor) blockade potentiates the vasodilatory effects of Ang-(1-7) in the coronary beds of pressure-overloaded rat hearts through NO-related AT2- and Mas-receptor-dependent mechanisms. These data suggest the association of Ang-(1-7) and AT1 receptor antagonists as a potential therapeutic avenue for coronary artery diseases.
Abstract
Riverine floodplains are biologically diverse and productive ecosystems. Although tropical floodplains remain relatively conserved and ecologically functional compared to those at higher ...latitudes, they face accelerated hydropower development, climate change, and deforestation. Alterations to the flood pulse could act synergistically with other drivers of change to promote profound ecological state change at a large spatial scale. State change occurs when an ecosystem reaches a critical threshold or tipping point, which leads to an alternative qualitative state for the ecosystem. Visualizing an alternative state for Amazonian floodplains is not straightforward. Yet, it is critical to recognize that changes to the flood pulse could push tropical floodplain ecosystems over a tipping point with cascading adverse effects on biodiversity and ecosystem services. We characterize the Amazonian flood pulse regime, summarize evidence of flood pulse change, assess potential ecological repercussions, and provide a monitoring framework for tracking flood pulse change and detecting biotic responses.
Cultural costs of tropical dams Anderson, Elizabeth P.; Veilleux, Jennifer C.
Science (American Association for the Advancement of Science),
04/2016, Letnik:
352, Številka:
6282
Journal Article
Despite their known transforming properties, the effects of leukemogenic FLT3-ITD mutations on hematopoietic stem and multipotent progenitor cells and on hematopoietic differentiation are not well ...understood. We report a mouse model harboring an ITD in the murine Flt3 locus that develops myeloproliferative disease resembling CMML and further identified FLT3-ITD mutations in a subset of human CMML. These findings correlated with an increase in number, cell cycling, and survival of multipotent stem and progenitor cells in an ITD dose-dependent manner in animals that exhibited alterations within their myeloid progenitor compartments and a block in normal B cell development. This model provides insights into the consequences of constitutive signaling by an oncogenic tyrosine kinase on hematopoietic progenitor quiescence, function, and cell fate.
We identified 18 patients with the distinct clinical phenotype of susceptibility to disseminated nontuberculous mycobacterial infections, viral infections, especially with human papillomaviruses, and ...fungal infections, primarily histoplasmosis, and molds. This syndrome typically had its onset in adulthood (age range, 7-60 years; mean, 31.1 years; median, 32 years) and was characterized by profound circulating monocytopenia (mean, 13.3 cells/μL; median, 14.5 cells/μL), B lymphocytopenia (mean, 9.4 cells/μL; median, 4 cells/μL), and NK lymphocytopenia (mean, 16 cells/μL; median, 5.5 cells/μL). T lymphocytes were variably affected. Despite these peripheral cytopenias, all patients had macrophages and plasma cells at sites of inflammation and normal immunoglobulin levels. Ten of these patients developed 1 or more of the following malignancies: 9 myelodysplasia/leukemia, 1 vulvar carcinoma and metastatic melanoma, 1 cervical carcinoma, 1 Bowen disease of the vulva, and 1 multiple Epstein-Barr virus+ leiomyosarcoma. Five patients developed pulmonary alveolar proteinosis without mutations in the granulocyte-macrophage colony-stimulating factor receptor or anti–granulocyte-macrophage colony-stimulating factor autoantibodies. Among these 18 patients, 5 families had 2 generations affected, suggesting autosomal dominant transmission as well as sporadic cases. This novel clinical syndrome links susceptibility to mycobacterial, viral, and fungal infections with malignancy and can be transmitted in an autosomal dominant pattern.
The tropical Andes harbor an extraordinarily varied concentration of species in a landscape under increasing pressure from human activities. Conservation of the region's native plants and animals has ...received considerable international attention, but the focus has been on terrestrial biota. The conservation of freshwater fauna, particularly the conservation of fishes, has not been emphasized. Tropical Andean fishes are among the most understudied vertebrates in the world. We estimate that between 400 and 600 fish species inhabit the diverse aquatic environments in the region. Nearly 40% of these species are endemic. Tropical Andean fishes are vulnerable to ongoing environmental changes related to deforestation, water withdrawals, water pollution, species introductions, and hydropower development. Additionally, their distributions and population dynamics may be affected by hydrologic alterations and warmer water temperatures associated with projected climate change. Presently, at least three species are considered extinct, some populations are endangered, and some species are likely to decline or disappear. The long-term persistence of tropical Andean fishes will depend on greater consideration of freshwater systems in regional conservation initiatives.
Energy development – as manifested by the proliferation of hydroelectric dams and increased oil and gas exploration – is a driver of change in Amazonian ecosystems. However, prevailing approaches to ...Amazonian ecosystem conservation that focus on terrestrial protected areas and Indigenous territories do not offer sufficient insurance against the risks associated with energy development. Here, we explore three related areas of concern: the exclusion of subsurface rights on Indigenous lands; the absence of frameworks for freshwater ecosystem conservation; and downgrading, downsizing, degazettement (loss of protection), and reclassification of protected areas. We consider these issues from the perspectives of multiple countries across the Amazon Basin, and link them directly to energy development. Finally, we offer suggestions for addressing the challenges of energy development for Amazon ecosystem conservation through existing policies, new approaches, and international collaboration.
The increasing availability of high‐frequency freshwater ecosystem metabolism data provides an opportunity to identify links between metabolic regimes, as gross primary production and ecosystem ...respiration patterns, and consumer energetics with the potential to improve our current understanding of consumer dynamics (e.g., population dynamics, community structure, trophic interactions). We describe a conceptual framework linking metabolic regimes of flowing waters with consumer community dynamics. We use this framework to identify three emerging research needs: (1) quantifying the linkage of metabolism and consumer production data via food web theory and carbon use efficiencies, (2) evaluating the roles of metabolic dynamics and other environmental regimes (e.g., hydrology, light) in consumer dynamics, and (3) determining the degree to which metabolic regimes influence the evolution of consumer traits and phenology. Addressing these needs will improve the understanding of consumer biomass and production patterns as metabolic regimes can be viewed as an emergent property of food webs.
COVID-19 emerged as a worldwide pandemic in early 2020, and while the rapid development of safe and efficacious vaccines stands as an extraordinary achievement, the identification of effective ...therapeutics has been less successful. This process has been limited in part by a lack of human-relevant preclinical models compatible with therapeutic screening on the native virus, which requires a high-containment environment. Here, we report SARS-CoV-2 infection and robust viral replication in PREDICT96-ALI, a high-throughput, human primary cell-based organ-on-chip platform. We evaluate unique infection kinetic profiles across lung tissue from three human donors by immunofluorescence, RT-qPCR, and plaque assays over a 6-day infection period. Enabled by the 96 devices/plate throughput of PREDICT96-ALI, we also investigate the efficacy of Remdesivir and MPro61 in a proof-of-concept antiviral study. Both compounds exhibit an antiviral effect against SARS-CoV-2 in the platform. This demonstration of SARS-CoV-2 infection and antiviral dosing in a high-throughput organ-on-chip platform presents a critical capability for disease modeling and therapeutic screening applications in a human physiology-relevant in vitro system.
Diminazene aceturate, a putative ACE2 activator, is susceptible to cleavage resulting in the formation of p-aminobenzamidine (PAB). This study aimed to investigate the effects of PAB in addressing ...cardiovascular dysfunctions in spontaneously hypertensive rats (SHR).
Acute effects of PAB on mean arterial pressure (MAP), heart rate (HR), and aortic (AVC) and mesenteric vascular conductance (MVC) were evaluated in anesthetized SHR. Isolated aortic rings and the Langendorff technique were used to investigate the acute and chronic effects of PAB in the artery and heart. Chronic treatment with PAB (1 mg/kg, gavage) was carried out for 60 days. During this period, systolic blood pressure (SBP) and HR were measured by tail-cuff plethysmography. After the treatment, the left ventricle was collected for histology analyses, western blotting, and ACE2 activity.
Bolus infusion of PAB acutely reduced MAP and increased both AVC and MVC in SHR. Additionally, PAB induced coronary and aorta vasodilation in isolated organs from Wistar and SHR in an endothelial-dependent manner. The chronic PAB treatment in SHR significantly attenuated the increase of SBP and improved the aorta vasorelaxation induced by acetylcholine and bradykinin-induced coronary vasodilation. In addition, chronic treatment with PAB attenuated the cardiomyocyte hypertrophy and extracellular matrix deposition in hearts from SHR. PAB did not alter the protein expression of the AT1, AT2, Mas, ACE, ACE2, or ACE2 activity.
PAB induced beneficial effects on cardiovascular dysfunctions induced by hypertension, suggesting that this molecule could be used in the development of new drugs for the treatment of cardiovascular diseases.
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