Pulmonary arterial hypertension (PAH) is a progressive lung disease characterized by pulmonary vasoconstriction and vascular remodelling, leading to increased pulmonary vascular resistance and right ...heart failure. Loss of nitric oxide (NO) signalling and increased endothelial nitric oxide synthase (eNOS)-derived oxidative stress are central to the pathogenesis of PAH, yet the mechanisms involved remain incompletely determined. In this study, we investigated the role activated CD47 plays in promoting PAH.
We report high-level expression of thrombospondin-1 (TSP1) and CD47 in the lungs of human subjects with PAH and increased expression of TSP1 and activated CD47 in experimental models of PAH, a finding matched in hypoxic human and murine pulmonary endothelial cells. In pulmonary endothelial cells CD47 constitutively associates with caveolin-1 (Cav-1). Conversely, in hypoxic animals and cell cultures activation of CD47 by TSP1 disrupts this constitutive interaction, promoting eNOS-dependent superoxide production, oxidative stress, and PAH. Hypoxic TSP1 null mice developed less right ventricular pressure and hypertrophy and markedly less arteriole muscularization compared with wild-type animals. Further, therapeutic blockade of CD47 activation in hypoxic pulmonary artery endothelial cells upregulated Cav-1, increased Cav-1CD47 co-association, decreased eNOS-derived superoxide, and protected animals from developing PAH.
Activated CD47 is upregulated in experimental and human PAH and promotes disease by limiting Cav-1 inhibition of dysregulated eNOS.
The ceque system of Cusco, the ancient capital of the Inca empire, was perhaps the most complex indigenous ritual system in the pre-Columbian Americas. From a center known as the Coricancha (Golden ...Enclosure) or the Temple of the Sun, a system of 328 huacas (shrines) arranged along 42 ceques (lines) radiated out toward the mountains surrounding the city. This elaborate network, maintained by ayllus (kin groups) that made offerings to the shrines in their area, organized the city both temporally and spiritually. From 1990 to 1995, Brian Bauer directed a major project to document the ceque system of Cusco. In this book, he synthesizes extensive archaeological survey work with archival research into the Inca social groups of the Cusco region, their land holdings, and the positions of the shrines to offer a comprehensive, empirical description of the ceque system. Moving well beyond previous interpretations, Bauer constructs a convincing model of the system's physical form and its relation to the social, political, and territorial organization of Cusco.
Pulmonary arterial hypertension is a progressive proliferative vasculopathy of the small pulmonary arteries that is characterized by a primary failure of the endothelial nitric oxide and prostacyclin ...vasodilator pathways, coupled with dysregulated cellular proliferation. We have recently discovered that the endogenous anion salt nitrite is converted to nitric oxide in the setting of physiological and pathological hypoxia. Considering the fact that nitric oxide exhibits vasoprotective properties, we examined the effects of nitrite on experimental pulmonary arterial hypertension.
We exposed mice and rats with hypoxia or monocrotaline-induced pulmonary arterial hypertension to low doses of nebulized nitrite (1.5 mg/min) 1 or 3 times a week. This dose minimally increased plasma and lung nitrite levels yet completely prevented or reversed pulmonary arterial hypertension and pathological right ventricular hypertrophy and failure. In vitro and in vivo studies revealed that nitrite in the lung was metabolized directly to nitric oxide in a process significantly enhanced under hypoxia and found to be dependent on the enzymatic action of xanthine oxidoreductase. Additionally, physiological levels of nitrite inhibited hypoxia-induced proliferation of cultured pulmonary artery smooth muscle cells via the nitric oxide-dependent induction of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). The therapeutic effect of nitrite on hypoxia-induced pulmonary hypertension was significantly reduced in the p21-knockout mouse; however, nitrite still reduced pressures and right ventricular pathological remodeling, indicating the existence of p21-independent effects as well.
These studies reveal a potent effect of inhaled nitrite that limits pathological pulmonary arterial hypertrophy and cellular proliferation in the setting of experimental pulmonary arterial hypertension.
Despite the development of effective therapies, a substantial proportion of asthmatics continue to have uncontrolled symptoms, airflow limitation, and exacerbations. Transient receptor potential ...cation channel member A1 (TRPA1) agonists are elevated in human asthmatic airways, and in rodents, TRPA1 is involved in the induction of airway inflammation and hyperreactivity. Here, the discovery and early clinical development of GDC-0334, a highly potent, selective, and orally bioavailable TRPA1 antagonist, is described. GDC-0334 inhibited TRPA1 function on airway smooth muscle and sensory neurons, decreasing edema, dermal blood flow (DBF), cough, and allergic airway inflammation in several preclinical species. In a healthy volunteer Phase 1 study, treatment with GDC-0334 reduced TRPA1 agonist-induced DBF, pain, and itch, demonstrating GDC-0334 target engagement in humans. These data provide therapeutic rationale for evaluating TRPA1 inhibition as a clinical therapy for asthma.
This paper assesses the original name of the Inca settlement now known as Machu Picchu. We examine three data sources: the field notes of Hiram Bingham, toponyms on nineteenth century maps, and ...information recorded in seventeenth century documents. The results uniformly suggest that the Inca city was originally called Picchu, or more likely Huayna Picchu, and that the name Machu Picchu became associated with the ruins starting in 1911 with Bingham's publications.
Este documento evalúa el nombre original de la ciudad inca ahora conocida como Machu Picchu. Examinamos tres fuentes de datos: las notas de Hiram Bingham, topónimos en mapas del siglo XIX, e información registrada en documentos del siglo XVII. Los resultados sugieren que la ciudad inca se llamaba originalmente Picchu o más probable Huayna Picchu y que el nombre de Machu Picchu se asoció con las ruinas a partir de 1911 con las publicaciones de Bingham.
Voices from Vilcabamba Brian S. Bauer; Madeleine Halac-Higashimori; Gabriel E. Cantarutti
03/2015
eBook
Odprti dostop
A rich new source of important archival information,Voices from Vilcabambaexamines the fall of the Inca Empire in unprecedented detail. Containing English translations of seven major documents from ...the Vilcabamba era (1536-1572), this volume presents an overview of the major events that occurred in the Vilcabamba region of Peru during the final decades of Inca rule.
Brian S. Bauer, Madeleine Halac-Higashimori, and Gabriel E. Cantarutti have translated and analyzed seven documents, most notablyDescription of Vilcabambaby Baltasar de Ocampo Conejeros and a selection from Martín de Murúa'sGeneral History of Peru, which focuses on the fall of Vilcabamba. Additional documents from a range of sources that include Augustinian investigations, battlefield reports, and critical eyewitness accounts are translated into English for the first time.
With a critical introduction on the history of the region during the Spanish Conquest and introductions to each of the translated documents, the volume provides an enhanced narrative on the nature of European-American relations during this time of important cultural transformation.
The Cuzco Valley of Peru was both the sacred and the political center of the largest state in the prehistoric Americas—the Inca Empire. From the city of Cuzco, the Incas ruled at least eight million ...people in a realm that stretched from modern-day Colombia to Chile. Yet, despite its great importance in the cultural development of the Americas, the Cuzco Valley has only recently received the same kind of systematic archaeological survey long since conducted at other New World centers of civilization. Drawing on the results of the Cuzco Valley Archaeological Project that Brian Bauer directed from 1994 to 2000, this landmark book undertakes the first general overview of the prehistory of the Cuzco region from the arrival of the first hunter-gatherers (ca. 7000 B.C.) to the fall of the Inca Empire in A.D. 1532. Combining archaeological survey and excavation data with historical records, the book addresses both the specific patterns of settlement in the Cuzco Valley and the larger processes of cultural development. With its wealth of new information, this book will become the baseline for research on the Inca and the Cuzco Valley for years to come.
To date, most obsidian sourcing studies in the Andes have concentrated on the highlands and Titicaca Basin of far southern Peru and northern Bolivia. Toward achieving a more complete understanding of ...the region, this paper offers new data on the long-term prehistoric obsidian procurement and consumption patterns in the Andahuaylas region of the south-central Peruvian highlands. Obsidian sourcing data from Andahuaylas are particularly interesting since the area is centrally located among several important regional obsidian sources. A total of 94 obsidian samples from a range of sites of different temporal periods were chemically analyzed using portable X-ray fluorescence (PXRF), as well as laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). The results demonstrate a number of interesting trends, the first of which is the long-term importance of the Potreropampa obsidian source to populations of the Andahuaylas region from at least the early Formative period (∼2500 BCE). Secondly, the results indicate that procurement strategies by local populations in Andahuaylas were primarily reliant on nearby (<150 km) obsidian sources. Finally, the paucity of more distant, yet widely exchanged, high quality obsidian (i.e., Chivay, Alca) confirm that as a region, Andahuaylas was more heavily connected economically (and likely culturally) with local areas to the south (Apurímac) and to the west (Ayacucho).
► PXRF and LA-ICP-MS analysis of archaeological obsidian from Andahuaylas, Peru. ► Results reflect a long-term dependence on local (<150 km away) obsidian sources. ► Results indicate the long-term dependence on Potreropampa obsidian. ► Local populations in Andahuaylas procured very little, high quality, distant obsidian.
•Distributions of state canons demonstrate power of ancient states archaeologically.•Regional survey data in Cusco, Peru, reveal large-scale Wari interaction patterns.•Survey data show that Wari ...power influenced only certain parts of the Cusco region.•GIS analysis of ceramic distribution indicates uneven and indirect Wari influence.•Wari regional power in Cusco suggests colonization rather than provincial rule.
The archaeological reconstruction of ancient states requires consistent regional measures of state-directed power and influence. This paper presents data from a series of systematic archaeological surveys in the Cusco region of highland Peru to evaluate patterns of influence by the Wari state during a period of colonization from ca. AD 600–1000. We discuss interpretive debates over the nature and intensity of Wari social power, suggesting that site-based studies can be contextualized meaningfully using our large-scale dataset, which offers settlement patterns at varying distances (0–70km) from Pikillacta, a Wari administrative center. We discuss local settlement patterns before and during Wari colonization, as well as the distribution of Wari pottery and local Wari-influenced wares. We then use a geographic information systems analysis of travel time from key sites to evaluate the broad regional distribution patterns of local and Wari ceramic styles. Although the regional survey data do not inform us reliably about all kinds of social power, we conclude that the Wari cultural, economic, and political influence over the Cusco region was limited and discontinuous—an example of colonization that resembles the practices of other early states.
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