Grosse Ile and the Irish Memorial National Historic Site, Parks Canada: A Case Study

Focuses on values and their protection by examining the place of values in management. Grosse Ile's management is still evolving, and the eventful first phases of planning are still fresh in the minds of staff

Chaco Culture National Historical Park: A Case Study

Looks at the management of CCNHP by the National Park Service. The long history of CCNHP as a heritage site provides an excellent illustration of how values emerge and evolve with new knowledge

Hadrian's Wall World Heritage Site: A Case Study

Focuses on the values-based management of Hadrian's Wall World Heritage Site -- consisting of Hadrian's Wall, its associated remains, and its immediate surroundings -- since the site's World Heritage listing in 1987

MicroRNA-143 activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension

Rationale: The pathogenesis of PAH remains unclear. The four microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered. Objective: To elucidate the transcriptional regulation of the miR-143/145 cluster, and the role of miR-143 in PAH. Methods and Results: We identified the promoter region that regulates miR-143/145 miRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signalling pathways, including estrogens receptor (ER), liver X factor/retinoic X receptor (LXR/RXR), TGF-β (Smads), and hypoxia (HRE) that regulated levels of all pri-miR stem loop transcription and resulting miRNA expression. We observed that miR-143-3p is selectively upregulated compared to miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMCs-derived exosomes. Using assays with pulmonary arterial endothelial cells (PAECs) we demonstrated a paracrine pro-migratory and pro-angiogenic effect of miR-143-3p enriched exosomes from PASMC. Quantitative PCR and in situ hybridisation showed elevated expression of miR-143 in calf models of PAH as well as in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role for miR-143 in experimental PH in vivo in miR-143-/- and antimiR143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings. Conclusions: MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, while inhibition of miR-143-3p blocked experimental PH. Taken together these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology

Urotensin receptor in GtoPdb v.2023.1

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 94]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 93]. Several structural forms of U-II exist in fish and amphibians [94]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [94]. The urotensinergic system displays an unprecedented repertoire of four or five ancient UT in some vertebrate lineages and five U-II family peptides in teleost fish [91]

Urotensin receptor in GtoPdb v.2021.3

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 93]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 92]. Several structural forms of U-II exist in fish and amphibians [93]. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [2, 20, 63, 69, 72]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [61, 53, 10]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [86]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [93]

Urotensin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The urotensin-II (U-II) receptor (UT, nomenclature as agreed by the NC-IUPHAR Subcommittee on the Urotensin receptor [26, 36, 89]) is activated by the endogenous dodecapeptide urotensin-II, originally isolated from the urophysis, the endocrine organ of the caudal neurosecretory system of teleost fish [7, 88]. Several structural forms of U-II exist in fish and amphibians. The goby orthologue was used to identify U-II as the cognate ligand for the predicted receptor encoded by the rat gene gpr14 [20, 62, 68, 70]. Human urotensin-II, an 11-amino-acid peptide [20], retains the cyclohexapeptide sequence of goby U-II that is thought to be important in ligand binding [53, 11]. This sequence is also conserved in the deduced amino-acid sequence of rat urotensin-II (14 amino-acids) and mouse urotensin-II (14 amino-acids), although the N-terminal is more divergent from the human sequence [19]. A second endogenous ligand for the UT has been discovered in rat [83]. This is the urotensin II-related peptide, an octapeptide that is derived from a different gene, but shares the C-terminal sequence (CFWKYCV) common to U-II from other species. Identical sequences to rat urotensin II-related peptide are predicted for the mature mouse and human peptides [32]. UT exhibits relatively high sequence identity with somatostatin, opioid and galanin receptors [89]

MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Illness meanings and experiences for pre-ulcer and ulcer conditions of Buruli ulcer in the Ga-West and Ga-South Municipalities of Ghana

ABSTRACT: BACKGROUND: Ghana is a Buruli ulcer (BU) endemic country yet there is paucity of socio-cultural research on BU. Examining distinctive experiences and meanings for pre-ulcers and ulcers of BU may clarify the disease burden, illness experience and local perceptions of causes and spread, and environmental features of BU, which are useful to guide public health programmes and future research. This study aimed to explain local meanings and experiences of BU for persons with pre-ulcers and ulcers in the Ga-West and Ga-South municipalities in Accra. METHODS: Semi-structured interviews based on the Explanatory Model Interview Catalogue framework were administered to 181 respondents comprising 15 respondents with pre-ulcers and 166 respondents with ulcers. The Wilcoxon rank-sum test was used to compare categories of illness experiences (PD) and perceived causes (PC) among respondents with pre-ulcer and ulcer conditions. The Fisher's exact test was used to compare the most troubling PD and the most important PC variables. Qualitative phenomenological analysis of respondents' narratives clarified illness experiences and meanings with reference to PC and PD variables. RESULTS: Families of respondents with pre-ulcers and the respondents themselves were often anxious about disease progression, while families of respondents with ulcers, who had to give care, worried about income loss and disruption of school attendance. Respondents with pre-ulcers frequently reported swimming in ponds and rivers as a perceived cause and considered it as the most important PC (53.3%). Respondents with ulcers frequently attributed their BU illness to witchcraft (64.5%) and respondents who claimed they had no water contact, questioned the credibility of health messages CONCLUSIONS: Affected persons with pre-ulcers are likely to delay treatment because of social and financial constraints and the absence of pain. Scepticism on the role of water in disease contagion and prolonged healin is perceived to make ideas of witchcraft as a PC more credible, among respondents with ulcers. Health messages should address issues of locally perceived risk and vulnerability. Guided by study findings, further research on the role of environmental, socio-cultural and genetic factors in BU contagion, is also needed to clarify and formulate health messages and strengthen public health initiative

Cardiovascular disease, chronic kidney disease, and diabetes mortality burden of cardiometabolic risk factors from 1980 to 2010: A comparative risk assessment

Background: High blood pressure, blood glucose, serum cholesterol, and BMI are risk factors for cardiovascular diseases and some of these factors also increase the risk of chronic kidney disease and diabetes. We estimated mortality from cardiovascular diseases, chronic kidney disease, and diabetes that was attributable to these four cardiometabolic risk factors for all countries and regions from 1980 to 2010. Methods: We used data for exposure to risk factors by country, age group, and sex from pooled analyses of population-based health surveys. We obtained relative risks for the effects of risk factors on cause-specific mortality from meta-analyses of large prospective studies. We calculated the population attributable fractions for each risk factor alone, and for the combination of all risk factors, accounting for multicausality and for mediation of the effects of BMI by the other three risks. We calculated attributable deaths by multiplying the cause-specific population attributable fractions by the number of disease-specific deaths. We obtained cause-specific mortality from the Global Burden of Diseases, Injuries, and Risk Factors 2010 Study. We propagated the uncertainties of all the inputs to the final estimates. Findings: In 2010, high blood pressure was the leading risk factor for deaths due to cardiovascular diseases, chronic kidney disease, and diabetes in every region, causing more than 40% of worldwide deaths from these diseases; high BMI and glucose were each responsible for about 15% of deaths, and high cholesterol for more than 10%. After accounting for multicausality, 63% (10·8 million deaths, 95% CI 10·1-11·5) of deaths from these diseases in 2010 were attributable to the combined effect of these four metabolic risk factors, compared with 67% (7·1 million deaths, 6·6-7·6) in 1980. The mortality burden of high BMI and glucose nearly doubled from 1980 to 2010. At the country level, age-standardised death rates from these diseases attributable to the combined effects of these four risk factors surpassed 925 deaths per 100 000 for men in Belarus, Kazakhstan, and Mongolia, but were less than 130 deaths per 100 000 for women and less than 200 for men in some high-income countries including Australia, Canada, France, Japan, the Netherlands, Singapore, South Korea, and Spain. Interpretation: The salient features of the cardiometabolic disease and risk factor epidemic at the beginning of the 21st century are high blood pressure and an increasing effect of obesity and diabetes. The mortality burden of cardiometabolic risk factors has shifted from high-income to low-income and middle-income countries. Lowering cardiometabolic risks through dietary, behavioural, and pharmacological interventions should be a part of the global response to non-communicable diseases. Funding: UK Medical Research Council, US National Institutes of Health. © 2014 Elsevier Ltd