scholarly journals The Role of RNA m6A Methylation in the Regulation of Postnatal Hypoxia-induced Pulmonary Hypertension

2020 ◽  
Author(s):  
shanshan xu ◽  
Xuefeng Xu ◽  
Ziming Zhang ◽  
Lingling Yan ◽  
Liyan Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Development ◽  
Systolic Pressure ◽  
Weight Ratio ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Adult Rats ◽  
The Impact

Abstract Background: Pulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that 1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and 2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH.Methods: Forty male Sprague-Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular systolic pressure (RVSP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue between 2 and 9 weeks following exposure to postnatal hypoxia.Results: mean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development.Conclusions: Our results indicate postnatal hypoxia dysregulates lung development, leading to PH, and may have a long-term effect on adult rat lung development via the alterations in pulmonary vasculature function. METTL3, a m6A methyltransferase, was elevated in rats exposed to postnatal hypoxia in both the postnatal period and in adulthood, suggesting that it contributes to the development of PH following postnatal hypoxia. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.

scholarly journals The role of RNA m6A methylation in the regulation of postnatal hypoxia-induced pulmonary hypertension

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Shanshan Xu ◽  
Xuefeng Xu ◽  
Ziming Zhang ◽  
Lingling Yan ◽  
Liyan Zhang ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Development ◽  
Weight Ratio ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Postnatal Exposure ◽  
Sprague Dawley ◽  
Adult Rats ◽  
The Impact

Abstract Background Pulmonary hypertension (PH) is a complex pulmonary vascular disease characterized by an imbalance in vasoconstrictor/vasodilator signaling within the pulmonary vasculature. Recent evidence suggests that exposure to hypoxia early in life can cause alterations in the pulmonary vasculature and lead to the development of PH. However, the long-term impact of postnatal hypoxia on lung development and pulmonary function remains unknown. N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of PH remains poorly characterized. Thus, the purpose of this investigation was to test the two-fold hypothesis that (1) postnatal exposure to hypoxia would alter lung development leading to PH in adult rats, and (2) m6A modification would change in rats exposed to hypoxia, suggesting it plays a role in the development of PH. Methods Twenty-four male Sprague–Dawley rats were exposed to a hypoxic environment (FiO2: 12%) within 24 h after birth for 2 weeks. PH was defined as an increased right ventricular pressure (RVP) and pathologic changes of pulmonary vasculature measured by α-SMA immunohistochemical staining. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) was performed to analyze m6A modification changes in lung tissue in 2- and 9-week-old rats that were exposed to postnatal hypoxia. Results Mean pulmonary arterial pressure, lung/body weight ratio, and the Fulton index was significantly greater in rats exposed to hypoxia when compared to control and the difference persisted into adulthood. m6A methyltransferase and demethylase proteins were significantly downregulated in postnatal hypoxia-induced PH. Distinct m6A modification peak-related genes differed between the two groups, and these genes were associated with lung development. Conclusions Our results indicate postnatal hypoxia can cause PH, which can persist into adulthood. The development and persistence of PH may be because of the continuous low expression of methyltransferase like 3 affecting the m6A level of PH-related genes. Our findings provide new insights into the impact of postnatal hypoxia and the role of m6A in the development of pulmonary vascular pathophysiology.

The unexpected role of PI3-kinase gamma in pulmonary hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
L Feik ◽  
E Berghausen ◽  
M Zierden ◽  
E Hirsch ◽  
S Baldus ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Specific Inhibitor ◽  
Left Ventricular ◽  
Brdu Incorporation ◽  
Pulmonary Vascular Disease ◽  
High Morbidity ◽  
Pulmonary Arterial ◽  
The Impact

Abstract Introduction Pulmonary hypertension (PH) is a pulmonary vascular disease that is associated with unacceptably high morbidity and mortality. PH is characterized by chronically increased pulmonary arterial pressure, increased pulmonary vascular resistance and right ventricular (RV) dysfunction and hypertrophy. Underlying mechanisms include increased proliferation and reduced apoptosis of both vascular smooth muscle cells (SMC) and endothelial cells (EC), as well as dysregulated immune responses. We have previously shown that class IA phosphatidylinositol-3-kinase (PI3K) isoforms, activated via receptor tyrosine kinases, are critically involved in the pathogenesis of PH. However, recent findings suggest that the class IB isoform PI3Kγ, which is activated downstream of G protein coupled receptors, is also important. It has been shown that PI3Kγ is involved in numerous processes that promote both vascular remodelling and maladaptive cardiac hypertrophy, including leukocyte recruitment, expression of proinflammatory chemokines and cytokines, as well as SMC and EC proliferation and survival. Therefore, the aim of our study was to investigate the role of PI3Kγ in the pathogenesis of PH. Methods The impact of PI3Kγ on the pathogenesis of PH was analysed in vivo using mice expressing a catalytically inactive form of PI3Kγ (PI3KγKD/KD) in the hypoxia-induced mouse model of PH. Mice were kept at 10%O2 (HOX) for 21 days or left under normoxic conditions (NOX). Subsequently, systolic right ventricular pressure (RVSP) was measured with a pressure catheter. RV hypertrophy was expressed as the ratio of RV weight to left ventricular + septum weight. Migration and proliferation of human pulmonary arterial SMC (hPASMC) as well as EC (hMVEC) were analysed using a PI3Kγ isoform-specific inhibitor (AS605240 [0.1; 0.3; 1μM]). Chemotaxis was determined by means of a modified Boyden chamber, and proliferation was quantified by a Bromodeoxyuridine (BrdU) incorporation assay. Results Whereas PI3Kγ inactivation had no effect on NOX animals, hypoxia led to increased RVSP and RV hypertrophy in WT animals (34.67±2.02 mmHg; 0.38±0.087) which were unexpectedly further increased in PI3KγKD/KD mice (37.67±1.3 mmHg, p=0.0104 vs. HOX WT; 0.47±0.06, p=0.0155 vs. HOX WT). Heart rate and systemic blood pressure remained unchanged. Inhibition of PI3Kγ by means of AS605240 did not affect proliferation of hPASMC and hMVEC, induced by multiple stimuli (FCS [10%], PDGF-BB [30ng/ml], or CXCL12 [100ng/ml], VEGF [50ng/ml]), respectively. However, FCS-induced migration of these cells was significantly reduced by AS605240 [0.3μM] (p<0.05). Conclusion Contrary to our expectations, the results show that kinase inactivation of PI3Kγ was not able to attenuate the pathogenesis of PH, but surprisingly led to a significant increase without critically changing cellular responses of SMC and EC. Therefore, our results indicate an unexpected protective effect of PI3Kγ on PH. Funding Acknowledgement Type of funding source: None

Covid-19 In Man: A Very Dangerous Affair.

2021 ◽  
Vol 21 ◽  
Author(s):  
Giuseppe Lisco ◽  
Vito A. Giagulli ◽  
Giovanni De Pergola ◽  
Anna De Tullio ◽  
Edoardo Guastamacchia ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Metabolic Diseases ◽  
Systemic Disease ◽  
Public Health Issue ◽  
Immune System Dysfunction ◽  
Data Support ◽  
Systemic Spread ◽  
The Impact

Background: The novel pandemic of Coronavirus disease 2019 (COVID-19) has becoming a public health issue since March 2020 considering that more than 30 million people were found to be infected worldwide. Particularly, recent evidences suggested that men may be considered as at higher risk of poor prognosis or death once the infection occurred and concerns surfaced in regard of the risk of a possible testicular injury due to SARS-CoV-2 infection. Results: Several data support the existence of a bivalent role of testosterone (T) in driving poor prognosis in patients with COVID-19. On one hand, this is attributable to the fact that T may facilitate SARS-CoV-2 entry in human cells by means of an enhanced expression of transmembrane serine-protease 2 (TMPRSS2) and angiotensin-converting enzyme 2 (ACE2). At the same time, younger man with normal testicular function compared to women of similar age are prone to develop a blunted immune response against SARS-CoV-2, being exposed to less viral clearance and more viral shedding and systemic spread of the disease. Conversely, low levels of serum T observed in hypogonadal men predispose them to a greater background systemic inflammation, cardiovascular and metabolic diseases, and immune system dysfunction, hence driving harmful consequences once SARS-CoV-2 infection occurred. Finally, SARS-CoV-2, as a systemic disease, may also affect testicles with possible concerns for current and future testicular efficiency. Preliminary data suggested that SARS-CoV-2 genome is not normally found in gonads and gametes, therefore sex transmission could be excluded as a possible way to spread the COVID-19. Conclusion: Most data support a role of T as a bivalent risk factor for poor prognosis (high/normal in younger; lower in elderly) in COVID-19. However, the impact of medical treatment aimed to modify T homeostasis for improving the prognosis of affected patients is unknown in this clinical setting. In addition, testicular damage may be a harmful consequence of the infection even in case it occurred asymptomatically but no long-term evidences are currently available to confirm and quantify this phenomenon. Different authors excluded the presence of SARS-CoV-2 in sperm and oocytes, thus limiting worries about both a potential sexual and gamete-to-embryos transmission of COVID-19. Despite these evidence, long-term and well-designed studies are needed to clarify these issues.

scholarly journals Long-term changes in the plant ecology of an African savanna landscape and the implications for ecosystem theory and conservation management

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
David Western ◽  
Victor N. Mose ◽  
David Maitumo ◽  
Caroline Mburu
Keyword(s):  
Human Impact ◽  
National Parks ◽  
Conservation Management ◽  
Plant Ecology ◽  
Ecological Resilience ◽  
Pasture Production ◽  
Ecosystem Theory ◽  
The Impact

Abstract Background Studies of the African savannas have used national parks to test ecological theories of natural ecosystems, including equilibrium, non-equilibrium, complex adaptive systems, and the role of top-down and bottom-up physical and biotic forces. Most such studies have excluded the impact of pastoralists in shaping grassland ecosystems and, over the last half century, the growing human impact on the world’s rangelands. The mounting human impact calls for selecting indicators and integrated monitoring methods able to track ecosystem changes and the role of natural and human agencies. Our study draws on five decades of monitoring the Amboseli landscape in southern Kenya to document the declining role of natural agencies in shaping plant ecology with rising human impact. Results We show that plant diversity and productivity have declined, biomass turnover has increased in response to a downsizing of mean plant size, and that ecological resilience has declined with the rising probability of extreme shortfalls in pasture production. The signature of rainfall and physical agencies in driving ecosystem properties has decreased sharply with growing human impact. We compare the Amboseli findings to the long-term studies of Kruger and Serengeti national parks to show that the human influence, whether by design or default, is increasingly shaping the ecology of savanna ecosystems. We look at the findings in the larger perspective of human impact on African grasslands and the world rangelands, in general, and discuss the implications for ecosystem theory and conservation policy and management. Conclusions The Amboseli study shows the value of using long-term integrated ecological monitoring to track the spatial and temporal changes in the species composition, structure, and function of rangeland ecosystems and the role of natural and human agencies in the process of change. The study echoes the widespread changes underway across African savannas and world’s rangelands, concluding that some level of ecosystem management is needed to prevent land degradation and the erosion of ecological function, services, and resilience. Despite the weak application of ecological theory to conservation management, a plant trait-based approach is shown to be useful in explaining the macroecological changes underway.

4971Blood viscosity and its relevance to the diagnosis and management of pulmonary hypertension: a new elephant in the cathlab

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kempny ◽  
K Dimopoulos ◽  
A E Fraisse ◽  
G P Diller ◽  
L C Price ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Cardiac Catheterization ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Significant Difference ◽  
The Difference ◽  
Clinically Significant ◽  
The Relationship

Abstract Background Pulmonary vascular resistance (PVR) is an essential parameter assessed during cardiac catheterization. It is used to confirm pulmonary vascular disease, to assess response to targeted pulmonary hypertension (PH) therapy and to determine the possibility of surgery, such as closure of intra-cardiac shunt or transplantation. While PVR is believed to mainly reflect the properties of the pulmonary vasculature, it is also related to blood viscosity (BV). Objectives We aimed to assess the relationship between measured (mPVR) and viscosity-corrected PVR (cPVR) and its impact on clinical decision-making. Methods We assessed consecutive PH patients undergoing cardiac catheterization. BV was assessed using the Hutton method. Results We included 465 patients (56.6% female, median age 63y). The difference between mPVR and cPVR was highest in patients with abnormal Hb levels (anemic patients: 5.6 [3.4–8.0] vs 7.8Wood Units (WU) [5.1–11.9], P<0.001; patients with raised Hb: 10.8 [6.9–15.4] vs. 7.6WU [4.6–10.8], P<0.001, respectively). Overall, 33.3% patients had a clinically significant (>2.0WU) difference between mPVR and cPVR, and this was more pronounced in those with anemia (52.9%) or raised Hb (77.6%). In patients in the upper quartile for this difference, mPVR and cPVR differed by 4.0WU [3.4–5.2]. Adjustment of PVR required Conclusions We report, herewith, a clinically significant difference between mPVR and cPVR in a third of contemporary patients assessed for PH. This difference is most pronounced in patients with anemia, in whom mPVR significantly underestimates PVR, whereas in most patients with raised Hb, mPVR overestimates it. Our data suggest that routine adjustment for BV is necessary.

The Role of UBI in Mitigating the Effects of Psychosocial Stressors: A Review and Proposal

2021 ◽  
pp. 003329412110051
Author(s):  
Rashmi Gupta ◽  
Jemima Jacob ◽  
Gaurav Bansal
Keyword(s):  
Role Stress ◽  
Psychosocial Stressors ◽  
Basic Income ◽  
Economic Stability ◽  
The Past ◽  
Individual Outcomes ◽  
Long Term Impact ◽  
The Impact

Psychosocial stressors and social disadvantages contribute to inequalities in opportunities and outcomes. In the current paper, we use an epidemiological perspective and highlight the role stress plays on individuals by reviewing the outcomes of major stressors such as poverty and unemployment. We further analyzed the psychological and physical cost of these stressors and their long-term impact. We examined the role of universal basic income and closely looked at income experiments that were implemented in the past, in terms of their effectiveness in enhancing the community as well as individual outcomes and propose the UBI as a tool for alleviating the impact of these stressors. At a time when a major pandemic (e.g., COVID-19) threatens economic stability and health globally, we believe the UBI is relevant now, more than ever.

Abstract 15388: Persistent Pulmonary Hypertension After Transcatheter Aortic Valve Implantation: Impact on Mortality

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Maria Drakopoulou ◽  
Konstantinos Stathogiannis ◽  
Konstantinos Toutouzas ◽  
George Latsios ◽  
Andreas Synetos ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Aortic Stenosis ◽  
Pulmonary Artery ◽  
Severe Aortic Stenosis ◽  
Systolic Pressure ◽  
Right Atrial ◽  
Pulmonary Artery Systolic Pressure ◽  
End Point ◽  
The Right ◽  
The Impact

Objective: Severe aortic stenosis leads to increased pulmonary arterial systolic pressure. A controversy still remains regarding the impact of persistent pulmonary hypertension (PHT) on prognosis of patients undergoing transcatheter aortic valve implantation (TAVI). We sought to investigate the impact of persistent PHT on 2-year all-cause mortality of patients with severe aortic stenosis following TAVI. Methods: Patients with severe and symptomatic aortic stenosis (effective orifice area [EOA]≤1 cm 2 ) who were scheduled for TAVI with a self-expanding valve at our institution were prospectively enrolled. Prospectively collected echocardiographic data before and after TAVI were retrospectively analyzed in all patients. Pulmonary artery systolic pressure was estimated as the sum of the right ventricular to the right atrial gradient during systole and the right atrial pressure. PHT following TAVI was classified as absent if <35 mmHg and persistent if ≥35 mmHg. Primary clinical end-point was 2-year all-cause mortality defined according to the criteria proposed by the Valve Academic Research Consortium-2. Results: Hundred and forty patients (mean age: 82±9 years) were included in the study. The primary clinical end point occurred in 17 patients (12%) during a median follow-up period of 2 years. Mean pulmonary artery systolic pressure was reduced in all patients following TAVI (45±9 versus 41±6 mmHg, p<0.01). Mortality rate was higher in patients with persistent PHT compared to patients with normal pulmonary artery systolic pressure following TAVI (26% versus 14 %, p<0.01). Patients that reached the primary clinical end point had a higher post procedural mean systolic pulmonary pressure (43±9 versus 39±6 mmHg, p=0.02). In multivariate regression analysis, persistence of PHT (OR: 2.51, 95% CI: 1.109-7.224, p=0.01) was an independent predictor of long-term mortality. Conclusions: The persistence of pulmonary hypertension after TAVI is associated with long term mortality. Identifying the population that will clearly benefit from TAVI is still need to be validated by larger trials.

The Sexual Experience of Married Middle-Aged Women as a Source of Mental Wellbeing: Perceptions, Challenges and Coping Mechanisms

2021 ◽  
Vol 30 (1) ◽  
pp. 181-203
Author(s):  
Tal Braverman-Uriel ◽  
Tal Litvak-Hirsch
Keyword(s):  
Quantitative Research ◽  
Sexual Experience ◽  
Women's Leadership ◽  
Mental Wellbeing ◽  
Structured Interviews ◽  
Significant Development ◽  
And Coping ◽  
The Impact

The impact of sexuality on mental wellbeing in women in long-term relationships has only been partially investigated. Emphasis has been on quantitative research studies that do not capture the breadth of the field. The present study looked at how and to what extent women maintain sexual desire in long-term relationships, and how sexuality affects their mental wellbeing. The study used a qualitative narrative approach and included semi-structured interviews with approximately 20 Israeli women aged 40–55 from similar socioeconomic backgrounds and in longstanding, permanent relationships. The findings indicate significant development over the years in the perception of the role of sexuality and its impact on mental wellbeing. The path to good sexuality can and should follow women’s leadership and initiative. Such women have the desire to make an impact, willingness to make an effort, and even an actual ability to exert influence. The interviewees’ tools, strategies, insights and ways of coping can serve as models for other women seeking better sexuality in a long-term relationship.

scholarly journals Has erosion globally increased? Long-term erosion rates as a function of climate derived from the impact crater inventory

2018 ◽  
Author(s):  
Stefan Hergarten ◽  
Thomas Kenkmann
Keyword(s):  
Time Scale ◽  
Impact Crater ◽  
Regional Effect ◽  
Tropical Zone ◽  
Erosion Rates ◽  
Continental Scale ◽  
River Loads ◽  
The Impact

Abstract. Worldwide erosion rates seem to have increased strongly since the beginning of the Quaternary, but there is still discussion about the role of glaciation as a potential driver and even whether the increase is real at all or an artefact due to losses in the long-term sedimentary record. In this study we derive estimates of average erosion rates on the time scale of some tens of million years from the terrestrial impact crater inventory. This approach is completely independent from all other methods to infer erosion rates such as river loads, preserved sediments, cosmogenic nuclides and thermochronometry. Our approach yields average erosion rates as a function of present-day topography and climate. The results confirm that topography accounts for the main part of the huge variation of erosion on Earth, but also identifies a significant systematic dependence on climate in contrast to several previous studies. We found a fivefold increase in erosional efficacy from the cold regimes to the tropical zone and that temperate and arid climates are very similar in this context. Combining our results to a worldwide mean erosion rate we found that erosion rates on the time scale of some tens of million years are at least as high as present-day rates and suggest that glaciation has a rather regional effect with a limited impact at the continental scale.

Persistent Pulmonary Hypertension of the Newborn: Role of Nitric Oxide

1995 ◽  
Vol 10 (6) ◽  
pp. 270-282
Author(s):  
Stella Kourembanas
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Hypertension ◽  
Structural Changes ◽  
Critical Role ◽  
Persistent Pulmonary Hypertension ◽  
Cell Contractility ◽  
Vasoactive Mediators ◽  
Nitric Oxide Therapy

Persistent pulmonary hypertension of the newborn (PPHN) is a common cause of respiratory failure in the full-term neonate. Molecular and cellular studies in vascular biology have revealed that endothelial-derived mediators play a critical role in the pathogenesis and treatment of PPHN. Endothelial-derived vasoconstrictors, like endothelin, may increase smooth muscle cell contractility and growth, leading to the physiologic and structural changes observed in the pulmonary arterioles of infants with this disease. On the other hand, decreased production of the endothelial-derived relaxing factor, nitric oxide, may exacerbate pulmonary vasoreactivity and lead to more severe pulmonary hypertension. Exogenous (inhaled) nitric oxide therapy reduces pulmonary vascular resistance and improves oxygenation. The safety and efficacy of this therapy in reducing the need for extracorporeal membrane oxygenation and decreasing long-term morbidity is being tested in several trials nationally and abroad. Understanding the basic mechanisms that regulate the gene expression and production of these vasoactive mediators will lead to improved preventive and therapeutic strategies for PPHN.

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