Serotonin signaling through the 5-HT1B receptor and NADPH oxidase 1 in pulmonary arterial hypertension

Objective: Serotonin can induce human pulmonary artery smooth muscle cell (hPASMC) proliferation through reactive oxygen species (ROS), influencing the development of pulmonary arterial hypertension (PAH). We hypothesise that in PASMCs, serotonin induces oxidative stress through NADPH-oxidase-derived ROS generation and reduced Nrf-2 anti-oxidant systems, promoting vascular injury. Approach and Results: HPASMCs from controls and PAH patients, and PASMCs from Nox1-/- mice, were stimulated with serotonin in the absence/presence of inhibitors of Src kinase, the 5-HT1B receptor and NADPH oxidase 1 (Nox1). Markers of fibrosis were also determined. The pathophysiological significance of our findings was examined in vivo in serotonin transporter overexpressing (SERT+) female mice, a model of pulmonary hypertension (PH). We confirmed serotonin increased superoxide and H2O2 production in these cells. For the first time, we show that serotonin increased oxidized protein tyrosine phosphatases and peroxiredoxin-SO3H and decreased Nrf-2 and catalase activity in hPASMCs. ROS generation was exaggerated, and dependent on c-Src, 5-HT1B receptor and the serotonin transporter in PAH-hPASMCs. Proliferation and extracellular matrix remodeling were exaggerated in PAH-hPASMCs and dependent on 5-HT1B receptor signaling and Nox1, confirmed in PASMCs from Nox1-/- mice. In SERT+ mice, SB216641, a 5-HT1B receptor antagonist, prevented development of PH in a ROS-dependent manner. Conclusions: Serotonin can induce c-Src-regulated Nox1-induced ROS and Nrf-2 dysregulation, contributing to increased post-translational oxidative modification of proteins, activation of redox-sensitive signaling pathways in hPASMCs; associated with mitogenic responses. 5-HT1B receptors contribute to experimental PH by inducing lung ROS production. Our results suggest 5-HT1B receptor-dependent c-Src-Nox1-pathways contribute to vascular remodeling in PAH

From Isotopes to TK Interviews: Towards Interdisciplinary Research in Fort Resolution and the Slave River Delta, Northwest Territories

Evolving research in Fort Resolution and the Slave River Delta, Northwest Territories, aims to improve understanding of how the natural ecosystem functions and responds to various environmental stressors, as well as to enhance the stewardship of natural resources and the capacity of local residents to respond to change. We seek to integrate approaches that span the natural and social sciences and traditional knowledge understandings of change, employing a research design developed in response to the concerns of a northern community. In doing so, we have strived for a research process that is collaborative, interdisciplinary, policy-oriented, and reflective of northern priorities. These elements characterize the new northern research paradigm increasingly promoted by various federal funding agencies, northern partners, and communities. They represent a holistic perspective in the pursuit of solutions to address complex environmental and socioeconomic concerns about impacts of climate change and resource development on northern societies. However, efforts to fulfill the objectives of this research paradigm are associated with a host of on-the-ground challenges. These challenges include (but are not restricted to) developing effective community partnerships and collaboration and documenting change through interdisciplinary approaches. Here we provide an overview of the components that comprise our interdisciplinary research program and offer an accounting of our formative experiences in confronting these challenges

Age truncation and portfolio effects in Puget Sound Pacific herring

Forage fish undergo dramatic changes in abundance through time. Long-term fluctuations, which have historically been attributed to changes in recruitment, may also be due to changes in adult mortality. Pacific herring, a lightly exploited forage fish in Puget Sound, WA, have exhibited shifts in age structure and decreases in spawning biomass during the past 30 years. Here, we investigate changes in adult mortality as a potential explanation for these shifts. Using a hierarchical, age-structured population model, we indicate that adult natural mortality for Puget Sound Pacific herring has increased since 1973. We find that natural mortality has increased for every age class of adult (age 3+), especially age 4 fish, whose estimated mortality has doubled over the survey time period (from M=0.84 to M=1.76). We demonstrate that long-term shifts in mortality explain changes in age structure, and may explain biomass declines and failure to reach management thresholds for some spawning sites in Puget Sound. Temporal shifts in natural adult mortality could have negative implications for herring and herring predators. For predators, these implications include a reduction in the stability of the herring resource

The Relationship Between Molecular Gas, HI, and Star Formation in the Low-Mass, Low-Metallicity Magellanic Clouds

The Magellanic Clouds provide the only laboratory to study the effect of metallicity and galaxy mass on molecular gas and star formation at high (~20 pc) resolution. We use the dust emission from HERITAGE Herschel data to map the molecular gas in the Magellanic Clouds, avoiding the known biases of CO emission as a tracer of H$_{2}$. Using our dust-based molecular gas estimates, we find molecular gas depletion times of ~0.4 Gyr in the LMC and ~0.6 SMC at 1 kpc scales. These depletion times fall within the range found for normal disk galaxies, but are shorter than the average value, which could be due to recent bursts in star formation. We find no evidence for a strong intrinsic dependence of the molecular gas depletion time on metallicity. We study the relationship between gas and star formation rate across a range in size scales from 20 pc to ~1 kpc, including how the scatter in molecular gas depletion time changes with size scale, and discuss the physical mechanisms driving the relationships. We compare the metallicity-dependent star formation models of Ostriker, McKee, and Leroy (2010) and Krumholz (2013) to our observations and find that they both predict the trend in the data, suggesting that the inclusion of a diffuse neutral medium is important at lower metallicity.Comment: 24 pages, 14 figures, accepted for publication in ApJ. FITS files of the dust-based estimates of the H2 column densities for the LMC and SMC (shown in Figures 2 and 3) will be available online through Ap

Nicotinamide adenine dinucleotide phosphate oxidase-mediated redox signaling and vascular remodeling by 16α-hydroxyestrone in human pulmonary artery cells

Estrogen and oxidative stress have been implicated in pulmonary arterial hypertension (PAH). Mechanisms linking these systems are elusive. We hypothesized that estrogen metabolite, 16α-hydroxyestrone (16αOHE1), stimulates nicotinamide adenine dinucleotide phosphate oxidase (Nox)-induced reactive oxygen species (ROS) generation and proliferative responses in human pulmonary artery smooth muscle cells (hPASMCs) and that in PAH aberrant growth signaling promotes vascular remodeling. The pathophysiological significance of estrogen-Nox-dependent processes was studied in female Nox1 -/- and Nox4 -/- mice with PAH. PASMCs from control subjects (control hPASMCs) and PAH patients (PAH-hPASMCs) were exposed to estrogen and 16αOHE1 in the presence/absence of inhibitors of Nox, cytochrome P450 1B1, and estrogen receptors. Estrogen, through estrogen receptor-α, increased Nox-derived ROS and redox-sensitive growth in hPASMCs, with greater effects in PAH-hPASMCs versus control hPASMCs. Estrogen effects were inhibited by cytochrome P450 1B1 blockade. 16αOHE1 stimulated transient ROS production in hPASMCs, with sustained responses in PAH-hPASMCs. Basal expression of Nox1/Nox4 was potentiated in PAH-hPASMCs. In hPASMCs, 16αOHE1 increased Nox1 expression, stimulated irreversible oxidation of protein tyrosine phosphatases, decreased nuclear factor erythroid-related factor 2 activity and expression of nuclear factor erythroid-related factor 2-regulated antioxidant genes, and promoted proliferation. This was further amplified in PAH-hPASMCs. Nox1 -/- but not Nox4 -/- mice were protected against PAH and vascular remodeling. Our findings demonstrate that in PAH-hPASMCs, 16αOHE1 stimulates redox-sensitive cell growth primarily through Nox1. Supporting this, in vivo studies exhibited protection against pulmonary hypertension and remodeling in Nox1 -/- mice. This study provides new insights through Nox1/ROS and nuclear factor erythroid-related factor 2 whereby 16αOHE1 influences hPASMC function, which when upregulated may contribute to vascular injury in PAH, particularly important in women

A new Holocene sea-level record for Singapore

Relative sea-level (RSL) records from far-field regions distal from ice sheets remain poorly understood, particularly in the early Holocene. Here, we extended the Holocene RSL data from Singapore by producing early Holocene sea-level index points (SLIPs) and limiting dates from a new ~40 m sediment core. We merged new and published RSL data to construct a standardized Singapore RSL database consisting of 88 SLIPs and limiting data. In the early Holocene, RSL rose rapidly from −21.0 to −0.7 m from ~9500 to 7000 cal. yrs. BP. Thereafter, the rate of RSL rise decelerated, reaching a mid-Holocene highstand of 4.0 ± 4.5 m at 5100 cal. yrs. BP, before falling to its present level. There is no evidence of any inflections in RSL when the full uncertainty of SLIPs is considered. When combined with other standardized data from the Malay-Thai Peninsula, our results also show substantial misfits between regional RSL reconstructions and glacial isostatic adjustment (GIA) model predictions in the rate of early Holocene RSL rise, the timing of the mid-Holocene highstand and the nature of late-Holocene RSL fall towards the present. It is presently unknown whether these misfits are caused by regional processes, such as subsidence of the continental shelf, or inaccurate parameters used in the GIA model

THE RELATIONSHIP BETWEEN MOLECULAR GAS, H I, AND STAR FORMATION IN THE LOW-MASS, LOW-METALLICITY MAGELLANIC CLOUDS

The Magellanic Clouds provide the only laboratory to study the effects of metallicity and galaxy mass on molecular gas and star formation at high (∼20 pc) resolution. We use the dust emission from HERITAGE Herschel data to map the molecular gas in the Magellanic Clouds, avoiding the known biases of CO emission as a tracer of . Using our dust-based molecular gas estimates, we find molecular gas depletion times () of ∼0.4 Gyr in the Large Magellanic Cloud and ∼0.6 in the Small Magellanic Cloud at 1 kpc scales. These depletion times fall within the range found for normal disk galaxies, but are shorter than the average value, which could be due to recent bursts in star formation. We find no evidence for a strong intrinsic dependence of the molecular gas depletion time on metallicity. We study the relationship between the gas and the star formation rate across a range of size scales from 20 pc to ≥1 kpc, including how the scatter in changes with the size scale, and discuss the physical mechanisms driving the relationships. We compare the metallicity-dependent star formation models of Ostriker et al. and Krumholz to our observations and find that they both predict the trend in the data, suggesting that the inclusion of a diffuse neutral medium is important at lower metallicit

From Isotopes to TK Interviews: Towards Interdisciplinary Research in Fort Resolution and the Slave River Delta, Northwest Territories

Evolving research in Fort Resolution and the Slave River Delta, Northwest Territories, aims to improve understanding of how the natural ecosystem functions and responds to various environmental stressors, as well as to enhance the stewardship of natural resources and the capacity of local residents to respond to change. We seek to integrate approaches that span the natural and social sciences and traditional knowledge understandings of change, employing a research design developed in response to the concerns of a northern community. In doing so, we have strived for a research process that is collaborative, interdisciplinary, policy-oriented, and reflective of northern priorities. These elements characterize the new northern research paradigm increasingly promoted by various federal funding agencies, northern partners, and communities. They represent a holistic perspective in the pursuit of solutions to address complex environmental and socioeconomic concerns about impacts of climate change and resource development on northern societies. However, efforts to fulfill the objectives of this research paradigm are associated with a host of on-the-ground challenges. These challenges include (but are not restricted to) developing effective community partnerships and collaboration and documenting change through interdisciplinary approaches. Here we provide an overview of the components that comprise our interdisciplinary research program and offer an accounting of our formative experiences in confronting these challenges.Des travaux de recherche en cours à Fort Resolution et dans le delta de la rivière des Esclaves, aux Territoires du Nord-Ouest, visent à mieux comprendre le fonctionnement de l’écosystème naturel, à réagir aux divers facteurs d’agression environnementaux ainsi qu’à rehausser la gérance des ressources naturelles et la capacité des habitants de la région à réagir au changement. Nous cherchons à intégrer des méthodes qui englobent les sciences naturelles et sociales et favorisent la compréhension du changement du point de vue des connaissances traditionnelles. Nous cherchons également à employer une méthodologie respectueuse des inquiétudes de la collectivité du Nord. Ce faisant, nous avons abouti à un processus de recherche caractérisé par la collaboration, l’interdisciplinarité et les politiques, processus qui tient également compte des priorités dans le Nord. Ces éléments définissent le nouveau paradigme de recherche dans le Nord qui est de plus en plus préconisé par divers organismes de subvention fédéraux, partenaires du Nord et collectivités. Ils représentent une perspective holistique en guise de solutions à des enjeux environnementaux et socioéconomiques complexes portant sur les incidences du changement climatique et de l’exploitation des ressources sur les sociétés du Nord. Toutefois, les efforts visant à concrétiser les objectifs de ce paradigme de recherche font face à une multitude de défis. Ces défis comprennent (mais sans s’y restreindre) la formation de partenariats efficaces avec les collectivités, des efforts de collaboration et la prise de notes sur les changements qui s’opèrent grâce à des méthodes interdisciplinaires. Ici, nous fournissons un aperçu des éléments de notre programme de recherche interdisciplinaire et donnons un aperçu de l’expérience formative qui a découlé de ces défis