Search

BACKGROUND: Pulmonary hypertension (PH) represents an important phenotype in heart failure with preserved ejection fraction (HFpEF). However, management of PH-HFpEF is challenging because mechanisms involved in the regulation of PH-HFpEF remain unclear. METHODS: We used a mass spectrometry-based comparative plasma proteomics approach as a sensitive and comprehensive hypothesis-generating discovery technique to profile proteins in patients with PH-HFpEF and control subjects. We then validated and investigated the role of one of the identified proteins using in vitro cell cultures, in vivo animal models, and independent cohort of human samples. RESULTS: Plasma proteomics identified high protein abundance levels of B2M (β2-microglobulin) in patients with PH-HFpEF. Interestingly, both circulating and skeletal muscle levels of B2M were increased in mice with skeletal muscle SIRT3 (sirtuin-3) deficiency or high-fat diet-induced PH-HFpEF. Plasma and muscle biopsies from a validation cohort of PH-HFpEF patients were found to have increased B2M levels, which positively correlated with disease severity, especially pulmonary capillary wedge pressure and right atrial pressure at rest. Not only did the administration of exogenous B2M promote migration/proliferation in pulmonary arterial vascular endothelial cells but it also increased PCNA (proliferating cell nuclear antigen) expression and cell proliferation in pulmonary arterial vascular smooth muscle cells. Finally, B2m deletion improved glucose intolerance, reduced pulmonary vascular remodeling, lowered PH, and attenuated RV hypertrophy in mice with high-fat diet-induced PH-HFpEF. CONCLUSIONS: Patients with PH-HFpEF display higher circulating and skeletal muscle expression levels of B2M, the magnitude of which correlates with disease severity. Our findings also reveal a previously unknown pathogenic role of B2M in the regulation of pulmonary vascular proliferative remodeling and PH-HFpEF. These data suggest that circulating and skeletal muscle B2M can be promising targets for the management of PH-HFpEF.

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α-null or ER-β-null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.

ObjectivePulmonary hypertension (PH) due to left heart disease (group 2), especially in the setting of heart failure with preserved ejection fraction (HFpEF), is the most common cause of PH worldwide; however, at present, there is no proven effective therapy available for its treatment. PH-HFpEF is associated with insulin resistance and features of metabolic syndrome. The stable prostacyclin analog, treprostinil, is an effective and widely used Food and Drug Administration-approved drug for the treatment of pulmonary arterial hypertension. While the effect of treprostinil on metabolic syndrome is unknown, a recent study suggests that the prostacyclin analog beraprost can improve glucose intolerance and insulin sensitivity. We sought to evaluate the effectiveness of treprostinil in the treatment of metabolic syndrome-associated PH-HFpEF. Approach and Results: Treprostinil treatment was given to mice with mild metabolic syndrome-associated PH-HFpEF induced by high-fat diet and to SU5416/obese ZSF1 rats, a model created by the treatment of rats with a more profound metabolic syndrome due to double leptin receptor defect (obese ZSF1) with a vascular endothelial growth factor receptor blocker SU5416. In high-fat diet-exposed mice, chronic treatment with treprostinil reduced hyperglycemia and pulmonary hypertension. In SU5416/Obese ZSF1 rats, treprostinil improved hyperglycemia with similar efficacy to that of metformin (a first-line drug for type 2 diabetes mellitus); the glucose-lowering effect of treprostinil was further potentiated by the combined treatment with metformin. Early treatment with treprostinil in SU5416/Obese ZSF1 rats lowered pulmonary pressures, and a late treatment with treprostinil together with metformin improved pulmonary artery acceleration time to ejection time ratio and tricuspid annular plane systolic excursion with AMPK (AMP-activated protein kinase) activation in skeletal muscle and the right ventricle.ConclusionsOur data suggest a potential use of treprostinil as an early treatment for mild metabolic syndrome-associated PH-HFpEF and that combined treatment with treprostinil and metformin may improve hyperglycemia and cardiac function in a more severe disease.

Star-galaxy separation is a crucial step in creating target catalogues for extragalactic spectroscopic surveys. A classifier biased towards inclusivity risks including high numbers of stars, wasting fibre hours, while a more conservative classifier might overlook galaxies, compromising completeness and hence survey objectives. To avoid bias introduced by a training set in supervised methods, we employ an unsupervised machine learning approach. Using photometry from the Wide Area VISTA Extragalactic Survey (WAVES)-Wide catalogue comprising nine-band |$u - K_s$| data, we create a feature space with colours, fluxes, and apparent size information extracted by ProFound. We apply the non-linear dimensionality reduction method UMAP (Uniform Manifold Approximation and Projection) combined with the classifier hdbscan (Hierarchical Density-Based Spatial Clustering of Applications with Noise) to classify stars and galaxies. Our method is verified against a baseline colour and morphological method using a truth catalogue from Gaia , SDSS (Sloan Digital Sky Survey), GAMA (Galaxy And Mass Assembly), and DESI (Dark Energy Spectroscopic Instrument). We correctly identify 99.75 per cent of galaxies within the AB magnitude limit of |$Z=21.2$|⁠ , with an F1 score of |$0.9971 \pm 0.0018$| across the entire ground truth sample, compared to |$0.9879 \pm 0.0088$| from the baseline method. Our method's higher purity (⁠|$0.9967 \pm 0.0021$|⁠) compared to the baseline (⁠|$0.9795 \pm 0.0172$|⁠) increases efficiency, identifying 11 per cent fewer galaxy or ambiguous sources, saving approximately 70 000 fibre hours on the 4MOST (4-m Multi-Object Spectroscopic Telescope) instrument. We achieve reliable classification statistics for challenging sources including quasars, compact galaxies, and low surface brightness galaxies, retrieving 92.7 per cent, 84.6 per cent, and 99.5 per cent of them, respectively. Angular clustering analysis validates our classifications, showing consistency with expected galaxy clustering, regardless of the baseline classification. [ABSTRACT FROM AUTHOR]

Humans living at high-altitude (HA) have adapted to this environment by increasing pulmonary vascular and alveolar growth. RNA sequencing data from a novel murine model that mimics this phenotypical response to HA suggested estrogen signaling via estrogen receptor alpha (ERα) may be involved in this adaptation. We hypothesized ERα was a key mediator in the cardiopulmonary adaptation to chronic hypoxia and sought to delineate the mechanistic role ERα contributes to this process by exposing novel loss-of-function ERα mutant (ERαMut) rats to simulated HA. ERα mutant or wild-type (wt) rats were exposed to normoxia or hypoxia starting at conception and continued postnatally until 6 wk of age. Both wt and ERαMut animals born and raised in hypoxia exhibited lower body mass and higher hematocrits, total alveolar volumes (Va), diffusion capacities of carbon monoxide (DLCO), pulmonary arteriole (PA) wall thickness, and Fulton indices than normoxia animals. Right ventricle adaptation was maintained in the setting of hypoxia. Although no major physiologic differences were seen between wt and ERαMut animals at either exposure, ERαMut animals exhibited smaller mean linear intercepts (MLI) and increased PA total and lumen areas. Hypoxia exposure or ERα loss-of-function did not affect lung mRNA abundance of vascular endothelial growth factor, angiopoietin 2, or apelin. Sexual dimorphisms were noted in PA wall thickness and PA lumen area in ERαMut rats. In summary, in room air-exposed rats and rats with peri- and postnatal hypoxia exposure, ERα loss-of-function was associated with decreased alveolar size (primarily driven by hypoxic animals) and increased PA remodeling. NEW & NOTEWORTHY By exposing novel loss-of-function estrogen receptor alpha (Erα) mutant rats to a novel model of human high-altitude exposure, we demonstrate that ERα has subtle but inconsistent effects on endpoints relevant to cardiopulmonary adaptation to chronic hypoxia. Given that we observed some histologic, sex, and genotype differences, further research into cell-specific effects of ERα during hypoxia-induced cardiopulmonary adaptation is warranted. [ABSTRACT FROM AUTHOR]

Introduction Pulmonary arterial hypertension (PAH) is characterized by dysregulated vasoconstriction, muscularization of precapillary arteries, and formation of complex obstructive plexiform lesions in the pulmonary vasculature (1). This leads to increased [...], Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17[beta]-estradiol (E2), through estrogen receptor a (ER-[alpha]), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-[alpha] and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-[alpha] agonist. Studies employing ER-[alpha]-null or ER-[beta]-null mice, ER-[alpha] loss-of-function mutant rats, or siRNA demonstrated that ER-[alpha] is necessary for E2 to upregulate RV apelin. E2 and ER-[alpha] increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-[alpha] binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-[alpha] agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-[alpha]/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.

Abstract: Herein, we report an euselachian assemblage from the late Campanian Bearpaw Formation recovered from southern Alberta, Canada. This small yet uniquely diverse fauna includes the northernmost occurrences of Paraorthacodus [...]

A rich elasmobranch assemblage was recovered from the early Eocene (Ypresian) Fishburne Formation in a limestone quarry at Jamestown, Berkeley County, South Carolina, USA. Reported herein are 22 species belonging to 8 orders, at least 15 families, and 21 genera. It includes the first occurrence of Protoginglymostoma from North America. Many of the reported species have large palaeobiogeographical ranges and inhabited waters on both sides of the Atlantic, whereas others were endemic to the east coast of North America. The paucity of sizeable dentition from several of the larger species in this assemblage, and the apparent absence of relatively large macrophagous species found in contemporaneous deposits elsewhere, suggests the Jamestown site may represent a nursery ground and refuge for young and smaller individuals. Un riche assemblage d'elasmobranches a ete recupere de la Formation de Fishburne de l'Eocene precoce (Ypresien), dans une carriere de calcaire a Jamestown (comte de Berkeley, Caroline du Sud, Etats-Unis). Nous faisons etat de 22 especes appartenant a 8 ordres, au moins 15 familles et 21 genres. Elles comprennent le premier signalement de Protoginglymostoma en Amerique du Nord. Bon nombre des especes signalees sont caracterisees par une vaste aire de repartition paleobiogeographique et habitaient dans les eaux de part et d'autre de l'Atlantique, alors que d'autres etaient endemiques a la cote est de l'Amerique du Nord. La rarete de dentitions de grande taille pour plusieurs des plus grandes especes de l'assemblage et l'absence apparente d'especes macrophages relativement grandes observees dans des depots contemporains en d'autres endroits donnent a penser que le site de Jamestown pourrait representer une aire de croissance et de refuge pour de jeunes individus de petite taille. [Traduit par la Redaction], Introduction Late Cretaceous and Paleogene elasmobranch (shark and ray) assemblages have been recovered from numerous marine deposits along the Atlantic and Gulf coastal plains of the USA. Herein, we describe [...]

The Fayum Depression of Egypt has produced a great diversity of fossil material, including marine and freshwater fishes. In contrast to the Eocene formations of the Fayum, the Oligocene Jbel Qatrani Formation has been more or less consistently considered to be deposited in a freshwater environment; however, the ichthyofauna indicates a more complex picture. Cenozoic fishes have been convincingly used to interpret the palaeoenvironment in which sediments were deposited. Based on the elasmobranch and osteichthyan faunas of the Jbel Qatrani Formation, we interpret that this formation was not deposited entirely in fresh waters, but had some marine influence, particularly in the lower part of the formation. The mixture of freshwater elements, such as polypterids and alestids, with brackish and marine elements, including myliobatid stingrays, in the Quarry E site suggests a local palaeoenvironment that was very close to the shoreline, in a less protected area, or under more seasonal influence than the rest of the sites in the formation. Additionally, the early Oligocene elasmobranch fishes from Quarry E have a strong biogeographic relationship with sites in Oman and Pakistan, in the eastern Tethys, representing a restricted fauna possibly limited in distribution by cooling global temperatures. La depression du Fayoum en Egypte a produit une grande variete de materiel fossile, dont des poissons marins et d'eau douce. Contrairement aux formations eocenes de la depression, la Formation oligocene de Jbel Qatrani est plus ou moins uniformement consideree comme ayant ete deposee dans un milieu dulcicole. Son ichtyofaune reflete toutefois un portrait plus complexe. Des poissons cenozoiques ont ete utilises de maniere convaincante pour interpreter le paleomilieu dans lequel les sediments ont ete deposes. A la lumiere des faunes d'elasmobranches et d'osteichtyens de la Formation de Jbel Qatrani, nous proposons que cette formation n'a pas ete deposee exclusivement en eau douce, mais qu'elle a egalement subi des influences marines, particulierement en ce qui concerne sa partie inferieure. Le melange, dans le site de la carriere E, d'elements d'eau douce, comme des polypterides et des alestides, et d'elements de milieu saumatre et marin, comme des myliobatides, donne a penser que le paleomilieu local etait tres proche du rivage, dans une zone moins protegee ou sous influence plus saisonniere que les autres sites de la formation. En outre, les elasmobranches de l'Oligocene precoce de la carriere E presentent un fort lien biogeographique avec des sites a Oman et au Pakistan, dans la Tethys orientale, representant une faune restreinte dont le refroidissement des temperatures planetaires a possiblement limite la repartition. [Traduit par le Redaction], Introduction The late Eocene to early Oligocene marked a period of transition from the warmer climates of the early Eocene to cooler global temperatures associated with the onset of glaciation [...]

Myledaphus bipartitus is a Late Cretaceous (75 Ma) freshwater guitarfish, commonly represented by teeth and vertebral centra. The species was first described in 1876, but until now, very little has been known about its ecology and life history. We analyzed the age and growth using 117 fossilized centra (74 hemisectioned) from the Oldman and Dinosaur Park formations of southern Alberta. The resulting estimated maximum age was 16 years. Radial distance (RD) at the estimated asymptotic growth was calculated, and average RD at birth and 3 years were compared with two extant marine species of Rhinobatos (R. productus and R. rhinobatos). Birth ring size ranged from 0.9 to 1.8 mm RD. At age three, centrum RD was between 2.8 and 4.6 mm RD for M. bipartitus and significantly less than R. productus and R. rhinobatos (5.0-6.6 mm RD). Myledaphus approached 'asymptotic' growth at 7.8 mm RD in the growth equation. The growth trajectory of Myledaphus had a similar slope to the Rhinobatos species, but with significantly smaller centrum RD. Rhinobatos rhinobatos also outlived Myledaphus by 8 years. Myledaphus bipartitus est un poisson-guitare d'eau douce du Cretace tardif (75 Ma) communement represente par des dents et des centres vertebraux. L'espece a ete decrite pour la premiere fois en 1876, mais jusqu'a present, les connaissances sur son ecologie et son cycle de vie etaient tres limitees. Nous en avons analyse l'age et la croissance a la lumiere de 117 centres fossilises (74 hemisectionnes) des Formations d'Oldman et de Dinosaur Park du sud de l'Alberta. L'age maximum ainsi estime etait de 16 ans. La distance radiale (RD) au taux de croissance asymptotique estime a ete calculee, et les RD moyennes a la naissance et a trois ans ont ete comparees a celles de deux especes marines actuelles de Rhinobatos (R. productus et R. rhinobatos). La taille des anneaux a la naissance, en termes de RD, va de 0,9 mm a 1,8 mm. A 3 ans, la RD des centres va de 2,8 mm a 4,6 mm pour M. bipartitus et est significativement plus faible que celles de R. productus et R. rhinobatos (RD de 5,0-6,6 mm). Myledaphus s'approche de la croissance << asymptotique >> a une RD de 7,8 mm dans l'equation de croissance. La trajectoire de croissance de Myledaphus presente une pente semblable a celle des especes de Rhinobatos, bien qu'avec des RD des centres significativement plus faibles. La duree de vie de Rhinobatos rhinobatos surpasse egalement de 8 ans celle de Myledaphus. [Traduit par la Redaction], Introduction Myledaphus bipartitus, Cope, 1876, is a Late Cretaceous enigmatic freshwater batoid represented predominantly by isolated teeth (Cappetta 2012). It is known from various Campanian formations such as the Oldman [...]

A euselachian assemblage was recovered from the middle Cenomanian Dunvegan Formation situated in northwestern Alberta. This assemblage is the most northern described within the Western Interior Seaway and provides an important insight into the euselachian faunal diversity of this little-known region of the seaway. Despite its high paleolatitude, the assemblage contains a number of elasmobranch taxa, including Hybodus, Squalicorax, Archaeolamna, Cretodus, Dallasiella, and Cretoxyrhina. The Dunvegan assemblage also contains the first known reports from Canada of the odontaspid shark Johnlongia parvidens, the cretoxyrhinid shark Protolamna carteri, and the ray Pseudohypolophus mcnultyi. This assemblage extends the northern geographical range of all taxa. Preliminary comparisons with other middle Cenomanian Western Interior Seaway assemblages show that the core composition of the Dunvegan assemblage is remarkably similar to that of other time-equivalent assemblages; however, conspicuously absent are species that are exceedingly common in other localities situated farther south. We suggest that absence of these taxa from the Dunvegan localities may be caused by a temperature intolerance associated with latitude and sea-water circulation patterns, or by an inability to inhabit environments that exhibit salinity variation. Resume : Un assemblage euselachien a ete recupere dans la Formation de Dunvegan du Cenomanien moyen du nord-ouest de l'Alberta. Cet assemblage est le plus septentrionaux decrits a ce jour provenant des depots de la mer interieure de l'Ouest et il jette un important eclairage sur la diversite faunique euselachienne dans cette region meconnue du bassin. Malgre sa haute paleolatitude, l'assemblage contient divers taxons d'elasmobranches, dont Hybodus, Squalicorax, Archaeolamna, Cretodus, Dallasiella et Cretoxyrhina. L'assemblage de Dunvegan contient egalement les premiers specimens signales au Canada du requin odontaspide Johnlongia parvidens, du requin cretoxyrhinide Protolamna carteri et de la raie Pseudohypolophus mcnultyi. L'assemblage repousse les limites septentrionales de la distribution geographique de tous ces taxons. Des comparaisons provisoires avec d'autres assemblages du Cenomanien moyen de la mer interieure de l'Ouest demontrent que la composition de base de l'assemblage de Dunvegan et celles d'autres assemblages contemporains presentent une remarquable similitude; certaines especes par ailleurs tres repandues en d'autres lieux plus meridionaux brillent toutefois par leur absence. Il est postule que l'absence de ces taxons dans l'assemblage de Dunvegan pourrait etre le resultat d'une intolerance a la temperature associee a la latitude et aux courants marins, ou encore de l'incapacite de ces taxons a s'implanter dans des milieux presentant des variations de salinite. [Traduit par la Redaction], Introduction An assemblage of euselachian remains of Cenomanian (early Late Cretaceous) age was recovered from the Dunvegan Formation of northwestern Alberta (Fig. 1). The assemblage not only provides records of [...]