We recently demonstrated that selective expression of the Rho GTPase-activating protein ARHGAP42 in smooth muscle cells (SMCs) controls blood pressure by inhibiting RhoA-dependent contractility, ...providing a mechanism for the blood pressure-associated locus within the ARHGAP42 gene. The goals of the current study were to identify polymorphisms that affect ARHGAP42 expression and to better assess ARHGAP42's role in the development of hypertension. Using DNase I hypersensitivity methods and ENCODE data, we have identified a regulatory element encompassing the ARHGAP42 SNP rs604723 that exhibits strong SMC-selective, allele-specific activity. Importantly, CRISPR/Cas9-mediated deletion of this element in cultured human SMCs markedly reduced endogenous ARHGAP42 expression. DNA binding and transcription assays demonstrated that the minor T allele variation at rs604723 increased the activity of this fragment by promoting serum response transcription factor binding to a cryptic cis-element. ARHGAP42 expression was increased by cell stretch and sphingosine 1-phosphate in a RhoA-dependent manner, and deletion of ARHGAP42 enhanced the progression of hypertension in mice treated with DOCA-salt. Our analysis of a well-characterized cohort of untreated borderline hypertensive patients suggested that ARHGAP42 genotype has important implications in regard to hypertension risk. Taken together, our data add insight into the genetic mechanisms that control blood pressure and provide a potential target for individualized antihypertensive therapies.
In this report, we describe the case of an adolescent male with an unusual case of fusion-negative, paratesticular alveolar rhabdomyosarcoma who presented with spontaneous tumour lysis syndrome and ...diffuse bony metastases throughout the axial and appendicular skeleton with additional significant bone marrow involvement. Both spontaneous tumour lysis syndrome and diffuse bony metastases are extremely unusual for rhabdomyosarcoma. On the backbone of standard vincristine, dactinomycin and cyclophosphamide (VAC) chemotherapy, the only local control was orchiectomy at 15 weeks, with no radiation administered due to the initially diffuse nature of the disease and rapid response to chemotherapy. Following 43 weeks of VAC, a year-long maintenance phase with pazopanib was given which was well tolerated. The patient remains in remission now 4 years after completion of therapy.
Adults with a history of very preterm birth (<32 wk gestational age; PRET) have reduced lung function and significantly lower lung diffusion capacity for carbon monoxide (DLCO) relative to ...individuals born at term (CONT). Low DLCO may predispose PRET to diffusion limitation during exercise, particularly while breathing hypoxic gas because of a reduced O2 driving gradient and pulmonary capillary transit time. We hypothesized that PRET would have significantly worse pulmonary gas exchange efficiency i.e., increased alveolar-to-arterial Po2 difference (AaDO2) during exercise breathing room air or hypoxic gas (FiO2 = 0.12) compared with CONT. To test this hypothesis, we compared the AaDO2 in PRET (n = 13) with a clinically mild reduction in DLCO (72 ± 7% of predicted) and CONT (n = 14) with normal DLCO (105 ± 10% of predicted) pre- and during exercise breathing room air and hypoxic gas. Measurements of temperature-corrected arterial blood gases, and direct measure of O2 saturation (SaO2), were made prior to and during exercise at 25, 50, and 75% of peak oxygen consumption (V̇o2peak) while breathing room air and hypoxic gas. In addition to DLCO, pulmonary function and exercise capacity were significantly less in PRET. Despite PRET having low DLCO, no differences were observed in the AaDO2 or SaO2 pre- or during exercise breathing room air or hypoxic gas compared with CONT. Although our findings were unexpected, we conclude that reduced pulmonary function and low DLCO resulting from very preterm birth does not cause a measureable reduction in pulmonary gas exchange efficiency.
New Findings
What is the central question of this study?
Do individuals with a patent foramen ovale (PFO+) have a lower lung transfer factor for carbon monoxide than those without (PFO−)?
What is the ...main finding and its importance?
We found a lower rate constant for carbon monoxide uptake in PFO+ compared with PFO− women, which was physiologically relevant (≥0.5 z‐score difference), but not for PFO+ versus PFO− men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.
The transfer factor of the lung for carbon monoxide (TLCO) measure assumes that all cardiac output flows through the pulmonary circuit. However, right‐to‐left blood flow through a shunt can result in a lower transfer factor than predicted. A patent foramen ovale (PFO) is a potential source of right‐to‐left shunt that is present in ∼35% of the population, but the effect of PFO on TLCO is unknown. We sought to determine the effect of PFO on the TLCO. We conducted a retrospective analysis of TLCO data from 239 (101 women) participants. Anthropometrics and lung function, including spirometry, plethysmography and TLCO, were compiled from our previously published work. Women, but not men, with a PFO had a significantly lower TLCO and rate constant for carbon monoxide uptake (KCO) (percentage of predicted and z‐score) than women without a PFO. Women and men with a PFO had normal alveolar volumes that did not differ from those without a PFO. Correcting the data for haemoglobin in a subset of subjects did not change the results (n = 58; 25 women). The lower KCO in women with versus without a PFO was physiologically relevant (≥0.5 z‐score difference). There was no effect of PFO in men. This suggests that factors independent of the PFO are responsible for our findings, possibly inherent structural differences in the lung.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Adults born very to extremely preterm, with or without bronchopulmonary dysplasia (BPD), have obstructive lung disease, but it is unknown whether this results in respiratory limitations, such as ...mechanical constraints to Vt expansion during exercise leading to intolerable dyspnea and reduced exercise tolerance, as it does in patients with chronic obstructive pulmonary disease.
To test the hypothesis that adult survivors of preterm birth (≤32 wk gestational age) with (n = 20) and without BPD (n = 15) with reduced exercise capacity demonstrate clinically important respiratory limitations at near-maximal exercise compared with full-term control subjects (n = 20).
Detailed ventilatory and sensory measurements were made before and during exercise on all patients in the three study groups.
During exercise at 90% of peak Formula: see texto2 (Formula: see texto2peak), inspiratory reserve volume decreased to ∼0.5 L in all groups, but this occurred at significantly lower absolute workloads and Formula: see texte in ex-preterm subjects with and without BPD compared with full-term control subjects. Severe dyspnea was present and similar at comparable Formula: see texte between all groups, but leg discomfort at comparable workloads was greater in ex-preterm subjects with and without BPD compared with control subjects. At 50 to 90% of Formula: see texto2peak, exercise-induced expiratory flow limitation was significantly greater in ex-preterm subjects with BPD compared with ex-preterm subjects without BPD and control subjects. The degree of expiratory flow limitation in ex-preterm subjects with and without BPD was significantly related to neonatal O2 therapy duration.
Severe dyspnea and leg discomfort associated with critical constraints on Vt expansion may lead to reduced exercise tolerance in adults born very or extremely preterm, whether or not their birth was complicated by BPD and despite differences in expiratory flow limitation. In this regard, adults born very or extremely preterm have respiratory limitations to exercise similar to patients with chronic obstructive pulmonary disease.
Context.
Observations of chemical species can provide insights into the physical conditions of the emitting gas however it is important to understand how their abundances and excitation vary within ...different heating environments. C
2
H is a molecule typically found in PDR regions of our own Galaxy but there is evidence to suggest it also traces other regions undergoing energetic processing in extragalactic environments.
Aims.
As part of the ALCHEMI ALMA large program, we map the emission of C
2
H in the central molecular zone of the nearby starburst galaxy NGC 253 at 1.6″ (28 pc) resolution and characterize it to understand its chemical origins.
Methods.
We used spectral modeling of the
N
= 1−0 through
N
= 4−3 rotational transitions of C
2
H to derive the C
2
H column densities towards the dense clouds in NGC 253. We then use chemical modeling, including photodissociation region (PDR), dense cloud, and shock models to investigate the chemical processes and physical conditions that are producing the molecular emission.
Results.
We find high C
2
H column densities of ∼10
15
cm
−2
detected towards the dense regions of NGC 253. We further find that these column densities cannot be reproduced if it is assumed that the emission arises from the PDR regions at the edge of the clouds. Instead, we find that the C
2
H abundance remains high even in the high visual extinction interior of these clouds and that this is most likely caused by a high cosmic-ray ionization rate.
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Cardiopulmonary function is reduced in adults born very preterm, but it is unknown if this results in reduced pulmonary gas exchange efficiency during exercise and, consequently, leads to reduced ...aerobic capacity in subjects with and without bronchopulmonary dysplasia (BPD). We hypothesized that an excessively large alveolar to arterial oxygen difference (AaDO2) and resulting exercise-induced arterial hypoxemia (EIAH) would contribute to reduced aerobic fitness in adults born very preterm with and without BPD. Measurements of pulmonary function, lung volumes and diffusion capacity for carbon monoxide (DLco) were made at rest. Measurements of maximal oxygen consumption, peak workload, temperature- and tonometry-corrected arterial blood gases, and direct measure of hemoglobin saturation with oxygen (SaO2) were made preexercise and during cycle ergometer exercise in ex-preterm subjects ≤32-wk gestational age, with BPD (n = 12), without BPD (PRE; n = 12), and full term controls (CONT; n = 12) breathing room air. Both BPD and PRE had reduced pulmonary function and reduced DLco compared with CONT. The AaDO2 was not significantly different between groups, and there was no evidence of EIAH (SaO2 < 95% and/or AaDO2 ≥ 40 Torr) in any subject group preexercise or at any workload. Arterial O2 content was not significantly different between the groups preexercise or during exercise. However, peak power output was decreased in BPD and PRE subjects compared with CONT. We conclude that EIAH in adult subjects born very preterm with and without BPD does not likely contribute to the reduction in aerobic exercise capacity observed in these subjects.
Context.
The interstellar medium is the locus of physical processes affecting the evolution of galaxies which drive or are the result of star formation activity, supermassive black hole growth, and ...feedback. The resulting physical conditions determine the observable chemical abundances that can be explored through molecular emission observations at millimeter and submillimeter wavelengths.
Aims.
Our goal is to unveiling the molecular richness of the central region of the prototypical nearby starburst galaxy NGC 253 at an unprecedented combination of sensitivity, spatial resolution, and frequency coverage.
Methods.
We used the Atacama Large Millimeter/submillimeter Array (ALMA), covering a nearly contiguous 289 GHz frequency range between 84.2 and 373.2 GHz, to image the continuum and spectral line emission at 1.6″(∼28 pc) resolution down to a sensitivity of 30 − 50 mK. This article describes the ALMA Comprehensive High-resolution Extragalactic Molecular Inventory (ALCHEMI) large program. We focus on the analysis of the spectra extracted from the 15″ (∼255 pc) resolution ALMA Compact Array data.
Results.
We modeled the molecular emission assuming local thermodynamic equilibrium with 78 species being detected. Additionally, multiple hydrogen and helium recombination lines are identified. Spectral lines contribute 5 to 36% of the total emission in frequency bins of 50 GHz. We report the first extragalactic detections of C
2
H
5
OH, HOCN, HC
3
HO, and several rare isotopologues. Isotopic ratios of carbon, oxygen, sulfur, nitrogen, and silicon were measured with multiple species.
Concluison.
Infrared pumped vibrationaly excited HCN, HNC, and HC
3
N emission, originating in massive star formation locations, is clearly detected at low resolution, while we do not detect it for HCO
+
. We suggest high temperature conditions in these regions driving a seemingly “carbon-rich” chemistry which may also explain the observed high abundance of organic species close to those in Galactic hot cores. The
L
vib
/
L
IR
ratio was used as a proxy to estimate a 3% contribution from the proto super star cluster to the global infrared emission. Measured isotopic ratios with high dipole moment species agree with those within the central kiloparsec of the Galaxy, while those derived from
13
C/
18
O are a factor of five larger, confirming the existence of multiple interstellar medium components within NGC 253 with different degrees of nucleosynthesis enrichment. The ALCHEMI data set provides a unique template for studies of star-forming galaxies in the early Universe.
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