Can high intensity workloads be simulated at moderate intensities by reduced breathing frequency?

Objectives: This study was designed to investigate whether reduced breathing frequency during moderate intensity exercise produces similar metabolic responses as during exercise with spontaneous breathing at higher absolute intensity.Methods: Eight healthy male subjects performed a constant load test with reduced breathing frequency at 10 breaths per minute to exhaustion (B10) at the peak power output obtained during the incremental test with RBF (peak power output increased every two minutes for 30 W). The subjects then performed a constant load test with the spontaneous breathing to exhaustion (SB) at peak power output obtained during the incremental test with spontaneous breathing. Results: Respiratory parameters (VE, PETO2, PETCO2), metabolic parameters (Vo2, Vco2) and oxygen saturation (SaO2) were measured during both constant load tests. Capillary blood samples were taken before and every minute during both constant load tests in order to measure lactate concentration ([LA-]) and parameters of capillary blood gases and acid base status (Po2, Pco2, pH). Regardless of the type of comparison (the data obtained at the defined time or maximum and minimum values during the exercise), there were significant differences between SB and B10 in all respiratory parameters, metabolic parameters and SaO2 (p ≤ 0.01 and 0.05). There were significantly lower [LA-] and Pco2 during B10, when compared to SB (p≤0.01). However, there were no significant differences in pH during the exercise between different breathing conditions. Conclusion: It can be concluded that reduced breathing frequency during exercise at lower absolute intensity did not produce similar conditions as during the exercise with spontaneous breathing at higher absolute intensity

FAUSTA: Scaling Dynamic Analysis with Traffic Generation at WhatsApp

We introduce Fausta, an algorithmic traffic gener-ation platform that enables analysis and testing at scale. Fausta has been deployed at Meta to analyze and test the WhatsApp plat-form infrastructure since September 2020, enabling WhatsApp developers to deploy reliable code changes to a code base of millions of lines of code, supporting over 2 billion users who rely on WhatsApp for their daily communications. Fausta covers expected and unexpected program behaviors in a privacy-safe controlled environment to support multiple use cases such as reliability testing, privacy analysis and performance regression detection. It currently supports three different algorithmic input generation strategies, each of which construct realistic backend server traffic that closely simulates production data, without replaying any real user data. Fausta has been deployed and closely integrated into the WhatsApp continuous integration process, catching bugs in development before they hit production. We report on the development and deployment of Fausta's reliability use case between September 2020 and August 2021. During this period it has found 1,876 unique reliability issues, with a fix rate of 74%, indicating a high degree of true positive fault revelation. We also report on the distribution of fault types revealed by Fausta, and the correlation between coverage and faults found. Overall, we do find evidence that higher coverage is correlated with fault revelation

Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition.

RATIONALE: Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH. OBJECTIVES: We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression. METHODS: SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats. MEASUREMENTS AND MAIN RESULTS: SMAD3 was downregulated in lungs of patients with PAH and in pulmonary arteries of three independent PAH animal models. TGF-β treatment replicated the loss of SMAD3 in human pulmonary artery smooth muscle cells (huPASMCs) and human pulmonary artery endothelial cells. SMAD3 silencing increased proliferation and migration in huPASMCs and human pulmonary artery endothelial cells. Coimmunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF-β-treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMCs, loss of SMAD3 or BMPR-II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented TGF-β-induced activation of an MRTF reporter and reduced actin stress fibers in BMPR2-silenced huPASMCs. MRTF inhibition attenuated PAH and lung vascular remodeling in Sugen/hypoxia rats. CONCLUSIONS: Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype

A Voltage-Gated H+ Channel Underlying pH Homeostasis in Calcifying Coccolithophores

Marine coccolithophorid phytoplankton are major producers of biogenic calcite, playing a significant role in the global carbon cycle. Predicting the impacts of ocean acidification on coccolithophore calcification has received much recent attention and requires improved knowledge of cellular calcification mechanisms. Uniquely amongst calcifying organisms, coccolithophores produce calcified scales (coccoliths) in an intracellular compartment and secrete them to the cell surface, requiring large transcellular ionic fluxes to support calcification. In particular, intracellular calcite precipitation using HCO3− as the substrate generates equimolar quantities of H+ that must be rapidly removed to prevent cytoplasmic acidification. We have used electrophysiological approaches to identify a plasma membrane voltage-gated H+ conductance in Coccolithus pelagicus ssp braarudii with remarkably similar biophysical and functional properties to those found in metazoans. We show that both C. pelagicus and Emiliania huxleyi possess homologues of metazoan Hv1 H+ channels, which function as voltage-gated H+ channels when expressed in heterologous systems. Homologues of the coccolithophore H+ channels were also identified in a diversity of eukaryotes, suggesting a wide range of cellular roles for the Hv1 class of proteins. Using single cell imaging, we demonstrate that the coccolithophore H+ conductance mediates rapid H+ efflux and plays an important role in pH homeostasis in calcifying cells. The results demonstrate a novel cellular role for voltage gated H+ channels and provide mechanistic insight into biomineralisation by establishing a direct link between pH homeostasis and calcification. As the coccolithophore H+ conductance is dependent on the trans-membrane H+ electrochemical gradient, this mechanism will be directly impacted by, and may underlie adaptation to, ocean acidification. The presence of this H+ efflux pathway suggests that there is no obligate use of H+ derived from calcification for intracellular CO2 generation. Furthermore, the presence of Hv1 class ion channels in a wide range of extant eukaryote groups indicates they evolved in an early common ancestor