We introduce wavelet phase harmonics (WPH) statistics: interpretable low-dimensional statistics that describe 2D non-Gaussian fields. These statistics are built from WPH moments, which were recently ...introduced in the data science and machine learning community. We apply WPH statistics to projected 2D matter density fields from the Quijote N -body simulations of the large-scale structure of the Universe. By computing Fisher information matrices, we find that the WPH statistics place more stringent constraints on four of five cosmological parameters when compared to statistics based on the combination of the power spectrum and bispectrum. We also use the WPH statistics with a maximum entropy model to statistically generate new 2D density fields that accurately reproduce the probability density function, the mean and standard deviation of the power spectrum, the bispectrum, and Minkowski functionals of the input density fields. Although other methods are efficient for either parameter estimates or statistical syntheses of the large-scale structure, WPH statistics are the first statistics that achieve state-of-the-art results for both tasks as well as being interpretable.
Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that ...metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G(0)/G(1). This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27(kip) protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.
Projections of stratospheric ozone from a suite of chemistry-climate models (CCMs) have been analyzed. In addition to a reference simulation where anthropogenic halogenated ozone depleting substances ...(ODSs) and greenhouse gases (GHGs) vary with time, sensitivity simulations with either ODS or GHG concentrations fixed at 1960 levels were performed to disaggregate the drivers of projected ozone changes. These simulations were also used to assess the two distinct milestones of ozone returning to historical values (ozone return dates) and ozone no longer being influenced by ODSs (full ozone recovery). The date of ozone returning to historical values does not indicate complete recovery from ODSs in most cases, because GHG-induced changes accelerate or decelerate ozone changes in many regions. In the upper stratosphere where CO2-induced stratospheric cooling increases ozone, full ozone recovery is projected to not likely have occurred by 2100 even though ozone returns to its 1980 or even 1960 levels well before (~2025 and 2040, respectively). In contrast, in the tropical lower stratosphere ozone decreases continuously from 1960 to 2100 due to projected increases in tropical upwelling, while by around 2040 it is already very likely that full recovery from the effects of ODSs has occurred, although ODS concentrations are still elevated by this date. In the midlatitude lower stratosphere the evolution differs from that in the tropics, and rather than a steady decrease in ozone, first a decrease in ozone is simulated from 1960 to 2000, which is then followed by a steady increase through the 21st century. Ozone in the midlatitude lower stratosphere returns to 1980 levels by ~2045 in the Northern Hemisphere (NH) and by ~2055 in the Southern Hemisphere (SH), and full ozone recovery is likely reached by 2100 in both hemispheres. Overall, in all regions except the tropical lower stratosphere, full ozone recovery from ODSs occurs significantly later than the return of total column ozone to its 1980 level. The latest return of total column ozone is projected to occur over Antarctica (~2045–2060) whereas it is not likely that full ozone recovery is reached by the end of the 21st century in this region. Arctic total column ozone is projected to return to 1980 levels well before polar stratospheric halogen loading does so (~2025–2030 for total column ozone, cf. 2050–2070 for Cly+60×Bry) and it is likely that full recovery of total column ozone from the effects of ODSs has occurred by ~2035. In contrast to the Antarctic, by 2100 Arctic total column ozone is projected to be above 1960 levels, but not in the fixed GHG simulation, indicating that climate change plays a significant role.
Birt-Hogg-Dubé syndrome (BHD) is a rare autosomal dominant disorder caused by mutations in the FLCN gene coding for folliculin. Its clinical expression includes cutaneous fibrofolliculomas, renal ...tumors, multiple pulmonary cysts, and recurrent spontaneous pneumothoraces. Data on lung function in BHD are scarce and it is not known whether lung function declines over time. We retrospectively assessed lung function at baseline and during follow-up in 96 patients with BHD.
Ninety-five percent of BHD patients had multiple pulmonary cysts on computed tomography and 59% had experienced at least one pneumothorax. Mean values of forced expiratory volume in 1 second (FEV
), forced vital capacity (FVC), FEV
/FVC ratio, and total lung capacity were normal at baseline. Mean (standard deviation) residual volume (RV) was moderately increased to 116 (36) %pred at baseline, and RV was elevated > 120%pred in 41% of cases. Mean (standard deviation) carbon monoxide transfer factor (DLco) was moderately decreased to 85 (18) %pred at baseline, and DLco was decreased < 80%pred in 33% of cases. When adjusted for age, gender, smoking and history of pleurodesis, lung function parameters did not significantly decline over a follow-up period of 6 years.
Cystic lung disease in BHD does not affect respiratory function at baseline except for slightly increased RV and reduced DLco. No significant deterioration of lung function occurs in BHD over a follow-up period of 6 years.
The impact of stratospheric ozone on the tropospheric general circulation of the Southern Hemisphere (SH) is examined with a set of chemistry‐climate models participating in the Stratospheric ...Processes and their Role in Climate (SPARC)/Chemistry‐Climate Model Validation project phase 2 (CCMVal‐2). Model integrations of both the past and future climates reveal the crucial role of stratospheric ozone in driving SH circulation change: stronger ozone depletion in late spring generally leads to greater poleward displacement and intensification of the tropospheric midlatitude jet, and greater expansion of the SH Hadley cell in the summer. These circulation changes are systematic as poleward displacement of the jet is typically accompanied by intensification of the jet and expansion of the Hadley cell. Overall results are compared with coupled models participating in the Intergovernmental Panel on Climate Change Fourth Assessment Report (IPCC AR4), and possible mechanisms are discussed. While the tropospheric circulation response appears quasi‐linearly related to stratospheric ozone changes, the quantitative response to a given forcing varies considerably from one model to another. This scatter partly results from differences in model climatology. It is shown that poleward intensification of the westerly jet is generally stronger in models whose climatological jet is biased toward lower latitudes. This result is discussed in the context of quasi‐geostrophic zonal mean dynamics.
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of ...white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
A quaternion-based feedback is developed for the attitude stabilization of rigid bodies. The control design takes into account a priori input bounds and is based on nested saturation approach. It ...results in a very simple controller suitable for an embedded use with low computational resources available. The proposed method is generic not restricted to symmetric rigid bodies and does not require the knowledge of the inertia matrix of the body. The control law can be tuned to force closed-loop trajectories to enter in some a priori fixed neighborhood of the origin in a finite time and remain thereafter. The global stability is guaranteed in the case where angular velocity sensors have limited measurement range. The control law is experimentally applied to the attitude stabilization of a quadrotor mini-helicopter.
► Attitude stabilization of rigid bodies with a bounded feedback is considered. ► The control is generic and suitable for embedded limited computational resources. ► The almost global stability is formally proved. ► The design considers the slew rate limits avoiding rate gyro saturations. ► Experiments are performed on a quadrotor helicopter.
We use observations of N2O and mean age to identify realistic transport in models in order to explain their ozone predictions. The results are applied to 15 chemistry climate models (CCMs) ...participating in the 2010 World Meteorological Organization ozone assessment. Comparison of the observed and simulated N2O, mean age and their compact correlation identifies models with fast or slow circulations and reveals details of model ascent and tropical isolation. This process‐oriented diagnostic is more useful than mean age alone because it identifies models with compensating transport deficiencies that produce fortuitous agreement with mean age. The diagnosed model transport behavior is related to a model's ability to produce realistic lower stratosphere (LS) O3 profiles. Models with the greatest tropical transport problems compare poorly with O3 observations. Models with the most realistic LS transport agree more closely with LS observations and each other. We incorporate the results of the chemistry evaluations in the Stratospheric Processes and their Role in Climate (SPARC) CCMVal Report to explain the range of CCM predictions for the return‐to‐1980 dates for global (60°S–60°N) and Antarctic column ozone. Antarctic O3 return dates are generally correlated with vortex Cly levels, and vortex Cly is generally correlated with the model's circulation, although model Cl chemistry and conservation problems also have a significant effect on return date. In both regions, models with good LS transport and chemistry produce a smaller range of predictions for the return‐to‐1980 ozone values. This study suggests that the current range of predicted return dates is unnecessarily broad due to identifiable model deficiencies.
Key Points
The trace gas, N2O, is an transport diagnostic
Observations can be used to evaluate model transport
Models with poor transport produce a wide range of ozone predictions
The goal of the Chemistry‐Climate Model Validation (CCMVal) activity is to improve understanding of chemistry‐climate models (CCMs) through process‐oriented evaluation and to provide reliable ...projections of stratospheric ozone and its impact on climate. An appreciation of the details of model formulations is essential for understanding how models respond to the changing external forcings of greenhouse gases and ozone‐depleting substances, and hence for understanding the ozone and climate forecasts produced by the models participating in this activity. Here we introduce and review the models used for the second round (CCMVal‐2) of this intercomparison, regarding the implementation of chemical, transport, radiative, and dynamical processes in these models. In particular, we review the advantages and problems associated with approaches used to model processes of relevance to stratospheric dynamics and chemistry. Furthermore, we state the definitions of the reference simulations performed, and describe the forcing data used in these simulations. We identify some developments in chemistry‐climate modeling that make models more physically based or more comprehensive, including the introduction of an interactive ocean, online photolysis, troposphere‐stratosphere chemistry, and non‐orographic gravity‐wave deposition as linked to tropospheric convection. The relatively new developments indicate that stratospheric CCM modeling is becoming more consistent with our physically based understanding of the atmosphere.
Pulmonary fibrosis is a devastating as yet untreatable disease. We previously investigated the endogenous mediators released on lung injury and showed that uric acid is a danger signal activating ...Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome in lung inflammation and fibrosis (Gasse et al., Am J Respir Crit Care Med 2009;179:903-913).
Here we address the role of extracellular adenosine triphosphate (eATP) in pulmonary inflammation and fibrosis.
ATP was quantified in bronchoalveolar lavage fluid (BALF) of control subjects and patients with idiopathic pulmonary fibrosis. The contribution of eATP as a danger signal was assessed in a murine model of lung fibrosis induced by airway-administered bleomycin (BLM), an intercalating agent that causes DNA strand breaks.
Fibrotic patients have elevated ATP content in BALF in comparison with control individuals. In mice, we report an early increase in eATP levels in BALF on BLM administration. Modulation of eATP levels with the ATP-degrading enzyme apyrase greatly reduced BLM-induced inflammatory cell recruitment, lung IL-1β, and tissue inhibitor of metalloproteinase (TIMP)-1 production, while administration of ATP-γS, a stable ATP derivative, enhanced inflammation. P2X(7) receptor-deficient mice presented dramatically reduced lung inflammation, with reduced fibrosis markers such as lung collagen content and matrix-remodeling proteins TIMP-1 and matrix metalloproteinase-9. The acute inflammation depends on a functional pannexin-1 hemichannel protein. In vitro, ATP is released by pulmonary epithelial cells on BLM-induced stress and this is partly dependent on the presence of functional P2X(7) receptor and pannexin-1 hemichannel.
ATP released from BLM-injured lung cells constitutes a major endogenous danger signal that engages the P2X(7) receptor/pannexin-1 axis, leading to IL-1β maturation and lung fibrosis.
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