Characterization of pollen tube development in distant hybridization of Chinese cork oak (Quercus variabilis L.).

MAIN CONCLUSION: This work mainly found that the stigma and style of Q. variabilis did not completely lose the specific recognition towards heterologous pollen, a fact which is different from previous studies. Quercus is the foundation species in the Northern Hemisphere, with extreme prevalence for interspecific hybridization. It is not yet entirely understood whether or how the pollen tube-female tissue interaction contributes to the "extensive hybridization" in oaks. Pollen storage conditions correlate with distant hybridization. We conducted hybridization experiments with Q. variabilis as female and Q. variabilis and Q. mongolica as male parents. And the differences in pollen tube (PT) development between intra- and distant interspecific hybridization were studied by fluorescence microscopy and scanning electron microscopy (SEM). Our results showed that -20 °C allowed pollen of both species to maintain some viability. Both Q. variabilis and Q. mongolica pollen germinated profusely on the stigmas. SEM results indicated that in the intraspecific hybridization, Q. variabilis pollen started to germinate at 6 h after pollination (hap), PTs elongated significantly at 12 hap, and entered the stigma at 24 hap. By contrast, Q. mongolica pollen germinated at 15 hap, and the PTs entered the stigma at 27 hap. By fluorescence microscopical studies it was observed that some PTs of Q. variabilis gathered at the style-joining at 96 hap, unlike the Q. mongolica which reached the style junction at 144 hap. The above results indicate that the abundant germination of heterologous pollen (HP) on the stigma and the "Feeble specificity recognition" of the stigma and transmitting tract to HP may create opportunities for the "extensive hybridization" of oaks. This work provides a sexual developmental reference for clarifying the causes of Quercus "extensive hybridization".

Rhodiola crenulata extract counteracts the effect of hypobaric hypoxia in rat heart via redirection of the nitric oxide and arginase 1 pathway.

BACKGROUND: Rhodiola crenulata is traditionally used as a folk medicine in Tibet for preventing high-altitude illnesses, including sudden cardiac death (SCD). The cardio-protective effects of Rhodiola crenulata root extract (RCE) against hypoxia in vivo have been recently confirmed. However, the way in which RCE produces these effects remains unclear. The present study is designed to confirm the protective effects of RCE on the heart in acute hypobaric hypoxia exposure and examine the mechanisms by which this occurs. METHODS: Sprague-Dawley (SD) rats were pretreated with or without RCE and then exposed to a simulated altitude of 8000 m in a hypobaric hypoxia chamber for 9 h. The expression of cardiac arginase 1 (Arg-1) and endothelial nitric oxide synthase (eNOS) and the activity of associated signaling pathways was examined. RESULTS: Hypoxia reduced cardiac eNOS phosphorylation and increased Arg-1 expression, but both responses were reversed by RCE pre-treatment. In addition, RCE decreased the hypoxia-induced oxidative stress markers of reactive oxygen species (ROS) production, malondialdehyde (MDA) level, and protein carbonyl content. Furthermore, RCE protected cardiomyocytes from hypoxia-induced cardiac apoptosis and restored the phosphorylation level of AKT and p38 MAPK as well as the superoxide dismutase 2 (SOD2) content in hypoxic animals. CONCLUSION: The findings provide evidence that the effects of Rhodiola crenulata against altitude illness are partially mediated by modulation of eNOS and Arg-1 pathways in the heart.

Rhodiola crenulata extract regulates hepatic glycogen and lipid metabolism via activation of the AMPK pathway.

BACKGROUND: Metabolic syndrome may lead to many complications, such as nonalcoholic fatty liver disease (NAFLD). A natural and effective therapeutic agent for patients with NAFLD is urgently needed. In a previous study, we showed that Rhodiola crenulata root extract (RCE) regulated hepatic gluconeogenesis through activation of AMPK signaling. However, the manner in which RCE regulates hepatic lipid and glycogen metabolism remains unclear. The current study was conducted to investigate the effects of RCE on hepatic glycogen and lipid metabolism, as well as the mechanisms underlying such effects. METHODS: Human hepatoma HepG2 cells were treated with RCE for 6 h under high glucose conditions, after which glycogen synthesis, lipogenesis, and relative gene expression were examined. In addition, lipogenesis-related genes were investigated in vivo. RESULTS: RCE significantly increased glycogen synthesis and inhibited lipogenesis, while regulating genes related to these processes, including glycogen synthase kinase 3ß (GSK3ß), glycogen synthase (GS), fatty acid synthase (FAS), CCAAT/enhancer-binding protein (C/EBP), and sterol regulatory element-binding protein 1c (SREBP-1c). However, the effects caused by RCE were neutralized by compound C, an AMPK antagonist. Further studies showed that expression levels of lipogenic genes decreased at the protein and mRNA levels in the rat liver. CONCLUSIONS: Our results demonstrate that RCE regulates hepatic glycogen and lipid metabolism through the AMPK signaling pathway. These results suggest that RCE is a potential intervention for patients with NAFLD.

Cytotoxic cardiac glycosides and coumarins from Antiaris toxicaria.

Eight new cardiac glycosides/aglycones (antiaritoxiosides A-G, 1-7, and antiarotoxinin B, 8), two new coumarins (anticarins A-B, 41-42), and two new flavanones (antiarones L-K, 43-44) were isolated from trunk bark of Antiaris toxicaria together with 53 known compounds. The new structures were established by extensive analysis of spectroscopic data. Compound 1 (10-carboxy and 3α-hydroxy) and compounds 3-6 (10-hydroxy) contain unique substituents that are rarely found in cardiac glycosides. The cytotoxic effects of isolated compounds against ten human cancer cell lines, KB, KB-VIN, A549, MCF-7, U-87-MG, PC-3, 1A9, CAKI-1, HCT-9 and S-KMEL-2, were tested using the sulforhodamine B assay. Five compounds (12, 16, 20, 22, and 31) showed significant cytotoxicity against all ten cancer cell lines, with notable potency at the ng/mL level against some cell lines, which merits further development as clinical trial candidates.

Effects of Vent Size and Pressure on Hydrogen Explosion Dynamic Characteristics.

Explosion venting is an effective method to reduce the explosion damage; in order to study the mechanism of an explosion venting process in internal and external space, this paper investigates the influence of vent parameters on hydrogen-air explosion in a rectangular duct through numerical simulation. The model including the internal and external space is first constructed, and then the explosion dynamic behaviors of the full flow field are analyzed under different vent pressures and sizes. The study aims to reveal the coupling effect of the flame, pressure, and flow field on hydrogen explosion venting. The results indicate that the explosion intensity increases with the growth of the vent pressure and the reduction of the vent size. The maximum external overpressure increases to 2.6 and 2.3 times as the vent pressure increased to 10 times or vent size reduced by 90%. The flame and combustible gas mixture evolve from a mushroom cloud into a jet form as the vent size decreases, and vortexes formed at the flame front suppress flame propagation. However, the flame speed increases significantly as the flame passes the vent under the impact of larger pressure gradient, which results in a more violent turbulence intensity and secondary external explosion.

Numerical Study on Thermal Stress of High Temperature Proton Exchange Membrane Fuel Cells during Start-Up Process.

High-temperature proton-exchange membrane fuel cells (HT-PEMFCs) with phosphoric-doped polybenzimidazole (PBI) membranes have a higher operating temperature compared to the PEMFCs operating below 373.15 K. The fuel cell is first heated from room temperature to the minimum operating temperature to avoid the generation of liquid water. The existence of liquid water can result in the loss of phosphoric acid and then affect the cell performance. In this study, the start-up process of HT-PEMFCs is numerically studied by establishing a three-dimensional non-isothermal mathematical model. Preheated gas is supplied into gas flow channels to heat the fuel cell, and then voltage load is applied to accelerate the start-up process. Effects of voltage (0.9 V, 0.7 V and 0.5 V) and flow arrangement (co-flow and counter flow) on temperature, current density, proton conductivity and stress distributions of fuel cells are examined. It is found that the maximum stress is increased when a lower voltage is adopted, and the counter-flow arrangement provides a more uniform stress distribution than that of co-flow arrangement.

Pore-Scale Modeling of Liquid Water Transport in Compressed Gas Diffusion Layer of Proton Exchange Membrane Fuel Cells Considering Fiber Anisotropy.

Water management of the gas diffusion layer (GDL) is crucial to the performance of proton exchange membrane fuel cells (PEMFCs). Appropriate water management ensures efficient transport of reactive gases and maintains wetting of the proton exchange membrane to enhance proton conduction. In this paper, a two-dimensional pseudo-potential multiphase lattice Boltzmann model is developed to study liquid water transport within the GDL. Liquid water transport from the GDL to the gas channel is the focus, and the effect of fiber anisotropy and compression on water management is evaluated. The results show that the fiber distribution approximately perpendicular to the rib reduces liquid water saturation within the GDL. Compression significantly changes the microstructure of the GDL under the ribs, which facilitates the formation of liquid water transport pathways under the gas channel, and the increase in the compression ratio leads to a decrease in liquid water saturation. The performed microstructure analysis and the pore-scale two-phase behavior simulation study comprise a promising technique for optimizing liquid water transport within the GDL.

Effects of Compression and Porosity Gradients on Two-Phase Behavior in Gas Diffusion Layer of Proton Exchange Membrane Fuel Cells.

Water management within the gas diffusion layer (GDL) plays an important role in the performance of the proton exchange membrane fuel cell (PEMFC) and its reliability. The compression of the gas diffusion layer during fabrication and assembly has a significant impact on the mass transport, and the porosity gradient design of the gas diffusion layer is an essential way to improve water management. In this paper, the two-dimensional lattice Boltzmann method (LBM) is applied to investigate the two-phase behavior in gas diffusion layers with different porosity gradients under compression. Compression results in an increase in flow resistance below the ribs, prompting the appearance of the flow path of liquid water below the channel, and liquid water breaks through to the channel more quickly. GDLs with linear, multilayer, and inverted V-shaped porosity distributions with an overall porosity of 0.78 are generated to evaluate the effect of porosity gradients on the liquid water transport. The liquid water saturation values within the linear and multilayer GDLs are significantly reduced compared to that of the GDL with uniform porosity, but the liquid water within the inverted V-shaped GDL accumulates in the middle region and is more likely to cause flooding.

Bulbospinal nociceptive ON and OFF cells related neural circuits and transmitters.

The rostral ventromedial medulla (RVM) is a bulbospinal nuclei in the descending pain modulation system, and directly affects spinal nociceptive transmission through pronociceptive ON cells and antinociceptive OFF cells in this area. The functional status of ON and OFF neurons play a pivotal role in pain chronification. As distinct pain modulative information converges in the RVM and affects ON and OFF cell excitability, neural circuits and transmitters correlated to RVM need to be defined for an in-depth understanding of central-mediated pain sensitivity. In this review, neural circuits including the role of the periaqueductal gray, locus coeruleus, parabrachial complex, hypothalamus, amygdala input to the RVM, and RVM output to the spinal dorsal horn are discussed. Meanwhile, the role of neurotransmitters is concluded, including serotonin, opioids, amino acids, cannabinoids, TRPV1, substance P and cholecystokinin, and their dynamic impact on both ON and OFF cell activities in modulating pain transmission. Via clarifying potential specific receptors of ON and OFF cells, more targeted therapies can be raised to generate pain relief for patients who suffer from chronic pain.

Verbascoside and isoverbascoside ameliorate transforming growth factor ß1-induced collagen expression by lung fibroblasts through Smad/non-Smad signaling pathways.

AIMS: Pulmonary fibrosis (PF) is a chronic, irreversible, and debilitating lung disease that typically leads to respiratory failure, and is a major cause of morbidity and mortality. Few drugs are effective for the treatment of patients with PF or for reducing the rate of disease progression. MAIN METHODS: Transforming growth factor-ß1 (TGF-ß1) is a profibrotic cytokine that signals through Smad and non-Smad pathways. Verbascoside (VB) and isoverbascoside (isoVB) exhibit anti-oxidative and anti-inflammatory activities, however, their anti-fibrotic effects remain unclear. This study evaluated the effects of VB and isoVB on TGF-ß1-stimulated murine lung fibroblasts (MLg 2908) and also human lung fibroblasts (confirmed by immunostaining). KEY FINDINGS: Neither VB nor isoVB had a cytotoxic effect on MLg 2908 fibroblasts. Both compounds (10 µM) reduced intracellular reactive oxygen species and markedly attenuated collagen I expression in TGF-ß1 (5 ng/ml)-induced MLg 2908 cells compared to TGF-ß1 alone. Both compounds suppressed the TGF-ß1-induced phosphorylation of Smad2/3 and ERK/p38 mitogen-activated protein kinases (MAPKs). VB and isoVB, but not pirfenidone and nintedanib, inhibited TGF-ß1-induced pSmad2/3, ERK/p38 MAPK, and collagen I expression. VB and isoVB also decreased collagen I deposition in TGF-ß1-induced MLg 2908 cells. Only isoVB significantly suppressed collagen I deposition in TGF-ß1-induced human pulmonary cells. Our results indicated that VB and isoVB may exert antifibrotic effects by inhibiting TGF-ß1-induced collagen I expression via inhibition of oxidative stress and downregulation of the Smad/non-Smad pathway. SIGNIFICANCE: The present findings suggest that VB or isoVB may be used as a supplement to alleviate PF.

Biologically active constituents from the fruiting body of Taiwanofungus camphoratus.

Five new benzenoids, benzocamphorins A-E (1-5), and 10 recently isolated triterpenoids, camphoratins A-J (16-25), together with 23 known compounds including seven benzenoids (6-12), three lignans (13-15), and 13 triterpenoids (26-38) were isolated from the fruiting body of Taiwanofungus camphoratus. Their structures were established by spectroscopic analysis. Selected compounds were examined for cytotoxic and anti-inflammatory activities. Compounds 9 and 21 showed moderate cytotoxicity against MCF-7 and Hep2 cell lines with ED(50) values of 3.4 and 3.0µg/mL, respectively. Compounds 21, 25, 26, 29-31, 33, and 36 demonstrated potent anti-inflammatory activity by inhibiting lipopolysaccharide (LPS)-induced nitric oxide (NO) production with IC(50) values of 2.5, 1.6, 3.6, 0.6, 4.1, 4.2, 2.5, and 1.5µM, respectively, which were better than those of the nonspecific nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (l-NAME) (IC(50): 25.8µM). These results may substantiate the use of T. camphoratus in traditional Chinese medicine (TCM) for the treatment of inflammation and cancer-related diseases. The newly discovered compounds deserve further development as anti-inflammatory candidates.

Impact of Membrane Phosphoric Acid Doping Level on Transport Phenomena and Performance in High Temperature PEM Fuel Cells.

In this work, a three-dimensional mathematical model including the fluid flow, heat transfer, mass transfer, and charge transfer incorporating electrochemical reactions was developed and applied to investigate the transport phenomena and performance in high-temperature proton exchange membrane fuel cells (HT-PEMFCs) with a membrane phosphoric acid doping level of 5, 7, 9, 11. The cell performance is evaluated and compared in terms of the polarization curve. The distributions of temperature, oxygen mass fraction, water mass fraction, proton conductivity, and local current density of four cases are given and compared in detail. Results show that the overall performance and local transport characteristics are significantly affected by the membrane phosphoric acid doping level.

Numerical study on the effect of discrete catalytic layer arrangement on methane steam reforming performance.

The arrangement of catalytic layers inside the reactor is an important factor that affects the efficiency of methane steam reforming to produce hydrogen, and the traditional continuous catalytic layer structure is limited by the heat and mass transfer, resulting in unbalanced heat distribution inside the reactor and poor reaction performance. In order to improve the performance of methane reforming and balance the internal temperature of the reactor, different catalytic layers were designed based on 2D numerical simulation, and different numbers of discrete catalytic layers were modeled to compare the heat and mass transfer, methane conversion rate and hydrogen yield between the walls and inside the reactor. The results show that the increase in the number of catalyst gaps improves the temperature gradient inside the reactor, reduces the average cold point temperature difference inside the reactor by up to 7.2%, maintains a better thermal balance inside the reactor, improves the reaction rate inside the reactor, and the methane conversion rate and hydrogen yield after the reaction have been improved by 28.46% and 12.7% respectively.

Effects of Hydration and Temperature on the Microstructure and Transport Properties of Nafion Polyelectrolyte Membrane: A Molecular Dynamics Simulation.

To investigate the effects of temperature and hydration on the microstructure of polymer electrolyte membrane and the transport of water molecules and hydronium ions, molecular dynamics simulations are performed on Nafion 117 for a series of water contents at different temperatures. The interactions among the sulfonate groups, hydronium ions, and water molecules are studied according to the analysis of radial distribution functions and coordination numbers. The sizes and connectivity of water clusters are also discussed, and it is found that the hydration level plays a key role in the phase separation of the membrane. However, the effect of the temperature is slight. When the water content increases from 3.5 to 16, the size of water clusters in the membrane increases, and the clusters connect to each other to form continuous channels for diffusion of water molecules and hydronium ions. The diffusion coefficients are estimated by studying the mean square displacements. The results show that the diffusion of water molecules and hydronium ions are both enhanced by the increase of the temperature and hydration level. Furthermore, the diffusion coefficient of water molecules is always much larger than that of hydronium ions. However, the ratio of the diffusion coefficient of water molecules to that of hydronium ions decreases with the increase of water content.

AST-120 Improves Cardiac Dysfunction in Acute Kidney Injury Mice via Suppression of Apoptosis and Proinflammatory NF-κB/ICAM-1 Signaling.

PURPOSE: Acute kidney injury (AKI) is a devastating disorder associated with considerably high morbidity and mortality. Reports have shown that AST-120, an oral charcoal adsorbent, can reduce oxidative stress by lowering serum indoxyl sulfate levels. The effects of AST-120 and indoxyl sulfate on kidney injury and cardiac dysfunction were investigated in vivo and in vitro. PATIENTS AND METHODS: Patients were tracked for enrollment upon receiving a diagnosis of AKI. Plasma was collected to determine the renal and inflammatory parameters. Renal ischemia/reperfusion (I/R) induced AKI or sham operation was performed in C57BL/6J mice. Animals were divided into sham, AKI+vehicle, and AKI+AST-120 groups. Plasma and tissues were assembled after 48 h to assess apoptotic and inflammatory responses. We also conducted human umbilical vein endothelial cell (HUVECs) and HL-1 cardiomyocyte culture studies to determine the underlying mechanisms of indoxyl sulfate's effects. Echocardiography, histopathology, biochemical indexes, ELISA, terminal dUTP nick-end labeling (TUNEL) and Western blot analysis were performed. RESULTS: The cohort included 25 consecutive patients with AKI and 25 non-AKI. Plasma levels of creatinine, indoxyl sulfate, IL-1ß and ICAM-1 were significantly higher in patients with AKI than in non-AKI controls. Plasma levels of blood urea nitrogen, creatinine, indoxyl sulfate, IL-1ß and renal tubular injury were increased in mice after renal I/R and were decreased by AST-120 treatment. In addition, AST-120 therapy not only improved the parameters assessed by echocardiography but also substantially attenuated the elevation of plasma BNP. Oral administration of AST-120 significantly downregulated NF-κB/ICAM-1 expression and reduced cell apoptosis in both kidney and heart after renal I/R injury. CONCLUSION: Our investigations demonstrated that AST-120 administration improves cardiac dysfunction in AKI mice via the suppression of apoptosis and proinflammatory NF-κB/ICAM-1 signaling.

Cardiac glycosides from Antiaris toxicaria with potent cardiotonic activity.

An ethanolic extract of Antiaris toxicaria trunk bark showed potent in vitro cardiotonic effect on isolated guinea pig atria. Bioassay-guided fractionation of the extract led to identification of nine new cardiac glycosides (1-9, named antiarosides A-I), antiarotoxinin A (10), and 18 known compounds. Their structures were established using MS and NMR spectroscopic studies, including homonuclear and heteronuclear correlation experiments. The ability of these cardiotonic compounds to produce positive inotropic action and their safety indexes were examined in comparison with those of ouabain, a classical inhibitor of Na(+)/K(+)-ATPase. Malayoside (23) was nearly equipotent and had a similar safety index to ouabain in guinea pig atria. However, the maximal positive inotropic effect and safety index of 23 in papillary muscle were better than those of ouabain. An electrophysiological recording showed that 23 inhibited the sodium pump current in a concentration-dependent manner.

Prokaryotic recombinant hemagglutinin-neuraminidase protein enhances the humoral response and efficacy of commercial Newcastle disease vaccines in chickens.

The hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) plays an important role in the pathogenesis of Newcastle disease (ND). Recombinant HN (rHN) protein, produced either by direct injection of recombinant viruses containing HN gene or baculovirus expression systems, has been used to elicit immunity against NDV in chickens. In the present study, a 60.4-kDa rHN was expressed by a prokaryotic expression system and formulated into ND vaccines. Inclusion of rHN (10 microg/ml) into conventional, inactivated ND vaccines significantly (P < 0.05) increased the titer of serum hemagglutination-inhibition Ab in specific-pathogen-free or commercial chickens. Furthermore, when the rHN protein was formulated into ND+IC (infectious coryza) bivalent or ND+IC+FC (fowl cholera) multivalent vaccines, the protection rate of immunized chickens increased from approximately 80%-90% to 100% after being challenged by a velogenic strain of NDV. Our data indicated that inclusion of rHN protein produced by an economical prokaryotic expression system could enhance the immunogenicity of traditional and multivalent inactivated ND vaccines. This approach may be adapted to improve the efficacy of ND vaccines currently used in the poultry industry.

Cytotoxic phenanthroindolizidine alkaloids from the roots of Ficus septica.

Activity-monitored fractionation of the CHCl3 solubles of the MeOH extract of the roots of Ficus septica using cytotoxicity assay led to the isolation of twenty phenanthroindolizidine alkaloids, including ten new ficuseptines E-N and ten known compounds. The cytotoxic effects of some of the isolates were tested on gastric adenocarcinoma (NUGC) and nasopharyngeal carcinoma (HONE-1) cell lines and the results demonstrated that, with the exception of dehydrotylophorine, all the tested compounds displayed pronounced cytotoxic activity with significant cell growth inhibitory effects. In addition, 13a R-antofine was found to be highly effective with ED(50) values of < 0.1 microg/mL against L-1210, P-388, A-549 and HCT-8 cell lines in another assay.

Risk Assessment of Miners' Unsafe Behaviors: A Case Study of Gas Explosion Accidents in Coal Mine, China.

China's coal mine production situation is grim and various types of accidents occur frequently, and gas explosion accidents are the highest incidence of coal mine accidents. The authors selected 200 gas explosion accidents of coal mine enterprises in recent years, and extracted a large number of workers' unsafe behaviors. Meanwhile, four working types related to gas explosion accidents were obtained, namely ventilation, gas prevention and fire extinguishing, blasting, and electrician. This article listed some influencing factors of unsafe behaviors and corrected the probability of unsafe behaviors. In addition, a probabilistic risk assessment model was established, and the Monte Carlo method was used to analyze the risks caused by unsafe behaviors of various working types. The results show that the risk of unsafe behaviors caused by the ventilation working type is the highest, followed by gas prevention and fire extinguishing, and finally blasting and electrician. This paper studies the influencing factors of miners' unsafe behaviors from the perspective of behavior, guarantees effectively the safety management of coal mine enterprises, and lays a foundation for studying unsafe behaviors related to coal mine gas explosions.

Advanced Molecular Knowledge of Therapeutic Drugs and Natural Products Focusing on Inflammatory Cytokines in Asthma.

Asthma is a common respiratory disease worldwide. Cytokines play a crucial role in the immune system and the inflammatory response to asthma. Abnormal cytokine expression may lead to the development of asthma, which may contribute to pathologies of this disease. As cytokines exhibit pleiotropy and redundancy characteristics, we summarized them according to their biologic activity in asthma development. We classified cytokines in three stages as follows: Group 1 cytokines for the epithelial environment stage, Group 2 cytokines for the Th2 polarization stage, and Group 3 cytokines for the tissue damage stage. The recent cytokine-targeting therapy for clinical use (anti-cytokine antibody/anti-cytokine receptor antibody) and traditional medicinal herbs (pure compounds, single herb, or natural formula) have been discussed in this review. Studies of the Group 2 anti-cytokine/anti-cytokine receptor therapies are more prominent than the studies of the other two groups. Anti-cytokine antibodies/anti-cytokine receptor antibodies for clinical use can be applied for patients who did not respond to standard treatments. For traditional medicinal herbs, anti-asthmatic bioactive compounds derived from medicinal herbs can be divided into five classes: alkaloids, flavonoids, glycosides, polyphenols, and terpenoids. However, the exact pathways targeted by these natural compounds need to be clarified. Using relevant knowledge to develop more comprehensive strategies may provide appropriate treatment for patients with asthma in the future.