40 research outputs found
Potential drug targets for asthma identified in the plasma and brain through Mendelian randomization analysis
BackgroundAsthma is a heterogeneous disease, and the involvement of neurogenic inflammation is crucial in its development. The standardized treatments focus on alleviating symptoms. Despite the availability of medications for asthma, they have proven to be inadequate in controlling relapses and halting the progression of the disease. Therefore, there is a need for novel drug targets to prevent asthma.MethodsWe utilized Mendelian randomization to investigate potential drug targets for asthma. We analyzed summary statistics from the UK Biobank and then replicated our findings in GWAS data by Demenais et al. and the FinnGen cohort. We obtained genetic instruments for 734 plasma and 73 brain proteins from recently reported GWAS. Next, we utilized reverse causal relationship analysis, Bayesian co-localization, and phenotype scanning as part of our sensitivity analysis. Furthermore, we performed a comparison and proteinâprotein interaction analysis to identify causal proteins. We also analyzed the possible consequences of our discoveries by the given existing asthma drugs and their targets.ResultsUsing Mendelian randomization analysis, we identified five proteinâasthma pairs that were significant at the Bonferroni level (P < 6.35 Ă 10â5). Specifically, in plasma, we found that an increase of one standard deviation in IL1R1 and ECM1 was associated with an increased risk of asthma, while an increase in ADAM19 was found to be protective. The corresponding odds ratios were 1.03 (95% CI, 1.02â1.04), 1.00 (95% CI, 1.00â1.01), and 0.99 (95% CI, 0.98â0.99), respectively. In the brain, per 10-fold increase in ECM1 (OR, 1.05; 95% CI, 1.03â1.08) and PDLIM4 (OR, 1.05; 95% CI, 1.04â1.07) increased the risk of asthma. Bayesian co-localization found that ECM1 in the plasma (coloc.abf-PPH4 = 0.965) and in the brain (coloc.abf-PPH4 = 0.931) shared the same mutation with asthma. The target proteins of current asthma medications were found to interact with IL1R1. IL1R1 and PDLIM4 were validated in two replication cohorts.ConclusionOur integrative analysis revealed that asthma risk is causally affected by the levels of IL1R1, ECM1, and PDLIM4. The results suggest that these three proteins have the potential to be used as drug targets for asthma, and further investigation through clinical trials is needed
Uncovering the ElectronâPhonon Interplay and Dynamical EnergyâDissipation Mechanisms of Hot Carriers in Hybrid Lead Halide Perovskites
The discovery of slow hot carrier cooling in hybrid organicâinorganic lead halide perovskites (HOIPs) has provided exciting prospects for efficient solar cells that can overcome the ShockleyâQueisser limit. Questions still loom over how electronâphonon interactions differ from traditional polar semiconductors. Herein, the electronâphonon coupling (EPC) strength of common perovskite films (MAPbBr3, MAPbI3, CsPbI3, and FAPbBr3) is obtained using transient absorption spectroscopy by analyzing the hot carrier cooling thermodynamics via a simplified twoâtemperature model. Density function theory calculations are numerically performed at relevant electronâtemperatures to confirm experiments. Further, the variation of carrierâtemperature over a large range of carrierâdensities in HOIPs is analyzed, and an âSâshapedâ dependence of the initial carrierâtemperature to carrierâdensity is reported. The phenomenon is attributed to the dominance of the large polaron screening and the destabilization effect which causes an increasingâdecreasing fluctuation in temperature at low excitation powers ; and a hotâphonon bottleneck which effectively increases the carrier temperature at higher carrierâdensities. The turning point in the relationship is indicative of the critical Mott density related to the nonmetalâmetal transition. The EPC analysis provides a novel perspective to quantify the energy transfer in HOIPs, electronâlattice subsystem, and the complicated screeningâbottleneck interplay is comprehensively described, resolving the existing experimental contradictions
Large difference of inhibitive effect of nitrogen deposition on soil methane oxidation between plantations with N-fixing tree species and non-N-fixing tree species
Direct Power Control for Three-Phase Two-Level Voltage-Source Rectifiers Based on Extended-State Observation
De Novo Tailoring Pore Morphologies and Sizes for Different Substrates in a Urea-Containing MOFs Catalytic Platform
To better understand
the structureâcatalytic property relationship,
a platform of urea-containing MOFs with diverse topologies as hydrogen-bonding
(H-bond) catalyst has been well established in the present work. During
the construction of MOFs, we proposed a new strategy called the isoreticular
functionalization approach in which the desired topological net is
first considered as a blueprint, and then two predesigned functionalized
polydentate ligands link to four different metal clusters by de novo
routes to achieve the MOFs with expected pore structure and catalytic
sites. By means of this strategy, we successfully synthesized four
programmed MOFs (named as <b>URMOF-1â4</b>) with diverse
topologies, pore morphologies, and sizes and distribution of active
sites. Subsequently, we systematically investigated the FriedelâCrafts
reactions of 1-methylpyrrole or 1-methylindole with nitroalkene derivatives
with diverse sizes to assess the catalytic properties of the above-mentioned
URMOFs. These four URMOFs can act as reusable H-bond catalysts and
show varied catalytic capacities and size-selectivity properties.
Most significantly, the open morphologies of pores, large channels
in the framework, and effective distribution of active sites on the
wall of the channel are proved to facilitate catalysis. This urea-containing
MOF catalytic platform provides new insight into the catalytic properties
of MOFs with the same kind of active sites but diverse topologies,
pore morphologies, and sizes and distributions of catalytic sites
Design and simulation of locally enhanced microchannel heat sink for diode partially pumped slab laser
With the power level of diode-pumped solid-state laser (DPSSL) rising continuously, its thermal effect has become the main problem limiting the laser performance. In this paper, based on the heat distribution of diode partially end-pumped slab (Innoslab) laser, a shunt rectangular microchannel heat sink with locally enhanced heat dissipation is designed. Firstly, multi-stage parallel short channels are designed in the heat concentration area to enhance the solid-liquid heat exchange in this area, and the effects of structure and working conditions on its heat dissipation performance are investigated. Secondly, the copper layer is introduced into the end face of the low thermal conductivity crystal to form a high thermal conductivity path, which alleviates the heat accumulation inside the crystal. Under a certain condition, compared with the traditional liquid-cooled plate system, the maximum temperature of the laser crystal is reduced from 169.62 to 118.18â°C, the pressure drop is reduced by 66.75%, and the total mass of the system is reduced to 4.87% of the original system, which effectively improves the practical performance of the device