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 protein–protein 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 protein–asthma pairs that were significant at the Bonferroni level (P < 6.35 × 10−5). 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, 1.02–1.04), 1.00 (95% CI, 1.00–1.01), and 0.99 (95% CI, 0.98–0.99), respectively. In the brain, per 10-fold increase in ECM1 (OR, 1.05; 95% CI, 1.03–1.08) and PDLIM4 (OR, 1.05; 95% CI, 1.04–1.07) 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 Electron‐Phonon Interplay and Dynamical Energy‐Dissipation Mechanisms of Hot Carriers in Hybrid Lead Halide Perovskites

The discovery of slow hot carrier cooling in hybrid organic–inorganic lead halide perovskites (HOIPs) has provided exciting prospects for efficient solar cells that can overcome the Shockley–Queisser limit. Questions still loom over how electron‐phonon interactions differ from traditional polar semiconductors. Herein, the electron‐phonon 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 two‐temperature model. Density function theory calculations are numerically performed at relevant electron‐temperatures to confirm experiments. Further, the variation of carrier‐temperature over a large range of carrier‐densities in HOIPs is analyzed, and an “S‐shaped” dependence of the initial carrier‐temperature to carrier‐density is reported. The phenomenon is attributed to the dominance of the large polaron screening and the destabilization effect which causes an increasing‐decreasing fluctuation in temperature at low excitation powers ; and a hot‐phonon bottleneck which effectively increases the carrier temperature at higher carrier‐densities. The turning point in the relationship is indicative of the critical Mott density related to the nonmetal‐metal transition. The EPC analysis provides a novel perspective to quantify the energy transfer in HOIPs, electron‐lattice subsystem, and the complicated screening‐bottleneck interplay is comprehensively described, resolving the existing experimental contradictions

De Novo Tailoring Pore Morphologies and Sizes for Different Substrates in a Urea-Containing MOFs Catalytic Platform

To better understand the structure–catalytic 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-1–4</b>) with diverse topologies, pore morphologies, and sizes and distribution of active sites. Subsequently, we systematically investigated the Friedel–Crafts 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 118.18 °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