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The inner ear is the hub where hair cells (HCs) transduce sound, gravity, and head acceleration stimuli to the brain. Hearing and balance rely on mechanosensation, the fastest sensory signals transmitted to the brain. The mechanoelectrical transducer (MET) channel is the entryway for the sound-balance-brain interface, but the channel-complex composition is not entirely known. Here, we report that the mouse utilizes Piezo1 (Pz1) and Piezo2 (Pz2) isoforms as MET-complex components. The Pz channels, expressed in HC stereocilia, and cell lines are co-localized and co-assembled with MET complex partners. Mice expressing non-functional Pz1 and Pz2 at the ROSA26 locus have impaired auditory and vestibular traits that can only be explained if the Pzs are integral to the MET complex. We suggest that Pz subunits constitute part of the MET complex and that interactions with other MET complex components yield functional MET units to generate HC MET currents.

Abstract Background Gene therapy holds great potential for treating various acquired and inherited pulmonary diseases. Adeno-associated viral (AAV) vectors have been thought to be primary candidates for gene delivery in patients with pulmonary diseases. However, the tropism of AAVs in the lungs remains largely unknown. Results Here, we investigate the tropism of twenty serotypes of AAVs by examining AAV-packed vector expression of the enhanced green fluorescent protein (eGFP) in mice. AAV1, AAV4, AAV5, AAV6, AAV6.2, AAV-PHP.B, and AAV-PHP.S exhibit high transduction rates in the airway epithelium. AAV1, AAV4, AAV5, AAV6, and AAV6.2 highly infect club cells. AAV1, AAV4, AAV5, AAV6, AAV6.2, and AAV-PHP.B efficiently infect ciliated cells. AAV8 and AAVrh10 can infect a few alveolar type I cells. AAV1, AAV5, AAV6, AAV6.2, AAV9, and AAVie can infect alveolar type II cells. AAV1, AAV5, AAVie, AAV-PHP.B, AAV-PHP.eB, and AAV-PHP.S can infect a few endothelial cells. However, none of these AAVs can efficiently infect neuroendocrine or smooth muscle cells. Conclusions Our findings provide comprehensive information about the tropism of AAVs in pulmonary epithelium in mice, which might be helpful in developing efficient AAV-mediated gene therapy strategies for pulmonary disease treatment.

Abstract Data-driven approaches offer novel opportunities for improving the performance of turbulent flow simulations, which are critical to wide-ranging applications from wind farms and aerodynamic designs to weather and climate forecasting. However, current methods for these simulations often require large amounts of data and computational resources. While data-driven methods have been extensively applied to the continuum Navier-Stokes equations, limited work has been done to integrate these methods with the highly scalable lattice Boltzmann method. Here, we present a physics-informed neural network framework for improving lattice Boltzmann-based simulations of near-wall turbulent flow. Using a small amount of data and integrating physical constraints, our model accurately predicts flow behaviour at a wide range of friction Reynolds numbers up to 1.0 × 106. In contradistinction with other models that use direct numerical simulation datasets, this approach reduces data requirements by three orders of magnitude and allows for sparse grid configurations. Our work broadens the scope of lattice Boltzmann applications, enabling efficient large-scale simulations of turbulent flow in diverse contexts.

Crude oil pipelines are considered as the lifelines of energy industry. However, accidents of the pipelines can lead to severe public health and environmental concerns, in which greenhouse gas (GHG) emissions, primarily methane, are frequently overlooked. While previous studies examined fugitive emissions in normal operation of crude oil pipelines, emissions resulting from accidents were typically managed separately and were therefore not included in the emission account of oil systems. To bridge this knowledge gap, we employed a bottom-up approach to conducted the first-ever inventory of GHG emissions resulting from crude oil pipeline accidents in the United States at the state level from 1968 to 2020, and leveraged Monte Carlo simulation to estimate the associated uncertainties. Our results reveal that GHG emissions from accidents in gathering pipelines (~720,000 tCO2e) exceed those from transmission pipelines (~290,000 tCO2e), although significantly more accidents have occurred in transmission pipelines (6883 cases) than gathering pipelines (773 cases). Texas accounted for over 40% of total accident-related GHG emissions nationwide. Our study contributes to enhanced accuracy of the GHG account associated with crude oil transport and implementing the data-driven climate mitigation strategies.

Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.

Shallow mixing layers developed in partially-distributed canopy flows (PCFs) are important for water conveyance, sediment transport and solute dispersion. In this paper, we address the response of shallow mixing layers in PCFs to several influential factors associated with bed friction, water shallowness and canopy denseness using depth-averaged Large Eddy Simulation (DA-LES). The results show that under certain canopy denseness, shallow mixing layers in PCFs display asymptotic behaviour for the variation of bed friction and water shallowness, consistent with classic shallow mixing layers. The canopy drag encourages the asymmetric growth of the inner and outer parts of the mixing layer, and this effect decreases when bed friction and water shallowness become pronounced. Characteristic velocity and length scales show similarity well delineated by exponential decay function regarding a stabilization efficiency parameter. The exception happens for the inner length scale of the mixing layer when only changing canopy density. We conclude that changing the canopy denseness can encourage the overall shift of mixing layer scaling regarding a broad range of bed friction and water shallowness. Furthermore, the bed friction parameter thresholding triggering flow instability of mixing layers in PCFs is found about 0.03, lower than 0.09 for splitter-plate induced mixing layers.

Background: Our previous research has demonstrated that electroacupuncture (EA) has the potential to mitigate depression-like symptoms resulting from chronic stress. However, further investigation is required to fully understand the underlying mechanisms. The regulatory role of γ-aminobutyric acid type B (GABAB) in synaptic plasticity and the involvement of NF-κB/NLRP3-mediated inflammation in the lateral habenula nucleus (LHb) are key factors in the development of depression. This study sought to investigate the potential of EA in mitigating depression-like symptoms induced by chronic stress through mechanisms such as enhancing GABAB levels, regulating synaptic plasticity in the LHb, and suppressing NF-κB/NLRP3-mediated inflammation. Methods: Sprague-Dawley rats were exposed to chronic unpredictable mild stress (CUMS) in order to create a model of depression. Subsequently, the weight and behavioral assessments of all rats were monitored, and samples of the lateral habenula and serum were collected. The protein expression levels were analyzed using western blotting. The 5-hydroxytryptophan (5-HT), Dopamine (DA), and Norepinephrine (NE) in the LHb and serum were measured using ELISA. The alterations in GABAB and NF-κB in the LHb were observed through immunofluorescence. The neuronal damage in the LHb was assessed using Nissl staining. Results: EA upregulated the expression of GABAB in the LHb of rats subjected to CUMS. Subsequent behavioral assessments indicated that blocking GABAB attenuated the antidepressant effects of EA in CUMS-exposed rats. Furthermore, EA enhanced synaptic plasticity in the LHb of CUMS-exposed rats and mitigated NF-κB/NLRP3-mediated inflammatory responses, with these effects potentially being reversed by GABAB inhibition. Conclusion: Through the promotion of GABAB levels, regulation of synaptic plasticity within the LHb, and inhibition of NF-κB/NLRP3-mediated neuroinflammation in the same region, electroacupuncture at Shangxing and Fengfu acupoints demonstrates efficacy in mitigating depression-like behaviors induced by CUMS.

Mountainous areas are of special hydrological concern because topography and atmospheric conditions can result in large and sudden floods, posing serious risks to water-related safety in neighbouring countries. The Yarlung Zangbo (YZ) River basin is the largest river basin on the Tibetan Plateau (TP), but how floods will discharge in this basin and how the role of glacier melt in floods will change throughout the 21st-century under shared socioeconomic pathways scenarios (SSP2-4.5 and SSP5-8.5) remain unclear. Here, we comprehensively address this scientific question based on a well-validated large-scale glacier-hydrology model. The results indicate that extreme floods was projected to increase in the YZ basin, and was mainly reflected in increased duration (4–10 d per decade) and intensity (153–985 m3 s−1 per decade). Glacier runoff was projected to increase (2–30 mm per decade) throughout the 21st-century, but there was also a noticeable decrease or deceleration in glacier runoff growth in the late first half of the century under the SSP2-4.5, and in the latter half of the century under the SSP5-8.5. Glacier melt was projected to enhance the duration (12%–23%) and intensity (15%–21%) of extreme floods under both SSPs, which would aggravate the impact of future floods on the socioeconomics of the YZ basin. This effect was gradually overwhelmed by precipitation-induced floods from glacier areas to YZ outlet. This study takes the YZ basin as a projection framework example to help enrich the understanding of future flood hazards in basins affected by rainfall- or meltwater across the TP, and to help policy-makers and water managers develop future plans.

Abstract Previous studies have shown that scutellarin inhibits the excessive activation of microglia, reduces neuronal apoptosis, and exerts neuroprotective effects. However, whether scutellarin regulates activated microglia-mediated neuronal apoptosis and its mechanisms remains unclear. This study aimed to investigate whether scutellarin can attenuate PC12 cell apoptosis induced by activated microglia via the JAK2/STAT3 signalling pathway. Microglia were cultured in oxygen–glucose deprivation (OGD) medium, which acted as a conditioning medium (CM) to activate PC12 cells, to investigate the expression of apoptosis and JAK2/STAT3 signalling-related proteins. We observed that PC12 cells apoptosis in CM was significantly increased, the expression and fluorescence intensity of the pro-apoptotic protein Bax and apoptosis-related protein cleaved caspase-3 were increased, and expression of the anti-apoptotic protein B-cell lymphoma-2 (Bcl-2) was decreased. Phosphorylation levels and fluorescence intensity of the JAK2/STAT3 signalling pathway-related proteins JAK2 and STAT3 decreased. After treatment with scutellarin, PC12 cells apoptosis as well as cleaved caspase-3 and Bax protein expression and fluorescence intensity decreased. The expression and fluorescence intensity of Bcl-2, phosphorylated JAK2, and STAT3 increased. AG490, a specific inhibitor of the JAK2/STAT3 signalling pathway, was used. Our findings suggest that AG490 attenuates the effects of scutellarin. Our study revealed that scutellarin inhibited OGD-activated microglia-mediated PC12 cells apoptosis which was regulated via the JAK2/STAT3 signalling pathway.

Abstract Quantum-confined CsPbBr3 perovskites are promising blue emitters for ultra-high-definition displays, but their soft lattice caused by highly ionic nature has a limited stability. Here, we endow CsPbBr3 nanoplatelets (NPLs) with atomic crystal-like structural rigidity through proper surface engineering, by using strongly bound N-dodecylbenzene sulfonic acid (DBSA). A stable, rigid crystal structure, as well as uniform, orderly-arranged surface of these NPLs is achieved by optimizing intermediate reaction stage, by switching from molecular clusters to mono-octahedra, while interaction with DBSA resulted in formation of a CsxO monolayer shell capping the NPL surface. As a result, both structural and optical stability of the CsPbBr3 NPLs is enhanced by strong covalent bonding of DBSA, which inhibits undesired phase transitions and decomposition of the perovskite phase potentially caused by ligand desorption. Moreover, rather small amount of DBSA ligands at the NPL surface results in a short inter-NPL spacing in their closely-packed films, which facilitates efficient charge injection and transport. Blue photoluminescence of the produced CsPbBr3 NPLs is bright (nearly unity emission quantum yield) and peaks at 457 nm with an extremely narrow bandwidth of 3.7 nm at 80 K, while the bandwidth of the electroluminescence (peaked at 460 nm) also reaches a record-narrow value of 15 nm at room temperature. This value corresponds to the CIE coordinates of (0.141, 0.062), which meets Rec. 2020 standards for ultra-high-definition displays.

This paper presents a novel approach to dynamic pricing and distributed energy management in virtual power plant (VPP) networks using multi-agent reinforcement learning (MARL). As the energy landscape evolves towards greater decentralization and renewable integration, traditional optimization methods struggle to address the inherent complexities and uncertainties. Our proposed MARL framework enables adaptive, decentralized decision-making for both the distribution system operator and individual VPPs, optimizing economic efficiency while maintaining grid stability. We formulate the problem as a Markov decision process and develop a custom MARL algorithm that leverages actor-critic architectures and experience replay. Extensive simulations across diverse scenarios demonstrate that our approach consistently outperforms baseline methods, including Stackelberg game models and model predictive control, achieving an 18.73% reduction in costs and a 22.46% increase in VPP profits. The MARL framework shows particular strength in scenarios with high renewable energy penetration, where it improves system performance by 11.95% compared with traditional methods. Furthermore, our approach demonstrates superior adaptability to unexpected events and mis-predictions, highlighting its potential for real-world implementation.