PM10 exposure induces bronchial hyperresponsiveness by upreguating acetylcholine muscarinic 3 receptor.

Exposure to particulate matter (PM10) can induce respiratory diseases that are closely related to bronchial hyperresponsiveness. However, the involved mechanism remains to be fully elucidated. This study aimed to demonstrate the effects of PM10 on the acetylcholine muscarinic 3 receptor (CHRM3) expression and the role of the ERK1/2 pathway in rat bronchial smooth muscle. A whole-body PM10 exposure system was used to stimulate bronchial hyperresponsiveness in rats for 2 and 4 months, accompanied by MEK1/2 inhibitor U0126 injection. The whole-body plethysmography system and myography were used to detect the pulmonary and bronchoconstrictor function, respectively. The mRNA and protein levels were determined by Western blotting, qPCR, and immunofluorescence. Enzyme-linked immunosorbent assay was used to detect the inflammatory cytokines. Compared with the filtered air group, 4 months of PM10 exposure significantly increased CHRM3-mediated pulmonary function and bronchial constriction, elevated CHRM3 mRNA and protein expression levels on bronchial smooth muscle, then induced bronchial hyperreactivity. Additionally, 4 months of PM10 exposure caused an increase in ERK1/2 phosphorylation and increased the secretion of inflammatory factors in bronchoalveolar lavage fluid. Treatment with the MEK1/2 inhibitor, U0126 inhibited the PM10 exposure-induced phosphorylation of the ERK1/2 pathway, thereby reducing the PM10 exposure-induced upregulation of CHRM3 in bronchial smooth muscle and CHRM3-mediated bronchoconstriction. U0126 could rescue PM10 exposure-induced pathological changes in the bronchus. In conclusion, PM10 exposure can induce bronchial hyperresponsiveness in rats by upregulating CHRM3, and the ERK1/2 pathway may be involved in this process. These findings could reveal a potential therapeutic target for air pollution induced respiratory diseases.

Solvent-Controlled Divergent Cyclization of 3-Ylideneoxindoles with Ethyl 2-Diazoacetate: Access to Spirocyclopropyl and Spiropyrazolines Oxindoles.

Herein a catalyst-free solvent-controlled method for the divergent synthesis of spirocyclopropyl and spiropyrazoline oxindoles from 3-ylideneoxindoles and ethyl diazoacetate was developed. With ClCH2CH2Cl as the solvent, spirocyclopropyl oxindoles were obtained in moderate to excellent yields, whereas the use of MeOH as solvent afforded spiropyrazoline oxindoles in moderate to good yields. The readily available substrates, simple operation and various product transformations further highlighted the utility of this method.

Efficient Three-Dimensional DNA Nanomachine Guided by a Robust Tetrahedral DNA Nanoarray Structure for the Rapid and Ultrasensitive Electrochemical Detection of Matrix Metalloproteinase 2.

Herein, a giant-sized DNA nanoarray was subtly assembled by two kinds of independent tetrahedral DNA structures as the DNA track for a multi-armed three-dimensional (3D) DNA nanomachine to perform signal transduction and amplification efficiently, which was developed as an electrochemical biosensor for the rapid and ultrasensitive detection of matrix metalloproteinase 2 (MMP-2). Impressively, in contrast to conventional DNA walkers with inefficiency, which walked on random DNA tracks composed of a two-dimensional (2D) probe or a one-dimensional (1D) single-stranded (ss)DNA probe, the multi-armed 3D DNA nanomachine from exonuclease III (Exo III) enzyme-assisted target recycling amplification would be endowed with faster reaction speed and better walking efficiency because of the excellent rigidity and orderliness of the tetrahedral DNA nanoarray structure. Once the hairpin H3-label with the signal substance ferrocene (Fc) was added to the modified electrode surface, the multi-armed 3D DNA nanomachine would be driven to move along the well-designed nanoarray tracks by toehold-mediated DNA strand displacement, resulting in most of the ferrocene (Fc) binding to the electrode surface and a remarkable increase in electrochemical signals within 60 min. As a proof of concept, the prepared biosensor attained a low detection limit of 11.4 fg/mL for the sensitive detection of the target MMP-2 and was applied in Hela and MCF-7 cancer cell lysates. As a result, this strategy provided a high-performance sensing platform for protein detection in tumor diagnosis.

Genome-wide association study on resistance of cultivated soybean to Fusarium oxysporum root rot in Northeast China.

BACKGROUND: Fusarium oxysporum is a prevalent fungal pathogen that diminishes soybean yield through seedling disease and root rot. Preventing Fusarium oxysporum root rot (FORR) damage entails on the identification of resistance genes and developing resistant cultivars. Therefore, conducting fine mapping and marker development for FORR resistance genes is of great significance for fostering the cultivation of resistant varieties. In this study, 350 soybean germplasm accessions, mainly from Northeast China, underwent genotyping using the SoySNP50K Illumina BeadChip, which includes 52,041 single nucleotide polymorphisms (SNPs). Their resistance to FORR was assessed in a greenhouse. Genome-wide association studies utilizing the general linear model, mixed linear model, compressed mixed linear model, and settlement of MLM under progressively exclusive relationship models were conducted to identify marker-trait associations while effectively controlling for population structure. RESULTS: The results demonstrated that these models effectively managed population structure. Eight SNP loci significantly associated with FORR resistance in soybean were detected, primarily located on Chromosome 6. Notably, there was a strong linkage disequilibrium between the large-effect SNPs ss715595462 and ss715595463, contributing substantially to phenotypic variation. Within the genetic interval encompassing these loci, 28 genes were present, with one gene Glyma.06G088400 encoding a protein kinase family protein containing a leucine-rich repeat domain identified as a potential candidate gene in the reference genome of Williams82. Additionally, quantitative real-time reverse transcription polymerase chain reaction analysis evaluated the gene expression levels between highly resistant and susceptible accessions, focusing on primary root tissues collected at different time points after F. oxysporum inoculation. Among the examined genes, only this gene emerged as the strongest candidate associated with FORR resistance. CONCLUSIONS: The identification of this candidate gene Glyma.06G088400 improves our understanding of soybean resistance to FORR and the markers strongly linked to resistance can be beneficial for molecular marker-assisted selection in breeding resistant soybean accessions against F. oxysporum.

Blood exosome sensing via neuronal insulin-like growth factor-1 regulates autism-related phenotypes.

The development and progression of autism spectrum disorder (ASD) is characterized by multiple complex molecular events, highlighting the importance of the prefrontal brain regions in this process. Exosomes are nanovesicles that play a critical role in intercellular communication. Peripheral systems influence brain function under both physiological and pathological conditions. We investigated whether this influence was mediated by the direct sensing of peripheral blood exosomes by brain cells. Administration of serum exosomes from rats with valproic acid-induced ASD resulted in ASD-related phenotypes in mice, whereas exosomes from normal rats did not exhibit such effects. RNA sequencing and bioinformatics analysis suggested that negative regulation of medial prefrontal cortex (mPFC) insulin-like growth factor 1 (IGF-1) by exosome-derived miR-29b-3p may contribute to these ASD-associated effects. Further evidence showed that miR-29b-3p-enriched exosomes crossed the blood-brain barrier to reach the mPFC, subsequently inducing the suppression of IGF-1 expression in neurons. Optogenetic activation of excitatory neurons in the mPFC improved behavioral abnormalities in exosome-treated mice. The addition of exogenous IGF-1 or inhibition of miR-29b-3p expression in the mPFC also rescued the ASD-related phenotypes in mice. Importantly, administration of miR-29b-3p-enriched serum exosomes from human donors with ASD into the mouse medial prefrontal cortex was sufficient to induce hallmark ASD behaviors. Together, our findings indicate that blood-brain cross-talk is crucial for ASD pathophysiology and that the brain may sense peripheral system changes through exosomes, which could serve as the basis for future neurological therapies.

Highly Efficient Quadruped DNA Walker Guided by Ordered DNA Tracks for Rapid and Ultrasensitive Electrochemical Detection of miRNA-21.

Herein, a long period liner DNA tandem (Lr-DNT) was intelligently designed as DNA track for quadruped DNA walker (q-walker) to run in an orderly and efficient manner, which could be applied to construct an electrochemical biosensor for rapid and ultrasensitive detection of microRNA-21 (miRNA-21). Impressively, benefiting from the orderliness and equidistance of Lr-DNT, the q-walker could be endowed with a high controllability, directionality as well as a quite short reaction time down to 20 min compared with those of traditional DNA walkers walked on the stochastic tracks. Once the target miRNA-21 interacted with the locked q-walker, the q-walker could be activated to expeditiously cleave Lr-DNT for releasing amounts of signal probes ferrocene (Fc) with the assistance of the Nt.BbvCI enzyme. This way, the developed q-walker could not only readily overcome the problem of low reaction efficiency but also address the drawback of time consumption in a previous strategy. As a proof of concept, the prepared biosensor could accomplish sensitive detection of target miRNA-21 with a detection limit down to 31 aM. As a result, this tactic gave impetus to design high-performance sensing platform with ultimate application in clinical sample analysis and nucleic acid based cancer diagnostics.

Single-cell RNA sequencing reveals the sustained immune cell dysfunction in the pathogenesis of sepsis secondary to bacterial pneumonia.

Sepsis is a leading cause of mortality in intensive care unit worldwide, it's accompanied by immune cell dysfunction induced by multiple factors. However, little is known about the specific alterations in immune cells in the dynamic pathogenesis of sepsis secondary to bacterial pneumonia. Here, we used single cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) in a healthy control and two patients with sepsis secondary to bacterial pneumonia, including acute, stable and recovery stage. We analyzed the quantity and function of immune cells. During disease course, interferon gamma response was upregulated; T/NK cell subtypes presented activation and exhaustion properties, which might be driven by monocytes through IL-1ß signaling pathways; The proportion of plasma cells was increased, which might be driven by NK cells through IFN signaling pathways; Additionally, interferon gamma response was upregulated to a greater degree in sepsis secondary to pneumonia induced by SARS-COV-2 compared with that induced by influenza virus and bacteria.

Does lock-down of Wuhan effectively restrict early geographic spread of novel coronavirus epidemic during chunyun in China? A spatial model study.

BACKGROUND: Prior to Wuhan lock-down in 2020, chunyun, the largest population mobility on this planet, had begun. We quantified impact of Wuhan lock-down on COVID-19 spread during chunyun across the nation. METHODS: During the period of January 1 to February 9, 2020, a total of 40,278 confirmed COVID-19 cases from 319 municipalities in mainland China were considered in this study. The cross-coupled meta-population methods were employed using between-city Baidu migration index. We modelled four scenarios of geographic spread of COVID-19 including the presence of both chunyun and lock-down (baseline); lock-down without chunyun (scenario 1); chunyun without lock-down (scenario 2); and the absence of both chunyun and lock-down (scenario 3). RESULTS: Compared with the baseline, scenario 1 resulted in 3.84% less cases by February 9 while scenario 2 and 3 resulted in 20.22 and 32.46% more cases by February 9. The geographic distribution of cases revealed that chunyun facilitated the COVID-19 spread in the majority but not all cities, and the effectiveness of Wuhan lock-down was offset by chunyun. Impacts of Wuhan lock-down during chunyun on the COVID-19 spread demonstrated heterogenetic geographic patterns. CONCLUSION: Our results strongly supported the travel restriction as one of the effective responses and highlighted the importance of developing area-specific rather than universal countermeasures.

Hydrogen Peroxide-Mediated Oxygen Enrichment Eradicates Helicobacter pylori In Vitro and In Vivo.

Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.

Nonreciprocal interference and coherent photon routing in a three-port optomechanical system.

We study the interference between different weak signals in a three-port optomechanical system, which is achieved by coupling three cavity modes to the same mechanical mode. If one cavity serves as a control port and is perturbed continuously by a control signal, nonreciprocal interference can be observed when another signal is injected upon different target ports. In particular, we exhibit frequency-independent perfect blockade induced by the completely destructive interference over the full frequency domain. Moreover, coherent photon routing can be realized by perturbing all ports simultaneously, with which the synthetic signal only outputs from the desired port. We also reveal that the routing scheme can be extended to more-port optomechanical systems. The results in this paper may have potential applications for controlling light transport and quantum information processing.

Dual-gate transistor amplifier in a multimode optomechanical system.

We present a dual-gate optical transistor based on a multimode optomechanical system, composed of three indirectly coupled cavities and an intermediate mechanical resonator pumped by a frequency-matched field. In this system, two cavities driven on the red mechanical sidebands are regarded as input/ouput gates/poles and the third one on the blue sideband as a basic/control gate/pole, while the resonator as the other basic/control gate/pole. As a nonreciprocal scheme, the significant unidirectional amplification can be resulted by controlling the two control gates/poles. In particular, the nonreciprocal direction of the optical amplification/rectification can be controlled by adjusting the phase differences between two red-sideband driving fields (the pumping and probe fields). Meanwhile, the narrow window that can be analyzed by the effective mechanical damping rate, arises from the extra blue-sideband cavity. Moreover, the tunable slow/fast light effect can be observed, i.e, the group velocity of the unidirectional transmission can be controlled, and thus the switching scheme of slow/fast light effect can also utilized to realize both slow and fast lights through opposite propagation directions, respectively. Such an amplification transistor scheme of controllable amplitude, direction and velocity may imply exciting opportunities for potential applications in photon networks and quantum information processing.

Chronic real-time particulate matter exposure causes rat pulmonary arteriole hyperresponsiveness and remodeling: The role of ETBR-ERK1/2 signaling.

Exposure to air pollution is associated with the incidence of respiratory diseases. The present study evaluated the pulmonary vascular system injury by chronic real-time particulate matter (PM10) exposure and investigated the underlying mechanisms. Rats were exposed to PM10 or filtered air for 2 to 4 months using a whole body exposure system, and intraperitoneally injected with the MEK1/2 inhibitor U0126. Right heart catheterization and myography were performed to detect lung function and pulmonary vascular reactivity, respectively. Western blotting, qRT-PCR, enzyme-linked immunosorbent assay and histological analyses were used to detect the effects and mechanisms by which PM10 exposure-induced pulmonary vascular dysfunction. Functional experiment results showed that PM10 exposure increased the pulmonary artery pressure of rats and caused endothelin B receptor (ETBR)-mediated pulmonary arteriole hyperreactivity. U0126 significantly rescued these pathological changes. PM10 exposure upregulated the contractile ETBR of pulmonary arteriolar smooth muscle, and damaged pulmonary artery endothelial cells to induce the release of more endothelin 1 (ET-1). The upregulated ETBR bound to increased ET-1 induced pulmonary arteriolar hyperresponsiveness and remodeling. U0126 inhibited the PM10 exposure-induced upregulation of ETBR in pulmonary arteriole, ETBR-mediated pulmonary arterial hyperresponsiveness and vascular remodeling. In conclusion, chronic real-time particulate matter exposure can activate the ERK1/2 signaling, thereby inducing the upregulation of contractile ETBR in pulmonary arteriole, which may be involved in pulmonary arteriole hyperresponsiveness and remodeling in rats. These findings provide new mechanistic evidence of PM10 exposure-induced respiratory diseases, and a new possible target for treatment.

Controllable optical response in a three-mode optomechanical system by driving the cavities on different sidebands.

We study the controllable optical response in a three-mode optomechanical system comprised of two indirectly coupled cavity modes and an intermediate mechanical mode. The two cavity modes are assumed to have different frequencies and driven by two control fields on the red and blue sidebands, respectively. When the system is perturbed by two probe fields satisfying the specific matching condition, a series of intriguing phenomena can be observed by adjusting phases and amplitudes of the control fields, such as absorption-amplification switching, ultra-narrow response windows, frequency-independent perfect reflection, and ultralong optical group delay. We also compare our system with conventional optomechanical systems to highlight its distinct features. Our results may have potential applications in optical communication and quantum information processing.

In vitro and in vivo metabolic activation of berbamine to quinone methide intermediate.

Berbamine (BBM) is a bisbenzylisoquinoline alkaloid isolated from herbal medicine Berberis amurensis. BBM has been widely used for the treatment of leukemia. Recent studies demonstrated that exposure to BBM can give rise to cytotoxicity. The major objective of this study was to explore the metabolic activation of BBM in vitro and in vivo. Two oxidative metabolites (M1 and M2) and an N-acetylcysteine (NAC) conjugate (M3) were detected in human liver microsomal incubations of BBM supplemented with NAC, and the formation of all metabolites was NADPH dependent. Microsomal inhibition and recombinant P450 enzyme incubation studies demonstrated that P450 3A4 was the major enzyme responsible for the metabolic activation of BBM. In addition, a BBM-cysteine conjugate (M4) was detected in the urine of rats given BBM. The metabolism study will facilitate the understanding of the biochemical mechanisms of BBM-induced cytotoxicity.

Mechanism-based inactivation of CYP2C9 by linderane.

1. Linderane (LDR), a furan-containing sesquiterpenoid, is found in Lindera aggregata (Sims) Kosterm, a common traditional Chinese herbal medicine. We thoroughly studied the irreversible inhibitory effect of LDR on cytochrome P450 2C9 (CYP2C9). 2. LDR caused a time- and concentration-dependent inactivation of CYP2C9. In addition, the inactivation of CYP2C9 by LDR was NADPH-dependent and irreversible. More than 50% of CYP2C9 activity was lost after its incubation with LDR at the concentration of 10 µM for 15 min at 30 °C. The maximal rate constant for inactivation (kinact) was found to be 0.0419 min(-1), and the concentration required for half-maximal inactivation (KI) was 1.26 µM, respectively. Glutathione (GSH), catalase, and superoxide dismutase (SOD) failed to protect CYP2C9 against inactivation by LDR. Diclofenac, a substrate of CYP2C9, prevented the enzyme from inactivation produced by LDR. The estimated partition ratio of the inactivation was approximately 227. 3. Two reactive intermediates, including furanoepoxide and γ-ketoenal, might be responsible for the observed enzyme inactivation. The formation of the intermediates was verified by chemical synthesis. Multiple P450 enzymes, including CYPs 1A2, 2B6, 2C9, 2C19, 2D6, 3A4, and 3A5, were found to be involved in the metabolic activation of LDR. In conclusion, LDR was characterized as a mechanism-based inactivator of CYP2C9.

Versatile preparation of nonspherical multiple hydrogel core PAM/PEG emulsions and hierarchical hydrogel microarchitectures.

The preparation of nonspherical materials composed of separated multicomponents by droplet-based microfluidics remains a challenge. Based on polymerization-induced phase separation and droplet coalescence in microfluidics, we prepared emulsions of variously shaped PAM/PEG core/shell droplets and hydrogels composed of two separated components, which show flexible and transformable hierarchical structures and microarchitectures. We find that AM/PEG aqueous droplets form a core/shell structure after polymerization resulting from phase separation. Thus multicore/shell droplets are easily produced by coalescence of core/shell structures. By changing the polymerization temperature and the flow rate, the morphology of the multicore droplets and the hydrogel can be easily adjusted. The hydrogels exhibit apparent anisotropy and different protein release rates depending on their structures. The preparation technique is simple and versatile and the resulting hydrogels have potential applications in many fields.

Road Performance and Self-Healing Property of Bituminous Mixture Containing Urea-Formaldehyde Microcapsules.

Urea-formaldehyde (UF) is a common shell material for self-healing microcapsules; however, the influence of urea-formaldehyde microcapsules (UFMs) on the road performance of bituminous mixtures and the sensitivity of their healing abilities remains unclear. In this paper, UFMs were prepared via in situ polymerization (ISP), followed by an investigation into the road performance of UFM self-healing bituminous mixtures through various tests, including wheel tracking, immersed Marshall, freeze-thaw splitting, low-temperature bending, and three-point bending fatigue tests. Subsequently, the impact of the damage degree, healing duration, and temperature on the self-healing property was discussed. The results indicated that incorporating 3 wt% UFMs into bitumen significantly improved the high-temperature stability and fatigue resistance of the bituminous mixture; for example, its dynamic stability and fatigue life could be increased by about 16.5% and 10%, respectively. However, it diminished the thermal crack resistance, as evidenced by decreases in bending tensile strength and strain by 3.7% and 10.1%, respectively. And it did not markedly improve the moisture susceptibility. Additionally, the maximum improvement observed in the healing rate was about 9%. Furthermore, the healing duration and temperature positively influenced the bituminous mixture's self-healing, whereas the degree of damage exerted a negative impact, with a relatively significant effect.

Regulating Desolvation Activation Energy and Zn Deposition via a CTAB-Intercalated Mg-Al-Layered Double-Hydroxide Protective Layer for Durable Zn Metal Anodes.

While aqueous Zn-ion batteries (AZIBs) are widely considered as a promising energy storage system due to their merits of low cost, high specific capacity, and safety, the practical implementation has been hindered by the Zn dendrite growth and undesirable parasitic reactions. To address these issues, a unique hydrophobic-ion-conducting cetyltrimethylammonium bromide-intercalated Mg-Al-layered double-hydroxide protective layer was constructed on the Zn anode (OMALDH-Zn) to modulate the nucleation behavior and desolvation process. The hydrophobic cetyl group long chain can inhibit the hydrogen evolution reaction and Zn corrosion by repelling water molecules from the anode surface and reducing the desolvation activation energy. Meanwhile, the Mg-Al LDH with abundant zincophilic active sites can modulate the Zn2+ ion flux, enabling the dendrite-free Zn deposition. Benefiting from this interfacial synergy, a long cycle life (>2300 h) with low and stable overpotential (<18 mV at 1 mA cm-2) and excellent Coulombic efficiency (99.4%) for symmetrical and asymmetrical batteries were achieved. More impressively, excellent rate performance and long cyclic stability have been realized by OMALDH-Zn//MnO2 batteries in both coin-type and pouch-type devices. This low-cost, simple, and high-efficiency coordinated modulation method provides a reliable strategy for the practical application of AZIBs.

Surgical strategy for intravenous leiomyomatosis spreading from uterine to the right atrium presenting with recurrent syncope.

Uterine leiomyoma invading internal iliac vein and consequently disseminating into the right atrium is an extremely rare condition, and surgical strategy is controversial. Here, we reported a specific case with successful surgical resection through one-stage total hysterectomy, bilateral oophorectomy, and the intracardiovascular lesion. This procedure would be an optimal choice for uterine leiomyoma invading inferior vena cava and spreading to right atrium.