Neurotoxicity of Combined Exposure to the Heavy Metals (Pb and As) in Zebrafish (Danio rerio).

Lead (Pb) and arsenic (As) are commonly occurring heavy metals in the environment and produce detrimental impacts on the central nervous system. Although they have both been indicated to exhibit neurotoxic properties, it is not known if they have joint effects, and their mechanisms of action are likewise unknown. In this study, zebrafish were exposed to different concentrations of Pb (40 µg/L, 4 mg/L), As (32 µg/L, 3.2 mg/L) and their combinations (40 µg/L + 32 µg/L, 4 mg/L + 3.2 mg/L) for 30 days. The histopathological analyses showed significant brain damage characterized by glial scar formation and ventricular enlargement in all exposed groups. In addition, either Pb or As staining inhibited the swimming speed of zebrafish, which was enhanced by their high concentrations in a mixture. To elucidate the underlying mechanisms, we examined changes in acetylcholinesterase (AChE) activity, neurotransmitter (dopamine, 5-hydroxytryptamine) levels, HPI axis-related hormone (cortisol and epinephrine) contents and neurodevelopment-related gene expression in zebrafish brain. The observations suggest that combined exposure to Pb and As can cause abnormalities in swimming behavior and ultimately exacerbate neurotoxicity in zebrafish by interfering with the cholinergic system, dopamine and 5-hydroxytryptamine signaling, HPI axis function as well as neuronal development. This study provides an important theoretical basis for the mixed exposure of heavy metals and their toxicity to aquatic organisms.

A commensal protozoan attenuates Clostridioides difficile pathogenesis in mice via arginine-ornithine metabolism and host intestinal immune response.

Antibiotic-induced dysbiosis is a major risk factor for Clostridioides difficile infection (CDI), and fecal microbiota transplantation (FMT) is recommended for treating CDI. However, the underlying mechanisms remain unclear. Here, we show that Tritrichomonas musculis (T.mu), an integral member of the mouse gut commensal microbiota, reduces CDI-induced intestinal damage by inhibiting neutrophil recruitment and IL-1ß secretion, while promoting Th1 cell differentiation and IFN-γ secretion, which in turn enhances goblet cell production and mucin secretion to protect the intestinal mucosa. T.mu can actively metabolize arginine, not only influencing the host's arginine-ornithine metabolic pathway, but also shaping the metabolic environment for the microbial community in the host's intestinal lumen. This leads to a relatively low ornithine state in the intestinal lumen in C. difficile-infected mice. These changes modulate C. difficile's virulence and the host intestinal immune response, and thus collectively alleviating CDI. These findings strongly suggest interactions between an intestinal commensal eukaryote, a pathogenic bacterium, and the host immune system via inter-related arginine-ornithine metabolism in the regulation of pathogenesis and provide further insights for treating CDI.

Influence of GPRC5A-Regulated ABCB1 Expression on Lung Adenocarcinoma Proliferation.

Objective Aberrant expression of ATP binding cassette subfamily B member 1 (ABCB1) plays a key role in several cancers. However, influence of G protein coupled receptor family C group 5 type A (GPRC5A)-regulated ABCB1 expression on lung adenocarcinoma proliferation remains unclear. Therefore, this study investigated the effect of GPRC5A regulated ABCB1 expression on the proliferation of lung adenocarcinoma. Methods ABCB1 expressions in lung adenocarcinoma cell lines, human lung adenocarcinoma tissues, and tracheal epithelial cells and lung tissues of GPRC5A knockout mice and wild-type mice were analyzed with RT-PCR, Western blot, or immunohistochemical analysis. Cell counting kit-8 assay was performed to analyze the sensitivity of tracheal epithelial cells from GPRC5A knockout mice to chemotherapeutic agents. Subcutaneous tumor formation assay was performed to confirm whether down-regulation of ABCB1 could inhibit the proliferation of lung adenocarcinoma in vivo. To verify the potential regulatory relationship between GPRC5A and ABCB1, immunofluorescence and immunoprecipitation assays were performed. Results ABCB1 expression was up-regulated in lung adenocarcinoma cell lines and human lung adenocarcinoma tissues. ABCB1 expression in the tracheal epithelial cells and lung tissues of GPRC5Adeficient mice was higher than that in the wild type mice. Tracheal epithelial cells of GPRC5A knockout mice were much more sensitive to tariquidar and doxorubicin than those of GPRC5A wild type mice. Accordingly, 28 days after injection of the transplanted cells, the volume and weight of lung tumor in ABCB1knockout cell-transplanted GPRC5A-/-C57BL/6 mice were significantly smaller than those in wild type cell-transplanted mice (P= 0.0043, P= 0.0060). Furthermore, immunofluorescence and immunoprecipitation assays showed that GPRC5A regulated ABCB1 expression by direct binding.Conclusion GPRC5A reduces lung adenocarcinoma proliferation via inhibiting ABCB1 expression. The pathway by which GPRC5A regulates ABCB1 expression needs to be investigated.

Separation techniques for manufacturing fruit spirits: From traditional distillation to advanced pervaporation process.

Separation process is one of the key processes in the production of fruit spirits, including the traditional distillation method and the new pervaporation membrane method. The separation process significantly determines the constituents and proportions of compounds in the fruit spirit, which has a significant impact on the spirit quality and consumer acceptance. Therefore, it is important and complex to reveal the changing rules of chemical substances and the principles behind them during the separation process of fruit spirits. This review summarized the traditional separation methods commonly used in fruit spirits, covering the types, principles, and corresponding equipment of distillation methods, focused on the enrichment or removal of aroma compounds and harmful factors in fruit spirits by distillation methods, and tried to explain the mechanism behind it. It also proposed a new separation technology for the production of fruit spirits, pervaporation membrane technology, summarized its working principle, operation, working parameters, and application in the production of fruit spirits, and outlined the impact of the separation method on the production of fruit spirits based on existing research, focusing on the separation of flavor compounds, sensory qualities, and hazard factors in fruit spirits, along with a preliminary comparison with distillation. Finally, according to the current researches of the separation methods and the development requirement of the separation process of fruit spirits, the prospect of corresponding research is put forward, in order to propose new ideas and development directions for the research in this field.

Antidepressant-like effects of Jieyu Chufan capsules in the olfactory bulbectomy rat model.

The olfactory bulbectomy (OBX) animal model of depression reproduces the behavioral and neurochemical changes observed in depressed patients. We assessed the therapeutic effects of the Jieyu Chufan (JYCF) capsule on OBX rats. JYCF ameliorated the hedonic and anxiety-like behavior of OBX rats and attenuated the cortical and hippocampal damage. JYCF enhanced the expression of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), fibroblast growth factor 2 (FGF2), and adiponectin (ADPN) in the cortex and hippocampus of OBX rats. JYCF also reduced cortisol levels and restored the levels of excitatory neurotransmitters, such as 5-hydroxytryptamine (5-HT), acetylcholine (ACH), and glutamic acid (Glu), in the brain tissue of OBX rats. Our results suggest that JYCF preserves the synaptic structure by increasing the levels of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) and alleviates the histological alterations of brain tissue by activating AKT/PKA-CREB-BDNF pathways, and by upregulating ADPN and FGF2 expression in OBX rats. JYCF exerts multiple therapeutic effects on depression, including modulating neurotransmitters, repairing neuronal damage, and maintaining synaptic integrity. These findings support the potential of JYCF as a novel antidepressant agent with therapeutic effects on depression and related neurological disorders.

Ultra-low time jitter transform-limited dissipative Kerr soliton microcomb.

Microresonator soliton frequency combs offer unique flexibility in synthesizing microwaves over a wide range of frequencies. Therefore, it is very important to study the time jitter of soliton microcombs. Here, we fabricate optical microresonators with perfect transmission spectrum that characterizes highly uniform extinction ratio and absence of mode interactions by laser machining high-purity silica fiber preforms. Based on such perfect whispering-gallery-mode cavity, We demonstrate that K-band microwave with ultra-low phase noise (-83 dBc/Hz@100 Hz; -112 dBc/Hz@1kHz; -133 dBc/Hz@10kHz) can be generated by photo-detecting the repetition rate of a soliton microcomb. Also, with the Raman scattering and dispersive wave emission largely restricted, we show that ultra-low time jitter soliton has a wide existence range. Our work illuminates a pathway toward low-noise photonic microwave generation as well as the quantum regime of soliton microcombs.

Structural insights into the allosteric inhibition of P2X4 receptors.

P2X receptors are ATP-activated cation channels, and the P2X4 subtype plays important roles in the immune system and the central nervous system, particularly in neuropathic pain. Therefore, P2X4 receptors are of increasing interest as potential drug targets. Here, we report the cryo-EM structures of the zebrafish P2X4 receptor in complex with two P2X4 subtype-specific antagonists, BX430 and BAY-1797. Both antagonists bind to the same allosteric site located at the subunit interface at the top of the extracellular domain. Structure-based mutational analysis by electrophysiology identified the important residues for the allosteric inhibition of both zebrafish and human P2X4 receptors. Structural comparison revealed the ligand-dependent structural rearrangement of the binding pocket to stabilize the binding of allosteric modulators, which in turn would prevent the structural changes of the extracellular domain associated with channel activation. Furthermore, comparison with the previously reported P2X structures of other subtypes provided mechanistic insights into subtype-specific allosteric inhibition.

Prediction of a reservoir of N-rich high-energy density material at the Earth's mantle.

Water and nitrogen are abundant in the Earth's interior and atmosphere, and their mixture under high pressure is a fundamental and valuable scientific issue for physics and chemical science. Based on structural prediction and first-principles simulations, we propose that the two nitrogen-rich stoichiometries, H2ON6 and H2ON10, become energetically stable above ∼70 GPa. Further ab initio molecular dynamics calculations indicate that H2ON6 and H2ON10 undergo phase transitions from solid to superionic and finally to fluid phase with increasing temperature. The superionic regions in their phase diagram correspond to the extreme conditions of Earth's mantle, implying that the Earth's interior might be a possible reservoir of the N-rich hydrates. In addition, H2ON6 remains dynamically stable under ambient conditions with an estimated energy density of 6.53 kJ g-1, indicating that it might be a high-energy density material. These results not only provide essential information for the understanding of the Earth's interior, but also provide guidance for the design of high-energy density materials.

The interplay between innate lymphoid cells and microbiota.

Innate lymphoid cells (ILCs) are mainly resident in mucosal tissues such as gastrointestinal tract and respiratory tract, so they are closely linked to the microbiota. ILCs can protect commensals to maintain homeostasis and increase resistance to pathogens. Moreover, ILCs also play an early role in defense against a variety of pathogenic microorganisms including pathogenic bacteria, viruses, fungi and parasites, before the intervention of adaptive immune system. Due to the lack of adaptive antigen receptors expressed on T cells and B cells, ILCs need to use other means to sense the signals of microbiota and play a role in corresponding regulation. In this review, we focus on and summarize three major mechanisms used in the interaction between ILCs and microbiota: the mediation of accessory cells represented by dendritic cells; the metabolic pathways of microbiota or diet; the participation of adaptive immune cells.

Visible light/copper catalysis enabled alkylation of silyl enol ethers with arylsulfonium salts.

An efficient protocol has been developed herein for the site-selective alkylation of silyl enol ethers with arylsulfonium salts giving access to valuable aryl alkyl thioethers under visible light conditions. Enabled by copper (I) photocatalysis, the C-S bond of arylsulfonium salts can be selectively cleaved to deliver C-centered radicals under mild conditions. This developed method provides a straightforward approach to utilize arylsulfonium salts as sulfur sources for the synthesis of aryl alkyl thioethers.

Visible-Light Copper Catalysis for the Synthesis of α-Alkyl-Acetophenones by the Radical-Type Ring Opening of Sulfonium Salts and Oxidative Alkylation of Alkenes.

Direct difunctionalization of simple alkenes has been treated as a powerful synthetic strategy for the construction of highly functionalized skeletons. In this study, direct oxidative coupling of sulfonium salts with alkenes was achieved under mild conditions by a blue-light-driven photoredox process using a copper complex as a photosensitizer. This protocol allows regioselective synthesis of aryl/alkyl ketones from simple sulfonium salts and aromatic alkenes via selective C-S bond cleavage of sulfonium salts and oxidative alkylation of aromatic alkenes using dimethyl sulfoxide (DMSO) as a mild oxidant.

Heavy metal stabilization remediation in polluted soils with stabilizing materials: a review.

The remediation of soil contaminated by heavy metals has long been a concern of academics. This is due to the fact that heavy metals discharged into the environment as a result of natural and anthropogenic activities may have detrimental consequences for human health, the ecological environment, the economy, and society. Metal stabilization has received considerable attention and has shown to be a promising soil remediation option among the several techniques for the remediation of heavy metal-contaminated soils. This review discusses various stabilizing materials, including inorganic materials like clay minerals, phosphorus-containing materials, calcium silicon materials, metals, and metal oxides, as well as organic materials like manure, municipal solid waste, and biochar, for the remediation of heavy metal-contaminated soils. Through diverse remediation processes such as adsorption, complexation, precipitation, and redox reactions, these additives efficiently limit the biological effectiveness of heavy metals in soils. It should also be emphasized that the effectiveness of metal stabilization is influenced by soil pH, organic matter content, amendment type and dosage, heavy metal species and contamination level, and plant variety. Furthermore, a comprehensive overview of the methods for evaluating the effectiveness of heavy metal stabilization based on soil physicochemical properties, heavy metal morphology, and bioactivity has also been provided. At the same time, it is critical to assess the stability and timeliness of the heavy metals' long-term remedial effect. Finally, the priority should be on developing novel, efficient, environmentally friendly, and economically feasible stabilizing agents, as well as establishing a systematic assessment method and criteria for analyzing their long-term effects.

Superconducting H7 chain in gallium hydrides at high pressure.

Pressure-stabilized hydrides have potential as an outstanding reservoir for high-temperature (Tc) superconductors. We undertook a systematic study of crystal structures and superconducting properties of gallium hydrides using an advanced structure-search method together with first-principles calculations. We identified an unconventional stoichiometric GaH7 gallium hydride that is thermodynamically stable at pressures above 247 GPa. Interestingly, the H atoms are clustered to form a unique H7 chain intercalating the Ga framework. Further calculations show a high estimated Tc above 100 K at 200-300 GPa for GaH7, closely related to the strong coupling between electrons of Ga and H atoms, and phonon vibrations of H7 chains. Our work provides an example of exploration for diverse superconducting hydrogen motifs under high pressure, and may stimulate further experimental syntheses.

Primary Malignant Peripheral Nerve Sheath Tumor of the Stomach: A Rare Case Report and Review of Literature.

Malignant peripheral nerve sheath tumor (MPNST) is a spindle cell sarcoma originating from peripheral nerves or showing differentiation of nerve sheath components. Primary MPNST of the stomach is an extremely rare neoplasm with only a few published reports in the literature. We present the case of a 58-year-old male patient with MPNST in the stomach. The patient was admitted due to upper abdomen discomfort. Gastroscopy revealed a huge ulcer lesion in the stomach, and biopsy revealed a spindle cell malignant neoplasm. No other specific findings were found in the whole-body imaging examination. Subtotal gastrectomy was performed. Histologically, an ulcer-type, push-infiltrating mass composed of dense, woven-like spindle cells with frequent mitosis could be seen. In immunohistochemistry, the tumor cells were negative for expression of H3K27 trimethylation (H3K27me3), keratin (AE1/AE3), epithelial membrane antigen (EMA), CD34, KIT, DOG1 (ANO1), S-100, SOX10, smooth muscle actin, desmin, myogenin, MDM2, CDK4, P16 (CDKN2A) and SS18-SSX (SS18::SSX). Primary MPNST of the stomach was diagnosed based on histological and immunohistochemical results. During the 2.5 years follow-up period after surgery, no recurrence was observed.

Vanilloid agonist-mediated activation of TRPV1 channels requires coordinated movement of the S1-S4 bundle rather than a quiescent state.

Transient receptor potential vanilloid1 (TRPV1) channel plays an important role in a wide range of physiological and pathological processes, and a comprehensive understanding of TRPV1 gating will create opportunities for therapeutic intervention. Recent incredible advances in cryo-electron microscopy (cryo-EM) have yielded high-resolution structures of all TRPV subtypes (TRPV1-6) and all of them share highly conserved six transmembrane (TM) domains (S1-S6). As revealed by the open structures of TRPV1 in the presence of a bound vanilloid agonist (capsaicin or resiniferatoxin), TM helicesS1 to S4 form a bundle that remains quiescent during channel activation, highlighting differences in the gating mechanism of TRPV1 and voltage-gated ion channels. Here, however, we argue that the structural dynamics rather than quiescence of S1-S4 domains is necessary for capsaicin-mediated activation of TRPV1. Using fluorescent unnatural amino acid (flUAA) incorporation and voltage-clamp fluorometry (VCF) analysis, we directly observed allostery of the S1-S4 bundle upon capsaicin binding. Covalent occupation of VCF-identified sites, single-channel recording, cell apoptosis analysis, and exploration of the role of PSFL828, a novel non-vanilloid agonist we identified, have collectively confirmed the essential role of this coordinated S1-S4 motility in capsaicin-mediated activation of TRPV1. This study concludes that, in contrast to cryo-EM structural studies, vanilloid agonists are also required for S1-S4 movement during TRPV1 activation. Redefining the gating process of vanilloid agonists and the discovery of new non-vanilloid agonists will allow the evaluation of new strategies aimed at the development of TRPV1 modulators.

Modulating the Schottky barrier of MXenes/2D SiC contacts via functional groups and biaxial strain: a first-principles study.

Two-dimensional (2D) graphene-like SiC has attracted intense interest recently due to its unique electrical and physical properties. In implementing 2D semiconductors in device applications, one of the main challenges so far has been the formation of a high-quality Schottky barrier owing to the strong Fermi level pinning (FLP) at the interface of traditional metal-2D semiconductor contacts. In this paper, the 2D MXenes Ti3C2T2 (T = F, O, OH) are proposed to serve as electrodes for 2D SiC. The structural and barrier properties of the Ti3C2T2/SiC contacts were systematically investigated based on first-principles calculations combined with the GGA-PBE and HSE06 functionals. It is found that Ti3C2T2 can be bonded with 2D SiC by van der Waals (vdW) interactions. Weak FLP is exhibited at Ti3C2T2/SiC vdW contacts. The type of contact can be tuned by changing the functional T group of Ti3C2T2. Ti3C2F2/SiC and Ti3C2O2/SiC contacts exhibit a p-type Schottky contact and p-type Ohmic contact, respectively, whereas an n-type Ohmic contact occurs in the Ti3C2(OH)2/SiC contact. In addition, the calculated tunneling possibility (TB) is ∼20% between Ti3C2T2 and SiC, indicating weak bonding at the Ti3C2T2/SiC vdW junctions. Furthermore, the Schottky barrier height and TB of the Ti3C2(OH)2/SiC contacts can be modulated via the biaxial strain. The controllable contact type and barrier in Ti3C2T2/SiC contacts provide guidelines for developing high-performance 2D SiC optoelectronic and electronic devices.

Radial Type Ring Opening of Sulfonium Salts with Dichalcogenides by Visible Light and Copper Catalysis.

Herein, a copper-catalyzed, blue-light-induced free radical type ring opening of sulfonium salts with dichalcogenides has been initially developed. The developed method features an inexpensive copper catalyst and a broad substrate scope, affording practical access to alkyl chalcogenides in high yields. This reaction presents a novel ring-opening model of sulfonium salts, which breaks the limitation that only the nucleophilic ring-opening reaction could form C-heteroatom bonds and C-C bonds.

Altered gut microbiota and metabolites profile are associated with reduced bone metabolism in ethanol-induced osteoporosis.

OBJECTIVE: Chronic heavy drinking causes ethanol-induced osteoporosis (EIO). The present study aimed to explore the role of GM in EIO. MATERIAL AND METHODS: A rat EIO model was established by chronic ethanol intake. Taking the antibiotic application as the matched group of dysbacteriosis, an integrated 16S rRNA sequencing and liquid chromatography-tandem mass spectrometry-based metabolomics in serum and faeces were applied to explore the association of differential metabolic phenotypes and screen out the candidate metabolites detrimental to ossification. The colon organoids were used to track the source of 5-HT and the effect of 5-HT on bone formation was examined in vitro. RESULTS: Compared with antibiotics application, ethanol-gavaged decreased the BMD in rats. We found that both ethanol and antibiotic intake affected the composition of GM, but ethanol intake increased the ratio of Firmicutes to Bacteroidetes. Elevated serotonin was proved to be positively correlated with the changes of the composition of GM and faecal metabolites and inhibited the proliferation and mineralization of osteogenesis-related cells. However, the direct secretory promotion of serotonin was absent in the colon organoids exposed to ethanol. CONCLUSION: This study demonstrated that ethanol consumption led to osteoporosis and intestinal-specific dysbacteriosis. Conjoint analysis of the genetic profiles of GM and metabolic phenotypes in serum and faeces allowed us to understand the endogenous metabolite, 5-HT, as detrimental regulators in the gut-bone axis to impair bone formation.

Momordica. charantia-Derived Extracellular Vesicles-Like Nanovesicles Protect Cardiomyocytes Against Radiation Injury via Attenuating DNA Damage and Mitochondria Dysfunction.

Thoracic radiotherapy patients have higher risks of developing radiation-induced heart disease (RIHD). Ionizing radiation generates excessive reactive oxygens species (ROS) causing oxidative stress, while Momordica. charantia and its extract have antioxidant activity. Plant-derived extracellular vesicles (EVs) is emerging as novel therapeutic agent. Therefore, we explored the protective effects of Momordica. charantia-derived EVs-like nanovesicles (MCELNs) against RIHD. Using density gradient centrifugation, we successfully isolated MCELNs with similar shape, size, and markers as EVs. Confocal imaging revealed that rat cardiomyocytes H9C2 cells internalized PKH67 labeled MCELNs time-dependently. In vitro assay identified that MCELNs promoted cell proliferation, suppressed cell apoptosis, and alleviated the DNA damage in irradiated (16 Gy, X-ray) H9C2 cells. Moreover, elevated mitochondria ROS in irradiated H9C2 cells were scavenged by MCELNs, protecting mitochondria function with re-balanced mitochondria membrane potential. Furthermore, the phosphorylation of ROS-related proteins was recovered with increased ratios of p-AKT/AKT and p-ERK/ERK in MCELNs treated irradiated H9C2 cells. Last, intraperitoneal administration of MCELNs mitigated myocardial injury and fibrosis in a thoracic radiation mice model. Our data demonstrated the potential protective effects of MCELNs against RIHD. The MCELNs shed light on preventive regime development for radiation-related toxicity.

P2X3-selective mechanism of Gefapixant, a drug candidate for the treatment of refractory chronic cough.

Gefapixant/AF-219, a selective inhibitor of the P2X3 receptor, is the first new drug other than dextromethorphan to be approved for the treatment of refractory chronic cough (RCC) in nearly 60 years. To date, seven P2X subtypes (P2X1-7) activated by extracellular ATP have been cloned, and subtype selectivity of P2X inhibitors is a prerequisite for reducing side effects. We previously identified the site and mechanism of action of Gefapixant/AF-219 on the P2X3 receptor, which occupies a pocket consisting of the left flipper (LF) and lower body (LB) domains. However, the mechanism by which AF-219 selectively acts on the P2X3 receptor is unknown. Here, we combined mutagenesis, chimera construction, molecular simulations, covalent occupation and chemical synthesis, and find that the negative allosteric site of AF-219 at P2X3 is also present in other P2X subtypes, at least for P2X1, P2X2 and P2X4. By constructing each chimera of AF-219 sensitive P2X3 and insensitive P2X2 subtypes, the insensitive P2X2 subtype was made to acquire the inhibitory properties of AF-219 and AF-353, an analog of AF-219 with higher affinity. Our results suggest that the selectivity of AF-219/AF-353 for P2X3 over the other P2X subtypes is determined by a combination of the accessibility of P2X3 binding site and the internal shape of this pocket, a finding that could provide new perspectives for drug design against P2X3-mediated diseases such as RCC, idiopathic pulmonary fibrosis, hypertension and overactive bladder disorder.