Single-cell RNA sequencing reveals peripheral immunological features in Parkinson's Disease.

Although many researchers of Parkinson's disease (PD) have shifted their focus from the central nervous system (CNS) to the peripheral blood, a significant knowledge gap remains between PD severity and the peripheral immune response. In the current study, we aimed to map the peripheral immunity atlas in peripheral blood mononuclear cells (PBMCs) from PD patients and healthy controls using single-cell RNA sequencing (scRNA-seq). Our study employed scRNA-seq analysis to map the peripheral immunity atlas in PD by profiling PBMCs from PD-Early, PD-Late patients and matched controls. By enlarging the blood sample size, we validated the roles of NK cells in numerous immune-related biological processes. We also detected the infiltration of NK cells into the cerebral motor cortex as the disease progressed, using human brain sections, and elucidated the communication between the periphery and CNS and its implications for PD. As a result, cell subpopulation atlases in PBMCs from PD patients and healthy controls along with differentially expressed genes in NK cells were identified by scRNA-seq analysis, representing 6 major immune cell subsets among which NK cells declined in the progression of PD. We further validated NK cell reduction in increasing samples and found that they participated in numerous immune-related biological processes and infiltration into the cerebral motor cortex as the disease proceeded, evidencingd the close communication between the peripheral immune response and CNS. Strikingly, XCL2 positively correlated with PD severity, with good predictive performance of PD and specific expression in subclusters C2 and C5 of NK cells. All these findings delineated the critical role of peripheral immune response mediated by NK cells in the pathogenesis of PD. NK cell-specific XCL2 could be used as a diagnostic marker for treating PD. The indispensable function of NK cells and NK cell-specific molecular biomarkers highlighted the implication of the peripheral immune response in PD progression. Trial registration: ChiCTR, ChiCTR1900023975. Registered 20 June 2019 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=31035 .

Hydrogen-Doped c-BN as a Promising Path to High-Temperature Superconductivity Above 120 K at Ambient Pressure.

Finding high-temperature superconductivity in light-weight element containing compounds at atmosphere pressure is currently a research hotspot but has not been reached yet. Here it is proposed that hard or superhard materials can be promising candidates to possess the desirable high-temperature superconductivity. By studying the electronic structures and superconducting properties of H and Li doped c-BN within the framework of the first-principles, it is demonstrated that the doped c-BN are indeed good superconductors at ambient pressure after undergoing the phase transition from the insulating to metallic behavior, though holding different nature of metallization. Li doped c-BN is predicted to exhibit the superconducting transition temperature of ≈58 K, while H doped c-BN has stronger electron-phonon interaction and possesses a higher transition temperature of 122 K. These results and findings thus point out a new direction for exploring the ambient-pressure higher-temperature superconductivity in hard or superhard materials.

A Wurster-Type Covalent Organic Framework with Internal Electron Transfer-Enhanced Catalytic Capacity for Tumor Therapy.

The low immunogenicity of tumors, along with the abnormal structural and biochemical barriers of tumor-associated vasculature, impedes the infiltration and function of effector T cells at the tumor site, severely inhibiting the efficacy of antitumor immunotherapy. In this study, a cobaloxime catalyst and STING agonist (MSA-2)-coloaded Wurster-type covalent organic framework (Co-TB COF-M) with internal electron transfer-enhanced catalytic capacity was developed as a COF-based immune activator. The covalently anchored cobaloxime adjusts the energy band structure of TB COF and provides it with good substrate adsorption sites, enabling it to act as an electron transmission bridge between the COF and substrate in proton reduction catalytic reactions. This property significantly enhances the sonodynamic catalytic performance. Under sono-irradiation, Co-TB COF-M can produce a substantial amount of reactive oxygen species (ROS) to induce Gasdermin D-mediated pro-inflammatory pyroptosis, thereby effectively enhancing the immunogenicity of tumors. Furthermore, MSA-2 is specifically released in response to ROS at the tumor site, minimizing the off-target side effects. More importantly, Co-TB COF-induced STING activation normalizes tumor vasculature and increases the expression of endothelial T cell adhesion molecules, which greatly enhance the infiltration and function of effector T cells. Thus, Co-TB COF-M as an immune activator could remold the tumor microenvironment, leading to increased infiltration and an improved function of T cells for immunotherapy.

Micro/Nanoplastic Exposure on Placental Health and Adverse Pregnancy Risks: Novel Assessment System Based upon Targeted Risk Assessment Environmental Chemicals Strategy.

Micro/nanoplastics (MNPs), as emerging pollutants, have been detected in both the maternal and fetal sides of the placenta in pregnant women, and their reproductive toxicity has been demonstrated in in vivo and in vitro experimental models. The Targeted Risk Assessment of Environmental Chemicals (TRAEC) strategy has been innovatively devised to facilitate valid risk assessment, encompassing a comprehensive evaluation of reliability, correlation, outcome fitness, and integrity across four dimensions based on the included published evidence and our own findings. This study serves as an application case of TRAEC, with 40 items of research evidence on the toxicity of MNPs to the placenta, which were rigorously screened and incorporated into the final scoring system. The final score for this TRAEC case study is 5.63, suggesting a moderate-to-low risk of reproductive toxicity associated with MNPs in the placenta, which may potentially increase with decreasing particle size. It is essential to emphasize that the findings also report original data from assays indicating that exposure to high-dose groups (100 µg/mL, 200 µg/mL) of 50 nm and 200 nm polystyrene nanoplastics (PS-NPs) induces HTR8/SVneo cell cycle arrest and cell apoptosis, which lead to reproductive toxicity in the placenta by disrupting mitochondrial function. Overall, this study employed the TRAEC strategy to provide comprehensive insight into the potential reproductive health effects of ubiquitous MNPs.

Intermolecular Regioselective Alkylarylation of Vinylarenes via Photoredox/Nickel Dual Catalysis.

A novel photoredox/nickel dual catalytic intermolecular alkylarylation of vinylarenes with tertiary and secondary alkyltrifluoroborates and aryl bromides is described, which affords 1,1-diarylalkane frameworks that are found in various natural products as well as functionalized molecules in good to excellent yield and regioselectivity through a radical relay process. Notably, this redox-neutral reaction could proceed efficiently with good tolerance of various substrates, including a great diversity of commercially available (hetero)aryl bromides, alkyltrifluoroborates, and vinylarenes.

All-RNA-mediated targeted gene integration in mammalian cells with rationally engineered R2 retrotransposons.

All-RNA-mediated targeted gene integration methods, rendering reduced immunogenicity, effective deliverability with non-viral vehicles, and a low risk of random mutagenesis, are urgently needed for next-generation gene addition technologies. Naturally occurring R2 retrotransposons hold promise in this context due to their site-specific integration profile. Here, we systematically analyzed the biodiversity of R2 elements and screened several R2 orthologs capable of full-length gene insertion in mammalian cells. Robust R2 system gene integration efficiency was attained using combined donor RNA and protein engineering. Importantly, the all-RNA-delivered engineered R2 system showed effective integration activity, with efficiency over 60% in mouse embryos. Unbiased high-throughput sequencing demonstrated that the engineered R2 system exhibited high on-target integration specificity (99%). In conclusion, our study provides engineered R2 tools for applications based on hit-and-run targeted DNA integration and insights for further optimization of retrotransposon systems.

In situ engineered magnesium alloy implant for preventing postsurgical tumor recurrence.

Invasive tumors are difficult to be completely resected in clinical surgery due to the lack of clear resection margins, which greatly increases the risk of postoperative recurrence. However, chemotherapy and radiotherapy as the traditional means of postoperative adjuvant therapy, are limited in postoperative applications, such as multi-drug resistance and low sensitivity, etc. Therefore, an engineered magnesium alloy rod is designed as a postoperative implant to completely remove postoperative residual tumor tissue and inhibit tumor recurrence by gas and mild magnetic hyperthermia therapy (MMHT). As a reactive metal, magnesium alloy responds to the acidic tumor microenvironment by continuously generating hydrogen. The in-situ generation of hydrogen not only protects the surrounding normal tissue, but also enables the magnesium alloy to achieve MMHT under low-intensity alternating magnetic field (AMF). Furthermore, the numerous reactive oxygen species (ROS) produced by heat stress will combine with nitric oxide (NO) generated in situ, to produce more toxic reactive nitrogen species (RNS) storm. In summary, engineered magnesium alloy can completely remove residual tumor tissue and inhibit tumor recurrence by MMHT and RNS storm under low-intensity AMF, and the biodegradability of magnesium alloy makes great potential for clinical application.

Role of Th2, Th17 and Treg Cells and relevant cytokines in pathogenesis of allergic rhinitis.

OBJECTIVE: To explore the role of different cells and molecules in the pathogenesis of allergic rhinitis (AR) with positive Artemisia allergen by detecting their expression levels. METHODS: From January 2021 to December 2022,200 AR patients diagnosed in the Otolaryngology Clinic of Ordos Central Hospital were selected as the AR group, and 50 healthy people who underwent physical examination in the hospital during the same period were randomly selected as the healthy control (HC) group. The levels of GATA-3mRNA, RORγtmRNA and FoxP3mRNA in peripheral blood mononuclear cells were detected by real-time fluorescence quantitative PCR (qRT-PCR). The proportions of Th2, Th17 and Treg cells were detected by flow cytometry. The concentrations of IL-4, IL-5, IL-17 and IL-10 in serum were detected by enzyme-linked immunosorbent assay. The differences of transcription gene level, immune cell ratio and cytokine concentration between the two groups were analyzed. RESULTS: There was no difference in age and gender between the two groups. The levels of GATA-3mRNA and RORγtmRNA transcription genes in peripheral blood mononuclear cells, the percentage of Th2, Th17 and Treg immune cells, the levels of eosinophils and basophils in peripheral blood, the concentrations of IL-4, IL-5, IL-17, IL-10 cytokines and IgE in serum of AR patients were significantly higher than those in HC group (P < 0.05). IL-4 and IL-17 were positively correlated with total IgE level. CONCLUSION: The secretion of immune cells and cytokines in peripheral blood of AR patients is abnormal. Th2, Th17, Treg specific transcription factors and related cells and cytokines are involved in the occurrence and development of allergic rhinitis.

Evaluation of the immunogenicity and protective efficacy of an inactivated vaccine candidate for sheep infected with ovine parainfluenza virus type 3.

Respiratory diseases constitute a major health problem for ruminants, resulting in considerable economic losses throughout the world. Parainfluenza type 3 virus (PIV3) is one of the most important respiratory pathogens of ruminants. The pathogenicity and phylogenetic analyses of PIV3 virus have been reported in sheep and goats. However, there are no recent studies of the vaccination of sheep or goats against PIV3. Here, we developed a purified inactivated ovine parainfluenza virus type 3 (OPIV3) vaccine candidate. In addition, we immunized sheep with the inactivated OPIV3 vaccine and evaluated the immune response and pathological outcomes associated with OPIV3 TX01 infection. The vaccinated sheep demonstrated no obvious symptoms of respiratory tract infection, and there were no gross lesions or pathological changes in the lungs. The average body weight gain significantly differed between the vaccinated group and the control group (P < 0.01). The serum neutralization antibody levels rapidly increased in sheep post-vaccination and post-challenge with OPIV3. Furthermore, viral shedding in nasal swabs and viral loads in the lungs were reduced. The results of this study suggest that vaccination with this candidate vaccine induces the production of neutralizing antibodies and provides significant protection against OPIV3 infection. These results may be helpful for further studies on prevention and control strategies for OPIV3 infections.

Dapagliflozin attenuates fat accumulation and insulin resistance in obese mice with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.

Optomechanical Frequency Comb Based on Multiple Nonlinear Dynamics.

Phonon-based frequency combs that can be generated in the optical and microwave frequency domains have attracted much attention due to the small repetition rates and the simple setup. Here, we experimentally demonstrate a new type of phonon-based frequency comb in a silicon optomechanical crystal cavity including both a breathing mechanical mode (∼GHz) and flexural mechanical modes (tens of MHz). We observe strong mode competition between two approximate flexural mechanical modes, i.e., 77.19 and 90.17 MHz, resulting in only one preponderant lasing, while maintaining the lasing of the breathing mechanical mode. These simultaneous observations of two-mode phonon lasing state and significant mode competition are counterintuitive. We have formulated comprehensive theories to elucidate this phenomenon in response to this intriguing outcome. In particular, the self-pulse induced by the free carrier dispersion and thermo-optic effects interacts with two approximate flexural mechanical modes, resulting in the repetition rate of the comb frequency-locked to exact fractions of one of the flexural mechanical modes and the mode hopping between them. This phonon-based frequency comb has at least 260 comblines and a repetition rate as low as a simple fraction of the flexural mechanical frequency. Our demonstration offers an alternative optomechanical frequency comb for sensing, timing, and metrology applications.

Metal-Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells.

Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal-organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells' membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating •O2-, and the Cu-THBQ/AX catalyzes O2 and H2O2 to •O2- and •OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of •OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from "cold" to "hot" conditions, making it an effective antigen pool. This transformation successfully activates the antitumor immune response, inhibiting tumor growth and metastasis.

Genetic characterization of bovine coronavirus strain isolated in Inner Mongolia of China.

BACKGROUND: Bovine coronavirus (BCoV) is implicated in severe diarrhea in calves and contributes to the bovine respiratory disease complex; it shares a close relationship with human coronavirus. Similar to other coronaviruses, remarkable variability was found in the genome and biology of the BCoV. In 2022, samples of feces were collected from a cattle farm. A virus was isolated from 7-day-old newborn calves. In this study, we present the genetic characteristics of a new BCoV isolate. The complete genomic, spike protein, and nucleocapsid protein gene sequences of the BCoV strain, along with those of other coronaviruses, were obtained from the GenBank database. Genetic analysis was conducted using MEGA7.0 and the Neighbor-Joining (NJ) method. The reference strains' related genes were retrieved from GenBank for comparison and analysis using DNAMAN. RESULTS: The phylogenetic tree and whole genome consistency analysis showed that it belonged to the GIIb subgroup, which is epidemic in Asia and America, and was quite similar to the Chinese strains in the same cluster. Significantly, the S gene was highly consistent with QH1 (MH810151.1) isolated from yak. This suggests that the strain may have originated from interspecies transmission involving mutations of wild strains. The N gene was conserved and showed high sequence identity with the epidemic strains in China and the USA. CONCLUSIONS: Genetic characterization suggests that the isolated strain could be a new mutant from a wild-type lineage, which is in the same cluster as most Chinese epidemic strains but on a new branch.

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy.

Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.

Chronic exposure to PM10 induces anxiety-like behavior via exacerbating hippocampal oxidative stress.

As one of the most environmental concerns, inhaled particulate matter (PM10) causes numerous health problems. However, the associations between anxiety behavior and toxicity caused by PM10 have rarely been reported so far. To investigate the changes of behavior after PM10 exposure and to identify the potential mechanisms of toxicity, PM10 samples (with doses of 15 mg/kg and 30 mg/kg) were intratracheally instilled into rats to simulate inhalation of polluted air by the lungs. After instillation for eight weeks, anxiety-like behavior was evaluated, levels of oxidative stress and morphological changes of hippocampus were measured. The behavioral results indicated that PM10 exposure induced obvious anxiety-like behavior in the open field and elevated plus maze tests. Both PM10 concentrations tested could increase whole blood viscosity and trigger hippocampal neuronal damage and oxidative stress by increasing superoxide dismutase (SOD) activities and malondialdehyde levels, and decreasing the expressions of antioxidant-related proteins (e.g., nuclear factor erythroid 2-related factor 2 (Nrf2), SOD1 and heme oxygenase 1). Furthermore, through collecting and analyzing questionnaires, the data showed that the participants experienced obvious anxiety-related emotions and negative somatic responses under heavily polluted environments, especially PM10 being the main pollutant. These results show that PM10 exposure induces anxiety-like behavior, which may be related to suppressing the Nrf2/Keap1-SOD1 pathway.

Multisource working condition recognition via nonlinear kernel learning and p-Laplacian manifold learning.

Effectively utilizing information from multiple sources and fewer labeled operating condition samples from a sucker-rod pumping system for oil production can improve the recognition effects and engineering practicability. Nevertheless, this is a challenging energy environment scientific application research subject, and therefore, this study proposes an operating state recognition scheme that relies on multisource nonlinear kernel learning and p-Laplacian high-order manifold regularization logistic regress. Specifically, three measured features are selected and extracted, i.e., wellhead temperature signal, electrical power signal, and ground dynamometer cards, based on mechanism analysis, expert experience, and prior knowledge. Finally, we establish the operating condition recognition model to recognize by the multisource p-Laplacian regularization kernel logistic regress algorithm. The experimental data are derived from 60 wells of a common high-pressure and low-permeability thin oil reservoir block of an oil field in China. The corresponding trials highlight that our scheme outperforms traditional recognition methods by exploiting single-source and multiple-feature data. In the context of fewer labeled samples, the proposed method has a greater recognition effect, engineering practicability, and better model robustness than the existing schemes based on other high-order manifold learning, verifying our method's effectiveness.

GLIMS: A two-stage gradual-learning method for cancer genes prediction using multi-omics data and co-splicing network.

Identifying cancer genes is vital for cancer diagnosis and treatment. However, because of the complexity of cancer occurrence and limited cancer genes knowledge, it is hard to identify cancer genes accurately using only a few omics data, and the overall performance of existing methods is being called for further improvement. Here, we introduce a two-stage gradual-learning strategy GLIMS to predict cancer genes using integrative features from multi-omics data. Firstly, it uses a semi-supervised hierarchical graph neural network to predict the initial candidate cancer genes by integrating multi-omics data and protein-protein interaction (PPI) network. Then, it uses an unsupervised approach to further optimize the initial prediction by integrating the co-splicing network in post-transcriptional regulation, which plays an important role in cancer development. Systematic experiments on multi-omics cancer data demonstrated that GLIMS outperforms the state-of-the-art methods for the identification of cancer genes and it could be a useful tool to help advance cancer analysis.

Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia.

BACKGROUND: A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in predicting ADH diagnosed by US-guided CNB that was upgraded to malignancy after surgery. METHODS: In this retrospective study, 110 CNB-diagnosed ADH lesions in 109 consecutive women who underwent US, CEUS, and surgery between June 2018 and June 2023 were included. CEUS was incorporated into US BI-RADS and yielded a CEUS-adjusted BI-RADS. The diagnostic performance of US BI-RADS and CEUS-adjusted BI-RADS for ADH were analyzed and compared. RESULTS: The mean age of the 109 women was 49.7 years ± 11.6 (SD). The upgrade rate of ADH at CNB was 48.2% (53 of 110). The sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for identification of malignant upgrading were 96.2%, 66.7%,72.9%, and 95.0%, respectively, based on BI-RADS category 4B threshold. The two false-negative cases were low-grade ductal carcinoma in situ. Compared with the US, CEUS-adjusted BI-RADS had better specificity for lesions smaller than 2 cm (76.7% vs. 96.7%, P = 0.031). After CEUS, 16 (10 malignant and 6 nonmalignant) of the 45 original US BI-RADS category 4A lesions were up-classified to BI-RADS 4B, and 3 (1 malignant and 2 nonmalignant) of the 41 original US BI-RADS category 4B lesions were down-classified to BI-RADS 4A. CONCLUSIONS: CEUS is helpful in predicting malignant upgrading of ADH, especially for lesions smaller than 2 cm and those classified as BI-RADS 4A and 4B on ultrasound.