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Yuting Liu,1,* Jie Tang,1,* Xiaolan Qiu,1,* Lucy A Teng,2 Mukesh K Sriwastva,2 Xuedong Han,1 Zhi Li,1 Minmin Liu,1 Shuangyue Liu,1 Dongzhu Da,1 Zhi Li,1 Linlin Zhen,1 Yi Ren1 1Department of Breast and Thyroid Surgery, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China; 2Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville, Louisville, KY, USA*These authors contributed equally to this workCorrespondence: Yi Ren; Linlin Zhen, Department of Breast and Thyroid Surgery, The Affiliated Huai’an No. 1 People’s Hospital, Nanjing Medical University, Huai’an, Jiangsu, People’s Republic of China, Email only_renyi@163.com; simu1027@sina.comBackground: Recent therapeutic approaches have improved survival rate for women with breast cancer, but the survival rate for metastatic breast cancer is still low. Exosomes released by various cells are involved in all steps of breast cancer development.Methods: We established the multimodal imaging report expression in breast cancer cells with lentivirus vectors pGluc and pBirA to investigate the secreted exosomes. Comparative microRNA (miRNA) analysis was performed with miRNA qPCR array in mice with breast cancer lung metastasis. The co-immunoprecipitation and chromatin immunoprecipitation assays were used to identify the mechanism of miRNA sorting to exosomes. The potential therapeutic strategy using an anti-sorting antibody was used to investigate breast cancer lung metastasis.Results: We identified 26 high- and 32 low-expression level miRNAs in exosomes from metastasis compared to those from primary tumors and normal tissues. The tumor suppressors, including miR-200c and let-7a, were reduced in tumor tissues and metastasis but increased in the respective exosomes compared to normal tissues. Furthermore, the Ras-related protein (Rab1A) facilitated miR-200c sorting to exosomes circumventing the influence of tumor suppressor miR-200c on tumor cells, while the metastatic exosome cargo miR-200c inhibited F4/80+ macrophage immune response. Administration of anti-Rab1A antibody significantly repressed the trafficking of miR-200c to exosomes and breast cancer lung metastasis.Conclusion: Our study has identified a novel molecular mechanism for breast cancer lung metastasis mediated by exosome cargo miRNAs and provided a new therapeutic strategy for cancer immunotherapy.Graphical Abstract: Keywords: extracellular vehicles, exosomes, breast cancer lung metastasis, miR-200c, Rab1A, miRNA sorting

Xianqin Tong,1,2,&ast; Yuanyuan Li,2,4,&ast; Gang Yang,1,2 Hao Zhang,2,3 Yiwei Jiang,2,3 Jin Yu,2,3 Dongxin Da,2,3 Xiaoli Zeng,2,3 Yuehua Liu1,2 1Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, People’s Republic of China; 3Department of Pediatric Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, People’s Republic of China; 4Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiaoli Zeng, Department of Preventive Dentistry, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, People’s Republic of China, Email lylyz97@163.com Yuehua Liu, Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, People’s Republic of China, Email liuyuehua@fudan.edu.cnPurpose: The prevalence of dentofacial deformity was reportedly higher than decades ago, to which upper airway (UA) obstruction-induced sleep-disordered breathing (SDB) might contribute a lot. Tonsil hypertrophy appears relatively common in the population of young children. Given that the association between tonsil hypertrophy and pediatric dentofacial deformity remained controversial, this cross-sectional research was designed to explore the internal relationship of those among young children in Shanghai, China.Patients and Methods: A stratified cluster sampling procedure was adopted, and a representative sample of 715 young children (8– 10 years old) was recruited. The OSA-18 quality-of-life questionnaires (OSA-18) were finished by their guardians, and well-trained orthodontists performed the oral examinations. After collecting the valuable information, the descriptions and analyses were run by statistical software (SPSS, version 26.0).Results: 715 participants (334 boys and 381 girls) were involved in the analyses. As calculated, the current prevalence of malocclusion identified by Angle’s classification was 45.6% in this sample. No evident relation between OSA-18 scores and dentofacial abnormalities (P > 0.05) was found. With the enlargement of tonsil size, the proportion of children with triangular dental arch form (P < 0.05) and high vault palate (P < 0.001) was increasingly higher. More children with protruding profiles and fewer upright profiles were observed as the tonsil size increased, although it did not show a statistical difference (P = 0.103).Conclusion: Dental and craniofacial growth deficiency has become more prevalent among children, demanding more concerns from health authorities. Tonsil hypertrophy plays an essential role in the direction of dentofacial development. More efforts from local health authorities should be made to enhance public propaganda and education on the prevention and interruption of tonsil hypertrophy and related dentofacial abnormalities.Keywords: dentofacial growth, malocclusion, tonsil enlargement, sleep-disordered breathing, OSA-18

This case report discusses a patient diagnosed with L1 burst fracture, right lateral femoral condyle and proximal tibial and fibular head and neck comminuted fractures, and left medial femoral condyle and suspected tibial fractures after a traffic accident. She received integrated Korean medicine treatment, including motion- style acupuncture treatment (MSAT), electroacupuncture, acupuncture, herbal medicine, moxibustion, and cupping therapy for 112 days. The scores improved for the low back pain Numeric Rating Scale (NRS) (from 7 to 3), Oswestry Disability Index (from 94 to 38), bilateral leg pain NRS (from 6 to 2), Lysholm Knee Scoring Scale (from 0 to 66), left ankle manual muscle test (from Poor− to Normal), Korean version of the modified Barthel index (from 32 to 92), and EuroQol 5-dimension 5-level (from 25 to 9), as did mobility. Radiological scans also showed fracture healing. This study suggests the potential of MSAT in high-energy polytrauma care, particularly for fractures.

Abstract Background Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. Methods We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. Results A functional assay identified that transforming growth factor-β1 (TGF-β1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-β1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. Conclusions These findings provide compelling evidence for the involvement of TGF-β1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-β1 may be used alone or combined with hOM-MSCs therapy for treating PD.

In the context of transit-oriented development (TOD), an essential objective in international city development is the creation of commercial spaces in front of stations that attract people from diverse backgrounds and of various nationalities. There remains a notable gap in research focusing on people’s staying in commercial spaces in front of stations from the perspective of foreign residents. This study aims to identify the key factors influencing the staying of Chinese residents in Japan regarding to commercial spaces in front of stations via questionnaire. Among them, the popularity of commercial spaces in front of stations and the diversity of business types were the most influential. Critical factors also included the area of station, the greenery, the distance from the station to stores, the ethnic cultural element, the percentage of foreign residents in station human traffic, and the area of commercial spaces in front of stations. This research also showed significant differences in the perceived importance of critical factors exhibited by population attributes across occupation, monthly income, and length of residence in Japan.

The current moral education component in primary schools faces significant challenges. Many elementary students’ everyday behavior appears excessively self-centered and pragmatic, potentially negatively impacting their future growth and character development. This could further influence the societal atmosphere for decades to come. Therefore, summarizing and reflecting on theories and methods in primary education, altering teaching approaches and enhancing moral education quality are crucial issues. This transformation requires a foundational philosophical theory. Research suggests that drawing from the concept of “righteousness and profit” rooted in pre-Qin Confucianism is a valuable reference. The pre-Qin Confucian perspective on righteousness and profit stands at the core of pre-Qin Confucian thought and has profoundly influenced Chinese history for millennia. Its contemplation on “righteousness” and “profit” continues to have a far-reaching impact in contemporary times. To provide a philosophical basis for primary education theory, the study examines the essence of the pre-Qin Confucian concept of “righteousness and profit.” Additionally, tracing its historical development provides insights. In terms of current educational theories, the review focuses on human-centric educational theories in primary education. Finally, a proposal is made to integrate the pre-Qin Confucian concept of “righteousness and profit” with human-centric theories in primary education, accompanied by corresponding teaching strategies. According to research findings, the concepts of righteousness and profit were completely mutually exclusive in their initial stages. However, during the evolution of several dynasties, the two concepts gradually gained mutually supportive elements. This research aims to improve the moral education level of current primary education and promote the inheritance of excellent traditional Chinese culture through the integration of the pre-Qin Confucian view of righteousness and profit and the people-oriented primary education theory.

Abstract Environmental stressors such as drought, salinity, and heavy metals pose significant obstacles to achieving sustainable food security, necessitating the development of universally applicable and cost-effective solutions to ameliorate soil under stress. Biochar, an eco-friendly material to increase crop yield, has been researched for almost two decades and has great potential for global use in enhancing stress resistance. However, there hasn't been comprehensive research on the impact of biochar application on soil properties, and root and crop growth. To optimize and promote biochar application in agriculture under stress, this study integrates over 100 peer-reviewed articles to explain how biochar promotes crop growth by enhancing soil resistance to stress. Biochar's distinctive properties, such as porous structure, alkaline nature, enriched surface functional groups, and nutrient content, are responsible for the following soil environment benefits: improved soil physiochemical properties, increased nutrient cycling, and boosted microbial growth. Moreover, the research emphasizes that the enhanced stress resistance of biochar optimizes nutrient absorption, alleviates soil pollutants, and thereby enhances overall crop productivity. The study discusses the roles and mechanisms of biochar on soil under stress, as well as the challenges linked to the sustainable and economical implementation of biochar in extreme soil conditions. This review aims to provide a theoretical basis for the widespread and cost-effective use of biochar in improving soil under stresses, thereby enhancing soil health and food security. Graphical Abstract

Abstract Asbestos is widely used in construction, manufacturing, and other common industrial fields. Human activities such as mining, processing, and transportation can release heavy metals from asbestos into the surrounding soil environment, posing a health hazard to the mining area's environment and its surrounding residents. The purpose of the present study was to determine the extent of ecological and human health damage caused by asbestos pollution, as well as the primary contributors to the contamination, by examining a large asbestos mine and the surrounding soil in China. The level of heavy metal pollution in soil and sources were analyzed using methods such as the geo-accumulation index (Igeo), potential ecological risk index (RI), and positive matrix factorization (PMF) model. A Monte Carlo simulation-based health risk model was employed to assess the health risks of heavy metals in the study area’s soil to human beings. The results showed that the concentrations of As, Pb, Cr, Cu, and Ni in the soil were 1.74, 0.13, 13.31, 0.33, and 33.37 times higher than the local soil background values, respectively. The Igeo assessment indicated significant accumulation effects for Ni, Cr, and As. The RI evaluation revealed extremely high comprehensive ecological risks (RI ≥ 444) in the vicinity of the waste residue heap and beneficiation area, with Ni exhibiting strong individual potential ecological risk (Eir ≥ 320). The soil health risk assessment demonstrated that As and Cr posed carcinogenic risks to adults, with mean carcinogenic indices (CR) of 1.56E − 05 and 4.14E − 06, respectively. As, Cr, and Cd posed carcinogenic risks to children, with mean CRs of 1.08E − 04, 1.61E − 05, and 2.68E − 06, respectively. Cr also posed certain non-carcinogenic risks to both adults and children. The PMF model identified asbestos contamination as the primary source of heavy metals in the soil surrounding the asbestos mining area, contributing to 79.0%. According to this study, it is recommended that management exercise oversight and regulation over the concentrations of Ni, Cr, Cd, and As in the soil adjacent to asbestos mines, establish a designated control zone to restrict population activities, and locate residential zones at a safe distance from the asbestos mine production zone.

Abstract The notion of the “Self” is one of the most critical issues in contemporary cognitive science. Whether the self is a single and independent real entity or a collection of constantly changing experiences has been at the core of debates between the substance theory and the illusion theory. Compared to the neglect of this issue in Western tradition studies, the meticulous practice of mindfulness/awareness in Eastern research traditions has long focused on this contradiction. This paper navigates the intricate dimensions of the “Self” by weaving together the Oriental framework of the five aggregates with the Middle Way, the principles of constructivism, and the empirical methodologies of experimental philosophy. This approach bridges the gap by synthesizing introspective first-person experiences with objective third-person scientific observations to enrich the understanding of self-constructivism. The implications of these findings extend into the practical realms of psychology and philosophy, offering a scaffold for future research to elucidate the multifaceted nature of the self further.

Infrared and visible image fusion can integrate rich edge details and salient infrared targets, resulting in high-quality images suitable for advanced tasks. However, most available algorithms struggle to fully extract detailed features and overlook the interaction of complementary features across different modal images during the feature fusion process. To address this gap, this study presents a novel fusion method based on multi-scale edge enhancement and a joint attention mechanism (MEEAFusion). Initially, convolution kernels of varying scales were utilized to obtain shallow features with multiple receptive fields unique to the source image. Subsequently, a multi-scale gradient residual block (MGRB) was developed to capture the high-level semantic information and low-level edge texture information of the image, enhancing the representation of fine-grained features. Then, the complementary feature between infrared and visible images was defined, and a cross-transfer attention fusion block (CAFB) was devised with joint spatial attention and channel attention to refine the critical supplemental information. This allowed the network to obtain fused features that were rich in both common and complementary information, thus realizing feature interaction and pre-fusion. Lastly, the features were reconstructed to obtain the fused image. Extensive experiments on three benchmark datasets demonstrated that the MEEAFusion proposed in this research has considerable strengths in terms of rich texture details, significant infrared targets, and distinct edge contours, and it achieves superior fusion performance.

Nitrogen fertilizer supports agricultural intensification, but its manufacturing results in substantial contaminated sites. Ammonia nitrogen is the main specific pollutant in retired nitrogen fertilizer sites with potential human health and odor risks. However, few studies focus on ammonia nitrogen risk assessment at contaminated sites, particularly considering its solid-liquid partitioning process (Kd) and ammonium/ammonia equilibrium process (R) in the soil. This study took a closed nitrogen fertilizer factory site as an example and innovatively introduced Kd and R to scientifically assess the human health and odor risk of ammonia nitrogen. The risk control values (RCVs) of ammonia nitrogen based on human health and odor risk were also derived. The maximum concentration of ammonia nitrogen was 3380 mg/kg in the unsaturated soil, which was acceptable for human health because the health RCVs were 5589 ∼ 137,471 mg/kg in various scenarios. However, odor risk was unacceptable for RCVs were 296 ∼ 1111 mg/kg under excavation scenarios and 1118 ∼ 35,979 mg/kg under non-excavation scenarios. Of particular concern, introducing Kd and R in calculation increased the human health and odor RCVs by up to 27.92 times. Despite the advancements in ammonia risk assessment due to the introduction of Kd and R, odor risk during excavation remains a vital issue. These findings inform a more scientific assessment of soil ammonia risk at contaminated sites and provide valuable insights for the management and redevelopment of abandoned nitrogen fertilizer plant sites.

Abstract Background Prostate cancer (PCa) is currently acknowledged as the second most widespread cancer among men worldwide. Yet, the lack of dependable diagnostic biomarkers and therapeutic targets has presented considerable hurdles to the progression of prostate cancer treatment. Circular RNAs are implicated in the pathogenesis of numerous diseases, positioning them as promising biomarkers for diverse medical conditions. This study aims to uncover a specific circRNA that could serve as a diagnostic and therapeutic target for detecting and treating PCa. Methods The change of circTENM3 expression levels in PCa was detected by qPCR. CCK8 assays, EdU assays, Scratch assay and Transwell migration assay conducted to detect the role of circTENM3 in PCa cells in vitro. RIP assay, RNA-pull down and luciferase reporter assay were performed to explore the mechanism of circTENM3. Gain-of-function analysis was performed to reveal the function of circTENM3 in PCa in vivo. Results The results revealed that the expression level of circTENM3 was significantly down-regulated in PCa. CircTENM3 overexpression alleviated the progression of PCa in vitro. Mechanistically, circTENM3 enhanced RUNX3 levels via miR-558 sponge. Gain-of-function analysis determined that circTENM3 overexpression could inhibit PCa progression in vitro. Conclusions Our research offers profound insights into the protective role played by circTENM3 in PCa. CircTENM3 operates as a sponge for miR-558, thereby triggering the elevation of RUNX3 expression, which subsequently curbs the progression of PCa.

Abstract Background and aims Refractory epilepsy is also known as drug-resistant epilepsy with limited clinical treatment. Benefitting from its safety and easy availability, olfactory mucosa mesenchymal stem cells (OM-MSCs) are considered a preferable MSC source for clinical application. This study aims to investigate whether OM-MSCs are a promising alternative source for treating refractory epilepsy clinically and uncover the mechanism by OM-MSCs administration on an epileptic mouse model. Methods OM-MSCs were isolated from turbinal and characterized by flow cytometry. Autologous human OM-MSCs treatment on a patient was carried out using intrathecal administration. Epileptic mouse model was established by 1 mg/kg scopolamine and 300 mg/kg pilocarpine treatment (intraperitoneal). Stereotaxic microinjection was employed to deliver the mouse OM-MSCs. Mouse electroencephalograph recording was used to investigate the seizures. Brain structure was evaluated by magnetic resonance imaging (MRI). Immunohistochemical and immunofluorescent staining of GFAP, IBA1, MAP2, TUBB3, OLIG2, CD4, CD25, and FOXP3 was carried out to investigate the neural cells and Treg cells. QRT-PCR and ELISA were performed to determine the cytokines (Il1b, Il6, Tnf, Il10) on mRNA and protein level. Y-maze, the object location test, and novel object recognition test were performed to measure the cognitive function. Footprint test, rotarod test, balance beam test, and grip strength test were conducted to evaluate the locomotive function. Von Frey testing was carried out to assess the mechanical allodynia. Results Many beneficial effects of the OM-MSC treatment on disease status, including seizure type, frequency, severity, duration, and cognitive function, and no apparent adverse effects were observed at the 8-year follow-up case. Brain MRI indicated that autologous OM-MSC treatment alleviated brain atrophy in epilepsy patients. A study in an epileptic mouse model revealed that OM-MSC treatment recruited Treg cells to the brain, inhibited inflammation, rebuilt the neural network, and improved the cognitive, locomotive, and perceptive functions of epileptic mice. Conclusions Autologous OM-MSC treatment is efficacious for improving chronic refractory epilepsy, suggesting a future therapeutic candidate for epilepsy. Trial registration: The study was registered with Chinese Clinical Trial Registry (ChiCTR2200055357).

Strong sun glint noise is an inevitable obstruction for tiny human object detection in maritime search and rescue (SAR) tasks, which can significantly deteriorate the performance of local contrast method (LCM)-based algorithms and cause high false alarm rates. For SAR tasks in noisy environments, it is more important to find tiny objects than localize them. Hence, considering background clutter and strong glint noise, in this study, a noise suppression methodology for maritime scenarios (HDetect-VS) is established to achieve tiny human object enhancement and detection based on visual saliency. To this end, the pixel intensity value distributions, color characteristics, and spatial distributions are thoroughly analyzed to separate objects from background and glint noise. Using unmanned aerial vehicles (UAVs), visible images with rich details, rather than infrared images, are applied to detect tiny objects in noisy environments. In this study, a grayscale model mapped from the HSV model (HSV-gray) is used to suppress glint noise based on color characteristic analysis, and large-scale Gaussian Convolution is utilized to obtain the pixel intensity surface and suppress background noise based on pixel intensity value distributions. Moreover, based on a thorough analysis of the spatial distribution of objects and noise, two-step clustering is employed to separate objects from noise in a salient point map. Experiments are conducted on the SeaDronesSee dataset; the results illustrate that HDetect-VS has more robust and effective performance in tiny object detection in noisy environments than other pixel-level algorithms. In particular, the performance of existing deep learning-based object detection algorithms can be significantly improved by taking the results of HDetect-VS as input.

The purpose of this note is to investigate the relation between the notions of robust stability and quadratic stability for uncertain systems with structured uncertainty due to both real and complex parameter variations. We present examples which demonstrate that for systems containing at least two uncertain blocks, the notions of robust stability for complex parameter variations and quadratic stability for real parameter variations are not equivalent; in fact neither implies the other. A byproduct of these examples is that, for this class of systems, quadratic stability for real perturbations need not imply quadratic stability for complex perturbations. This is in stark contrast with the situation in the case of unstructured uncertainty, for which it is known that quadratic stability for either real or complex perturbations is equivalent to robust stability for complex perturbations, and thus equivalent to a small gain condition on the transfer matrix that the perturbation experiences.

Abstract In recent years, scholarly attention has shifted within urban informality research from informal settlements to the appropriation of public spaces in formal urban settings. Overflow, a common research subject within this context, has drawn particular interest. This study investigates overflow dynamics in a representative district of Hong Kong, utilizing the overflow rate as a measure of the extent to which overflow occurs. Three‐dimensional (3D) scanning technology was applied to collect spatial data from back alleys. Multiple linear regression analyses were conducted to identify the spatial characteristics of back alleys that influence overflow rates. The results revealed that back alleys with a flatter spatial interface, more overhead shelter, greater numbers of alley‐shops, and shorter overall length corresponded to a higher number of overflow occurrences. Two novel findings emerged: First, a negative correlation between spatial interface unevenness and overflow rates, and second, differential impacts of the shop density and number of alley‐shops on overflow rates. These findings may serve as a valuable reference for governmental policy formulation regarding overflow management and may offer architects workable insights for designing back alleys and street spaces conducive to public use.

Abstract Mutations in the extracellular matrix gene Fibrillin-2 (FBN2) are related to genetic macular degenerative disorders including age-related macular degeneration (AMD) and early-onset macular degeneration (EOMD). It was reported that the retinal protein expression of FBN2 was reduced in patients with AMD and EOMD. The effect of exogenously supplied fbn2 recombinant protein on fbn2-deficiency-related retinopathy was not known. Here we investigated the efficacy and molecular mechanism of intravitreally applied fibrin-2 recombinant protein in mice with fbn2-deficient retinopathy. The experimental study included groups (all n = 9) of adult C57BL/6J male mice which underwent no intervention, intravitreal injection of adeno-associated virus (AAV) empty vector or intravitreal injection of AAV-sh-fbn2 (adeno-associated virus for expressing short hairpin RNA for fibrillin-2) followed by three intravitreal injections of fbn2 recombinant protein, given in intervals of 8 days in doses of 0.30 μg, 0.75 μg, 1.50 μg, and 3.00 μg, respectively. Eyes with intravitreally applied AAV-sh-fbn2 as compared to eyes with injection of AAV-empty vector or developed an exudative retinopathy with involvement of the deep retinal layers, reduction in axial length and reduction in ERG amplitudes. After additional and repeated application of fbn2 recombinant protein, the retinopathy improved with an increase in retinal thickness and ERG amplitude, the mRNA and protein expression of transforming growth factor-beta (TGF-β1) and TGF-β binding protein (LTBP-1) increased, and axial length elongated, with the difference most marked for the dose of 0.75 μg of fbn2 recombinant protein. The observations suggest that intravitreally applied fbn2 recombinant protein reversed the retinopathy caused by an fbn2 knockdown.

As efforts to mitigate soil and groundwater pollution intensify nationwide, the incidence of volatile organic compound (VOC) contaminated sites has risen significantly. These sites exhibit continuous release and dispersion of VOCs during and after remediation/control processes, thereby adversely affecting the local environment and residents. This issue has emerged as a prominent concern in contemporary society. This study takes a representative pesticide-contaminated site as the research subject. The pollutant levels, composition, spatiotemporal distribution, and source characteristics of VOCs in the ambient air environment from 2016 to 2021 were investigated by statistical analysis, Geographic Information System (GIS) spatial interpolation, Positive Matrix Factorization (PMF) model, and characteristic ratio source. The results showed that the average mass concentration proportions of the five types of pollutants are: benzene, toluene, ethylbenzene, and xylenes (BTEX) (29.73%) > alkanes (26.85%) > oxygenated hydrocarbons (21.96%) > halogenated hydrocarbons (19.12%) > sulfides (2.35%). M-/p-xylenes and toluene were the main contributing pollutants of BTEX and appeared frequently in the lists of top three pollutant in the contribution rates at various sites. The average concentration range of VOCs inside (EA1∼EA5) and outside the site (CK1∼CK4) were 810.71–1437.24 μg/m³, and 784.47–1358.16 μg/m³, respectively. The spatial distribution and variation trend in concentrations of halogenated hydrocarbons and alkanes were similar, with both being high in the middle of the site in 2017 and high in the south in 2018, and then sharply falling to a lower level in 2019. The source analysis results showed that the main contribution sources of environmental air varied over time. There were three types of emission sources for VOCs during the monitoring periods in 2016 and 2018. The maximum contributions to total volatile organic compounds (TVOCs) in 2016 and 2018 were volatile sources of characteristic pollutants within the site (45.6%) and volatile source of fuel (70.6%), respectively. This study provides scientific evidence for the environmental management, planning, and VOCs pollution control of pesticide-contaminated sites in China.

Less attention was paid to the remediation of volatile organic compounds (VOCs) contaminated soil treated by thermal conduction heating (TCH) coupled with chemical oxidization. In this study, the lab-scale remediation experiments of trichloroethylene (TCE)-contaminated soil by TCH and TCH coupled with persulfate (TCH + PS) were performed to explore the influences of PS usage, temperature, reaction time, and the variation of soil properties. TCE was removed from contaminated soils using TCH with a temperature lower than boiling point, and the removal ratio of TCE reached 78.21% with a reaction time of 6h at 60 °C. In the TCH + PS treatments, the removal ratio increased to 87.60~99.50% when the PS dosage was increased from 7.0 mmol/kg to 17.5 mmol/kg at 60 °C. However, the usage efficiency of PS had no positive relationship with oxidant usage and temperature. The treatment with 14 mmol/kg PS after 3h at 50 °C had the highest PS usage ratio of 3.05. In addition, soil pH and soil organic matter (SOM) did not decrease significantly in the TCH-only treatment, while the content of SOM declined by almost 50% after the TCH + PS treatment. Overall, it was concluded that TCH + PS achieved higher removal efficiency, whereas TCH had less disturbance on soil pH and SOM. As such, the applicability of TCH-only or TCH + PS treatments is site-specific.

Highlights A comprehensive review of technology has been undertaken from biochar-based nitrogen fertilizers (BBNFs). Kinetics and mechanisms of the slow-release of N from BBNFs are revealed. BBNFs enhanced soil properties, N retention in soil and crop yield, and improved N use efficiency.

BTEX (benzene, toluene, ethylbenzene, and xylene), as characteristic pollutants in chemical plant sites, are widely present in the environment and pose a serious threat to the health and safety of nearby residents. Studying the spatial distribution characteristics and transport fluxes of BTEX in soil and air at contaminated sites and the health risks they pose to humans is of great significance for fine pollution control and environmental management. This study took a typical decommissioned steel plant as a case study. A total of 23 soil and air samples were collected from different locations to investigate the spatial distribution characteristics of BTEX in soil and air. The transport and fate of BTEX in soil and air were evaluated using the fugacity model, and finally, a human health risk assessment was conducted. The results indicate a relatively severe level of benzene pollution in both soil and air. The maximum exceedance factor of benzene in soil samples is 31.5, with the concentration exceedance depth at 1.5 m. The maximum concentration of benzene in air samples is 4.98 μg·m−3. Benzene, at 5.9% of the site, shows a low flux with negative values, while other components at various locations all exhibit a trend of transport from the soil phase to the atmospheric phase. Benzene is the pollutant that contributes the most to the transport flux from soil to air within the site. The coking area and sewage treatment area are key areas within the steel mill where BTEX accumulate easily in the soil. The non-carcinogenic risk values of the individual components of BTEX in the soil are below the acceptable risk level. However, the carcinogenic risk value of benzene in the children’s exposure scenario exceeds the carcinogenic risk level of 10−6. The carcinogenic risk range of various components of BTEX in the air is 2.63 × 10−6~3.88 × 10−5, with 28.6% of the locations exceeding the threshold of 10−6. The range of the total HI (hazard index) is 2.08 × 10−4~1.81 × 10−1, all of which is below the safety threshold of 1. The results of this study will provide scientific support for the fine pollution control and environmental management of industrial contaminated sites with BTEX as their typical pollutants.

The COVID-19 pandemic caused by the coronavirus SARS-CoV-2 is continuing to spread globally. SARS-CoV-2 infections of feline and canine species have also been reported. However, it is not entirely clear to what extent natural SARS-CoV-2 infection of pet dogs and cats is in households. We have developed enzyme-linked immunosorbent assays (ELISAs) using recombinant SARS-CoV-2 nucleocapsid (N) protein and the receptor-binding-domain (RBD) of the spike protein, and the SARS-CoV-2 spike-pseudotyped vesicular stomatitis virus (VSV)-based neutralization assay to screen serum samples of 239 pet cats and 510 pet dogs in Minnesota in the early phase of the COVID-19 pandemic from mid-April to early June 2020 for evidence of SARS-CoV-2 exposures. A cutoff value was used to identify the seropositive samples in each experiment. The average seroprevalence of N- and RBD-specific antibodies in pet cats were 8% and 3%, respectively. Among nineteen (19) N-seropositive cat sera, fifteen (15) exhibited neutralizing activity and seven (7) were also RBD-seropositive. The N-based ELISA is also specific and does not cross react with antigens of common feline coronaviruses. In contrast, SARS-CoV-2 antibodies were detected at a very low percentage in pet dogs (~ 1%) and were limited to IgG antibodies against SARS-CoV-2 N protein with no neutralizing activities. Our results demonstrate that SARS-CoV-2 seropositive rates are higher in pet cats than in pet dogs in MN early in the pandemic and that SARS-CoV-2 N-specific IgG antibodies can detect SARS-CoV-2 infections in companion animals with higher levels of specificity and sensitivity than RBD-specific IgG antibodies in ELISA-based assays.

Abstract Mesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration, such as the induction of angiogenesis, particularly under hypoxic conditions. However, the molecular mechanisms underlying hypoxic MSC activation remain largely unknown. MSC-derived extracellular vesicles (EVs) are vital mediators of cell-to-cell communication and can be directly utilized as therapeutic agents for tissue repair and regeneration. Here, we explored the effects of EVs from human hypoxic olfactory mucosa MSCs (OM-MSCs) on angiogenesis and its underlying mechanism. EVs were isolated from normoxic (N) OM-MSCs (N-EVs) and hypoxic (H) OM-MSCs (H-EVs) using differential centrifugation and identified by transmission electron microscopy and flow cytometry. In vitro and in vivo, both types of OM-MSC-EVs promoted the proliferation, migration, and angiogenic activities of human brain microvascular endothelial cells (HBMECs). In addition, angiogenesis-stimulatory activity in the H-EV group was significantly enhanced compared to the N-EV group. MicroRNA profiling revealed a higher abundance of miR-612 in H-EVs than in N-EVs, while miR-612 inactivation abolished the N-EV treatment benefit. To explore the roles of miR-612, overexpression and knock-down experiments were performed using a mimic and inhibitor or agomir and antagomir of miR-612. The miR-612 target genes were confirmed using the luciferase reporter assay. Gain- and loss-of-function studies allowed the validation of miR-612 (enriched in hypoxic OM-MSC-EVs) as a functional messenger that stimulates angiogenesis and represses the expression of TP53 by targeting its 3′-untranslated region. Further functional assays showed that hypoxic OM-MSC-EVs promote paracrine Hypoxia-inducible factor 1-alpha (HIF-1α)-Vascular endothelial growth factor (VEGF) signaling in HBMECs via the exosomal miR-612-TP53-HIF-1α-VEGF axis. These findings suggest that hypoxic OM-MSC-EVs may represent a promising strategy for ischemic disease by promoting angiogenesis via miR-612 transfer. Graphical Abstract

ABSTRACT Antibiotic-resistant bacteria have become a public health problem. Thus, antimicrobial peptides (AMPs) have been evaluated as substitutes for antibiotics. Herein, we investigated PN5 derived from Pinus densiflora (pine needle). PN5 exhibited antimicrobial activity without causing cytotoxic effects. Based on these results, we examined the mode of action of PN5 against Gram-negative and -positive bacteria. PN5 exhibited membrane permeabilization ability, had antimicrobial stability in the presence of elastase, a proteolytic enzyme, and did not induce resistance in bacteria. Bacterial lipopolysaccharide (LPS) induces an inflammatory response in RAW 264.7 macrophages. PN5 suppressed proinflammatory cytokines mediated by NF-κB and mitogen-activated protein kinase signaling. In C57BL/6J mice treated with LPS and d-galactosamine, PN5 exhibited anti-inflammatory activity in inflamed mouse livers. Our results indicate that PN5 has antimicrobial and anti-inflammatory activities and thus may be useful as an antimicrobial agent to treat septic shock caused by multidrug-resistant (MDR) Escherichia coli without causing further resistance. IMPORTANCE Antibiotic-resistant bacteria are a global health concern. There is no effective treatment for antibiotic-resistant bacteria, and new alternatives are being suggested. The present study found antibacterial and anti-inflammatory activities of PN5 derived from Pinus densiflora (pine needle), and further investigated the therapeutic effect in a mouse septic model. As a mechanism of antibacterial activity, PN5 exhibited the membrane permeabilization ability of the toroidal model, and treated strains did not develop drug resistance during serial passages. PN5 showed immunomodulatory properties of neutralizing LPS in a mouse septic model. These results indicate that PN5 could be a new and promising therapeutic agent for bacterial infectious disease caused by antibiotic-resistant strains.

The American psychoanalyst and developmental psychologist Daniel Stern’s idea of vitality forms might suggest a new solution to explain how other minds are intensely expressed in their actions. Vitality forms characterize the expressive style of actions. The effective perception of vitality forms allows people to recognize the affective states and intentions of others in their actions, and could even open the possibility of properties of objects that are indicated by the given actions. Currently, neurophysiological studies present that there might be a neural mirror mechanism in the dorso-central insula (DCI), middle cingulate cortex (MCC), and other related cerebral areas, which serve to preferably perceive and deliver vitality forms of actions. In this article, possible types of vitality forms related to other minds, which have been brought to particular attention in recent years, have been collected and discussed in the following four areas: (1) Vitality forms on understanding non-verbal intention, (2) on understanding verbal intention, (3) vitality forms as grounding social cognition, and (4) as grounding social emotion. These four areas, however, might refer to an entirety of a binary actor-observer communicative landscape. In this review, we try to simplify the analysis by relying on two fundamental dimensions of criteria: first, the idea of vitality forms is conceived as the most basic way of observing subsequent higher-order dimensions of action, that is, understanding intention in the style of action. Thus, in the first two subsections, the relationships between vitality forms and their roles in understanding non-verbal and verbal intention have been discussed. Second, vitality forms could also be conceived as background conditions of all the other mental categories, that is, vitality forms can ground cognition and emotion in a social context. In the second dimension, the existence of social cognition or emotion depends on the existence of the stylistic kinematics of action. A grounding relation is used to distinguish a ground, that is, vitality forms, and its grounded mental categories. As relating with the domain of social perception, in this review, it has been discussed vitality forms possibly could ground social cognition and social emotion, respectively.

Seepage erosion is one of the main reasons for the local collapse or instability of embankments. To investigate the characteristics and mechanism of seepage erosion for cohesionless soils, model tests using an independently developed seepage erosion device and numerical simulations based on a discrete element method-computational fluid dynamics (DEM-CFD) coupling model were carried out. The results show that the seepage erosion process of cohesionless soil could be characterized by four stages: stable seepage, upward migration of fine particles, boiling of sand samples, and erosion damage. The skeleton structure of a soil sample under seepage flow was continually changed due to the loss of fine soil particles, which resulted in a significant decrease in the sample strength and could, ultimately, lead to the failure of the sample. The results of this study can provide references and bases for the design, construction, and long-term service of embankments or earth dams under complex seepage conditions, reducing the risk of seepage erosion.

BackgroundIndividuals who use methamphetamine (MA) for a long period of time may experience decreased inhibition and increased impulsivity. In order to reduce impulsivity or improve inhibitory control ability, high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has attracted much attention of researchers. Recent studies on addiction have shown that rTMS can stimulate different brain regions to produce different therapeutic effects. Recent work also suggests that HF-rTMS over right dorsolateral prefrontal cortex (DLPFC) does not affect the impulsivity of patients with alcohol use disorder; while HF-rTMS over left DLPFC could improve the impulsivity of patients with alcohol use disorder and cigarette smokers. However, it should be noted that empirical studies applying HF-rTMS over left DLPFC of patients with MA use disorders (MAUD) (to evaluate its effect on impulsivity) are still lacking.MethodsTwenty-nine patients with MAUD underwent five sessions of HF-rTMS on the left DLPFC per week for 4 consecutive weeks. The cue-induced craving and stop-signal and NoGo task were assessed pre-rTMS and post-rTMS (at the end of the 4-week rTMS treatment). In addition, 29 healthy controls were recruited. There was no rTMS intervention for the controls, the performance of the stop-signal and NoGo task was evaluated on them.ResultsIn total, HF-rTMS of the left DLPFC significantly decreased MA-dependent patients’ cue-induced craving and stop-signal reaction time (SSRT). For SSRT, the pre-test of experimental group was significantly higher than the score of control group. In the experimental group, the pre-test score was significantly higher than the post-test score. For Go and stop-signal delay (SSD), the pre-test scores of the experimental group was significantly lower than the scores of the control group. No significant difference was found between the pre-test and the post-test scores of the experimental group.ConclusionAdd-on HF-rTMS of left DLPFC may be an effective intervention for reducing impulsivity and cue-induced craving of patients with MAUD. Future research with a control group of MAUD that does not undergo the treatment is needed to confirm the effectiveness.

An important number of studies have been conducted on the potential association between human leukocyte antigen (HLA) genes and COVID-19 susceptibility and severity since the beginning of the pandemic. However, case–control and peptide-binding prediction methods tended to provide inconsistent conclusions on risk and protective HLA alleles, whereas some researchers suggested the importance of considering the overall capacity of an individual’s HLA Class I molecules to present SARS-CoV-2-derived peptides. To close the gap between these approaches, we explored the distributions of HLA-A, -B, -C, and -DRB1 1st-field alleles in 142 Iranian patients with COVID-19 and 143 ethnically matched healthy controls, and applied in silico predictions of bound viral peptides for each individual’s HLA molecules. Frequency comparison revealed the possible predisposing roles of HLA-A*03, B*35, and DRB1*16 alleles and the protective effect of HLA-A*32, B*58, B*55, and DRB1*14 alleles in the viral infection. None of these results remained significant after multiple testing corrections, except HLA-A*03, and no allele was associated with severity, either. Compared to peptide repertoires of individual HLA molecules that are more likely population-specific, the overall coverage of virus-derived peptides by one’s HLA Class I molecules seemed to be a more prominent factor associated with both COVID-19 susceptibility and severity, which was independent of affinity index and threshold chosen, especially for people under 60 years old. Our results highlight the effect of the binding capacity of different HLA Class I molecules as a whole, and the more essential role of HLA-A compared to HLA-B and -C genes in immune responses against SARS-CoV-2 infection.

Asbestos has been confirmed as a major pollutant in asbestos-mining areas that are located in western China. In general, asbestos-fibre dust will is released into the environment due to the effect of intensive industrial activities and improper environmental management, such that the health of residents in and around mining areas is jeopardised. A typical asbestos mining area served as an example in this study to analyse the content and fibre morphology of asbestos in soil and air samples in the mining area. The effects of asbestos pollution in and around the mining areas on human health were also assessed based on the U.S. Superfund Risk Assessment Framework in this study. As indicated by the results, different degrees of asbestos pollutions were present in the soil and air, and they were mainly concentrated in the mining area, the ore-dressing area, and the waste pile. The concentration of asbestos in the soil ranged from 0.3% to 91.92%, and the concentration of asbestos fibres in the air reached 0.008–0.145 f·cc−1. The results of the scanning-electron microscope (SEM) energy suggested that the asbestos was primarily strip-shaped, short columnar, and granular, and the asbestos morphology of the soils with higher degrees of pollution exhibited irregular strip-shaped fibre agglomeration. The excess lifetime cancer risk (ELCR) associated with the asbestos fibres in the air of the mining area was at an acceptable level (10−4–10−6), and 40.6% of the monitoring sites were subjected to unacceptable non-carcinogenic risks (HQ > 1). Moreover, the waste pile was the area with the highest non-carcinogenic risk, followed by the ore dressing area, a residential area, and a bare-land area in descending order. In the three scenarios of adult offices or residences in the mining area, adults’ outdoor activities in the peripheral residence areas, and children’s outdoor activities, the carcinogenic-and non-carcinogenic-risk-control values in the air reached 0.1438, 0.2225 and 0.1540 f·cc−1, and 0.0084, 0.0090 and 0.0090 f·cc−1, respectively. The results of this study will lay a scientific basis for the environmental management and governance of asbestos polluted sites in China.

Background and AimsIn this brief report, we compare the effectiveness and safety of intermittent theta burst stimulation (iTBS) and conventional 10 Hz repetitive transcranial magnetic stimulation (rTMS) in patients with methamphetamine use disorder (MAUD). Our study suggests that iTBS would also reduce drug craving in patients with MAUD just as the 10 Hz; thus, there may be no difference in treatment effects between these two methods.MethodsIn total twenty male methamphetamine (MA) addicts were randomly assigned to iTBS (n = 10) or 10 Hz (n = 10) groups for 12 treatments. Cue-evoked cravings, anxiety, depression, and withdrawal symptoms were measured at baseline before the first treatment, and post-tests after days 10, 15, and 20.ResultsThe results showed that iTBS and 10 Hz treatment had similar effectiveness in reducing cue-induced craving in male addicts for MA. Both 10 Hz and iTBS improved withdrawal symptoms of patients with MAUD.ConclusionsIntermittent theta burst stimulation may be similar in effectiveness as 10 Hz in treating patients with MAUD. The clinical usefulness of rTMS could be improved substantially because of the increase in its capacity, cost, and accessibility. Importantly, the effectiveness of rTMS in the treatment of patients with MAUD is not yet proven, and should be tested in the large double-blind sham-controlled studies.

Most human protein-coding genes are expressed as multiple isoforms. Here the authors present ORF Capture-seq that uses cloned ORFs as probes to capture and sequence full length transcript sequences. This enables highly sensitive characterization of eukaryotic transcriptomes.

Human natural killer (NK) cells can target tumor cells in an antigen-specific manner by the recognition of cell bound antibodies. This process induces antibody-dependent cell-mediated cytotoxicity (ADCC) and is exclusively mediated by the low affinity IgG Fc receptor CD16A (FcγRIIIA). Exploiting ADCC by NK cells is a major area of emphasis for advancing cancer immunotherapies. CD64 (FcγRI) is the only high affinity IgG FcR and it binds to the same IgG isotypes as CD16A, but it is not expressed by human NK cells. We have generated engineered human NK cells expressing recombinant CD64 with the goal of increasing their ADCC potency. Preclinical testing of this approach is essential for establishing efficacy and safety of the engineered NK cells. The dog provides particular advantages as a model, which includes spontaneous development of cancer in the setting of an intact and outbred immune system. To advance this immunotherapy model, we cloned canine CD16A and CD64 and generated specific mAbs. We report here for the first time the expression patterns of these FcγRs on dog peripheral blood leukocytes. CD64 was expressed by neutrophils and monocytes, but not lymphocytes, while canine CD16A was expressed at high levels by a subset of monocytes and lymphocytes. These expression patterns are similar to that of human leukocytes. Based on phenotypic characteristics, the CD16A+ lymphocytes consisted of T cells (CD3+ CD8+ CD5dim α/β TCR+) and NK cells (CD3− CD5− CD94+), but not B cells. Interestingly, the majority of canine CD16A+ lymphocytes were from the T cell population. Like human CD16A, canine CD16A was downregulated by a disintegrin and metalloproteinase 17 (ADAM17) upon leukocyte activation, revealing a conserved means of regulation. We also directly demonstrate that both canine CD16A and CD64 can induce ADCC when expressed in the NK cell line NK-92. These findings pave the way to engineering canine NK cells or T cells with high affinity recombinant canine CD64 to maximize ADCC and to test their safety and efficacy to benefit both humans and dogs.

Single crystal is the most advantageous of the crystalline states of halide perovskites. It displays better optical and electrical capabilities than polycrystalline films and microcrystals due to their inherent structural advantages, such as free grain boundaries, long-range ordered structure, and high orientation. Single-crystal perovskite materials can theoretically enable optoelectronic devices with higher performance and stronger stability. In this review, the intrinsic physical properties of perovskite single crystals are analyzed. The most recent advances in single-crystal optoelectronic devices are reviewed, and the design principles of the devices under different application conditions are revealed. It provides potential solutions for remaining challenges, and it is expected to accelerate the development of perovskite based optoelectronic devices.

RIG-I and MDA5 are major cytoplasmic innate-immune sensor proteins that recognize aberrant double-stranded RNAs generated during virus infection to activate type 1 interferon (IFN-I) and IFN-stimulated gene (ISG) expressions to control virus infection. The roles of RIG-I and MDA5 in controlling replication of Pichinde virus (PICV), a mammarenavirus, in mice have not been examined. Here, we showed that MDA5 single knockout (SKO) and RIG-I/MDA5 double knockout (DKO) mice are highly susceptible to PICV infection as evidenced by their significant reduction in body weights during the course of the infection, validating the important roles of these innate-immune sensor proteins in controlling PICV infection. Compared to the wildtype mice, SKO and DKO mice infected with PICV had significantly higher virus titers and lower IFN-I expressions early in the infection but appeared to exhibit a late and heightened level of adaptive immune responses to clear the infection. When a recombinant rPICV mutant virus (rPICV-NPmut) that lacks the ability to suppress IFN-I was used to infect mice, as expected, there were heightened levels of IFN-I and ISG expressions in the wild-type mice, whereas infected SKO and DKO mice showed delayed mouse growth kinetics and relatively low, delayed, and transient levels of innate and adaptive immune responses to this viral infection. Taken together, our data suggest that PICV infection triggers activation of immune sensors that include but might not be necessarily limited to RIG-I and MDA5 to stimulate effective innate and adaptive immune responses to control virus infection in mice.

On January 1, 2020, the Compulsory Mental Health Care Act took effect in the Netherlands. It contains provisions for compulsory community treatment (CCT) and compulsory treatment at home (CTH). In this study, we collected the opinions of patients and their significant others on CTH and on their preferences regarding compulsory care in their homes. Patients and their significant others were involved in the experience-based co-design of a purpose-built online questionnaire. This questionnaire was completed by 624 patients and 531 significant others. Sixty-one percent of the patients and 62% of the significant others did not want compulsory treatment to take place at home but in hospital or elsewhere. Patients’ and significant others’ opinion showed few differences, except with regard to the involvement of the significant others in CTH. As the respective views of patients and significant others were mixed, we recommend that crisis plans and compulsory treatment plans should be individually tailored to the needs and wishes of patients and their significant others regarding CTH.

Mesenchymal stromal cells (MSCs) have been used for the treatment of neuronal injury and neurodegenerative diseases. Their underlying mechanism may involve increased secretion of paracrine factors, which promotes tissue repair. Presently, exosomes have been regarded as important components of paracrine secretion and paracrine factors. MSC exosomes represent a promising opportunity to develop novel cell-free therapy approaches. In this study, exosomes from nasal olfactory mucosa MSCs (OM-MSCs) were extracted and purified using ultracentrifugation, resulting in exosome diameters of 40–130 nm. Similar to other exosomes, OM-MSC exosomes were CD63- and CD81-positive and calnexin-negative. Functionally, OM-MSC exosomes promoted human brain microvascular endothelial cell (HBMEC) proliferation and migration. The present study analyzed the OM-MSC exosome paracrine proteome. A total of 304 exosome-associated proteins were identified by LC–MS/MS, including plasminogen activator inhibitor 1 (SERPINE 1), insulin-like growth factor binding protein family members (IGFBP 4 and 5), epidermal growth factor receptor (EGFR), neurogenic locus notch homolog protein 2 (NOTCH 2), apolipoprotein E (APOE), and heat shock protein HSP90-beta (HSP90AB1). These molecules are known to be important in neurotrophic, angiogenesis, cell growth, differentiation, apoptosis, and inflammation and are highly correlated with the mechanism of tissue repair and neural restoration. These observations may provide a basis for further evaluation of OM-MSC exosome potential as a novel therapeutic modality.

Mesenchymal stem cells (MSCs) have presented a promising neuroprotective effect in cerebral ischemia/reperfusion (I/R). Olfactory mucosa MSCs (OM-MSCs), a novel source of MSCs located in the human nasal cavity, are easy to obtain and situated for autologous transplantation. The present study was designed to evaluate the neuroprotective effects of OM-MSCs on cerebral I/R injury and the possible mechanisms. In the transient middle cerebral artery occlusion (t-MCAO) model, excessive oxidative stress and increased swollen mitochondria were observed in the peri-infarct cortex. Intravenous injection of OM-MSCs ameliorated mitochondrial damage and restored oxidant/antioxidant imbalance. Using the oxygen glucose deprivation/reperfusion (OGD/R) model in vitro, we discovered that the exposure of mouse neuroblastoma N2a cells to OGD/R triggers excessive reactive oxygen species (ROS) generation and induces mitochondrial deterioration with decreased mitochondrial membrane potential and reduces ATP content. OM-MSC transwell coculture attenuated the above perturbations accompanied with increased UbiA prenyltransferase domain-containing 1 (UBIAD1) expression, whereas these protective effects of OM-MSCs were blocked when UBIAD1 was knocked down. UBIAD1-specific small interfering RNA (siRNA) reversed the increased membrane potential and ATP content promoted by OM-MSCs. Additionally, UBIAD1-specific siRNA blocked the oxidant/antioxidant balance treated by OM-MSCs. Overall, our results suggested that OM-MSCs exert neuroprotective effects in cerebral I/R injury by attenuating mitochondrial dysfunction and enhancing antioxidation via upregulation of UBIAD1.