Apoptotic Extracellular Vesicles Induced Endothelial Cell-Mediated Autologous Stem Cell Recruitment Dominates Allogeneic Stem Cell Therapeutic Mechanism for Bone Repair.

Although stem cell therapy is proved to be a promising strategy for bone repair and regeneration, transplanted allogeneic stem cells generally suffer from unfavorable apoptosis instead of differentiation into osteocytes. How the apoptotic stem cells promote bone regeneration still needs to be uncovered. In this work, we found that apoptotic extracellular vesicles released by allogeneic stem cells are critical mediators for promoting bone regeneration. Based on the results of in vivo experiments, a mechanism of apoptotic stem cells determined autologous stem cell recruitment and enhance osteogenesis was proposed. The nanoscaled apoptotic extracellular vesicles released from transplanted stem cells were endocytosed by vascular endothelial cells and preferentially distribute at endoplasmic reticular region. The oxidized phosphatidylcholine enriched in the vesicles activated the endoplasmic reticulum stress and triggered the reflective elevation of adhesion molecules, which induced the recruitment of autologous stem cells located in the blood vessels, transported them into the defect region, and promoted osteogenesis and bone repair. These findings not only reveal the mechanism of stem cell therapy of bone defects but also provide a cue for investigation of the biological process of stem cell therapy for other diseases and develop stem cell therapeutic strategies.

Construction of Multifunctional Luminescent Lanthanide MOFs for Luminescent Sensing of Temperature, Trifluoroacetic Acid Vapor and Explosives.

Metal-organic frameworks (MOFs) with multifunctional and tunable optical properties have unique advantages in the field of sensing, and the structure and properties of MOFs are significantly influenced by the ligands. In this study, a Y-type tricarboxylic acid ligand containing amide bonds was synthesized through functional guidance, and three isomorphic and heterogeneous three-dimensional MOFs (Eu-MOF, Tb-MOF, and Gd-MOF) were obtained by solvothermal reaction. Further studies revealed that both the Tb-MOF and Eu-MOF could selectively detect picric acid (PA). The luminescence quenching of the two MOFs by PA was attributed to competing absorption and photoelectron energy transfer mechanisms. In addition, due to the energy transfer between Tb and Rhodamine B, Rhodamine B was encapsulated into Tb-MOF. The obtained material exhibited a linear relationship between the temperature parameters I544/I584 and temperature within the range of 280-400 K, the correlation coefficient (R2) reached an impressive value of 0.999, and the absolute sensitivity of the sample used for temperature sensing was 1.534% K-1. What is more, the material exhibited a good response to trifluoroacetic acid vapor, which suggests the potential of the material for temperature sensing and detection of trifluoroacetic acid vapor. The designed and investigated strategy can also serve as a reference for further research on excellent multifunctional sensors.

Cross-Modal Federated Human Activity Recognition.

Federated human activity recognition (FHAR) has attracted much attention due to its great potential in privacy protection. Existing FHAR methods can collaboratively learn a global activity recognition model based on unimodal or multimodal data distributed on different local clients. However, it is still questionable whether existing methods can work well in a more common scenario where local data are from different modalities, e.g., some local clients may provide motion signals while others can only provide visual data. In this paper, we study a new problem of cross-modal federated human activity recognition (CM-FHAR), which is conducive to promote the large-scale use of the HAR model on more local devices. CM-FHAR has at least three dedicated challenges: (1) distributive common cross-modal feature learning, (2) modality-dependent discriminate feature learning, (3) modality imbalance issue. To address these challenges, we propose a modality-collaborative activity recognition network (MCARN), which can comprehensively learn a global activity classifier shared across all clients and multiple modality-dependent private activity classifiers. To produce modality-agnostic and modality-specific features, we learn an altruistic encoder and an egocentric encoder under the constraint of a separation loss and an adversarial modality discriminator collaboratively learned in hyper-sphere. To address the modality imbalance issue, we propose an angular margin adjustment scheme to improve the modality discriminator on modality-imbalanced data by enhancing the intra-modality compactness of the dominant modality and increase the inter-modality discrepancy. Moreover, we propose a relation-aware global-local calibration mechanism to constrain class-level pairwise relationships for the parameters of the private classifier. Finally, through decentralized optimization with alternative steps of adversarial local updating and modality-aware global aggregation, the proposed MCARN obtains state-of-the-art performance on both modality-balanced and modality-imbalanced data.

MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation.

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

Bone-Targeting Peptide and RNF146 Modified Apoptotic Extracellular Vesicles Alleviate Osteoporosis.

Background: Osteoporosis is a highly prevalent disease that causes fractures and loss of motor function. Current drugs targeted for osteoporosis often have inevitable side effects. Bone marrow mesenchymal stem cell (BMSCs)-derived apoptotic extracellular vesicles (ApoEVs) are nanoscale extracellular vesicles, which has been shown to promote bone regeneration with low immunogenicity and high biological compatibility. However, natural ApoEVs cannot inherently target bones, and are often eliminated by macrophages in the liver and spleen. Thus, our study aimed to reconstruct ApoEVs to enhance their bone-targeting capabilities and bone-promoting function and to provide a new method for osteoporosis treatment. Methods: We conjugated a bone-targeting peptide, (Asp-Ser-Ser)6 ((DSS)6), onto the surface of ApoEVs using standard carbodiimide chemistry with DSPE-PEG-COOH serving as the linker. The bone-targeting ability of (DSS)6-ApoEVs was determined using an in vivo imaging system and confocal laser scanning microscopy (CLSM). We then loaded ubiquitin ligase RING finger protein146 (RNF146) into BMSCs via adenovirus transduction to obtain functional ApoEVs. The bone-promoting abilities of (DSS)6-ApoEVs and (DSS)6-ApoEVsRNF146 were measured in vitro and in vivo. Results: Our study successfully synthesized bone-targeting and gained functional (DSS)6-ApoEVsRNF146 and found that engineered ApoEVs could promote osteogenesis in vitro and exert significant bone-targeting and osteogenesis-promoting effects to alleviate osteoporosis in a mouse model. Conclusion: To promote the bone-targeting ability of natural ApoEVs, we successfully synthesized engineered ApoEVs, (DSS)6-ApoEVsRNF146 and found that they could significantly promote osteogenesis and alleviate osteoporosis compared with natural ApoEVs, which holds great promise for the treatment of osteoporosis.

MSC-derived exosomes protect auditory hair cells from neomycin-induced damage via autophagy regulation

BACKGROUND: Sensorineural hearing loss (SNHL) poses a major threat to both physical and mental health; however, there is still a lack of effective drugs to treat the disease. Recently, novel biological therapies, such as mesenchymal stem cells (MSCs) and their products, namely, exosomes, are showing promising therapeutic potential due to their low immunogenicity, few ethical concerns, and easy accessibility. Nevertheless, the precise mechanisms underlying the therapeutic effects of MSC-derived exosomes remain unclear. RESULTS: Exosomes derived from MSCs reduced hearing and hair cell loss caused by neomycin-induced damage in models in vivo and in vitro. In addition, MSC-derived exosomes modulated autophagy in hair cells to exert a protective effect. Mechanistically, exogenously administered exosomes were internalized by hair cells and subsequently upregulated endocytic gene expression and endosome formation, ultimately leading to autophagy activation. This increased autophagic activity promoted cell survival, decreased the mitochondrial oxidative stress level and the apoptosis rate in hair cells, and ameliorated neomycin-induced ototoxicity. CONCLUSIONS: In summary, our findings reveal the otoprotective capacity of exogenous exosome-mediated autophagy activation in hair cells in an endocytosis-dependent manner, suggesting possibilities for deafness treatment.

Phenomenological characteristics of autobiographical future thinking in nurses with burnout: a case-control study.

Objective: Nurses constitute the largest group of healthcare workers worldwide, and job burnout is very common among them. This study aims to explore abnormal future thinking in nurses with burnout. Additionally, the study investigates whether these manifestations worsen as burnout progresses. Methods: The study was conducted in inpatient ward nurses at a tertiary hospital in Hangzhou, China. In the first phase, two group of nurses were recruited: nurses with burnout (N = 70) and nurses without burnout (N = 70). In the second phase, three groups were recruited according to the burnout levels: mild burnout (N = 43), moderate burnout (N = 42) and severe burnout (N = 43). Data on job burnout were obtained using the Chinese Maslach Burnout Inventory. The Sentence Completion for Events in the Future Test (SCEFT) was employed to measure the content of future thinking, which was evaluated by two raters in terms of the specificity, emotional valence, and concrete content of the imagined future events. The proportions of specific types of events among all the produced events were calculated. Results: The results revealed that nurses with burnout, compared to nurses without burnout, imagined fewer specific future events, positive events, and events related to relationships and achievement. They also had more omissions. As the level of burnout increased, their impairment in future thinking worsened. Furthermore, the results also revealed that the scores of emotional exhaustion, depersonalization, and personal accomplishment had significant correlations with the proportions of positive events and events related to relationships and achievement/mastery in nurses' future thinking content. Conclusion: The future thinking ability of nurses with burnout was impaired, and this impairment worsened as the symptoms of burnout progressed. The findings of the present study have important implications for nurse caring and advocate effective interventions targeting positive future thinking to mitigate nurses' burnout.

Adverse effects of knocking down chitin synthase A on female reproduction in Culex pipiens pallens (Diptera: Culicidae).

BACKGROUND: Current mosquito-borne disease vector control strategies, largely based on chemical insecticides, are seriously threatened by increasing resistance worldwide. There is also growing concerned about the adverse effects of insecticides on nontarget organisms and the environment, therefore effective and ecologically friendly alternative approaches are urgently needed. Targeting critical steps of reproduction is considered a potential way to control mosquito populations. Herein, we focused on the roles of chitin synthase A (encoded by chsa) in the reproduction of female mosquitoes. RESULTS: The injection of small interfering RNA targeting Cpchsa in female Culex pipiens pallens (Diptera: Culicidae) had antireproductive effects, including decreased follicle numbers, egg-laying, and hatching rate. Scanning electron microscopy observations showed that Cpchsa silencing caused a defective egg envelope, including absence of the vitelline membrane and cracked chorion layers, which resulted in abnormal permeability. Widely distributed nurse cell apoptosis and follicular epithelial cell autophagy were observed in Cpchsa-silenced ovaries during the vitellogenesis phase. Consistent with the detective egg envelope formation during oogenesis, the exochorionic eggshell structures were also affected in eggs deposited by Cpchsa-silenced mosquitoes. CONCLUSION: This study provided fundamental evidence for the role of chitin synthase A in the female reproductive process of mosquitoes and might result in a novel alternative strategy for mosquito control. © 2023 Society of Chemical Industry.

O­GlcNAcylation mediates endometrial cancer progression by regulating the Hippo­YAP pathway.

The incidence of endometrial cancer (EC) is rapidly increasing worldwide. The majority of endometrial cancers are diagnosed at an early stage and are associated with a good prognosis; however, patients with advanced­stage EC have a poor prognosis and present with invasive metastasis. The mechanisms responsible for the invasion and metastasis of endometrial cancer remain unknown. Here, the present study aimed to examine the effects of O­GlcNAcylation on the malignancy of EC and its association with Yes­associated protein (YAP). It was found that the expression of O­GlcNAc transferase (OGT) and O­GlcNAcylation were increased in EC tissues; the decrease in O­GlcNAcylation levels was found to lead to the decreased proliferation, migration and invasion of EC cells. Mass spectrometric analysis revealed that OGT knockdown reduced the O­GlcNAcylation of YAP. Furthermore, it was found that the reduction in the O­GlcNAcylation of YAP promoted its phosphorylation, which in turn inhibited the access of YAP to the nucleus and downstream target gene activation, demonstrating that the level of O­GlcNAcylation affects the development of EC. On the whole, the findings of the present study indicate that YAP is a key molecule linking the O­GlcNAcylation and Hippo pathways, which together regulate the progression of EC.

Category Knowledge-guided Parameter Calibration for Few-shot Object Detection.

Few-shot object detection (FSOD) aims to adapt generic detectors to the novel categories with only a few annotations, which is an important and realistic task. Although the generic object detection has been widely studied over the past years, the FSOD is under explored. In this paper, we propose a novel Category Knowledge-guided Parameter Calibration (CKPC) framework to solve the FSOD task. We first propagate the category relation information to explore the representative category knowledge. Then, we explore the RoI-RoI and RoI-Category relations to capture the local-global context information to enhance the RoI (Region of Interest) features. Next, we project the knowledge representations of foreground categories into a parameter space by a linear transformation to generate the parameters of the category-level classifier. For the background, we learn a proxy category by concluding the global characteristics of all foreground categories to help ensure the discrepancy between the foreground and background, which is then projected into the parameter space by the same linear transformation. Finally, we leverage the parameters of the category-level classifier to explicitly calibrate the instance-level classifier learned on the enhanced RoI features for both the foreground and background categories to improve the detection performance. We conduct extensive experiments on two popular FSOD benchmarks (i.e., Pascal VOC and MS COCO), and the experimental results show that the proposed framework can outperform state-of-the-art methods.

Humoral regulation of iron metabolism by extracellular vesicles drives antibacterial response.

Immediate restriction of iron initiated by the host is a critical process to protect against bacterial infections and has been described in the liver and spleen, but it remains unclear whether this response also entails a humoral mechanism that would enable systemic sequestering of iron upon infection. Here we show that upon bacterial invasion, host macrophages immediately release extracellular vesicles (EVs) that capture circulating iron-containing proteins. Mechanistically, in a sepsis model in female mice, Salmonella enterica subsp. enterica serovar Typhimurium induces endoplasmic reticulum stress in macrophages and activates inositol-requiring enzyme 1α signaling, triggering lysosomal dysfunction and thereby promoting the release of EVs, which bear multiple receptors required for iron uptake. By binding to circulating iron-containing proteins, these EVs prevent bacteria from iron acquisition, which inhibits their growth and ultimately protects against infection and related tissue damage. Our findings reveal a humoral mechanism that can promptly regulate systemic iron metabolism during bacterial infection.

The lead and cadmium content in rice and risk to human health in China: A systematic review and meta-analysis.

Numerous studies have investigated concentrations of lead (Pb) and cadmium (Cd) in rice in China, but have come to divergent conclusions. Therefore we systematically reviewed and meta-analyzed the available evidence on levels of Pb and Cd in rice in different regions of China in order to assess the potential risk to human health. The meta-analysis included 24 studies of Pb levels and 29 studies of Cd levels, published in 2011-2021. The pooled Pb concentration in rice was 0.10 mg per kg dry weight (95% CI 0.08-0.11), while the pooled Cd concentration was 0.16 mg per kg dry weight (95% CI 0.14-0.18). These levels are within the limits specified by national food safety standards. However, the total target hazard quotient for both metals exceeded 1.0 for adults and children, suggesting that rice consumption poses a health risk.

Construction of a series of Ln-MOF luminescent sensors based on a functional "V" shaped ligand.

It is necessary to decrease the application cost of luminescent Ln-MOF sensors to develop multiple functionalities. The ingenious design of ligands and the rational doping of Ln3+ ions are the main approaches to endowing Ln-MOFs with more functionalities. "V" shaped ligands can cause diamond pore channels commonly. "OC-NH" groups as hydrogen bonding sites not only can participate in supramolecular self-assembly but also can achieve molecular recognition. Based on the above considerations, a "V" shaped ligand, H2L, with a suitable triplet state and "OC-NH" groups was designed and synthesized firstly. And the Ln-MOFs (Ln = Eu, Gd, Tb) were obtained by solvothermal reactions. Single crystal X-ray diffraction showed that Ln-MOFs had two types of diamond pore channels where "OC-NH" groups adhered to the surface. "OC-NH" groups not only played an important role in the stacking process of 2D coordinated layers but also can reduce the non-radiative transition resulting from molecular vibration. The Eu-MOF and Tb-MOF not only can emit strong "f-f" transitions characteristic of luminescence but also can detect o-phenylenediamine (OPD) and p-phenylenediamine (PPD) by luminescence quenching. Besides, EuxTb1-x-MOFs (x = 0.02, 0.05, 0.1) were synthesized and can be used as ratio luminescence thermometers whose maximum relative sensitivities were 1.19% K-1 at 400 K. It is pointed out specifically that the relationship between the relative sensitivities and the Eu3+ content was studied. What's more, our work not only developed a series of Ln-MOF luminescent sensors by designing functional ligands and doping Ln3+ rationally but also provided valuable knowledge for the following work.

Computed tomography-guided lung biopsy for molecular tests: a meta-analysis.

Introduction: Computed tomography (CT)-guided lung biopsy has been widely used for molecular testing. Aim: To evaluate the potential clinical effectiveness of computed tomography (CT)-guided lung biopsy in molecular tests. Material and methods: We searched the related studies from the PubMed, Embase, and Cochrane Library until July 2021. The endpoints included adequacy rates for molecular tests, positive rates of epidermal growth factor receptor (EGFR) mutations, anaplastic lymphoma kinase (ALK) translocation, and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations. Results: Initially, we were able to identify 1783 potentially relevant studies, among which only 12 were ultimately included in the present meta-analysis. All the studies were retrospective in nature. A total of 2559 patients underwent CT-guided lung biopsy and 1414 of them received molecular testing. We found that the pooled adequacy rate for molecular tests, positive rate of EGFR mutations, and positive rate of ALK translocation were 95%, 49%, and 7%, respectively. Significant heterogeneity was detected in the endpoints of adequacy rate for molecular tests (I 2 = 86.2%) and positive rate of EGFR mutations (I 2 = 77.7%). We did not identify any variables that could significantly influence the adequacy rate for molecular tests and positive rate of EGFR mutations. A high risk of publication bias was also found in the endpoint of adequacy rate for molecular tests. Conclusions: CT-guided lung biopsy can serve as an effective method to provide sufficient lung cancer samples for molecular testing. The EGFR gene was found to be the most frequently mutated during the analysis.

Hybrid Biomaterial Initiates Refractory Wound Healing via Inducing Transiently Heightened Inflammatory Responses.

Inflammation plays a crucial role in triggering regeneration, while inadequate or chronic inflammation hinders the regenerative process, resulting in refractory wounds. Inspired by the ideal regeneration mode in lower vertebrates and the human oral mucosa, realigning dysregulated inflammation to a heightened and acute response provides a promising option for refractory wound therapy. Neutrophils play important roles in inflammation initiation and resolution. Here, a hybrid biomaterial is used to stimulate transiently heightened inflammatory responses by precise tempospatial regulation of neutrophil recruitment and apoptosis. The hybrid biomaterial (Gel@fMLP/SiO2 -FasL) is constructed by loading of formyl-met-leu-phe (fMLP) and FasL-conjugated silica nanoparticles (SiO2 -FasL) into a pH-responsive hydrogel matrix. This composition enables burst release of fMLP to rapidly recruit neutrophils for heightened inflammation initiation. After neutrophils act to produce acids, the pH-responsive hydrogel degrades to expose SiO2 -FasL, which induces activated neutrophils apoptosis via FasL-Fas signaling triggering timely inflammation resolution. Apoptotic neutrophils are subsequently cleared by macrophages, and this efferocytosis activates key signalings to promote macrophage anti-inflammatory phenotypic transformation to drive regeneration. Ultimately, Gel@fMLP/SiO2 -FasL successfully promotes tissue regeneration by manipulating inflammation in critical-sized calvarial bone defects and diabetic cutaneous wound models. This work provides a new strategy for refractory wound therapy via inducing transiently heightened inflammatory responses.

Apoptotic vesicles activate autophagy in recipient cells to induce angiogenesis and dental pulp regeneration.

Extracellular vesicles (EVs) derived from living cells play important roles in donor cell-induced recipient tissue regeneration. Although numerous studies have found that cells undergo apoptosis after implantation in an ischemic-hypoxic environment, the roles played by the EVs released by apoptotic cells are largely unknown. In this study, we obtained apoptotic vesicles (apoVs) derived from human deciduous pulp stem cells and explored their effects on the dental pulp regeneration process. Our work showed that apoVs were ingested by endothelial cells (ECs) and elevated the expression of angiogenesis-related genes, leading to pulp revascularization and tissue regeneration. Furthermore, we found that, at the molecular level, apoV-carried mitochondrial Tu translation elongation factor was transported and regulated the angiogenic activation of ECs via the transcription factor EB-autophagy pathway. In a beagle model of dental pulp regeneration in situ, apoVs recruited endogenous ECs and facilitated the formation of dental-pulp-like tissue rich in blood vessels. These findings revealed the significance of apoptosis in tissue regeneration and demonstrated the potential of using apoVs to promote angiogenesis in clinical applications.

An HPLC-MS/MS Method Using a Multitoxin Clean up Column for Analysis of Seven Mycotoxins in Aquafeeds.

BACKGROUND: In Guangdong Province of China, the climate is very wet, so there are many different fungi living in aquatic feeds, which produce mycotoxins. These compounds contaminate agricultural products worldwide and present a great threat to human health. It is necessary to determine their contamination level in aquatic feeds. OBJECTIVE: A high performance liquid chromatography (HPLC) tandem mass spectrometry (MS/MS) method was developed for the quantitative analysis of aflatoxin B1, aflatoxin M1, T-2 toxin, HT-2 toxin, deoxynivalenol, ochratoxin, and zearalenone in fish and shrimp feed. METHODS: Samples were extracted with acetonitrile-water (3+1, v/v), and degreased with acetonitrile-saturated hexane. The extract was cleaned up with a multitoxin column. The target compounds were separated on a C18 chromatographic column and analyzed simultaneously by electrospray ionization mass spectrometry in both positive and negative ion mode. Detected compounds were quantified using the matrix-matched external standard method. RESULTS: Under the optimized conditions, good linearities for the analytes in the corresponding concentration range were obtained, with correlation coefficients (r2) higher than 0.9948. LODs ranged from 1.83 to 12.63 µg/kg, and LOQs ranged from 5.49 to 37.89 µg/kg. Average recoveries for the target mycotoxins at three spiked levels ranged from 80.5 to 116.5% with RSD ranging from 2.4 to 10.4%. Twenty-three real aquafeed samples were determined by this method, and seven kinds of toxins were detected. CONCLUSION: The results show that the developed method can be successfully applied for the simultaneous determination of mycotoxins in aquatic feeds. HIGHLIGHTS: Multitoxin purification columns proved to be a powerful technique for determining seven mycotoxins simultaneously. This method ensured simple sample pretreatment and less operation time. The established method was successfully applied to the analysis of seven mycotoxins species in aquatic feeds.

Inductions of a CYP6 cluster conferring deltamethrin resistance in colonized and field-collected Culex pipiens pallens.

Mosquitoes transmit many damaging vector-borne diseases. Unfortunately, the rise of insecticide resistance has become a major obstacle to mosquito control. A preliminary study showed that a CYP6 cluster is significant for deltamethrin resistance in colonized Culex pipiens pallens. Here, several field strains were collected to explore the association of the cluster in deltamethrin tolerance. We examined the effect of deltamethrin treatment on the cluster expression at a deltamethrin concentration of LC50 in these strains using five time points. As a result, both P450 induction and constitutive overexpression were associated with deltamethrin resistance. Deltamethrin could stimulate different expression sets in the P450 cluster in different strains, predominately correlated with the resistance level of the strain. Our results will offer more insight into working with the characterization of P450s related to insecticide resistance.