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BACKGROUND: Osteoporosis is a major global health issue, weakening bones and increasing fracture risk. Dual-energy X-ray absorptiometry (DXA) is the standard for measuring bone mineral density (BMD) and diagnosing osteoporosis, but its costliness and complexity impede widespread screening adoption. Predictive modeling using genetic and clinical data offers a cost-effective alternative for assessing osteoporosis and fracture risk. This study aims to develop BMD prediction models using data from the UK Biobank (UKBB) and test their performance across different ethnic and geographical populations. METHODS AND FINDINGS: We developed BMD prediction models for the femoral neck (FNK) and lumbar spine (SPN) using both genetic variants and clinical factors (such as sex, age, height, and weight), within 17,964 British white individuals from UKBB. Models based on regression with least absolute shrinkage and selection operator (LASSO), selected based on the coefficient of determination (R2) from a model selection subset of 5,973 individuals from British white population. These models were tested on 5 UKBB test sets and 12 independent cohorts of diverse ancestries, totaling over 15,000 individuals. Furthermore, we assessed the correlation of predicted BMDs with fragility fractures risk in 10 years in a case-control set of 287,183 European white participants without DXA-BMDs in the UKBB. With single-nucleotide polymorphism (SNP) inclusion thresholds at 5×10-6 and 5×10-7, the prediction models for FNK-BMD and SPN-BMD achieved the highest R2 of 27.70% with a 95% confidence interval (CI) of [27.56%, 27.84%] and 48.28% (95% CI [48.23%, 48.34%]), respectively. Adding genetic factors improved predictions slightly, explaining an additional 2.3% variation for FNK-BMD and 3% for SPN-BMD over clinical factors alone. Survival analysis revealed that the predicted FNK-BMD and SPN-BMD were significantly associated with fragility fracture risk in the European white population (P < 0.001). The hazard ratios (HRs) of the predicted FNK-BMD and SPN-BMD were 0.83 (95% CI [0.79, 0.88], corresponding to a 1.44% difference in 10-year absolute risk) and 0.72 (95% CI [0.68, 0.76], corresponding to a 1.64% difference in 10-year absolute risk), respectively, indicating that for every increase of one standard deviation in BMD, the fracture risk will decrease by 17% and 28%, respectively. However, the model's performance declined in other ethnic groups and independent cohorts. The limitations of this study include differences in clinical factors distribution and the use of only SNPs as genetic factors. CONCLUSIONS: In this study, we observed that combining genetic and clinical factors improves BMD prediction compared to clinical factors alone. Adjusting inclusion thresholds for genetic variants (e.g., 5×10-6 or 5×10-7) rather than solely considering genome-wide association study (GWAS)-significant variants can enhance the model's explanatory power. The study highlights the need for training models on diverse populations to improve predictive performance across various ethnic and geographical groups.
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At present, there have only been a few DNA sequencing-based studies to explore the genetic determinants of bone mineral density (BMD). We carried out the largest whole genome sequencing analysis to date for femoral neck and spine BMD (n = 4981), with one of the highest average sequencing depths implemented thus far at 22×, in a multiethnic sample (58% Caucasian and 42% African American) from the Louisiana Osteoporosis Study (LOS). The LOS samples were combined with summary statistics from the GEFOS consortium and several independent samples of various ethnicities to perform GWAS meta-analysis (n = 44 506). We identified 31 and 30 genomic risk loci for femoral neck and spine BMD, respectively. The findings substantiate many previously reported susceptibility loci (e.g. WNT16 and ESR1) and reveal several others that are either novel or have not been widely replicated in GWAS for BMD, including two for femoral neck (IGF2 and ZNF423) and one for spine (SIPA1). Although we were not able to uncover ethnicity specific differences in the genetic determinants of BMD, we did identify several loci which demonstrated sex-specific associations, including two for women (PDE4D and PIGN) and three for men (TRAF3IP2, NFIB and LYSMD4). Gene-based rare variant association testing detected MAML2, a regulator of the Notch signaling pathway, which has not previously been suggested, for association with spine BMD. The findings provide novel insights into the pathophysiological mechanisms of osteoporosis.
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Densidade Óssea , Estudo de Associação Genômica Ampla , Densidade Óssea/genética , Feminino , Colo do Fêmur/fisiologia , Humanos , Masculino , Polimorfismo de Nucleotídeo Único/genética , Sequenciamento Completo do GenomaRESUMO
Organophosphate pesticides (OPs) are widely utilized in agricultural production, and the residues threaten public health and environmental safety due to their toxicity. Herein, a novel and simple DNA aptamer-based sensor has been fabricated for the rapid, visual, and quantitative detection of profenofos and isocarbophos. The proposed DNA aptamers with a G-quadruplex spatial structure could be recognized by SYBR Green I (SG-I), resulting in strong green fluorescence emitted by SG-I. The DNA aptamers exhibit a higher specific binding ability to target OP molecules through aromatic ring stacking, disrupting the interaction between SG-I and DNA aptamers to induce green fluorescence quenching. Meanwhile, the fluorescence wavelength of G-quadruplex fluorescence emission peaks changes, accompanied by an obvious fluorescence variation from green to blue. SG-I-modified aptasensor without any additive reference fluorescence units for use in multicolor fluorescence assay for selective monitoring of OPs was first developed. The developed aptasensor provides a favorable linear range from 0 to 200 nM, with a low detection limit of 2.48 and 3.01 nM for profenofos and isocarbophos, respectively. Moreover, it offers high selectivity and stability in real sample detection with high recoveries. Then, a self-designed portable smartphone sensing platform was successfully used for quantitative result outputs, demonstrating experience in designing a neotype sensing strategy for point-of-care pesticide monitoring.
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Aptâmeros de Nucleotídeos , Benzotiazóis , Diaminas , Corantes Fluorescentes , Compostos Orgânicos , Praguicidas , Quinolinas , Espectrometria de Fluorescência , Aptâmeros de Nucleotídeos/química , Quinolinas/química , Praguicidas/análise , Diaminas/química , Corantes Fluorescentes/química , Benzotiazóis/química , Compostos Orgânicos/química , Técnicas Biossensoriais/métodos , Limite de Detecção , Quadruplex G , Malation/análogos & derivadosRESUMO
Harnessing the developmental events of mesenchymal condensation to direct postnatal dental stem cell aggregation represents a cutting-edge and promising approach to tooth regeneration. Tooth avulsion is among the most prevalent and serious dental injuries, and odontogenic aggregates assembled by stem cells from human exfoliated deciduous teeth (SHED) have proven effective in revitalizing avulsed teeth after replantation in the clinical trial. However, whether and how SHED aggregates (SA) communicate with recipient components and promote synergistic tissue regeneration to support replanted teeth remains elusive. Here, it is shown that SA-mediated avulsed tooth regeneration involves periodontal restoration and recovery of recipient Gli1+ stem cells, which are mobilized and necessarily contribute to the reestablishment of the tooth-periodontal ligament-bone interface. Mechanistically, the release of extracellular vesicles (EVs) is revealed indispensable for the implanted SA to mobilize recipient Gli1+ cells and regenerate avulsed teeth. Furthermore, SHED aggregates-released EVs (SA-EVs) are featured with odontogenic properties linked to tissue regeneration, which enhance migration, proliferation, and differentiation of Gli1+ cells. Importantly, local application of SA-EVs per se empowers recipient Gli1+ cells and safeguards regeneration of avulsed teeth. Collectively, the findings establish a paradigm in which odontogenesis-featured EVs govern donor-recipient stem cell interplay to achieve tooth regeneration, inspiring cell-free translational regenerative strategies.
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Optical camera communication (OCC) shows promise for optical wireless communication (OWC) in vehicular networks. However, vehicle mobility-induced angular distortions hinder system throughput by degrading non-isotropic vehicular OCC channel gain. Few of the prior works have ever made a comprehensive analysis of their impact, especially based on the pixel value which reflects the camera imaging features. To address this knowledge gap, a pixel value-described vehicular OCC system model accounting for transmitter imaging location and intensity from the geometry and radiometry aspects is presented in this paper with common types of the offset and rotation angles included. We integrate a MATLAB-based simulated vehicular OCC system with an experimentally designed testbed for validation and performance analysis. For a single-time snapshot, we investigate the impacts of common angular distortion types in vehicular OCC systems on maximum pixel value, imaging location, and communication-related metrics. Furthermore, we statistically analyze their influences by considering two driving scenarios with respective angular distributions. The angular distortion characterization from this work is expected to lay a stepping stone to addressing mobility in vehicular OCC systems.
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Hip fracture risk assessment is an important but challenging task. Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur. We developed a global FEA-computed fracture risk index to increase the prediction accuracy of hip fracture incidence. PURPOSE: Quantitative CT-based patient-specific finite element (FE) analysis (FEA) incorporates bone geometry and bone density in the proximal femur to compute the force (fracture load) and energy necessary to break the proximal femur in a particular loading condition. The fracture loads and energies-to-failure are individually associated with incident hip fracture, and provide different structural information about the proximal femur. METHODS: We used principal component analysis (PCA) to develop a global FEA-computed fracture risk index that incorporates the FEA-computed yield and ultimate failure loads and energies-to-failure in four loading conditions of 110 hip fracture subjects and 235 age- and sex-matched control subjects from the AGES-Reykjavik study. Using a logistic regression model, we compared the prediction performance for hip fracture based on the stratified resampling. RESULTS: We referred the first principal component (PC1) of the FE parameters as the global FEA-computed fracture risk index, which was the significant predictor of hip fracture (p-value < 0.001). The area under the receiver operating characteristic curve (AUC) using PC1 (0.776) was higher than that using all FE parameters combined (0.737) in the males (p-value < 0.001). CONCLUSIONS: The global FEA-computed fracture risk index increased hip fracture risk prediction accuracy in males.
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Fraturas do Quadril , Fraturas Proximais do Fêmur , Masculino , Humanos , Fraturas do Quadril/epidemiologia , Fraturas do Quadril/etiologia , Densidade Óssea , Fêmur/diagnóstico por imagem , Curva ROC , Análise de Elementos FinitosRESUMO
Exploring a novel natural cryoprotectant and understanding its antifreeze mechanism allows the rational design of future sustainable antifreeze analogues. In this study, various antifreeze polysaccharides were isolated from wheat bran, and the antifreeze activity was comparatively studied in relation to the molecular structure. The antifreeze mechanism was further revealed based on the interactions of polysaccharides and water molecules through dynamic simulation analysis. The antifreeze polysaccharides showed distinct ice recrystallization inhibition activity, and structural analysis suggested that the polysaccharides were arabinoxylan, featuring a xylan backbone with a majority of Araf and minor fractions of Manp, Galp, and Glcp involved in the side chain. The antifreeze arabinoxylan, characterized by lower molecular weight, less branching, and more flexible conformation, could weaken the hydrogen bonding of the surrounding water molecules more evidently, thus retarding the transformation of water molecules into the ordered ice structure.
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Fibras na Dieta , Xilanos , Fibras na Dieta/análise , Xilanos/química , Polissacarídeos/química , Crioprotetores/química , Cristalização , Ligação de Hidrogênio , Água/química , Simulação de Dinâmica Molecular , Proteínas Anticongelantes/química , GeloRESUMO
Cyprinid herpesvirus 3 (CyHV-3) has caused severe economic losses to carp culture, but its pathogenicity is far from clear. Our previous study has revealed that microRNA (miR)-722 was upregulated during CyHV-3 infection, indicating that miR-722 might play an important role in CyHV-3 replication. In this study, we found that overexpression of miR-722 inhibited CyHV-3 replication and promoted IFN expression. The putative target gene of miR-722 was searched over the CyHV-3 genome, and ORF89 was identified and validated as a target gene of miR-722. Overexpression of ORF89 markedly reduced the expression of IFN and IFN-stimulated genes. Mechanistically, ORF89 interacted with and degraded IFN regulatory factor 3 (IRF3), and inhibited the entry of IRF3 into the nucleus by suppressing the dimerization of IRF3. Moreover, ORF89-mediated suppression of IFN expression could be restored by adding miR-722. To our knowledge, our findings confirm a novel virus-host combat, in which CyHV-3 evades host antiviral immunity by its ORF89 protein, whereas host miR-722, upregulated on CyHV-3 infection, targets ORF89 to impede CyHV-3 replication.
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Evasão da Resposta Imune , MicroRNAs , Fator Regulador 3 de Interferon/genética , Proteínas Virais/genética , MicroRNAs/genéticaRESUMO
Atmospheric deposition of Cd poses a serious threat to ecosystem security. Biochar is widely used for polluted soil remediation, however, whether biochar already applied to the soil can reduce the hazards of newly deposited Cd remains to be studied. Thus, an indoor cultural experiment and static adsorption method were conducted to study the isothermal and kinetic adsorption processes of three types of biochar (rice husk, rubber wood, and tobacco stem biochars) on Cd in iron rich soils and the effect of biochar on the morphological distribution of Cd in the soil and the soil pH. The results showed that the soil with biochar in our study could quickly fix "the new deposited Cd" in the soil in 3 h with the maximum adsorption capacity in rubber wood biochar-treated sample (3227.34 mg/kgï¼. The addition of all three biochar treatments significantly increased the soil pH and reduced the soil exchange state Cd content, with a 13.69-17.32% increase in the pH and a 13.22-54.39% reduction in the exchange state Cd content when contrasted with the control, which could promote those Cd converting into unavailable Cd (carbonate-bound form Cd, Fe-Mn oxide-bound form Cd, or residual form Cd) for crops. In summary, the addition of three kinds of biochar treatments could effectively reduce the ecological and environmental risk of soil that was contaminated by Cd and could provide a reliable theoretical basis for the effect of biochar on the improvement of the quality of soil that is contaminated by heavy metals.
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Cádmio , Poluentes do Solo , Cádmio/análise , Ferro , Solo/química , Ecossistema , Poluentes do Solo/análise , Carvão Vegetal/químicaRESUMO
Detection of pavement diseases is crucial for road maintenance. Traditional methods are costly, time-consuming, and less accurate. This paper introduces an enhanced pavement disease recognition algorithm, MS-YOLOv8, which modifies the YOLOv8 model by incorporating three novel mechanisms to improve detection accuracy and adaptability to varied pavement conditions. The Deformable Large Kernel Attention (DLKA) mechanism adjusts convolution kernels dynamically, adapting to multi-scale targets. The Large Separable Kernel Attention (LSKA) enhances the SPPF feature extractor, boosting multi-scale feature extraction capabilities. Additionally, Multi-Scale Dilated Attention in the network's neck performs Spatially Weighted Dilated Convolution (SWDA) across different dilatation rates, enhancing background distinction and detection precision. Experimental results show that MS-YOLOv8 increases background classification accuracy by 6%, overall precision by 1.9%, and mAP by 1.4%, with specific disease detection mAP up by 2.9%. Our model maintains comparable detection speeds. This method offers a significant reference for automatic road defect detection.
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Algoritmos , HumanosRESUMO
Quasi-2D perovskites, multiquantum well materials with the energy cascade structure, exhibit impressive optoelectronic properties and a wide range of applications in various optoelectronic devices. However, the insufficient exciton energy transfer caused by the excess of small-n phases that induce nonradiative recombination and the spatially random phase distribution that impedes charge transport severely inhibit the device performance of light-emitting diodes (LEDs). Here, a faster energy transfer process and efficient carrier recombination are achieved by introducing the multifunctional additive 2-(methylsulfonyl)-4-(trifluoromethyl)benzoic acid (MTA) to manipulate the crystallization process of perovskites. The introduction of MTA not only constrains the PEA and restrains the formation of small-n phases to improve the energy transfer process but also optimizes the crystal orientation to promote charge transport. As a result, highly efficient pure green quasi-2D perovskite LEDs with a peak EQE of 25.9%, a peak current efficiency of 108.1 cd A-1, and a maximum luminance of 288798 cd m-2 are achieved.
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Although colloidal perovskite nanocrystal (PNC) solution has exhibited near-unity photoluminescence quantum yield (PLQY), the luminance would be severely quenched when the PNC solution is assembled into thin films due to the agglomeration and fusion of NCs caused by the exfoliation of surface ligands and non-radiative Förster resonance energy transfer (FRET) from small to large particle sizes, which seriously affected the performances of light-emitting diodes (LEDs). Here, we used Guanidine thiocyanate (GASCN) and Sodium thiocyanate (NaSCN) to achieve effective CsPbI3 PNC surface reconstruction. Due to the strong coordination ability of these small molecules with the anions and cations on the surface of the PNCs, they can provide strong surface protection against PNC fusion during centrifugal purification process and repair the surface defects of PNCs, so that the original uniform size distribution of PNCs can be maintained and FRET between close-packed PNC films is effectively suppressed, which allows the emission characteristics of the films to be preserved. As a result, highly oriented, smooth and nearly defect-free high-quality PNC thin films are obtained, with PLQY as high as 95.1 %, far exceeding that of the original film, and corresponding LEDs exhibit a maximum external quantum efficiency of 24.5 %.
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Assays for carbendazim (Car) with high sensitivity and on-site screening have been urgently required to protect the ecosystem and prevent disease. In this work, a simple, sensitive, and reliable sensing system based on photoinduced electron transfer was established to detect carbendazim utilizing ultrathin graphitic carbon nitride (g-C3N4) nanosheets and rhodamine B (RB). Carbendazim reacts with g-C3N4 by electrostatic interactions to form π-π stacking, and the quenching of the blue fluorescence is caused by electron transfer. While RB works as a reference fluorescence sensor without any fluorescence change, leading to obvious ratiometric fluorescence variation from blue to purple. Under optimal conditions, a favorable linear range from 20 to 180 nM was obtained, with a low detection limit of 5.89 nM. In addition, a portable smartphone sensing platform was successfully used for carbendazim detection in real samples with excellent anti-interference capability, demonstrating the potential applications of carbendazim monitoring.
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The frequent outbreak of grass carp hemorrhagic disease caused by grass carp reovirus (GCRV), especially the mainly prevalent type II GCRV (GCRV-II), has seriously affected the grass carp culture in China. However, its pathogenic mechanism is still far from clear. In this study, the GCRV-II outer capsid protein VP35 was used as bait to capture interacting partners from Ctenopharyngon idellus kidney (CIK) cells, and heat shock protein 90 (Hsp90) was selected and confirmed interacting with VP35 through the C-terminal domain of Hsp90. Knockdown of Hsp90 or inhibition of Hsp90 activity suppressed GCRV-II proliferation, demonstrating that Hsp90 is an essential factor for GCRV-II proliferation. The confocal microscopy and flow cytometry showed that Hsp90 localized at both membrane and cytoplasm of CIK cells. The entry of GCRV-II into CIK cells was efficiently blocked by incubating the cells with Hsp90 antibody or by pretreating the virus with recombinant Hsp90 protein. Whereas overexpression of Hsp90 in CIK cells, grass carp ovary (GCO) cells, or 293T cells promoted GCRV-II entry, indicating that the membrane Hsp90 functions as a receptor of GCRV-II. Furthermore, Hsp90 interacted with clathrin and mediated GCRV-II entry into CIK cells through clathrin endocytosis pathway. In addition, we found that the cytoplasmic Hsp90 acted as a chaperone of VP35 because inhibition of Hsp90 activity enhanced VP35 polyubiquitination and degraded VP35 through the proteasome pathway. Collectively, our data suggest that Hsp90 functions both as a receptor for GCRV-II entry and a chaperone for the maturation of GCRV-II VP35, thus ensuring efficient proliferation of GCRV-II. IMPORTANCE Identification of viral receptors has always been the research hot spot in virus research field as receptor functions at the first stage of viral infection, which can be designed as efficient antiviral drug targets. GCRV-II, the causative agent of the grass carp epidemic hemorrhagic disease, has caused tremendous losses in grass carp culture in China. To date, the receptor of GCRV-II remains unknown. This study focused on identifying cellular receptor interacting with the GCRV-II outer capsid protein VP35, studying the effects of their interaction on GCRV-II proliferation, and revealing the underlying mechanisms. We demonstrated that Hsp90 acts both as a receptor of GCRV-II by interacting with VP35 and as a chaperone for the maturation of VP35, thus ensuring efficient proliferation of GCRV-II. Our data provide important insights into the role of Hsp90 in GCRV-II life cycle, which will help understand the mechanism of reovirus infection.
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Proteínas do Capsídeo , Doenças dos Peixes , Proteínas de Choque Térmico , Infecções por Reoviridae , Reoviridae , Animais , Anticorpos Antivirais/metabolismo , Proteínas do Capsídeo/metabolismo , Carpas/virologia , Proliferação de Células , Clatrina/metabolismo , Doenças dos Peixes/virologia , Proteínas de Choque Térmico/metabolismo , Chaperonas Moleculares/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores Virais/metabolismo , Reoviridae/fisiologia , Infecções por Reoviridae/veterináriaRESUMO
To analyze the application effect of anti-tuberculosis therapy (ATT) combined with all-in-one nursing care on pulmonary tuberculosis (PT). Seventy-four PT patients who received ATT in our hospital between December 2015 and June 2016 were selected as the research participants and randomized into a research group (RG; n=37) and a control group (CG; n=37) that were given all-in-one nursing care and routine care, respectively. The cure rate and treatment compliance were compared between groups, and the awareness of disease prevention and treatment was investigated. Patients' psychological status and quality of life were evaluated using the Self-Rating Depression/Anxiety Scale (SAS/SDS) and the Quality of Life Questionnaire Core 30 (QLQ-C30), respectively. RG and CG were not statistically different in the clinical cure rate (P>0.05), but the X-ray cure rate was higher and the recurrence rate was lower in RG (P<0.05). In addition, RG showed higher medication compliance rate, regular reexamination rate and awareness of disease prevention and treatment than CG (P<0.05). Reductions in SAS/SDS scores were observed in both groups after care, with even lower levels in RG, while the QLQ-C30 score increased and was higher in RG as compared to CG (P<0.05). Therefore, All-in-one nursing care can effectively enhance the level of treatment compliance and awareness of disease prevention and treatment of PT patients. In the future, when treating PT patients in the clinic, the effectiveness of ATT can be improved by implementing all-in-one nursing care to provide more reliable prognosis for patients.
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Tuberculose Pulmonar , Tuberculose , Humanos , Antituberculosos/uso terapêutico , Inflamação , Qualidade de Vida , Tuberculose Pulmonar/tratamento farmacológicoRESUMO
Renal interstitial fibrosis (RIF) is an incurable pathological lesion in chronic kidney diseases. Pericyte activation is the major pathological characteristic of RIF. Fibroblast and macrophage activation are also involved in RIF. Studies have revealed that core fucosylation (CF), an important post-translational modification of proteins, plays a key role in pericyte activation and RIF by regulating multiple profibrotic signaling pathways as a hub-like target. Here, we reveal that mesenchymal stem cell (MSC)-derived exosomes reside specifically in the injured kidney and deliver microRNA (miR)-34c-5p to reduce cellular activation and RIF by inhibiting CF. Furthermore, we showed that the CD81-epidermal growth factor receptor (EGFR) ligand-receptor complex aids the entry of exosomal miR-34c-5p into pericytes, fibroblasts, and macrophages. Altogether, our findings reveal a novel role of MSC-derived exosomes in inhibiting multicellular activation via CF and provide a potential intervention strategy for renal fibrosis.
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Exossomos , Nefropatias , Células-Tronco Mesenquimais , MicroRNAs , Exossomos/metabolismo , Fibrose , Humanos , Rim/patologia , Nefropatias/metabolismo , Nefropatias/terapia , Células-Tronco Mesenquimais/metabolismo , MicroRNAs/administração & dosagem , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
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.
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Polpa Dentária , Vesículas Extracelulares , Animais , Autofagia , Cães , Células Endoteliais , Humanos , Fatores de Alongamento de Peptídeos , Regeneração , Fatores de TranscriçãoRESUMO
Toxoplasma gondii is a widespread eukaryotic pathogen that causes life-threatening diseases in humans and diverse animals. It has a complex life cycle with multiple developmental stages, which are timely adjusted according to growth conditions. But the regulatory mechanisms are largely unknown. Here we show that the AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in eukaryotes, plays crucial roles in controlling the cell cycle progression and bradyzoite development in Toxoplasma. Deleting the ß regulatory subunit of AMPK in the type II strain ME49 caused massive DNA damage and increased spontaneous conversion to bradyzoites (parasites at chronic infection stage), leading to severe growth arrest and reduced virulence of the parasites. Under alkaline stress, all Δampkß mutants converted to a bradyzoite-like state but the cell division pattern was significantly impaired, resulting in compromised parasite viability. Moreover, we found that phosphorylation of the catalytic subunit AMPKα was greatly increased in alkaline stressed parasites, whereas AMPKß deletion mutants failed to do so. Phosphoproteomics found that many proteins with predicted roles in cell cycle and cell division regulation were differentially phosphorylated after AMPKß deletion, under both normal and alkaline stress conditions. Together, these results suggest that the parasite AMPK has critical roles in safeguarding cell cycle progression, and guiding the proper exist of the cell cycle to form mature bradyzoites when the parasites are stressed. Consistent with this model, growth of parasites was not significantly altered when AMPKß was deleted in a strain that was naturally reluctant to bradyzoite development.
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Parasitos , Toxoplasma , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Ciclo Celular , Divisão Celular , Humanos , Parasitos/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismoRESUMO
Constructing visible-light driven semiconductor heterojunction with high redox bifunctional characteristics is a promising approach to deal with the increasingly serious environmental pollution problems, especially the coexistence of organic/heavy metal pollutants. Herein, a simple in-situ interfacial engineering strategy for the fabrication of 0D/3D hierarchical Bi2WO6@CoO (BWO) heterojunction with an intimate contact interface was successfully developed. The superior photocatalytic property was reflected not only in individual tetracycline hydrochloride (TCH) oxidation or Cr(VI) reduction, but also in their simultaneous redox reaction, which could be predominantly attributed to the outstanding light-harvesting, high carrier separation efficiency and enough redox potentials. In the simultaneous redox system, TCH acted as a hole-scavenger for Cr(VI) reduction, replacing the additional reagent. Interestingly, superoxide radical (·O2-) played the role as oxidants in TCH oxidation but as electron transfer media in Cr(VI) reduction. On account of the interlaced energy band and tight interfacial contact, a direct Z-scheme charge transfer model was established, which was verified by the active species trapping experiments, spectroscopy, and electrochemical tests. This work provided a promising strategy for the design/fabrication of highly efficient direct Z-scheme photocatalysts in environmental remediation.
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Antibacterianos , Tetraciclina , Oxirredução , OxidantesRESUMO
An atmospheric pressure glow discharge ionisation source was constructed and utilized to study the dopamine (DA) oxidation process coupling with mass spectrometry. During the DA oxidation process catalysed by polyphenol oxidase (PPO), six cationic intermediates were directly detected by the atmospheric pressure glow discharge mass spectrometry (APGD-MS). Combined with tandem mass spectrometry, the structures of the dopamine o-semiquinone radical (DASQ) and leukodopaminochrome radical (LDACâ) intermediates and structures of the isomers of dopaminochrome (DAC) and 5,6-dihydroxyindole (DHI) were further characterised with the introduction of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and deuterium oxide (D2O) to APGD-MS. Meanwhile, UV-Vis studies confirmed the important role of PPO in catalyzing the DA oxidation reaction. Based on APGD-MS studies, a possible mechanism could be proposed for DA oxidation catalysed by PPO. Furthermore, APGD-MS could provide possibilities for the effective detection and characterisation of short-lived intermediates, even in complicated systems.