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Osteoarthritis (OA) is a common joint degenerative disease which currently lacks satisfactory disease-modifying treatments. Oxidative stress-mediated senescent chondrocytes accumulation is closely associated with OA progression, which abrogates cartilage metabolism homeostasis by secreting senescence-associated secretory phenotype (SASP) factors. Numerous studies suggested mesenchymal stem cells-derived small extracellular vesicles (MSC-sEVs) have been regarded as promising candidates for OA therapy. However, MSC-sEVs were applied before the occurrence of cartilage degeneration or at early-stage OA, while in clinical practice, most OA patients who present with pain are already in non-early-stage. Recently, embryonic stem cells-derived sEVs (ESC-sEVs) have been reported to possess powerful anti-aging effects. However, whether ESC-sEVs could attenuate non-early-stage OA progression remains unknown. In this study, we demonstrated ESC-sEVs ameliorated senescent phenotype and cartilage destruction in both mechanical stress-induced non-early-stage posttraumatic OA and naturally aged mice. More importantly, we found ESC-sEVs alleviated senescent phenotype by rejuvenating aged chondrocytes but not inducing apoptosis. We also provided evidence that the FOXO1A-autophagy axis played an important role in the anti-aging effects of ESC-sEVs. To promote clinical translation, we confirmed ESC-sEVs reversed senescent phenotype in ex-vivo cultured human end-stage OA cartilage explants. Collectively, our findings reveal that ESC-sEVs-based therapy is of high translational value in non-early-stage OA treatment.

Identifying priority conservation areas (PCAs) on the basis of ecosystem services (ESs) trade-offs is a crucial step in achieving optimal ecosystem management in the BTH, noting the complex spatio-temporal and scaling effects inherent in these ecosystems. A cross-scale quantification of spatial and temporal changes in ecosystem services and their correlations was conducted in the BTH. Furthermore, the Ordered Weighting Algorithm (OWA) was introduced to simulate a variety of scenarios in order to determine the PCAs and to explore the drivers of ES in the PCAs. The results indicated that Food supply (FS), Water yield (WY), and Soil retention (SR) in the BTH increased by 16.4 × 104t/hm2, 81.81 mm, and 37081.29 t/hm2, respectively. In contrast, Carbon storage (CS) and Habit quality (HQ) exhibited a decrease of 0.01 t/hm2 and 0.03. Spatially, the high-value areas of ESs at the county scale exhibited greater clustering. At the county scale, there were two trade-offs and eight synergies in 2000, and four trade-offs and six synergies by 2020. In contrast, at the raster scale, there were two trade-offs and eight synergies from 2000 to 2020. The mechanisms of change were similar and exhibited spatial heterogeneity. Scenario 6 represents the optimal priority conservation area, exhibiting the most balanced conservation efficiency of each ecosystem service. This scenario enables the simultaneous conservation of multiple ESs. The natural factors within the PCAs exert a stronger influence on ESs than socio-economic factors. The inclusion of interacting factor effects will enhance the explanatory power of the drivers. The findings of this study can serve as a theoretical foundation for cross-scale ecosystem service management decisions.

IntroductionAlzheimer’s disease (AD) is highly heterogeneous, with substantial individual variabilities in clinical progression and neurobiology. Amyloid deposition has been thought to drive cognitive decline and thus a major contributor to the variations in cognitive deterioration in AD. However, the clinical heterogeneity of patients with early symptomatic AD (mild cognitive impairment or mild dementia due to AD) already with evidence of amyloid abnormality in the brain is still unknown.MethodsParticipants with a baseline diagnosis of mild cognitive impairment or mild dementia, a positive amyloid-PET scan, and more than one follow-up Alzheimer’s Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) administration within a period of 5-year follow-up were selected from the Alzheimer’s Disease Neuroimaging Initiative database (n = 421; age = 73±7; years of education = 16 ± 3; percentage of female gender = 43%; distribution of APOE4 carriers = 68%). A non-parametric k-means longitudinal clustering analysis in the context of the ADAS-Cog-13 data was performed to identify cognitive subtypes.ResultsWe found a highly variable profile of cognitive decline among patients with early AD and identified 4 clusters characterized by distinct rates of cognitive progression. Among the groups there were significant differences in the magnitude of rates of changes in other cognitive and functional outcomes, clinical progression from mild cognitive impairment to dementia, and changes in markers presumed to reflect neurodegeneration and neuronal injury. A nomogram based on a simplified logistic regression model predicted steep cognitive trajectory with an AUC of 0.912 (95% CI: 0.88 – 0.94). Simulation of clinical trials suggested that the incorporation of the nomogram into enrichment strategies would reduce the required sample sizes from 926.8 (95% CI: 822.6 – 1057.5) to 400.9 (95% CI: 306.9 – 516.8).DiscussionOur findings show usefulness in the stratification of patients in early AD and may thus increase the chances of finding a treatment for future AD clinical trials.

Abstract Pluripotent stem cell‐derived small extracellular vesicles (PSC‐sEVs) have demonstrated great clinical translational potential in multiple aging‐related degenerative diseases. Characterizing the PSC‐sEVs is crucial for their clinical applications. However, the specific marker pattern of PSC‐sEVs remains unknown. Here, the sEVs derived from two typical types of PSCs including induced pluripotent stem cells (iPSC‐sEVs) and embryonic stem cells (ESC‐sEVs) were analysed using proteomic analysis by liquid chromatography with tandem mass spectrometry (LC‐MS/MS), and surface marker phenotyping analysis by nanoparticle flow cytometry (NanoFCM). A group of pluripotency‐related proteins were found to be enriched in PSC‐sEVs by LC‐MS/MS and then validated by Western Blot analysis. To investigate whether these proteins were specifically expressed in PSC‐sEVs, sEVs derived from seven types of non‐PSCs (non‐PSC‐sEVs) were adopted for analysis. The results showed that PODXL, OCT4, Dnmt3a, and LIN28A were specifically enriched in PSC‐sEVs but not in non‐PSC‐sEVs. Then, commonly used surface antigens for PSC identification (SSEA4, Tra‐1‐60 and Tra‐1‐81) and PODXL were gauged at single‐particle resolution by NanoFCM for surface marker identification. The results showed that the positive rates of PODXL (>50%) and SSEA4 (>70%) in PSC‐sEVs were much higher than those in non‐PSC‐sEVs (

Abstract Background Given the complex and progressive nature of mild cognitive impairment (MCI), the ability to delineate and understand the heterogeneous cognitive trajectories is crucial for developing personalized medicine and informing trial design. The primary goals of this study were to examine whether different cognitive trajectories can be identified within subjects with MCI and, if present, to characterize each trajectory in relation to changes in all major Alzheimer’s disease (AD) biomarkers over time. Methods Individuals with a diagnosis of MCI at the first visit and ≥ 1 follow-up cognitive assessment were selected from the Alzheimer’s Disease Neuroimaging Initiative database (n = 936; age 73 ± 8; 40% female; 16 ± 3 years of education; 50% APOE4 carriers). Based on the Alzheimer’s Disease Assessment Scale-Cognitive Subscale-13 (ADAS-Cog-13) total scores from baseline up to 5 years follow-up, a non-parametric k-means longitudinal clustering method was performed to obtain clusters of individuals with similar patterns of cognitive decline. We further conducted a series of linear mixed-effects models to study the associations of cluster membership with longitudinal changes in other cognitive measures, neurodegeneration, and in vivo AD pathologies. Results Four distinct cognitive trajectories emerged. Cluster 1 consisted of 255 individuals (27%) with a nearly non-existent rate of change in the ADAS-Cog-13 over 5 years of follow-up and a healthy-looking biomarker profile. Individuals in the cluster 2 (n = 336, 35%) and 3 (n = 240, 26%) groups showed relatively mild and moderate cognitive decline trajectories, respectively. Cluster 4, comprising about 11% of our study sample (n = 105), exhibited an aggressive cognitive decline trajectory and was characterized by a pronouncedly abnormal biomarker profile. Conclusions Individuals with MCI show substantial heterogeneity in cognitive decline. Our findings may potentially contribute to improved trial design and patient stratification.

Tendinopathy is a common musculoskeletal disorder which results in chronic pain and reduced performance. The therapeutic effect of stem cell derived-small extracellular vesicles (sEVs) for tendinopathy has been validated in recent years. However, whether large extracellular vesicles (lEVs), another subset of extracellular vesicles, possesses the ability for the improvement of tendinopathy remains unknown. Here, we showed that lEVs secreted from iPSC-derived MSCs (iMSC-lEVs) significantly mitigated pain derived from tendinopathy in rats. Immunohistochemical analysis showed that iMSC-lEVs regulated the heterogeneity of infiltrated macrophages and several inflammatory cytokines in rat tendon tissue. Meanwhile, in vitro experiments revealed that the M1 pro-inflammatory macrophages were repolarized towards M2 anti-inflammatory macrophages by iMSC-lEVs, and this effect was mediated by regulating p38 MAPK pathway. Moreover, liquid chromatography-tandem mass spectrometry analysis identified 2208 proteins encapsulated in iMSC-lEVs, including 134 new-found proteins beyond current Vesiclepedia database. By bioinformatics and Western blot analyses, we showed that DUSP2 and DUSP3, the negative regulator of p38 phosphorylation, were enriched in iMSC-lEVs and could be transported to macrophages. Further, the immunomodulatory effect of iMSC-lEVs on macrophages was validated in explant tendon tissue from tendinopathy patients. Taken together, our results demonstrate that iMSC-lEVs could reduce inflammation in tendinopathy by regulating macrophage heterogeneity, which is mediated via the p38 MAPK pathway by delivery of DUSP2 and DUSP3, and might be a promising candidate for tendinopathy therapy.

The closed-form solution of each rotation joint angle is the most direct and convenient method for humanoid robot arms to imitate the real-time motion of the human arm. Occasionally, the human structure differs from that of a robot, and sensor information is inadequate. Therefore, it is difficult to obtain a closed-form solution for the inverse kinematics (IK) of a robot when using the Denavit–Hartenberg (D–H) method or screw theory alone. This study proposes combining the screw theory and the D–H method to solve the closed-form solution of the IK of a robotic arm with two unique structures: the elbow joint offset and the non-vertical state at the shoulder joint of the robotic arm. The proposed combination method first solves the elbow joint angle using screw theory. Then, the other rotation joint angles are solved using the D–H method. With the proposed method, human arm motion is successfully mapped to the corresponding joint of the robotic arm, and the closed-form solution allows the robotic arm to imitate human arm motion in real–time. Simulation results show that IK can be used to obtain high–precision angles and positions. Experiments show that the robotic arm has an accurate imitation performance, the accuracy of the $z$ -axis of the manipulator is significantly improved by 73.6%, and that of the $x$ -axis and $y$ -axis is also improved by 37.36% and 21.89%, respectively.

Background: Right ventricle-pulmonary arterial (RV-PA) coupling is considered the gold standard for assessing right ventricular (RV) function and can be evaluated noninvasively by echocardiography. The ratios of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP), RV global longitudinal strain (G-RVLS)/PASP, and stroke volume/end-systolic volume (SV/ESV) have been proposed as surrogates of RV-PA coupling. The relationship of these parameters remains incompletely understood in patients with volume and pressure loading conditions. We aimed to compare these parameters and evaluate their relationship with 3D RV data in patients with RV pressure and volume overload. Methods: This study was performed on 110 individuals who underwent 2D and 3D echocardiography. Fifty-four patients had RV volume overload (atrial septal defect (ASD) group), 34 patients had RV pressure overload (pulmonary hypertension (PH) group), and 22 were controls. TAPSE/PASP, G-RVLS/PASP and SV/ESV ratios were calculated. Correlations between parameters of RV-PA coupling and 3D data were assessed using general linear mixed models. Results: Compared with the ASD group, the PH group had lower TAPSE/PASP and G-RVLS/PASP ratios. The SV/ESV ratio had a strong correlation with right ventricle ejection fraction (RVEF) in both ASD and PH patients (r = 0.8703, p < 0.001 and r = 0.9388, p < 0.001, respectively). The G-RVLS/PASP ratio showed a strong or moderately negative relationship with end-diastolic volume (EDV), ESV and SV (r = –0.7768, p = 0.001; r = –0.7327, p = 0.0005 and r = –0.6816, p = 0.0018, respectively) in PH patients. The TAPSE/PASP ratio showed moderately negative correlations with EDV and ESV (r = –0.5712, p = 0.0012 and r = –0.5594, p = 0.0016, respectively) in PH patients. Conclusions: Non-invasive RV-PA coupling parameters derived from echocardiography appear similar, but not identical to profiles in pressure-overloaded and volume-overloaded patients. The correlations between non-invasive RV-PA coupling parameters and 3D data displayed various degrees of correlation.

Abstract Small extracellular vesicles derived from human pluripotent stem cells (hPSC‐sEVs) have shown great application potential in regenerative medicine. To standardise its research and clinical application, the first set of guidelines on hPSC‐sEVs in China ‘Requirements for human pluripotent stem cell derived small extracellular vesicles’ was released by the Chinese Research Hospital Association on 28 December 2021 and came into effect on 1 January 2022. It was jointly drafted and agreed upon by the experts from the Chinese Society of Extracellular Vesicles. This standard specifies the technical requirements, test methods and regulations, packaging, instructions for use, labelling, storage, transportation, and waste handling for hPSC‐sEVs, which apply to the production and quality control of hPSC‐sEVs. We hope that the publication of these guidelines will make it one step closer to international standardisation of hPSC‐sEVs for research and application.

Abstract “Requirements for human mesenchymal stem cell‐derived small extracellular vesicles” is the first set of guidelines on human mesenchymal stem cell‐derived small extracellular vesicles (hMSC‐sEVs) in China, jointly drafted and agreed upon by experts from the Chinese Society for Extracellular Vesicles. It was released by the Chinese Research Hospital Association on 28 December 2021 and came into effect on 1 January 2022. This standard specifies the technical requirements, test methods and regulations, packaging, instructions for use, labeling, storage, transportation, and waste handling for hMSC‐sEVs, which apply to the production and quality control of hMSC‐sEVs. We hope that the publication of these guidelines will promote consensus on the research and application of human mesenchymal stem cell‐derived small extracellular vesicles and accelerate its international standardization.

Yushu Tibetan Autonomous Prefecture is located in the Three Rivers Source area, which is known as the "water tower of China". However, due to the restriction of natural conditions, the ecological environment of Yushu Prefecture is extremely fragile and its self-recovery ability is poor. Based on the DPSIR concept model, this study collected the ecological environment and socio-economic data of Yushu Tibetan Autonomous Prefecture in 2000, 2005, 2010 and 2015, and established a dynamic evaluation model of ecological security by using expert scoring method and analytic hierarchy process. The weights of each index are determined and the data are standardized to analyze the temporal and spatial changes of ecological security in Yushu area. The results show that the change range of ecological security in Yushu Prefecture is less than 5%, and there is a weak tendency to develop to both ends. In terms of space, the ecological security situation in the southeast of Yushu Prefecture is better than that in the northwest, showing the distribution characteristics of insecurity in the northwest, early warning in the middle and safety in the southeast.

The lubricating oil heat diffusion ejector of a certain aircraft engine under the condition of engine idling on ground in the hot weather has the problem of low lubricating oil temperature drop after its turning on. The flow process of cool-side air flue of lubricating oil heat diffusion system is analyzed, and the ejector performance analysis method under severe conditions is explored. Based on N-S equations and k-ε turbulence model, the ejector performance is calculated and verified by test, and the lubricating oil temperature drop values before/after ejector turning on under severe conditions are obtained. The improvement scheme of ejector performance available in engineering is proposed on the basis of numerical calculation results. The results of the on-board ground test show that the calculation method is reasonable, and numerical simulation results are consistent with the test results, which meets the requirements of general engineering calculations, and provides a theoretical method for the performance analysis of an ejector.

ObjectiveThere is growing evidence that testosterone may be implicated in the pathogenesis of Alzheimer’s disease (AD). We aimed to examine the relationship between plasma total testosterone levels and change in brain glucose metabolism over time among non-demented older people.MethodsThe association of plasma total testosterone levels with change in brain glucose metabolism among non-demented older people was investigated cross-sectionally and longitudinally. Given a significant difference in levels of plasma total testosterone between gender, we performed our analysis in a sex-stratified way. At baseline, 228 non-demented older people were included: 152 males and 76 females.ResultsIn the cross-sectional analysis, no significant relationship between plasma total testosterone levels and brain glucose metabolism was found in males or females. In the longitudinal analysis, we found a significant association of plasma total testosterone levels with change in brain glucose metabolism over time in males, but not in females. More specifically, in males, higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism.ConclusionWe found that higher levels of total testosterone in plasma at baseline were associated with slower decline in brain glucose metabolism in males without dementia, indicating that testosterone may have beneficial effects on brain function.

Objective: To investigate whether APOE ε4 affects the association of verbal memory with neurodegeneration presented by the hippocampal volume/intracranial volume ratio (HpVR).Methods: The study sample included 371 individuals with normal cognition (NC), 725 subjects with amnestic mild cognitive impairment (aMCI), and 251 patients with mild Alzheimer’s disease (AD) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) who underwent the rey auditory verbal learning test (RAVLT). Multiple linear regression models were conducted to assess the effect of the APOE ε4∗HpVR interaction on RAVLT in all subjects and in each diagnostic group adjusting for age, gender and educational attainment, and global cognition.Results: In all subjects, there was no significant APOE ε4 × HpVR interaction for immediate recall or delayed recall (p > 0.05). However, in aMCI subjects, there was a significant APOE ε4 × HpVR interaction for delayed recall (p = 0.008), but not immediate recall (p = 0.15). More specifically, the detrimental effect of APOE ε4 on delayed recall altered by HpVR such that this effect was most evident among subjects with small to moderate HpVR, but this disadvantage was absent or even reversed among subjects with larger HpVR. No significant interaction was observed in the NC or AD group.Conclusion: These findings highlight a potential role of APOE ε4 status in affecting the association of hippocampus size with delayed recall memory in the early stage of AD.

GaN nucleation layers were grown on sapphire substrate by metal organic chemical vapor deposition (MOCVD) with different carrier gas. The morphology of nucleation layer which is crucial to GaN crystal quality was systematically studied using nitrogen and hydrogen as carrier gas. The GaN nucleation layer tends to form larger islands under H2 ambient, and forms higher density nucleation islands and thicker nucleation layer under N2 ambient.

The wide range of pressure detection and the exceptional linearity are essential performance parameters for flexible pressure sensors, enabling them to adapt to diverse scenarios and acquire information accurately. However, currently available "ultra‐wide range" piezoresistive sensors lack an optimal solution that effectively balances sensing properties, device thickness, and process cost. This study proposes a distinctive approach by introducing a Janus conductive structure assembled with dual resistive sensitive layers. The design allows for a pressure‐induced staged transformation of the current transport path, effectively mitigating variations and saturation in sensor resistance over a wide pressure range. The resulting piezoresistive sensor demonstrates an unprecedented detection range of 0–3800 kPa, showcasing remarkable sensitivity of 4.11 kPa−1 and outstanding linearity of 99.9% within the range of 0–1000 kPa. Additionally, the sensor boasts a thickness of only ≈200 µm, made possible through the utilization of a cellulose nanofibers material matrix. These performance achievements stand at the forefront when compared to existing reports. This research explores the potential applications of these sensors and extended arrays in the domains of human health and motion monitoring. It investigates their utility in gait analysis for assisted posture correction, as well as in the assessment and rehabilitation of gait instability. [ABSTRACT FROM AUTHOR]

Berberine (BBR), as a natural isoquinoline alkaloid, has demonstrated various pharmacological activities, and is widely applied in the treatment of diseases. The quantitative analysis of BBR is important for pharmacological studies and clinical applications. In this work, utilizing the specific interaction between BBR and triplex DNA, a sensitive and selective fluorescent detecting method was established with DNA-templated silver nanoclusters (DNA-AgNCs). After binding with the triplex structure in the template of DNA-AgNCs, BBR quenched the fluorescence of DNA-AgNCs and formed BBR-triplex complex with yellow–green fluorescence. The ratiometric fluorescence signal showed a linear relationship with BBR concentration in a range from 10 nM to 1000 nM, with a detection limit of 10 nM. Our method exhibited excellent sensitivity and selectivity, and was further applied in BBR detection in real samples. [ABSTRACT FROM AUTHOR]

This article aims to improve the inefficiency of the sports service supply chain (SC) caused by the unscientific management of stakeholders in the sports service SC. First, combined with the literature, the identification and management of the service SC domestically and internationally are explained, providing a meaningful reference for improving sports service bases. Second, fuzzy comprehensive appraisal (FCA) algorithm process and artificial intelligence (AI) technology are used to evaluate and manage the risk of sports service SC. The FCA algorithm provides a comprehensive evaluation factor set for the sports service SC risk evaluation. Then, the complete evaluation set is established. To obtain the evaluation matrix, the 'expert' carries out fuzzy evaluation on each single factor. AI provides a data analysis platform for integrated SC risk management. The platform can realize the logical hierarchical relationship between indicators and rules, systematically standardize the sports service SC and rules, and conduct unified display, monitoring, and trend analysis. Finally, the FCA method is used to evaluate the risks of the sports service SC, and the results of the comprehensive management of the dangers of the SC are analysed. The results show that the evaluation indicators of sports service venues' SC service capabilities have a good consistency. The highest weight score of government service capability in the sports service SC is 0.2413, and the lowest weight score of the service capability index of the sports operation platform is 0.1708. Sports service venues' SC capacity in NANCHANG City is relatively average. This article deeply understands the structure of the sports service SC. It provides relevant basis and guidance for sports service integrators, service providers, and other market entities to adjust management strategies and improve market competitiveness. It also clarifies the risks and management results of the sports service SC, provides academic help for the researchers and enriches and develops the theory of the reform and construction of the Chinese sports service SC. [ABSTRACT FROM AUTHOR]