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Introduction: Osteoarthritis (OA) is a devastating whole-joint disease affecting a large population worldwide with no cure; its mechanism remains poorly defined. Abnormal mechanical stress is the main pathological factor of OA. Objectives: To investigate the effects of Piezo1 activation on OA development and progression and to explore Piezo1-targeting OA treatment. Methods: The expression levels of Piezo1 were determined in human OA cartilage and experimental OA mice. Mice with genetic Piezo1 deletion in chondrocytes or intra-articular injection of the Piezo1 activator Yoda1 were utilized to determine the effects on DMM-induced OA progression. Effects of artemisinin (ART), a potent antimalarial drug, on Piezo1 activation, chondrocyte metabolism and OA lesions were determined. Results: Piezo1 expression was elevated in articular chondrocytes in human OA and DMM-induced mouse OA cartilage. Piezo1 deletion in chondrocytes largely attenuates DMM-induced OA-like phenotypes. In contrast, intra-articular injection of Yoda1 aggravates the knee joint OA lesions in mice. PIEZO1 activation increases, while PIEZO1 siRNA knockdown decreases, expression of RUNX2 and catabolic enzymes MMP13 and ADAMTS5 in primary human articular chondrocytes in a PI3K-AKT dependent manner. We have provided strong evidence supporting that ART is a novel and potent inhibitor of Piezo1 activation in primary OA-HACs and all cell lines examined, including human endothelial HUVEC cells, ATDC5 chondrocyte-like cells and MLO-Y4 osteocytes-like cells. Results from in vitro experiments confirmed that ART decreases the Yoda1-induced increases in the levels of OA-related genes and p-PI3K and p-AKT proteins in OA-HACs and alleviates DMM-induced OA lesions in mice. Conclusions: We establish a critical role of Piezo1 in promoting OA development and progression and define ART as a potential OA treatment.

Abstract Background The coronavirus disease 2019 (COVID-19) rapidly spreads worldwide and causes more suffering. The relation about the aggravation of inguinal pain and COVID-19 was unclear in patients with total hip arthroplasty (THA). This study aimed to evaluate the risk of groin pain aggravation in short-term THA patients after COVID-19. Methods Between 2020 and 2022, 129 patients with THA who were affected COVID-19 were enrolled. A short-standardized questionnaire was administered during follow-up to inquire about the aggravation of groin ache before and after SARS-COV-2 affection. Furthermore, we evaluated the potential association between the presence of increased pain and various factors, including age, gender, body mass index, diagnosis, and length of hospital stay. Results The case-crossover study revealed an increased risk of inguinal soreness aggravation when comparing 8 weeks after COVID-19 with 12 weeks before COVID-19 (Relative risk [RR], 9.5; 95% Confidence intervals [CI], 2.259–39.954). For COVID-19 positive patients, multivariate analysis showed length of stay was an independent factor significantly associated with increased risk of aggravation of groin pain (Odds ratio [OR], 1.26; 95%CI, 1.03–1.55, p = 0.027). Conclusion This study confirms the association between COVID-19 and the exacerbation of soreness in the groin region in THA patients and extended length of stay is a possible contributing factor. This study expands the current literature by investigating the risk of aggravation of inguinal pain in patients with THA after COVID-19, providing valuable insights into postoperative outcomes in this specific population. Trial registration This retrospective study was approved by the Institutional Review Board of Shanghai general hospital (No.2023-264).

With the increase of traffic flow in modern urban areas, traffic congestion has become a serious problem that affects people’s normal production and life. Using target detection technology instead of manual labor can quickly detect the road traffic situation and provide timely information about the traffic flow. However, when using drones to observe the traffic flow in the air, the perspective effect will cause the detected vehicles and pedestrians to be very small, and the scale difference between different categories of targets is large, which increases the detection difficulty of a single convolutional neural network model. In order to solve the problem of low accuracy of traditional single-stage target detection models, this study proposes an improved Yolov5 vehicle target detection model with Vision Transformer (VIT) backbone, You Only Look Once-HyperVision (YOLO-HV), which aims to solve the problem of poor multi-scale target recognition performance caused by the inability of traditional CNN networks to integrate contextual information, and help drones achieve more efficient and accurate traffic flow recognition functions. This study deeply integrates the Vision Transformer (VIT) backbone and Convolutional Neural Network (CNN), effectively combining the multi-scale detection advantages of Vision Transformer and the inductive bias ability of Convolutional Neural Network, and adds multi-scale residual modules and context correlation enhancement modules, which greatly improves the recognition accuracy of single-stage detectors for drone images. Through comparative experiments on the VisDrone dataset, it is found that the detection performance of this model is improved compared with several commonly used detection models. YOLO-HV can increase the mean average precision (mAP) by 3.3% compared with the pure convolutional network of the same model size. YOLO-HV model has achieved excellent performance in the task of traffic flow image detection taken by drones, and can more accurately identify and classify road vehicles than various target detection models.

Research background: The role of osteocytes in maintaining bone mass has been progressively emphasized. Pip5k1c is the most critical isoform among PIP5KIs, which can regulate cytoskeleton, biomembrane, and Ca2+ release of cells and participate in many processes, such as cell adhesion, differentiation, and apoptosis. However, its expression and function in osteocytes are still unclear. Materials and methods: To determine the function of Pip5k1c in osteocytes, the expression of Pip5k1c in osteocytes was deleted by breeding the 10-kb mouse Dmp1-Cre transgenic mice with the Pip5k1cfl/fl mice. Bone histomorphometry, micro-computerized tomography analysis, immunofluorescence staining and western blotting were used to determine the effects of Pip5k1c loss on bone mass. In vitro, we explored the mechanism by siRNA knockdown of Pip5k1c in MLO-Y4 cells. Results: Pip5k1c expression was decreased in osteocytes in senescent and osteoporotic tissues both in humans and mice. Loss of Pip5k1c in osteocytes led to a low bone mass in long bones and spines and impaired biomechanical properties in femur, without changes in calvariae. The loss of Pip5k1c resulted in the reduction of the protein level of type 1 collagen in tibiae and MLO-Y4 cells. Osteocyte Pip5k1c loss reduced the osteoblast and bone formation rate with high expression of sclerostin, impacting the osteoclast activities at the same time. Moreover, Pip5k1c loss in osteocytes reduced expression of focal adhesion proteins and promoted apoptosis. Conclusion: Our studies demonstrate the critical role and mechanism of Pip5k1c in osteocytes in regulating bone remodeling. The translational potential of this article: Osteocyte has been considered to a key role in regulating bone homeostasis. The present study has demonstrated that the significance of Pip5k1c in bone homeostasis by regulating the expression of collagen, sclerostin and focal adhesion expression, which provided a possible therapeutic target against human metabolic bone disease.

ObjectivesAiming at the challenge of accurate diving modeling of a smart float, an anti-saturation and noise least squares (ASNLS) algorithm is proposed in this paper to achieve diving multi-parameter identification and depth prediction. MethodsFirstly, the nonlinear motion characteristics of the smart float actuator were included in the gray box-based diving model to better fit the actual model, and the continuous diving motion equation was transformed into a discrete form to match the real-world discrete data sampling. Subsequently, the aforementioned discrete diving model was constructed into a correlation form to attenuate the influence of data noise. Finally, by adjusting the values of the covariance matrix, the designed diving parameter identification algorithm achieved resistance to data saturation. ResultsBased on the data of the South China Sea deep diving experiment of the smart float in 2021, diving model parameter identification and depth prediction are carried out. The results demonstrate that the ASNLS algorithm has faster convergence speed (31.8% higher than the least squares algorithm) and smaller depth prediction error (average absolute percentage errors less than 9% at different depths) than both the traditional least squares algorithm and supports the vector machine algorithm.ConclusionsConsequently, the ASNLS algorithm can provide effective support for the depth control and prediction of the smart float.

BackgroundFerroptosis has been proven to contribute to the progression of myocardial ischemia/reperfusion (I/R) injury and can be inhibited or promoted by ATF3. Short-chain fatty acids (SCFAs) have shown benefits in various cardiovascular diseases with anti-inflammatory and antioxidant effects. However, the impact of SCFAs on ferroptosis in ischemic-stimulated cardiomyocytes remains unknown. This study aimed to investigate the effect of SCFAs on cardiomyocyte ferroptosis, the expression of ATF3, and its potential upstream regulators.Methods and resultsThe expression of ATF3, ferroptosis pathway geneset (FPG), and geneset of potential regulators for ATF3 (GPRA, predicted by the PROMO database) was explored in the public human myocardial infarction single-cell RNA-seq (sma) dataset. Cardiomyocyte data was extracted from the dataset and re-clustered to explore the FPG, ATF3, and GPRA expression patterns in cardiomyocyte subclusters. A dose-dependent toxic experiment was run to detect the suitable dose for SCFA treatment. The erastin-induced ferroptosis model and hypoxia-reoxygenation (H/R) model (10 h of hypoxia followed by 6 h of reoxygenation) were adopted to assess the effect of SCFAs via the CCK8 assay. Gene expression was examined via RT-PCR and western blot. Ferroptosis markers, including lipid peroxides and Fe2+, were detected using the liperfluo and ferroOrange probes, respectively. In the sma dataset, upregulated ferroptosis pathway genes were mainly found in the infarction-stimulated cardiac cells (border zone and fibrotic zone), particularly the cardiomyocytes and adipocytes. The ATF3 and some of its potential transcription factors (VDR, EGR3, PAX5, and SP1) can be regulated by SCFA. SCFA can attenuate erastin-induced lipid peroxidation in cardiomyocytes. SCFA treatment can also reverse erastin-induced Fe2+ increase but may strengthen the Fe2+ in the H/R model. We also precisely defined a ferroptosis subcluster of cardiomyocytes (CM09) that highly expressed FPG, ATF3, and GPRA.ConclusionThe ATF3 and the ferroptosis pathway are elevated in cardiomyocytes of injury-related cardiac regions (border zone, ischemic zone, and fibrotic zone). SCFA can attenuate cardiomyocyte ferroptosis and regulate the expression of ATF3. Our study offers novel insights into the potential targets of SCFAs in the cardiovascular system.

The efficient utilization of renewable energy is a key technology area of high domestic and international concern, and the research and development of DC–DC photovoltaic converters with high conversion efficiency is of great significance for improving performance and reducing the cost of solar power generation systems. In order to improve the conversion efficiency of solar energy, this paper proposes the design of a high-efficiency photovoltaic DC–DC converter with a non-isolated DC–DC converter as the object of the study. Solar power conversion is accomplished by designing a simple and reliable snubber circuit and a triode auxiliary circuit and tracking the maximum power point by combining the perturbation observation method with variable step size. The snubber circuit can effectively suppress the problems of pulse spikes and oscillations, and the triode auxiliary circuit prevents the reverse current and improves the switching speed, which reduces the switching loss and combines with the perturbation observation method with variable step size for fast and stable tracking of the maximum power point. In order to verify the feasibility of the converter, a 600 W prototype is designed. The experimental results show that using the snubber circuit reduces the pulse spike by 4.2 V and the overshoot is reduced by 4.3%. The maximum conversion efficiency is increased by 0.88% with the use of the transistor-assisted circuit, and the tracking efficiency of the MPPT is still stable under cloudy conditions. The maximum conversion efficiency of the prototype is finally measured to be up to 98.12%.

Abstract Background Spinal cord ischemia–reperfusion injury (SCII) is a catastrophic event, which can cause paraplegia in severe cases. In the reperfusion stage, oxidative stress was up-regulated, which aggravated the injury and apoptosis of neurons. As the main active ingredient of garlic, diallyl trisulfide (DATS) displays strong antioxidant capacity. However, it is unknown whether DATS can protect the neurons of SCII. Materials and methods In this study, the descending aorta at the distal end of the left subclavian artery was ligated and perfused again after 14 min. Samples including blood and spinal cord (L2–L5) were taken 24 h later for morphological and biochemical examination. Results After SCII, the rats showed motor dysfunction, increase apoptosis, malondialdehyde content, mitochondrial biogenesis and dynamic balance disorder. After the application of DATS, the adenosine monophosphate activated protein kinase (AMPK) was activated, the mitochondrial damage was improved, the oxidative stress was weakened, and the neuronal damage was recovered to some extent. However, the addition of compound C significantly weakened the protective effect of DATS. Conclusion Oxidative stress caused by mitochondrial damage was one of the important mechanisms of neuronal damage in SCII. DATS could activate AMPK, stabilize mitochondrial biogenesis and dynamic balance, and reduce neuronal damage caused by oxidative stress.

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ObjectivesThis study focuses on how the sampling efficiency of a free-diving sediment trap (FST) is affected by its body posture, and uses quantitative analysis to describe the changes of the center of gravity and attitude angles. MethodsAn FST is designed which consists of a sampling module and a buoyancy control system. A 3D model of the FST is built using SolidWorks. Kinematic analysis is completed using Matlab, and the offset of the center of gravity at each moment in the whole working cycle is obtained by simulation. The principle of moments is used to derive its attitude changes caused by the offset of the center of gravity. The influence of the attitude changes on the effective collection area is then quantitatively analyzed using projective transformation. ResultsThe result shows that the offset of the center of gravity is limited to a circle with the origin of the body-fixed coordinate system as the center and a radius of \begin{document}$ 8 \times {10^{ - 3}}\;{\text{m}} $\end{document}. It is seen that the domains of x and y are \begin{document}${x_{\text{g}}} \in ( - 6 \times {10^{ - 3}}\;{\text{m}},{\text{ }}3 \times {10^{ - 3}}\;{\text{m}})$\end{document}, \begin{document}${y_{\text{g}}} \in ( - 1 \times {10^{ - 3}}\;{\text{m}},{\text{ }}7 \times {10^{ - 3}}\;{\text{m}})$\end{document}, and the domains of the attitude angles are \begin{document}$ \theta \in ( - 1.5^\circ ,{\text{ }}16.6^\circ ) $\end{document} and \begin{document}$\phi \in ( - {2.6^ \circ },{16.8^ \circ })$\end{document}. When \begin{document}$\theta = 14.7^\circ {\text{ and }}\phi {\text{ = 13}}^\circ$\end{document}, the effective collection area is reduced to 94.27% of the original value. Compared with the 100% effective collection area, it takes 1.06 times the original collection time to collect the same volume of sinking particles. ConclusionsThe results of this study can provide useful references for FST stability analysis and buoyancy regulation system design.

Grain refinement via severe plastic deformation (SPD) can induce the decomposition of Al–Zn supersaturated solid solution, resulting in strain softening rather than hardening. So far, it is very challenging to improve the strength of binary Al–Zn alloy by refining grains through SPD. Herein, a single-phase supersaturated solid solution nanostructure with relaxed grain boundaries has been successfully generated in Al–21.7 at% Zn alloy by cryogenic high-pressure torsion. Instead of softening, giant hardening is achieved. The nanocrystalline Al–Zn alloy with grain size of 15 nm has an ultrahigh yield strength of about 642 MPa.

Abstract Background Thoracic aortic aneurysm or dissections (TAADs) represent a group of life-threatening diseases. Genetic aetiology can affect the age of onset, clinical phenotype, and timing of intervention. We conducted a prospective trial to determine the prevalence of pathogenic variants in TAAD patients and to elucidate the traits related to harbouring the pathogenic variants. One hundred and one unrelated TAAD patients underwent genetic sequencing and analysis for 23 TAAD-associated genes using a targeted PCR and next-generation sequencing-based panel. Results A total of 47 variants were identified in 52 TAAD patients (51.5%), including 5 pathogenic, 1 likely pathogenic and 41 variants of uncertain significance. The pathogenic or likely pathogenic (P/LP) variants in 4 disease-causing genes were carried by 1 patient with familial and 5 patients with sporadic TAAD (5.9%). In addition to harbouring one variant causing familial TAAD, the FBN1 gene harboured half of the P/LP variants causing sporadic TAAD. Individuals with an age of onset less than 50 years or normotension had a significantly increased genetic risk. Conclusions TAAD patients with a younger age at diagnosis or normotension were more likely to carry a P/LP variant; thus, routine genetic testing will be beneficial to a better prognosis through genetically personalized care prior to acute rupture or dissection.

ABSTRACTRefining grains to sub-10 nm size is extremely difficult in pure aluminum due to its high stacking fault energy and low melting point. Herein, we experimentally demonstrate that Schwarz crystal (SC) structure with minimal interfaces constrained by coherent twin boundaries was induced in extremely fine grains (6 nm) of pure aluminum (99.995%) under extremely high shear strain via cryogenic high-pressure torsion. The SC structure exhibits an unprecedented hardness of 2.51 GPa and keeps stable up to 928 K (about 0.99 Tm).

Background: Platelet endothelial cell adhesion molecule (PECAM-1) is present in the vascular endothelium and plays important roles in various biological processes. Several recent studies have reported associations between PECAM-1 and certain subtypes of cardiovascular diseases (CVDs). However, further research is necessary to clarify the causal effects of PECAM-1 on CVDs. To determine whether PECAM-1 and CVDs are causally associated, we conducted a two-sample Mendelian randomization (TSMR) study. Methods: Single nucleotide polymorphisms (SNPs) associated with PECAM-1 were used as instrumental variants (IVs) to estimate the causal effects of PECAM-1 on CVDs. Six SNPs were included in our TSMR study. The inverse-variance weighted (IVW) method was applied in the primary analysis. To confirm the initial results, we conducted several complementary analyses and pleiotropy analyses. Results: In the IVW analysis, higher genetically predicted PECAM-1 levels were associated with lower risk of coronary artery disease (CAD) (OR, 0.835; CI, 0.757–0.92; P = 3 × 10 −4 ) and myocardial infarction (MI) (OR, 0.79; CI, 0.709–0.881; P = 2.03 × 10 −5 ). Conclusions: The findings confirmed that elevated PECAM-1 levels may decrease the risk of CAD and MI. These results confirm the causal effect of PECAM-1 on CVDs and may facilitate further investigation of the mechanism of PECAM-1 in CVD pathogenesis.

The emerging high-bandwidth services of 6G, such as high-definition video transmission and real-time interaction, have promoted the progress of the fiber optic access network industry, driving its development towards the next-generation PON with higher speed and larger system capacity. In response to the future requirements of 200 Gb/s/λ PON for both 20 km and 30 km downlink transmission scenarios, this paper proposes a Simplified Volterra Equalization (SVLE) scheme based on Nyquist PAM4 single-sideband modulation direct detection (SSBM-DD) scheme. In order to verify its advantages, the IQ-modulated Kramers–Kronig reception (KK) scheme is introduced for comparison. Simulation validation platforms for two schemes are conducted, and the performance comparison of the SVLE and KK schemes is carried out. In both, the impact of the carrier signal power ratio (CSPR) on receiver sensitivity, the influence of input optical power on power budget and receiver sensitivity, and the tolerance of receiver sensitivity to the linewidth of the DFB laser are investigated in the simulation. Finally, a comprehensive comparison of the two schemes is presented in terms of system performance, cost, and DSP complexity. In the 20 km downlink transmission scenario, the SVLE scheme outperforms the KK scheme by 4.9 dB in terms of power budget. The total number of multiplications of the SVLE scheme is 37, while that of the KK scheme is 4358. Therefore, the DSP complexity of the SVLE scheme is much lower than that of the KK scheme. The results of the comparison demonstrate that, in downlink transmission scenarios, the SVLE scheme is more suitable than the KK scheme as it exhibits a higher power budget, lower DSP complexity, and lower cost. Consequently, the proposed SVLE scheme could be a highly promising solution for future ultra-high-speed PON downlink transmission.

Abstract Background Bladder cancer is one of the most common malignant tumors of the urinary system and is associated with a poor prognosis once invasion and distant metastases occur. Epithelial-mesenchymal transition (EMT) drives metastasis and invasion in bladder cancer. Transforming growth factor β1 (TGF-β1) and stromal fibroblasts, especially cancer-associated fibroblasts (CAFs), are positive regulators of EMT in bladder cancer. However, it remains unclear how TGF-β1 mediates crosstalk between bladder cancer cells and CAFs and how it induces stromal fibroblast-mediated EMT in bladder cancer. We aimed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. Methods Primary CAFs with high expression of fibroblast activation protein (FAP) were isolated from bladder cancer tissue samples. Subsequently, different conditioned media were used to stimulate the bladder cancer cell line T24 in a co-culture system. Gene set enrichment analysis, a human cytokine antibody array, and cytological assays were performed to investigate the mechanism of TGF-β1 regulation of stromal fibroblast-mediated EMT in bladder cancer cells. Results Among the TGF-β family, TGF-β1 was the most highly expressed factor in bladder cancer tissue and primary stromal fibroblast supernatant. In the tumor microenvironment, TGF-β1 was mainly derived from stromal fibroblasts, especially CAFs. In stimulated bladder cells, stromal fibroblast-derived TGF-β1 promoted bladder cancer cell migration, invasion, and EMT. Furthermore, TGF-β1 promoted the activation of stromal fibroblasts, inducing CAF-like features, by upregulating FAP in primary normal fibroblasts and a normal fibroblast cell line. Stromal fibroblast-mediated EMT was induced in bladder cancer cells by TGF-β1/FAP. Versican (VCAN), a downstream molecule of FAP, plays an essential role in TGF-β1/FAP axis-induced EMT in bladder cancer cells. VCAN may also function through the PI3K/AKT1 signaling pathway. Conclusions TGF-β1 is a critical mediator of crosstalk between stromal fibroblasts and bladder cancer cells. We revealed a new mechanism whereby TGF-β1 dominated stromal fibroblast-mediated EMT of bladder cancer cells via the FAP/VCAN axis and identified potential biomarkers (FAP, VCAN, N-cadherin, and Vimentin) of bladder cancer. These results enhance our understanding of bladder cancer invasion and metastasis and provide potential strategies for diagnosis, treatment, and prognosis.

Abstract Myocardial infarction (MI) is a major cause of mortality worldwide. The major limitation of regenerative therapy for MI is poor cardiac retention of therapeutics, which results from an inefficient vascular network and poor targeting ability. In this study, a two‐layer intrinsically magnetic epicardial patch (MagPatch) prepared by 3D printing with biocompatible materials like poly (glycerol sebacate) (PGS) is designed, poly (ε‐caprolactone) (PCL), and NdFeB. The two‐layer structure ensured that the MagPatch multifariously utilized the magnetic force for rapid vascular reconstruction and targeted drug delivery. MagPatch accumulates superparamagnetic iron oxide (SPION)‐labelled endothelial cells, instantly forming a ready‐implanted organization, and rapidly reconstructs a vascular network anastomosed with the host. In addition, the prefabricated vascular network within the MagPatch allowed for the efficient accumulation of SPION‐labelled therapeutics, amplifying the therapeutic effects of cardiac repair. This study defined an extendable therapeutic platform for vascularization‐based targeted drug delivery that is expected to assist in the progress of regenerative therapies in clinical applications.

Corneal neovascularization (CoNV)-induced blindness is an enduring and challenging condition with limited management options. Small interfering RNA (siRNA) is a promising strategy for preventing CoNV. This study reported a new strategy using siVEGFA to silence vascular endothelial growth factor A (VEGFA) for CoNV treatment. To improve the efficacy of siVEGFA delivery, a pH-sensitive polycationic mPEG2k-PAMA30-P(DEA29-D5A29) (TPPA) was fabricated. TPPA/siVEGFA polyplexes enter cells via clathrin-mediated endocytosis, resulting in higher cellular uptake efficiency and comparable silencing efficiency than that of Lipofectamine 2000 in vitro. Hemolytic assays verified that TPPA safe in normal physiological environments (pH 7.4) but can easily destroy membranes in acidic mature endosomes (pH 4.0). Studies on the distribution of TPPA in vivo showed that it could prolong the retention time of siVEGFA and promote its penetration in the cornea. In a mouse model induced by alkali burn, TPPA efficiently delivered siVEGFA to the lesion site and achieved VEGFA silencing efficiency. Importantly, the inhibitory effect of TPPA/siVEGFA on CoNV was comparable to that of the anti-VEGF drug ranibizumab. Delivering siRNA using pH-sensitive polycations to the ocular environment provides a new strategy to efficiently inhibit CoNV.

The skeletal system, which contains bones, joints, tendons, ligaments and other elements, plays a wide variety of roles in body shaping, support and movement, protection of internal organs, production of blood cells and regulation of calcium and phosphate metabolism. The prevalence of skeletal diseases and disorders, such as osteoporosis and bone fracture, osteoarthritis, rheumatoid arthritis, and intervertebral disc degeneration, increases with age, causing pain and loss of mobility and creating a huge social and economic burden globally. Focal adhesions (FAs) are macromolecular assemblies that are composed of the extracellular matrix (ECM), integrins, intracellular cytoskeleton and other proteins, including kindlin, talin, vinculin, paxillin, pinch, Src, focal adhesion kinase (FAK) and integrin-linked protein kinase (ILK) and other proteins. FA acts as a mechanical linkage connecting the ECM and cytoskeleton and plays a key role in mediating cell–environment communications and modulates important processes, such as cell attachment, spreading, migration, differentiation and mechanotransduction, in different cells in skeletal system by impacting distinct outside-in and inside-out signaling pathways. This review aims to integrate the up-to-date knowledge of the roles of FA proteins in the health and disease of skeletal system and focuses on the specific molecular mechanisms and underlying therapeutic targets for skeletal diseases.

Abstract Osteoarthritis (OA) is a chronic degenerative joint disorder that leads to disability and affects more than 500 million population worldwide. OA was believed to be caused by the wearing and tearing of articular cartilage, but it is now more commonly referred to as a chronic whole-joint disorder that is initiated with biochemical and cellular alterations in the synovial joint tissues, which leads to the histological and structural changes of the joint and ends up with the whole tissue dysfunction. Currently, there is no cure for OA, partly due to a lack of comprehensive understanding of the pathological mechanism of the initiation and progression of the disease. Therefore, a better understanding of pathological signaling pathways and key molecules involved in OA pathogenesis is crucial for therapeutic target design and drug development. In this review, we first summarize the epidemiology of OA, including its prevalence, incidence and burdens, and OA risk factors. We then focus on the roles and regulation of the pathological signaling pathways, such as Wnt/β-catenin, NF-κB, focal adhesion, HIFs, TGFβ/ΒΜP and FGF signaling pathways, and key regulators AMPK, mTOR, and RUNX2 in the onset and development of OA. In addition, the roles of factors associated with OA, including MMPs, ADAMTS/ADAMs, and PRG4, are discussed in detail. Finally, we provide updates on the current clinical therapies and clinical trials of biological treatments and drugs for OA. Research advances in basic knowledge of articular cartilage biology and OA pathogenesis will have a significant impact and translational value in developing OA therapeutic strategies.

Background: Inflammation plays a crucial role in the initiation and progression of cerebral ischemia-reperfusion injury and has gained much scholarly interest. However, this research field has not yet been examined bibliometrically. We intended to utilize bibliometrics to highlight the research hotspots and developing trends of inflammation in cerebral ischemia-reperfusion injury and provide an objective foundation for basic and clinical research. Methods: The Web of Science database was combed for articles relating to inflammation in cerebral ischemia-reperfusion injury from 2002 to 2022. CiteSpace and VOSviewer were used to visualize and analyze data pertaining to countries, institutions, journals, authors, references, and keywords. Results: There were a total of 1183 papers included in this analysis. Every year, the number of articles on inflammation research in cerebral ischemia-reperfusion injury increases. Brain Research and Stroke are, respectively, the most published and most cited academic journals in this discipline. We identified 646 scholars, with Zhao,jing producing the most publications and Longa EZ receiving the most citations. Inflammation, stroke, oxidative stress, and apoptosis were found to be the most frequently used terms after analysis. The main areas of current research on inflammation in cerebral ischemia-reperfusion injury involve non-coding rna, myeloperoxidase, Toll-like receptor-4, and neurotrophic factor. Conclusion: The importance of inflammation in cerebral ischemia-reperfusion injury diseases has been widely recognized. After decades of constant research, we are not yet sufficiently knowledgeable in this sector.Microglial activation, signaling pathway, protection and pathophysiology will be the new hot and new direction in this research field in the future.

Abstract The high‐temperature molten salt pump (MSP) is the core equipment of the thermal storage system for concentrating solar power plants, which circulates the molten salt of the thermal storage medium. This study employs numerical simulation of a two‐stage MSP with a storage tank to find the correlation between pressure pulsations and the evolutions of vortical structures based on renormalization group k‐ε turbulence model. It is shown that rotor/stator interaction is the most significant excitation source of pressure pulsations with the prominent excitations being the diffuser passing frequency (fDPF) in the impeller and the blade passing frequency (fBPF). Furthermore, Q‐criterion is employed to capture the periodic shedding vortexes with a frequency of about 3fR at the suction surface and the trailing edge in diffusers. Impinging vortex and shedding vortex with the frequency 6fR on the leading edge of the diffuser is captured. The vortex shedding characteristics are significantly different under various conditions, and the separation vortexes appear at the leading edge of pressure surface in the diffusers at higher flow rates. Finally, it is obvious that the excited components and their magnitudes in the pressure spectrum are closely associated with the unsteady vortical structures within the model pump.

Endplate osteochondritis is considered one of the major causes of intervertebral disc degeneration (IVDD) and low back pain. Menopausal women have a higher rate of endplate cartilage degeneration than similarly aged men, but the related mechanisms are still unclear. Subchondral bone changes, mainly mediated by osteoblasts and osteoclasts, are considered an important reason for the degeneration of cartilage. This work explored the role of osteoclasts in endplate cartilage degeneration, as well as its underlying mechanisms. A rat ovariectomy (OVX) model was used to induce estrogen deficiency. Our experiments indicated that OVX significantly promoted osteoclastogenesis and anabolism and catabolism changes in endplate chondrocytes. OVX osteoclasts cause an imbalance between anabolism and catabolism in endplate chondrocytes, as shown by a decrease in anabolic markers such as Aggrecan and Collagen II, and an increase in catabolic markers such as a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5) and matrix metalloproteinases (MMP13). Osteoclasts were also confirmed in this study to be able to secrete HtrA serine peptidase 1 (HTRA1), which resulted in increased catabolism in endplate chondrocytes through the NF-κB pathway under estrogen deficiency. This study demonstrated the involvement and mechanism of osteoclasts in the anabolism and catabolism changes of endplate cartilage under estrogen deficiency, and proposed a new strategy for the treatment of endplate osteochondritis and IVDD by targeting HTRA1.

Abstract CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of “CIC-rearranged” sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.

Photodynamic therapy (PDT) is an important technique to deal with drug-resistant bacterial infections in the post-antibiotic era. However, the hypoxic environment in intractable infections such as refractory keratitis and periodontitis, makes PDT more difficult. In this work, spontaneous oxygen-producing cyanobacteria were used as the carrier of photosensitizer (Ce6), and ultrasmall Cu5.4O nanoparticles (Cu5.4O USNPs) with catalase activity for infection and inflammation elimination and rapid tissue repair (CeCycn-Cu5.4O). The loading of Ce6 and Cu5.4O USNPs onto cyanobacteria surface were confirmed by transmission electron microscopy, nano particle size analyzer, scanning electron microscopy. In vitro sterilization and biofilm removal experiments demonstrated that the restriction of hypoxic environment to PDT was significantly alleviated due to the oxygen production of cyanobacteria. Under laser irradiation, the close transfer of energy photons to oxygen produced by cyanobacteria reduced more than 90% of Ce6 dosages (660 nm, 200 mW/cm2, 2 min). It is worth mentioning that both rapid sterilization through PDT and long-term oxidized free radicals elimination were achieved by adjusting the ratio of Ce6 and Cu5.4O USNPs. Both periodontitis and refractory keratitis animal models proved the excellent self-oxygenation enhanced antibacterial property and promotion of tissue repair.

BackgroundThe imbalance of gut microbiota (GM) is associated with a higher risk of thrombosis in patients with atrial fibrillation (AF). Oral anticoagulants (OACs) have been found to significantly reduce the risk of thromboembolism and increase the risk of bleeding. However, the OAC-induced alterations in gut microbiota in patients with AF remain elusive.MethodsIn this study, the microbial composition in 42 AF patients who received long-term OAC treatment (AF-OAC group), 47 AF patients who did not (AF group), and 40 volunteers with the risk of AF (control group) were analyzed by 16S rRNA gene sequencing of fecal bacterial DNA. The metagenomic functional prediction of major bacterial taxa was performed using the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) software package.ResultsThe gut microbiota differed between the AF-OAC and AF groups. The abundance of Bifidobacterium and Lactobacillus decreased in the two disease groups at the genus level, but OACs treatment mitigated the decreasing tendency and increased beneficial bacterial genera, such as Megamonas. In addition, OACs reduced the abundance of pro-inflammatory taxa on the genus Ruminococcus but increased certain potential pathogenic taxa, such as genera Streptococcus, Escherichia-Shigella, and Klebsiella. The Subgroup Linear discriminant analysis effect size (LEfSe) analyses revealed that Bacteroidetes, Brucella, and Ochrobactrum were more abundant in the anticoagulated bleeding AF patients, Akkermansia and Faecalibacterium were more abundant in the non-anticoagulated-bleeding-AF patients. The neutrophil-to-lymphocyte ratio (NLR) was lower in the AF-OAC group compared with the AF group (P < 0.05). Ruminococcus was positively correlated with the NLR and negatively correlated with the CHA2DS2-VASc score (P < 0.05), and the OACs-enriched species (Megamonas and Actinobacteria) was positively correlated with the prothrombin time (PT) (P < 0.05). Ruminococcus and Roseburia were negatively associated with bleeding events (P < 0.05).ConclusionsOur study suggested that OACs might benefit AF patients by reducing the inflammatory response and modulating the composition and abundance of gut microbiota. In particular, OACs increased the abundance of some gut microbiota involved in bleeding and gastrointestinal dysfunction indicating that the exogenous supplementation with Faecalibacterium and Akkermansia might be a prophylactic strategy for AF-OAC patients to lower the risk of bleeding after anticoagulation.

Abstract Background Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn’t been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo. Methods LPS (10 µg/ml) and IL-1β (10 ng/ml) were employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs). The effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD. Results We found that TOD inhibited the expression of inflammatory and catabolic mediators (IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in inflammatory chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of osteoclast marker genes. Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis via inhibiting the activation of NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated cartilage erosion and inhibited bone resorption. Conclusions These results showed that TOD can be adopted as a potential therapeutic agent for OA.

Here, the authors show that expression of kindlin-2 is increased in patients with nonalcoholic fatty liver disease (NAFLD). In mouse models, specific deletion of kindlin-2 in liver ameliorates, while its overexpression exacerbates, NAFLD by modulating Foxo1 in hepatocytes.

Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss. Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.

Cartilage-targeting delivery of therapeutic agents is still an effective strategy for osteoarthritis (OA) therapy. Recently, scavenging for reactive oxygen species (ROS) and activating autophagy have been increasingly reported to treat OA effectively. In this study, we designed, for the first time, a dual-drug delivery system based on metal organic framework (MOF)-decorated mesoporous polydopamine (MPDA) which composed of rapamycin (Rap) loaded into the mesopores and bilirubin (Br) loaded onto the shell of MOF. The collagen II-targeting peptide (WYRGRL) was then conjugated on the surface of above nanocarrier to develop a cartilage-targeting dual-drug delivery nanoplatform (RB@MPMW). Our results indicated the sequential release of two agents from RB@MPMW could be achieved via near-infrared (NIR) laser irritation. Briefly, the rapid release of Br from the MOF shell exhibited excellent ROS scavenging ability and anti-apoptosis effects, however responsively reduced autophagy activity, to a certain extent. Meanwhile, following the NIR irradiation, Rap was rapidly released from MPDA core and further enhanced autophagy activation and chondrocyte protection. RB@MPMW continuously phosphorylated AMPK and further rescued mitochondrial energy metabolism of chondrocytes following IL-1β stimulation via activating SIRT1-PGC-1α signaling pathway. Additionally, the cartilage-targeting property of peptide-modified nanocarrier could be monitored via Magnetic Resonance (MR) and IVIS imaging. More significantly, RB@MPMW effectively delayed cartilage degeneration in ACLT rat model. Overall, our findings indicated that the as-prepared dual-drug delivery nanoplatform exerted potent anti-inflammation and anti-apoptotic effects, rescued energy metabolism of chondrocytes in vitro and prevented cartilage degeneration in vivo, which thereby showed positive performance for OA therapy.

BackgroundPulmonary arterial hypertension (PAH) is a devastating cardio-pulmonary vascular disease in which chronic elevated pulmonary arterial pressure and pulmonary vascular remodeling lead to right ventricular failure and premature death. However, the exact molecular mechanism causing PAH remains unclear.MethodsRNA sequencing was used to analyze the transcriptional profiling of controls and rats treated with monocrotaline (MCT) for 1, 2, 3, and 4 weeks. Weighted gene co-expression network analysis (WGCNA) was employed to identify the key modules associated with the severity of PAH. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to explore the potential biological processes and pathways of key modules. Real-time PCR and western blot analysis were used to validate the gene expression. The hub genes were validated by an independent dataset obtained from the Gene Expression Omnibus database.ResultsA total of 26 gene modules were identified by WGCNA. Of these modules, two modules showed the highest correlation with the severity of PAH and were recognized as the key modules. GO analysis of key modules showed the dysregulated inflammation and immunity, particularly B-cell-mediated humoral immunity in MCT-induced PAH. KEGG pathway analysis showed the significant enrichment of the B-cell receptor signaling pathway in the key modules. Pathview analysis revealed the dysregulation of the B-cell receptor signaling pathway in detail. Moreover, a series of humoral immune response-associated genes, such as BTK, BAFFR, and TNFSF4, were found to be differentially expressed in PAH. Additionally, five genes, including BANK1, FOXF1, TLE1, CLEC4A1, and CLEC4A3, were identified and validated as the hub genes.ConclusionThis study identified the dysregulated B-cell receptor signaling pathway, as well as novel genes associated with humoral immune response in MCT-induced PAH, thereby providing a novel insight into the molecular mechanisms underlying inflammation and immunity and therapeutic targets for PAH.

The neutron reflector is a general component in the nuclear reactor design. The original SMART reactor design used light water as a reflector surrounding the fission zone. However, this design has low uranium utilization rates in the outermost fuel assemblies, so poor fuel economy. In this study, six potential reflector materials, i.e., heavy water, graphite, beryllium metal and its oxide, steel, and tungsten carbide has been investigated as the neutron reflector for SMART. Firstly, the materials’ cross-sections of neutron scattering and (n, 2n) reactions have been cited from ENDF data libraries and analyzed. This analysis found for the neutrons with energy lower than 1 eV, the 9Be atom has six barn elastic scattering cross-sections, and the 9Be(n, 2n)8Be reaction can compensate for neutron leakage. Then, OpenMC is employed to simulate the effect of these reflector materials on power distribution and depletion. Compared with the original design, the beryllium oxide can improve the initial keff from 1.22906 to 1.27446, flat the radial direction power distribution. The analysis on both scales agrees that the beryllium oxide is an efficient neutron reflector choice with good material properties.

SMART is an integral small pressurized water nuclear reactor design with a rated power output of 100 MWe from 330 MWth, but it needs a higher power output for the United Kingdom energy market. This study applies Monte Carlo code OpenMC to build a full-core model and innovatively adjust the simulation coefficients to approach the reactor operating conditions. The analysis results point out the reasonable optimization’s technical direction. The model’s sensitivity to ENDF and JEFF nuclear data libraries and spatial division is tested and verified. Then it performs a series of simulations to obtain the core’s neutronic parameters, such as neutron energy and spatial distributions, effective neutron multiplication factor keff and its variation versus depletion. The analysis found that the initially designed core’s keff is 1.22906, and the temperature reactivity defect is 11612 pcm. In 1129 full-power operating days, the keff will decrease to 0.99126, and the reactor depletes 8.524 × 1026235U atoms. However, the outermost fuel assemblies’ 235U depletion rate is lower than 45% in this extended refuelling cycle, and their ending enrichment is higher than 2.4%. That means the fuel economy of the original design’s two-batch refuelling scheme core layout is insufficient. Improving the thermal neutron fluence in these assemblies may optimize the SMART power performance effectively.

Clear cell renal cell carcinoma (ccRCC) is one of the most prevalent cancers, and PANoptosis is a distinct, inflammatory-programmed cell death regulated by the PANoptosome. The essential regulators of cancer occurrence and progression are microRNAs (miRNAs). However, the potential function of PANoptosis-related microRNAs (PRMs) in ccRCC remains obscure. This study retrieved ccRCC samples from The Cancer Genome Atlas database and three Gene Expression Omnibus datasets. PRMs were recognized based on previous reports in the scientific literature. Regression analyses were used to identify the prognosis PRMs and construct a PANoptosis-related miRNA prognostic signature based on the risk score. We discovered that high-risk patients had poorer survival prognoses and were significantly linked to high-grade and advanced-stage tumors, using a variety of R software packages and web analysis tools. Furthermore, we demonstrated that the low-risk group had significant changes in their metabolic pathways. In contrast, the high-risk group was characterized by high immune cell infiltration, immune checkpoint expression, and low half-maximum inhibition concentration (IC50) values of chemotherapeutic agents. This suggests that high-risk patients may benefit more from immunotherapy and chemotherapy. In conclusion, we constructed a PANoptosis-related microRNA signature and revealed its potential significance in clinicopathological features and tumor immunity, thereby providing new precise treatment strategies.

This paper combines the piecewise Cubic Hermite (CH) interpolation algorithm and the weighted least square support vector machine (WLS-SVM) to improve identification accuracy for marine crafts built based on the characteristic model. The characteristic model is first used to describe the heading dynamics of marine crafts and is a superior model to the traditional response model in both accuracy and complexity. Especially in order to improve identification accuracy, a CH-based data preprocessing strategy is utilized to densify and smooth data for further accurate identification. Subsequently, the combination of the linear kernel function and the Gaussian kernel function is introduced in the conventional WLS-SVM method, which renders global and local performance improvements compared with the conventional WLS-SVM method. Finally, informative maneuvers composed of Zigzag and Sine are carried out to test the performance of the improved identification method. Compared to the conventional LS-SVM method based on the response model, the root mean square error of the proposed CH-MK-WLS-SVM method based on the characteristic model is reduced by an order of magnitude in the presence of sensor noise.

Abstract Background Few studies have evaluated the clinical presentation, management, and outcomes of patients with end-stage renal disease (ESRD) presenting with acute aortic dissection (AAD) in real-world clinical practice. Thus, this study investigated the clinical characteristics, management, and outcomes of AAD patients with ESRD. Methods A total of 217 patients were included. We evaluated the differences in the clinical features, management, and in-hospital outcomes of patients with and without a history of ESRD presenting with AAD. Results A history of ESRD was present in 71 of 217 patients. Patients with ESRD had atypical clinical manifestations (p 0.05). Multivariate analysis identified Type A aortic dissection as an independent predictor of in-hospital mortality among patients without ESRD (OR, 13.68; 95% CI, 1.92 to 98.90; P = 0.006). Conclusions This study highlights differences in the clinical characteristics, management, and outcomes of AAD patients with ESRD. These patients usually have atypical symptoms and more comorbid conditions and are managed more conservatively. However, these patients have no in-hospital survival disadvantage over those without ESRD. Further studies are needed to better understand and optimize care for patients with ESRD presenting with AAD.

Abstract Fibrotic diseases remain a substantial health burden with few therapeutic approaches. A hallmark of fibrosis is the aberrant activation and accumulation of myofibroblasts, which is caused by excessive profibrotic cytokines. Conventional anticytokine therapies fail to undergo clinical trials, as simply blocking a single or several antifibrotic cytokines cannot abrogate the profibrotic microenvironment. Here, biomimetic nanoparticles based on autologous skin fibroblasts are customized as decoys to neutralize multiple fibroblast‐targeted cytokines. By fusing the skin fibroblast membrane onto poly(lactic‐co‐glycolic) acid cores, these nanoparticles, termed fibroblast membrane‐camouflaged nanoparticles (FNPs), are shown to effectively scavenge various profibrotic cytokines, including transforming growth factor‐β, interleukin (IL)‐11, IL‐13, and IL‐17, thereby modulating the profibrotic microenvironment. FNPs are sequentially prepared into multiple formulations for different administration routines. As a proof‐of‐concept, in three independent animal models with various organ fibrosis (lung fibrosis, liver fibrosis, and heart fibrosis), FNPs effectively reduce the accumulation of myofibroblasts, and the formation of fibrotic tissue, concomitantly restoring organ function and indicating that FNPs are a potential broad‐spectrum therapy for fibrosis management.

Abstract Vascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE−/− mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.

Homocysteine, inversely related to folate and vitamin B12, is an independent risk factor for several age-related disorders. However, little is known about the association of homocysteine and related vitamins with osteoarthritis (OA). This study aimed to elucidate the potential causal effects of homocysteine, folate, and vitamin B12 on site- and gender-specific OA by applying the two-sample Mendelian randomization (MR) approach. Genetically predicted homocysteine showed adverse effects on overall OA (95% confidence interval (CI): 1.044–1.155), knee OA (95% CI: 1.000–1.167), hip OA (95% CI: 1.057–1.297), and spine OA (95% CI: 1.017–1.216). Genetically predicted folate showed protective effects on overall OA (95% CI: 0.783–0.961) and spine OA (95% CI: 0.609–0.954). Folate (95% CI: 0.887–1.004) and vitamin B12 (95% CI: 0.886–1.009) showed a protective trend against knee OA. The patterns of associations were site and gender specific. In conclusion, homocysteine had adverse effects on OA, especially on OA at weight-bearing joints and in females. Folate and vitamin B12 had protective effects on OA. Homocysteine-lowering interventions may be a potential option in the treatment and prevention of OA.

Pandanus amaryllifolius Roxb. is a special tropical spice crop resource with broad development prospects. It is widely cultivated under a Hevea brasiliensis (Willd. ex A. Juss.) Muell. Arg. canopy to improve the comprehensive benefits to Hevea brasiliensis plantations in Hainan Provence, China. However, the effects of intercropping with Hevea brasiliensis on the component number and relative contents of volatile substances in different categories in the Pandanus amaryllifolius leaves are still unknown. Therefore, a Hevea brasiliensis and Pandanus amaryllifolius intercropping experiment was set up to clarify the differences between several cultivated patterns on volatile substances in the Pandanus amaryllifolius leaves, and the key regulatory factors of volatile substances. The results showed that the soil pH was significantly decreased, while soil bulk density, alkali-hydrolyzable nitrogen and available phosphorus contents were significantly increased under the intercropping pattern. The component numbers of esters in volatile substances were increased by 6.20%, while the component numbers of ketones were decreased by 4.26% under the intercropping pattern. Compared with the Pandanus amaryllifolius monoculture, the relative contents of pyrroles, esters and furanones were significantly increased by 8.83%, 2.30% and 8.27%, respectively, while the relative contents of ketones, furans and hydrocarbons were decreased by 1.01%, 10.55% and 9.16% under the intercropping pattern, respectively. The relative contents of pyrroles, esters, furanones, ketones, furans and hydrocarbons were associated with changes in soil pH, soil available phosphorus content and air temperature. The results indicated that the reduction in soil pH and enhancement in soil-available phosphorus may be the main reasons for promoting the relative content of pyrroles and reducing the relative content of hydrocarbons under an intercropping pattern. Overall, Hevea brasiliensis intercropping with Pandanus amaryllifolius could not only improve soil properties, but also significantly increase the relative contents of the main volatile substances in Pandanus amaryllifolius leaves, which could provide a theoretical basis for the application and promotion of high-quality production patterns of Pandanus amaryllifolius.

The zinc finger protein of the cerebellum (ZIC) family comprises five members (ZIC1-5), homologous with the odd-paired (OPA) gene in Drosophila melanogila. These transcription factors contain five Cys2His zinc finger domains, constituting one of the most abundant transcription factor families in human cells. ZIC proteins significantly contribute to transcriptional regulation and chromatin remodeling. As a member of the ZIC family, ZIC5 is essential for animal growth and development. Numerous studies have investigated the connection between ZIC proteins and cancer as well as tumor metastases in recent years. Many studies have found that within tumor tissues, the transcription and translation processes increase the expression of ZIC5 which is linked to tumor aggressiveness. This review aims to provide an objective summary of the impact of ZIC5 on tumor metastasis and consider the potential application of ZIC5 targets in both tumor therapy and the early detection of cancer. [ABSTRACT FROM AUTHOR]