FGF, Mechanism of Action, Role in Parkinson’s Disease, and Therapeutics

Parkinson’s disease (PD) is a neurodegenerative disease associated with severe disability and adverse effects on life quality. In PD, motor dysfunction can occur, such as quiescence, muscle stiffness, and postural instability. PD is also associated with autonomic nervous dysfunction, sleep disorders, psychiatric symptoms, and other non-motor symptoms. Degeneration of dopaminergic neurons in the substantia nigra compact (SNPC), Lewy body, and neuroinflammation are the main pathological features of PD. The death or dysfunction of dopaminergic neurons in the dense part of the substantia nigra leads to dopamine deficiency in the basal ganglia and motor dysfunction. The formation of the Lewy body is associated with the misfolding of α-synuclein, which becomes insoluble and abnormally aggregated. Astrocytes and microglia mainly cause neuroinflammation, and the activation of a variety of pro-inflammatory transcription factors and regulatory proteins leads to the degeneration of dopaminergic neurons. At present, PD is mainly treated with drugs that increase dopamine concentration or directly stimulate dopamine receptors. Fibroblast growth factor (FGF) is a family of cellular signaling proteins strongly associated with neurodegenerative diseases such as PD. FGF and its receptor (FGFR) play an essential role in the development and maintenance of the nervous system as well as in neuroinflammation and have been shown to improve the survival rate of dopaminergic neurons. This paper summarized the mechanism of FGF and its receptors in the pathological process of PD and related signaling pathways, involving the development and protection of dopaminergic neurons in SNPC, α-synuclein aggregation, mitochondrial dysfunction, and neuroinflammation. It provides a reference for developing drugs to slow down or prevent the potential of PD

A novel flow-vector generation approach for malicious traffic detection

Malicious traffic detection is one of the most important parts of cyber security. The approaches of using the flow as the detection object are recognized as effective. Benefiting from the development of deep learning techniques, raw traffic can be directly used as a feature to detect malicious traffic. Most existing work usually converts raw traffic into images or long sequences to express a flow and then uses deep learning technology to extract features and classify them, but the generated features contain much redundant or even useless information, especially for encrypted traffic. The packet header field contains most of the packet characteristics except the payload content, and it is also an important element of the flow. In this paper, we only use the fields of the packet header in the raw traffic to construct the characteristic representation of the traffic and propose a novel flow-vector generation approach for malicious traffic detection. The preprocessed header fields are embedded as field vectors, and then a two-layer attention network is used to progressively generate the packet vectors and the flow vector containing context information. The flow vector is regarded as the abstraction of the raw traffic and is used to classify. The experiment results illustrate that the accuracy rate can reach up to 99.48% in the binary classification task and the average of AUC-ROC can reach 0.9988 in the multi-classification task

The Beneficial Effects of Bisphosphonate-enoxacin on Cortical Bone Mass and Strength in Ovariectomized Rats

Osteoporosis is a major age-related bone disease characterized by low bone mineral density and a high risk of fractures. Bisphosphonates are considered as effective agents treating osteoporosis. However, long-term use of bisphosphonates is associated with some serious side effects, which limits the widespread clinical use of bisphosphonates. Here, we demonstrate a novel type of bone-targeting anti-resorptive agent, bisphosphonate-enoxacin (BE). In this study, ovariectomized rat model was established and treated with PBS, zoledronate (50 μg/kg) and different dose of BE (5 mg/kg and 10 mg/kg), respectively. The rats subjected to sham-operation and PBS treatment were considered as control group. Then, micro-computed tomography scanning, biomechanical tests, nano-indentation test and Raman analysis were used to compare the effects of zoledronate and BE on cortical bone mass, strength, and composition in ovariectomized rats. We found that both zoledronate and BE were beneficial to cortical bone strength. Three-point bending and nano-indentation tests showed that zoledronate- and BE-treated groups had superior general and local biomechanical properties compared to the ovariectomized groups. Interestingly, it seemed that BE-treated group got a better biomechanical property than the zoledronate-treated group. Also, BE-treated group showed significantly increased proteoglycan content compared with the zoledronate-treated group. We hypothesized that the increased bone strength and biomechanical properties was due to altered bone composition after treatment with BE. BE, a new bone-targeting agent, may be considered a more suitable anti-resorptive agent to treat osteoporosis and other bone diseases associated with decreased bone mass

Targeting Anion Exchange of Osteoclast, a New Strategy for Preventing Wear Particles Induced- Osteolysis

Joint replacement is essential for the treatment of serious joint disease. However, prosthetic failure remains an important clinical issue, with periprosthesis osteolysis (PO), caused by osteoclastic bone resorption induced by wear particles, being the leading cause of failure. Nuclear factor of activated T cells c1 (NFATc1) appears to play an important role in wear particle-induced osteoclastogenesis, with bicarbonate/chloride exchanger, solute carrier family 4, anion exchanger, member 2, (SLC4A2) being upregulated during osteoclastogenesis in an NFATc1-dependent manner. Anion exchange mediated by SLC4A2 in osteoclasts could affect the bone resorption activity by regulating pHi. This study investigated the role and mechanism of SLC4A2 in wear particle-induced osteoclast differentiation and function in vitro. The use of 4, 4′-diisothiocyano-2,2′-stilbenedisulfonic acid (DIDS), an anion exchange inhibitor, suppressed wear particle-induced PO in vivo. Furthermore, controlled release of DIDS from chitosan microspheres can strengthen the PO therapy effect. Therefore, anion exchange mediated by osteoclastic SLC4A2 may be a potential therapeutic target for the treatment of aseptic loosening of artificial joints

Oxygen-deficient SnO2 nanoparticles with ultrathin carbon shell for efficient electrocatalytic N2 reduction

For high-efficiency NH3 synthesis via ambient-condition electrohydrogenation of inert N2, it is pivotal to ingeniously design an active electrocatalyst with multiple features of abundant surfacial deficiency, good conductivity and large surface area. Here, oxygen-deficient SnO2 nanoparticles encapsulated by ultrathin carbon layer (d-SnO2@C) are developed by hydrothermal deposition coupled with annealing process, as promising catalysts for ambient electrocatalytic N2 reduction. d-SnO2@C exhibits high activity and excellent selectivity for electrocatalytic conversion of N2 to NH3 in acidic electrolytes, with Faradic efficiency as high as 12.7% at ???0.15 V versus the reversible hydrogen electrode (RHE) and large NH3 yield rate of 16.68 ??g h???1 mgcat???1 at ???0.25 V vs. RHE in 0.1 mol L???1 HCl. Benefiting from the structural superiority of enhanced charge transfer efficiency and optimized surface states, d-SnO2@C also achieves excellent long-term stability

Identification of Key Gene Networks Associated With Cell Wall Components Leading to Flesh Firmness in Watermelon

Flesh firmness of watermelon is an important quality trait for commercial fruit values, including fruit storability, transportability, and shelf life. To date, knowledge of the gene networks underlying this trait is still limited. Herein, we used weighted genes co-expression network analysis (WGCNA) based on correlation and the association of phenotypic data (cell wall contents) with significantly differentially expressed genes between two materials, a near isogeneic line “HWF” (with high average flesh firmness) and inbred line “203Z” (with low average flesh firmness), to identify the gene networks responsible for changes in fruit flesh firmness. We identified three gene modules harboring 354 genes; these gene modules demonstrated significant correlation with water-soluble pectin, cellulose, hemicellulose, and protopectin. Based on intramodular significance, eight genes involved in cell wall biosynthesis and ethylene pathway are identified as hub genes within these modules. Among these genes, two genes, Cla012351 (Cellulose synthase) and Cla004251 (Pectinesterase), were significantly correlated with cellulose (r2 = 0.83) and protopectin (r2 = 0.81); three genes, Cla004120 (ERF1), Cla009966 (Cellulose synthase), and Cla006648 (Galactosyltransferase), had a significant correlation with water-soluble pectin (r2 = 0.91), cellulose (r2 = 0.9), and protopectin (r2 = 0.92); and three genes, Cla007092 (ERF2a), Cla004119 (probable glycosyltransferase), and Cla018816 (Xyloglucan endotransglucosylase/hydrolase), were correlated with hemicellulose (r2 = 0.85), cellulose (r2 = 0.8), and protopectin (r2 = 0.8). This study generated important insights of biosynthesis of a cell wall structure and ethylene signaling transduction pathway, the mechanism controlling the flesh firmness changes in watermelon, which provide a significant source to accelerate future functional analysis in watermelon to facilitate crop improvement

Biomechanical evaluation of a novel individualized zero-profile cage for anterior cervical discectomy and fusion: a finite element analysis

Introduction: Anterior cervical discectomy and fusion (ACDF) is a standard procedure for treating symptomatic cervical degenerative disease. The cage and plate constructs (CPCs) are widely employed in ACDF to maintain spinal stability and to provide immediate support. However, several instrument-related complications such as dysphagia, cage subsidence, and adjacent segment degeneration have been reported in the previous literature. This study aimed to design a novel individualized zero-profile (NIZP) cage and evaluate its potential to enhance the biomechanical performance between the instrument and the cervical spine.Methods: The intact finite element models of C3-C7 were constructed and validated. A NIZP cage was designed based on the anatomical parameters of the subject’s C5/6. The ACDF procedure was simulated and the CPCs and NIZP cage were implanted separately. The range of motion (ROM), intradiscal pressure (IDP), and peak von Mises stresses of annulus fibrosus were compared between the two surgical models after ACDF under four motion conditions. Additionally, the biomechanical performance of the CPCs and NIZP cage were evaluated.Results: Compared with the intact model, the ROM of the surgical segment was significantly decreased for both surgical models under four motion conditions. Additionally, there was an increase in IDP and peak von Mises stress of annulus fibrosus in the adjacent segment. The NIZP cage had a more subtle impact on postoperative IDP and peak von Mises stress of annulus fibrosus in adjacent segments compared to CPCs. Meanwhile, the peak von Mises stresses of the NIZP cage were reduced by 90.0–120.0 MPa, and the average von Mises stresses were reduced by 12.61–17.56 MPa under different motion conditions. Regarding the fixation screws, the peak von Mises stresses in the screws of the NIZP cage increased by 10.0–40.0 MPa and the average von Mises stresses increased by 2.37–10.10 MPa.Conclusion: The NIZP cage could effectively reconstruct spinal stability in ACDF procedure by finite element study. Compared with the CPCs, the NIZP cage had better biomechanical performance, with a lower stress distribution on the cage and a more moderate effect on the adjacent segmental discs. Therefore, the NIZP cage could prevent postoperative dysphagia as well as decrease the risk of subsidence and adjacent disc degeneration following ACDF. In addition, this study could serve as a valuable reference for the development of personalized instruments

Coagulant Effects and Mechanism of Schefflera heptaphylla (L.) Frodin

Schefflera heptaphylla (L.) Frodin, are commonly used in anti-inflammatory, analgesic, traumatic bleeding and hemostasisas. In this paper, the coagulation effect of the ethanol extract (Set), ethyl acetate phase (Sea) and n-butanol phase (Sbu) was evaluated by prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen content (FIB) assays in vitro. Then, Three main lupanine triterpenes (compounds A–C) were isolated and identified from Sea and Sbu by a bioassay-guided method and their structure were identified as 3α-Hydroxy-lup-20(29)-ene-23, 28-dioic acid, betulinic acid 3-O-sulfate and 3α-Hydroxy-lup-20(29)-ene-23, 28-dioic acid 28-O-(α-l-rhamnopyranosyl(1→4)-O-β-d-glucopyranosyl(1→6))-β-d-glucopyranoside) by spectroscopic data analysis. Among of them, compound B was confirmed to have significant coagulant effect in vitro. Furthermore, the pro-coagulation mechanism of S. heptaphylla extracts and compound B were investigated by measuring whole blood viscosity (WBV), plasma viscosity (PV), erythrocyte sedimentetion rate (ESR), pack cell volume (PCV), APTT, PT, TT, and FIB in vivo. Meanwhile, the levels of thromboxane B2 (TXB2), 6-keto prostaglandin F1α (6-keto-PGF1α), endothelial nitric oxide synthase (eNOS) and (endothelin-1) ET-1 were detected. The bleeding time (BT) was tested by tail bleeding method, which proved the traumatic bleeding and hemostasis activities of S. heptaphylla. The pharmacology experiments showed that the Set, Sea, Sbu and compound B has significant pro-coagulation effect. In addition, compound B might be the main constituent of pro-coagulation in S. heptaphylla These results could support the fact that S. heptaphylla could be used traditionally to cure traumatic bleeding, and the pro-coagulation effects were associated with the regulation of vascular endothelium active substance and hemorheology parameters

Speech Sentiment Analysis Using Hierarchical Conformer Networks

Multimodality has been widely used for sentiment analysis tasks, especially for speech sentiment analysis. Compared with the emotion expression of most text languages, speech is more intuitive for human emotion, as speech contains more and richer emotion features. Most of the current studies mainly involve the extraction of speech features, but the accuracy and prediction rate of the models still need to be improved. To improve the extraction and fusion of speech sentiment feature information, we present a new framework. The framework adopts a hierarchical conformer model and an attention-based GRU model to increase the accuracy of the model. The method has two main parts: a local feature learning group and a global feature learning group. The local feature learning group is mainly used to learn the spatio-temporal feature information of speech emotion features through the conformer model, and a combination of convolution and transformer is used to be able to enhance the extraction of long and short-term feature information. The global features are then extracted by the AUGRU model, and the fusion of features is performed by the attention mechanism to access the weights of feature information. Finally, the sentiment is identified by a fully connected network layer, and then classified by a central loss function and a softmax function. Compared with existing speech sentiment analysis models, we obtained better sentiment classification results on the IEMOCAP and RAVDESS benchmark datasets

Rotation Invariant Predictor-Corrector for Smoothed Particle Hydrodynamics Data Visualization

In order to extract the vortex features more accurately, a new method of vortex feature extraction on the Smoothed Particle Hydrodynamics data is proposed in the current study by combining rotation invariance and predictor-corrector method. There is a limitation in the original rotation invariance, which can only extract the vortex features that perform equal-speed rotations. The limitation is slightly weakened to a situation that the rotation invariance can be used, given that a specific axis is existed in the fluid to replace the axis needed for it. Therefore, as long as the axis exists, the modified rotation invariant method can be used. Meanwhile, the vortex features are extracted by predictor-corrector method. By calculating the cross product of the parallel vector field, the seed candidates of vortex core lines can be obtained, and the real seed points can be gained from the rotation invariant Jacobian. Finally, the seed point and a series of candidates based on the predictor-corrector method are connected to draw the vortex core lines. Compared with the original method, the rotation invariant predictor-corrector method not only expands the application scope, but also ensures the accuracy of extraction. Our method adds the steps of calculating the rotation invariant Jacobian, the performance is slightly lower, but with the increase of the particle number, the performance gradually tends to the original method