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Synaptic efficacy is critical for memory formation and consolidation. Accumulating evidence suggest that synapses are impaired during Wilson’s disease (WD), contributing to neuronal dysfunction and cognitive decline. WD is a prototypical condition among the copper metabolism disorders. Cognitive impairment is a common feature of affected patients with neurological symptoms, presenting as memory deficits, decreased cognitive flexibility, and impaired learning capabilities. These cognitive deficits can significantly impact the quality of life, affecting work and academic performance. However, the mechanisms mediating the inhibitory synaptic dysfunction in WD are incompletely understood. We investigated the effects of the double-stranded RNA-dependent protein kinase/eukaryotic initiation factor 2α (PKR/eIF2α) pathway on synaptic structure and function in WD using a murine model, toxic milk (TX mice). During mouse open-field tests, we noted a substantial rise in the mobility/immobility ratio among WD model animals compared to that in WT mice. Additionally, WD mice exhibited diminished central area exploration, as evidenced by reduced travel distance. Moreover, they displayed prolonged escape latency in the Barnes maze, suggesting that chronic copper accumulation is associated with neuropsychiatric alterations and cognitive impairment. We also found a decrease in the expression of synapse-associated proteins (synapsin 1, synaptophysin, postsynaptic density protein-93 [PSD93], postsynaptic density protein-95 [PSD95]), and vesicle-associated membrane protein2 [VAMP2]) besides abnormal neurotransmitter levels (including glutamate and GABA), indicating the presence of synaptic dysfunction in TX mice. Inhibiting PKR via C16 prevented these changes, suggesting that dysfunctional cognition is associated with the PKR/eIF2α pathway. We also observed changes in synapses, vesicles, dendritic spine density, and dendritic length that were associated with the presence of cognitive dysfunction. Further investigation revealed that C16 treatment decreased the TUNEL-positive cell numbers in the hippocampus of TX mice and prevented 8-OHdG-induced synaptic dysfunction. Results suggest that PKR downregulation prevents copper-induced synaptic dysfunction in the murine WD model. Therefore, targeting PKR pharmacologically may be a potential therapeutic strategy for treating the copper-induced neuropathology of patients with WD.

Abstract Clear cell renal cell carcinoma (ccRCC) is a prevalent malignancy with complex heterogeneity within epithelial cells, which plays a crucial role in tumor progression and immune regulation. Yet, the clinical importance of the malignant epithelial cell-related genes (MECRGs) in ccRCC remains insufficiently understood. This research aims to undertake a comprehensive investigation into the functions and clinical relevance of malignant epithelial cell-related genes in ccRCC, providing valuable understanding of the molecular mechanisms and offering potential targets for treatment strategies. Using data from single-cell sequencing, we successfully identified 219 MECRGs and established a prognostic model MECRGS (MECRGs’ signature) by synergistically analyzing 101 machine-learning models using 10 different algorithms. Remarkably, the MECRGS demonstrated superior predictive performance compared to traditional clinical features and 92 previously published signatures across six cohorts, showcasing its independence and accuracy. Upon stratifying patients into high- and low-MECRGS subgroups using the specified cut-off threshold, we noted that patients with elevated MECRGS scores displayed characteristics of an immune suppressive tumor microenvironment (TME) and showed worse outcomes after immunotherapy. Additionally, we discovered a distinct ccRCC tumor cell subtype characterized by the high expressions of PLOD2 (procollagen-lysine,2-oxoglutarate 5-dioxygenase 2) and SAA1 (Serum Amyloid A1), which we further validated in the Renji tissue microarray (TMA) cohort. Lastly, ‘Cellchat’ revealed potential crosstalk patterns between these cells and other cell types, indicating their potential role in recruiting CD163 + macrophages and regulatory T cells (Tregs), thereby establishing an immunosuppressive TME. PLOD2 + SAA1 + cancer cells with intricate crosstalk patterns indeed show promise for potential therapeutic interventions.

Abstract Background The most recommended method for treating transverse patella fractures is modified tension band wiring (MTBW). However, the optimal instrument for use with MTBW is still undetermined. Hence, we aimed to design a novel screw-cable integrated system (SCIS) and compare its biomechanical characteristics with Kirschner-wire, SCIS, and Cable-Pin systems in treating transverse patellar fracture. Methods A finite-element (FE) model of transverse patella fracture was created. The fracture model was fixed with either K-wire, SCIS, or Cable-pin. Different tension force loading (400 N and 800 N), direction(0° and 45°), and screw or K-wire depth(5 mm and 10 mm) were set. The maximum displacement of the fragment and maximum gap opening were measured by using FE analysis. Results Compared with the K-wire and Cable-pin system, SCIS increased the stability of the fractured patella by reducing fragment displacement and gap opening. Under 400 N loading in the direction 45°, SCIS with screw placing at 5-mm depth reduced the maximum fragment displacement (0.43 mm) by 49.62% and 26%, respectively, compared with the K-wire (0.22 mm) and Cable-pin (0. 22 mm) group. Meanwhile, the gap opening in SCIS (0.05 mm) was reduced by 83% and 59.8% (0.05 to 0.18) compared with the K-wire (0.30 mm) and Cable-pin (0.18 mm) group. Conclusion SCIS demonstrated improved biomechanical stability for treating transverse patellar fractures compared to MTBW with Kirschner wire and the Cable-Pin system. Finite element analysis showed SCIS substantially reduced fracture fragment displacement and gap opening under various loading conditions.

Background: Pancreatic fistula (PF) and biliary fistula (BF) are two major leakage complications after pancreatoduodenectomy (PD). The aim of this study is to investigate the risk factors of PF and BF after laparoscopic PD (LPD). Materials and Methods: We conducted a retrospective analysis of 500 patients who underwent LPD from 1 April 2015 to 31 March 2020. Clinical data from patients were analysed using multivariate logistic regression analysis. Results: PF occurred in 86 (17.2%) patients. Univariate and multivariate analysis indicated that the soft texture of the pancreas (P = 0.001) was the independent risk factor for PF. BF occurred in 32 (6.4%) patients. Univariate and multivariate analysis indicated that history of cardiovascular disease (P < 0.001), surgical time (P = 0.005), pre-operative CA125 (P = 0.036) and pre-operative total bilirubin (P = 0.044) were independent risk factors for BF. Conclusion: The texture of the pancreas was an independent risk factor for PF after LPD, which was consistent with the literatures. In addition, history of cardiovascular disease, surgical time, pre-operative CA125 and pre-operative total bilirubin were new independent risk factors for BF after LPD. Therefore, patients with high-risk factors of BF should be informed that they are at a high risk for this complication.

Energy is one of the primary challenges in the long-term operation of robotic fish. The research on combining wave energy-harvesting technology with robotic fish for energy supplementation is not extensive, and there is insufficient comprehensive analysis on energy harvesting from waves and energy costs during swimming. Therefore, the energy self-sufficiency of multi-joint robotic fish is investigated by employing the coupling method of smoothed particle hydrodynamics (SPH) and multi-body dynamics in this study. A reversible energy conversion mechanism is applied to the robotic fish, serving as a driving system during swimming and as a power take-off (PTO) system during energy harvesting. The energy costs of the multi-joint robotic fish under various undulation parameters (including amplitude, frequency, and body wavelength) are analyzed, along with an examination of the influence of the PTO system on energy harvesting. The results show that, compared to the undulation amplitude and body wavelength, the undulation frequency has the greatest impact on swimming efficiency and energy costs, with low-frequency swimming being advantageous for efficient energy utilization. Additionally, the damping coefficient of the PTO system directly affects energy-harvesting efficiency, with higher energy-harvesting power achievable with an optimal PTO system parameter. Through a comprehensive analysis of energy costs and energy harvesting, it is concluded that the achievement of energy self-sufficiency for multi-joint robotic fish in marine environments is highly feasible.

A novel double-cycle alternating-flow diode-pumped potassium vapor laser is proposed, theoretically modeled and simulated. The results show that the optical-to-optical efficiency of the laser increases with increasing gas flow rates, although at high flow rates the rate of increase in efficiency decreases. The optical-to-optical efficiency reaches 74.8% at a pump power density of 30 kW/cm2 and a gas flow rate of 50 m/s. The optical-to-optical efficiency of the laser is greater with a narrow linewidth pump and high buffer gas pressure. The optical-to-optical efficiency of a flow gas cell is higher than that of a static gas cell. There is an optimal gas cell length that provides the highest optical-to-optical efficiency. At higher pump power densities, higher flow rates are required to obtain higher optical-to-optical efficiencies.

A challenge for synthetic biology is the design and construction of prototissue. Here, the authors spatially segregate layers of enzyme-decorated coacervate protocells as a model prototissue capable of chemical signal processing and modulating outputs of nitric oxide to inhibit blood clot formation.

The mechanical properties of biological soft tissues are inextricably linked to the field of health care, and their mechanical properties can be important indicators for diagnosing and detecting diseases; they can also be used to analyze the causes of organ diseases from a pathological point of view and thus guide the deployment of medical solutions. As an effective method to characterize the mechanical properties of materials, mechanical loading experiments have been successfully applied to the mechanical properties of materials, including tension, compression, pure shear, and so on. Under quasi-static loading, when the material is a biological soft tissue material between a solid and an ideal fluid, its viscoelastic properties strongly respond to the force stimulus, and the stress-strain-time in the elastic phase will have obvious disturbance characteristics. Therefore, the existing statistical methods are often difficult to quantitatively describe the mechanical properties of materials. Therefore, this study proposes an Interval Capture Point based on the principle of integration. The experimental data based on this method can characterize its nonlinear mechanical properties well, especially when the loading speed is extremely low and the soft materials show strong disturbance characteristics. The proposed method can still accurately characterize the hyperelastic and viscoelastic properties of the mechanical properties of biological soft tissues under quasi-static loading.

Nerves within bone play an irreplaceable role in promoting bone regeneration. Crosstalk between the nerve system and bone has arisen to the attention of researchers in the field of basic medicine, clinical medicine, and biomaterials science. Successful bone regeneration relies on the appropriate participation of neural system components including nerve fibers, signaling molecules, and neural-related cells. Furthermore, more about the mechanisms through which nerves took part in bone regeneration and how these mechanisms could be integrated into tissue engineering scaffolds were under exploration. In the present review, we aimed to systematically elaborate on the structural and functional interrelationship between the nerve system and bone. In particular, peripheral nerves interact with the bone through innervated axons, multiple neurotrophins, and bone resident cells. Also, we aimed to summarize research that took advantage of the neuro-osteogenic network to design tissue engineering scaffolds for bone repair.

Triptolide (TPL) is a diterpenoid triepoxide with broad antitumor efficacy, while lack of mechanism of action, severe systemic toxicity, and poor water solubility of TPL limited its usage. To unveil the mechanism of action and improve the pharmaceutical properties of TPL, here we explored the molecular mechanism of TPL and then fabricated TPL-loaded membrane protein-chimeric liposomes (TPL@MP-LP) and tested its anticancer efficacy against hepatocellular carcinoma (HCC). CCK8 assay, colony formation assay, EdU assay, and flow cytometry were used to examine the activity of TPL. RNA sequence and gain-and-loss of function assays were used to explore the molecular mechanisms. TPL@MP-LP was characterized by size, zeta potential, polydispersity index, and transmission electron microscopy. Cellular uptake and cell viability assay were performed to evaluate the internalization and anticancer efficacy of TPL@MP-LP in vitro. Biodistribution and in vivo antitumor efficacy of TPL@MP-LP were evaluated on orthotopic HCC mice models. TPL robustly inhibited HCC cells by inducing cell proliferation arrest, apoptosis via the mitochondrial pathway, and necroptosis via RIPK1/RIPK3/MLKL signaling. TPL was successfully loaded into MP-LP, with a drug-loading capacity of 5.62 ± 0.80%. MP-LP facilitated TPL internalization and TPL@MP-LP exerted enhanced anticancer efficacy against Huh7 cells. TPL@MP-LP showed targeting ability to the tumor site. More importantly, TPL@MP-LP treatment suppressed tumor growth but showed minimal damage to liver and renal functions. TPL exerted anticancer effects on HCC via inducing cell proliferation arrest, apoptosis, and necroptosis, and the MP-LP might be a promising delivery strategy to improve the antitumor efficacy while mitigating toxicity of TPL for HCC therapy.

It is urgent to improve the comprehensive utilization rate of tailings, especially to solve the problem of fine iron ore tailings treatment and the shortage of natural sand, so iron ore tailings concrete with different replace rates was prepared in this paper. At the same time, in order to further popularize the wide application of iron tailings concrete, it is of great significance to study the frost resistance and life prediction of it in cold regions. Thereby, a series of experimental research on iron ore tailings concrete under freezing-thawing cycles was carried out to analyze the attenuation law of quality, compressive strength, and relative dynamic elastic modulus after different freezing-thawing cycles. In this paper, the relative dynamic elastic modulus was used to define the damage factor, and the freezing-thawing damage model of iron ore tailings concrete was established based on Weibull distribution. Here, the specific function form of two-parameter Weibull distribution of iron ore tailings concrete under freezing-thawing cycle was proposed, and the model was used to predict life of it. The results showed that, compared with the replacement rates of 20%, 60%, and 80%, the iron ore tailings with 40% replacement rate had the best improvement effect on the frost resistance of concrete and can delay the attenuation of the compressive strength of concrete. This model can not only predict the durability life of iron ore tailings concrete under freezing-thawing conditions, but also provide theoretical reference for the application of iron ore tailings concrete in cold areas.

Abstract Background The Cadherin-11 and PI3K/Akt pathway are increasingly recognized as the potential therapeutic target of osteoarthritis (OA) synovitis. The study aimed to investigate the role of PI3K/Akt signaling pathway in the expression of Cadherin-11 and migration and invasive capacity of fibroblast-like synoviocytes (FLS) of OA patients under stimulation of TNF-α and to explore the effect of the PI3K/Akt inhibitor and Cadherin-11 antibody in the therapy of the collagenase-induced osteoarthritis (CIOA) mice. Methods FLS were primarily cultured from synovium of osteoarthritic patients during total knee arthroplasty. Under the simulation of TNF-α, with or without PI3K/Akt inhibitor LY294002, Cadherin-11 expression was detected by real-time PCR and Western blot, as well as the migration and invasive capacity changes of OA FLS. Cadherin-11 antibody was injected intraarticularly or LY294002 was injected intraperitoneally in CIOA mice to evaluate the changes of synovitis score, cartilage damage, and Cadherin-11 expression. Results TNF-α stimulation increased Cadherin-11 expression at mRNA and protein level in OA FLS and also increased the phosphorylation-dependent activation of Akt. PI3K inhibitor LY294002 attenuated TNF-α-induced overexpression of Cadherin-11 and decreased the invasive capacity of OA FLS. Intraperitoneal injection of PI3K inhibitor LY294002 could decrease the Cadherin-11 protein expression in synovium of CIOA mice, although it has no significant inhibitory effect on synovitis and cartilage damage. Intraarticular injection of Cadherin-11 antibody attenuated the synovitis and cartilage damage in the CIOA joints and decreased Cadherin-11 expression in the synovial lining. Conclusions PI3K/Akt pathway was associated with TNF-α-induced activation of OA FLS, which may involve in the pathogenesis of osteoarthritis. Anti-Cadherin-11 therapy in CIOA mice could attenuate the pathological changes of OA joints.

Abstract Background Emerging evidence indicates that Long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) play crucial roles in tumor progression, including hepatocellular carcinoma (HCC). However, whether there is a crosstalk between LncRNA pituitary tumor-transforming 3 (PTTG3P) and miR-383 in HCC remains unknown. This study is designed to explore the underlying mechanism by which LncRNA PTTG3P sponges miR-383 during HCC progression. Methods qPCR and Western blot were used to analyze LncRNA PTTG3P, miR-383 and other target genes’ expression. CCK-8 assay was performed to examine cell proliferation. Annexin V-PE/PI and PI staining were used to analyze cell apoptosis and cell cycle distribution by flow cytometry, respectively. Transwell migration and invasion assays were used to examine cell migration and invasion abilities. An in vivo xenograft study was performed to detect tumor growth. Luciferase reporter assay and RNA pull-down assay were carried out to detect the interaction between miR-383 and LncRNA PTTG3P. RIP was carried out to detect whether PTTG3P and miR-383 were enriched in Ago2-immunoprecipitated complex. Results In this study, we found that PTTG3P was up-regulated in HCC tissues and cells. Functional experiments demonstrated that knockdown of PTTG3P inhibited cell proliferation, migration and invasion, and promoted cell apoptosis, acting as an oncogene. Mechanistically, PTTG3P upregulated the expression of miR-383 targets Cyclin D1 (CCND1) and poly ADP-ribose polymerase 2 (PARP2) by sponging miR-383, acting as a competing endogenous RNA (ceRNA). The PTTG3P-miR-383-CCND1/PARP2 axis modulated HCC phenotypes. Moreover, PTTG3P also affected the PI3K/Akt signaling pathway. Conclusion The data indicate a novel PTTG3P-miR-383-CCND1/PARP2 axis in HCC tumorigenesis, suggesting that PTTG3P may be used as a potential therapeutic target in HCC. Graphical Abstract

In this study, the large eddy simulation method and the actuator line model are used to investigate the wake redirection of two turbines. Different turbine spacings and yaw-based control of the upstream turbine are considered. The effects of yaw angle and turbine spacing on the output power of two turbines are comprehensively analyzed, and the physical mechanisms of the wake deficit, deflection and interaction are revealed from the distributions of the wake velocity, turbulence intensity and the structures of wake vortices. The results show that the overall power of two turbines is related to the yaw angle of the upstream turbine and the spacing between two turbines. We find yaw angle is the dominant factor in the total power improvement compared to turbine spacing. Still, a large yaw angle causes significant power fluctuations of the downstream turbine. The deficit of wake velocity and the change of output power are determined by the characteristics of the wake flow field, which the yaw control regulates.

Studies have indicated that oxidative stress plays a crucial role in the development of Parkinson’s disease (PD) and other neurodegenerative conditions. Research has also revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) triggers the expression of antioxidant genes via a series of antioxidant response elements (AREs), thus preventing oxidative stress. Thymoquinone (TQ) is the bioactive component of Nigella sativa, a medicinal plant that exhibits antioxidant and neuroprotective effects. In the present study we examined whether TQ alleviates in vivo and in vitro neurodegeneration induced by 1-methyl-4-phenylpyridinium (MPP+) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by acting as an activator of the Nrf2/ARE cascade. We showed that TQ significantly reduced MPP+-mediated cell death and apoptosis. Moreover, TQ significantly elevated the nuclear translocation of Nrf2 and significantly increased the subsequent expression of antioxidative genes such as Heme oxygenase 1 (HO-1), quinone oxidoreductase (NQO1) and Glutathione-S-Transferase (GST). The application of siRNA to silence Nrf2 led to an abolishment in the protective effects of TQ. We also found that the intraperitoneal injection of TQ into a rodent model of PD ameliorated oxidative stress and effectively mitigated nigrostriatal dopaminergic degeneration by activating the Nrf2-ARE pathway. However, these effects were inhibited by the injection of a lentivirus wrapped Nrf2 siRNA (siNrf2). Collectively, these findings suggest that TQ alleviates progressive dopaminergic neuropathology by activating the Nrf2/ARE signaling cascade and by attenuating oxidative stress, thus demonstrating that TQ is a potential novel drug candidate for the treatment of PD.

Abstract Background Angioleiomyoma is a very rare benign solitary soft tissue neoplasm originating from smooth muscle layer of blood vessels. The tumor is usually located in the subcutis or the superficial fasciae, but less often in the deep fasciae, especially rare in the knee joint cavity. Diagnosis is frequently delayed or misdiagnosed as loose body or anterior knee pain because of its rare occurrence and poor awareness of physicians. Few studies have presented intra-articular angioleiomyoma and such cases become rarer and more difficult to diagnose when it presents as loose body. Case presentation Two patients, a middle-aged man and an old woman, presented to our outpatient clinic with persistent anterior knee pain and both of them suffered from a solitary mass in the right knee that had slowly enlarged. One of two patients showed negative in the routine radiographic imaging and the other showed a “loose body” beside the lateral femoral condyle in the knee. MRI showed both a well-demarcated intra-articular mass of isointense signal to muscle on T1-weighted images and heterogeneous intensity on T2-weighted images. Their tumors were excised under arthroscopy finally, with the pathological results revealed vascular leiomyomas. They both recovered well with pain free after operation and no signs of recurrence were seen at the 7-year follow-up. Conclusions This case report illustrates the atypical locations of angioleiomyoma in the knee joint should arouse our attention and be included in the differential diagnosis of nodular lesions mimicking loose bodies.

Superconducting single crystal of Ca _10 (Pt _4 As _8 )((Fe _0.92 Pt _0.08 ) _2 As _2 ) _5 has been prepared using flux method, and the physical properties of which are careful examined. Resistivity anisotropy between ab plane and c -axis is observed, T ^−0.5 term originated from the interlayer Josephson coupling is essential to be added to the formula used to describe the out-of-plane resistivity. The density of state (DOS) value at Fermi level derived from the fitting of specific heat data is consistent with the calculation results. Both direct and indirect platinum doping effect have influences on the superconducting transition temperature (T _c ) of Ca 10-3(4)-8 system, the T _c of our sample falls well into the trend strip formed by the data reported previously.

Peripheral nerve injury (PNI) occurs frequently, and the prognosis is unsatisfactory. As the gold standard of treatment, autologous nerve grafting has several disadvantages, such as lack of donors and complications. The use of functional biomaterials to simulate the natural microenvironment of the nervous system and the combination of different biomaterials are considered to be encouraging alternative methods for effective tissue regeneration and functional restoration of injured nerves. Considering the inherent presence of an electric field in the nervous system, electrically conductive biomaterials have been used to promote nerve regeneration. Due to their singular physical properties, hydrogels can provide a three-dimensional hydrated network that can be integrated into diverse sizes and shapes and stimulate the natural functions of nerve tissue. Therefore, conductive hydrogels have become the most effective biological material to simulate human nervous tissue’s biological and electrical characteristics. The principal merits of conductive hydrogels include their physical properties and their electrical peculiarities sufficient to effectively transmit electrical signals to cells. This review summarizes the recent applications of conductive hydrogels to enhance peripheral nerve regeneration.