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Abstract Background The progression of diabetic cardiomyopathy (DCM) is noticeably influenced by mitochondrial dysfunction. Variants of caveolin 3 (CAV3) play important roles in cardiovascular diseases. However, the potential roles of CAV3 in mitochondrial function in DCM and the related mechanisms have not yet been elucidated. Methods Cardiomyocytes were cultured under high-glucose and high-fat (HGHF) conditions in vitro, and db/db mice were employed as a diabetes model in vivo. To investigate the role of CAV3 in DCM and to elucidate the molecular mechanisms underlying its involvement in mitochondrial function, we conducted Liquid chromatography tandem mass spectrometry (LC–MS/MS) analysis and functional experiments. Results Our findings demonstrated significant downregulation of CAV3 in the cardiac tissue of db/db mice, which was found to be associated with cardiomyocyte apoptosis in DCM. Importantly, cardiac-specific overexpression of CAV3 effectively inhibited the progression of DCM, as it protected against cardiac dysfunction and cardiac remodeling associated by alleviating cardiomyocyte mitochondrial dysfunction. Furthermore, mass spectrometry analysis and immunoprecipitation assays indicated that CAV3 interacted with NDUFA10, a subunit of mitochondrial complex I. CAV3 overexpression reduced the degradation of lysosomal pathway in NDUFA10, restored the activity of mitochondrial complex I and improved mitochondrial function. Finally, our study demonstrated that CAV3 overexpression restored mitochondrial function and subsequently alleviated DCM partially through NDUFA10. Conclusions The current study provides evidence that CAV3 expression is significantly downregulated in DCM. Upregulation of CAV3 interacts with NDUFA10, inhibits the degradation of lysosomal pathway in NDUFA10, a subunit of mitochondrial complex I, restores the activity of mitochondrial complex I, ameliorates mitochondrial dysfunction, and thereby protects against DCM. These findings indicate that targeting CAV3 may be a promising approach for the treatment of DCM.

With the development of cloud computing and big data, data security and privacy protection in multi-user environments have become particularly important. Existing encryption schemes exhibit significant deficiencies in addressing the flexible revocation of user attributes and dynamic changes in access permissions, leading to unauthorized users illicitly accessing and tampering with data. Therefore, we propose a Blockchain-based Traceable Multi-Level Revocable Attribute-Based Encryption Scheme (BTMAR-ABE). This scheme combines the advantages of Attribute-Based Encryption (ABE) technology and blockchain, achieving real-time attribute updates and verification through smart contracts, thereby avoiding reliance on a single centralized management server and introducing uniquely associated random numbers to prevent collusion attacks. To achieve flexible and secure data access control, we designed a multi-level revocation mechanism for both temporary and permanent revocation to address short-term and long-term permission change requirements. Performance evaluation and security analysis indicate that the BTMAR-ABE scheme can effectively resist chosen plaintext attacks, attribute revocation attacks, and collusion attacks, while demonstrating significant efficiency advantages in computational cost. Simulation results further demonstrate that this scheme has high practical value in data security and access control.

With the intensifying global warming trend, extreme heat and drought are becoming more frequent, seriously impacting potato yield and quality. To maintain sustainable potato production, it is necessary to breed new potato varieties that are adaptable to environmental changes and tolerant to adversity. Despite its importance, there is a significant gap in research focused on the potential mechanisms of potato resistance to abiotic stresses like drought and high temperatures. This article provides a comprehensive review of the recent research available in academic databases according to subject keywords about potato drought tolerance and high temperature tolerance with a view to providing an important theoretical basis for the study of potato stress mechanism and the selection and breeding of potato varieties with drought and high-temperature resistance. The suitable relative soil moisture content for potato growth and development is 55% to 85%, and the suitable temperature is 15 °C to 25 °C. The growth and development of potato plants under drought and high-temperature stress conditions are inhibited, and plant morphology is altered, which affects the process of potato stolon formation, tuberization and expansion, ultimately leading to a significant reduction in potato tuber yields and a remarkable degradation of the market grade of tubers, the specific gravity of tubers, and the processing quality of tubers. In addition, stress also adversely affects potato physiological and biochemical characteristics, such as reduction in root diameter and leaf area, decrease in net photosynthetic rate of leaves, production of reactive oxygen species (ROS), and increase in membrane lipid peroxidation. In addition, various types of genes and transcription factors are involved in the response to drought and heat at the molecular level in potato. This paper illustrates the effects of stress on potato growth and development and the molecular mechanisms of potato response to adversity in detail, which is intended to reduce the damage caused by drought and high temperature to potato in the context of global warming and frequent occurrence of extreme weather to ensure potato yield and quality and to further safeguard food security.

AbstractObjective This study aimed to compare the efficacy and safety of focused ultrasound (FU) at different focal depths in treating vulvar lichen sclerosus (VLS).Methods A retrospective study was conducted on 84 patients with VLS. Among them, 43 cases were treated with FU at a focal depth of 2.5 mm and 41 cases at a focal depth of 4.0 mm. Therapeutic time, treatment energy, postoperative efficacy, complications and recurrence rates were compared.Results No statistically substantially differences in age, disease course, history of immune system diseases, lesion size and severity of symptoms were found between the two groups. All patients successfully received FU therapy. No significant difference in curative rate was observed between the two groups at 3, 6 and 12 months after FU therapy. At 12 months after FU therapy, the recurrence rate of the experimental group (FU treatment at 2.5 mm focal depth) was lower than the control group (FU treatment at 4.0 mm focal depth) (7.0% vs 24.4%, p = 0.027). The experimental group was treated for a shorter period of time [22.69 ± 0.64 (min) vs 24.93 ± 0.72(min), p = 0.022] and at a lower dose[5,026.05 ± 148.00(J) vs 5,484.26 ± 160.60(J) p = 0.039].Conclusion Compared with that at the routine focal depth (4.0 mm), FU therapy at a low treatment depth (2.5 mm) can achieve a similar therapeutic effect but lower recurrence rate, therapeutic time and treatment energy. This work provides insight into the optimization of clinical protocols.

AbstractObjective To use logistic regression to analyze the attributes underlying patients’ treatment options for low-grade squamous intraepithelial lesion (LSIL) complicated with high-risk human papillomavirus (HR-HPV) infection, and identify the best benefit group of different treatment options.Methods Clinical data of 197 LSIL patients with HR-HPV infection between June 2009 and February 2022 were collected. According to the treatment options chosen by the patients, they were divided into the interferon, photodynamic therapy, follow-up observation, and focused ultrasound (FUS) treatment groups. One-way analysis of variance (ANOVA) and multivariate logistic regression analysis were used to analyze the influencing factors, including age, occupation, education level, maternity history, reason for encounter, route of consultation, annual personal and household income, screening for related risk factors, and identifying the best benefit group of different treatment options.Results One-way ANOVA revealed a statistically significant difference in age, education level, maternity history, reason for encounter, and annual household income (p

NMDA receptors are glutamate-gated ion channels that regulate fast signaling in the brain. Here, the authors show that the opening and closing patterns of the channel derive from the action of two gates that are regulated by distinct subunits.

In this study, a novel artificial intervertebral disc implant with modified “Bucklicrystal” structure was designed and 3D printed using thermoplastic polyurethane. The new implant has a unique auxetic structure with building blocks joined “face-to-face”. The accompanied negative Poisson’s ratio enables its excellent energy absorption and stability under compression. The deformation and load distribution behavior of the implant under various loading conditions (bending, torsion, extension and flexion) has been thoroughly evaluated through finite element method. Results show that, compared to natural intervertebral disc and conventional 3D implant, our new implant exhibits more effective stress transfer and attenuation under practical loading conditions. The implant's ability to contract laterally under compression can be potentially used to alleviate the symptoms of lumbar disc herniation. Finally, the biocompatibility of the implant was assessed in vitro and its ability to restore the physiological function of the disc segment was validated in vivo using an animal model.

Abstract Background The antiphagocytic molecule CD47 is overexpressed in a wide variety of cancer cells, and antibodies targeting CD47 for cancer therapies are currently under intensive investigation. However, owing to the ubiquitous expression of CD47 on healthy cells, anti-CD47 therapies often achieve only weak therapeutic benefits and can induce severe side effects. Here, we report the generation of a pH-dependent anti-CD47 antibody (BC31M4) which selectively binds to tumors under the acidic solid tumor microenvironment. Methods BC31M4 was generated using antibody phage display and a pH-dependent selection strategy. The pH-dependent binding and blocking activities of BC31M4 were verified using in vitro assays, and the structural basis of the pH-dependent binding property was characterized. BC31M4’s antitumor effect was confirmed by both phagocytosis assays and studies in xenograft models. The tumor selectivity, mechanism of action, PK properties, side effects, and therapeutic efficacy were further evaluated in humanized (hCD47 and its receptor hSIRPα) immunocompetent syngeneic mouse models. Results The crystal structure reveals that two histidines locate within the CDRs of the light chain directly contribute to the pH-dependent binding of BC31M4. BC31M4 promotes macrophage phagocytosis of tumor cells more potently at acidic-pH than at physiological-pH. Our hCD47/hSIRPα humanized syngeneic mouse model results demonstrated that BC31M4 selectively accumulates in tumors but not in normal tissues. BC31M4 causes minimal side effects and exhibits superior PK properties as compared to the other examined anti-CD47 antibodies. When combined with adoptive T cell transfer, BC31M4 efficiently promotes adaptive immune responses against tumors and also induces immune memory. Moreover, we show that BC31M4’s antitumor effects rely on an Fc that mediates strong effector functions. Conclusions Our study illustrates that the development of a tumor-selective, pH-dependent anti-CD47 antibody safely confers strong therapeutic effects against solid tumors, thus providing a promising therapeutic strategy to overcome the challenges of anti-CD47 therapy.

Abstract Osteosarcoma is an aggressive malignant tumor that primarily develops in children and adolescents. The conventional treatments for osteosarcoma often exert negative effects on normal cells, and chemotherapeutic drugs, such as platinum, can lead to multidrug resistance in tumor cells. Herein, this work reports a new bioinspired tumor‐targeting and enzyme‐activatable cell‐material interface system based on DDDEEK‐pY‐phenylboronic acid (SAP‐pY‐PBA) conjugates. Using this tandem‐activation system, this work selectively regulates the alkaline phosphatase (ALP) triggered anchoring and aggregation of SAP‐pY‐PBA conjugates on the cancer cell surface and the subsequent formation of the supramolecular hydrogel. This hydrogel layer can efficiently kill osteosarcoma cells by enriching calcium ions from tumor cells and forming a dense hydroxyapatite layer. Owing to the novel antitumor mechanism, this strategy neither hurts normal cells nor causes multidrug resistance in tumor cells, thereby showing an enhanced tumor treatment effect than the classical antitumor drug, doxorubicin (DOX). The outcome of this research demonstrates a new antitumor strategy based on a bioinspired enzyme‐responsive biointerface combining supramolecular hydrogels with biomineralization.

Abstract Antibacterial dynamic therapy (ADT) triggered by reactive oxygen species (ROS) is promising for diabetic infectious disease treatment. However, the limited local O2/H2O2 production and post‐treatment inflammation remain long‐standing issues. To address these challenges, a novel H2‐evolving bio‐heterojunction enzyme (Bio‐HJzyme) consisting of graphite‐phase carbon nitride/copper sulfide (CN/Cu2−xS) heterojunction and glucose oxidase (GOx) is created. The Bio‐HJzyme offers glutathione peroxidase (GPx), peroxidase (POD), and catalase (CAT) mimetic activities; provides anti‐pathogen properties via programmed light activation; and effectively promotes diabetic wound healing. Specifically, its GPx‐mimetic activity and the presence of GOx significantly enhance the yield of H2O2, which can be catalyzed through POD‐mimetic activity to produce highly germicidal •OH. The H2O2 can also be catalyzed to H2O and O2, assisted by the CAT‐mimetic activity. The catalyzed products can then be catalyzed into germicidal •OH and •O2− under NIR light irradiation, giving enhanced ADT. Further, CN can split water to form H2 under solar light, which dramatically suppresses the inflammation caused by excessive ROS. In vivo evaluation confirms that Bio‐HJzyme promotes the regeneration of diabetic infectious skin through killing bacteria, enhancing angiogenesis, promoting wound bed epithelialization, and reinforcing anti‐inflammatory responses; hence, providing a revolutionary approach for diabetic wounds healing.

Abstract Background The variance in clinical responses to polyetheretherketone (PEEK) cages with titanium (Ti) and hydroxyapatite (HA) coatings (PEEK-Ti-HA cages) is still not clear. In this study, we aimed to evaluate the radiographic and clinical outcomes of patients undergoing TLIF using PEEK-Ti-HA cages with a particular focus on fusion rate. Methods A prospective and nonrandomized study was conducted to compare the outcomes of PEEK-Ti-HA cages (group A, n = 32) and uncoated PEEK cages (group B, n = 32). The follow up time was at least 2 years. The radiographic assessments included the regional lordosis (RL), disc height (DH), and fusion rate. The clinical indexes included the Japanese Orthopedic Association (JOA) scores and visual analog scale (VAS) scores (back and leg). Results No significant differences were found in the pre- and postoperative RL and DH between Group A and Group B. And RL and DH, even if there were any variance initially, were restored not long after surgery in both groups. Though Group A had a significantly higher fusion rate than group B at 3 months post-surgery (93.7% vs. 75.0%), the fusion rates for the two groups reached the same level (100%) when it comes to the final follow-up. Additionally, differences of VAS and JOA scores for the two groups in general approximate. Conclusions PEEK-Ti-HA cages, in contrast with uncoated PEEK cages, produced a better fusion rate at 3 months after single-level TLIF. The fusion rates of both groups could get 100% at the final follow-up. PEEK-Ti-HA cages could achieve similar RL, DH, JOA scores and VAS scores in comparison with uncoated PEEK cages post-surgery.

Postpericardial injury syndrome (PPIS) is defined as pericarditis or pericardial effusion that results from recent myocardial infarction or intracardiac interventions. These symptoms typically include fever, leukocytosis, a high erythrocyte sedimentation rate, and elevated C-reactive protein levels. Additionally, pericardial effusion and pleural effusion may be present. It is considered to be a common complication in cardio-surgery with an occurrence of 3–30%. In the past 20 years, a high number of patients with atrial fibrillation have suffered from PPIS following radiofrequency catheter ablation. However, previous reports focused on identifying cardiac tamponade and pericardial effusion as their main clinical manifestations. Solitary pulmonary involvement following PPIS with the radiofrequency catheter ablation may occur. We report a case of PPIS that presented pleural effusion as the dominant feature soon after the operation and systematic review to illustrate the clinical characteristics of PPIS.

Intervertebral disc (IVD) degeneration (IDD) is a common musculoskeletal disease and its treatment remains a clinical challenge. It is characterised by reduced cell numbers and degeneration of the extracellular matrix (ECM). Nucleus pulposus (NP) cells play a crucial role in this process. The purpose of this study is to explore the role of bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, in the treatment of IDD through local drug delivery. High expression of VEGF was observed in degenerating human and rat IVDs. We demonstrated that MMP3 expression was decreased and COL II synthesis was promoted, when VEGF expression was inhibited by bevacizumab, thereby improving the degree of disc degeneration. Thus, these findings provide strong evidence that inhibition of VEGF expression by local delivery of bevacizumab is safe and effective in ameliorating disc degeneration in rats. The injectable thermosensitive PLGA-PEG-PLGA hydrogels loaded with bevacizumab is a potential therapeutic option for disc degeneration.

Abstract Background Currently, there are limited reports regarding investigation of the biological properties of polyetheretherketone (PEEK) coated with titanium (Ti) and hydroxyapatite (HA) in human. The objective of this study is to evaluate the in vivo response of the PEEK cages coated with Ti and HA versus uncoated PEEK cages after anterior cervical discectomy and fusion (ACDF) in patients with single-level cervical degenerative disc disease (CDDD). Methods Twenty-four patients with PEEK cages coated with Ti and HA (PEEK/Ti/HA group) were matched one-to-one with patients with uncoated PEEK cages (PEEK group) based on age, gender, and operative segment. All patients had been followed up for more than 2 years. Radiological assessments included intervertebral height (IH), C2-7 angle (C2-7a), segmental alignment (SA), and fusion rate. Clinical parameters included Visual Analogue Scale (VAS) and Japanese Orthopedic Association (JOA) scores. Results There was no statistical difference in SA, IH, and C2-7a between the two groups before and after surgery and all these parameters were restored postoperatively. The fusion rate of PEEK/Ti/HA group was significantly higher than PEEK group at 3-month post-operation (87.5% vs. 62.5%). At the last follow-up, the fusion rate of the both groups achieved 100%. The VAS and JOA scores were comparable between two groups and improved postoperatively. Conclusions In patients with single-level ACDF, PEEK cage coated with Ti and HA provided a higher fusion rate than uncoated PEEK cage at 3-month post-operation, while both two cages could achieve solid osseous fusion at the last follow up. Compared with the uncoated PEEK cage, PEEK/Ti/HA cage yielded similar favorable segmental and overall cervical lordosis, IH, and clinical outcomes after the surgery.

Hypertrophic cardiomyopathy is an inherited cardiovascular disease, and 70% of patients have left ventricular outflow tract obstruction. Ventricular septal myectomy has been the gold standard treatment for most patients with refractory symptoms. Due to higher mortality associated with medical facilities with less experience, alcohol septal ablation has been accepted as an alternative to conventional surgical myectomy. It offers lower all-cause in-hospital complications and mortality, which could be potentially more preferable for patients with serious comorbidities. In recent years, radiofrequency ablation, providing another option with reproducibility and a low risk of permanent atrioventricular block, has become an effective invasive treatment to relieve left ventricular outflow tract obstruction. Moreover, substantial progress has been made in gene therapy for hypertrophic cardiomyopathy. The principal objective of this review is to present recent advances in non-pharmaceutical interventions in hypertrophic cardiomyopathy.

To improve the performance of polyether ether ketone matrix (PEEK) in hard tissue repair and replacement applications, we fabricated graphene nanoplatelet (G) reinforced PEEK with different filler weight concentrations (0.1%–5%) through injection moulding. The mechanical properties, surface morphology, chemical composition and thermal stability of the composites have been characterized. The biocompatibility has been assessed in vitro and the bone repair function of the composite implants have been assessed in vivo using a rabbit mandibular bone defect model. Mechanical testing results suggest that the composite samples have compressive moduli similar to that of the natural bone. Although addition of G into PEEK does not significantly influence the composite tensile, flexural or compressive moduli, it can significantly enhance the ductility and toughness of the material. On the other hand, all G-reinforced PEEK implants demonstrated enhanced adhesion and differentiation of rat bone marrow stromal cells (BMSCs), with 5% G-PEEK showing the highest bioactivity among all samples. The in vivo osseointegration data further revealed that 5% G-PEEK has the best effect in promoting osseointegration and bone regeneration, in both early stage and late stage bone re-growth. Study shows that our G-reinforced PEEK-based implants provides a promising strategy for enhancing the performance of future regenerative bone implants.

Fungalysin metallopeptidase (M36), a hydrolase, catalyzes the hydrolysis of alanine, glycine, etc. Normally, it is considered to play an important role in the progress of fungal infection. However, the function of fungalysin metallopeptidase (M36) in Fusarium graminearum has not been reported. In this study, we explored the biological functions of FgFly1, a fungalysin metallopeptidase (M36) of F. graminearum. We found that ΔFgFly1 did not affect the ability to produce DON toxin, although it inhibited spore germination during asexual reproduction and reduction in pathogenicity compared with PH-1. Therefore, we speculated that FgFly1 affects the pathogenicity of F.graminearum by affecting pathways related to wheat disease resistance. Target protein TaCAMTA (calmodulin-binding transcription activator) was selected by a yeast two-hybrid (Y2H) system. Then, the interaction between FgFly1 and TaCAMTA was verified by bimolecular fluorescent complimentary (BiFC) and luciferase complementation assay (LCA). Furthermore, compared with wild-type Arabidopsis thaliana, the morbidity level of ΔAtCAMTA was increased after infection with F.graminearum, and the expression level of NPR1 was significantly reduced. Based on the above results, we concluded that FgFly1 regulated F. graminearum pathogenicity by interacting with host cell CAMTA protein.

In this work, a multi-layer wound dressing consisting of polyvinyl alcohol (PVA) foam and electrospun sodium carboxymethylcellulose (CMC) surface mesh was developed and characterized. Antimicrobial drug stearyl trimethyl ammoium chloride (STAC) was loaded into the PVA foam for infection control and the CMC surface mesh offers effective hemostatic function. Additionally, the potential of laser photodynamic response of the loaded methylene blue (MB) and its effect in enhancing the wound dressing's bacterial inhibition has been investigated. The antibacterial drug and laser photodynamic therapy (PDT) were jointly deployed, which demonstrated greater potential in killing both S. aureus and E. coli bacteria strains. In addition, the unique color changing property of MB has enabled real time bacterial infection monitoring of the wound dressing. The multi-layer wound dressing with ideal material combination and unique multifunctionality may be a promising option for wound management in the future healthcare sector.

The late blight caused by Phytophthora infestans (P. infestans) has been a major constraint for worldwide sustainable potato production. Chinese potato cultivar Qingshu 9 has shown excellent field performance against late blight. To understand the mechanism underlying its resistance, the transcriptomic dynamics of Qingshu 9 infected with P. infestans was systematically investigated to identify the resistance-related genes. In total, 2027 shared differentially expressed genes (DEGs) were identified when infected with P. infestans at 24, 48 and 72 h post-inoculation. Based on k-mean cluster analysis, the DEGs showed four types of expression patterns, suggesting their divergent functions in response to P. infestans infection. KEGG enrichment analysis showed that the significantly enriched DEGs were involved in the biosynthesis of secondary metabolites, plant–pathogen interaction, and photosynthesis. Furthermore, 980 transcription factor genes belonging to 68 families were found in the DEGs, of which AP2-EREBP and MYB genes were the most abundant. Moreover, many genes related to disease resistance showed differential expression during infection. Finally, the expression of nine DEGs was validated by quantitative real-time PCR. These results provide valuable information for understanding late resistance in potato cultivar Qingshu 9.

An important task in facilitating the development of thermally conducting graphene/polymer nanocomposites is to suppress the intrinsically strong intersheet π-π stacking of graphene, and thereby to improve the exfoliation and dispersion of graphene in the matrix. Here, a pre-programmed intercalation approach to realize the in situ growth of graphene nanosheets at the inorganic template is demonstrated. Specifically, microsized MgO granules with controlled geometrical size were synthesized using a precipitation method, allowing the simultaneous realization of high surface activity. In the presence of a carbon and nitrogen source, the MgO granules were ready to induce the formation of graphene nanosheets (G@MgO), which allowed for the creation of tenacious linkages between graphene and template. More importantly, the incorporation of G@MgO into polymer composites largely pushed up the thermal conductivity, climbing from 0.39 W/m∙K for pristine polyethylene to 8.64 W/m∙K for polyethylene/G@MgO (60/40). This was accompanied by the simultaneous promotion of mechanical properties (tensile strength of around 30 MPa until 40 wt % addition of G@MgO), in contrast to the noteworthy decline of tensile strength for MgO-filled composites with over 20 wt.% fillers.

BackgroundPharmacological intervention of redox balance in cancer cells often results in oxidative stress-mediated apoptosis, attracting much attention for the development of a new generation of targeted therapy in cancer. However, little is known about mechanisms underlying the conversion from oxidative signaling to downstream activities leading cells to death.Methodology/principal findingsWe here report a systematic detection of transcriptome changes in response to oxidative signals generated in leukemia cells upon fenretinide treatment, implicating the occurrence of numerous stress-responsive events during the fenretinide induced apoptosis, such as redox response, endoplasmic reticulum stress/unfolded protein response, translational repression and proteasome activation. Moreover, the configuration of these relevant events is primarily orchestrated by stress responsive transcription factors, as typically highlighted by NF-E2-related factor-2 (NRF2) and heat shock factor 1 (HSF1). Several lines of evidence suggest that the coordinated regulation of these transcription factors and thus their downstream genes are involved in converting oxidative signaling into downstream stress-responsive events regulating pro-apoptotic and apoptotic activities at the temporal and spatial levels, typifying oxidative stress-mediated programmed death rather than survival in cancer cells.Conclusions/significanceThis study provides a roadmap for understanding oxidative stress-mediated apoptosis in cancer cells, which may be further developed into more sophisticated therapeutic protocols, as implicated by synergistic induction of cell apoptosis using proteasome inhibitors with fenretinide.