Relationship between cathepsins and cardiovascular diseases: a Mendelian randomized study.

Background: Cardiovascular diseases (CVDs) are the leading age-related disorders worldwide, with their prevalence increasing annually. Cathepsins are protein-degrading enzymes essential for processes such as intracellular protein breakdown, apoptosis, and immune responses. Recent studies suggest a potential link between cathepsins and CVDs, yet the exact causal relationship remains to be elucidated. To address this, we propose using Mendelian randomization (MR) to explore the causal relationships between cathepsins and CVDs. Methods: We obtained single nucleotide polymorphism (SNP) data for cathepsins from the INTERVAL study, a publicly accessible genome-wide association study (GWAS) dataset. Outcome SNP data were sourced from seven distinct GWAS datasets, ensuring a comprehensive analysis across multiple cardiovascular outcomes. For MR analysis, we primarily employed the inverse variance weighted (IVW) method, known for its efficiency when all SNPs are valid instruments. This was supplemented by the weighted median and MR-Egger methods to provide robustness against potential violations of MR assumptions, such as pleiotropy. The IVW method offers precision and efficiency, the weighted median method adds robustness against invalid instruments, and the MR-Egger method helps identify and correct for pleiotropic biases. Cochran's Q test was utilized to assess heterogeneity, and sensitivity analyses were conducted using MR-PRESSO and the leave-one-out approach. Results: The strength of the associations between exposure and outcome was measured using odds ratios (ORs), and results were presented with 95% confidence intervals (CIs). The cathepsin E increases the risk of myocardial infarction (MI) (OR = 1.053%, 95% CI: 1.007-1.101, p = 0.024) and ischemic stroke (IS) (OR = 1.06%, 95% CI: 1.019-1.103, p = 0.004). Conversely, cathepsin L2 decreases the risk of chronic heart failure (CHF) (OR = 0.922%, 95% CI: 0.859-0.99, p = 0.025) and atrial fibrillation (AF) (OR = 0.956%, 95% CI: 0.918-0.996, p = 0.033). Cathepsin O was associated with an increased risk of IS (OR = 1.054%, 95% CI: 1.008-1.102, p = 0.021) and AF (OR = 1.058%, 95% CI: 1.02-1.098, p = 0.002). Conclusion: Our MR analysis reveals that cathepsin E is a risk factor for MI and IS, cathepsin L2 offers protective effects against CHF and AF, and cathepsin O increases the risk for IS and AF.

Relationship between Parkinson's disease and cardio-cerebrovascular diseases: a Mendelian randomized study.

Parkinson's disease (PD) and cardio-cerebrovascular diseases are related, according to earlier studies, but these studies have some controversy. Our aim was to assess the impact of PD on cardiocerebrovascular diseases using a Mendelian randomization (MR) method. The data for PD were single nucleotide polymorphisms (SNPs) from a publicly available genome-wide association study (GWAS) dataset containing data on 482,730 individuals. And the outcome SNPs data is were derived from five different GWAS datasets. The basic method for MR analysis was the inverse variance weighted (IVW) approach. We use the weighted median method and the MR-Egger method to supplement the MR analysis conclusion. Finally, We used Cochran's Q test to test heterogeneity, MR-PRESSO method and leave-one-out analysis method to perform sensitivity analysis. We used ratio ratios (OR) to assess the strength of the association between exposure and outcome, and 95% confidence intervals (CI) to show the reliability of the results. Our findings imply that PD is linked to a higher occurrence of coronary artery disease (CAD) (OR = 1.055, 95% CI 1.020-1.091, P = 0.001), stroke (OR = 1.039, 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and cardioembolic stroke (CES) also yielded positive results, respectively (OR = 1.043, 95% CI 1.008-1.079, P = 0.013), (OR = 1.076, 95% CI 1.008-1.149, P = 0.026). There is no evidence of a relationship between PD and other cardio-cerebrovascular diseases. Additionally, sensitivity analysis revealed reliable outcomes. Our MR study analysis that PD is related with an elevated risk of CAD, stroke, IS, and CES.

An efficient ptychography reconstruction strategy through fine-tuning of large pre-trained deep learning model.

With pre-trained large models and their associated fine-tuning paradigms being constantly applied in deep learning, the performance of large models achieves a dramatic boost, mostly owing to the improvements on both data quantity and quality. Next-generation synchrotron light sources offer ultra-bright and highly coherent X-rays, which are becoming one of the largest data sources for scientific experiments. As one of the most data-intensive scanning-based imaging methodologies, ptychography produces an immense amount of data, making the adoption of large deep learning models possible. Here, we introduce and refine the architecture of a neural network model to improve the reconstruction performance, through fine-tuning large pre-trained model using a variety of datasets. The pre-trained model exhibits remarkable generalization capability, while the fine-tuning strategy enhances the reconstruction quality. We anticipate this work will contribute to the advancement of deep learning methods in ptychography, as well as in broader coherent diffraction imaging methodologies in future.

Ventricular Arrest With a Duration of 23.8 Seconds.

This case report describes a patient in their late 40s undergoing a surgical procedure and experiencing a 23.8-second ventricular asystole.

Effects of different doses of glucocorticoids on postoperative atrial fibrillation: a meta-analysis.

BACKGROUND: Postoperative atrial fibrillation (POAF) is the most common arrhythmia after cardiac surgery, and its occurrence is closely related to inflammation. This paper intends to apply meta-analysis to investigate the effect of glucocorticoids on POAF. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched using the internationally recognized systematic evaluation and retrieval strategy. Two review authors independently selected relevant studies and extracted data based on the Cochrane handbook for systematic reviews of interventions approach. Stata 17 was used for data analysis. In the subgroup analysis, we grouped the participant data according to differences in glucocorticoids dose and type of surgery. At the same time, we also conducted a meta-analysis on the possible infection and gastrointestinal injury caused by glucocorticoids use. RESULTS: 27 studies and 14,442 patients were finally included. Results from the random-effects model indicated that the incidence of POAF was lower in glucocorticoid group (RR 0.80, 95% CI 0.71-0.92, P = 0.001). According to the subgroup analysis result, low doses of glucocorticoids reduced the incidence of POAF (RR 0.81, 95% CI 0.71-0.92, P = 0.001). The effect of high doses glucocorticoids on the POAF was not statistically significant (RR 0.81, 95% CI 0.56-1.19, P = 0.286). In the coronary artery bypass grafting (CABG) subgroup, the glucocorticoids reduced the incidence of POAF (RR 0.71, 95% CI 0.58-0.87, P = 0.001). In the CABG OR Valvular Surgery group, the effect of glucocorticoids on POAF was not statistically significant (RR 0.88, 95% CI 0.75-1.03, P = 0.108). 15 studies documented postoperative complications of infection, two studies were excluded from the system because the end point event was 0, and meta-analysis showed no increased risk of infection from glucocorticoid use (RR 0.85, 95% CI 0.68-1.06, P = 0.158). Eight studies documented the effects of glucocorticoids on gastrointestinal diseases, and meta-analysis showed no differences between the two groups (RR 1.12, 95% CI 0.83-1.50, P = 0.450). CONCLUSION: The use of glucocorticoids can reduce the incidence of POAF. The subgroup analysis result showed that low-dose glucocorticoids were more effective than high-dose glucocorticoids in inhibiting POAF. The use of glucocorticoids in CABG alone can better inhibit the occurrence of POAF. The effects of glucocorticoids on infection and gastrointestinal injury were not statistically significant. REVIEW REGISTRATION: PROSPERO, CRD42022304521.

The complex hydrogel based on diatom biosilica and hydroxybutyl chitosan for wound healing.

In this study, doxycycline (DOXY)-loaded diatom biosilica (DBs) were developed and coated with hydroxybutyl chitosan (HBC) hydrogel for wound healing. The HBC/DBs/DOXY composite hydrogel had significant inhibitory activity against S. aureus (100%) and E. coli (98%). In addition, the HBC/DBs/DOXY hydrogel showed minimum cytotoxicity on L929 cells in vitro, indicating the great biocompatibility of the composite hydrogel. The in vivo results demonstrated that HBC/DBs/DOXY composite hydrogel could promote the wound re-epithelialization and accelerate the healing. The wound closure was evaluated to be 99.4 ± 0.4% at day 12 after treated with the hydrogel, with the presence of neovascularization and collagen deposition, all indicating the great potential of HBC/DBs/DOXY hydrogel in wound healing.

A Freestanding Chitin-Derived Hierarchical Nanocomposite for Developing Electrodes in Future Supercapacitor Industry.

Crustacean cuticles are receiving extensive attention for its potential in developing environmentally friendly and high energy density electrodes for supercapacitor applications. In the current work, the demineralized tergite cuticle of mantis shrimp was employed as a precursor for the fabrication porous biochar. The structural benefits of the cuticle, including the hierarchical nanofiber networks, and the interpenetrating pore systems were maximumly retained, providing a high carbon content and specific surface area scaffold. Graphene oxide sheets were deposited across the biochar through the pore canal systems to further increase the conductivity of the biochar, forming a novel freestanding carbon composite. Throughout the modification process, the material products were examined by a range of methods, which showed desired structural, chemical and functional properties. Our work demonstrates that high performance carbon materials can be manufactured using a simple and green process to realize the great potential in energy storage applications.

Construction and characterization of degradable fish scales for enhancing cellular adhesion and potential using as tissue engineering scaffolds.

As a framework for tissue engineering regeneration, the characteristics of cell scaffold materials directly affect cell adhesion, migration and metabolism. In this study, we have fabricated decellularized and decalcified fish scale-derived scaffolds and determined its basic physicochemical properties to serve as cell scaffolds in tissue engineering. Scanning electron microscopy (SEM) results showed that there were radial grooves and ring ridges on the surface of the scale-derived scaffolds, which could simulate three-dimensional microenvironment for cells culture. Similarity to the bone extracellular matrix, the main components of the fish scales were hydroxyapatite (HA) and type I collagen fibers, which were conducive to cells spreading and proliferation. Moreover, for culturing L929 cells and rat bone marrow mesenchymal stem cells (BMSCs), the fish scales as cell scaffolds exhibited high cytocompatibility to enhance cells adhesion and proliferation, and also displayed the ability to guide cells migration along the ridge channels. Accordingly, the results suggested that the fish scale-derived scaffolds had a great potential as a natural extracellular matrix for tissue engineering.

Mechanically and functionally strengthened tissue adhesive of chitin whisker complexed chitosan/dextran derivatives based hydrogel.

Schiff base reaction crosslinking hydrogels are advantageous by rapid formation and absence of external crosslinkers. However, poor mechanical hindered their broader applications. Here, a mechanically strengthened tissue adhesive was constructed through incorporation of chitin nano-whiskers (CtNWs) with a Schiff base crosslinking hydrogel of carboxymethyl chitosan (CMCS) and dextran dialdehyde (DDA). The optimal formulation of complexed hydrogel exhibited 1.87 folds higher compressive stress than non-complexed and 1.51 time higher adhesive strength on porcine skin. The complexed hydrogel exhibited negligible cytotoxicity, anti-swelling performance in PBS, optimum antibacterial and hemostatic capacities. In vivo implantation studies confirmed the complexed hydrogel was degradable without long-term inflammatory responses. Desirable efficacy of injectable complexed hydrogel as hemostat was demonstrated in rat liver injury model, which could avoid severe postoperative adhesion and necrosis as observed in the treatment with commercial 3 M™ vetbond™ tissue adhesive. The results highlighted that the complexed hydrogel potentiated rapid hemostasis and wound repair applications.

Thermo/photo dual-crosslinking chitosan-gelatin methacrylate hydrogel with controlled shrinking property for contraction fabrication.

Stimuli-responsive gel volume variation is reversible and has shown promising applications, which may be potential for contraction or expansion fabrication, generating shrinking or swelling volume of the original. In this study, a thermo/photo dual-crosslinking hydrogel is prepared with methacrylated hydroxylbutyl chitosan (MHBC) and gelatin methacrylate (GelMA). The M/G hydrogel undergoes sol-gel phase transition under room temperature and shrinking deformation upon elevating temperature. Besides nontoxicity and biodegradability, dual crosslink endowed the composite hydrogel with strengthened and tunable mechanical property, controlled and repeatable contraction property in response to temperature elevation from 25 ℃ to 37 ℃, and enhanced cell adhesion in 3D culture. These peculiarities of M/G hydrogel provide great potential for application in contraction fabrication to acquire high resolution or small scale features that may be limited by fabrications devices.

Construction of physical-crosslink chitosan/PVA double-network hydrogel with surface mineralization for bone repair.

Weak mechanical properties, lack biocompatibility and relatively bioinert are formidable obstruct in application of bone repair materials. Multifunctional composite materials have been considered as a viable solution to this problem. Here, a new double network (DN) hydrogel was constructed by physical cross-linking of medical grade poly (vinyl alcohol) (PVA) and chitosan in KOH/urea dissolution system. The obtained hydrogel demonstrated excellent tensile strength (0.24 MPa), elongation at break (286%), and high compressive strength (0.11 MPa on the strain of 60%). Our studies showed that the prepared hydrogel had excellent biocompatibility in vitro and the introduction of hydroxyapatite (HAp) by surface mineralization imparted hydrogel the ability to induce rat bone marrow stem cells (rBMSCs) differentiation. The in vivo experiments revealed that the surface mineralized double network hydrogel significantly accelerated simultaneous regeneration of bone defects in a rabbit bone defect model. All the results indicated that this hydrogel has the potential as a bone repair material.

A surface charge dependent enhanced Th1 antigen-specific immune response in lymph nodes by transfersome-based nanovaccine-loaded dissolving microneedle-assisted transdermal immunization.

The efficient delivery of vaccines to draining lymph nodes and the induction of robust local immune responses are crucial for immunotherapy. Transdermal administration has been evidenced to facilitate the delivery of ingredients to lymph nodes. In this study, transfersomes with opposite surface charges were applied for antigen encapsulation and these were integrated with dissolving microneedles to investigate their effects on immune responses via transdermal immunization. The microneedles were easily inserted into mouse skin and achieved the local release of nanovaccines into the dermis through dissolution. Although anionic nanovaccines promoted cellular uptake via DC2.4, cationic nanovaccines exhibited stronger escape capacities from endocytic compartments, facilitating antigen processing via an MHC-I presentation pathway, and formed larger accumulations in lymph nodes. Compared with their anionic counterparts, the cationic nanovaccines more efficiently activated DC maturation and induced Th1 immunity; this was suggested by the significantly increased IgG2a/IgG1 ratio and elevated cytokine secretion from Th1 cells, without an enhancement in the Th2 response. Such an enhanced Th1 antigen-specific immune response in lymph nodes via a transdermal vaccine delivery platform is beneficial for potential immunotherapy approaches.

Optimization of the preparation conditions of thermo-sensitive chitosan hydrogel in heterogeneous reaction using response surface methodology.

A thermo-sensitive hydroxybutyl chitosan (HBC) hydrogel was prepared by using 1,2­butene oxide as an etherification modifying agent. To obtain the maximum yield of HBC, response surface methodology (RSM) was applied to optimize its preparation conditions. Key factors were chosen firstly by Plackett-Burman design (PBD) experiments, such as the concentration of NaOH, the ratio of isopropanol to water and reaction temperature. Steepest ascent experiments were employed to reach the top region of the response and determine the appropriate levels of three key factors. A three-level-three-variable Box-Behnken design (BBD) was used to further optimize the synthesis parameters. The results indicated that when the concentration of NaOH and the ratio of isopropyl alcohol to water were 40.65% and 2.68:1 at reaction temperature of 59 °C, respectively, the yield of HBC production was 5.897 ±â€¯0.112 g and close to the predicted value (6.002 g), which demonstrated that the effectiveness of BBD model and the controllability for the yield of HBC in the heterogeneous reaction system.

Enhanced transdermal lymphatic delivery of doxorubicin via hyaluronic acid based transfersomes/microneedle complex for tumor metastasis therapy.

Tumor-draining lymph nodes (TDLN) are major metastatic sites for many solid tumor to support tumor progression and metastasis. Lymphatic delivery is regarded as a desirable route to promote adoptive immune response via vaccination, or to achieve efficient chemotherapy for tumor metastasis. In this study, a novel dissolving microneedle was fabricated using hyaluronic acid, integrated with transfersome (T) to break the limit of transdermal cargo transit. In virtue of the insertion capacity of microneedle and the lymphatic delivering ability of transfersomes, such transfersome/microneedles complex (T/MNs) was expected to enhance lymphatic delivery. The results revealed that the microneedles were able to efficiently insert into rat skin and release the doxorubicin loaded transfersome (DOX-T) in dermis via self-dissolution. DOX-T would maintain their multilayer structure as released from dissolved microneedles. DOX-T/MN could significantly promote accumulation of DOX in lymph nodes compared to epidermal diffusion, and increased its transdermal bioavailability in plasma. The results not only are promising for chemo-therapy of tumor through lymphatic drug delivery, especially for killing the metastasized tumor cells appeared in draining lymph nodes, they also provide an efficient strategy for tumor immune-therapy using transdermal administration.

A novel pH-responsive quaternary ammonium chitosan-liposome nanoparticles for periodontal treatment.

The aim of this study was to evaluate the antibacterial activity and cytocompatibility of novel pH-activated nanoparticles (NPs) in vitro and in vivo. The NPs were synthesized from a quaternary ammonium chitosan, i.e., N,N,N-trimethyl chitosan, a liposome, and doxycycline (TMC-Lip-DOX NPs). The cytocompatibility of the NPs was evaluated. The TMC-Lip-DOX NPs achieved superb inhibition of free mixed bacteria and biofilm formation. They also showed excellent biocompatibility with human periodontal ligament fibroblasts. Animal experiments showed that the NPs strongly inhibited biofilm formation and prevented alveolar bone absorption in vivo. All the results indicate that the TMC-Lip-DOX NPs have good potential for use in the treatment of periodontal and other inflammatory diseases.

A thermosensitive RGD-modified hydroxybutyl chitosan hydrogel as a 3D scaffold for BMSCs culture on keloid treatment.

Cell therapy with bone marrow-derived mesenchymal stem cells (BMSCs) is a potential method for many disease treatments, including keloid. In the present study, an Arg-Gly-Asp (RGD) modified hydroxybutyl chitosan (HBC) hydrogel (HBC-RGD) was developed to enhance the adhesion and proliferation of BMSCs within the hydrogel. The successful synthesis of HBC-RGD was confirmed by FTIR and 1H NMR. Both HBC and HBC-RGD hydrogel had desired thermosensitivity, biocompatibility and enzymatic degradability in vitro. Compared with HBC hydrogel, HBC-RGD hydrogel was more beneficial for the adhesion and proliferation of BMSCs. Furthermore, the BMSCs incorporated HBC-RGD (BMSCs/HBC-RGD) hydrogel could inhibit the proliferation of keloid fibroblasts (Kfs) and suppress the nodular collagenous fibers of keloid tissue. These results suggested that the HBC-RGD hydrogel could be applied as a potential 3D hydrogel scaffold for cell culture, and BMSCs/HBC-RGD hydrogel was potential to be applied for keloid therapy with subcutaneous in-situ injection in the future.

The green and stable dissolving system based on KOH/urea for homogeneous chemical modification of chitosan.

The novel solvent (0.25 M KOH/0.01 M urea alkaline solution) was used to successfully dissolve chitosan without freezing-thawing cycles, for the first time. The results from XRD, FTIR, and 13CNRM proved that KOH/urea solution could destroy the hydrogen bonds between chitosan chains more efficiently than NaOH/urea solution. The dynamic light scattering, rheology, viscosity and elemental analysis confirmed that the KOH/urea hydrogen-bonded chitosan complex had a better thermal stability at 40 °C, and no obvious deacetylation and degradation appeared in dissolution process. Subsequently, the homogeneous chemical modification of chitosan based on KOH/urea dissolution system solution was conducted at 25 °C. The FTIR and microscopic observation indicated that the carboxymethyl chitosan, N,N,N-trimethyl chitosan and hydroxyl butyl chitosan were synthetized successfully. This work provided a green and stable solvent for homogeneous chemical modification of chitosan.

Reinforcement of thermoplastic chitosan hydrogel using chitin whiskers optimized with response surface methodology.

To strengthen the mechanical strength of thermo-sensitive hydroxybutyl chitosan (HBC) hydrogel, chitin whiskers were used as sticker to fabricate reinforced HBC (HBCW) hydrogel by using response surface methodology. Unlike the intrinsic network of HBC hydrogel, HBCW hydrogel showed a laminar shape with firm structure. The preparation condition was optimized by three-factor-three-level Box-Behnken design. The maximum mechanical strength (1011.11 Pa) was achieved at 50 °C, when the concentrations of HBC and chitin whiskers were 5.1 wt% and 2.0 wt%, respectively. The effects of temperature, pH value and NaCl concentration on mechanical strength of HBCW hydrogels were investigated via the oscillatory stress sweeps. The results showed that HBCW hydrogel could reach the maximum stiffness (∼1126 Pa) at 37 °C pH 12.0. Low pH and high salty ions could decrease the stability of hydrogel, while chitin whiskers could increase the stress tolerance and related ruptured strain of HBCW hydrogels.

Preparation of composite hydroxybutyl chitosan sponge and its role in promoting wound healing.

In this work, a composite sponge was produced by physically mixing hydroxybutyl chitosan with chitosan to form a porous spongy material through vacuum freeze-drying. Hydrophilic and macroporous composite hydroxybutyl chitosan sponge was developed via the incorporation of chitosan into hydroxybutyl chitosan. The composite sponge showed higher porosity (about 85%), greater water absorption (about 25 times), better softness and lower blood-clotting index (BCI) than those of chitosan sponge and hydroxybutyl chitosan sponge. The composite sponge with good hydrophilic could absorb the moisture in the blood to increase blood concentration and viscosity, and become a semi-swelling viscous colloid to clog the capillaries. Cytocompatibility tests with L929 cells and HUVEC cells demonstrated that composite sponge were no cytotoxicity, and could promote the growth of fibroblasts. It made up for the shortcomings of hydroxybutyl chitosan with unfavorable antibacterial effect to achieve a higher level of antibacterial (>99.99% reduction). Eventually, the vivo evaluations in Sprague-Dawley rats revealed that epithelial cells attached to the composite sponge and penetrated into the interior, in addition to this, it was also proved that the composite sponge (HC-1) had a better ability to promote wound healing and helped for faster formation of skin glands and re-epithelialization. The obtained data encourage the use of this composite sponge for wound dressings.