Crystallographic plane-induced selective mineralization of nanohydroxyapatite on fibrous-grained titanium promotes osteointegration and biocorrosion resistance.

The (002) crystallographic plane-oriented hydroxyapatite (HA) and anatase TiO2 enable favorable hydrophilicity, osteogenesis, and biocorrosion resistance. Thus, the crystallographic plane control in HA coating and crystalline phase control in TiO2 is vital to affect the surface and interface bioactivity and biocorrosion resistance of titanium (Ti) implants. However, a corresponding facile and efficient fabrication method is absent to realize the HA(002) mineralization and anatase TiO2 formation on Ti. Herein, we utilized the predominant Ti(0002) plane of the fibrous-grained titanium (FG Ti) to naturally form anatase TiO2 and further achieve a (002) basal plane oriented nanoHA (nHA) film through an in situ mild hydrothermal growth strategy. The formed FG Ti-nHA(002) remarkably improved hydrophilicity, mineralization, and biocorrosion resistance. Moreover, the nHA(002) film reserved the microgroove-like topological structure on FG Ti. It could enhance osteogenic differentiation through promoted contact guidance, showing one order of magnitude higher expression of osteogenic-related genes. On the other hand, the nHA(002) film restrained the osteoclast activity by blocking actin ring formation. Based on these capacities, FG Ti-nHA(002) improved new bone growth and binding strength in rabbit femur implantation, achieving satisfactory osseointegration within 2 weeks.

Inverse design of skull osteoinductive implants with multi-level pore structures through machine learning.

How to accurately design a personalized matching implant that can induce skull regeneration is the focus of current research. However, the design space for the porous structure of implants is extensive, and the mapping relationships between these structures and their mechanical and osteogenic properties are complex. At present, the forward design of skull implants mainly relies on expert experience, leading to high cost and a lengthy process, while the existing inverse design approaches face challenges due to data dependence and manufacturing process errors. This study presents an efficient inverse design method for personalized multilevel structures of skull implants using a machine learning pipeline composed of a finite element method, topological optimization, and neural networks. Based on the mechanical response of the human body falls, this method can tailor multi-level structures for implants in various defect positions. The results show that the proposed method establishes a bidirectional relationship between topological parameters and mechanical properties, enabling the customization of mechanical behavior at low computational cost while accounting for manufacturing errors in the 3D printing process. Additionally, the design results are also mutually consistent with analytical relationships between lattice parameters and the elastic modulus obtained from experiments and finite element simulations. Thus, this study provides a general and practical approach to rapidly design skull osteoinductive implants.

Enhancing melanoma therapy by modulating the immunosuppressive microenvironment with an MMP-2 sensitive and nHA/GNE co-encapsulated hydrogel.

The immunosuppressive tumor microenvironment, such as lactic acid and matrix metalloproteinases (MMPs) overexpression, has been well confirmed to be adverse for tumor therapy. In current study, a tumor microenvironment modulatory hydrogel was successfully developed to treat melanoma by taking advantage of the synergistic effects of nano-hydroxyapatite (nHA) with well-documented selective anti-tumor action, lactate dehydrogenase A inhibitor (R)-GNE-140 (GNE), and matrix metalloproteinase-2 (MMP-2) sensitive peptide. The hydrogel was acquired by the reaction of 4-arm-polyethylene glycol-maleic anhydride (4-arm-PEG-MAL) and MMP-2 sensitive peptide (CC-14), in which nHA and GNE were co-encapsulated physically. The in vitro degradation tests confirmed the accelerated release of nHA and GNE from the hydrogel under less-acidic (pH 6.8) and MMP-2 containing conditions compared to those neutral or without MMP-2 conditions, demonstrating the pH and MMP-2 responsive properties of as-prepared hydrogel. Findings from in vitro cell experiments revealed that the hydrogel could stop the proliferation of melanoma cells by stacking cell cycle via lactic acid metabolic dysregulation and boosting cell apoptosis via nHA direct killing effect. Moreover, after hydrogel treatment, the rate of migration and aggressiveness of melanoma cells both reduced significantly. An in vivo anti-melanoma study showed that the hydrogel could inhibit tumor growth significantly and result in more CD8+ T cells and antigen-presenting cells but less Treg cells infiltration, ultimately leading to an enhanced therapeutic efficacy. As thus, the fabricated hydrogel demonstrated great promise for treating melanoma and could be a new potent strategy for efficient melanoma therapy. STATEMENT OF SIGNIFICANCE: Nano-hydroxyapatite (nHA) has the capability of selectively killing cancer cells. The study reported a tumor microenvironment (TME) modulatory hydrogel with the goal of enhancing melanoma therapy efficacy by combining nHA administration with immunosuppressive microenvironment modulation. The hydrogel demonstrated pH and MMP-2 sensitivity. Hence, controlled release of nHA and lactate dehydrogenase A inhibitor (GNE) could be observed, and in situ MMP-2 consumption at the tumor site occurred. The hydrogel effectively inhibited the growth of melanoma cells. Furthermore, hydrogel increased the production of CD8+ T cells and antigen-presenting cells while decreasing the infiltration of Treg cells at the tumor site. This could transform the initial "cold" tumor into a "hot" tumor, ultimately resulting in an enhanced therapeutic effect.

Osteoinductive biomaterials: Machine learning for prediction and interpretation.

Biomaterials with osteoinductivity are widely used for bone defect repair due to their unique structures and functions. Machine learning (ML) is pivotal in analyzing osteoinductivity and accelerating new material design. However, challenges include creating a comprehensive database of osteoinductive materials and dealing with low-quality, disparate data. As a standard for evaluating the osteoinductivity of biomaterials, ectopic ossification has been used. This paper compiles research findings from the past thirty years, resulting in a robust database validated by experts. To tackle issues of limited data samples, missing data, and high-dimensional sparsity, a data enhancement strategy is developed. This approach achieved an area under the curve (AUC) of 0.921, a precision of 0.839, and a recall of 0.833. Model interpretation identified key factors such as porosity, bone morphogenetic protein-2 (BMP-2), and hydroxyapatite (HA) proportion as crucial determinants of outcomes. Optimizing pore structure and material composition through partial dependence plot (PDP) analysis led to a new bone area ratio of 14.7 ± 7 % in animal experiments, surpassing the database average of 10.97 %. This highlights the significant potential of ML in the development and design of osteoinductive materials. STATEMENT OF SIGNIFICANCE: This study leverages machine learning to analyze osteoinductive biomaterials, addressing challenges in database creation and data quality. Our data enhancement strategy significantly improved model performance. By optimizing pore structure and material composition, we increased new bone formation rates, showcasing the vast potential of machine learning in biomaterial design.

PI3K/AKT/mTOR signaling regulates BCP ceramic-induced osteogenesis.

An increasing number of studies demonstrate that biphasic calcium phosphate (BCP) ceramics can induce bone regeneration. However, the underlying molecular mechanisms involved are still poorly understood. This work was proposed to investigate how PI3K/AKT/mTOR signaling influenced the osteogenesis mediated by BCP ceramics. The results showed that incubation with BCP ceramics promoted the proliferation of murine bone marrow-derived mesenchymal stem cells (BMSCs) in a time-dependent manner. The resulting cell proliferation was then suppressed by the selective inhibition of either PI3K, AKT, or mTOR signaling activation. Next, we confirmed that BCP ceramics up-regulated the phosphorylation levels of AKT and mTOR in BMSCs, suggesting the ability of BCP ceramics to drive the activation of PI3K/AKT/mTOR signaling in BMSCs. Furthermore, the blockade of PI3K/AKT/mTOR signaling prevented BCP ceramics-induced osteogenic differentiation and pro-angiogenesis of BMSCs by down-regulating the expression of genes encoding OPN, RUNX2 or VEGF. Moreover, the PI3K/AKT/mTOR signaling blockade suppressed stem cell infiltration and new bone formation in the implants following intra-muscular implantation of BCP ceramics in mice. Therefore, our results suggested that PI3K/AKT/mTOR signaling played a critical regulatory role in BCP ceramic-induced osteogenesis.

3D printing calcium phosphate ceramics with high osteoinductivity through pore architecture optimization.

The osteoinductivity of 3D printed calcium phosphate (CaP) ceramics has a large gap compared with those prepared by conventional foaming methods, and improving the osteoinductivity of 3D printing CaP ceramics is crucial for successful application in bone regeneration. Pore architecture plays a critical role in osteoinductivity. In this study, CaP ceramics with a hexagonal close-packed (HCP) spherical pore structure were successfully fabricated using DLP printing technology. Additionally, octahedral (Octahedral), diamond (Diamond), and helical (Gyroid) structures were constructed with similar porosity and macropore diameter. CaP ceramics with the HCP structure exhibited higher compression strength (8.39 ± 1.82 MPa) and lower permeability (6.41 × 10-11 m2) compared to the Octahedral, Diamond, and Gyroid structures. In vitro cellular responses indicated that the macropore architecture strongly influenced the local growth rate of osteoblast-formed cell tissue; cells grew uniformly and formed circular rings in the HCP group. Furthermore, the HCP group promoted the expression of osteogenic genes and proteins more effectively than the other three groups. The outstanding osteoinductivity of the HCP group was confirmed in canine intramuscular implantation studies, where the new bone area reached up to 8.02 ± 1.94 % after a 10-week implantation. Additionally, the HCP group showed effective bone regeneration in repairing femoral condyle defects. Therefore, our findings suggest that 3D printed CaP bioceramics with an HCP structure promote osteoinductivity and can be considered as candidates for personalized precise treatment of bone defects in clinical applications. STATEMENT OF SIGNIFICANCE: 1. 3D printing BCP ceramics with high osteoinductivity were constructed through pore architecture optimization. 2. BCP ceramics with HCP structure exhibited relatively higher mechanical strength and lower permeability than those with Octahedral, Diamond and Gyroid structures. 3. BCP ceramics with HCP structure could promote the osteogenic differentiation of MC3T3-E1, and showed the superior in-vivo osteoinductivity and bone regeneration comparing with the other structures.

Survival and Neurologic Outcomes From Pharmacologic Peptide Administration During Cardiopulmonary Resuscitation of Pulseless Electrical Activity.

BACKGROUND: Outcomes from cardiopulmonary resuscitation (CPR) following sudden cardiac arrest are suboptimal. Postresuscitation targeted temperature management has been shown to have benefit in subjects with sudden cardiac arrest due to ventricular fibrillation, but there are few data for outcomes from sudden cardiac arrest due to pulseless electrical activity. In addition, intra-CPR cooling is more effective than postresuscitation cooling. Physical cooling is associated with increased protein kinase B activity. Therefore, our group developed a novel peptide, TAT-PHLPP9c, which regulates protein kinase B. We hypothesized that when given during CPR, TAT-PHLPP9c would improve survival and neurologic outcomes following pulseless electrical activity arrest. METHODS AND RESULTS: In 24 female pigs, pulseless electrical activity was induced by inflating balloon catheters in the right coronary and left anterior descending arteries for ≈7 minutes. Advanced life support was initiated. In 12 control animals, epinephrine was given after 1 and 3 minutes. In 12 peptide-treated animals, 7.5 mg/kg TAT-PHLPP9c was also administered at 1 and 3 minutes of CPR. The balloons were removed after 2 minutes of support. Animals were recovered and neurologically scored 24 hours after return of spontaneous circulation. Return of spontaneous circulation was more common in the peptide group, but this difference was not significant (8/12 control versus 12/12 peptide; P=0.093), while fully intact neurologic survival was significantly more common in the peptide group (0/12 control versus 11/12 peptide; P<0.00001). TAT-PHLPP9c significantly increased myocardial nicotinamide adenine dinucleotide levels. CONCLUSIONS: TAT-PHLPP9c resulted in improved survival with full neurologic function after sudden cardiac arrest in a swine model of pulseless electrical activity, and the peptide shows potential as an intra-CPR pharmacologic agent.

Study on the mechanism of modified Gegen Qinlian decoction in regulating the intestinal flora-bile acid-TGR5 axis for the treatment of type 2 diabetes mellitus based on macro genome sequencing and targeted metabonomics integration.

BACKGROUND: Currently, there are many drugs available for the treatment of type 2 diabetes mellitus (T2DM), but most of them cause various side effects due to the need for long-term use. As a traditional Chinese medicine, Gegen Qinlian Decoction (GQD) has shown good efficacy and low side effects in the treatment of T2DM in both clinical and basic research. Based on relevant traditional Chinese medicine theories, dried ginger is innovatively added the formula of traditional GQD to create a modified GQD. This modification reduces the side effects of traditional GQD while exerting its therapeutic effect on T2DM. Previous studies have found that the modified GQD can regulate endoplasmic reticulum stress in the liver, inhibit hepatic gluconeogenesis, protect pancreatic islet ß cells, and control blood sugar levels by inhibiting the FXR/neuronal ceramide signaling pathway. GQD can also regulate the intestinal microbiota to achieve therapeutic and protective effects in various gastrointestinal diseases. However, there is no research exploring whether the modified GQD achieves its therapeutic mechanism for T2DM by regulating the intestinal microbiota. PURPOSE: To explore the mechanism of modified GQD in the treatment of T2DM based on multi-omics, focusing on its effect on the "intestinal flora bile acid TGR5'' axis. METHODS: The T2DM model was established using db/db mice, which were randomly divided into a model group, metformin group, high-dose GQD group, medium-dose GQD group, low-dose GQD group, while m/m mice were used as blank control. The drug intervention lasted for 12 weeks, during which the general conditions, oral glucose tolerance (OGT), blood glucose, and lipid-related indexes were recorded. Additionally, the fasting insulin (FINS), c-peptide, GLP-1 in serum, and cAMP in the ileum were measured by ELISA assay. Furthermore, the composition, abundance, and function of the intestinal microbiota were determined by macro genome sequencing, while bile acid was detected by targeted metabonomics. For histological evaluation, HE staining was used to observe the pathological changes of the ileum and pancreas, and the ultrastructure of the ileum and pancreas was observed by transmission electron microscopy. Apoptosis in the ileum tissue was detected by Tunel staining. Moreover, the mRNA and protein expressions of TGR5, PKA, CREB, PC1/3, GLP-1, and their phosphorylation levels in the ileum were detected by qPCR, immunohistochemistry, and Western blot; The expression of INS in the pancreas was also evaluated using immunohistochemistry. Finally, double immunofluorescence staining was used to detect the co-localization expression of TGR5 and GLP-1, NeuroD1, and GLP-1 in the ileum. RESULTS: The modified GQD was found to significantly reduce blood glucose, improve oral glucose tolerance, and blood lipid levels, as well as alleviate the injury of the ileum and pancreas in T2DM mice. Furthermore, modified GQD was found to effectively regulate intestinal flora, improve bile acid metabolism, activate the TRG5/cAMP/PKA/CREB signal pathway, and stimulate GLP-1 secretion. CONCLUSION: GQD can regulate the "intestinal flora-bile acid-TGR5" axis and has a therapeutic effect on T2DM in mice.

TriticeaeSSRdb: a comprehensive database of simple sequence repeats in Triticeae.

Microsatellites, known as simple sequence repeats (SSRs), are short tandem repeats of 1 to 6 nucleotide motifs found in all genomes, particularly eukaryotes. They are widely used as co-dominant markers in genetic analyses and molecular breeding. Triticeae, a tribe of grasses, includes major cereal crops such as bread wheat, barley, and rye, as well as abundant forage and lawn grasses, playing a crucial role in global food production and agriculture. To enhance genetic work and expedite the improvement of Triticeae crops, we have developed TriticeaeSSRdb, an integrated and user-friendly database. It contains 3,891,705 SSRs from 21 species and offers browsing options based on genomic regions, chromosomes, motif types, and repeat motif sequences. Advanced search functions allow personalized searches based on chromosome location and length of SSR. Users can also explore the genes associated with SSRs, design customized primer pairs for PCR validation, and utilize practical tools for whole-genome browsing, sequence alignment, and in silico SSR prediction from local sequences. We continually update TriticeaeSSRdb with additional species and practical utilities. We anticipate that this database will greatly facilitate trait genetic analyses and enhance molecular breeding strategies for Triticeae crops. Researchers can freely access the database at http://triticeaessrdb.com/.

A robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) electrospun membrane for dura repair.

Typically occurring after trauma or neurosurgery treatments, dura mater defect and the ensuing cerebrospinal fluid (CSF) leakage could lead to a number of serious complications and even patient's death. Although numerous natural and synthetic dura mater substitutes have been reported, none of them have been able to fulfill the essential properties, such as anti-adhesion, leakage blockage, and pro-dura rebuilding. In this study, we devised and prepared a series of robust and biodegradable hydroxyapatite/poly(lactide-co-ε-caprolactone) (nHA/PLCL) membranes for dura repair via an electrospinning technique. In particular, PLLA/PCL (80/20) was selected for electrospinning due to its mechanical properties that most closely resembled natural dural tissue. Studies by SEM, XRD, water contact angle and in vitro degradation showed that the introduction of nHA would destroy PLCL's crystalline structure, which would further affect the mechanical properties of the nHA/PLCL membranes. When the amount of nHA added increased, so did the wettability and in vitro degradation rate, which accelerated the release of nHA. In addition, the high biocompatibility of nHA/PLCL membranes was demonstrated by in vitro cytotoxicity data. The in vivo rabbit dura repair model results showed that nHA/PLCL membranes provided a strong physical barrier to stop tissue adhesion at dura defects. Meanwhile, the nHA/PLCL and commercial group's CSF had a significantly lower number of inflammatory cells than the control groups, validating the nHA/PLCL's ability to effectively lower the risk of intracranial infection. Findings from H&E and Masson-trichrome staining verified that the nHA/PLCL electrospun membrane was more favorable for fostering dural defect repair and skull regeneration. Moreover, the relative molecular weight of PLCL declined dramatically after 3 months of implantation, according to the results of the in vivo degradation test, but it retained the fiber network structure and promoted tissue growth, demonstrating the good stability of the nHA/PLCL membranes. Collectively, the nHA/PLCL electrospun membrane presents itself as a viable option for dura repair.

Osteo-immunomodulatory effects of macrophage-derived extracellular vesicles treated with biphasic calcium phosphate ceramics on bone regeneration.

Literature on osteoimmunology has demonstrated that macrophages have a great influence on biomaterial-induced bone formation. However, there are almost no reports clarifying the osteo-immunomodulatory capacity of macrophage-derived extracellular vesicles (EVs). This study comprehensively investigated the effects of EVs derived from macrophages treated with biphasic calcium phosphate (BCP) ceramics (BEVs) on vital events associated with BCP-induced bone formation such as immune response, angiogenesis, and osteogenesis. It was found that compared with EVs derived from macrophages alone (control, CEVs), BEVs preferentially promoted macrophage polarization towards a wound-healing M2 phenotype, enhanced migration, angiogenic differentiation, and tube formation of human umbilical vein endothelial cells, and induced osteogenic differentiation of mesenchymal stem cells. Analysis of 15 differentially expressed microRNAs (DEMs) related to immune, angiogenesis, and osteogenesis suggested that BEVs exhibited good immunomodulatory, pro-angiogenic, and pro-osteogenic abilities, which might be attributed to their specific miRNA cargos. These findings not only deepen our understanding of biomaterial-mediated osteoinduction, but also suggest that EVs derived from biomaterial-treated macrophages hold great promise as therapeutic agents with desired immunomodulatory capacity for bone regeneration.

Nano-hydroxyapatite promotes cell apoptosis by co-activating endoplasmic reticulum stress and mitochondria damage to inhibit glioma growth.

Despite a growing body of studies demonstrating the specific anti-tumor effect of nano-hydroxyapatite (n-HA), the underlying mechanism remained unclear. Endoplasmic reticulum (ER) and mitochondria are two key players in intracellular Ca2+ homeostasis and both require Ca2+ to participate. Moreover, the ER-mitochondria interplay coordinates the maintenance of cellular Ca2+ homeostasis to prevent any negative consequences from excess of Ca2+, hence there needs in-depth study of n-HA effect on them. In this study, we fabricated needle-like n-HA to investigate the anti-tumor effectiveness as well as the underlying mechanisms from cellular and molecular perspectives. Data from in vitro experiments indicated that the growth and invasion of glioma cells were obviously reduced with the aid of n-HA. It is interesting to note that the expression of ER stress biomarkers (GRP78, p-IRE1, p-PERK, PERK, and ATF6) were all upregulated after n-HA treatment, along with the activation of the pro-apoptotic transcription factor CHOP, showing that ER stress produced by n-HA triggered cell apoptosis. Moreover, the increased expression level of intracellular reactive oxygen species and the mitochondrial membrane depolarization, as well as the downstream cell apoptotic signaling activation, further demonstrated the pro-apoptotic roles of n-HA induced Ca2+ overload through inducing mitochondria damage. The in vivo data provided additional evidence that n-HA caused ER stress and mitochondria damage in cells and effectively restrain the growth of glioma tumors. Collectively, the work showed that n-HA co-activated intracellular ER stress and mitochondria damage are critical triggers for cancer cells apoptosis, offering fresh perspectives on ER-mitochondria targeted anti-tumor therapy.

Aptly chosen, effectively emphasizing the action and mechanism of antimycin A1.

Rhizoctonia solani Kühn, a plant pathogenic fungus that can cause diseases in multiple plant species is considered one of the common and destructive pathogens in many crops. This study investigated the action of antimycin A1, which was isolated from Streptomyces AHF-20 found in the rhizosphere soil of an ancient banyan tree, on Rhizoctonia solani and its mechanism. The inhibitory effect of antimycin A1 on R. solani was assessed using the comparative growth rate method. The results revealed that antimycin A1 exhibited a 92.55% inhibition rate against R. solani at a concentration of 26.66 µg/mL, with an EC50 value of 1.25 µg/mL. To observe the impact of antimycin A1 on mycelial morphology and ultrastructure, the fungal mycelium was treated with 6.66 µg/mL antimycin A1, and scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were employed. SEM analysis demonstrated that antimycin A1 caused mycelial morphology to become stripped, rough, and folded. The mycelium experienced severe distortion and breakage, with incomplete or locally enlarged ends, shortened branches, and reduced numbers. TEM observation revealed thickened cell walls, indistinct organelle boundaries, swollen mitochondria, exosmotic substances in vesicles, slow vesicle fusion, and cavitation. Real-time quantitative PCR and enzyme activity assays were conducted to further investigate the impact of antimycin A1 on mitochondria. The physiological and biochemical results indicated that antimycin A1 inhibited complexes III and IV of the mitochondrial electron transport chain. RT-PCR analysis demonstrated that antimycin A1 controlled the synthesis of relevant enzymes by suppressing the transcription levels of ATP6, ATP8, COX3, QCR6, CytB, ND1, and ND3 genes in mitochondria. Additionally, a metabolomic analysis revealed that antimycin A1 significantly impacted 12 metabolic pathways. These pathways likely experienced alterations in their metabolite profiles due to the inhibitory effects of antimycin A1. Consequently, the findings of this research contribute to the potential development of novel fungicides.

Continuous and low-carbon production of biomass flash graphene.

Flash Joule heating (FJH) is an emerging and profitable technology for converting inexhaustible biomass into flash graphene (FG). However, it is challenging to produce biomass FG continuously due to the lack of an integrated device. Furthermore, the high-carbon footprint induced by both excessive energy allocation for massive pyrolytic volatiles release and carbon black utilization in alternating current-FJH (AC-FJH) reaction exacerbates this challenge. Here, we create an integrated automatic system with energy requirement-oriented allocation to achieve continuous biomass FG production with a much lower carbon footprint. The programmable logic controller flexibly coordinated the FJH modular components to realize the turnover of biomass FG production. Furthermore, we propose pyrolysis-FJH nexus to achieve biomass FG production. Initially, we utilize pyrolysis to release biomass pyrolytic volatiles, and subsequently carry out the FJH reaction to focus on optimizing the FG structure. Importantly, biochar with appropriate resistance is self-sufficient to initiate the FJH reaction. Accordingly, the medium-temperature biochar-based FG production without carbon black utilization exhibited low carbon emission (1.9 g CO2-eq g-1 graphene), equivalent to a reduction of up to ~86.1% compared to biomass-based FG production. Undoubtedly, this integrated automatic system assisted by pyrolysis-FJH nexus can facilitate biomass FG into a broad spectrum of applications.

Analysis of the sodium pump subunit ATP1A3 in glioma patients: Potential value in prognostic prediction and immunotherapy.

The ATP1A3 gene is associated with the development and progression of neurological diseases. However, the pathological function and therapeutic value of ATP1A3 in glioblastoma (GBM) remains unknown. In this study, we tried to explore the correlation between the ATP1A3 gene expression and immune features in GBM samples. We found that ATP1A3 gene expression levels showed significant negative correlation with immune checkpoints such as PD-L1, CTLA-4 and IDO1. Next, ATP1A3 gene expression levels showed significant negative correlation with the anti-cancer immune cell process, the immune score and stromal score. By grouping ATP1A3 expression levels, we found that that immunomodulator-related genes and tumor-associated immune cell effector gene expression levels were associated with lower ATP1A3 expression. In addition, immunotherapy prediction pathway activity and a majority of the anti-cancer immune cell process activity levels were also showed to be correlated with lower ATP1A3 gene expression. Further, nine prognostic factors were identified by prognostic analysis, and a GBM prognostic model (risk score) was established. We applied the model to the TCGA GBM training set sample and the GSE4412 validation set sample and found that patients in the high risk score subgroup had significantly shorter survival time, demonstrating the prognostic value and prognostic efficacy of the risk score. Furthermore, ATP1A3 overexpression has also been found to sensitize cancer cells to anti-PD-1 therapy. In conclusion, we showed that ATP1A3 is a highly promising treatment target in GBM and the risk score is an independent prognostic factor for cancer and can be used to help guide the prediction of survival time in patients with GBM.

Analysis of Fluid Replacement in Two Fluidic Chambers for Oblique-Incidence Reflectivity Difference (OI-RD) Biosensor.

Optical biosensors have a significant impact on various aspects of our lives. In many applications of optical biosensors, fluidic chambers play a crucial role in facilitating controlled fluid delivery. It is essential to achieve complete liquid replacement in order to obtain accurate and reliable results. However, the configurations of fluidic chambers vary across different optical biosensors, resulting in diverse fluidic volumes and flow rates, and there are no standardized guidelines for liquid replacement. In this paper, we utilize COMSOL Multiphysics, a finite element analysis software, to investigate the optimal fluid volume required for two types of fluidic chambers in the context of the oblique-incidence reflectivity difference (OI-RD) biosensor. We found that the depth of the fluidic chamber is the most crucial factor influencing the required liquid volume, with the volume being a quadratic function of the depth. Additionally, the required fluid volume is also influenced by the positions on the substrate surface bearing samples, while the flow rate has no impact on the fluid volume.

Preparation of an injectable and photocurable carboxymethyl cellulose/hydroxyapatite composite and its application in cranial regeneration.

Limited bone regeneration, uncontrollable degradation rate, mismatched defect zone and poor operability have plagued the reconstruction of irregular bone defect by tissue-engineered materials. A combination of biomimetic scaffolds with hydroxyapatite has gained great popularity in promoting bone regeneration. Therefore, we designed an injectable, photocurable and in-situ curing hydrogel by methacrylic anhydride -modified carboxymethyl cellulose (CMC-MA) loading with spherical hydroxyapatite (HA) to highly simulate the natural bony matrix and match any shape of damaged tissue. The prepared carboxymethyl cellulose-methacrylate/ hydroxyapatite(CMC-MA/HA) composite presented good rheological behavior, swelling ratio and mechanical property under light illumination. Meanwhile, this composite hydrogel promoted effectively proliferation, supported adhesion and upregulated the osteogenic-related genes expression of MC3T3-E1 cells in vitro, as well as the activity of the osteogenic critical protein, Integrin α1, ß1, Myosin 9, Myosin 10, BMP-2 and Smad 1 in Integrin/BMP-2 signal pathway. Together, the composite hydrogels realized promotion of bone regeneration, deformity improvement, and the enhanced new bone strength in skull defect. It also displayed a good histocompatibility and stability of subcutaneous implantation in vivo. Overall, this study laid the groundwork for future research into developing a novel biomaterial and a minimally invasive therapeutic strategies for reconstructing bone defects and contour deficiencies.

Traditional Chinese medicine and its active substances reduce vascular injury in diabetes via regulating autophagic activity.

Due to its high prevalence, poor prognosis, and heavy burden on healthcare costs, diabetic vascular complications have become a significant public health issue. Currently, the molecular and pathophysiological mechanisms underlying diabetes-induced vascular complications remain incompletely understood. Autophagy, a highly conserved process of lysosomal degradation, maintains intracellular homeostasis and energy balance via removing protein aggregates, damaged organelles, and exogenous pathogens. Increasing evidence suggests that dysregulated autophagy may contribute to vascular abnormalities in various types of blood vessels, including both microvessels and large vessels, under diabetic conditions. Traditional Chinese medicine (TCM) possesses the characteristics of "multiple components, multiple targets and multiple pathways," and its safety has been demonstrated, particularly with minimal toxicity in liver and kidney. Thus, TCM has gained increasing attention from researchers. Moreover, recent studies have indicated that Chinese herbal medicine and its active compounds can improve vascular damage in diabetes by regulating autophagy. Based on this background, this review summarizes the classification, occurrence process, and related molecular mechanisms of autophagy, with a focus on discussing the role of autophagy in diabetic vascular damage and the protective effects of TCM and its active compounds through the regulation of autophagy in diabetes. Moreover, we systematically elucidate the autophagic mechanisms by which TCM formulations, individual herbal extracts, and active compounds regulate diabetic vascular damage, thereby providing new candidate drugs for clinical treatment of vascular complications in diabetes. Therefore, further exploration of TCM and its active compounds with autophagy-regulating effects holds significant research value for achieving targeted therapeutic approaches for diabetic vascular complications.

Research progress on ethnobotany, phytochemistry, pharmacological action, and applications of Engelhardia roxburghiana Wall: a review.

OBJECTIVES: Engelhardia roxburghiana Wall is a plant of the Juglandaceae family, and its leaves is the main part used as a medicine. It is used to relieve heat and pain, gasification, and dampness. The purpose of this review is to provide a systematic review about the botany, traditional uses, phytochemistry, pharmacology, and toxicology of this plant. KEY FINDINGS: Many compounds have been isolated and identified from the plant, including flavonoids, triterpenoids, steroids, quinones, essential oils, and other types of chemical constituents. Extensive pharmacological activities of the extracts or compounds of E. roxburghiana Wall in vivo and in vitro were mainly confirmed, including anti-cancer, anti-diabetic, anti-inflammatory, and anti-allergic effects. SUMMARY: In this paper, the botany, traditional uses, phytochemistry, and pharmacology of E. roxburghiana Wall were reviewed. In the future, E. roxburghiana Wall needs further study, such as paying more attention to quality control and the utilization on agriculture. In addition, discussing the medicinal components of decoction as well as the toxicity will also contribute to the progress of clinical trial studies.

Matched Kinetics Process Over Fe2O3-Co/NiO Heterostructure Enables Highly Efficient Nitrate Electroreduction to Ammonia.

Tandem nitrate electroreduction reaction (NO3 -RR) is a promising method for green ammonia (NH3) synthesis. However, the mismatched kinetics processes between NO3 --to-NO2 - and NO2 --to-NH3 results in poor selectivity for NH3 and excess NO2 - evolution in electrolyte solution. Herein, a Ni2+ substitution strategy for developing oxide heterostructure in Co/Fe layered double oxides (LDOs) was designed and employed as tandem electrocataltysts for NO3 -RR. (Co0.83Ni0.16)2Fe exhibited a high NH3 yield rate of 50.4 mg ⋅ cm-2 ⋅ h-1 with a Faradaic efficiency of 97.8 % at -0.42 V vs. reversible hydrogen electrode (RHE) in a pulsed electrolysis test. By combining with in situ/operando characterization technologies and theoretical calculations, we observed the strong selectivity of NH3 evolution over (Co0.83Ni0.16)2Fe, with Ni playing a dual role in NO3 -RR by i) modifying the electronic behavior of Co, and ii) serving as complementary site for active hydrogen (*H) supply. Therefore, the adsorption capacity of *NO2 and its subsequent hydrogenation on the Co sites became more thermodynamically feasible. This study shows that Ni substitution promotes the kinetics of the NO3 -RR and provides insights into the design of tandem electrocatalysts for NH3 evolution.