Regeneration of the human segmentation clock in somitoids in vitro.

Each vertebrate species appears to have a unique timing mechanism for forming somites along the vertebral column, and the process in human remains poorly understood at the molecular level due to technical and ethical limitations. Here, we report the reconstitution of human segmentation clock by direct reprogramming. We first reprogrammed human urine epithelial cells to a presomitic mesoderm (PSM) state capable of long-term self-renewal and formation of somitoids with an anterior-to-posterior axis. By inserting the RNA reporter Pepper into HES7 and MESP2 loci of these iPSM cells, we show that both transcripts oscillate in the resulting somitoids at ~5 h/cycle. GFP-tagged endogenous HES7 protein moves along the anterior-to-posterior axis during somitoid formation. The geo-sequencing analysis further confirmed anterior-to-posterior polarity and revealed the localized expression of WNT, BMP, FGF, and RA signaling molecules and HOXA-D family members. Our study demonstrates the direct reconstitution of human segmentation clock from somatic cells, which may allow future dissection of the mechanism and components of such a clock and aid regenerative medicine.

Soil and stone terraces offset the negative impacts of sloping cultivation on soil microbial diversity and functioning by protecting soil carbon.

Cultivation of sloping land is a main cause for soil erosion. Conservation practices, such as soil and stone terraces, may reduce the impacts of erosion but their impacts on soil microbial diversity and functioning related to carbon (C) and nutrient metabolisms remain unclear. This study was conducted to evaluate the effects of slope gradients (5°, 8°, 15°, 25°) and conservation practices (cultivated, uncultivated, soil terrace, and stone terrace) on bacterial and fungal diversities, metagenomic and metabolomic functioning associated with basic soil properties. Our results showed that steep slopes at 25° significantly decreased soil pH, silt percentage, and bacterial and fungal abundances, but that soil and stone terraces increased soil organic C (SOC), silt and clay contents, and fungal abundance compared to sloping cultivated lands. In addition, soil and stone terraces increased both bacterial and fungal alpha diversities, and relative abundances of Crenarchaeota, Nitrospirota, and Latescibacterota, but reduced the proportions of Actinobacteriota and Patescibacteria, thus shifting microbial beta diversities, which were significantly associated with increased SOC and silt content. For metagenomics, soil and stone terraces greatly increased the relative abundance of functional genes related to Respiration, Virulence, disease and defense, Stress response, and nitrogen and potassium metabolisms, such as Denitrification and Potassium homeostasis. For soil metabolomics, a total of 22 soil metabolites was enriched by soil and stone terraces, such as Lipids and lipid-like molecules (Arachidonic acid, Gamma-Linolenic acid, and Pentadecanoic acid), and Organoheterocyclic compounds (Adenine, Laudanosine, Methylpyrazine, and Nicotinic acid). To sum up, soil and stone terraces could reduce some of the negative impacts of steep slope cultivation on soil microbial diversity as well as their metagenomic and metabolomic functioning related to C and nutrient metabolism useful for soil health improvement, potentially bolstering the impact of sustainable practices in erosion hotspots around the world.

High-performance Complementary Electrochromic Batteries using Nb18W16O93 by the Synergistic Effects of Aqueous Al3+/K+ Dual-ion.

Multivalent ions, especially Al3+ in aqueous electrolyte contributes to higher capacity and color contrast for more sustainable post-lithium electrochromism and energy storages. However, the lack of suitable cathodic and anodic electrochromic materials is a major challenge for Al-ion electrochromic batteries, which limits their optical contrast and lifespan. Herein, we report that Wadsley-Roth phase Nb18W16O93 with open structure achieves Al3+ intercalation/extraction reversibly. The complementary electrochromic energy storage devices based on Nb18W16O93 coupled with Prussian blue using hybrid Al3+/K+ aqueous electrolytes show a fast response, a high capacity and a large coloring efficiency. The superior performances are due to the cations of Al3+ and K+ selectively insert/extract in the electrode of Nb18W16O93 and Prussian blue, respectively. This work provides an effective strategy for high-performance and low-cost electrochromic batteries with higher sustainability.

Enhancing Reversibility and Kinetics of Anionic Redox in O3-NaLi1/3Mn2/3O2 through Controlled P2 Intergrowth.

Anionic redox chemistry can surpass theoretical limits of conventional layered oxide cathodes in energy density. A recent model system of sodium-ion batteries, O3-NaLi1/3Mn2/3O2, demonstrated full anionic redox capacity but is limited in reversibility and kinetics due to irreversible structural rearrangement and oxygen loss. Solutions to these issues are missing due to the challenging synthesis. Here, we harness the unique structural richness of sodium layered oxides and realize a controlled ratio of P2 structural intergrowth in this model compound with the overall composition maintained. The resulted O3 with 27 % P2 intergrowth structure delivers an excellent initial Coulombic efficiency of 87 %, comparable to the state-of-the-art Li-rich NMCs. This improvement is attributed to the effective suppression of irreversible oxygen release and structural changes, evidenced by operando Differential Electrochemical Mass Spectroscopy and X-ray Diffraction. The as-prepared intergrowth material, based on the environmentally benign Mn, exhibits a reversible capacity of 226 mAh g-1 at C/20 rate with excellent cycling stability stemming from the redox reactions of oxygen and manganese. Our work isolates the role of P2 structural intergrowth and thereby introduces a novel strategy to enhance the reversibility and kinetics of anionic redox reactions in sodium layered cathodes without compromising capacity.

NOX4-derived ROS-induced overexpression of FOXM1 regulates aerobic glycolysis in glioblastoma.

BACKGROUND: Increased expression of the transcription factor Forkhead box M1 (FOXM1) has been reported to play an important role in the progression and development of multiple tumors, but the molecular mechanisms that regulate FOXM1 expression remain unknown, and the role of FOXM1 in aerobic glycolysis is still not clear. METHODS: The expression of FOXM1 and NADPH oxidase 4 (NOX4) in normal brain tissues and glioma was detected in data from the TCGA database and in our specimens. The effect of NOX4 on the expression of FOXM1 was determined by Western blot, qPCR, reactive oxygen species (ROS) production assays, and luciferase assays. The functions of NOX4 and FOXM1 in aerobic glycolysis in glioblastoma cells were determined by a series of experiments, such as Western blot, extracellular acidification rate (ECAR), lactate production, and intracellular ATP level assays. A xenograft mouse model was established to test our findings in vivo. RESULTS: The expression of FOXM1 and NOX4 was increased in glioma specimens compared with normal brain tissues and correlated with poor clinical outcomes. Aberrant mitochondrial reactive oxygen species (ROS) generation of NOX4 induced FOXM1 expression. Mechanistic studies demonstrated that NOX4-derived MitoROS exert their regulatory role on FOXM1 by mediating hypoxia-inducible factor 1α (HIF-1α) stabilization. Further research showed that NOX4-derived MitoROS-induced HIF-1α directly activates the transcription of FOXM1 and results in increased FOXM1 expression. Overexpression of NOX4 or FOXM1 promoted aerobic glycolysis, whereas knockdown of NOX4 or FOXM1 significantly suppressed aerobic glycolysis, in glioblastoma cells. NOX4-induced aerobic glycolysis was dependent on elevated FOXM1 expression, as FOXM1 knockdown abolished NOX4-induced aerobic glycolysis in glioblastoma cells both in vitro and in vivo. CONCLUSION: Increased expression of FOXM1 induced by NOX4-derived MitoROS plays a pivotal role in aerobic glycolysis, and our findings suggest that inhibition of NOX4-FOXM1 signaling may present a potential therapeutic target for glioblastoma treatment.

Effect of miR-106b on Invasiveness of Pituitary Adenoma via PTEN-PI3K/AKT.

BACKGROUND Pituitary adenomas are mostly benign tumors, although certain cases have invasiveness, which might be related with high expression of miR-106b. The PTEN-PI3K/AKT signal pathway is known to be related with cell migration and invasion. Among these, PTEN is the target gene for miR-106b. Whether miR-106b affects invasiveness of pituitary adenoma via PTEN-PI3K/AKT is unclear. MATERIAL AND METHODS Both invasive and non-invasive pituitary adenoma tissue samples were collected from our Neurosurgery Department, in parallel with brain tissues after head contusion surgery. Pituitary adenoma cell line HP75 was cultured in vitro and divided into NC and miR-106b inhibitor groups for measuring cell cycle/proliferation. Malignant growth of cells was measured by agarose gel clonal assay, while cell migration and invasion were reflected by starch assay and Transwell assay, respectively. The expression of PTEN, PI3K/AKT, and MMP-9 was measured. RESULTS MiR-106b was significantly up-regulated in pituitary adenoma but PTEN was down-regulated, especially in invasive tumors. The inhibition of miR-106b remarkably suppressed proliferation and anchorage-independent growth of HP75 cells, with major arrest of cell cycles. The inhibition of miR-106b significantly depressed starch healing and invasive potency of cells. A negative targeted regulation existed between miR-106b and PTEN, as the inhibition of miR-106b significantly enhanced PTEN expression, affecting the activity of downstream PI3K/AKT signaling pathway, thus affecting migration and invasion of pituitary adenoma. CONCLUSIONS MiR-106b can affect migration and invasion of pituitary adenoma cells via regulating PTEN and further activity of the PI3K/AKT signaling pathway and MMP-9 expression.

Convolutional transformer-driven robust electrocardiogram signal denoising framework with adaptive parametric ReLU.

The electrocardiogram (ECG) is a widely used diagnostic tool for cardiovascular diseases. However, ECG recording is often subject to various noises, which can limit its clinical evaluation. To address this issue, we propose a novel Transformer-based convolutional neural network framework with adaptively parametric ReLU (APtrans-CNN) for ECG signal denoising. The proposed APtrans-CNN architecture combines the strengths of transformers in global feature learning and CNNs in local feature learning to address the inadequacy of learning with long sequence time-series features. By fully exploiting the global features of ECG signals, our framework can effectively extract critical information that is necessary for signal denoising. We also introduce an adaptively parametric ReLU that can assign a value to the negative information contained in the ECG signal, thereby overcoming the limitation of ReLU to retain negative information. Additionally, we introduce a dynamic feature aggregation module that enables automatic learning and retention of valuable features while discarding useless noise information. Results obtained from two datasets demonstrate that our proposed APtrans-CNN can accurately extract pure ECG signals from noisy datasets and is adaptable to various applications. Specifically, when the input consists of ECG signals with a signal-to-noise ratio (SNR) of -4 dB, APtrans-CNN successfully increases the SNR to more than 6 dB, resulting in the diagnostic model's accuracy exceeding 96%.

NAD+ metabolism and therapeutic strategies in cardiovascular diseases.

Nicotinamide adenine dinucleotide (NAD+) is a central and pleiotropic metabolite involved in cellular energy metabolism, cell signaling, DNA repair, and protein modifications. Cardiovascular diseases (CVDs) are the leading cause of death worldwide. Metabolic stress and aging directly affect the cardiovascular system. Compelling data suggest that NAD + levels decrease with age, obesity, and hypertension, which are all notable risk factors for CVD. In addition, the therapeutic elevation of NAD + levels reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular disorders. In preclinical models, NAD + boosting can also expand the health span, prevent metabolic syndrome, and decrease blood pressure. Moreover, NAD + storage by genetic, pharmacological, or natural dietary NAD + -increasing strategies has recently been shown to be effective in improving the pathophysiology of cardiac and vascular health in different animal models, and human health. Here, we review and discuss NAD + -related mechanisms pivotal for vascular health and summarize recent experimental evidence in NAD + research directly related to vascular disease, including atherosclerosis, and coronary artery disease. Finally, we comparatively assess distinct NAD + precursors for their clinical efficacy and the efficiency of NAD + elevation in the treatment of major CVD. These findings may provide ideas for new therapeutic strategies to prevent and treat CVD in the clinic.

Photopolymerization-Based Three-Dimensional Ceramic Printing Technology.

Ceramics have many applications in mechanics, electronics, aerospace, and biomedicine because of their high mechanical strength, high-temperature resistance, and excellent chemical stability. Three-dimensional (3D) printing is a fast, efficient, and intelligent technology that has revolutionized the manufacturing of complex structural parts. Among many ceramic 3D printing technologies, photopolymerization-based 3D printing techniques print out molded ceramic components with high molding accuracy and surface finish and have received widespread attention. This article reviews the current research status and problems experienced by three mainstream ceramic photocuring technologies, namely stereoscopic, digital light processing, and two-photon polymerization.

Biosynthesis of ß-nicotinamide mononucleotide from glucose via a new pathway in Bacillus subtilis.

Introduction: ß-nicotinamide mononucleotide (ß-NMN) is an essential precursor of nicotinamide adenine dinucleotide (NAD+) and plays a key role in supplying NAD+ and maintaining its levels. Existing methods for NMN production have some limitations, including low substrate availability, complex synthetic routes, and low synthetic efficiency, which result in low titers and high costs. Methods: We constructed high-titer, genetically engineered strains that produce NMN through a new pathway. Bacillus subtilis WB600 was used as a safe chassis strain. Multiple strains overexpressing NadE, PncB, and PnuC in various combinations were constructed, and NMN titers of different strains were compared via shake-flask culture. Results: The results revealed that the strain B. subtilis PncB1-PnuC exhibited the highest total and extracellular NMN titers. Subsequently, the engineered strains were cultured in a 5-L fermenter using batch and fed-batch fermentation. B. subtilis PncB1-PnuC achieved an NMN titer of 3,398 mg/L via fed-batch fermentation and glucose supplementation, which was 30.72% higher than that achieved via batch fermentation. Discussion: This study provides a safe and economical approach for producing NMN on an industrial scale.

Preparation and anti-inflammatory effect of mercury sulphide nanoparticle-loaded hydrogels.

We successfully prepared mercury sulphide nanoparticle hydrogels by physical encapsulation method. The successfully prepared mercuric sulphide nanoparticle hydrogel was a zinc folate hydrogel, which showed an obvious porous structure with interconnected and uniformly distributed pores and a pore size range of about 20 µm. The maximum drug loading of the hydrogels was 3%, and the in vitro cumulative release degree was in accordance with the first-order kinetic equation Mt = 149.529 (1 - e-0.026t). The particles in mercuric sulphide nanoparticle hydrogels significantly down-regulated the expression of the cell surface co-stimulatory molecule CD86 (p < .0001). Meanwhile, the inflammatory response was regulated through the NF-κB pathway in LPS-induced inflammatory cells. Later, it was observed that mercuric sulphide nanoparticle hydrogels could significantly counteract the inflammatory and immune models through a mouse ear swelling model, a rat foot-plantar swelling model and a rheumatoid arthritis model. This design targets the immunomodulatory, and anti-inflammatory effects through nanocomposite hydrogel technology. It reduces the drawbacks of low mercury utilisation and susceptibility to accumulation of toxicity. It aims to provide an experimental basis for the development of mercuric sulphide and the treatment of inflammatory and immune-related diseases.HighlightsMercury sulphide nanoparticle hydrogel has an optimal mercury sulphide nanoparticle content of 2%, is structurally homogeneous and stable, and does not exhibit significant liver or kidney toxicity.Mercuric sulphide nanoparticle hydrogel exerts anti-inflammatory effects in cells and rats, and regulates the expression of macrophage surface molecules and factors related to the NF-κB pathway.Mercuric sulphide nanoparticle hydrogel improves the condition of ankle synovial joints in a rat model of rheumatoid arthritis.

Factors influencing residual air saturation during consecutive imbibition processes in an air-water two-phase fine sandy medium - A laboratory-scale experimental study.

The residual air saturation plays a crucial role in modeling hydrological processes of groundwater and the migration and distribution of contaminants in subsurface environments. However, the influence of factors such as media properties, displacement history, and hydrodynamic conditions on the residual air saturation is not consistent across different displacement scenarios. We conducted consecutive drainage-imbibition cycles in sand-packed columns under hydraulic conditions resembling natural subsurface environments, to investigate the impact of wetting flow rate, initial fluid state, and number of imbibition rounds (NIR) on residual air saturation. The results indicate that residual air saturation changes throughout the imbibition process, with variations separated into three distinct stages, namely, unstable residual air saturation (Sgr-u), momentary residual air saturation (Sgr-m), and stable residual air saturation (Sgr). The results also suggest that the transition from Sgr-u to Sgr is driven by changes in hydraulic pressure and gradient; the calculated values followed the following trend: Sgr > Sgr-u > Sgr-m. An increase in capillary number, which ranged from 1.46 × 10-7 to 3.07 × 10-6, increased Sgr-u and Sgr-m in some columns. The increase in Sgr ranged from 0.034 to 0.117 across all the experimental columns; this consistent increase can be explained by water film expansion at the primary wetting front along with a strengthening of the hydraulic gradient during water injection. Both the pre-covered water film on the sand grain surface and a pore-to-throat aspect ratio of up to 4.42 were identified as important factors for the increased residual air saturation observed during the imbibition process. Initial air saturation (Sai) positively influenced all three types of residual air saturation, while initial capillary pressure (Pci) exhibited a more pronounced inhibitory effect on residual air saturation, as it can partly characterized the initial connectivity of the air phase generated under different drying flow rates. Under identical wetting flow rate conditions, Sgr was higher during the second imbibition than during the first imbibition due to variations in initial fluid state, involving both fluid distribution and the concentration of dissolved air in the pore water. In contrast, NIR did not have an obvious effect on the three types of residual air saturation. This work aims to provide empirical evidences and offer further insights into the capture of non-wetting phases in groundwater environments, as well as to put forward some potential suggestion for future investigations on the retention and migration of contaminants that involves multiphase interface interactions in subsurface environments.

A multifunctional Ag NPs/guar gum hydrogel as versatile platform for catalysts, antibacterial agents, and construction of oil-water separation interfaces.

The frequently encountered wastewater contaminations, including soluble aromatic compound and dye pollutants, pathogenic bacteria, and insoluble oils, have resulted in significant environmental and human health issues. It poses a challenge to utilize identical materials for the treatment of complex wastewater. Herein, in this research, multifunctional Ag NPs/guar gum hybrid hydrogels were fabricated using a facile in situ reduction and self-crosslinking method for efficient remediation of complex wastewater. The Ag NPs/guar gum hybrid hydrogel showed remarkable remodeling, adhesive, and self-healing characteristics, which was favorable for its versatile applications. The combination of Ag NPs with the guar gum skeleton endowed the hybrid hydrogel with exceptional catalytic activity for reducing aromatic compounds and dye pollutants, as well as remarkable antibacterial efficacy against pathogenic bacteria. In addition, the Ag NPs/guar gum hybrid hydrogel could be employed to coat a variety of substrates, including cotton fabrics and stainless steel meshes. The hydrogel coated cotton fabrics and meshes presented superhydrophilicity/underwater superoleophobicity, excellent antifouling capacity, and outstanding recyclability, which could be successfully applied for efficient separation of oil-water mixtures. The findings of this work provide a feasible and cost-effective approach for the remediation of intricate wastewater.

Random walks in unweighted and weighted modular scale-free networks with a perfect trap.

Designing optimal structure favorable to diffusion and effectively controlling the trapping process are crucial in the study of trapping problem--random walks with a single trap. In this paper, we study the trapping problem occurring on unweighted and weighted networks, respectively. The networks under consideration display the striking scale-free, small-world, and modular properties, as observed in diverse real-world systems. For binary networks, we concentrate on three cases of trapping problems with the trap located at a peripheral node, a neighbor of the root with the least connectivity, and a farthest node, respectively. For weighted networks with edge weights controlled by a parameter, we also study three trapping problems, in which the trap is placed separately at the root, a neighbor of the root with the least degree, and a farthest node. For all the trapping problems, we obtain the analytical formulas for the average trapping time (ATT) measuring the efficiency of the trapping process, as well as the leading scaling of ATT. We show that for all the trapping problems in the binary networks with a trap located at different nodes, the dominating scalings of ATT reach the possible minimum scalings, implying that the networks have optimal structure that is advantageous to efficient trapping. Furthermore, we show that for trapping in the weighted networks, the ATT is controlled by the weight parameter, through modifying which, the ATT can behave superlinearly, linearly, sublinearly, or logarithmically with the system size. This work could help improving the design of systems with efficient trapping process and offers new insight into control of trapping in complex systems.

Optimal scale-free network with a minimum scaling of transport efficiency for random walks with a perfect trap.

Average trapping time (ATT) is central in the trapping problem since it is a key indicator characterizing the efficiency of the problem. Previous research has provided the scaling of a lower bound of the ATT for random walks in general networks with a deep trap. However, it is still not well understood in which networks this minimal scaling can be reached. Particularly, explicit quantitative results for ATT in such networks, even in a specific network, are lacking, in spite that such networks shed light on the design for optimal networks with the highest trapping efficiency. In this paper, we study the trapping problem taking place on a hierarchical scale-free network with a perfect trap. We focus on four representative cases with the immobile trap located at the root, a peripheral node, a neighbor of the root with a single connectivity, and a farthest node from the root, respectively. For all the four cases, we obtain the closed-form formulas for the ATT, as well as its leading scalings. We show that for all the four cases of trapping problems, the dominating scalings of ATT can reach the predicted minimum scalings. This work deepens the understanding of behavior of trapping in scale-free networks, and is helpful for designing networks with the most efficient transport process.

Critical transition of soil microbial diversity and composition triggered by plant rhizosphere effects.

Over the years, microbial community composition in the rhizosphere has been extensively studied as the most fascinating topic in microbial ecology. In general, plants affect soil microbiota through rhizodeposits and changes in abiotic conditions. However, a consensus on the response of microbiota traits to the rhizosphere and bulk soils in various ecosystems worldwide regarding community diversity and structure has not been reached yet. Here, we conducted a meta-analysis of 101 studies to investigate the microbial community changes between the rhizosphere and bulk soils across various plant species (maize, rice, vegetables, other crops, herbaceous, and woody plants). Our results showed that across all plant species, plant rhizosphere effects tended to reduce the rhizosphere soil pH, especially in neutral or slightly alkaline soils. Beta-diversity of bacterial community was significantly separated between into rhizosphere and bulk soils. Moreover, r-strategists and copiotrophs (e.g. Proteobacteria and Bacteroidetes) enriched by 24-27% in the rhizosphere across all plant species, while K-strategists and oligotrophic (e.g. Acidobacteria, Gemmatimonadete, Nitrospirae, and Planctomycetes) decreased by 15-42% in the rhizosphere. Actinobacteria, Firmicutes, and Chloroflexi are also depleted by in the plant rhizosphere compared with the bulk soil by 7-14%. The Actinobacteria exhibited consistently negative effect sizes across all plant species, except for maize and vegetables. In Firmicutes, both herbaceous and woody plants showed negative responses to rhizosphere effects, but those in maize and rice were contrarily enriched in the rhizosphere. With regards to Chloroflexi, apart from herbaceous plants showing a positive effect size, the plant rhizosphere effects were consistently negative across all other plant types. Verrucomicrobia exhibited a significantly positive effect size in maize, whereas herbaceous plants displayed a negative effect size in the rhizosphere. Overall, our meta-analysis exhibited significant changes in microbial community structure and diversity responding to the plant rhizosphere effects depending on plant species, further suggesting the importance of plant rhizosphere to environmental changes influencing plants and subsequently their controls over the rhizosphere microbiota related to nutrient cycling and soil health.

Intracranial dissemination of glioblastoma multiforme: a case report and literature review.

Intracranial dissemination is rare among patients with glioblastoma multiforme (GBM). Very few GBM patients develop symptoms from intracranial dissemination, as most do not surviving long enough for intracranial dissemination to become clinically evident. Herein, we report a case of GBM in a 39-year-old woman who underwent surgical resection, concomitant chemoradiotherapy, and seven courses of adjuvant chemotherapy with temozolomide. The patient then complained of an instable gait and hearing loss. Imaging studies demonstrated that although the primary intracranial tumors were well-controlled by treatment, contralateral cerebellopontine angle seeding dissemination was present. The patient died 3 months after the diagnosis of seeding dissemination. In light of a previous report and our current case, heightened awareness could promote surgical strategies that minimize the possibility of dissemination, including avoiding ventricular entry or a no-touch strategy.

RAGE Inhibitors as Alternatives to Dexamethasone for Managing Cerebral Edema Following Brain Tumor Surgery.

Resection of brain tumors frequently causes injury to the surrounding brain tissue that exacerbates cerebral edema by activating an inflammatory cascade. Although corticosteroids are often utilized peri-operatively to alleviate the symptoms associated with brain edema, they increase operative morbidities and suppress the efficacy of immunotherapy. Thus, novel approaches to minimize cerebral edema caused by neurosurgical procedures will have significant utility in the management of patients with brain tumors. We have studied the role of the receptor for advanced glycation end products (RAGE) and its ligands on inflammatory responses to neurosurgical injury in mice and humans. Blood-brain barrier (BBB) integrity and neuroinflammation were characterized by Nanostring, flow cytometry, qPCR, and immunoblotting of WT and RAGE knockout mice brains subjected to surgical brain injury (SBI). Human tumor tissue and fluid collected from the resection cavity of patients undergoing craniotomy were also analyzed by single-cell RNA sequencing and ELISA. Genetic ablation of RAGE significantly abrogated neuroinflammation and BBB disruption in the murine SBI model. The inflammatory responses to SBI were associated with infiltration of S100A9-expressing myeloid-derived cells into the brain. Local release of pro-inflammatory S100A9 was confirmed in patients following tumor resection. RAGE and S100A9 inhibitors were as effective as dexamethasone in attenuating neuroinflammation. However, unlike dexamethasone and S100A9 inhibitor, RAGE inhibition did not diminish the efficacy of anti-PD-1 immunotherapy in glioma-bearing mice. These observations confirm the role of the RAGE axis in surgically induced neuroinflammation and provide an alternative therapeutic option to dexamethasone in managing post-operative cerebral edema.

Regional Control and Optimization of Heat Input during CMT by Wire Arc Additive Manufacturing: Modeling and Microstructure Effects.

Wire arc additive manufacturing (WAAM) of aluminum-magnesium (Al-Mg) ER5356 alloy deposits is accomplished by cold metal transfer (CMT). During the process, the temperature change of the alloy deposits has a great influence on molding quality, and the microstructure and properties of alloy deposits are also affected by the complex thermal history of the additive manufacturing process. Here, we used an inter-layer cooling process and controlled the heat input process to attempt to reduce the influence of thermal history on alloy deposits during the additive process. The results showed that inter-layer cooling can optimize the molding quality of alloy deposits, but with the disadvantages of a long test time and slow deposition rate. A simple and uniform reduction of heat input makes the molding quality worse, but controlling the heat input by regions can optimize the molding quality of the alloy deposits. The thermophysical properties of Al-Mg alloy deposits were measured, and we found that the specific heat capacity and thermal diffusivity of alloy deposits were not obviously affected by the temperature. The microstructure and morphology of the deposited specimens were observed and analyzed by microscope and electron back-scatter diffraction (EBSD). The process of controlled heat input results in a higher deposition rate, less side-wall roughness, minimum average grain size, and less coarse recrystallization. In addition, different thermal histories lead to different texture types in the inter-layer cooling process. Finally, a controlled heat input process yields the highest average microhardness of the deposited specimen, and the fluctuation range is small. We expect that the process of controlling heat input by model height region will be widely used in the WAAM field.

NOX4-Derived ROS Mediates TGF-ß1-Induced Metabolic Reprogramming during Epithelial-Mesenchymal Transition through the PI3K/AKT/HIF-1α Pathway in Glioblastoma.

Current studies on tumor progression focus on the roles of cytokines in the tumor microenvironment (TME), and recent research shows that transforming growth factor-ß1 (TGF-ß1) released from TME plays a pivotal role in tumor development and malignant transformation. The alteration in cellular metabolism is a hallmark of cancer, which not only provides cancer cells with ATP for fuel cellular reactions, but also generates metabolic intermediates for the synthesis of essential cellular ingredients, to support cell proliferation, migration, and invasion. Interestingly, we found a distinct metabolic change during TGF-ß1-induced epithelial-mesenchymal transition (EMT) in glioblastoma cells. Indeed, TGF-ß1 participates in metabolic reprogramming, and the molecular basis is still not well understood. NADPH oxidases 4 (NOX4), a member of the Nox family, also plays a key role in the biological effects of glioblastoma. However, the relationship between NOX4, TGF-ß1, and cellular metabolic changes during EMT in glioblastoma remains obscure. Here, our findings demonstrated that TGF-ß1 upregulated NOX4 expression accompanied by reactive oxygen species (ROS) through Smad-dependent signaling and then induced hypoxia-inducible factor 1α (HIF-1α) overexpression and nuclear accumulation resulting in metabolic reprogramming and promoting EMT. Besides, inhibition of glycolysis reversed EMT suggesting a causal relationship between TGF-ß1-induced metabolic changes and tumorigenesis. Moreover, TGF-ß1-induced metabolic reprogramming and EMT which modulated by NOX4/ROS were blocked when the phosphoinositide3-kinase (PI3K)/AKT/HIF-1α signaling pathways were inhibited. In conclusion, these suggest that NOX4/ROS induction by TGF-ß1 can be one of the main mechanisms mediating the metabolic reprogramming during EMT of glioblastoma cells and provide promising strategies for cancer therapy.