Predicting recurrent glioblastoma clinical outcome to immune checkpoint inhibition and low-dose bevacizumab with tumor in situ fluid circulating tumor DNA analysis.

OBJECTIVE: Most recurrent glioblastoma (rGBM) patients do not benefit from immune checkpoint inhibition, emphasizing the necessity for response biomarkers. This study evaluates whether tumor in situ fluid (TISF) circulating tumor DNA (ctDNA) could serve as a biomarker for response to low-dose bevacizumab (Bev) plus anti-PD-1 therapy in rGBM patients, aiming to enhance systemic responses to immunotherapy. METHODS: In this phase II trial, 32 GBM patients with first recurrence after standard therapy were enrolled and then received tislelizumab plus low-dose Bev each cycle. TISF samples were analyzed for ctDNA using a 551-gene panel before each treatment. RESULTS: The median progression-free survival (mPFS) and overall survival (mOS) were 8.2 months (95% CI, 5.2-11.1) and 14.3 months (95% CI, 6.5-22.1), respectively. The 12-month OS was 43.8%, and the objective response rate was 56.3%. Patients with more than 20% reduction in the mutant allele fraction and tumor mutational burden after treatment were significantly associated with better prognosis compared to baseline TISF-ctDNA. Among detectable gene mutations, patients with MUC16 mutation, EGFR mutation & amplification, SRSF2 amplification, and H3F3B amplification were significantly associated with worse prognosis. CONCLUSIONS: Low-dose Bev plus anti-PD-1 therapy significantly improves OS in rGBM patients, offering guiding significance for future individualized treatment strategies. TISF-ctDNA can monitor rGBM patients' response to combination therapy and guide treatment. CLINICAL TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, NCT05540275.

Symmetry breaking through molecular engineering to achieve "on-off-on" nonlinear optical switch in a [SnCl6]2- framework.

The impact of molecular point groups on phase transition materials has been seldom discussed. Two organic cations with different symmetries were incorporated into a [SnCl6]2- framework. By breaking the symmetry of cations, a novel hybrid material with two successive phase transitions featuring a rare "on-off-on" nonlinear optical switch was obtained.

Comparison of toxic effects and underlying mechanisms of carbon quantum dots and CdSe quantum dots on Chromochloris zofingiensis from the chemical composition perspective.

Quantum dots (QDs) are widely utilized semiconductor nanocrystal materials with both nanotoxicity and composition-related toxicity. To determine the toxicological impacts and underlying mechanisms of QDs with different compositions on microalgae, carbon QDs (CQDs) and CdSe QDs were used in the present study. Results showed that QDs composed of CdSe were more toxic than QDs composed of carbon, which inhibited cell growth, with reductions in chl b content, chlorophyll fluorescence parameters, and increases in lipids and starch (two major storage substances). In addition, CdSe QDs elevated reactive oxygen species (ROS), resulting in oxidative damage, while CQDs had little effect on antioxidants. Comparative transcriptome analysis showed that gene expression was accelerated by CdSe QDs, and there was a compensatory upregulation of porphyrin metabolism, potentially to support chlorophyll synthesis. In addition, an MYB transcription factor was predicted by weighted gene co-expression network analysis (WGCNA) to serve as regulator in nanoparticle toxicity, while glutathione peroxidase (GPX) and dual-specificity tyrosine phosphorylation regulated kinases 2/3/4 (DYRK2/3/4) may be key mediators of the composition-related toxicity of CdSe QDs. This study highlights the critical role of QDs' composition in determining their impacts on aquatic microalgae, providing a theoretical reference for selecting appropriate QDs materials for various industrial applications.

A primitive cell model involving Vesicles, microtubules and asters.

HYPOTHESIS: Simple single-chain amphiphiles (sodium monododecyl phosphate, SDP) and organic small molecules (isopentenol, IPN), both of primitive relevance, are proved to have been the building blocks of protocells on the early Earth. How do SDP-based membrane and coexisting IPN come together in specific ways to produce more complex chemical entities? What kind of cell-like behavior can be endowed with this protocell model? These are important questions in the pre-life chemical origin scenario that have not been answered to date. EXPERIMENTS: The phase behavior and formation mechanism of the aggregates for SDP/IPN/H2O ternary system were characterized and studied by different electron microscopy, fluorescent probe technology, DLS, IR, ESI-MS, SAXS, etc. The stability (freeze-thaw and wet-dry treatments) and cell-like behavior (chemical signaling communication) were tested via simulating particular scenarios. FINDINGS: Vesicles, microtubules and asters phases resembling the morphology and structure of modern cells/organelles were obtained. The intermolecular hydrogen bonding is the main driving force for the emergence of the aggregates. The protocell models not only display remarkable stabilities by simulating the primordial Earth's diurnal temperature differences and ocean tides but also are able to exhibit cell-like behavior of chemical signaling transition.

The Role of LC3-Associated Phagocytosis Inhibits the Inflammatory Response in Aspergillus fumigatus Keratitis.

Purpose: The purpose of this study was to investigate the role and mechanism of microtubule-associated protein light chain-3 (LC3)-associated phagocytosis (LAP) in the immune response to Aspergillus fumigatus (A. fumigatus) keratitis. Methods: The formation of single-membrane phagosomes was visualized in the corneas of healthy or A. fumigatus-infected humans and C57BL/6 mice using transmission electron microscopy (TEM). Rubicon siRNA (si-Rubicon) was used to block Rubicon expression. RAW 264.7 cells or mice corneas were infected with A. fumigatus with or without pretreatment of si-Rubicon and scrambled siRNA. RAW 264.7 cells were pretreated with Dectin-1 antibody or Dectin-1 overexpressed plasmid and then stimulated with A. fumigatus. Flow cytometry was used to label macrophages in normal and infected corneas of mice. In mice with A. fumigatus keratitis, the severity of the disease was assessed using clinical scores. We used lentiviral technology to transfer GV348-Ubi-GFP-LC3-II-SV40-Puro Lentivirus into the mouse cornea. The GFP-LC3 fusion protein was visualized in corneal slices using a fluorescence microscope. We detected the mRNA and protein expressions of the inflammatory factors IL-6, IL-1ß, and IL-10 using real-time PCR (RT-PCR) and ELISA. We detected the expression of LAP-related proteins Rubicon, ATG-7, Beclin-1, and LC3-II using Western blot or immunofluorescence. Results: Accumulation of single-membrane phagosomes within macrophages was observed in the corneas of patients and mice with A. fumigatus keratitis using TEM. Flow cytometry (FCM) analysis results show that the number of macrophages in the cornea of mice significantly increases after infection with A. fumigatus. LAP-related proteins were significantly elevated in the corneas of mice and RAW 264.7 cells after infection with A. fumigatus. The si-Rubicon treatment elevated the clinical score of mice. In A. fumigatus keratitis mice, the si-Rubicon treated group showed significantly higher expression of IL-6 and IL-1ß and lower expression of IL-10 and LC3-II compared to the control group. In RAW 264.7 cells, treatment with the Dectin-1 overexpressed plasmid upregulated the expression of LAP-related proteins, a process that was significantly inhibited by the Dectin-1 antibody. Conclusions: LAP participates in the anti-inflammatory immune process of fungal keratitis (FK) and exerts an anti-inflammatory effect. LAP is regulated through the Dectin-1 signaling pathway in A. fumigatus keratitis.

In vitro and in vivo evaluation of osteogenesis and antibacterial activity of MgGa alloys.

MgGa alloys are considered highly potential biodegradable materials, owing to its good mechanical properties and appropriate corrosion resistance. However, it is still far from application due to the lack of biological evaluation. In the present study, biocompatibility, osteogenesis and antibacterial activity of extruded Mg-xGa (x = 1 and 5 wt%) alloys were investigated by in vitro cell culture experiments and in vivo implantation. The cell adhesion and proliferation of osteoblast precursor cells (MC3T3-E1) showed the excellent cytocompatibility of Mg-1Ga and poor cytocompatibility of Mg-5Ga. The osteogenic activity was evaluated and revealed that Ga3+ in the Mg-1Ga extract had the ability to enhance osteogenic differentiation through the facilitation of its early stages. In vivo studies in a rat femoral condyle model revealed that both Mg-1Ga and Mg-5Ga significantly promoted new bone formation without causing any adverse effects. Mg-5Ga exhibited a much higher corrosion rate in vivo than Mg-1Ga. Its osteogenic activity was better due to the rapid release of Mg2+ and Ga3+, but this caused premature structural integrity loss. Mg-1Ga and Mg-5Ga released Ga3+ to inhibit E. coli and S. aureus, with antibacterial rate increasing with Ga content. Our studies demonstrate that Mg-Ga alloys have the potential to be used as osteogenic and antibacterial implant materials. STATEMENT OF SIGNIFICANCE: This study evaluates the biocompatibility, osteogenesis, and antibacterial activity of Mg-Ga alloys, which are promising biodegradable materials for medical applications. The study finds that Mg-1Ga exhibits excellent cytocompatibility and promotes osteogenic differentiation, facilitating the early stages of osteoblast precursor cell development. In vivo studies in a rat femoral condyle model reveal that Mg-1Ga and Mg-5Ga significantly promote new bone formation without causing any adverse effects. The antibacterial activity of both alloys is evaluated against E. coli and S. aureus, with the inhibition rate increasing with Ga content. These findings suggest that Mg-Ga alloys have the potential to serve as osteogenic and antibacterial implant materials, providing significant insights into the development of novel biomedical implants.

An ultra-deep TSV technique enabled by the dual catalysis-based electroless plating of combined barrier and seed layers.

Silicon interposers embedded with ultra-deep through-silicon vias (TSVs) are in great demand for the heterogeneous integration and packaging of opto-electronic chiplets and microelectromechanical systems (MEMS) devices. Considering the cost-effective and reliable manufacturing of ultra-deep TSVs, the formation of continuous barrier and seed layers remains a crucial challenge to solve. Herein, we present a novel dual catalysis-based electroless plating (ELP) technique by tailoring polyimide (PI) liner surfaces to fabricate dense combined Ni barrier/seed layers in ultra-deep TSVs. In additional to the conventional acid catalysis procedure, a prior catalytic step in an alkaline environment is proposed to hydrolyze the PI surface into a polyamide acid (PAA) interfacial layer, resulting in additional catalysts and the formation of a dense Ni layer that can function as both a barrier layer and a seed layer, particularly at the bottom of the deep TSV. TSVs with depths larger than 500 µm and no voids are successfully fabricated in this study. The fabrication process involves low costs and temperatures. For a fabricated 530-µm-deep TSV with a diameter of 70 µm, the measured depletion capacitance and leakage current are approximately 1.3 pF and 1.7 pA at 20 V, respectively, indicating good electrical properties. The proposed fabrication strategy can provide a cost-effective and feasible solution to the challenge of manufacturing ultra-deep TSVs for modern 3D heterogeneous integration and packaging applications.

Regulatory network analysis based on integrated miRNA-TF reveals key genes in heart failure.

The etiology and pathophysiology of heart failure are still unknown. Increasing evidence suggests that abnormal microRNAs (miRNAs) and transcription factors (TFs) expression may be associated with the development of heart failure. Therefore, this study aims to explore key miRNAs, TFs, and related genes in heart failure to gain a greater understanding of the pathogenesis of heart failure. To search and download the dataset of mRNA chips related to heart failure from the GEO database (GSE59867, GSE9128, and GSE134766), we analyzed differential genes and screened the common differentially expressed genes on two chips using R language software. The binary interactions and circuits among miRNAs, TFs, and corresponding genes were determined by Pearson correlation coefficient. A regulatory network of miRNAs, TFs, and target genes was constructed based on bioinformatics. By comparing the sequences of patients with and without heart failure, five downregulated genes with hypermethylated mRNA and three upregulated genes with hypomethylated mRNA were identified. The miRNA-TF gene regulatory network consisted of 26 miRNAs, 22 TFs and six genes. GO and KEGG analysis results revealed that BP terms like cellular response to organic substance, cellular response to cytokine stimulus, and KEGG pathways like osteoclast differentiation, MAPK signaling pathway, and legionellosis were enriched of the DEGs. TMEM87A, PPP2R2A, DUSP1, and miR-92a have great potential as biomarkers for heart failure. The integrated analysis of the mRNA expression spectrum and microRNA-transcription factor-gene revealed the regulatory network of heart failure, which may provide clues to its alternative treatment.

A Fusion-Growth Protocell Model Based on Vesicle Interactions with Pyrite Particles.

Protocell models play a pivotal role in the exploration of the origin of life. Vesicles are one type of protocell model that have attracted much attention. Simple single-chain amphiphiles (SACs) and organic small molecules (OSMs) possess primitive relevance and were most likely the building blocks of protocells on the early Earth. OSM@SAC vesicles have been considered to be plausible protocell models. Pyrite (FeS2), a mineral with primitive relevance, is ubiquitous in nature and plays a crucial role in the exploration of the origin of life in the mineral-water interface scenario. "How do protocell models based on OSM@SAC vesicles interact with a mineral-water interface scenario that simulates a primitive Earth environment" remains an unresolved question. Hence, we select primitive relevant sodium monododecyl phosphate (SDP), isopentenol (IPN) and pyrite (FeS2) mineral particles to build a protocell model. The model investigates the basic physical and chemical properties of FeS2 particles and reveals the effects of the size, content and duration of interaction of FeS2 particles on IPN@SDP vesicles. This deepens the understanding of protocell growth mechanisms in scenarios of mineral-water interfaces in primitive Earth environments and provides new information for the exploration of the origin of life.

Thermodynamic Simulation Calculations of Phase Transformations in Low-Aluminum Zn-Al-Mg Coatings.

This study delves into the formation, transformation, and impact on coating performance of MgZn2 and Mg2Zn11 phases in low-aluminum Zn-Al-Mg alloy coatings, combining thermodynamic simulation calculations with experimental verification methods. A thermodynamic database for the Zn-Al-Mg ternary system was established using the CALPHAD method, and this alloy's non-equilibrium solidification process was simulated using the Scheil model to predict phase compositions under varying cooling rates and coating thicknesses. The simulation results suggest that the Mg2Zn11 phase might predominate in coatings under simulated production-line conditions. However, experimental results characterized using XRD phase analysis show that the MgZn2 phase is the main phase existing in actual coatings, highlighting the complexity of the non-equilibrium solidification process and the decisive effect of experimental conditions on the final phase composition. Further experiments confirmed that cooling rate and coating thickness significantly influence phase composition, with faster cooling and thinner coatings favoring the formation of the metastable phase MgZn2.

Self-Healing Conductive Hydrogels with Dynamic Dual Network Structure Accelerate Infected Wound Healing via Photothermal Antimicrobial and Regulating Inflammatory Response.

Wound infections are an escalating clinical challenge with continuous inflammatory response and the threat of drug-resistant bacteria. Herein, a series of self-healing conductive hydrogels were designed based on carboxymethyl chitosan/oxidized sodium alginate/polymerized gallic acid/Fe3+ (CMC/OSA/pGA/Fe3+, COGFe) for promoting infected wound healing. The Schiff base and catechol-Fe3+ chelation in the dynamical dual network structure of the hydrogels endowed dressings with good toughness, conductivity, adhesion, and self-healing properties, thus flexibly adapting to the deformation of skin wounds. In terms of ultraviolet (UV) resistance and scavenging of reactive oxygen species (ROS), the hydrogels significantly reduced oxidative stress at the wound site. Additionally, the hydrogels with photothermal therapy (PTT) achieved a 95% bactericidal rate in 5 min of near-infrared (NIR) light radiation by disrupting the bacterial cell membrane structure through elevated temperature. Meanwhile, the inherent antimicrobial properties of GA could reduce healthy tissue damage caused by excessive heat. The composite hydrogels could effectively promote the proliferation and migration of fibroblasts and possess good biocompatibility and hemostatic effect. In full-thickness infected wound repair experiments in rats, the COGFe5 hydrogel combined with NIR effectively killed bacteria, modulated macrophage polarization (M1 to M2 phenotype) to improve the immune microenvironment of the wound, and shortened the repair time by accelerating the expression of collagen deposition (TGF-ß) and vascular factors (CD31). This combined therapy might provide a prospective strategy for infectious wound treatment.

Capacity enhancement through entropy loading with probabilistically shaped signals in a frequency comb-based transmission system.

We demonstrate a multichannel entropy loading mechanism in an optical frequency comb-based coherent communication system. In high-capacity wavelength division multiplexing communications, the individual laser sources can be replaced by an optical frequency comb, thus reducing the complexity and energy consumption of the transmitter. However, the power variation among different comb lines will lead to performance discrepancies. Spectral flattening filters can be adopted to suppress the variation at the expense of an additional system loss. Alternatively, by applying probabilistic shaping, we have implemented multichannel entropy loading to facilitate a continuous adaptation of the source entropy. The data rate can be dynamically allocated according to the performance of each channel. Through the loading scheme, the non-uniform performances across the channels are effectively mitigated, achieving a capacity enhancement of 34.91 Gbit/s.

[Prdx1 regulates macrophage polarization by maintaining mitochondrial homeostasis].

In order to investigate the role of Prdx1 in macrophage polarization, mouse leukemia cells of monocyte macrophage (RAW264.7) were treated with lipopolysaccharides (LPS)+ interferon gamma (IFNγ) or IL-4 to induce type 1 macrophage (M1) and type 1 macrophage (M2) macrophages, respectively. The Prdx1 gene knockout cells (Prdx1-/-) were used for the study. Flow cytometry was conducted to detect M1/M2 macrophage markers, and ELISA kits were used to measure M1/M2 cytokine levels. Inducible nitric-oxide synthase (iNOS) activity, arginase-1 (Arg-1) activity, and oxidative damage were also assessed. The Seahorse XFe24 Extracellular Flux Analyzer was employed to measure extracellular acidification rate and oxygen consumption rate. The mitochondrial membrane potential was analyzed using the mitochondrial membrane potential dye (JC-1) fluorescent probe, and mitochondrial superoxide was detected through fluorescence staining. Additionally, the impact of adding a mitochondrial reactive oxygen species (ROS) scavenger on RAW264.7 macrophage polarization was examined. The results demonstrated an increase in ROS, hydrogen peroxide, and 8-hydroxy-2 deoxyguanosine (8-OHDG). Cytotoxicity and mitochondrial toxic effects, including mitochondrial superoxide accumulation, decreased adenosine-triphosphate (ATP) production, reduced mitochondrial membrane potential, and decreased mitochondrial DNA copy number, were observed. Furthermore, down-regulation of translocase of inner mitochondrial membrane 23 (TIM23) mitochondrial protein and mitochondrial stress protein heat shock protein 60 (HSP60) was noted. The extra cellular acidification rate (ECAR) in M1 macrophage polarization in RAW264.7 cells was increased, while oxygen consumption rate (OCR) in M2 macrophages was reduced. These findings indicate that Prdx1 knockout in RAW264.7 cells can inhibit M2 macrophage polarization but promote M1 macrophage polarization by impairing mitochondrial function and reducing oxidative phosphorylation.

Strategies to enhance the ability of nerve guidance conduits to promote directional nerve growth.

Severely damaged peripheral nerves will regenerate incompletely due to lack of directionality in their regeneration, leading to loss of nerve function. To address this problem, various nerve guidance conduits (NGCs) have been developed to provide guidance for nerve repair. However, their clinical application is still limited, mainly because its effect in promoting nerve repair is not as good as autologous nerve transplantation. Therefore, it is necessary to enhance the ability of NGCs to promote directional nerve growth. Strategies include preparing various directional structures on NGCs to provide contact guidance, and loading various substances on them to provide electrical stimulation or neurotrophic factor concentration gradient to provide directional physical or biological signals.

The Impact of Valve Surgery on the Safety and Cardiac Function of Patients with Valvular Heart Disease Complicated by Pulmonary Arterial Hypertension.

Objective: This study evaluates the effects of valve surgery on safety and cardiac function in patients with valvular heart disease complicated by pulmonary arterial hypertension (PAH), focusing on postoperative outcomes influenced by age, heart function grade, and PAH severity. Methods: A retrospective analysis was conducted on 307 valve surgery patients from April 2017 to April 2022. The cohort had a mean age of 57.6 years, with 56.9% males, and was stratified by NYHA functional class II-IV. Outcomes assessed included mortality, complication rates, left ventricular ejection fraction (LVEF), and pulmonary artery systolic pressure (PASP), with statistical analysis performed using t-tests and chi-square tests for continuous and categorical data, respectively. Results: Postoperative outcomes varied significantly with age, NYHA class, and PASP grade. Patients aged ≤60 exhibited an average PASP reduction of 44.46% in the male group and 44.44% in the female group and an LVEF improvement of 5.28% in the male group and 5.80% in the female group. However, these patients showed a higher risk of postoperative complications, such as renal failure, arrhythmia, low cardiac output syndrome, respiratory insufficiency, (23.31%), and a higher mortality rate (13.53%)(P < .05). Higher NYHA classes correlated with increased postoperative risks of complications and mortality rates, and elevated PASP grades were associated with larger improvements in PASP and LVEF but also higher postoperative risks. Conclusion: Valve surgery in valvular heart disease with PAH is influenced by patient age, functional status, and PAH severity. Despite advances in surgical techniques, there remains a notable gap in understanding the nuanced interplay between these conditions and the variable outcomes of valve surgery. This study addresses this research gap, offering comprehensive insights into how age, heart function, and PAH severity influence postoperative outcomes. These findings are crucial for clinicians, providing a more informed basis for tailored treatment strategies, and ultimately enhancing patient care in this complex clinical scenario.Healthcare providers should consider the age-specific benefits and risks of valve surgery in patients with valvular heart disease and pulmonary arterial hypertension. Tailored decision-making, particularly for those aged ≤60, higher NYHA classes, or severe PAH, is essential for optimizing individual outcomes.

Integrating Machine Learning in Metabolomics: A Path to Enhanced Diagnostics and Data Interpretation.

Metabolomics, leveraging techniques like NMR and MS, is crucial for understanding biochemical processes in pathophysiological states. This field, however, faces challenges in metabolite sensitivity, data complexity, and omics data integration. Recent machine learning advancements have enhanced data analysis and disease classification in metabolomics. This study explores machine learning integration with metabolomics to improve metabolite identification, data efficiency, and diagnostic methods. Using deep learning and traditional machine learning, it presents advancements in metabolic data analysis, including novel algorithms for accurate peak identification, robust disease classification from metabolic profiles, and improved metabolite annotation. It also highlights multiomics integration, demonstrating machine learning's potential in elucidating biological phenomena and advancing disease diagnostics. This work contributes significantly to metabolomics by merging it with machine learning, offering innovative solutions to analytical challenges and setting new standards for omics data analysis.

Plasmonic Alloys Enhanced Metabolic Fingerprints for the Diagnosis of COPD and Exacerbations.

Accurate diagnosis of chronic obstructive pulmonary disease (COPD) and exacerbations by metabolic biomarkers enables individualized treatment. Advanced metabolic detection platforms rely on designed materials. Here, we design mesoporous PdPt alloys to characterize metabolic fingerprints for diagnosing COPD and exacerbations. As a result, the optimized PdPt alloys enable the acquisition of metabolic fingerprints within seconds, requiring only 0.5 µL of native plasma by laser desorption/ionization mass spectrometry owing to the enhanced electric field, photothermal conversion, and photocurrent response. Machine learning decodes metabolic profiles acquired from 431 individuals, achieving a precise diagnosis of COPD with an area under the curve (AUC) of 0.904 and an accurate distinction between stable COPD and acute exacerbations of COPD (AECOPD) with an AUC of 0.951. Notably, eight metabolic biomarkers identified accurately discriminate AECOPD from stable COPD while providing valuable information on disease progress. Our platform will offer an advanced nanoplatform for the management of COPD, complementing standard clinical techniques.

Enhancing osteoblast proliferation and bone regeneration by poly (amino acid)/selenium-doped hydroxyapatite.

Among various biomaterials employed for bone repair, composites with good biocompatibility and osteogenic ability had received increasing attention from biomedical applications. In this study, we doped selenium (Se) into hydroxyapatite (Se-HA) by the precipitation method, and prepared different amounts of Se-HA-loaded poly (amino acid)/Se-HA (PAA/Se-HA) composites (0, 10 wt%, 20 wt%, 30 wt%) byin-situmelting polycondensation. The physical and chemical properties of PAA/Se-HA composites were characterized by x-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), scanning electron microscopy (SEM) and their mechanical properties. XRD and FT-IR results showed that PAA/Se-HA composites contained characteristic peaks of PAA and Se-HA with amide linkage and HA structures. DSC and TGA results specified the PAA/Se-HA30 composite crystallization, melting, and maximum weight loss temperatures at 203.33 °C, 162.54 °C, and 468.92 °C, respectively, which implied good thermal stability. SEM results showed that Se-HA was uniformly dispersed in PAA. The mechanical properties of PAA/Se-HA30 composites included bending, compressive, and yield strengths at 83.07 ± 0.57, 106.56 ± 0.46, and 99.17 ± 1.11 MPa, respectively. The cellular responses of PAA/Se-HA compositesin vitrowere studied using bone marrow mesenchymal stem cells (BMSCs) by cell counting kit-8 assay, and results showed that PAA/Se-HA30 composites significantly promoted the proliferation of BMSCs at the concentration of 2 mg ml-1. The alkaline phosphatase activity (ALP) and alizarin red staining results showed that the introduction of Se-HA into PAA enhanced ALP activity and formation of calcium nodule. Western blotting and Real-time polymerase chain reaction results showed that the introduction of Se-HA into PAA could promoted the expression of osteogenic-related proteins and mRNA (integrin-binding sialoprotein, osteopontin, runt-related transcription factor 2 and Osterix) in BMSCs. A muscle defect at the back and a bone defect at the femoral condyle of New Zealand white rabbits were introduced for evaluating the enhancement of bone regeneration of PAA and PAA/Se-HA30 composites. The implantation of muscle tissue revealed good biocompatibility of PAA and PAA/Se-HA30 composites. The implantation of bone defect showed that PAA/Se-HA30 composites enhanced bone formation at the defect site (8 weeks), exhibiting good bone conductivity. Therefore, the PAA-based composite was a promising candidate material for bone tissue regeneration.

Failure of lipid control by PCSK9 inhibitors in compound heterozygous familial hypercholesterolemia complicated with premature myocardial infarction: A case report.

Key Clinical Message: A certain level of low-density lipoprotein receptor activity is crucial for the efficacy of PCSK9i. Therapeutic strategies for familial hypercholesterolemia patients should consider drug efficacy, and genetic testing will be helpful. Abstract: Familial hypercholesterolemia (FH) is a serious autosomal dominant disorder. Managing blood lipids in FH patients poses greater challenges for clinicians. Drug therapy may not always yield satisfactory results, particularly in individuals with low-density lipoprotein receptor (LDLR) negative mutations. Herein, we report a young female harboring an LDLR frameshift mutation. This patient developed xanthomas at 7 months old and underwent several years of treatment involving four classes of lipid-lowering drugs, including PCSK9i. However, the response to drug therapy was limited in this patient and eventually culminated in premature myocardial infarction. The efficacy of PCSK9i depends on the activity of LDLR. The inefficacy of PCSK9i may arise from the extensive mutations which leading to loss of LDLR activity. Therapy plans for these patients should take into account the efficacy of drug therapy. Early genetic testing is crucial for clinicians to make informed decisions regarding therapy options.

Polystyrene microplastics induce anxiety via HRAS derived PERK-NF-κB pathway.

Exposure to environmentally hazardous substances is recognized as a significant risk factor for neurological associated disorders. Among these substances, polystyrene microplastics (PS-MPs), widely utilized in various consumer products, have been reported to exhibit neurotoxicity. However, the potential association of PS-MPs with abnormal anxiety behaviors, along with the underlying molecular mechanisms and key proteins involved, remains insufficiently explored. Here, we delineated the potential mechanisms of PS-MPs-induced anxiety through proteomics and molecular investigations. We characterized the PS-MPs, observed their accumulation in the brain, leading to anxiety-like behavior in mice, which is correlated with microglia activation and pro-inflammatory response. Consistent with these findings, our studies on BV2 microglia cells showed that PS-MPs activated NF-κB-mediated inflammation resulting in the upregulation of pro-inflammatory cytokines such as TNFα and IL-1ß. Of particular significance, HRAS was identified as a key factor in the PS-MPs induced pro-inflammatory response through whole proteomics analysis, and knockdown of H-ras effectively inhibited PS-MPs induced PERK-NF-κB activation and associated pro-inflammatory response in microglia cells. Collectively, our findings highlight that PS-MPs induce anxiety of mice via the activation of the HRAS-derived PERK-NF-κB pathway in microlglia. Our results contribute valuable insights into the molecular mechanisms of PS-MPs-induced anxiety, and may offer implications for addressing neurotoxicity and prevention the adverse effects of environmentally hazardous substances, including microplastics.