High expression of LncRNA HOTAIR is a risk factor for temozolomide resistance in glioblastoma via activation of the miR-214/ß-catenin/MGMT pathway.

HOX transcript antisense RNA (HOTAIR) is upregulated in glioblastoma (GBM) and associated with temozolomide (TMZ) resistance. However, the mechanisms underlying HOTAIR-mediated TMZ resistance remains poorly understood. HOTAIR expression in glioma-related public datasets and drug response estimation were analyzed using bioinformatics. These findings were verified by overexpressing HOTAIR in TMZ-sensitive U251 cells and/or silencing HOTAIR in resistant U251 cells (U251R). The cytotoxic effects were evaluated using cell viability assay and flow cytometry analysis of cell cycle and apoptosis. In this study, we found that HOTAIR was upregulated in TMZ-resistant GBM cell lines and patients with high HOTAIR expression responded poorly to TMZ therapy. HOTAIR knockdown restored TMZ sensitivity in U251R cells, while HOTAIR overexpression conferred TMZ resistance in U251 cells. Wnt/ß-catenin signaling was enriched in patients with high HOTAIR expression; consistently, HOTAIR positively regulated ß-catenin expression in U251 cells. Moreover, HOTAIR-mediated TMZ resistance was associated with increased MGMT protein level, which resulted from the HOTAIR/miR-214-3p/ß-catenin network. Besides, GBM with high HOTAIR expression exhibited sensitivity to methotrexate. Methotrexate enhanced TMZ sensitivity in U251R cells, accompanied by reduced expression of HOTAIR and ß-catenin. Thus, we conlcude that HOTAIR is a risk factor for TMZ resistance and methotrexate may represent a potential therapeutic drug for patients with high HOTAIR expression level.

VEGF-loaded ROS-responsive nanodots improve the structure and function of sciatic nerve lesions in type II diabetic peripheral neuropathy.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of diabetes mellitus (DM), significantly contributing to the risk of amputation and mortality. Reactive oxygen species (ROS) can induce both neurological and structural harm through direct impact and pyroptosis, underscoring the critical role of ROS regulation in mitigating DPN. In this research endeavor, we propose harnessing the inherent antioxidant properties of sulfhydryl groups by grafting them onto gold nanodots through an amidation reaction, resulting in the creation of ROS-responsive AuNDs. Additionally, we aim to synthesize AuNDs-VEGF, wherein VEGF is attached to AuNDs via electrostatic interactions, as a therapeutic strategy for addressing DPN in rat models. The results of in vivo experiments showed that AuNDs and AuNDs-VEGF nanoparticles could increase the nerve conduction velocity, shorten the latency of nerve conduction in the sciatic nerve, promote the regeneration of nerve trophectodermal vessels, improve the structure and function of the sciatic nerve, reduce the apoptosis of neural cells, and alleviate the atrophy of the gastrocnemius muscle. Thus, VEGF-loaded ROS-responsive nanodots present a promising avenue for ameliorating diabetic peripheral neuropathy. This innovative approach not only extends the application possibilities of nanodots but also introduces a novel avenue for the treatment of diabetic neuropathy.

In Situ Construction of SnS2@SnO2 Heterostructure for Photo-Assisted Electrocatalysis of Oxygen Evolution Reaction.

Photo-assisted electrocatalysis has arisen as a promising approach for hydrogen generation by incorporating photocatalysts into electrocatalysts. 2D SnS2 is a photocatalyst that absorbs visible light. However, the rapid recombination of photo-generated electron-hole pairs significantly reduces the overall photocatalytic efficiency of SnS2, limiting its practical application. Thus, this study prepares an in situ heterojunction SnS2@SnO2 using a one-step hydrothermal method. The degradation efficiency of methyl orange (MO) using SnS2@SnO2 is measured, achieving a degradation rate of 92.75% within 1 h, which is 1.9 times higher than that of pure SnS2. Additionally, FeNiS/SnS2@SnO2 is synthesized and exhibited significant improvements in the photo-assisted oxygen evolution reaction (OER). It achieves an overpotential of 260 mV and a Tafel slope of 65.1 mV dec-1 at 10 mA cm-2, showing reductions of 11.8% and 31.8%, respectively, compared to FeNiS alone. These enhancements highlight the strong photo-response capability of SnS2@SnO2. Under the internal electric field of SnS2@SnO2, the photogenerated electrons in the conduction band of SnS2 quickly move toward SnO2, facilitating efficient photocatalytic reactions. FeNiS, with a lower Fermi energy level (EF), facilitates electron transfer from SnS2@SnO2 and enhances OER performance by efficiently participating in the reaction. This study paves a new path for 2D photocatalyst materials.

Superior Piezoelectric Performance in Textured CaBi2Nb2O9 Ferroelectric Ceramics through Rare-Earth Gadolinium Doping and Spark Plasma Sintering.

High-performance piezoelectric ceramics with excellent thermal stability are crucial for high-temperature piezoelectric sensor applications. However, conventional fabrication processes offer limited enhancements in piezoelectric performance. In this study, we achieved a significant breakthrough in the piezoelectric performance of highly textured CaBi2Nb2O9 (CBN) ceramics by incorporating rare-earth gadolinium doping and utilizing spark plasma sintering. The resulting Ca0.97Gd0.03Bi2Nb2O9 (CBN-3Gd) ceramics exhibited superior piezoelectric properties, with a high piezoelectric constant d33 of 26 pC/N and a high Curie temperature TC of 946 °C. We employed piezoresponse force microscopy (PFM) to observe the morphology and dimensions of the ferroelectric domains, revealing a rod-shaped 3D domain configuration. This configuration facilitated polarization rotation in the textured ceramics, as analyzed using X-ray photoelectron spectroscopy (XPS) and polarization-electric field (P-E) hysteresis loops. Furthermore, the textured CBN-3Gd ceramics demonstrated exceptional thermal stability and reliability. The piezoelectric constant d33 decreased by only 11.8% over a temperature range of room temperature to 500 °C, and the DC electrical resistivity remained at 6.7 × 105 Ω cm at 600 °C. This work not only highlights the great potential of textured CBN-based ceramics for high-temperature piezoelectric sensors but also provides a viable strategy for enhancing the performance of piezoelectric materials with large aspect ratio micromorphology.

Feasibility study of opportunistic osteoporosis screening on chest CT using a multi-feature fusion DCNN model.

A multi-feature fusion DCNN model for automated evaluation of lumbar vertebrae L1 on chest combined with clinical information and radiomics permits estimation of volumetric bone mineral density for evaluation of osteoporosis. PURPOSE: To develop a multi-feature deep learning model based on chest CT, combined with clinical information and radiomics to explore the feasibility in screening for osteoporosis based on estimation of volumetric bone mineral density. METHODS: The chest CT images of 1048 health check subjects were retrospectively collected as the master dataset, and the images of 637 subjects obtained from a different CT scanner were used for the external validation cohort. The subjects were divided into three categories according to the quantitative CT (QCT) examination, namely, normal group, osteopenia group, and osteoporosis group. Firstly, a deep learning-based segmentation model was constructed. Then, classification models were established and selected, and then, an optimal model to build bone density value prediction regression model was chosen. RESULTS: The DSC value was 0.951 ± 0.030 in the testing dataset and 0.947 ± 0.060 in the external validation cohort. The multi-feature fusion model based on the lumbar 1 vertebra had the best performance in the diagnosis. The area under the curve (AUC) of diagnosing normal, osteopenia, and osteoporosis was 0.992, 0.973, and 0.989. The mean absolute errors (MAEs) of the bone density prediction regression model in the test set and external testing dataset are 8.20 mg/cm3 and 9.23 mg/cm3, respectively, and the root mean square errors (RMSEs) are 10.25 mg/cm3 and 11.91 mg/cm3, respectively. The R-squared values are 0.942 and 0.923, respectively. The Pearson correlation coefficients are 0.972 and 0.965. CONCLUSION: The multi-feature fusion DCNN model based on only the lumbar 1 vertebrae and clinical variables can perform bone density three-classification diagnosis and estimate volumetric bone mineral density. If confirmed in independent populations, this automated opportunistic chest CT evaluation can help clinical screening of large-sample populations to identify subjects at high risk of osteoporotic fracture.

Modified mRNA-based gene editing reveals sarcomere-based regulation of gene expression in human induced-pluripotent stem cell-derived cardiomyocytes.

Mutations in genes coding sarcomere components are the major causes of human inherited cardiomyopathy. Genome editing is widely applied to genetic modification of human pluripotent stem cells (hPSCs) before hPSCs were differentiated into cardiomyocytes to model cardiomyopathy. Whether genetic mutations influence the early hPSC differentiation process or solely the terminally differentiated cardiomyocytes during cardiac pathogenesis remains challenging to distinguish. To solve this problem, here we harnessed chemically modified mRNA (modRNA) and synthetic single-guide RNA to develop an efficient genome editing approach in hPSC-derived cardiomyocytes (hPSC-CMs). We showed that modRNA-based CRISPR/Cas9 mutagenesis of TNNT2, the coding gene for cardiac troponin T, results in sarcomere disassembly and contractile dysfunction in hPSC-CMs. These structural and functional phenotypes were associated with profound downregulation of oxidative phosphorylation genes and upregulation of cardiac stress markers NPPA and NPPB. These data confirmed that sarcomeres regulate gene expression in hPSC-CMs and highlighted the RNA technology as a powerful tool to achieve stage-specific genome editing during hPSC differentiation.

Functional Carbon Springs Enabled Dynamic Tunable Microwave Absorption and Thermal Insulation.

Electromagnetic (EM) wave pollution and thermal damage pose serious hazards to delicate instruments. Functional aerogels offer a promising solution by mitigating EM interference and isolating heat. However, most of these materials struggle to balance thermal protection with microwave absorption (MA) efficiency due to a previously unidentified conflict between the optimizing strategies of the two properties. Herein, this study reports a solution involving the design of a carbon-based aerogel called functional carbon spring (FCS). Its unique long-range lamellar multi-arch microstructure enables tunable MA performance and excellent thermal insulation capability. Adjusting compression strain from 0% to 50%, the adjustable effective absorption bandwidth (EAB) spans up to 13.4 GHz, covering 84% of the measured frequency spectrum. Notably, at 75% strain, the EAB drops to 0 GHz, demonstrating a novel "on-off" switchability for MA performance. Its ultralow vertical thermal conductivity (12.7 mW m-1 K-1) and unique anisotropic heat transfer mechanism endow FCS with superior thermal protection effectiveness. Numerical simulations demonstrate that FCS outperforms common honeycomb structures and isotropic porous aerogels in thermal management. Furthermore, an "electromagnetic-thermal" dual-protection material database is established, which intuitively demonstrates the superiority of the solution. This work contributes to the advancement of multifunctional MA materials with significant potential for practical applications.

Identification of novel biomarkers, shared molecular signatures and immune cell infiltration in heart and kidney failure by transcriptomics.

Introduction: Heart failure (HF) and kidney failure (KF) are closely related conditions that often coexist, posing a complex clinical challenge. Understanding the shared mechanisms between these two conditions is crucial for developing effective therapies. Methods: This study employed transcriptomic analysis to unveil molecular signatures and novel biomarkers for both HF and KF. A total of 2869 shared differentially expressed genes (DEGs) were identified in patients with HF and KF compared to healthy controls. Functional enrichment analysis was performed to explore the common mechanisms underlying these conditions. A protein-protein interaction (PPI) network was constructed, and machine learning algorithms, including Random Forest (RF), Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Least Absolute Shrinkage and Selection Operator (LASSO), were used to identify key signature genes. These genes were further analyzed using Gene Set Variation Analysis (GSVA) and Gene Set Enrichment Analysis (GSEA), with their diagnostic values validated in both training and validation sets. Molecular docking studies were conducted. Additionally, immune cell infiltration and correlation analyses were performed to assess the relationship between immune responses and the identified biomarkers. Results: The functional enrichment analysis indicated that the common mechanisms are associated with cellular homeostasis, cell communication, cellular replication, inflammation, and extracellular matrix (ECM) production, with the PI3K-Akt signaling pathway being notably enriched. The PPI network revealed two key protein clusters related to the cell cycle and inflammation. CDK2 and CCND1 were identified as signature genes for both HF and KF. Their diagnostic value was validated in both training and validation sets. Additionally, docking studies with CDK2 and CCND1 were performed to evaluate potential drug candidates. Immune cell infiltration and correlation analyses highlighted the immune microenvironment, and that CDK2 and CCND1 are associated with immune responses in HF and KF. Discussion: This study identifies CDK2 and CCND1 as novel biomarkers linking cell cycle regulation and inflammation in heart and kidney failure. These findings offer new insights into the molecular mechanisms of HF and KF and present potential targets for diagnosis and therapy.

HiMul-LGG: A hierarchical decision fusion-based local-global graph neural network for multimodal emotion recognition in conversation.

Emotion recognition in conversation (ERC) is a vital task that requires deciphering human emotions through analysis of contextual and multimodal information. However, extant research on ERC concentrates predominantly on investigating multimodal fusion while overlooking the model's constraints in dealing with unimodal representation discrepancy and speaker dependencies. To address the aforementioned problems, this paper proposes a Hierarchical decision fusion-based Local-Global Graph Neural Network for multimodal ERC (HiMul-LGG). HiMul-LGG employs a hierarchical decision fusion strategy to ensure feature alignment across modalities. Moreover, HiMul-LGG also adopts a local-global graph neural network architecture to reinforce inter-modality and intra-modality speaker dependency. Additionally, HiMul-LGG utilizes a cross-modal multi-head attention mechanism to promote interplay between modalities. We evaluate HiMul-LGG on two emotion recognition datasets, IEMOCAP and MELD, where HiMul-LGG outperforms existing methods. The results of the ablation study also imply the effectiveness of the proposed hierarchical decision fusion strategy and local-global structure of Graph construction.

Immune Indicator Changes in Hepatocellular Carcinoma Undergoing TACE Plus ICIs and Anti-VEGF Antibodies/TKIs: A Prognostic Biomarker Analysis.

Objective: To explore changing trends in circulating immune indicators of hepatocellular carcinoma (HCC) undergoing TACE plus immune checkpoint inhibitors (ICIs) and anti-VEGF antibodies/TKIs and to elucidate the relationship between immune response and tumor prognosis. Materials: This single-center retrospective study included patients with unresectable HCC undergoing TACE plus ICIs and anti-VEGF antibodies/TKIs from March 11, 2019, to February 15, 2024. Peripheral blood samples were collected at baseline and every cycle, from which blood cell counts and immune indicators were analyzed. The primary outcome was the objective response rate (ORR) at the first evaluation. According to the first evaluation based on mRECIST, patients were classified into PD, SD, and OR groups for analysis. Further subgroup analysis was performed on the OR group based on whether experiencing progression after the first evaluation. Lymphocyte subsets were measured by flow cytometry. Immunoglobulins were measured using the immune turbidimetric method. The neutrophil-to-lymphocyte ratio (NLR) was measured by the complete blood count. Simple linear regression was employed to examine the dynamic trends. Results: A total of 63 patients were enrolled, with an ORR of 55.6% and a disease control rate (DCR) of 87.3% at the first evaluation. The median overall survival (mOS) was 27.5 months (95% CI: 22.5-32.5 months). In the OR group (n=35), more active immune responses, expressed in a decrease in CD3-CD19+ (p=0.004), CFB (p=0.027), NLR (p<0.001) and an increase in Ig λ (p=0.010), Ig κ (p=0.037), Ig A (p=0.005), Ig G (p=0.006), were related to better prognosis, while similar patterns seen in the OR-nPD subgroup. Concurrently, no significant differences were noted in the PD group (n=8). Conclusion: The combination therapy may modify the tumor microenvironment of HCC. Changing trends in circulating immune indicators and NLR can serve as potential biomarkers for predicting tumor response and guiding clinical treatment.

Reversible Antireflection Materials Inspired by Cicada Wings for Anticounterfeit and Photovoltaic Cells.

Antireflection (AR) surfaces are essential for the fields of flexible displays, photovoltaic industry, medical endoscope, intelligent windows, etc. Although natural creatures with well-organized micro/nanostructures have provided some coupling design principles for the rapid development of bioinspired AR materials, the mechanical vulnerability, poor flexibility, and nonadjustability have been pointed out as the drawback of these nanostructures. Here, a bioinspired reversible AR film with 4% reflectivity, 90% transmittance, and 9% haze in broadband (400-900 nm) was prepared. The flexible switching of AR performance enhancement and weakening throughout the visible wavelength band has been achieved by controlling the reversible change in the morphology of the interface structure. A variety of patterned film samples can be obtained by simply changing the template, which can be used in intelligent identification fields such as anticounterfeiting. The cycle test and photoelectric test show that the bionic reversible antireflection structure has certain stability and can effectively reduce the loss of photovoltaic cell conversion efficiency caused by mechanical deformation. It has broad application prospects in the fields of anticounterfeiting, intelligent window, flexible display, photoelectric element, and so on.

A Bacterial Platform for Studying Ubiquitination Cascades Anchored by SCF-Type E3 Ubiquitin Ligases.

Ubiquitination is one of the most important post-translational modifications in eukaryotes. The ubiquitination cascade includes ubiquitin-activating enzymes (E1), ubiquitin-conjugating enzymes (E2), and ubiquitin ligases (E3). The E3 ligases, responsible for substrate recognition, are the most abundant and varied proteins in the cascade and the most studied. SKP1-CUL1-F-Box (SCF)-type E3 ubiquitin ligases are multi-subunit RING (Really Interesting New Gene) E3 ubiquitin ligases, composed of CUL1 (Cullin 1), RBX1 (RING BOX 1), SKP1 (S-phase Kinase-associated Protein 1), and F-box proteins. In vitro ubiquitination assays, used for studying the specific recognition of substrate proteins by E3 ubiquitin ligases, require the purification of all components involved in the cascade, and for assays with SCF-type E3 ligases, additional proteins (several SCF complex subunits). Here, the Duet expression system was used to co-express E1, E2, ubiquitin, ubiquitylation target (substrate), and the four subunits of a SCF-type E3 ligase in E. coli. When these proteins co-exist in bacterial cells, ubiquitination occurs and can be detected by Western Blot. The effectiveness of this bacterial system for detecting ubiquitination cascade activity was demonstrated by replicating both AtSCFTIR1-mediated and human SCFFBXO28-mediated ubiquitylation in bacteria. This system provides a basic but adaptable platform for the study of SCF-type E3 ubiquitin ligases.

Impact of NBP on acute ischemic stroke: Tracking therapy effect on neuroinflammation.

BACKGROUND: Ischemic stroke is the leading cause of death and long-term disability worldwide. After stroke, microglia exhibit not only pro-inflammatory phenotype to aggravate the neuroinflammation, but also anti-inflammatory phenotype to play a neuroprotective role. Studies on the spatial and temporal changes in microglia and the underlying mechanisms help to elucidate the inflammatory cascade after stroke. The regulation of microglia polarization provides new insights for the intervention of post-stroke inflammation. OBJECTIVE: We aimed to investigate the phenotypic change of microglia in the acute phase of ischemic stroke and the effects of Dl-3-n-butylphthalide (NBP) on microglia. TSPO-PET was used to image microglia and evaluate the efficacy of NBP. METHODS: We constructed an MCAO model in rats and administered NBP daily. The infarct volumes in the NBP-treated and control groups were measured. TSPO-PET/CT was used to demonstrate the activation of microglia and the effects of NBP. Additionally, we investigated the effects of NBP on TSPO expression. In vitro, microglia were exposed to glucose oxygen deprivation, and the effects of NBP on microglia and TSPO expression were verified. RESULTS: NBP improved neurological severity scores and reduced infarct volume in the acute phase of ischemic stroke. NBP facilitated microglia to adopt the anti-inflammatory phenotype and reduce the pro-inflammatory phenotype. NBP decreased the expressions of inflammatory cytokines. TSPO-PET/CT observed increase in uptake in the infarct lesion, and this uptake was reduced in response to NBP. NBP reduced TSPO expression in microglia after stroke. In vitro experiments further verified that NBP facilitated the transition of microglia towards the anti-inflammatory phenotype, and inhibited inflammatory cytokine secretion and TSPO expression. CONCLUSION: We illustrated that NBP fosters the shift of microglia towards the anti-inflammatory phenotype while diminishing their inclination towards the pro-inflammatory phenotype, thereby exerting neuroprotective effects. NBP reduces TSPO expression in microglia, which can be observed by TSPO-PET/CT imaging.

Graphene derivative based hydrogels in biomedical applications.

Graphene and its derivatives are widely used in tissue-engineering scaffolds, especially in the form of hydrogels. This is due to their biocompatibility, electrical conductivity, high surface area, and physicochemical versatility. They are also used in tissue engineering. Tissue engineering is suitable for 3D printing applications, and 3D printing makes it possible to construct 3D structures from 2D graphene, which is a revolutionary technology with promising applications in tissue and organ engineering. In this review, the recent literature in which graphene and its derivatives have been used as the major components of hydrogels is summarized. The application of graphene and its derivative-based hydrogels in tissue engineering is described in detail from different perspectives.

Hyaluronic acid/chitin thermosensitive hydrogel loaded with TGF-ß1 promotes meniscus repair in rabbit meniscus full-thickness tear model.

Repair of the damaged meniscus is a scientific challenge owing to the poor self-healing potential of the white area of the meniscus. Tissue engineering provides a new method for the repair of meniscus injuries. In this study, we explored the superiority of 2% hyaluronic acid chitin hydrogel in temperature sensitivity, in vitro degradation, biocompatibility, cell adhesion, and other biological characteristics, and investigated the advantages of hyaluronic acid (HA) and Transforming Growth Factor ß1 (TGF-ß1) in promoting cell proliferation and a matrix formation phenotype. The hydrogel loaded with HA and TGF-ß1 promoted cell proliferation. The HA + TGF-ß1 mixed group showed the highest glycosaminoglycan (GAG) content and promoted cell migration. Hydroxypropyl chitin (HPCH), HA, and TGF-ß1 were combined to form a composite hydrogel with a concentration of 2% after physical cross-linking, and this was injected into a rabbit model of a meniscus full-thickness tear. After 12 weeks of implantation, the TGF-ß1 + HA/HPCH composite hydrogel was significantly better than HPCH, HA/HPCH, TGF-ß1 + HPCH, and the control group in promoting meniscus repair. In addition, the new meniscus tissue of the TGF-ß1 + HA/HPCH composite hydrogel had a tissue structure and biochemical content similar to that of the normal meniscus tissue.

CHK1 attenuates cardiac dysfunction via suppressing SIRT1-ubiquitination.

BACKGROUND: Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation, however, its role on mitochondrial function in I/R injury remains unknown. METHODS: To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/overexpression mouse models were generated. Adult mouse cardiomyocytes (AMCMs) were isolated for in vitro study. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism. RESULTS: CHK1 was downregulated in myocardium post I/R and AMCMs post oxygen-glucose deprivation/re­oxygenation (OGD/R). In vivo, CHK1 overexpression protected against I/R induced cardiac dysfunction, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro, CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. The role of CHK1 in maintaining mitochondrial dynamics control and myocardial protection is abolished by SIRT1 inhibition, while inactivated mutation of SIRT1 Thr530 fails to reverse the impaired mitochondrial dynamics following CHK1 knockdown. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown attenuated the protective role of CHK1 in I/R injury. CONCLUSIONS: Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.

Long-Term Neurotoxic Effects and Alzheimer's Disease Risk of Early EHDPP Exposure in Zebrafish: Insights from Molecular Mechanisms to Adult Pathology.

2-Ethylhexyl diphenyl phosphate (EHDPP), ubiquitously monitored in environmental media, is highly bioaccumulative and may pose long-term risks, even after short-term exposure. In this investigation, larval zebrafish were exposed to 0.05, 0.5, and 5.0 µg/L EHDPP from 4 to 120 h postfertilization (hpf) to examine the long-term neurotoxicity effects of early exposure. Exposure to 5.0 µg/L EHDPP yielded hyperactive locomotor behavior, which was characterized by increased swimming speed, larger turning angles, and heightened sensitivity to light-dark stimulation. The predicted targets of EHDPP (top 100 potential macromolecules) were primarily associated with brain diseases like Alzheimer's disease (AD). Comparisons of differentially expressed genes (DEGs) from AD patients (GSE48350) and RNA-seq data from EHDPP-exposed zebrafish confirmed consistently abnormal regulatory pathways. EHDPP's interaction with M1 and M5 muscarinic acetylcholine receptors likely disrupted calcium homeostasis, leading to mitochondrial dysfunction and neurotransmitter imbalance as well as abnormal locomotor behavior. Especially, 5.0 µg/L EHDPP exposure during early development (4-120 hpf) triggered early- and midstage AD-like symptoms in adulthood (180 dpf), characterized by cognitive confusion, aggression, blood-brain barrier disruption, and mitochondrial damage in brains. These findings provide deep insights into the long-term neurotoxicity effects and Alzheimer's disease risks of early EHDPP exposure at extremely low dosages.

One arrow two eagles: Multifunctional nano-system for macrophage reprogramming and osteoclastogenesis inhibition against inflammatory osteolysis.

Inflammatory osteolysis poses a significant worldwide threat to public health. However, current monotherapies, which target either the prevention of the inflammatory response or the attenuation of osteoclast (OC) formation, have limited efficacy due to the complexity of the bone immune system being overlooked. Herein, by means of modifying salmon calcitonin (sCT), a multifunctional nano-system (AuNDs-sCT) was designed to synergistically inhibit OC differentiation and reverse the inflammatory microenvironment against inflammatory osteolysis. On the one hand, AuNDs-sCT effectively restrained OC differentiation by binding to the calcitonin receptors on the surface of OC precursors, resulting in the down-regulation of OC-specific genes and proteins. The targeted capacity of AuNDs-sCT provided a more durable and precise therapeutic effect. On the other hand, AuNDs-sCT exhibited antioxidant and anti-inflammatory effects, which regulated the polarization "switch" from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype in macrophages by the inhibition of NF-κB p65 phosphorylation, thereby effectively reversed the local inflammatory microenvironment. Additionally, AuNDs-sCT served as a promising fluorescent probe, enabling real-time visualization of the therapeutic process. This capability is expected to optimize drug administration and evaluate therapeutic effects. In summary, by inhibiting OC differentiation and reprogramming macrophages, AuNDs-sCT successfully realized drug repurposing and achieved the "one arrow two eagles" therapeutic strategy, which offers a synergistic and effective treatment option for the clinical management of inflammatory osteolysis.

Intestinal deguelin drives resistance to acetaminophen-induced hepatotoxicity in female mice.

Acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury (DILI), with gender-specific differences in susceptibility. However, the mechanism underlying this phenomenon remains unclear. Our study reveals that the gender-specific differences in susceptibility to APAP-induced hepatotoxicity are due to differences in the gut microbiota. Through microbial multi-omics and cultivation, we observed increased gut microbiota-derived deguelin content in both women and female mice. Administration of deguelin was capable of alleviating hepatotoxicity in APAP-treated male mice, and this protective effect was associated with the inhibition of hepatocyte oxidative stress. Mechanistically, deguelin reduced the expression of thyrotropin receptor (TSHR) in hepatocytes with APAP treatment through direct interaction. Pharmacologic suppression of TSHR expression using ML224 significantly increased hepatic glutathione (GSH) in APAP-treated male mice. These findings suggest that gut microbiota-derived deguelin plays a crucial role in reducing APAP-induced hepatotoxicity in female mice, offering new insights into therapeutic strategies for DILI.

Effect of single blastocyst-stage versus single cleavage-stage embryo transfer on cumulative live births in women with good prognosis undergoing in vitro fertilization: Multicenter Randomized Controlled Trial.

In this multicenter, non-inferiority, randomized trial, we randomly assigned 992 women undergoing in-vitro fertilization (IVF) with a good prognosis (aged 20-40, ≥3 transferrable cleavage-stage embryos) to strategies of blastocyst-stage (n = 497) or cleavage-stage (n = 495) single embryo transfer. Primary outcome was cumulative live-birth rate after up to three transfers. Secondary outcomes were cumulative live-births after all embryo transfers within 1 year of randomization, pregnancy outcomes, obstetric-perinatal complications, and livebirths outcomes. Live-birth rates were 74.8% in blastocyst-stage group versus 66.3% in cleavage-stage group (relative risk 1.13, 95%CI:1.04-1.22; Pnon-inferiority < 0.001, Psuperiority = 0.003) (1-year cumulative live birth rates of 75.7% versus 68.9%). Blastocyst transfer increased the risk of spontaneous preterm birth (4.6% vs 2.0%; P = 0.02) and neonatal hospitalization >3 days. Among good prognosis women, a strategy of single blastocyst transfer increases cumulative live-birth rates over single cleavage-stage transfer. Blastocyst transfer resulted in higher preterm birth rates. This information should be used to counsel patients on their choice between cleavage-stage and blastocyst-stage transfer (NCT03152643, https://clinicaltrials.gov/study/NCT03152643 ).