Vertically-stacked W/W2C heterojunctions with high electrocatalytic capability for the hydrogen evolution reaction in a wide pH range.

The hydrogen evolution reaction (HER) in water splitting is among the foremost methods to produce clean and green hydrogen from renewable sources. The practical use of the HER technology is however hindered by the high price and/or the relatively low efficiency of the currently used catalysts. Herein, we report a heterostructured W/W2C electrocatalyst featuring vertically stacked interfaces and embedded in N-doped porous graphitic carbon (denoted as W/W2C@N-PGC) as a high-performance electrocatalyst for the HER in a wide pH range. The catalyst synthesis, accomplished through a straightforward one-pot method, is both facile and highly efficient, involving freeze-drying a suspension of the starting materials followed by pyrolyzing the obtained dry gel. Density functional theory calculations revealed the crucial role of the W/W2C heterojunction in promoting the two key steps of the HER, viz. HOH bond scission and H2 emission. Electrochemical data confirmed the excellent electrocatalytic capability of W/W2C@N-PGC toward the HER process in a wide pH range including alkaline, acidic, and neutral electrolytes. In 1.0 M KOH, we measured a low overpotential of 102 mV to drive a current density of 10 mA cm-2; a long-term stability (up to 24 h) was also realized. The data presented in this work highlight the importance of electrocatalysts with heterojunctions for the HER and the methodology presented in this work may be extended to other contemporary energy-related technologies such as CO2 reduction, oxygen evolution, and oxygen reduction reactions.

Evaluation of a three-gene methylation model for correlating lymph node metastasis in postoperative early gastric cancer adjacent samples.

Background: Lymph node metastasis (LNM) has a profound impact on the treatment and prognosis of early gastric cancer (EGC), yet the existing evaluation methods lack accuracy. Recent research has underscored the role of precancerous lesions in tumor progression and metastasis. The objective of this study was to utilize the previously developed EGC LNM prediction model to further validate and extend the analysis in paired adjacent tissue samples. Methods: We evaluated the model in a monocentric study using Methylight, a methylation-specific PCR technique, on postoperative fresh-frozen EGC samples (n = 129) and paired adjacent tissue samples (n = 129). Results: The three-gene methylation model demonstrated remarkable efficacy in both EGC and adjacent tissues. The model demonstrated excellent performance, with areas under the curve (AUC) of 0.85 and 0.82, specificities of 85.1% and 80.5%, sensitivities of 83.3% and 73.8%, and accuracies of 84.5% and 78.3%, respectively. It is noteworthy that the model demonstrated superior performance compared to computed tomography (CT) imaging in the adjacent tissue group, with an area under the curve (AUC) of 0.86 compared to 0.64 (p < 0.001). Furthermore, the model demonstrated superior diagnostic capability in these adjacent tissues (AUC = 0.82) compared to traditional clinicopathological features, including ulceration (AUC = 0.65), invasional depth (AUC = 0.66), and lymphovascular invasion (AUC = 0.69). Additionally, it surpassed traditional models based on these features (AUC = 0.77). Conclusion: The three-gene methylation prediction model for EGC LNM is highly effective in both cancerous and adjacent tissue samples in a postoperative setting, providing reliable diagnostic information. This extends its clinical utility, particularly when tumor samples are scarce, making it a valuable tool for evaluating LNM status and assisting in treatment planning.

Early prediction of radiotherapy outcomes in pharyngeal cancer using deep learning on baseline [18F]Fluorodeoxyglucose positron emission Tomography/Computed tomography.

OBJECTIVES: This study aimed to develop an integrated segmentation-free deep learning (DL) framework to predict multiple aspects of radiotherapy outcome in pharyngeal cancer patients by analyzing pretreatment 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET/CT). METHODS: We utilized baseline 18F-FDG-PET/CT scans from patients newly diagnosed with oropharyngeal or hypopharyngeal cancer. The study cohort comprised 162 patients for training and 32 for validation, all of whom completed definitive chemoradiotherapy or radiotherapy for organ-preservation. Following image augmentation, fused PET and CT images were used to train three distinct DL models. An ensemble voting classifier was then employed to predict local recurrence (LR), neck lymph node relapse (NR), and distant metastases (DM). Model performance was evaluated using receiver operating characteristic curve analysis. RESULTS: With a median follow-up of 36 months, the training cohort experienced, LR in 45 (27.8 %), NR in 32 (19.8 %), and DM in 21 (13.0 %) patients. By optimizing single models and finalizing with an ensemble voting classifier, the area under the curve for the occurrence of LR, NR, and DM was 0.850, 0.878, and 0.893, whereas the accuracy for the three endpoints were 87.5 %, 68.8 %, and 78.1 %, respectively. CONCLUSIONS: By utilizing baseline 18F-FDG-PET/CT, our proposed DL models can provide a supplemental prediction for various therapeutic outcome in patients with pharyngeal cancer undergoing radiotherapy-based treatment. The accuracy for NR and DM predictions requires further optimization through additional technological breakthrough or combing clinical parameters. External validation is an important future step to confirm the model's generalizability and clinical utility.

Isoliquiritigenin alleviates neuropathic pain by reducing microglia inflammation through inhibition of the ERK signaling pathway and decreasing CEBPB transcription expression.

BACKGROUND: Natural compounds are invaluable for their therapeutic effects in treating various diseases. Isoliquiritigenin (ISL) stands out due to its potent anti-inflammatory and antioxidative properties, offering significant therapeutic effects in many diseases. However, there is currently no existing literature on the role of ISL in neuropathic pain treatment. METHODS: We used lipopolysaccharide to stimulate BV-2 microglia in order to evaluate the inhibitory effects of ISL on neuroinflammation. Proteomics data and protein-protein interaction network analysis were used to identify differential proteins expressed in BV-2 microglia treated with ISL. This allowed for the identification of targets impacted by ISL action. Additionally, we assessed the analgesic efficacy of ISL in a mouse model of chronic constriction injury of the sciatic nerve (CCI) and investigated its inhibitory influence on pro-inflammatory cytokine production and spinal microglia activation. RESULTS: Our results indicate that ISL efficiently inhibits BV-2 microglia activation and pro-inflammatory cytokine expression. Furthermore, CEBPB has been recognized as a possible target for ISL activity. Crucially, microglia activation was successfully reduced by CEBPB knockdown. Functional recovery tests carried out later on validated that ISL works by specifically inhibiting the ERK/CEBPB signaling pathway. In vivo studies showed that giving mice ISL reduces the mechanical and thermal pain caused on by chronic contraction injuries. CONCLUSION: The analgesic effect of ISL on neuropathic pain primarily stems from its ability to inhibit the activation of spinal microglia and neuroinflammation. This mechanism may be attributed to the capacity of ISL to suppress microglial activation, reduce the expression of pro-inflammatory cytokines by inhibiting the ERK signaling pathway, and decrease transcriptional expression of CEBPB.

Coordinatively Unsaturated Co Single-Atom Catalysts Enhance the Performance of Lithium-Sulfur Batteries by Triggering Strong d-p Orbital Hybridization.

The catalytic activities displayed by single-atom catalysts (SACs) depend on the coordination structure. SACs supported on carbon materials often adopt saturated coordination structures with uneven distributions because they require high-temperature conditions during synthesis. Herein, bisnitrogen-chelated Co SACs that are coordinatively unsaturated are prepared by integrating a Co complex into a conjugated microporous polymer (CMP-CoN2). Compared with saturated analogues, i.e., tetranitrogen-chelated Co SACs (denoted as CMP-CoN4), CMP-CoN2 exhibits higher electrocatalytic activity in polysulfide conversions due to an enhanced hybridization between the 3d orbitals of the Co atoms and the 3p orbitals of the S atoms in the polysulfide. As a result, sulfur cathodes prepared with CoN2 deliver outstanding performance metrics, including a high specific capacity (1393 mA h g-1 at 0.1 C), a superior rate capacity (673.2 mA h g-1 at 6 C), and a low capacity decay rate (of only 0.045% per cycle at 2 C over 1000 cycles). They also outperform sulfur cathodes that contain CMP-CoN4 or CMPs that are devoid of Co SACs. This work reveals how the catalytic activity displayed by SACs is affected by their coordination structures, and the rules that underpin the structure-activity relationship may be extended to designing electrocatalysts for use in other applications.

Bioactive proteins and antioxidant peptides from Litsea cubeba fruit meal: Preparation, characterization and ameliorating function on high-fat diet-induced NAFLD through regulating lipid metabolism, oxidative stress and inflammatory response.

Non-alcoholic fatty liver disease (NAFLD) plays an increasingly significant threat to human health. In this study, the processing by-products of Litsea cubeba fruit meal were defatted by ultrasound-assisted methods, then the acetone-precipitated protein of L. cubeba (LCP) was obtained and structural analysis was performed. LCP was hydrolyzed by a two-step sequential hydrolysis method using alcalase and papain. Subsequently, antioxidant peptide fraction (IV2) was isolated and identified from the resultant hydrolysate through membrane ultrafiltration, Sephadex G-15 chromatography, and liquid chromatograph mass spectrometer (LC-MS). Animal experimentation indicated the potential of IV2 to mitigate hepatic steatosis. Moreover, IV2 could effectively reduce oxidative stress-induced damage by modulating the Keap1-Nrf2 pathway to activate downstream heme oxygenase-1 (HO-1) and NAD(P) H quinone oxidoreductase 1 (NQO1). Integrating metabolomics and transcriptomics revealed enrichment in pathways associated with glycerolipid metabolism and fatty acid ß-oxidation, suggesting the principal mechanisms underlying IV2's ameliorative effects on NAFLD. Transcriptome sequencing identified 3092 up-regulated and 3010 down-regulated genes following IV2 treatment. Interaction analyses based on different lipid compositions (DELs) and differentially expressed genes (DEGs) indicated that IV2 primarily alleviated hepatic steatosis by modulating peroxisome proliferator-activated receptor α (PPAR-α) related pathways, thereby augmenting fatty acid ß-oxidation within liver cells. These results indicate that IV2 shows potential in improving high-fat diet (HFD)-induced NAFLD, with improved fatty acid ß-oxidation and reduced triglyceride biosynthesis emerging as underlying mechanisms.

An In Situ Generated Organic/Inorganic Hybrid SEI Layer Enables Li Metal Anodes with Dendrite Suppression Ability, High-Rate Capability, and Long-Life Stability.

High-quality solid electrolyte interphase (SEI) layers can effectively suppress the growth of Li dendrites and improve the cycling stability of lithium metal batteries. Herein, 1-(6-bromohexanoyl)-3-butylurea is used to construct an organic/inorganic hybrid (designated as LiBr-HBU) SEI layer that features a uniform and compact structure. The LiBr-HBU SEI layer exhibits superior electrolyte wettability and air stability as well as strong attachment to Li foils. The LiBr-HBU SEI layer achieves a Li+ conductivity of 2.75 × 10-4 S cm-1, which is ≈50-fold higher than the value measured for a native SEI layer. A Li//Li symmetric cell containing the LiBr-HBU SEI layer exhibits markedly improved cyclability when compared with the cell containing a native SEI layer, especially at a high current density (e.g., cycling life up to 1333 h at 15 mA cm-2). The LiBr-HBU SEI layer also improves the performance of lithium-sulfur cells, particularly the rate capability (548 mAh g-1 at 10 C) and cycling stability (513 mAh g-1 at 0.5 C after 500 cycles). The methodology described can be extended to the commercial processing of Li metal anodes as the artificial SEI layer also protects Li metal against corrosion.

Green innovation imperative for natural resource-driven sustainable economic recovery: Linking rights Structure, corporate social responsibility, and renewable energy contracts.

This study examines the complex relationships necessary for a sustainable economic recovery, focusing on the interplay between contracts for renewable energy, natural resource use, corporate social responsibility (CSR), and rights frameworks. Motivated by the increasing scrutiny of environmental practices, this research aims to highlight the need for sustainable business models during the transition to a more environmentally sensitive economy. The study area encompasses diverse sectors where CSR goals can be aligned with renewable energy project frameworks through natural resource utilization. Methodologies include a novel composite CSR evaluation indicator designed to complement industry rankings and a thorough analysis of CSR within the mining industry. Results demonstrate how aligning CSR with renewable energy initiatives can reshape profit models for stakeholders and emphasize the changing green product market as a catalyst for economic resurgence. Recommendations in the area of policies focus on the reasoned utilization of natural resources and the application of innovations following the principles of CSR. This research provides critical guidance to relevant authorities and institutions charged with ethical responsibility, ensuring the proper utilization and implementation of renewable energy sources to create a more ecological future based on green technology and sustainable resource management.

DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer.

Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.

Green pepper fruits counting based on improved DeepSort and optimized Yolov5s.

Introduction: Green pepper yield estimation is crucial for establishing harvest and storage strategies. Method: This paper proposes an automatic counting method for green pepper fruits based on object detection and multi-object tracking algorithm. Green pepper fruits have colors similar to leaves and are often occluded by each other, posing challenges for detection. Based on the YOLOv5s, the CS_YOLOv5s model is specifically designed for green pepper fruit detection. In the CS_YOLOv5s model, a Slim-Nick combined with GSConv structure is utilized in the Neck to reduce model parameters while enhancing detection speed. Additionally, the CBAM attention mechanism is integrated into the Neck to enhance the feature perception of green peppers at various locations and enhance the feature extraction capabilities of the model. Result: According to the test results, the CS_YOLOv5s model of mAP, Precision and Recall, and Detection time of a single image are 98.96%, 95%, 97.3%, and 6.3 ms respectively. Compared to the YOLOv5s model, the Detection time of a single image is reduced by 34.4%, while Recall and mAP values are improved. Additionally, for green pepper fruit tracking, this paper combines appearance matching algorithms and track optimization algorithms from SportsTrack to optimize the DeepSort algorithm. Considering three different scenarios of tracking, the MOTA and MOTP are stable, but the ID switch is reduced by 29.41%. Based on the CS_YOLOv5s model, the counting performance before and after DeepSort optimization is compared. For green pepper counting in videos, the optimized DeepSort algorithm achieves ACP (Average Counting Precision), MAE (Mean Absolute Error), and RMSE (Root Mean Squared Error) values of 95.33%, 3.33, and 3.74, respectively. Compared to the original algorithm, ACP increases by 7.2%, while MAE and RMSE decrease by 6.67 and 6.94, respectively. Additionally, Based on the optimized DeepSort, the fruit counting results using YOLOv5s model and CS_YOLOv5s model were compared, and the results show that using the better object detector CS_YOLOv5s has better counting accuracy and robustness.

Generation of two induced pluripotent stem cell lines from an Usher syndrome type 1B patient with the homozygous c.496del MYO7A variant.

Usher syndrome (USH) is the most common cause of inherited deaf-blindness. Here, we produced the LEIi020-A and LEIi020-B induced pluripotent stem cell (iPSC) lines from dermal fibroblasts derived from a patient with USH1B caused by inheritance of homozygous c.496del variants in MYO7A using episomal plasmids encoding OCT4, SOX2, KLF4, L-MYC, LIN28, mir302/367 microRNA and shRNA for TP53. Both iPSC lines expressed pluripotency markers, demonstrated trilineage differentiation potential and displayed a 46,XY karyotype. These cell lines represent a valuable resource for the production of retinal and otic tissues to support research into the pathogenesis and treatment of USH1B.

AoUPRS: A Cost-Effective and Versatile PRS Calculator for the All of Us Program.

Background: The All of Us (AoU) Research Program provides a comprehensive genomic dataset to accelerate health research and medical breakthroughs. Despite its potential, researchers face significant challenges, including high costs and inefficiencies associated with data extraction and analysis. AoUPRS addresses these challenges by offering a versatile and cost-effective tool for calculating polygenic risk scores (PRS), enabling both experienced and novice researchers to leverage the AoU dataset for significant genomic discoveries. Results: AoUPRS is implemented in Python and utilizes the Hail framework for genomic data analysis. It offers two distinct approaches for PRS calculation: the Hail MatrixTable (MT) and the Hail Variant Dataset (VDS). The MT approach provides a dense representation of genotype data, while the VDS approach offers a sparse representation, significantly reducing computational costs. In performance evaluations, the VDS approach demonstrated a cost reduction of up to 99.51% for smaller scores and 85% for larger scores compared to the MT approach. Both approaches yielded similar predictive power, as shown by logistic regression analyses of PRS for coronary artery disease, atrial fibrillation, and type 2 diabetes. The empirical cumulative distribution functions (ECDFs) for PRS values further confirmed the consistency between the two methods. Conclusions: AoUPRS is a versatile and cost-effective tool that addresses the high costs and inefficiencies associated with PRS calculations using the AoU dataset. By offering both dense and sparse data processing approaches, AoUPRS allows researchers to choose the approach best suited to their needs, facilitating genomic discoveries. The tool's open-source availability on GitHub, coupled with detailed documentation and tutorials, ensures accessibility and ease of use for the scientific community.

Biomarkers Screening and Mechanisms Analysis of the Restraint Stress-Induced Myocardial Injury in Hyperlipidemia ApoE-/- Mice.

OBJECTIVES: To explore the biomarkers and potential mechanisms of chronic restraint stress-induced myocardial injury in hyperlipidemia ApoE-/- mice. METHODS: The hyperlipidemia combined with the chronic stress model was established by restraining the ApoE-/- mice. Proteomics and bioinformatics techniques were used to describe the characteristic molecular changes and related regulatory mechanisms of chronic stress-induced myocardial injury in hyperlipidemia mice and to explore potential diagnostic biomarkers. RESULTS: Proteomic analysis showed that there were 43 significantly up-regulated and 58 significantly down-regulated differentially expressed proteins in hyperlipidemia combined with the restraint stress group compared with the hyperlipidemia group. Among them, GBP2, TAOK3, TFR1 and UCP1 were biomarkers with great diagnostic potential. KEGG pathway enrichment analysis indicated that ferroptosis was a significant pathway that accelerated the myocardial injury in hyperlipidemia combined with restraint stress-induced model. The mmu_circ_0001567/miR-7a/Tfr-1 and mmu_circ_0001042/miR-7a/Tfr-1 might be important circRNA-miRNA-mRNA regulatory networks related to ferroptosis in this model. CONCLUSIONS: Chronic restraint stress may aggravate myocardial injury in hyperlipidemia mice via ferroptosis. Four potential biomarkers are selected for myocardial injury diagnosis, providing a new direction for sudden cardiac death (SCD) caused by hyperlipidemia combined with the restraint stress.

Comprehensive genomic profiling and therapeutic implications for Taiwanese patients with treatment-naïve breast cancer.

BACKGROUND: Breast cancer is a heterogeneous disease categorized based on molecular characteristics, including hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression levels. The emergence of profiling technology has revealed multiple driver genomic alterations within each breast cancer subtype, serving as biomarkers to predict treatment outcomes. This study aimed to explore the genomic landscape of breast cancer in the Taiwanese population through comprehensive genomic profiling (CGP) and identify diagnostic and predictive biomarkers. METHODS: Targeted next-generation sequencing-based CGP was performed on 116 archived Taiwanese breast cancer specimens, assessing genomic alterations (GAs), including single nucleotide variants, copy number variants, fusion genes, tumor mutation burden (TMB), and microsatellite instability (MSI) status. Predictive variants for FDA-approved therapies were evaluated within each subtype. RESULTS: In the cohort, frequent mutations included PIK3CA (39.7%), TP53 (36.2%), KMT2C (9.5%), GATA3 (8.6%), and SF3B1 (6.9%). All subtypes had low TMB, with no MSI-H tumors. Among HR + HER2- patients, 42% (27/65) harbored activating PIK3CA mutations, implying potential sensitivity to PI3K inhibitors and resistance to endocrine therapies. HR + HER2- patients exhibited intrinsic hormonal resistance via FGFR1 gene gain/amplification (15%), exclusive of PI3K/AKT pathway alterations. Aberrations in the PI3K/AKT/mTOR and FGFR pathways were implicated in chemoresistance, with a 52.9% involvement in triple-negative breast cancer. In HER2+ tumors, 50% harbored GAs potentially conferring resistance to anti-HER2 therapies, including PIK3CA mutations (32%), MAP3K1 (2.9%), NF1 (2.9%), and copy number gain/amplification of FGFR1 (18%), FGFR3 (2.9%), EGFR (2.9%), and AKT2 (2.9%). CONCLUSION: This study presents CGP findings for treatment-naïve Taiwanese breast cancer, emphasizing its value in routine breast cancer management, disease classification, and treatment selection.

Photosensitive and dual-targeted chromium nanoparticle delivering small interfering RNA YTHDF1 for molecular-targeted immunotherapy in liver cancer.

Tumor-associated macrophages (TAMs) are a promising target for cancer immunotherapy, but delivering therapeutic agents to TAMs within the tumor microenvironment (TME) is challenging. In this study, a photosensitive, dual-targeting nanoparticle system (M.RGD@Cr-CTS-siYTHDF1 NPs) was developed. The structure includes a shell of DSPE-modified RGD peptides targeting integrin receptors on tumor cells and carboxymethyl mannose targeting CD206 receptors on macrophages, with a core of chitosan adsorbing m6A reading protein YTHDF1 siRNA and chromium nanoparticles (Cr NPs). The approach is specifically designed to target TAM and cancer cells, utilizing the photothermal effect of Cr NPs to disrupt the TME and deliver siYTHDF1 to TAM. In experiments with tumor-bearing mice, M.RGD@Cr-CTS-siYTHDF1 NPs, when exposed to laser irradiation, effectively killed tumor cells, disrupted the TME, delivered siYTHDF1 to TAMs, silenced the YTHDF1 gene, and shifted the STAT3-STAT1 equilibrium by reducing STAT3 and enhancing STAT1 expression. This reprogramming of TAMs towards an anti-tumor phenotype led to a pro-immunogenic TME state. The strategy also suppressed immunosuppressive IL-10 production, increased expression of immunostimulatory factors (IL-12 and IFN-γ), boosted CD8 + T cell infiltration and M1-type TAMs, and reduced Tregs and M2-type TAMs within the TME. In conclusion, the dual-targeting M.RGD@Cr-CTS-siYTHDF1 NPs, integrating dual-targeting capabilities with photothermal therapy (PTT) and RNA interference, offer a promising approach for molecular targeted cancer immunotherapy with potential for clinical application.

Establishment of an induced pluripotent stem cell line LEIi019-A from an early-onset retinal dystrophy patient with the autosomal dominant OTX2 c.259G>A variant.

The human induced pluripotent stem cell (iPSC) line LEIi019-A was generated from a patient with early-onset pattern dystrophy caused by a heterozygous mutation NM_001270525.1:c.259G>A (p.Glu87Lys) in OTX2. Patient-derived dermal fibroblasts were reprogrammed using episomal plasmids containing reprogramming factors OCT4, SOX2, KLF4, MYCL, LIN28, TP53 shRNA and miR-302/367. The iPSC line expressed pluripotency markers, displayed a normal 46,XY karyotype and demonstrated the ability to differentiate into the three primary germ layers, retinal organoids and retinal pigment epithelial cells.

Exosomes from umbilical cord mesenchymal stem cells ameliorate intervertebral disc degeneration via repairing mitochondrial dysfunction.

Background: Reactive oxygen species (ROS), predominantly generated by mitochondria, play a crucial role in the pathogenesis of intervertebral disc degeneration (IVDD). Reduction of ROS levels may be an effective strategy to delay IVDD. In this study, we assessed whether umbilical cord mesenchymal stem cell-exosomes (UCMSC-exos) can be used to treat IVDD by suppressing ROS production caused by mitochondrial dysfunction. Materials and methods: Human UCMSC-exos were isolated and identified. Nucleus pulposus cells (NPCs) were stimulated with H2O2 in the presence or absence of exosomes. Then, 4D label free quantitative (4D-LFQ) proteomics were used to analyze the differentially expressed (DE) proteins. Mitochondrial membrane potential (MMP), mitochondrial ROS and protein levels were determined via immunofluorescence staining, flow cytometry and western blotting respectively. Additionally, high-throughput sequencing was performed to identify the DE miRNAs in NPCs. Finally, therapeutic effects of UCMSC-exos were investigated in a puncture-induced IVDD rat model. Degenerative grades of rat IVDs were assessed using magnetic resonance imaging and histochemical staining. Results: UCMSC-exos effectively improved the viability of NPCs and restored the expression of the extracellular matrix (ECM) proteins, collagen type II alpha-1 (COL2A1) and matrix metalloproteinase-13 induced by H2O2. Additionally, UCMSC-exos not only reduced the total intracellular ROS and mitochondrial superoxide levels, but also increased MMP in pathological NPCs. 4D-LFQ proteomics and western blotting further revealed that UCMSC-exos up-regulated the levels of the mitochondrial protein, mitochondrial transcription factor A (TFAM), in H2O2-induced NPCs. High-throughput sequencing and qRT-PCR uncovered that UCMSC-exos down-regulated the levels of miR-194-5p, a potential negative regulator of TFAM, induced by H2O2. Finally, in vivo results showed that UCMSC-exos injection improved the histopathological structure and enhanced the expression levels of COL2A1 and TFAM in the rat IVDD model. Conclusions: Our findings suggest that UCMSC-exos promote ECM synthesis, relieve mitochondrial oxidative stress, and attenuate mitochondrial dysfunction in vitro and in vivo, thereby effectively treating IVDD. The translational potential of this article: This study provides solid experimental data support for the therapeutic effects of UCMSC-exos on IVDD, suggesting that UCMSC-exos will be a promising nanotherapy for IVDD.

Combined lineage tracing and scRNA-seq reveal the activation of Sox9+ cells in renal regeneration with PGE2 treatment.

Uncovering mechanisms of endogenous regeneration and repair through resident stem cell activation will allow us to develop specific therapies for injuries and diseases by targeting resident stem cell lineages. Sox9+ stem cells have been reported to play an essential role in acute kidney injury (AKI). However, a complete view of the Sox9+ lineage was not well investigated to accurately elucidate the functional end state and the choice of cell fate during tissue repair after AKI. To identify the mechanisms of fate determination of Sox9+ stem cells, we set up an AKI model with prostaglandin E2 (PGE2) treatment in a Sox9 lineage tracing mouse model. Single-cell RNA sequencing (scRNA-seq) was performed to analyse the transcriptomic profile of the Sox9+ lineage. Our results revealed that PGE2 could activate renal Sox9+ cells and promote the differentiation of Sox9+ cells into renal proximal tubular epithelial cells and inhibit the development of fibrosis. Furthermore, single-cell transcriptome analysis demonstrated that PGE2 could regulate the restoration of lipid metabolism homeostasis in proximal tubular epithelial cells by participating in communication with different cell types. Our results highlight the prospects for the activation of endogenous renal Sox9+ stem cells with PGE2 for the regenerative therapy of AKI.

Proteomic analysis reveals potential therapeutic targets for childhood asthma through Mendelian randomization.

BACKGROUND: Asthma is the most common chronic disease among children and poses a significant threat to their health. This study aims to assess the relationship between various plasma proteins and childhood asthma, thereby identifying potential therapeutic targets. METHODS: Based on publicly available genome-wide association study summary statistics, we employed a two-sample Mendelian randomization (MR) approach to elucidate the causal relationship between plasma proteins and asthma. Mediation analysis was then conducted to evaluate the indirect influence of plasma proteins on childhood asthma mediated through risk factors. Comprehensive analysis was also conducted to explore the association between plasma proteins and various phenotypes using the UK Biobank dataset. RESULTS: MR analysis uncovered a causal relationship between 10 plasma proteins and childhood asthma. Elevated levels of seven proteins (TLR4, UBP25, CBR1, Rac GTPase-activating protein 1 [RGAP1], IL-21, MICB, and PDE4D) and decreased levels of three proteins (GSTO1, LIRB4 and PIGF) were associated with an increased risk of childhood asthma. Our findings further validated the connections between reported risk factors (body mass index, mood swings, hay fever or allergic rhinitis, and eczema or dermatitis) and childhood asthma. Mediation analysis revealed the influence of proteins on childhood asthma outcomes through risk factors. Furthermore, the MR analysis identified 73 plasma proteins that exhibited causal associations with at least one risk factor for childhood asthma. Among them, RGAP1 mediates a significant proportion (25.10%) of the risk of childhood asthma through eczema or dermatitis. Finally, a phenotype-wide association study based on these 10 proteins and 1403 diseases provided novel associations between these biomarkers and multiple phenotypes. CONCLUSION: Our study comprehensively investigated the causal relationship between plasma proteins and childhood asthma, providing novel insights into potential therapeutic targets.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.