Independent organelle and organelle-organelle interactions: essential mechanisms for malignant gynecological cancer cell survival.

Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle-organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.

Injectable Thermosensitive Gel CH-BPNs-NBP for Effective Periodontitis Treatment through ROS-Scavenging and Jaw Vascular Unit Protection.

Periodontitis, a prevalent inflammatory condition in the oral cavity, is closely associated with oxidative stress-induced tissue damage mediated by excessive reactive oxygen species (ROS) production. The jaw vascular unit (JVU), encompassing both vascular and lymphatic vessels, plays a crucial role in maintaining tissue fluid homeostasis and contributes to the pathological process in inflammatory diseases of the jaw. This study presents a novel approach for treating periodontitis through the development of an injectable thermosensitive gel (CH-BPNs-NBP). The gel formulation incorporates black phosphorus nanosheets (BPNs), which are notable for their ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator that promotes lymphatic vessel function within the JVU. These results demonstrate that the designed thermosensitive gel serve as a controlled release system, delivering BPNs and NBP to the site of inflammation. CH-BPNs-NBP not only protects macrophages and human lymphatic endothelial cells from ROS attack but also promotes M2 polarization and lymphatic function. In in vivo studies, this work observes a significant reduction in inflammation and tissue damage, accompanied by a notable promotion of alveolar bone regeneration. This research introduces a promising therapeutic strategy for periodontitis, leveraging the unique properties of BPNs and NBP within an injectable thermosensitive gel.

Uncovering novel drug targets for bipolar disorder: a Mendelian randomization analysis of brain, cerebrospinal fluid, and plasma proteomes.

BACKGROUND: There is a clear demand for innovative therapeutics for bipolar disorder (BD). METHODS: We integrated the largest BD genome-wide association study (GWAS) dataset (NCase = 41 917, NControl = 371 549) with protein quantitative trait loci from brain, cerebrospinal fluid, and plasma. Using a range of integrative analyses, including Mendelian randomization (MR), Steiger filter analysis, Bayesian colocalization, and phenome-wide MR analysis, we prioritized novel drug targets for BD. Additionally, we incorporated data from the UK Biobank (NCase = 1064, NControl = 365 476) and the FinnGen study (NCase = 7006, NControl = 329 192) for robust biological validation. RESULTS: Through MR analysis, we found that in the brain, downregulation of DNM3, MCTP1, ABCB8 and elevation of DFNA5 and PDF were risk factors for BD. In cerebrospinal fluid, increased BD risk was associated with increased levels of FRZB, AGRP, and IL36A and decreased CTSF and LRP8. Plasma analysis revealed that decreased LMAN2L, CX3CL1, PI3, NCAM1, and TIMP4 correlated with increased BD risk, but ITIH1 did not. All these proteins passed Steiger filtering, and Bayesian colocalization confirmed that 12 proteins were colocalized with BD. Phenome-wide MR analysis revealed no significant side effects for potential drug targets, except for LRP8. External validation further underscored the concordance between the primary and validation cohorts, confirming MCTP1, DNM3, PDF, CTSF, AGRP, FRZB, LMAN2L, NCAM1, and TIMP4 are intriguing targets for BD. CONCLUSIONS: Our study identified druggable proteins for BD, including MCTP1, DNM3, and PDF in the brain; CTSF, AGRP, and FRZB in cerebrospinal fluid; and LMAN2L, NCAM1, and TIMP4 in plasma, delineating promising avenues to development of novel therapies.

An Injectable Black Phosphorus Hydrogel for Rapid Tooth Extraction Socket Healing.

The excess production of reactive oxygen species (ROS) will delay tooth extraction socket (TES) healing. In this study, we developed an injectable thermosensitive hydrogel (NBP@BP@CS) used to treat TES healing. The hydrogel formulation incorporated black phosphorus (BP) nanoflakes, recognized for their accelerated alveolar bone regeneration and ROS-scavenging properties, and dl-3-n-butylphthalide (NBP), a vasodilator aimed at enhancing angiogenesis. In vivo investigations strongly demonstrated that NBP@BP@CS improved TES healing due to antioxidation and promotion of alveolar bone regeneration by BP nanoflakes. The sustained release of NBP from the hydrogel promoted neovascularization and vascular remodeling. Our results demonstrated that the designed thermosensitive hydrogel provided great opportunity not only for ROS elimination but also for the promotion of osteogenesis and angiogenesis, reflecting the "three birds with one stone" concept, and has tremendous potential for rapid TES healing.

Advances in biosensors for major depressive disorder diagnostic biomarkers.

Depression is one of the most common mental disorders and is mainly characterized by low mood or lack of interest and pleasure. It can be accompanied by varying degrees of cognitive and behavioral changes and may lead to suicide risk in severe cases. Due to the subjectivity of diagnostic methods and the complexity of patients' conditions, the diagnosis of major depressive disorder (MDD) has always been a difficult problem in psychiatry. With the discovery of more diagnostic biomarkers associated with MDD in recent years, especially emerging non-coding RNAs (ncRNAs), it is possible to quantify the condition of patients with mental illness based on biomarker levels. Point-of-care biosensors have emerged due to their advantages of convenient sampling, rapid detection, miniaturization, and portability. After summarizing the pathogenesis of MDD, representative biomarkers, including proteins, hormones, and RNAs, are discussed. Furthermore, we analyzed recent advances in biosensors for detecting various types of biomarkers of MDD, highlighting representative electrochemical sensors. Future trends in terms of new biomarkers, new sample processing methods, and new detection modalities are expected to provide a complete reference for psychiatrists and biomedical engineers.

16S rRNA seq-identified Corynebacterium promotes pyroptosis to aggravate diabetic foot ulcer.

BACKGROUND: Diabetic foot ulcer (DFU) is one of the main chronic complications caused by diabetes, leading to amputation in severe cases. Bacterial infection affects the wound healing in DFU. METHODS: DFU patients who met the criteria were selected, and the clinical data were recorded in detail. The pus exudate from the patient's foot wound and venous blood were collected for biochemical analysis. The distribution of bacterial flora in pus exudates of patients was analyzed by 16S rRNA sequencing, and the correlation between DFU and pathogenic variables, pyroptosis and immunity was analyzed by statistical analysis. Then, the effects of key bacteria on the inflammation, proliferation, apoptosis, and pyroptosis of polymorphonuclear leukocytes were investigated by ELISA, CCK-8, flow cytometry, RT-qPCR and western blot. RESULTS: Clinical data analysis showed that Wagner score was positively correlated with the level of inflammatory factors, and there was high CD3+, CD4+, and low CD8+ levels in DFU patients with high Wagner score. Through alpha, beta diversity analysis and species composition analysis, Corynebacterium accounted for a large proportion in DFU. Logistics regression model and Person correlation analysis demonstrated that mixed bacterial infections could aggravate foot ulcer, and the number of bacteria was closely related to inflammatory factors PCT, PRT, immune cells CD8+, and pyroptosis-related proteins GSDMD and NLRP3. Through in vitro experiments, Corynebacterium inhibited cell proliferation, promoted inflammation (TNF-α, PCT, CRP), apoptosis and pyroptosis (IL-1ß, LDH, IL-18, GSDMD, NLRP3, and caspase-3). CONCLUSION: Mixed bacterial infections exacerbate DFU progression with a high predominance of Corynebacterium, and Corynebacterium promotes inflammation, apoptosis and pyroptosis to inhibit DFU healing.

Roles of parents in life satisfaction and educational hope among Chinese high school students.

The well-being of the Chinese high school students linked to the National Higher Education Entrance Examination, known as gaokao, has been a spotlight education issue in China. This study employed self-determination theory and Bourdieu's sociocultural theory to examine the relationship between life satisfaction, educational hope, and parental support among Chinese high school students. A number of 3,810 high school students from eight schools in Jiangsu, China, completed a validated context-relevant questionnaire. Structural equation model analysis suggested that parental support significantly impacted students' life satisfaction and educational hope. Findings showed that parental intangible support in terms of providing information, advice, encouragement, praise, and care has a direct and significant impact on the life satisfaction of Chinese youth. The extent to which students attach importance to and put effort into achieving their educational aspirations, known as goal commitment, mediated the relationship between parental support and life satisfaction. Moreover, Chinese high school students' educational hope is shaped by their family. Parental support moderates goal commitment, which varies based on parental education background. In short, parents play a critical role in the growth and development of Chinese high school students.

The Neurovascular Unit Dysfunction in the Molecular Mechanisms of Epileptogenesis and Targeted Therapy.

Epilepsy is a multifaceted neurological syndrome characterized by recurrent, spontaneous, and synchronous seizures. The pathogenesis of epilepsy, known as epileptogenesis, involves intricate changes in neurons, neuroglia, and endothelium, leading to structural and functional disorders within neurovascular units and culminating in the development of spontaneous epilepsy. Although current research on epilepsy treatments primarily centers around anti-seizure drugs, it is imperative to seek effective interventions capable of disrupting epileptogenesis. To this end, a comprehensive exploration of the changes and the molecular mechanisms underlying epileptogenesis holds the promise of identifying vital biomarkers for accurate diagnosis and potential therapeutic targets. Emphasizing early diagnosis and timely intervention is paramount, as it stands to significantly improve patient prognosis and alleviate the socioeconomic burden. In this review, we highlight the changes and molecular mechanisms of the neurovascular unit in epileptogenesis and provide a theoretical basis for identifying biomarkers and drug targets.

Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer.

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and ß-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.

Pan-cancer analysis reveals IL32 is a potential prognostic and immunotherapeutic biomarker in cancer.

Interleukin 32 (IL32) is a pro-inflammatory cytokine that plays a key role in promoting sterile inflammation by modulating immune responses. However, the role of IL32 in various cancers remains unclear. This research aimed to investigate the correlation between IL32 expression and immunity and visualize its prognostic landscape in pan-cancer. We investigated gene expression, genomic alterations, and survival analysis of IL32 in pan-cancer in numerous databases including TCGA, GTEx, cBioPortal, and GDC databases. Tumor immune cell infiltration was assessed using the CIBERSORT computational method as well as the ESTIMATE method to analyze the correlation of IL32 expression with stromal and immune components. Protein-protein interaction analysis was performed in the STRING and GeneMANIA databases, and gene function enrichment was performed by GO set enrichment analysis. Tumor tissues had higher IL32 expression levels than normal tissues. Elevated IL32 expression was associated with poor OS and prognosis. In addition, tumor stemness, TMB, MSI, and immune checkpoint genes were also associated with IL32 expression. Correlations were observed between IL32 expression and B cell, CD4T cell, CD8T cell, neutrophil, macrophage, and DC infiltration in multiple cancers. GO enrichment analysis showed that IL32 expression was associated with cancer pathways, cytokine-receptor interactions, and NOD-like receptor signaling pathways. These findings suggest that IL32 may serve as a biomarker of cancer immune infiltration and poor prognosis, providing new therapeutic targets for cancer treatment.

Advances of biological macromolecules hemostatic materials: A review.

Achieving hemostasis is a necessary intervention to rapidly and effectively control bleeding. Conventional hemostatic materials currently used in clinical practice may aggravate the damage at the bleeding site due to factors such as poor adhesion and poor adaptation. Compared to most traditional hemostatic materials, polymer-based hemostatic materials have better biocompatibility and offer several advantages. They provide a more effective method of stopping bleeding and avoiding additional damage to the body in case of excessive blood loss. Various hemostatic materials with greater functionality have been developed in recent years for different organs using diverse design strategies. This article reviews the latest advances in the development of polymeric hemostatic materials. We introduce the coagulation cascade reaction after bleeding and then discuss the hemostatic mechanisms and advantages and disadvantages of various polymer materials, including natural, synthetic, and composite polymer hemostatic materials. We further focus on the design strategies, properties, and characterization of hemostatic materials, along with their applications in different organs. Finally, challenges and prospects for the application of hemostatic polymeric materials are summarized and discussed. We believe that this review can provide a reference for related research on hemostatic materials, contributing to the further development of polymer hemostatic materials.

Next-generation neonicotinoid: The impact of cycloxaprid on the crustacean decapod Penaeus vannamei.

Cycloxaprid, a new neonicotinoid pesticide, poses ecological risks, particularly in aquatic environments, due to its unique action and environmental dispersal. This study investigated the ecotoxicological effects of various concentrations of cycloxaprid on Penaeus vannamei over 28 days. High cycloxaprid levels significantly altered shrimp physiology, as shown by changes in the hepatosomatic index and fattening. Indicators of oxidative stress, such as increased serum hemocyanin, respiratory burst, and nitric oxide, as well as decreased phenol oxidase activity, were observed. Additionally, elevated activities of lactate dehydrogenase, succinate dehydrogenase, and isocitrate dehydrogenase indicated disrupted energy metabolism in the hepatopancreas. Notably, analyses of the nervous system revealed marked disturbances in neural signaling, as evidenced by elevated acetylcholine, octopamine, and acetylcholinesterase levels. Transcriptomic analysis highlighted significant effects on gene expression and metabolic processes in the hepatopancreas and nervous system. This study demonstrated that cycloxaprid disrupts neural signaling and oxidative balance in P. vannamei, potentially affecting its growth, and provides key insights into its biochemical and transcriptomic toxicity in aquatic systems.

Correction: Verification in the Early Stages of the COVID-19 Pandemic: Sentiment Analysis of Japanese Twitter Users.

[This corrects the article DOI: 10.2196/37881.].

Associations between type 2 diabetes mellitus and chronic liver diseases: evidence from a Mendelian ranldomization study in Europeans and East Asians.

Objective: Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups. Methods: We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results. Results: In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV. Conclusion: Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.

Microfluidic-based preparation of artificial antigen-presenting gel droplets for integrated and minimalistic adoptive cell therapy strategies.

Adoptive T-cell transfer for cancer therapy is limited by the inefficiency ofin vitroT-cell expansion and the ability ofin vivoT-cells to infiltrate tumors. The construction of multifunctional artificial antigen-presenting cells is a promising but challenging approach to achieve this goal. In this study, a multifunctional artificial antigen-presenting gel droplet (AAPGD) was designed. Its surface provides regulated T-cell receptor (TCR) stimulation and co-stimulation signals and is capable of slow release of mitogenic cytokines and collagen mimetic peptide. The highly uniform AAPGD are generated by a facile method based on standard droplet microfluidic devices. The results of the study indicate that, T-cell proliferatedin vitroutilizing AAPGD have a fast rate and high activity. AAPGD increased the proportion ofin vitroproliferating T cells low differentiation and specificity. The starting number of AAPGDs and the quality ratio of TCR-stimulated and co-stimulated signals on the surface have a large impact on the rapid proliferation of low-differentiated T cellsin vitro. During reinfusion therapy, AAPGD also enhanced T-cell infiltration into the tumor site. In experiments using AAPGD for adoptive T cell therapy in melanoma mice, tumor growth was inhibited, eliciting a potent cytotoxic T-lymphocyte immune response and improving mouse survival. In conclusion, AAPGD promotes rapid low-differentiation proliferation of T cellsin vitroand enhances T cell infiltration of tumorsin vivo. It simplifies the preparation steps of adoptive cell therapy, improves the therapeutic effect, and provides a new pathway for overdosing T cells to treat solid tumors.

[Effect of high selenium on insulin signaling pathway PI3K-AKT-mTOR in L02 cells].

OBJECTIVE: To observe the effect of high selenium on insulin signaling pathway PI3K-AKT-mTOR in L02 cells. METHODS: One group of L02 cell was treated with different concentrations of selenomethionine(SeMet, 0.001, 0.0025, 0.005, 0.0075, 0.01, 0.025, 0.05, 0.075 and 0.1µmol/L) for 48 h, then cultured with serum-free medium for 4 h and stimulated with 1 µmol/L insulin for 15 min. The insulin signaling pathway(PI3K-AKT-mTOR) was detected by WB. Another group of L02 cell was treated with the same concentrations of SeMet as above for 48 h. The cell supernatant and lysates were collected for the analysis of SELENOP and GPX1, respectively by WB. RESULTS: The expressions of P-AKT-(Ser-473), P-AKT-(Thr-308), PI3K and mTOR in L02 cells under high-Se were decreased with the increase of SeMet concentration. The expressions of GPX1 and SELENOP were enhanced with the increase of SeMet. CONCLUSION: The insulin signaling pathway, PI3K-AKT-mTOR, was damaged in L02 cell under high-Se stress.

The hydrophobic cluster on the surface of protein is the key structural basis for the SDS-resistance of chondroitinase VhChlABC.

The application of chondroitinase requires consideration of the complex microenvironment of the target. Our previous research reported a marine-derived sodium dodecyl sulfate (SDS)-resistant chondroitinase VhChlABC. This study further investigated the mechanism of VhChlABC resistance to SDS. Focusing on the hydrophobic cluster on its strong hydrophilic surface, it was found that the reduction of hydrophobicity of surface residues Ala181, Met182, Met183, Ala184, Val185, and Ile305 significantly reduced the SDS resistance and stability. Molecular dynamics (MD) simulation and molecular docking analysis showed that I305G had more conformational flexibility around residue 305 than wild type (WT), which was more conducive to SDS insertion and binding. The affinity of A181G, M182A, M183A, V185A and I305G to SDS was significantly higher than that of WT. In conclusion, the surface hydrophobic microenvironment composed of six residues was the structural basis for SDS resistance. This feature could prevent the binding of SDS and the destruction of hydrophobic packaging by increasing the rigid conformation of protein and reducing the binding force of SDS-protein. The study provides a new idea for the rational design of SDS-resistant proteins and may further promote chondroitinase research in the targeted therapy of lung diseases under the pressure of pulmonary surfactant. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00201-1.

Assessing ammonium pollution and mitigation measures through a modified watershed non-point source model.

Watershed water quality modeling is a valuable tool for managing ammonium (NH4+) pollution. However, simulating NH4+ pollution presents unique challenges due to the inherent instability of NH4+ in natural environment. This study modified the widely-used Soil and Water Assessment Tool (SWAT) model to simulate non-point source (NPS) NH4+ processes, specifically incorporating the simulation of land-to-water NH4+ delivery. The Jiulong River Watershed (JRW) is the study area, a coastal watershed in Southeast China with substantial sewage discharge, livestock farming, and fertilizer application. The results demonstrate that the modified model can effectively simulate the NPS NH4+ processes. It is recommended to use multiple sets of observations to calibrate NH4+ simulation to enhance model reliability. Despite constituting a minor proportion (5.6 %), point source inputs significantly contribute to NH4+ load at watershed outlet (32.4∼51.9 %), while NPS inputs contribute 15.3∼17.3 % of NH4+ loads. NH4+ primarily enters water through surface runoff and lateral flow, with negligible leaching. Average NH4+ land-to-water delivery rate is about 2.35 to 2.90 kg N/ha/a. High delivery rates mainly occur at agricultural areas. Notably, proposed NH4+ mitigation measures, including urban sewage treatment enhancement, livestock manure management improvement, and fertilizer application reduction, demonstrate potential to collectively reduce the NH4+ load at watershed outlet by 1/4 to 1/3 and significantly enhance water quality standard compliance frequency. Insights gained from modeling experience in the JRW offer valuable implications for NH4+ modeling and management in regions with similar climates and significant anthropogenic nitrogen inputs.

Development and validation of a deep learning model for predicting postoperative survival of patients with gastric cancer.

BACKGROUND: Deep learning (DL), a specialized form of machine learning (ML), is valuable for forecasting survival in various diseases. Its clinical applicability in real-world patients with gastric cancer (GC) has yet to be extensively validated. METHODS: A combined cohort of 11,414 GC patients from the Surveillance, Epidemiology and End Results (SEER) database and 2,846 patients from a Chinese dataset were utilized. The internal validation of different algorithms, including DL model, traditional ML models, and American Joint Committee on Cancer (AJCC) stage model, was conducted by training and testing sets on the SEER database, followed by external validation on the Chinese dataset. The performance of the algorithms was assessed using the area under the receiver operating characteristic curve, decision curve, and calibration curve. RESULTS: DL model demonstrated superior performance in terms of the area under the curve (AUC) at 1, 3, and, 5 years post-surgery across both datasets, surpassing other ML models and AJCC stage model, with AUCs of 0.77, 0.80, and 0.82 in the SEER dataset and 0.77, 0.76, and 0.75 in the Chinese dataset, respectively. Furthermore, decision curve analysis revealed that the DL model yielded greater net gains at 3 years than other ML models and AJCC stage model, and calibration plots at 3 years indicated a favorable level of consistency between the ML and actual observations during external validation. CONCLUSIONS: DL-based model was established to accurately predict the survival rate of postoperative patients with GC.