ß-Elemene promotes ferroptosis and reverses radioresistance in gastric cancer by inhibiting the OTUB1-GPX4 interaction.

Introduction: ß-Elemene, derived from Curcuma zedoaria (Wenyujin), is clinically recognized for inducing apoptosis, inhibiting cell cycle progression, and reversing chemotherapy resistance in various cancers. However, its effects on radioresistant gastric cancer (GC) remain unclear. Methods: In this study, radioresistant GC cell lines (MKN45/IR and AGS/IR) were established via multiple low-dose radiations. The impact of ß-elemene on radiosensitivity was assessed using CCK-8 and clonogenic assays, with ferroptosis markers such as ROS, MDA, and Fe2+ levels measured. Additionally, the influence of ß-elemene on GPX4 and its interaction with OTUB1 was examined through qRT-PCR, Western blot, immunofluorescence, co-immunoprecipitation, and in vivo studies. Results: Our findings indicate that ß-elemene reverses radioresistance in GC cells and significantly inhibits cell growth when combined with radiotherapy. ß-Elemene treatment elevated ROS, MDA, and Fe2+ levels, enhancing ferroptosis, which was confirmed by Ferrostatin-1 and Deferoxamine inhibition studies. Mechanistic analysis revealed that ß-elemene disrupts the OTUB1-GPX4 interaction, leading to increased GPX4 ubiquitination and degradation, thus promoting ferroptosis. In vivo studies further demonstrated that ß-elemene combined with radiotherapy significantly suppressed tumor growth compared to radiotherapy alone. Discussion: These results suggest that ß-elemene effectively modulates radioresistance in GC by targeting the GPX4 pathway and inducing ferroptosis. This highlights its potential as a therapeutic adjunct in radiotherapy for resistant GC cases.

Long non-coding RNA AC010457.1 promotes the growth and EMT of gastric cancer via the PI3K/AKT axis.

Gastric cancer (GC) is a malignancy with a relatively high mortality rate. This study aimed to ascertain the prognostic significance of long non-coding RNA (lncRNA) AC010457.1 in GC and elucidate its role in disease progression. The Cancer Genome Atlas (TCGA) database was used to screen the prognosis-associated differentially expressed lncRNAs in GC patients. Kaplan-Meier curves, univariate and multivariate Cox regression analyses were applied to assess the prognostic significance of AC010457.1. In vitro and in vivo functional assays were performed to evaluate the effects of AC010457.1 on cellular proliferation and metastasis. Mechanistic investigations, including Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Western blotting (WB), Immunofluorescence (IF), and Immunohistochemistry (IHC), were used to explore the signaling pathways activated by AC010457.1. We demonstrated that AC010457.1 was abnormally upregulated in GC tissues, and that this aberrant upregulation was associated with a poor prognosis for GC patients. The functional experiments proved that the downregulated of AC010457.1 hindered GC cell proliferation, migration, and invasive potential. Furthermore, KEGG analysis revealed a significant association between AC010457.1 and the PI3K/AKT signaling pathway, which was further corroborated by WB analysis. Rescue experiments provided additional confirmation that AC010457.1 regulated PI3K/AKT promote GC proliferation, migration, and epithelial-mesenchymal transition (EMT). Collectively, our findings suggest that AC010457.1 overexpression serves as a distinct prognostic risk factor in GC and may represent a promising therapeutic target for the treatment of this malignancy.

Fluorescence labeling-based differential scanning fluorimetry, an effective method for protein thermal stability and protein-compound binding analysis.

Differential scanning fluorimetry (DSF) is widely used to assess protein thermal stability and protein-ligand interaction. However, its utility is often limited by the presence of detergents, which can affect hydrophobic binding. To tackle this issue, we developed an effective fluorescence-labeled DSF (FL-DSF) technique that tracks protein denaturation by monitoring the labeling fluorescence decrease, thus overcoming challenges typically encountered with traditional DSF methods. In this research, FL-DSF was first validated using Peroxisome Proliferators-Activated Receptor γ (PPARγ), Retinoid X Receptor α (RXRα), and Lysozyme, confirming its accuracy in determining melting curves. Expectedly, FL-DSF also exhibited strong compatibility with detergents in our investigations. Besides this, a new calculation method was proposed to characterize the protein denaturation process and evaluate protein-ligand binding. This mathematical model goes beyond traditional approaches, which simply treated the melting temperature (TM) shift as a concentration-dependent variable. Instead, it comprehensively incorporates the influence of irreversible denaturation-induced native protein loss on the equilibrium of protein-ligand binding. This methodology was successfully applied into the evaluation of binding affinity for 2 classical binding systems of PPARγ-Rosiglitazone and RXRα-CD3254. It was also utilized for the following binding screening studies, leading to the discovery of promising ligands for PPARγ, RXRα, and Lysozyme.

Granular Porous Nanofibrous Microspheres Enhance Cellular Infiltration for Diabetic Wound Healing.

Diabetic foot ulcers (DFUs) are a significant challenge in the clinical care of diabetic patients, often necessitating limb amputation and compromising the quality of life and life expectancy of this cohort. Minimally invasive therapies, such as modular scaffolds, are at the forefront of current DFU treatment, offering an efficient approach for administering therapeutics that accelerate tissue repair and regeneration. In this study, we report a facile method for fabricating granular nanofibrous microspheres (NMs) with predesigned structures and porosities. The proposed technology combines electrospinning and electrospraying to develop a therapeutic option for DFUs. Specifically, porous NMs were constructed using electrospun poly(lactic-co-glycolic acid) (PLGA):gelatin short nanofibers, followed by gelatin cross-linking. These NMs demonstrated enhanced cell adhesion to human dermal fibroblasts (HDF) during an in vitro cytocompatibility assessment. Notably, porous NMs displayed superior performance owing to their interconnected pores compared to nonporous NMs. Cell-laden NMs demonstrated higher Young's modulus values than NMs without loaded cells, suggesting improved material resiliency attributed to the reinforcement of cells and their secreted extracellular matrix. Dynamic injection studies on cell-laden NMs further elucidated their capacity to safeguard loaded cells under pressure. In addition, porous NMs promoted host cell infiltration, neovascularization, and re-epithelialization in a diabetic mouse wound model, signifying their effectiveness in healing diabetic wounds. Taken together, porous NMs hold significant potential as minimally invasive, injectable treatments that effectively promote tissue integration and regeneration.

A predictive model for secondary central nervous system infection after craniotomy based on machine learning.

To analyze the risk factors of secondary Central nervous system infections (CNSIs) after craniotomy, and to establish an individualized predictive model for CNSIs risk. The independent risk factors were screened by univariate and multivariate logistic regression analysis. Logistic regression, naive bayes, random forest, light GBM and adaboost algorithms were used to establish predictive models for secondary CNSIs after craniotomy. The predictive model based on the Adaboost algorithm demonstrated superior prediction performance compared to the other four models. Under 5-fold cross validation, the accuracy was 0.80, the precision was 0.69, the recall was 0.85, the F1-score was 0.76, the area under the ROC curve was 0.897,and the average precision was 0.880. The top 5 variables of importance in Adaboost model were operation time, indwelling time of lumbar drainage tube, indwelling lumbar drainage tube during operation, indwelling epidural drainage tube during operation, and GCS score. In addition, Adaboost model with the best prediction performance was used for clinical verification, and the prediction results were compared with the actual occurrence of CNSIs after surgery. The results showed that the accuracy of Adaboost model in predicting CNSIs was 60%, the accuracy of Adaboost model in predicting non-CNSIS was 92%, and the overall prediction accuracy was 76%.

Identification and expression profiling of neuropeptides and neuropeptide receptor genes in a natural enemy, Coccinella septempunctata.

Introduction: Neuropeptides and their receptors constitute diverse and abundant signal molecules in insects, primarily synthesized and released primarily from neurosecretory cells within the central nervous system Neuropeptides act as neurohormones and euromodulators, regulating insect behavior, lifecycle, and physiology by binding to receptors on cell surface. As a typical natural predator of agricultural pests, the lady beetle, Coccinella septempunctata, has been commercially mass-cultured and widely employed in pest management. Insect diapause is a physiological and ecological adaptative strategy acquired in adverse environments. In biological control programs, knowledge about diapause regulation in natural enemy insects provides important insight for improving long-term storage, transportation, and field adoption of these biological control agents. However, little is known about the function of neuropeptides and their receptors in controlling reproductive diapause of C. septempunctata. It is unclear which neuropeptides affect diapause of C. septempunctata. Methods: In this study, RNA-seq technology and bioinformatics were utilized to investigate genes encoding neuropeptides and their receptors in female adults of C. septempunctata. Quantitative real-time PCR (qRT-PCR) analysis was employed to examine gene expression across different development/diapause stages. Results: A total of 17 neuropeptide precursor genes and 9 neuropeptide receptor genes were identified, implicated in regulating various behaviors such as feeding, reproduction, and diapause. Prediction of partial mature neuropeptides from precursor sequences was also performed using available information about these peptides from other species, conserved domains and motifs. During diapause induction, the mRNA abundance of AKH was notably higher on the 10th day compared to non-diapause females, but decreased by the 20th day. In contrast, GPHA showed lower expression levels on the 5th day of diapause induction compared to non-diapause females, but increased significantly by the 15th and 20th days. NPF was higher expressed in head and midgut while DH showed higher expression in the fat body and midgut. Additionally, NPF expression remained consistently lower throughout all stages of diapause induction compared to non-diapause conditions in females. Discussion: This study represents the first sequencing, identification, and expression analysis of neuropeptides and neuropeptide receptor genes in C. septempunctata. Our results could provide a foundational framework for further investigations into the presence, functions, and potential targets of neuropeptides and their receptors, particularly in devising novel strategies for diapause regulation in C. septempunctata.

Bilateral duplex kidney and ureter with multiple stones: a case report.

BACKGROUND: Bilateral duplicated kidney and ureter is a rare condition in urology, and it is even rarer for patients to have multiple stones simultaneously. We delineate the diagnostic and therapeutic trajectory of a patient presenting with bilateral duplex kidneys and ureters, characterized by the presence of multiple stones. Notably, the left kidney is a complete duplication, whereas the right kidney exhibits an incomplete duplication. CASE PRESENTATION: A 47-year-old male patient was diagnosed with bilateral duplex kidney and ureter combined with multiple stones. Ureteral flexible lithotripsy and percutaneous nephrolithotomy were performed successively in our hospital. On the postoperative five day, he was discharged from the hospital without apparent discomfort.The double J tube was pulled out one month later, and no stone recurrence was found after 3 months of follow-up. CONCLUSIONS: Bilateral duplicated renal ureteral malformations combined with multiple stones are very rare. Stones can be removed by ureteroscopic lithotripsy or percutaneous nephrolithotripsy and sometimes multiple procedures are required, which should be chosen according to the patient's relevant condition.

PotatoG-DKB: a potato gene-disease knowledge base mined from biological literature.

Background: Potato is the fourth largest food crop in the world, but potato cultivation faces serious threats from various diseases and pests. Despite significant advancements in research on potato disease resistance, these findings are scattered across numerous publications. For researchers, obtaining relevant knowledge by reading and organizing a large body of literature is a time-consuming and labor-intensive process. Therefore, systematically extracting and organizing the relationships between potato genes and diseases from the literature to establish a potato gene-disease knowledge base is particularly important. Unfortunately, there is currently no such gene-disease knowledge base available. Methods: In this study, we constructed a Potato Gene-Disease Knowledge Base (PotatoG-DKB) using natural language processing techniques and large language models. We used PubMed as the data source and obtained 2,906 article abstracts related to potato biology, extracted entities and relationships between potato genes and related disease, and stored them in a Neo4j database. Using web technology, we also constructed the Potato Gene-Disease Knowledge Portal (PotatoG-DKP), an interactive visualization platform. Results: PotatoG-DKB encompasses 22 entity types (such as genes, diseases, species, etc.) of 5,206 nodes and 9,443 edges between entities (for example, gene-disease, pathogen-disease, etc.). PotatoG-DKP can intuitively display associative relationships extracted from literature and is a powerful assistant for potato biologists and breeders to understand potato pathogenesis and disease resistance. More details about PotatoG-DKP can be obtained at https://www.potatogd.com.cn/.

SCYL1-mediated regulation of the mTORC1 signaling pathway inhibits autophagy and promotes gastric cancer metastasis.

BACKGROUND: The SCY1-like (SCYL) family has been reported to be closely related to cancer metastasis, but it has not been reported in gastric cancer (GC), and its specific mechanism is not clear. METHODS: We utilized databases like Deepmap, TCGA, and GEO to identify SCYL1's role in GC. Clinical samples were analyzed for SCYL1 expression and its correlation with patient prognosis. In vitro and in vivo experiments were conducted to assess SCYL1's function in GC cell migration, invasion, and autophagy. RESULTS: SCYL1 showed an increased expression in GC tissues, which correlated with a negative prognosis. In vitro experiments demonstrated that SCYL1 promotes GC cell migration and invasion and inhibits autophagy. GSEA indicated an inverse relationship between SCYL1 and autophagy, while a direct relationship was observed with the mTORC1 signaling pathway. Knockdown of SCYL1 enhanced autophagy, while activation of mTORC1 reversed this effect. CONCLUSIONS: SCYL1 is a significant contributor to GC progression, promoting metastasis by activating the mTORC1 signaling pathway and inhibiting autophagy. These findings suggest SCYL1 as a potential therapeutic target for GC treatment.

Ligand-Free Iron-Catalyzed Carbonylation of Aryl Iodides with Alkenyl Boronic Acids: Access to α,ß-Unsaturated Ketones.

The application of earth-abundant and low-toxicity iron catalysts as replacements for palladium in carbonylative coupling reactions remains challenging and largely unexplored. Reported here is a highly efficient iron-catalyzed carbonylation of aryl iodides with alkenyl boronic acids under ligand-free conditions, enabling the synthesis of α,ß-unsaturated ketones even at atmospheric CO pressure. The broad applicability, including its effectiveness with α-branched enones and biologically active molecules, along with high yields and selectivity, underlines the general applicability of this catalytic system.

How is the quality of randomized controlled trials (RCTs) for acupuncture treatment of post-stroke aphasia? A report quality assessment.

OBJECTIVE: This study aimed to assess the quality of randomized controlled trials (RCTs) that have reported the use of acupuncture for the treatment of post-stroke aphasia (PSA). METHODS: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), Wanfang data Information Site, and China Science and Technology Journal Database from January 2013 to June 2023. RCTs utilizing acupuncture as an intervention for the treatment of post-stroke aphasia were included in this study. The overall quality score (OQS) of RCTs was independently evaluated by two researchers using the Consolidated Standards for Reporting Trials (CONSORT) and the Standards for Reporting Interventions in Controlled Trials of Acupuncture (STRICTA) guidelines, with the agreement between researchers calculated using Cohen's kappa statistics. RESULTS: In conclusion, we included 38 RCTs in this study. The median OQS of the 38 RCTs was 13 (minimum 8, maximum 20) based on the CONSORT statement. Out of all CONSORT items, 10 (27%) had a positive rate of greater than 80%, while 17 (46%) had a positive rate of less than 10%. The median OQS of the 38 RCTs was 12 (minimum 6, maximum 14) based on the STRICTA guideline. Within the STRICTA guideline, 6 items (35%) had a positive rate of greater than 80%, and 3 items (18%) had a positive rate of less than 10%. Most items based on the CONSORT and STRICTA guidelines were observed to have a perfect or good degree of agreement. CONCLUSIONS: The overall reporting quality of RCTs for acupuncture treatment of PSA was found to be suboptimal. Notably, the reporting quality of the STRICTA guideline is higher compared to the CONSORT statement. Therefore, strict adherence to both the CONSORT and STRICTA statements is recommended to enhance the quality of RCT reports on acupuncture treatment for post-stroke aphasia.

Enhancing Superconductor Critical Temperature Prediction: A Novel Machine Learning Approach Integrating Dopant Recognition.

Doping plays a crucial role in determining the critical temperature (Tc) of superconductors, yet accurately predicting its effects remains a significant challenge. Here, we introduce a novel doping descriptor that captures the complex influence of dopants on superconductivity. By integrating the doping descriptor with elemental and physical features within a Mixture of Experts (MoE) model, we achieve a remarkable R2 of 0.962 for Tc prediction, surpassing all published prediction models. Our approach successfully identifies optimal doping levels in the Bi2-xPbxSr2Ca2-yCuyOz system, with predictions closely aligning with experimental results. Leveraging this model, we screen compounds from the Inorganic Crystal Structure Database and employ a generative approach to explore new doped superconductors. This process reveals 40 promising candidates for high Tc superconductivity among existing and hypothetical doped materials. By explicitly accounting for doping effects, our method offers a powerful tool for guiding the experimental discovery of new superconductors, potentially accelerating progress in high-temperature superconductivity research and opening new avenues for material design.

Evaluating Performance of Different RNA Secondary Structure Prediction Programs Using Self-cleaving Ribozymes.

Accurate identification of the correct, biologically relevant RNA structures is critical to understanding various aspects of RNA biology since proper folding represents the key to the functionality of all types of RNA molecules and plays pivotal roles in many essential biological processes. Thus, a plethora of approaches have been developed to predict, identify, or solve RNA structures based on various computational, molecular, genetic, chemical, or physicochemical strategies. Purely computational approaches hold distinct advantages over all other strategies in terms of the ease of implementation, time, speed, cost, and throughput, but they strongly underperform in terms of accuracy that significantly limits their broader application. Nonetheless, the advantages of these methods led to a steady development of multiple in silico RNA secondary structure prediction approaches including recent deep learning-based programs. Here, we compared the accuracy of predictions of biologically relevant secondary structures of dozens of self-cleaving ribozyme sequences using seven in silico RNA folding prediction tools with tasks of varying complexity. We found that while many programs performed well in relatively simple tasks, their performance varied significantly in more complex RNA folding problems. However, in general, a modern deep learning method outperformed the other programs in the complex tasks in predicting the RNA secondary structures, at least based on the specific class of sequences tested, suggesting that it may represent the future of RNA structure prediction algorithms.

[3D bioprinting: classification, evaluation, and application in vascular tissue engineering].

Cardiovascular diseases are major diseases, and there is lack of artificial blood vessels with small diameters which can be applied in coronary artery bypass surgery. The conventional vascular scaffold preparation techniques in tissue engineering have shortcomings in regulating the diameter, geometric shape, and interconnectivity of the scaffold. 3D bioprinting can simulate the natural structure of the vascular tissue, accurately print live cells and biomaterials, and regulate the microstructure and porosity of scaffolds on the nanoscale, providing new ideas for vascular tissue engineering. This article systematically evaluates the classification of 3D bioprinting technologies and reviews the latest research progress of 3D bioprinting in vascular tissue engineering. It summarizes the advantages of 3D bioprinting and points out the problems that need to be solved, such as the immune rejection of blood vessel materials, providing reference for the further research.

Optimal methods for analyzing targeted pairwise knockout screens.

Background: Synthetic lethality offers a promising strategy for cancer treatment by targeting genetic vulnerabilities unique to tumor cells, leading to selective tumor cell death. However, single-gene knockout screens often miss functional redundancy due to paralog genes. Multiplex CRISPR systems, including various Cas9 and Cas12a platforms, have been developed to assay genetic interactions, yet no systematic comparison of method to identify synthetic lethality from CRISPR screens has been conducted. Results: We evaluated data from four in4mer CRISPR/Cas12a screens in cancer cell lines, using three bioinformatic approaches to identify synthetic lethal interactions: delta log fold change (dLFC), Z-transformed dLFC (ZdLFC), and rescaled dLFC (RdLFC). Both ZdLFC and RdLFC provided more consistent identification of synthetic lethal pairs across cell lines compared to the unscaled dLFC method. Conclusions: The ZdLFC method offers a robust framework for scoring synthetic lethal interactions from paralog screens, providing consistent results across different cell lines without requiring a training set of known positive interactors.

In vivo CRISPR screens identify Mga as an immunotherapy target in triple-negative breast cancer.

Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. This valuable high-confidence dataset is available for the further understanding of tumor intrinsic immunomodulators, which may lead to the discovery of effective anticancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga influences various immune-related pathways in the tumor microenvironment. Our findings suggest that Mga may play a role in modulating the tumor immune landscape, though the precise mechanisms require further investigation. Interestingly, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-γ signaling. These observations provide insights into tumor immune escape mechanisms and suggest that further exploration of MGA's function could potentially lead to effective therapeutic strategies in TNBC.

The use of ectopic volar fibroblasts to modify skin identity.

Skin identity is controlled by intrinsic features of the epidermis and dermis and their interactions. Modifying skin identity has clinical potential, such as the conversion of residual limb and stump (nonvolar) skin of amputees to pressure-responsive palmoplantar (volar) skin to enhance prosthesis use and minimize skin breakdown. Greater keratin 9 (KRT9) expression, higher epidermal thickness, keratinocyte cytoplasmic size, collagen length, and elastin are markers of volar skin and likely contribute to volar skin resiliency. Given fibroblasts' capacity to modify keratinocyte differentiation, we hypothesized that volar fibroblasts influence these features. Bioprinted skin constructs confirmed the capacity of volar fibroblasts to induce volar keratinocyte features. A clinical trial of healthy volunteers demonstrated that injecting volar fibroblasts into nonvolar skin increased volar features that lasted up to 5 months, highlighting a potential cellular therapy.

Metabolic tumor volume from baseline [18 F]FDG PET/CT at diagnosis improves the IPI stratification in patients with diffuse large B-cell lymphoma.

PURPOSE: Although several different parameters of PET/CT were reported to be predictive of survival in DLBCL, the best parameter remains to be elucidated and whether it could improve the risk stratification of IPI in patients with DLBCL. PROCEDURES: 262 DLBCL patients including in the training and validation cohort were retrospectively analyzed in this study. RESULTS: Among different parameters, MTV was identified as the optimal prognostic parameter with a maximum area under the curve (AUC) of 0.652 ± 0.112 than TLG and SDmax (0.645 ± 0.113 and 0.600 ± 0.117, respectively). Patients with high MTV were associated with inferior PFS (p < 0.001 and p = 0.021, respectively) and OS (p < 0.001 and p < 0.001, respectively) in both the training and validation cohort. The multivariate analysis revealed that high MTV was an unfavorable factor for PFS (relative ratio [RR], 2.295; 95% confidence interval [CI], 1.457-3.615; p < 0.01) and OS (RR, 2.929; 95% CI 1.679-5.109; p < 0.01) independent of IPI. CONCLUSIONS: Further analysis showed MTV could improve the risk stratification of IPI for both PFS and OS (p < 0.01 and p < 0.01, respectively). In conclusion, our study suggests that MTV was an optimal prognostic parameter of PET/CT for survival and it could improve the risk stratification of IPI in DLBCL, which may help to guide treatment in clinical trial.

Filicinic acid based meroterpenoids from Hypericum elodeoides and their anti-Alzheimer's disease effects.

(±)-Elodeoidileons A-L (1-12), 12 pairs of previously undescribed filicinic acid based meroterpenoids were isolated from Hypericum elodeoides with unique linear or angular 6/6/6 ring core. Modern spectroscopic techniques, modified Mosher's method and quantum chemical calculations were used to identify the planner structures and configurations of 1-12. Additionally, the potential biosynthetic pathways for 1-12 were anticipated. Moreover, biological activity assessments suggested that 1a, 5a, and 11b could activate Retinoid X receptor-α (RXRα) transcription and enhance the ATP-binding cassette transporter A1 (ABCA1) protein's expression. Fluorescence titration assay suggested that 1a might have a direct interaction with the RXRα-LBD protein, with an estimated Kd value of 5.85 µM. Moreover, molecular docking study confirmed the binding of 1a to RXRα and further validated by cellular thermal shift assay (CETSA). Thus, compound 1a may promote ß-amyloid (Aß) clearance by targeting RXRα and upregulating the expression of the ABCA1 protein, showing promise as anti-Alzheimer's agent.