Pt/Zn-TCPP Nanozyme-Based Flexible Immunoassay for Dual-Mode Pressure-Temperature Monitoring of Low-Abundance Proteins.

Pressure and temperature, as common physical parameters, are important for monitoring human health. In contrast, single-mode monitoring is prone to causing experimental errors. Herein, we innovatively designed a dual-mode flexible sensing platform based on a platinum/zinc-meso-tetrakis(4-carboxyphenyl)porphyrin (Pt/Zn-TCPP) nanozyme for the quantitative monitoring of carcinoembryonic antigen (CEA) in biological fluids with pressure and temperature readouts. The Pt/Zn-TCPP nanozyme with catalytic and photothermal efficiencies was synthesized by means of integrating photosensitizers into porous materials. The flexible sensing system after the antigen-antibody reaction recognized the pressure using a flexible skin-like pressure sensor with a digital multimeter readout, whereas the temperature was acquired via the photoheat conversion system of the Pt/Zn-TCPP nanozyme under 808 nm near-infrared (NIR) irradiation using a portable NIR imaging camera on a smartphone. Meanwhile, the dual-mode flexible sensing system was carried out on a homemade three-dimensional (3D)-printed device. Results revealed that the developed dual-mode immunosensing platform could exhibit good pressure and temperature responses within the dynamic range of 0.5-100 ng mL-1 CEA with the detection limits of 0.24 and 0.13 ng mL-1, respectively. In addition, the pressure and temperature were sensed simultaneously without crosstalk interference. Importantly, the dual-mode flexible immunosensing system can effectively avoid false alarms during the measurement, thus providing great potential for simple and low-cost development for point-of-care testing.

PITX2 functions as a transcription factor for GPX4 and protects pancreatic cancer cells from ferroptosis.

Ferroptosis inhibits tumor progression in pancreatic cancer cells, while PITX2 is known to function as a pro-oncogenic factor in various tumor types, protecting them from ferroptosis and thereby promoting tumor progression. In this study, we sought to investigate the regulatory role of PITX2 in tumor cell ferroptosis within the context of pancreatic cancer. We conducted PITX2 knockdown experiments using lentiviral infection in two pancreatic cancer cell lines, namely PANC-1 and BxPC-3. We assessed protein expression through immunoblotting and mRNA expression through RT-PCR. To confirm PITX2 as a transcription factor for GPX4, we employed Chromatin Immunoprecipitation (ChIP) and Dual-luciferase assays. Furthermore, we used flow cytometry to measure reactive oxygen species (ROS), lipid peroxidation, and apoptosis and employed confocal microscopy to assess mitochondrial membrane potential. Additionally, electron microscopy was used to observe mitochondrial structural changes and evaluate PITX2's regulation of ferroptosis in pancreatic cancer cells. Our findings demonstrated that PITX2, functioning as a transcription factor for GPX4, promoted GPX4 expression, thereby exerting an inhibitory effect on ferroptosis in pancreatic cancer cells and consequently promoting tumor progression. Moreover, PITX2 enhanced the invasive and migratory capabilities of pancreatic cancer cells by activating the WNT signaling pathway. Knockdown of PITX2 increased ferroptosis and inhibited the proliferation of PANC-1 and BxPC-3 cells. Notably, the inhibitory effect on ferroptosis resulting from PITX2 overexpression in these cells could be countered using RSL3, an inhibitor of GPX4. Overall, our study established PITX2 as a transcriptional regulator of GPX4 that could promote tumor progression in pancreatic cancer by reducing ferroptosis. These findings suggest that PITX2 may serve as a potential therapeutic target for combating ferroptosis in pancreatic cancer.

The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation.

The LAT1-4F2hc complex (SLC7A5-SLC3A2) facilitates uptake of essential amino acids, hormones and drugs. Its dysfunction is associated with many cancers and immune/neurological disorders. Here, we apply native mass spectrometry (MS)-based approaches to provide evidence of super-dimer formation (LAT1-4F2hc)2. When combined with lipidomics, and site-directed mutagenesis, we discover four endogenous phosphatidylethanolamine (PE) molecules at the interface and C-terminus of both LAT1 subunits. We find that interfacial PE binding is regulated by 4F2hc-R183 and is critical for regulation of palmitoylation on neighbouring LAT1-C187. Combining native MS with mass photometry (MP), we reveal that super-dimerization is sensitive to pH, and modulated by complex N-glycans on the 4F2hc subunit. We further validate the dynamic assemblies of LAT1-4F2hc on plasma membrane and in the lysosome. Together our results link PTM and lipid binding with regulation and localisation of the LAT1-4F2hc super-dimer.

Dual-mode photoelectrochemical radar based on CdS quantum dot and Ce-MOF for detection of low-abundance disease-associated proteins.

Herein, we developed a convenient and versatile dual-mode electrochemiluminescence (ECL) and photoelectrochemistry (PEC) sensing radar for the detection of Prostate-specific antigen (PSA), which has important implications for detection of low-abundance disease-associated proteins. Cerium-based metal-organic framework (Ce-MOFs) were firstly modified on the electrode, showing well ECL and PEC property. In particular, a unique multifunctional Au@CdS quantum dots (QDs) probe loaded numerous QDs and antibody was fabricated, not only displaying strong ECL and PEC signals, but also having specific recognition to PSA. After the signal probe was linked to the electrode by immune reaction, much amplified signals of ECL and PEC were generated for double-mode detection of PSA. Therefore, this work proposed a multifunctional Au@CdS QDs signal probe with excellent ECL and PEC performance, and developed an ultrasensitive photoelectric biosensing platform for dual-mode detection, which provides an effective method for health monitoring of cancer patients.

Discovery of novel pyridone-benzamide derivatives possessing a 1-methyl-2-benzimidazolinone moiety as potent EZH2 inhibitors for the treatment of B-cell lymphomas.

Enhancer of zeste homolog 2 (EZH2) is a promising therapeutic target for diffuse large B-cell lymphoma. In this study, based on the binding model of 1 (tazemetostat) with polycomb repressive complex 2 (PRC2), we designed and synthesized a series of tazemetostat analogs bearing a 1-methyl-2-benzimidazolinone moiety to improve the inhibitory activity of EZH2 wild-type (WT) and Y641 mutants and enhance metabolic stability. After the assessment of the structure-activity relationship at enzymatic and cellular levels, compound N40 was identified. Biochemical assays showed that compound N40 (IC50 = 0.32 nM) exhibited superior inhibitory activity against EZH2 WT, compared with 1 (IC50 = 1.20 nM), and high potency against EZH2 Y641 mutants (EZH2 Y641F, IC50 = 0.03 nM; EZH2 Y641N, IC50 = 0.08 nM), which were approximately 10-fold more active than those of 1 (EZH2 Y641F, IC50 = 0.37 nM; EZH2 Y641N, IC50 = 0.85 nM). Furthermore, compound N40 (IC50 = 3.52 ±â€¯1.23 nM) effectively inhibited the proliferation of Karpas-422 cells and was more potent than 1 (IC50 = 35.01 ±â€¯1.28 nM). Further cellular experiments showed that N40 arrested Karpas-422 cells in the G1 phase and induced apoptosis in a dose-dependent manner. Moreover, N40 inhibited the trimethylation of lysine 27 on histone H3 (H3K27Me3) in Karpas-422 cells bearing the EZH2 Y641N mutant. Additionally, N40 (T1/2 = 177.69 min) showed improved metabolic stability in human liver microsomes compared with 1 (T1/2 = 7.97 min). Our findings suggest N40 as a promising EZH2 inhibitor; further investigation remains warranted to confirm our findings and further develop N40.

The crucial relationship between miRNA-27 and CSE/H2S, and the mechanism of action of GLP-1 in myocardial hypertrophy.

Cardiac hypertrophy is the most prevalent compensatory heart disease that ultimately leads to spontaneous heart failure. Mounting evidence suggests that microRNAs (miRs) and endogenous hydrogen sulfide (H2S) play a crucial role in the regulation of cardiac hypertrophy. In this study, we aimed to investigate whether inhibition of miR-27a could protect against cardiac hypertrophy by modulating H2S signaling. We established a model of cardiac hypertrophy by obtaining hypertrophic tissue from mice subjected to transverse aortic constriction (TAC) and from cells treated with angiotensin-II. Molecular alterations in the myocardium were quantified using quantitative real time PCR (qRT-PCR), Western blotting, and ELISA. Morphological changes were characterized by hematoxylin and eosin (HE) staining and Masson's trichrome staining. Functional myocardial changes were assessed using echocardiography. Our results demonstrated that miR-27a levels were elevated, while H2S levels were reduced in TAC mice and myocardial hypertrophy. Further luciferase and target scan assays confirmed that cystathionine-γ-lyase (CSE) was a direct target of miR-27a and was negatively regulated by it. Notably, enhancement of H2S expression in the heart was observed in mice injected with recombinant adeno-associated virus vector 9 (rAAV9)-anti-miR-27a and in cells transfected with a miR-27a inhibitor during cardiac hypertrophy. However, this effect was abolished by co-transfection with CSE siRNA and the miR-27a inhibitor. Conversely, injecting rAAV9-miR-27a yielded opposite results. Interestingly, our findings demonstrated that glucagon-like peptide-1 (GLP-1) agonists could mitigate myocardial damage by down-regulating miR-27a and up-regulating CSE. In summary, our study suggests that inhibition of miR-27a holds therapeutic promise for the treatment of cardiac hypertrophy by increasing H2S levels. Furthermore, our findings unveil a novel mechanism of GLP-1 agonists involving the miR-27a/H2S pathway in the management of cardiac hypertrophy.

Morin-Based Nanoparticles for Regulation of Blood Glucose.

Morin, a naturally occurring bioactive compound shows great potential as an antioxidant, anti-inflammatory agent, and regulator of blood glucose levels. However, its low water solubility, poor lipid solubility, limited bioavailability, and rapid clearance in vivo hinder its application in blood glucose regulation. To address these limitations, we report an enzymatically synthesized nanosized morin particle (MNs) encapsulated in sodium alginate microgels (M@SA). This approach significantly enhances morin's delivery efficiency and therapeutic efficacy in blood glucose regulation. Utilizing horseradish peroxidase, we synthesized MNs averaging 305.7 ± 88.7 nm in size. These MNs were then encapsulated via electrohydrodynamic microdroplet spraying to form M@SA microgels. In vivo studies revealed that M@SA microgels demonstrated prolonged intestinal retention and superior efficacy compared with unmodified morin and MNs alone. Moreover, MNs notably improved glucose uptake in HepG2 cells. Furthermore, M@SA microgels effectively regulated blood glucose, lipid profiles, and oxidative stress in diabetic mice while mitigating liver, kidney, and pancreatic damage and enhancing anti-inflammatory responses. Our findings propose a promising strategy for the oral administration of natural compounds for blood glucose regulation, with implications for broader therapeutic applications.

Potential Role of MAP3K14 in Hepatocellular Carcinoma: A Study Based on Comprehensive Bioinformatical Analysis and Validation.

According to reports, MAP3K14 is considered an oncogene and is aberrantly expressed in various types of tumor cells. Its abnormal expression is closely associated with the occurrence and progression of various cancers. MAP3K14 also plays a significant role in the development of non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma and its connection to tumor stem cells. The prognostic value of MAP3K14 in HCC, as well as its potential functions and roles, requires further elucidation. We evaluated the potential role of MAP3K14 in HCC based on data mining from a range of public databases. The bioinformatics analysis of TCGA, GEO, TIMER, cBioportal, Kaplan-Meier plotter, MethSurv, ENCORI and CellMiner databases was carried out. The expression of MAP3K14 protein in HCC was detected by immunohistochemical method. The mRNA and protein expression levels of MAP3K14 in tumor tissues were higher than those in normal tissues (p < 0.05). The expression of MAP3K14 was correlated with Pathologic T stage (p=0.026), Pathologic stage (p=0.032), Tumor status (p=0.024) and AFP (p=0.002). HCC patients with high expression of MAP3K14 had poor overall survival (OS), progression free survival (PFS) and recurrence free survival (RFS). Multivariate Cox regression analysis showed that the Pathologic stage (p < 0.001) and MAP3K14 expression levels (p < 0.05) is an independent prognostic factor affecting the survival of patients with liver cancer. GO/KEGG analysis suggested that key biological processes (PI3K-Akt signaling pathway) may be the mechanism promoting HCC development. In addition, MAP3K14 was significantly correlated with the infiltrating levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells (p < 0.05). MAP3K14 is up-regulated in HCC and is closely related to the prognosis of HCC patients. MAP3K14 may serve as a potential biomarker for poor prognosis of HCC.

ARID1B Deficiency Leads to Impaired DNA Damage Response and Activated cGAS-STING Pathway in Non-Small Cell Lung Cancer.

Purpose: Lung cancer is a major cause of morbidity and mortality globally, necessitating the identification of predictive markers for effective immunotherapy. Mutations in SWI/SNF chromatin remodeling complex genes were reported sensitized human tumors to immune checkpoint inhibitors (ICIs), but the underlying mechanisms are unclear. This study aims to investigate the association between SWI/SNF gene ARID1B mutation and ICI response in non-small cell lung cancer (NSCLC) patients, to explore the functional consequences of ARID1B mutation on DNA damage response, immune microenvironment, and cGAS-STING pathway activation. Methods: TCGA LUAD, LUSC, and AACR GENIE data are analyzed to assess ARID1B mutation status in NSCLC patients. Prognostic analysis evaluates the effect of ARID1B mutation on patient outcomes. In vitro experiments carried to investigate the consequences of ARID1B knockdown on DNA damage response and repair. The immune microenvironment is assessed based on ARID1B expression, and the relationship between ARID1B and the cGAS-STING pathway is explored. Results: ARID1B mutation frequency is 5.7% in TCGA databases and 4.4% in the AACR GENIE project. NSCLC patients with ARID1B mutation showed improved overall and progression-free survival following ICIs treatment. ARID1B knockdown in lung cancer cell lines enhances DNA damage, impairs DNA repair, alters chromatin accessibility, and activates the cGAS-STING pathway. ARID1B deficiency is associated with immune suppression, indicated by reduced immune scores, decreased immune cell infiltration, and negative correlations with immune-related cell types and functions. Conclusion: ARID1B mutation may predict improved response to ICIs in NSCLC patients. ARID1B mutation leads to impaired DNA damage response and repair, altered chromatin accessibility, and cGAS-STING pathway activation. These findings provide insights into ARID1B's biology and therapeutic implications in lung cancer, highlighting its potential as a target for precision medicine and immunotherapy. Further validation and clinical studies are warranted.

Retraction Notice to: circRASGRF2 functions as an oncogenic gene in hepatocellular carcinoma by acting as a miR-1224 sponge.

[This retracts the article DOI: 10.1016/j.omtn.2020.10.035.].

METTL14 promotes neuroblastoma formation by inhibiting YWHAH via an m6A-YTHDF1-dependent mechanism.

Neuroblastoma (NB) is a common childhood tumor with a high incidence worldwide. The regulatory role of RNA N6-methyladenosine (m6A) in gene expression has attracted significant attention, and the impact of methyltransferase-like 14 (METTL14) on tumor progression has been extensively studied in various types of cancer. However, the specific influence of METTL14 on NB remains unexplored. Using data from the Target database, our study revealed significant upregulation of METTL14 expression in high-risk NB patients, with strong correlation with poor prognosis. Furthermore, we identified ETS1 and YY1 as upstream regulators that control the expression of METTL14. In vitro experiments involving the knockdown of METTL14 in NB cells demonstrated significant inhibition of cell proliferation, migration, and invasion. In addition, suppressing METTL14 inhibited NB tumorigenesis in nude mouse models. Through MeRIP-seq and RNA-seq analyses, we further discovered that YWHAH is a downstream target gene of METTL14. Mechanistically, we observed that methylated YWHAH transcripts, particularly those in the 5' UTR, were specifically recognized by the m6A "reader" protein YTHDF1, leading to the degradation of YWHAH mRNA. Moreover, the downregulation of YWHAH expression activated the PI3K/AKT signaling pathway, promoting NB cell activity. Overall, our study provides valuable insights into the oncogenic effects of METTL14 in NB cells, highlighting its role in inhibiting YWHAH expression through an m6A-YTHDF1-dependent mechanism. These findings also suggest the potential utility of a biomarker panel for prognostic prediction in NB patients.

Characterization and Discrimination of Marigold Oleoresin from Different Origins Based on UPLC-QTOF-MS Combined Molecular Networking and Multivariate Statistical Analysis.

Marigold oleoresin is an oil-soluble natural colorant mainly extracted from marigold flowers. Xinjiang of China, India, and Zambia of Africa are the three main production areas of marigold flowers. Therefore, this study utilized ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) technology, combined with Global Natural Products Social Molecular Networking (GNPS) and multivariate statistical analysis, for the qualitative and discriminant analysis of marigold oleoresin obtained from three different regions. Firstly, 83 compounds were identified in these marigold oleoresin samples. Furthermore, the results of a principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) indicated significant differences in the chemical compositions of the marigold oleoresin samples from different regions. Finally, 12, 23, and 38 differential metabolites were, respectively, identified by comparing the marigold oleoresin from Africa with Xinjiang, Africa with India, and Xinjiang with India. In summary, these results can be used to distinguish marigold oleoresin samples from different regions, laying a solid foundation for further quality control and providing a theoretical basis for assessing its safety and nutritional aspects.

Semantic uncertainty Guided Cross-Transformer for enhanced macular edema segmentation in OCT images.

Macular edema, a prevalent ocular complication observed in various retinal diseases, can lead to significant vision loss or blindness, necessitating accurate and timely diagnosis. Despite the potential of deep learning for segmentation of macular edema, challenges persist in accurately identifying lesion boundaries, especially in low-contrast and noisy regions, and in distinguishing between Inner Retinal Fluid (IRF), Sub-Retinal Fluid (SRF), and Pigment Epithelial Detachment (PED) lesions. To address these challenges, we present a novel approach, termed Semantic Uncertainty Guided Cross-Transformer Network (SuGCTNet), for the simultaneous segmentation of multi-class macular edema. Our proposed method comprises two key components, the semantic uncertainty guided attention module (SuGAM) and the Cross-Transformer module (CTM). The SuGAM module utilizes semantic uncertainty to allocate additional attention to regions with semantic ambiguity, improves the segmentation performance of these challenging areas. On the other hand, the CTM module capitalizes on both uncertainty information and multi-scale image features to enhance the overall continuity of the segmentation process, effectively minimizing feature confusion among different lesion types. Rigorous evaluation on public datasets and various OCT imaging device data demonstrates the superior performance of our proposed method compared to state-of-the-art approaches, highlighting its potential as a valuable tool for improving the accuracy and reproducibility of macular edema segmentation in clinical settings, and ultimately aiding in the early detection and diagnosis of macular edema-related diseases and associated retinal conditions.

CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma.

Super enhancers (SEs) are genomic regions comprising multiple closely spaced enhancers, typically occupied by a high density of cell-type-specific master transcription factors (TFs) and frequently enriched in key oncogenes in various tumors, including neuroblastoma (NB), one of the most prevalent malignant solid tumors in children originating from the neural crest. Cyclin-dependent kinase 5 regulatory subunit-associated protein 3 (CDK5RAP3) is a newly identified super-enhancer-driven gene regulated by master TFs in NB; however, its function in NB remains unclear. Through an integrated study of publicly available datasets and microarrays, we observed a significantly elevated CDK5RAP3 expression level in NB, associated with poor patient prognosis. Further research demonstrated that CDK5RAP3 promotes the growth of NB cells, both in vitro and in vivo. Mechanistically, defective CDK5RAP3 interfered with the UFMylation system, thereby triggering endoplasmic reticulum (ER) phagy. Additionally, we provide evidence that CDK5RAP3 maintains the stability of MEIS2, a master TF in NB, and in turn, contributes to the high expression of CDK5RAP3. Overall, our findings shed light on the molecular mechanisms by which CDK5RAP3 promotes tumor progression and suggest that its inhibition may represent a novel therapeutic strategy for NB.

Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.

The cyclic-oligonucleotide-based anti-phage signalling system (CBASS) is a type of innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS uses cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homologue of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, using biochemical, genetic, cryo-electron microscopy and mass spectrometry investigations, we discover that the E2 enzyme from Serratia marcescens regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities.

Genome maintenance is an enabling characteristic that allows neoplastic cells to tolerate the inherent stresses of tumorigenesis and evade therapy-induced genotoxicity. Neoplastic cells also deploy many mis-expressed germ cell proteins termed Cancer Testes Antigens (CTAs) to promote genome maintenance and survival. Here, we present the first comprehensive characterization of the DNA Damage Response (DDR) and CTA transcriptional landscapes of endometrial cancer in relation to conventional histological and molecular subtypes. We show endometrial serous carcinoma (ESC), an aggressive endometrial cancer subtype, is defined by gene expression signatures comprising members of the Replication Fork Protection Complex (RFPC) and Fanconi Anemia (FA) pathway and CTAs with mitotic functions. DDR and CTA-based profiling also defines a subset of highly aggressive endometrioid endometrial carcinomas (EEC) with poor clinical outcomes that share similar profiles to ESC yet have distinct characteristics based on conventional histological and genomic features. Using an unbiased CRISPR-based genetic screen and a candidate gene approach, we confirm that DDR and CTA genes that constitute the ESC and related EEC gene signatures are required for proliferation and therapy-resistance of cultured endometrial cancer cells. Our study validates the use of DDR and CTA-based tumor classifiers and reveals new vulnerabilities of aggressive endometrial cancer where none currently exist.

Construction and Properties of Oil-Loaded Soybean Protein Isolate/Polysaccharide-Based Meat Analog Fibers.

Rationally designing the fibrous structure of artificial meat is a challenge in enriching the organoleptic quality of meat analogs. High-quality meat analog fibers have been obtained by wet-spinning technique in our previous study, whereas introducing oil droplets will further achieve their fine design from the insight of microstructure. Herein, in this current work, oil was introduced to the soybean protein isolate/polysaccharide-based meat analog fibers by regulating the oil droplets' size and content, which, importantly, controlled the spinning solution characterization as well as structure-related properties of the meat analog fiber. Results showed that the oil dispersed in the matrix as small droplets with regular shapes, which grew in size as the oil content increased. Considering the effect of oil droplets' size and content on the spinnability of the spinning solution, the mechanical stirring treatment was chosen as the suitable treatment method. Importantly, increasing the oil content has the potential to enhance the juiciness of meat analog fibers through improvements in water-holding capacity and alterations in water mobility. Overall, the successful preparation of oil-loaded plant-based fiber not only mimicked animal muscle fiber more realistically but also provided a general platform for adding fat-soluble nutrients and flavor substances.

Numerical Simulation of Fracture Propagation during Temporary Plugging Staged Fracturing in Tight-Oil Horizontal Wells.

Fracture propagation with temporary plugging hydraulic fracturing in tight-oil reservoirs is simulated in this study. The research considers dynamic fluid redistribution, with stress differences among multiple fractures. The fracture morphology during temporary plugging staged fracturing (TPSF) is investigated by using a user-defined perforation element combined with a pore-pressure finite-element model. The precision of the integrated model is verified by using the standard finite-element approach. Then, case studies are presented to investigate the influence of cluster spacing, horizontal stress difference coefficients (SDC), injection rates, and barrier tensile strengths. The simulation results show that central cluster fractures are hampered by side-cluster fractures, while TPSF can alleviate the effect and lead to a more uniform propagation of all fractures. Stress interference weakens as cluster spacing increases, and propagation patterns are minimally influenced once spacing reaches 40 m. Higher injection rates can improve the injection pressure, enlarging fracture width, and potentially increasing the risk of fracture penetration. Barrier tensile strength and horizontal SDC can modify fracture geometries and determine the penetration behavior of multiple fractures.

Enhancing Fatigue Performance of Coal Gangue Concrete (CGC) through Polypropylene Fiber Modification: Experimental Evaluation.

Coal gangue is a byproduct of coal mining and processing, and according to incomplete statistics, China has amassed a substantial coal gangue stockpile exceeding 2600 large mountains, which poses a serious threat to the ecological environment. Utilizing gangue as a coarse aggregate to produce gangue concrete (GC) presents a promising avenue for addressing the disposal of coal gangue; however, gangue concrete presents several challenges that need to be tackled, such as low strength and poor resistance to repeated loads. In this study, polypropylene fibers (PPFs) were incorporated into gangue concrete to enhance its utilization rate. Uniaxial compressive and repeated loading experiments were then conducted to investigate the uniaxial strength and fatigue properties of polypropylene fiber-reinforced gangue concrete (PGC) with varying gangue substitution rates (20%, 40%, and 60%) and different polypropylene fiber admixtures (0, 0.1%, 0.2%, and 0.3%). The findings indicate that incorporating gangue at a substitution rate of 40% could notably enhance the uniaxial compressive strength of PGC, resulting in a maximum increase of 19.4%. In the repeated loading experiments, the ductility of PGC was enhanced with the incorporation of PPFs, resulting in a reduction of 33.76% in the damage factor and 19.42% in residual strain for PGC-40-0.2 compared to PGC-40-0. A PPF content of 0.2% was found to be optimal for enhancing the fatigue performance of PGC. Scanning electron microscope (SEM) testing proved the improvement effect of polypropylene fiber on gangue concrete from a microscopic perspective. This study provides crucial experimental data and a theoretical foundation for the utilization of gangue concrete in complex stress environments.

Tumor extrachromosomal DNA: Biogenesis and recent advances in the field.

Extrachromosomal DNA (ecDNA) is a self-replicating circular DNA originating from the chromosomal genome and exists outside the chromosome. It contains specific gene sequences and non-coding regions that regulate transcription. Recent studies have demonstrated that ecDNA is present in various malignant tumors. Malignant tumor development and poor prognosis may depend on ecDNA's distinctive ring structure, which assists in amplifying oncogenes. During cell division, an uneven distribution of ecDNA significantly enhances tumor cells' heterogeneity, allowing tumor cells to adapt to changes in the tumor microenvironment and making them more resistant to treatments. The application of ecDNA as a cancer biomarker and therapeutic target holds great potential. This article examines the latest advancements in this area and discusses the potential clinical applications of ecDNA.