Compressive Properties of Basalt Fibers and Polypropylene Fiber-Reinforced Lightweight Concrete.

With the development of high-rise and large-scale modern structures, traditional concrete has become a design limitation due to its excessive dead weight. High-strength lightweight concrete is being emphasized. Lightweight concrete has low density and the characteristics of a brittle material. This is an important factor affecting the strength and ductility of the lightweight concrete. To improve these shortcomings and proffer solutions, a three-phase composite lightweight concrete was prepared using a combination of tumbling and molding methods. This paper investigates the various influencing factors such as the stacking volume fraction of GFR-EMS, the type of fiber, and the content and length of fiber in the matrix. Studies have shown that the addition of fibers significantly increases the compressive strength of the concrete. The compressive strength of concrete with a 12 mm basalt fiber (BF) (1.5%) admixture is 9.08 MPa, which is 62.43% higher than that of concrete without the fiber admixture. The compressive strength was increased by 27.53 and 21.88% compared to concrete containing 3 mm BF (1.5%) and 0.5% BF (12 mm), respectively. Fibers can fill the pore defects within the matrix. Mutually overlapping fibers easily form a network structure to improve the bond between the cement matrix and the aggregate particles. The compressive strength of lightweight concrete with the addition of BF was 16.71% higher than that with the addition of polypropylene fiber (PPF) with the same length and content of fibers. BF has been shown to be more effective in improving the mechanical properties of concrete. In this work, the compressive mechanism and optimum preparation parameters of a three-phase composite lightweight concrete were analyzed through compression tests. This provides some insights into the development of lightweight concrete.

Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer.

KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.

[Preparation and in vivo osteogenesis of acellular dermal matrix/dicalcium phosphate composite scaffold for bone repair].

Objective: To investigate the physicochemical properties, osteogenic properties, and osteogenic ability in rabbit model of femoral condylar defect of acellular dermal matrix (ADM)/dicalcium phosphate (DCP) composite scaffold. Methods: ADM/DCP composite scaffolds were prepared by microfibril technique, and the acellular effect of ADM/DCP composite scaffolds was detected by DNA residue, fat content, and α-1，3-galactosyle (α-Gal) epitopes; the microstructure of scaffolds was characterized by field emission scanning electron microscopy and mercury porosimetry; X-ray diffraction was used to analyze the change of crystal form of scaffold; the solubility of scaffolds was used to detect the pH value and calcium ion content of the solution; the mineralization experiment in vitro was used to observe the surface mineralization. Twelve healthy male New Zealand white rabbits were selected to prepare the femoral condylar defect models, and the left and right defects were implanted with ADM/DCP composite scaffold (experimental group) and skeletal gold ® artificial bone repair material (control group), respectively. Gross observation was performed at 6 and 12 weeks after operation; Micro-CT was used to detect and quantitatively analyze the related indicators [bone volume (BV), bone volume/tissue volume (BV/TV), bone surface/bone volume (BS/BV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), bone mineral density (BMD)], and HE staining and Masson staining were performed to observe the repair of bone defects and the maturation of bone matrix. Results: Gross observation showed that the ADM/DCP composite scaffold was a white spongy solid. Compared with ADM, ADM/DCP composite scaffolds showed a significant decrease in DNA residue, fat content, and α-Gal antigen content ( P<0.05). Field emission scanning electron microscopy showed that the ADM/DCP composite scaffold had a porous structure, and DCP particles were attached to the porcine dermal fibers. The porosity of the ADM/DCP composite scaffold was 76.32%±1.63% measured by mercury porosimetry. X-ray diffraction analysis showed that the crystalline phase of DCP in the ADM/DCP composite scaffolds remained intact. Mineralization results in vitro showed that the hydroxyapatite layer of ADM/DCP composite scaffolds was basically mature. The repair experiment of rabbit femoral condyle defect showed that the incision healed completely after operation without callus or osteophyte. Micro-CT showed that bone healing was complete and a large amount of new bone tissue was generated in the defect site of the two groups, and there was no difference in density between the defect site and the surrounding bone tissue, and the osteogenic properties of the two groups were equivalent. There was no significant difference in BV, BV/TV, BS/BV, Tb.Th, Tb.N, and BMD between the two groups ( P>0.05), except that the Tb.Sp in the experimental group was significantly higher than that in the control group ( P<0.05). At 6 and 12 weeks after operation, HE staining and Masson staining showed that the new bone and autogenous bone fused well in both groups, and the bone tissue tended to be mature. Conclusion: The ADM/DCP composite scaffold has good biocompatibility and osteogenic ability similar to the artificial bone material in repairing rabbit femoral condylar defects. It is a new scaffold material with potential in the field of bone repair.

Tumour microenvironment programming by an RNA-RNA-binding protein complex creates a druggable vulnerability in IDH-wild-type glioblastoma.

Patients with IDH-wild-type glioblastomas have a poor five-year survival rate along with limited treatment efficacy due to immune cell (glioma-associated microglia and macrophages) infiltration promoting tumour growth and resistance. To enhance therapeutic options, our study investigated the unique RNA-RNA-binding protein complex LOC-DHX15. This complex plays a crucial role in driving immune cell infiltration and tumour growth by establishing a feedback loop between cancer and immune cells, intensifying cancer aggressiveness. Targeting this complex with blood-brain barrier-permeable small molecules improved treatment efficacy, disrupting cell communication and impeding cancer cell survival and stem-like properties. Focusing on RNA-RNA-binding protein interactions emerges as a promising approach not only for glioblastomas without the IDH mutation but also for potential applications beyond cancer, offering new avenues for developing therapies that address intricate cellular relationships in the body.

The mechanism of Laceyella sacchari FBKL4.010 produced tetramethylpyrazine in the liquid fermentation by comparative transcriptomic techniques.

Tetramethylpyrazine (TTMP) is considered a crucial flavor component in Moutai-flavored liquor. Laceyeella sacchari FBKL4.010 (L. sacchari) is the dominant species found in Moutai-flavor Daqu, and this study aims to determine the mechanism by which L. sacchari produces TTMP during liquid fermentation of Moutai-flavor Daqu. The results of the liquid fermentation performance demonstrated a gradual increase in biomass over time, while there was a gradual decline in residual glucose content and pH value. Furthermore, analysis of volatile components revealed that liquid fermentation significantly enhanced the production of TTMP in Moutai-flavor Daqu, with the relative content of TTMP reaching 14.24 mg/L after 96 h of liquid fermentation. Additionally, to explore the synthesis mechanism of TTMP, we compared differentially expressed genes (DEGs) of L. sacchari between 24 and 96 h using comparative transcriptomic techniques. The results indicated that DEGs involved in isoleucine, valine, and leucine biosynthesis pathway were upregulated, while those associated with isoleucine, valine, and leucine degradation pathway were downregulated, suggesting that the valine, leucine, and isoleucine biosynthesis pathway primarily contributes ammonia for TTMP synthesis. The findings of this study present an opportunity for further elucidating the production process of TTMP in Moutai-flavor Daqu during liquid fermentation.

Implementing Accelerated Rehabilitation Nursing to Facilitate Intestinal Function Recovery Following Cytoreductive Surgery for Gynecological Ovarian Cancer.

Background: Cytoreductive surgery for gynecological ovarian cancer involves the removal of tumor masses and affected tissue, aiming to achieve optimal debulking. Accelerated recovery nursing, a comprehensive care model, focuses on expediting post-surgical recovery and enhancing patient satisfaction. It has emerged as a vital approach to optimize post-surgical outcomes and patient satisfaction. Objective: This study evaluates the impact of accelerated recovery care on surgical patients to enhance recovery outcomes and patient satisfaction post-surgery. Methods: The study utilized an observational and control group design and selected 72 patients undergoing ovarian tumor cytoreductive surgery at The First Affiliated Hospital of Nanjing Medical University between October 1st, 2019, and May 31st, 2020. These patients were divided into two groups: an observation group and a control group, each comprising 36 patients, with one group receiving standard care and the other accelerated recovery care. Nursing staff provided comprehensive pre-and post-operative care, monitoring patients' vital signs using Mindray iPM10 monitors. Postoperative rehabilitation training and dietary guidance were administered. Complication rates, recovery indicators, and patient satisfaction were compared between the groups. Results: The observation group exhibited a significantly lower complication rate (2.78%) compared to the control group (11.11%) (P < .05). Patients in the observation group demonstrated faster recovery indicators, including time to first flatulence, first defecation, and first mobilization from bed (P < .05). Additionally, abdominal distension and pain scores were lower in the observation group, with 100% patient satisfaction. Conclusions: Implementation of accelerated recovery nursing significantly reduces surgical patient complication rates, facilitates recovery, and enhances patient satisfaction. Nursing attention and guidance throughout the surgical process are crucial for optimal patient outcomes. This study emphasizes the importance of thorough care protocols in improving surgical recovery.

Utilizing Accelerated Rehabilitation Nursing in Restoring Intestinal Function Following Cytoreductive Surgery for Gynecologic Ovarian Cancer.

Background: Accelerated recovery programs have gained recognition for their potential to enhance postoperative outcomes. However, their effectiveness in gynecological oncology remains understudied. Objective: This study aims to assess the efficacy of accelerated recovery care in enhancing postoperative outcomes and patient satisfaction following surgery. Methods: A quasi-experimental design was employed, and we included 72 patients undergoing cytoreductive surgery for ovarian tumors at The First Affiliated Hospital of Nanjing Medical University between October 1st, 2019, and May 31st, 2020. The patients were divided into two groups: an observation group receiving accelerated recovery care and a control group receiving standard care. Nursing staff administered comprehensive pre-and postoperative care, utilizing Mindray iPM10 monitors to monitor vital signs. Additionally, postoperative rehabilitation training and dietary guidance were provided. Complication rates, recovery indicators, and patient satisfaction were compared between the two groups. Results: The complication rate in the observation group was significantly lower at 2.78% compared to 11.11% in the control group (P < .05). Patients in the observation group exhibited significantly faster recovery indicators, including time to first flatulence, first defecation, and time to ambulation (P < .05). Moreover, patients in the observation group reported lower abdominal distension and pain scores, with 100% satisfaction rates. Conclusion: Implementing accelerated recovery nursing demonstrates a notable reduction in postoperative complication rates among surgical patients, concurrently fostering an expedited recovery process and heightened patient satisfaction. The provision of comprehensive nursing attention and guidance throughout the perioperative continuum emerges as indispensable for optimizing patient recovery outcomes.

Topological oscillated edge states in trimer lattices.

We investigate a 1D trimer optical lattice model. Two kinds of topological oscillating optical transmission phenomena at edges are shown. The exact and the approximate solutions of the system's edge states are obtained with and without the inversion symmetry for this system respectively. Based on the solutions, the existence and the periods of the oscillations can be controlled arbitrarily. Moreover, in a system without inversion symmetry, controlling the incident beam can eliminate both types of oscillations, resulting in a more stable edge state compared to the one with inversion symmetry. This prompts us to reconsider topological systems under symmetry protection.

Enhanced properties of the mid-infrared superluminescent emitter with a composite waveguide.

This study reports on a composite structure composing tilted taper, and tilted and curved waveguides with the aim of enhancing the spectral width and output power of mid-infrared quantum cascade superluminescent emitters (QC-SLEs). The computational results indicate that a tilt angle of 10° and a curved angle of 20° can avoid the selectivity of a certain wavelength due to interference effects at tilt angles of 6° and 8°, resulting in the minimum reflectivity of 1.3×10-4 and 4.4×10-4 for each wide and narrow cavity surface. Simultaneously, the modes propagating perpendicular to the cavity surface exist the least. The corresponding experimental results show a significant enhancement in the spectral width to 168.5c m -1 and a high power output of 5.1 mW for the device. This study presents what we believe to be a novel concept for the designing of superluminescent emitters with both a broadband and high power output.

Psammaplin A analogues with modified disulfide bond targeting histone deacetylases: Synthesis and biological evaluation.

Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed.

LncRNA CRNDE promotes hepatoma cell proliferation by regulating the metabolic reprogramming of M2 macrophages via ERK pathway.

BACKGROUND: LncRNA colorectal neoplasia differentially expressed (CRNDE) was found to be an important regulator in many cancers. This project focuses on the function of CRNDE on macrophage metabolic reprogramming and Hepatocellular carcinoma (HCC). METHOD: qRT-PCR and Immunofluorescence were used to analyze Arg-1, IL-10, CD163, CCL-18, CD206, and CRNDE expression in HCC tissues and macrophages. Western Blotting was used to analyze ERK and p-ERK expression. Edu assay, transwell assay and xenograft experiments were carried out to study cell viability, migrated and invasive capability. Immunohistochemical staining was used to evaluate Ki67 expression. A liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed for macrophages metabolites analysis. RESULTS: Arg-1, IL-10, CD163, CD206, and CRNDE were significantly up-regulated in HCC tissues, M2 macrophage and M0 macrophage with CRNDE overexpressed (OV-CRNDE-M0), which downregulated in M0 macrophage with CRNDE knockdown (sh-CRNDE-M0). The conditioned medium (CM) of M2 cells and OV-CRNDE-M0 cells promoted cell viability, invasion, and migration of HCC cells, the effect was reversed by sh-CRNDE-M0 cells CM. OV-CRNDE-M0 cells promoted tumor growth, Ki67 and CD206 expression in xenograft model. 61 metabolites were detected, of which 18 metabolites changed significantly in OV-CRNDE-M0 group compared to M0 group, with 9 upregulated and 9 downregulated. KEGG analysis showed the enrichment pathways were biosynthesis, glyoxylate and dicarboxylate metabolism. SMPDB analysis showed the enrichment pathways were hypoacetylaspartia, canavan disease, and aspartate metabolism. CONCLUSION: CRNDE regulated the metabolic reprogramming of M2 macrophage via ERK pathway, which thereby contributed to HCC proliferation, migration, and invasion.

Weakly-Supervised Segmentation-Based Quantitative Characterization of Pulmonary Cavity Lesions in CT Scans.

OBJECTIVE: Pulmonary cavity lesion is one of the commonly seen lesions in lung caused by a variety of malignant and non-malignant diseases. Diagnosis of a cavity lesion is commonly based on accurate recognition of the typical morphological characteristics. A deep learning-based model to automatically detect, segment, and quantify the region of cavity lesion on CT scans has potential in clinical diagnosis, monitoring, and treatment efficacy assessment. METHODS: A weakly-supervised deep learning-based method named CSA2-ResNet was proposed to quantitatively characterize cavity lesions in this paper. The lung parenchyma was firstly segmented using a pretrained 2D segmentation model, and then the output with or without cavity lesions was fed into the developed deep neural network containing hybrid attention modules. Next, the visualized lesion was generated from the activation region of the classification network using gradient-weighted class activation mapping, and image processing was applied for post-processing to obtain the expected segmentation results of cavity lesions. Finally, the automatic characteristic measurement of cavity lesions (e.g., area and thickness) was developed and verified. RESULTS: the proposed weakly-supervised segmentation method achieved an accuracy, precision, specificity, recall, and F1-score of 98.48%, 96.80%, 97.20%, 100%, and 98.36%, respectively. There is a significant improvement (P < 0.05) compared to other methods. Quantitative characterization of morphology also obtained good analysis effects. CONCLUSIONS: The proposed easily-trained and high-performance deep learning model provides a fast and effective way for the diagnosis and dynamic monitoring of pulmonary cavity lesions in clinic. Clinical and Translational Impact Statement: This model used artificial intelligence to achieve the detection and quantitative analysis of pulmonary cavity lesions in CT scans. The morphological features revealed in experiments can be utilized as potential indicators for diagnosis and dynamic monitoring of patients with cavity lesions.

Enantioselective Ni-Catalyzed 1,2-Borylalkynylation of Unactivated Alkenes.

Enantioselective three-component difunctionalization of alkenes with boron reagents represents an attractive strategy for assembling three-dimensional chiral organoboron compounds. However, regio- and enantiocontrol comprise the pivot challenges in these transformations, which predominantly require the use of activated conjugated alkenes. Herein, by utilizing various carbonyl directing groups, including amides, sulfinamides, ketones, and esters, we succeed in realizing a nickel-catalyzed 1,2-borylalkynylation of unactivated alkenes to enable the simultaneous incorporation of a boron entity and an sp-fragment across the double bond. The products contain boryl, alkynyl, and carbonyl functional groups with orthogonal synthetic reactivities, offering three handles for further derivatization to access valuable intermediates. The utility of this ligand-enabled asymmetric protocol has been highlighted through the late-stage decoration of drug-relevant molecules.

Amplified and distinctive genotoxicity of titanium dioxide nanoparticles in transformed yeast reporters with human cytochrome P450 (CYP) genes.

Titanium dioxide nanoparticles (nTiO2) have been considered a possible carcinogen to humans, but most existing studies have overlooked the role of human enzymes in assessing the genotoxicity of nTiO2. Here, a toxicogenomics-based in vitro genotoxicity assay using a GFP-fused yeast reporter library was employed to elucidate the genotoxic potential and mechanisms of nTiO2. Moreover, two new GFP-fused yeast reporter libraries containing either human CYP1A1 or CYP1A2 genes were constructed by transformation to investigate the potential modulation of nTiO2 genotoxicity in the presence of human CYP enzymes. This study found a lack of appreciable nTiO2 genotoxicity as indicated by the yeast reporter library in the absence of CYP expression but a significantly elevated indication of genotoxicity in either CYP1A1- or CYP1A2-expressing yeast. The intracellular reactive oxygen species (ROS) measurement indicated significantly higher ROS in yeast expressing either enzyme. The detected mitochondrial DNA damage suggested mitochondria as one of the target sites for oxidative damage by nTiO2 in the presence of either one of the CYP enzymes. The results thus indicated that the genotoxicity of nTiO2 was enhanced by human CYP1A1 or CYP1A2 enzyme and was associated with elevated oxidative stress, which suggested that the similar mechanisms could occur in human cells.

Copper induces cytotoxicity in freshwater bivalve Anodonta woodiana hemocytes.

Hemocytes of freshwater bivalves are an important target model for evaluating copper (Cu) toxicity in vitro, with excess Cu causing adverse responses in these organisms. Despite this, the mechanisms underlying cytotoxicity remain poorly understood. The freshwater bivalve Anodonta woodiana, employed as a model organism in freshwater environments, was utilized in this study. Hemocytes of A. woodiana were exposed to various aqueous Cu treatments (0.001, 0.01, 0.1, 1, and 10 mg/L), and a control group (no Cu added) for 3 h to investigate the cytotoxic mechanisms of Cu. The results showed a significant increase in the production of reactive oxygen species in hemocytes of all Cu exposed groups compared to the control (p < 0.05). Remarkably, Cu treatments disrupted the cellular membrane (p < 0.05) but did not induce significant changes in the stability of the lysosomal membrane. Cu targeted the mitochondria, leading to a reduction in mitochondrial membrane potential. Additionally, all Cu treatments significantly increased the degree of DNA damage (p < 0.05). Cellular damage and a significant decline in cell viability were observed when the Cu exposure concentration reached 0.1, 1, and 10 mg/L (p < 0.05). Our study provides new insights into the cytotoxicity mechanisms triggered by Cu in hemocytes of the freshwater bivalve A. woodiana, even under environmentally relevant conditions of 0.01 mg/L exposure.

Association of prenatal multiple metal exposures with child neurodevelopment at 3 years of age: A prospective birth cohort study.

Prenatal exposures to toxic metals and trace elements have been linked to childhood neurodevelopment. However, existing evidence remains inconclusive, and further research is needed to investigate the mixture effects of multiple metal exposures on childhood neurodevelopment. We aimed to examine the associations between prenatal exposure to specific metals and metal mixtures and neurodevelopment in children. In this prospective cohort study, we used the multivariable linear regressions and the robust modified Poisson regressions to explore the associations of prenatal exposure to 25 specific metals with neurodevelopment among children at 3 years of age in 854 mother-child pairs from the Jiangsu Birth Cohort (JBC) Study. The Bayesian kernel machine regression (BKMR) was employed to assess the joint effects of multiple metals on neurodevelopment. Prenatal manganese (Mn) exposure was negatively associated with the risk of non-optimal cognition development of children, while vanadium (V), copper (Cu), zinc (Zn), antimony (Sb), cerium (Ce) and uranium (U) exposures were positively associated with the risk of non-optimal gross motor development. BKMR identified an interaction effect between Sb and Ce on non-optimal gross motor development. Additionally, an element risk score (ERS), representing the mixture effect of multiple metal exposures including V, Cu, Zn, Sb, Ce and U was constructed based on weights from a Poisson regression model. Children with ERS in the highest tertile had higher probability of non-optimal gross motor development (RR = 2.37, 95 % CI: 1.15, 4.86) versus those at the lowest tertile. Notably, Sb [conditional-posterior inclusion probabilities (cPIP) = 0.511] and U (cPIP = 0.386) mainly contributed to the increased risk of non-optimal gross motor development. The findings highlight the importance of paying attention to the joint effects of multiple metals on children's neurodevelopment. The ERS score may serve as an indicator of comprehensive metal exposure risk for children's neurodevelopment.

Dihydrotanshinone I targets ESR1 to induce DNA double-strand breaks and proliferation inhibition in hepatocellular carcinoma.

BACKGROUND: Due to its high incidence and elevated mortality, hepatocellular carcinoma (HCC) has emerged as a formidable global healthcare challenge. The intricate interplay between gender-specific disparities in both incidence and clinical outcomes has prompted a progressive recognition of the substantial influence exerted by estrogen and its corresponding receptors (ERs) upon HCC pathogenesis. Estrogen replacement therapy (ERT) emerged for the treatment of HCC by administering exogenous estrogen. However, the powerful side effects of estrogen, including the promotion of breast cancer and infertility, hinder the further application of ERT. Identifying effective therapeutic targets for estrogen and screening bioactive ingredients without E2-like side effects is of great significance for optimizing HCC ERT. METHODS: In this study, we employed an integrative approach, harnessing data from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, clinical paraffin sections, adenoviral constructs as well as in vivo studies, to unveil the association between estrogen, estrogen receptor α (ESR1) and HCC. Leveraging methodologies encompassing molecular dynamics simulation and cellular thermal shift assay (CETSA) were used to confirm whether ESR1 is a molecular target of DHT. Multiple in vitro and in vivo experiments were used to identify whether i) ESR1 is a crucial gene that promotes DNA double-strand breaks (DSBs) and proliferation inhibition in HCC, ii) Dihydrotanshinone I (DHT), a quinonoid monomeric constituent derived from Salvia miltiorrhiza (Dan shen) exerts anti-HCC effects by regulating ESR1 and subsequent DSBs, iii) DHT has the potential to replace E2. RESULTS: DHT could target ESR1 and upregulate its expression in a concentration-dependent manner. This, in turn, leads to the downregulation of breast cancer type 1 susceptibility protein (BRCA1), a pivotal protein involved in the homologous recombination repair (HRR) process. The consequence of this downregulation is manifested through the induction of DSBs in HCC, subsequently precipitating a cascade of downstream events, including apoptosis and cell cycle arrest. Of particular significance is the comparative assessment of DHT and isodose estradiol treatments, which underscores DHT's excellent HCC-suppressive efficacy without concomitant perturbation of endogenous sex hormone homeostasis. CONCLUSION: Our findings not only confirm ESR1 as a therapeutic target in HCC management but also underscores DHT's role in upregulating ESR1 expression, thereby impeding the proliferation and invasive tendencies of HCC. In addition, we preliminarily identified DHT has the potential to emerge as an agent in optimizing HCC ERT through the substitution of E2.

Exploring the mechanism of enterotoxicity mediated by the microbiome-butyrate-PPAR axis in podophyllotoxin through the toxicological evidence chain (TEC) concept.

Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.

Implications of ozone transport on air quality in the Sichuan Basin, China.

Ozone pollution is formed through complex chemical and physical processes closely associated with emissions, photochemical reactions, and meteorological conditions. The objective of this study is to quantify the contributions of meteorological chemical formation, vertical transport, and horizontal transport to air quality during spring and summer in different regions of the Sichuan Basin. The Community Multi-scale Air Quality (CMAQ) with the Integrated Process Rate (IPR) was employed to simulate the months of April and July 2021 in the Sichuan Basin. The results indicate that both the spring and summer chemical formation of ozone in the urban centre show negative values, while the surrounding urban areas contribute positively, with chemical formation ranging from 0 to 10 µg·m-3. The maximum ozone level due to horizontal transport in the urban centre exceeds 20 µg·m-3, whereas horizontal transport in the surrounding urban areas exhibits negative values, with transport contributions concentrated within the range of -5 to 0 µg·m-3. The vertical transport in the central and southern parts of the basin shows positive values, with transport contributions ranging from 0 to 10 µg·m-3, and the urban centre exhibits relatively stronger vertical transport with contributions ranging from 10 to 20 µg·m-3. Although the chemical formation contribution in the urban centre is relatively small due to high nitrogen oxide emissions, vertical and horizontal transport play significant roles and are among the key factors contributing to ozone pollution formation.