The role of DNA topoisomerase 1α (AtTOP1α) in regulating arabidopsis meiotic recombination and chromosome segregation.

Meiosis is a critical process in sexual reproduction, and errors during this cell division can significantly impact fertility. Successful meiosis relies on the coordinated action of numerous genes involved in DNA replication, strand breaks, and subsequent rejoining. DNA topoisomerase enzymes play a vital role by regulating DNA topology, alleviating tension during replication and transcription. To elucidate the specific function of DNA topoisomerase 1α ( A t T O P 1 α ) in male reproductive development of Arabidopsis thaliana, we investigated meiotic cell division in Arabidopsis flower buds. Combining cytological and biochemical techniques, we aimed to reveal the novel contribution of A t T O P 1 α to meiosis. Our results demonstrate that the absence of A t T O P 1 α leads to aberrant chromatin behavior during meiotic division. Specifically, the top1α1 mutant displayed altered heterochromatin distribution and clustered centromere signals at early meiotic stages. Additionally, this mutant exhibited disruptions in the distribution of 45s rDNA signals and a reduced frequency of chiasma formation during metaphase I, a crucial stage for genetic exchange. Furthermore, the atm-2×top1α1 double mutant displayed even more severe meiotic defects, including incomplete synapsis, DNA fragmentation, and the presence of polyads. These observations collectively suggest that A t T O P 1 α plays a critical role in ensuring accurate meiotic progression, promoting homologous chromosome crossover formation, and potentially functioning in a shared DNA repair pathway with ATAXIA TELANGIECTASIA MUTATED (ATM) in Arabidopsis microspore mother cells.

FOSL1 promotes stem cell­like characteristics and anoikis resistance to facilitate tumorigenesis and metastasis in osteosarcoma by targeting SOX2.

Metastasis is the leading cause of cancer­related death in osteosarcoma (OS). OS stem cells (OSCs) and anoikis resistance are considered to be essential for tumor metastasis formation. However, the underlying mechanisms involved in the maintenance of a stem­cell phenotype and anoikis resistance in OS are mostly unknown. Fos­like antigen 1 (FOSL1) is important in maintaining a stem­like phenotype in various cancers; however, its role in OSCs and anoikis resistance remains unclear. In the present study, the dynamic expression patterns of FOSL1 were investigated during the acquisition of cancer stem­like properties using RNA sequencing, PCR, western blotting and immunofluorescence. Flow cytometry, tumor­sphere formation, clone formation assays, anoikis assays, western blotting and in vivo xenograft and metastasis models were used to further investigate the responses of the stem­cell phenotype and anoikis resistance to FOSL1 overexpression or silencing in OS cell lines. The underlying molecular mechanisms were evaluated, focusing on whether SOX2 is crucially involved in FOSL1­mediated stemness and anoikis in OS. FOSL1 expression was observed to be upregulated in OSCs and promoted tumor­sphere formation, clone formation and tumorigenesis in OS cells. FOSL1 expression correlated positively with the expression of stemness­related factors (SOX2, NANOG, CD117 and Stro1). Moreover, FOSL1 facilitated OS cell anoikis resistance and promoted metastases by regulating the expression of apoptosis related proteins BCL2 and BAX. Mechanistically, FOSL1 upregulated SOX2 expression by interacting with the SOX2 promoter and activating its transcription. The results also showed that SOX2 is critical for FOSL1­mediated stem­like properties and anoikis resistance. The current findings indicated that FOSL1 is an important regulator that promotes a stem cell­like phenotype and anoikis resistance to facilitate tumorigenesis and metastasis in OS by regulating the transcription of SOX2. Thus, FOSL1 might represent an attractive target for therapeutic interventions in OS.

A FRET biosensor constructed using pH sensitive G-quadruplex DNA for detecting mitochondrial autophagy.

Mitochondria are crucial powerhouses and central organelles for maintaining normal physiological activities in eukaryotic cells. The use of highly specific optical biosensors to monitor mitochondrial autophagy (mitophagy) is an important way for detecting mitochondrial abnormalities. Herein, we report a pH responsive G-quadruplex (G4) structure folded by the oligonucleotide named P24. P24 is composed of four GGCCTG repeating units, and the high guanine content allows it to form an antiparallel G4 topology at pH 4.5 (lysosomal pH). However, when pH increases to around 7.4 (mitochondrial pH), P24 further transforms into a double-stranded structure. Unlike most oligonucleotides that enter lysosomes, P24 highly targets mitochondria in live cells. These characteristics enable P24 to construct a pH responsive optical biosensor by linking a pair of fluorescence resonance energy transfer (FRET) fluorophores. The P24 based biosensor demonstrates reliable applications in detecting mitophagy in live cells.

High Stability Hydrogel Magnetic Relaxation Switch Sensor Driven by pH for the Sensitive Detection of Cd2.

The traditional magnetic relaxation switching (MRS) sensors have excellent sensitivity, but their stability is poor because the magnetic relaxation signal is easily affected by the external magnetic field or environmental oxidation. In this study, a highly stable hydrogel bead-based MRS (Gel-MRS) sensor was established for the accurate and sensitive detection of Cd2+ in rice. A pH-responsive hydrogel bead was applied as a core element for the target stimulus and transverse relaxation signal transduction. The stability experiments showed that the transverse relaxation time (T2) change of the Gel-MRS sensor was one-seventh that of traditional magnetic nanoparticles under an external magnetic field and less than a fifth that of Fe2+/Fe3+ conversion in air. The excellent stability was due to the fact that T2 of the Gel-MRS sensor came from the swelling system mediated by pH rather than the traditional aggregation/dispersion or Fe2+/Fe3+ conversion of magnetic nanoparticles. In addition, the target Cd2+ could exclusively trigger a pH response of the hydrogel beads, altering the T2, thus resulting in excellent relaxation properties (R2 = 56.89) and pH responsiveness of the Gel-MRS sensor. The swelling process of the hydrogel beads followed quasi-second-order dynamics. The Gel-MRS sensor demonstrated a remarkable limit of detection as low as 0.009 ng/mL for Cd2+, with a linear range of 0.01-5 ng/mL. The excellent stability and sensitivity made the Gel-MRS sensor have great application potential in food and environmental detection.

LONP1 alleviates ageing-related renal fibrosis by maintaining mitochondrial homeostasis.

Mitochondrial dysfunction is a pivotal event contributing to the development of ageing-related kidney disorders. Lon protease 1 (LONP1) has been reported to be responsible for ageing-related renal fibrosis; however, the underlying mechanism(s) of LONP1-driven kidney ageing with respect to mitochondrial disturbances remains to be further explored. The level of LONP1 was tested in the kidneys of aged humans and mice. Renal fibrosis and mitochondrial quality control were confirmed in the kidneys of aged mice. Effects of LONP1 silencing or overexpression on renal fibrosis and mitochondrial quality control were explored. In addition, N6-methyladenosine (m6A) modification and methyltransferase like 3 (METTL3) levels, the relationship between LONP1 and METTL3, and the impacts of METTL3 overexpression on mitochondrial functions were confirmed. Furthermore, the expression of insulin-like growth factor 2 mRNA binding protein 2 (IGF2BP2) and the regulatory effects of IGF2BP2 on LONP1 were confirmed in vitro. LONP1 expression was reduced in the kidneys of aged humans and mice, accompanied by renal fibrosis and mitochondrial dysregulation. Overexpression of LONP1 alleviated renal fibrosis and maintained mitochondrial homeostasis, while silencing of LONP1 had the opposite effect. Impaired METTL3-m6A signalling contributed at least in part to ageing-induced LONP1 modification, reducing subsequent degradation in an IGF2BP2-dependent manner. Moreover, METTL3 overexpression alleviated proximal tubule cell injury, preserved mitochondrial stability, inhibited LONP1 degradation, and protected mitochondrial functions. LONP1 mediates mitochondrial function in kidney ageing and that targeting LONP1 may be a potential therapeutic strategy for improving ageing-related renal fibrosis.

Hyperkalemia burden and treatment patterns in Chinese patients on hemodialysis: final analysis of a prospective multicenter cohort study (PRECEDE-K).

OBJECTIVES: Patients with end-stage renal disease (ESRD) on hemodialysis (HD) are at risk for hyperkalemia (HK), associated with cardiac arrhythmia and sudden death. Data on the burden of HK and management techniques among HD patients in China are still scarce. This study assessed the treatment modalities, recurrence, and prevalence of HK in Chinese HD patients. METHODS: In this prospective cohort study conducted from May 2021 to July 2022, patients aged ≥18 years who had ESRD and were on HD were enrolled from 15 centers in China (up to 6 months). RESULTS: Overall, 600 patients were enrolled. At the baseline visit, mean (± standard deviation) urea reduction ratio was 68.0% ± 9.70 and Kt/V was 1.45 ± 0.496. Over 6 months, 453 (75.5%) patients experienced HK, of whom 356 (78.6%) recurred. Within 1, 2, 3, 4, 5, and 6 months, 203 (44.8%), 262 (57.8%), 300 (66.2%), 326 (72.0%), 347 (76.6%), and 356 (78.6%) patients had at least one HK recurrence event, respectively. The proportions of patients with ≥1, 2, 3, 4, 5, or 6 HK recurrence events were 356 (78.6%), 306 (67.5%), 250 (55.2%), 208 (45.9%), 161 (35.5%), and 110 (24.3%), respectively. Among the 453 patients who experienced HK, only 24 (5.3%) were treated with potassium binders: seven (1.5%) with sodium polystyrene sulfonate, 13 (2.9%) with calcium polystyrene sulfonate, and six (1.3%) with sodium zirconium cyclosilicate. CONCLUSION: Since HK is a chronic illness, long-term care is necessary. Patients on HD should have effective potassium management on non-dialysis days, yet our real-world population rarely used potassium binders. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04799067.

Electrochemical lithium storage of a biactive organic molecule containing cyano and imine groups.

With an electron-deficient rigid planar structure and excellent π-π stacking ability, hexaazatriphenylene (HAT) and its derivatives are widely used as basic building blocks for constructing covalent organic frameworks (COFs), components of organic light-emitting diodes and solar cells, and electrode materials for lithium-ion batteries (LIBs). Here, a HAT derivative, hexaazatriphenylenehexacarbonitrile, is explored as an anode material for LIBs. The HAT anode exhibited high initial reversible capacities of 672 mA h g-1 at 100 mA g-1 and 550 mA h g-1 at 400 mA g-1 and stable cycling with a capacity of 503 mA h g-1 after 1000 cycles at 400 mA g-1 corresponding to a capacity retention of 91.5%. Furthermore, the lithium storage mechanism and the cause of the first irreversible capacity loss of the HAT anode were investigated by X-ray photoelectron spectroscopy (XPS) analysis and density functional theory (DFT) calculations. We have carried out a series of analyses on the mechanism of initial capacity loss. This study provides new insight on initial capacity loss and provides valuable insights into the molecular design and the electrochemical properties of HAT-based anode materials.

Breaking New Ground: Unraveling the USP1/ID3/E12/P21 Axis in Vascular Calcification.

Vascular calcification (VC) poses significant challenges in cardiovascular health. This study employs single-cell transcriptome sequencing to dissect cellular dynamics in this process. We identify distinct cell subgroups, notably in vascular smooth muscle cells (VSMCs), and observe differences between calcified atherosclerotic cores and adjacent regions. Further exploration reveals ID3 as a key gene regulating VSMC function. In vitro experiments demonstrate ID3's interaction with USP1 and E12, modulating cell proliferation and osteogenic differentiation. Animal models confirm the critical role of the USP1/ID3/E12/P21 axis in VC. This study sheds light on a novel regulatory mechanism, offering potential therapeutic targets.

Low-cost signal enhanced colorimetric and SERS dual-mode paper sensor for rapid and ultrasensitive screening of mercury ions in tea.

Mercury ions (Hg2+) are highly toxic heavy metals that are commonly found in natural environments. Owning to their non-biodegradability and accumulation in the food chain, the precise detection of trace amounts of Hg2+ is essential for preventing chronic accumulation and ensuring food safety. In this study, we present a dual-mode paper sensor for simultaneous colorimetric and Surface-Enhanced Raman Spectroscopy (SERS) detection of Hg2+ in tea, achieving ultrasensitive, rapid, and on-site screening. 4-Mercaptopyridine (4-MPY) was effectively chemisorbed onto the gold nanoparticles (AuNPs), acting as a signal probe for colorimetric methods. Moreover, it can produce plasmonic hot spots for SERS by interacting with the pyridine ring. To enhance the signal intensity of both colorimetry and SERS, a silver shell is in-situ grown on the surface of AuNPs captured on the paper sensor by reduction of Ag+, achieving signal amplification. The visual limit of detection (LOD) for the colorimetric biosensor is 2.5 pM, while the LOD of SERS is 0.48 pM with this dual-mode paper sensor. The sensitivity of both the colorimetric method and SERS was improved by approximately 200 and 500 times, respectively, with the designed signal amplification strategy. The system allows for multiple parallel screening of the same sample, ensuring accurate results without any false-positive or false-negative. This study provides a valuable platform for the accurate detection of various other heavy metal ions and provides effective strategies for improving the performance of colorimetric methods.

Effects of cell culture time and cytokines on migration of dental pulp stem cell-derived chondrogenic cells in collagen hydrogels.

The transplantation of collagen hydrogels encapsulating human dental pulp stem cell (DPSC)-derived chondrogenic cells is potentially a novel approach for the regeneration of degenerated nucleus pulposus (NP) and cartilage. Grafted cell migration allows cells to disperse in the hydrogels and the treated tissue from the grafted location. We previously reported the cell migration in type I and type II hydrogels. It is important to explore further how cell culture time affect the cell motility. In this study, we observed the decreased motility of DPSC-derived chondrogenic cells after culturing for 2 weeks compared with cells cultured for 2 days in these gels. The Alamarblue assay showed the cell proliferation during the two-week cell culture period. The findings suggest that the transitions of cell motility and proliferation during the longer culture time. The result indicates that the early culture stage is an optimal time for cell transplantation. In a degenerated disc, the expression of IL-1ß and TNFα increased significantly compared with healthy tissue and therefore may affect grafted cell migration. The incorporation of IL-1ß and TNFα into the collagen hydrogels decreased cell motility. The study indicates that the control of IL-1ß and TNFα production may help to maintain cell motility after transplantation.

Three-Dimensional Reconstruction of Indoor Scenes Based on Implicit Neural Representation.

Reconstructing 3D indoor scenes from 2D images has always been an important task in computer vision and graphics applications. For indoor scenes, traditional 3D reconstruction methods have problems such as missing surface details, poor reconstruction of large plane textures and uneven illumination areas, and many wrongly reconstructed floating debris noises in the reconstructed models. This paper proposes a 3D reconstruction method for indoor scenes that combines neural radiation field (NeRFs) and signed distance function (SDF) implicit expressions. The volume density of the NeRF is used to provide geometric information for the SDF field, and the learning of geometric shapes and surfaces is strengthened by adding an adaptive normal prior optimization learning process. It not only preserves the high-quality geometric information of the NeRF, but also uses the SDF to generate an explicit mesh with a smooth surface, significantly improving the reconstruction quality of large plane textures and uneven illumination areas in indoor scenes. At the same time, a new regularization term is designed to constrain the weight distribution, making it an ideal unimodal compact distribution, thereby alleviating the problem of uneven density distribution and achieving the effect of floating debris removal in the final model. Experiments show that the 3D reconstruction effect of this paper on ScanNet, Hypersim, and Replica datasets outperforms the state-of-the-art methods.

Tumor Microenvironment-Responsive Magnetotactic Bacteria-Based Multi-Drug Delivery Platform for MRI-Visualized Tumor Photothermal Chemodynamic Therapy.

Cancer cells display elevated reactive oxygen species (ROS) and altered redox status. Herein, based on these characteristics, we present a multi-drug delivery platform, AMB@PDAP-Fe (APPF), from the magnetotactic bacterium AMB-1 and realize MRI-visualized tumor-microenvironment-responsive photothermal-chemodynamic therapy. The Fe3+ in PDAP-Fe is reduced by the GSH at the tumor site and is released in the form of highly active Fe2+, which catalyzes the generation of ROS through the Fenton reaction and inhibits tumor growth. At the same time, the significant absorption of the mineralized magnetosomes in AMB-1 cells in the NIR region enables them to efficiently convert near-infrared light into heat energy for photothermal therapy (PTT), to which PDAP also contributes. The heat generated in the PTT process accelerates the process of Fe2+ release, thereby achieving an enhanced Fenton reaction in the tumor microenvironment. In addition, the magnetosomes in AMB-1 are used as an MRI contrast agent, and the curing process is visualized. This tumor microenvironment-responsive MTB-based multi-drug delivery platform displays the potency to combat tumors and demonstrates the utility and practicality of understanding the cooperative molecular mechanism when designing multi-drug combination therapies.

Comparison of drug-induced liver injury risk between propylthiouracil and methimazole: A quantitative systems toxicology approach.

Propylthiouracil (PTU) and methimazole (MMI), two classical antithyroid agents possess risk of drug-induced liver injury (DILI) with unknown mechanism of action. This study aimed to examine and compare their hepatic toxicity using a quantitative system toxicology approach. The impact of PTU and MMI on hepatocyte survival, oxidative stress, mitochondrial function and bile acid transporters were assessed in vitro. The physiologically based pharmacokinetic (PBPK) models of PTU and MMI were constructed while their risk of DILI was calculated by DILIsym, a quantitative systems toxicology (QST) model by integrating the results from in vitro toxicological studies and PBPK models. The simulated DILI (ALT >2 × ULN) incidence for PTU (300 mg/d) was 21.2%, which was within the range observed in clinical practice. Moreover, a threshold dose of 200 mg/d was predicted with oxidative stress proposed as an important toxic mechanism. However, DILIsym predicted a 0% incidence of hepatoxicity caused by MMI (30 mg/d), suggesting that the toxicity of MMI was not mediated through mechanism incorporated into DILIsym. In conclusion, DILIsym appears to be a practical tool to unveil hepatoxicity mechanism and predict clinical risk of DILI.

Gegen Qinlian Decoction reverses oxaliplatin resistance in colorectal cancer by inhibiting YTHDF1-regulated m6A modification of GLS1.

BACKGROUND: Colorectal cancer (CRC) and its chemoresistance pose significant threats to human health. Gegen Qinlian Decoction (GQD) is frequently employed alongside chemotherapy drugs for the treatment of CRC and various intestinal disorders. Despite its widespread use, there is limited research investigating the mechanisms through which GQD reverses chemoresistance. PURPOSE: This study investigated the mechanism by which GQD reverses oxaliplatin (OXA) resistance in CRC. METHODS: A YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-knockdown OXA-resistant cell line was constructed by lentivirus to clarify YTHDF1-mediated chemoresistance through the regulation of glutaminase 1 (GLS1). The efficacy of GQD in reversing OXA resistance in CRC in vitro was evaluated by Cell Counting Kit-8, western blotting, quantitative real-time polymerase chain reaction, and glutaminase activity assays. In vivo validation was performed by constructing tumor xenografts in nude mice with OXA-resistant cells. In addition, mouse feces were collected and a 16S rDNA assay was performed to assess the regulation of intestinal flora by GQD. RESULTS: Overexpression of YTHDF1 upregulated GLS1 expression and induced OXA-resistance in CRC. GQD induced apoptosis in LoVo/OXAR, increased OXA accumulation in LoVo/OXAR, inhibited expression of YTHDF1 and GLS1 when administered alone and in combination with OXA, and suppressed GLS1 activity to reverse drug resistance with good synergistic effects. GQD and OXA combination or GLS1 inhibitor alleviated OXA toxicity, reduced the volume of tumor xenografts in nude mice, inhibited YTHDF1 and GLS1 protein expression and GLS1 activity, adjusted the intestinal flora, and significantly reversed the increased Firmicutes/Bacteroidetes ratio. CONCLUSION: GQD has shown superior efficacy in reversing OXA-resistance and increasing sensitivity. These findings indicate that the therapy combined with GQD has potential utility in the treatment of OXA-resistant CRC.

Determination of ligand selectivity to G-tetrad through an AMCA fluorescence quenching approach.

The selective binding of ligand molecules towards the 5' and 3' ends of G-quadruplex (G4) may differentially affect the physiological function of G4s. However, there is still a lack of sensitive and low-cost approaches to accurately measure the binding preference of ligands on G4s, although multiple ways have been developed to evaluate the interaction between ligands and G4s. Here, we propose a new protocol named G4-AFQ to test the selectivity of ligands towards the two terminal G-tetrads of G4s. In this protocol, the fluorophore AMCA is respectively modified at the 5' or 3' end of G4, and which end of AMCA fluorescence is quenched means that the ligand binds to the G-tetrad at that end. Through G4-AFQ, the affinity constant of ligands towards the binding site can also be obtained. Compared with the commonly used nuclear magnetic resonance (NMR) method, G4-AFQ is more convenient, sensitive, cost-effective, and suitable for the measurement of the vast majority of G4 ligands, with a great potential for widespread application.