The synthetic chemistry of sarpagine-ajmaline-type alkaloids.

The sarpagine-ajmaline type monoterpenoid indole alkaloids are among the most important groups of natural alkaloids, and the complex polycyclic and cage-like architectures present significant synthetic challenges. Because of their characteristic indole-fused azabicyclo[3.3.1]nonane structures and prominent biological activities, sarpagine-ajmaline related alkaloids have captured the attention of organic synthetic chemists for decades. In this chapter, the strategies employed in the synthesis of sarpagine-ajmaline related alkaloids are outlined, and the synthetic progress during the period of 2019-2023 is provided in detail. To provide potential targets for future synthetic endeavors, some sarpagine/ajmaline type alkaloids isolated in recent years with novel structures and biological activities are also summarized.

Analysis of Fetal Growth and Pregnancy Outcome in Pregnant Women Infected with Novel Coronavirus in Mid-Pregnancy.

Purpose: To investigate whether fetal prenatal ultrasound, fetal growth rate, and pregnancy outcome statistically differ between women infected with novel coronavirus (COVID-19) in mid-pregnancy and an uninfected control group. Patients and Methods: A retrospective analysis of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), femur length (FL), and z-scores for each among 46 pregnant women diagnosed with COVID-19 in mid-pregnancy between December 01, 2022 and June 31, 2023 was conducted. A control group included 92 pregnant women negative for COVID-19 during the same period and was also analyzed. To examine fetal growth, rate of increase in BPD, HC, AC, FL, and estimated fetal weight (EFW) between second and third trimester scans were analyzed. In addition, pregnancy outcome, maternal comorbidities, and neonatal prognosis were assessed. Results: The occurrence of gestational diabetes differed significantly between groups, but the fetal growth rate and EFW did not. Similarly, pregnancy outcomes and neonatal prognoses did not differ significantly between groups. Conclusion: Gestational diabetes was a complication that differed between patients with and without COVID-19 in this study. COVID-19 in pregnant women did not affect fetal development. Therefore, these preliminary data suggest that increased fetal monitoring is not necessary for women infected with COVID-19 during the second trimester, and these women should be reassured of the low risk of adverse fetal outcomes.

Collective Syntheses of Corynanthe Alkaloids Based on a Chirality-Tunable Structure Unit.

A novel strategy based on a common intermediate bearing a chirality-tunable structure unit for the collective syntheses of corynantheine-type and heteroyohimbine-type alkaloids has been developed. Key transformations of the synthetic strategy are a sequential nucleophilic C-N bond formation/Mannich-type cyclization to construct the highly functional C/D rings, a stereocontrolled introduction of the C15 and C20 chiral centers based on the chirality-tunable structure unit, and an amine-directed addition of Me3Al to construct the C18 methyl group.

Active learning-based automated construction of Hamiltonian for structural phase transitions: A case study on BaTiO3.

The effective Hamiltonians have been widely applied to simulate the phase transitions in polarizable materials, with coefficients obtained by fitting to accurate first-principles calculations. However, it is tedious to generate distorted structures with symmetry constraints, in particular when high-ordered terms are considered. In this work, we implement and apply a Bayesian optimization-based approach to sample the potential energy surface, automating the Hamiltonian construction by selecting distorted structures via active learning. Taking BaTiO3 (BTO) as an example, we demonstrate that the Hamiltonian can be obtained using fewer than 30 distorted structures. Follow-up Monte Carlo simulations can reproduce the structural phase transition temperatures of BTO, comparable to experimental values with an error < 10%. Our approach can be straightforwardly applied on other polarizable materials and paves the way for quantitative atomistic modelling of diffusionless phase transitions.

TDT-MIL: a framework with a dual-channel spatial positional encoder for weakly-supervised whole slide image classification.

The classic multiple instance learning (MIL) paradigm is harnessed for weakly-supervised whole slide image (WSI) classification. The spatial position relationship located between positive tissues is crucial for this task due to the small percentage of these tissues in billions of pixels, which has been overlooked by most studies. Therefore, we propose a framework called TDT-MIL. We first serially connect a convolutional neural network and transformer for basic feature extraction. Then, a novel dual-channel spatial positional encoder (DCSPE) module is designed to simultaneously capture the complementary local and global positional information between instances. To further supplement the spatial position relationship, we construct a convolutional triple-attention (CTA) module to attend to the inter-channel information. Thus, the spatial positional and inter-channel information is fully mined by our model to characterize the key pathological semantics in WSI. We evaluated TDT-MIL on two publicly available datasets, including CAMELYON16 and TCGA-NSCLC, with the corresponding classification accuracy and AUC up to 91.54%, 94.96%, and 90.21%, 94.36%, respectively, outperforming state-of-the-art baselines. More importantly, our model possesses a satisfactory capability in solving the imbalanced WSI classification task using an ingenious but interpretable structure.

Study on the Rheological Behaviors, Thixotropy, and Printing Characteristics of Screen Printing Slurry for Nd-Fe-B.

The rheological behavior and printing characteristics of the screen-printing slurry for Nd-Fe-B grain boundary diffusion are key factors that determine the quality of printing and magnetic performance. However, few studies have focused on the organic medium, a crucial material for slurry. In this paper, the rheology, thixotropy, and thermal decomposition behavior of the organic vehicle in Nd-Fe-B screen printing slurry were studied. The results show that the organic vehicle formed by terpineol and polyvinyl butyral (PVB) exhibits typical non-Newtonian fluid characteristics, with excellent rheology and thixotropy, ensuring that the slurry prepared from it has excellent static stability and printing consistency. Additionally, the carbon residue of the organic vehicle formed by terpineol and PVB is less than 0.1% at 900 °C, avoiding excessive carbon entering the magnet during the diffusion process. Moreover, studying the rheology and thixotropy of the organic vehicle through a rheometer can quickly screen the slurry system. This work provides valuable guidance for designing an organic vehicle for screen-printing slurry for Nd-Fe-B grain boundary diffusion in future research.

Visible-Photo-Assisted Phase Switching of Antiferroelectric-to-Ferroelectric Orders in an I3--Intercalated 2D Perovskite.

Antiferroelectric (AFE) has emerged as a promising branch of electroactive materials, due to their intriguing physical attributes stemming from the electric field-induced antipolar-to-polar phase transformation. However, the requirement of an extremely high electric field strength to switch adjacent sublattice polarization poses great challenges for exploiting molecular AFE system. Although photoirradiation is striking as a noncontact and nondestructive manipulation tool to optimize physical properties, the optical control of antiferroelectricity is still unexplored. Here, by adopting light-sensitive triiodide I3- anion into the 2D perovskite family, we have designed the first I3--intercalated molecular AFE of (t-ACH)2EA2Pb3I10(I3)0.5·((H3O)(H2O))0.5 (1, t-ACH = trans-4-aminomethyl-1-cyclohexanecarboxylate, EA = ethylammonium). The I3--intercalating gives an ultra-narrow bandgap of 1.65 eV with strong absorption. In terms of AFE structure, the anti-parallel alignment of electric dipoles results in a spontaneous polarization of 4.3 µC/cm2. Strikingly, 1 merely shows AFE behaviour in the dark even under ultrahigh voltage, while the field-induced ferroelectric state can be facilely obtained upon visible illumination. Such unprecedented photo-assisted phase switching ascribes to the incorporation of photoactive I3- anions, which reduce the AFE-to-ferroelectric switching barrier for 1. This pioneering work on the photo-assisting transformation of ferroic orders paves a new way to develop future photoactive materials with significant potential applications.

Positioning exercises in improving the quality of magnetic-controlled capsule endoscopy.

BACKGROUND: Good gastric preparation is indispensable for Magnetic-controlled Capsule Endoscopy (MCE) examination, but there is no consensus yet. We aim to explore the clinical application value of positioning exercises in improving the quality of MCE examination. METHODS: Clinical data of 326 patients who underwent MCE examination from January 2020 to December 2023 were collected. The included patients were divided into two groups: the conventional medication preparation group (CMP group, accepted mucosal cleansing medication only) and the positioning exercises group (PE group, accepted mucosal cleansing medication plus positioning exercises). A comparison was made between the two groups in terms of gastric cavity cleanliness score, visibility score, and detection rate of positive lesions. RESULTS: The examination time was (21.29 ± 5.82) minutes in the PE group and (30.54 ± 6.37) minutes in the CMP group, showing a significant difference between the two groups (P < 0.001). The total cleanliness score and visibility score in the CMP group were 15.89 ± 2.82 and 10.93 ± 2.12, respectively. In contrast, the total cleanliness score and visibility score in the PE group were 19.52 ± 2.26 and 15.09 ± 2.31, respectively. The PE group showed significantly better cleanliness scores and visibility scores in all six anatomical regions compared to the CMP group (All P < 0.001). However, there was no significant difference in the detection rate of positive lesions between the two groups (All P > 0.05). CONCLUSION: Positioning exercises before MCE examination can improve the quality of gastric mucosal images and reduce the duration of the examination for patients.

High-throughput calculations and machine learning modeling of 17O NMR in non-magnetic oxides.

The only NMR-active oxygen isotope, oxygen-17 (17O), serves as a sensitive probe due to its large chemical shift range, the electric field gradient at the oxygen site, and the quadrupolar interaction. Consequently, 17O solid-state NMR offers unique insights into local structures and finds significant applications in the studies of disorder, reactivity, and host-guest chemistry. Despite recent advances in sensitivity enhancement, isotopic labeling, and NMR crystallography, the application of 17O solid-state NMR is still hindered by low natural abundance, costly enrichment, and challenges in handling spectrum signals. Density functional theory calculations and machine learning techniques offer an alternative approach to mapping the local crystal structures to NMR parameters. However, the lack of high-quality data remains a challenge, despite the establishment of some datasets. In this study, we implement and execute a high-throughput workflow combining AiiDA and CASTEP to evaluate the NMR parameters. Focusing on non-magnetic oxides, we have chosen over 7100 binary, ternary, and quaternary compounds from the Materials Project database and performed calculations. Furthermore, using various descriptors for the local crystalline environments, we model the 17O NMR parameters using machine learning techniques, further enhancing our ability to predict and understand 17O NMR parameters in oxide crystals.

Downregulation of Brf1 Induces Liver Failure and Inhibits Hepatocellular Carcinoma Progression by Promoting Apoptosis.

The occurrence and development of hepatocellular carcinoma (HCC) are closely related to abnormal apoptosis. Brf1 is highly expressed in HCC and has clinical prognostic value. Here, attenuation of Brf1-induced apoptosis was found, and the related mechanism was explored. In the study, general bioinformatics data for Brf1 were obtained from The Human Protein Atlas (HPA). Analyses of the clinical prognostic value of Brf1 in HCC were performed with the Xiantao Academic web server using R software. The basic data were obtained from the GTEx database and TCGA database. Brf1 conditional knockout mice were obtained by repeated mating of C57BL/6 Brf1LoxP/LoxP and C57BL/6 NS5A-alb-Cre-ERT2 mice and verified by genotyping. Liver function measurements, hematoxylin and eosin staining (HE), and immunohistochemistry (IHC) were performed to explore the cause of mouse death after Brf1 knockout. The Brf1 knockdown HCC cell model was generated using lentiviral vector-based shRNA transduction. Cell proliferation assays, plate colony formation assays, anchorage-independent colony formation assays and mouse subcutaneous tumor models were used to evaluate the progression of HCC. Western blot (WB) analysis, flow cytometry, and TUNEL assays were used to detect apoptosis. DNA sequencing, transcriptomics, and proteomics analyses were carried out to explore the antiapoptotic mechanism of Brf1. We found that Brf1 was highly expressed in HCC and had clinical prognostic value. Brf1 knockout led to liver failure and hepatocyte apoptosis in mice. Downregulation of Brf1 slowed HCC cell proliferation, colony growth, and mouse subcutaneous tumor growth and increased the sensitivity of HCC cells to apoptosis induced by chemotherapy drugs. The expression of Brf1 was positively related to that of the apoptosis gene Bcl-2. The sequencing, transcriptomics and proteomics analyses consistently showed that energy metabolism played an important role in Brf1 function, that protein-protein interaction was the primary mode, and that organelles such as mitochondria were the main sites. In Conclusions, downregulation of Brf1 inhibits HCC development by inducing apoptosis. Energy metabolism plays an important role in Brf1 function. These results provide a scientific basis for combating HCC.

[Site-directed mutagenesis enhances the activity of dextranase from Arthrobacter oxidans KQ11].

Dextranase is an enzyme that specifically hydrolyzes the α-1, 6 glucoside bond. In order to improve the activity of dextranase from Arthrobacter oxidans KQ11, site-directed mutagenesis was used to modify the amino acids involved in the "tunnel-like binding site". A saturating mutation at position 507 was carried out on this basis. The mutant enzymes A356G, S357W, W507Y, and W507F with improved enzyme activities and catalytic efficiency were successfully obtained. Compared with wild type (WT), W507Y showed the specific activity increasing by 3.00 times, the kcat value increasing by 3.62 times, the Km value decreasing by 54%, and the catalytic efficiency (kcat/Km) increasing by 8.98 times. The three-dimensional structure analysis showed that the increase of the number of hydrogen bonds and the distance between "tunnel-like binding sites" were important factors affecting enzyme activity. Compared with WT, W507Y had a shortened distance from the residues on the other side of the "tunnel-like binding site", which made it easier to generate hydrogen binding forces. Accordingly, the substrate hydrolysis and product efflux were accelerated, which dramatically increased the enzyme activity and catalytic efficiency.

Unprecedented Silver-Based Hybrid Pyroelectric Enabling Wide Spectral Photo-Pyroelectricity for Birefringence Photomodulation.

Birefringent crystal, which has the capacity to manipulate polarization light, holds an indispensable position in optics and optoelectronics, while it remains challenging to fulfill the modulation of birefringence. Here, we present wide spectral photo-pyroelectric effect in a silver-based hybrid pyroelectric, (N-CHM)Ag2I3 (N-CHM = N-cyclohexylmethylamine), serving as a feasible strategy to regulate birefringence through light stimuli. As the first silver-based hybrid pyroelectric, (N-CHM)Ag2I3 exhibits strong room-temperature photo-pyroelectricity with a large polarization of ~3.23 µC/cm2 and high voltage responsivity of ~0.96 m2/C across the UV-NIR spectral region. Strikingly, the photomodulation of its in-plane birefringence is established through pyroelectric effect, giving a saturation value of ~1.68×10-2 that is among the highest level achieved to date. This study on the birefringence photomodulation of lead-free hybrid pyroelectric is anticipated to boost future development of new smart optical and optoelectronic devices.

Robotic-assisted extended thymectomy for large resectable thymoma: 21 years' experience.

OBJECTIVE: This study aims to evaluate the perioperative and midterm oncological outcomes of robotic-assisted thoracic surgery extended thymectomy for patients with large resectable thymomas compared with small thymomas. METHODS: This retrospective single-center study included 204 patients with thymomas who underwent robotic-assisted thoracic surgery extended thymectomy between January 2003 and February 2024. Patients were divided into 2 groups based on the thymoma size (5-cm threshold). RESULTS: The study comprised 114 patients (55.9%) in the small thymoma group and 90 patients (44.1%) in the large thymoma group. No significant differences were found between the groups regarding gender, age, proportion of elderly patients, or pathologic high-risk classifications. Apart from a longer operative time (P = .009) in the large thymoma group, no differences were observed between the 2 groups regarding surgical parameters and postoperative outcomes. No deaths occurred within 30 days in either group. During a median follow-up of 61.0 months (95% CI, 48.96-73.04), 4 patients experienced recurrence (1.96%). No significant differences in the 5-year overall survival (P = .25) or recurrence-free survival (P = .43) were observed between groups. CONCLUSIONS: Robotic-assisted thoracic surgery extended thymectomy is technically feasible, safe, and effective for treating large resectable thymomas. Moreover, midterm outcomes for patients with completely resected large thymomas were comparable to those with small thymomas during a median follow-up period of up to 5 years.

Genomic mutation patterns and prognostic value in de novo and secondary acute myeloid leukemia: A multicenter study from China.

Acute myeloid leukemia (AML) can manifest as de novo AML (dn-AML) or secondary AML (s-AML), with s-AML being associated with inferior survival and distinct genomic characteristics. The underlying reasons for this disparity remain to be elucidated. In this multicenter study, next-generation sequencing (NGS) was employed to investigate the mutational landscape of AML in 721 patients from June 2020 to May 2023.Genetic mutations were observed in 93.34% of the individuals, with complex variations (more than three gene mutations) present in 63.10% of them. TET2, ASXL1, DNMT3A, TP53 and SRSF2 mutations showed a higher prevalence among older individuals, whereas WT1 and KIT mutations were more commonly observed in younger patients. BCOR, BCORL1, ZRSR2, ASXL1 and SRSF2 exhibited higher mutation frequencies in males. Additionally, ASXL1, NRAS, PPMID, SRSF2, TP53 and U2AF1 mutations were more common in patients with s-AML, which PPM1D was more frequently associated with therapy-related AML (t-AML). Advanced age and hyperleukocytosis independently served as adverse prognostic factors for both types of AML; however, s-AML patients demonstrated a greater number of monogenic adverse prognostic factors compared to dn-AML cases (ASXL1, PPM1D, TP53 and U2AF1 in s-AML vs. FLT3, TP53 and U2AF1 in dn-AML). Age and sex-related gene mutations suggest epigenetic changes may be key in AML pathogenesis. The worse prognosis of s-AML compared to dn-AML could be due to the older age of s-AML patients and more poor-prognosis gene mutations. These findings could improve AML diagnosis and treatment by identifying potential therapeutic targets and risk stratification biomarkers.

[Clinical Analysis of Epstein-Barr Virus Infection after Allogeneic Hematopoietic Stem Cell Transplantation].

OBJECTIVE: To analyze the risk factors of Epstein-Barr virus (EBV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and its impact on survival. METHODS: The clinical data of 347 patients who underwent their first allo-HSCT in our hospital from January 2014 to June 2021 were retrospectively analyzed. Patients were divided into EBV (n =114) and Non-EBV (n =233) groups according to whether they were infected with EBV. The incidence of EBV infection after allo-HSCT was calculated, and the risk factors of EBV infection were analyzed. RESULTS: A total of 114(32.8%) patients presented EBV infection (all peripheral blood EBV-DNA were positive). EBV infection occurred in 88 patients within 100 days after transplantation, which accounted for 77.2% of all patients with EBV infection. 5 cases (1.44%) were confirmed as post-transplant lymphoproliferative disorder (PTLD). The median onset time of patients was 57(7-486) days after transplantation. Multivariate analysis showed that the use of ATG/ATG-F, occurrence of CMV viremia, and grade III-IV aGVHD were risk factors for EBV infection. Furthermore, compared to BUCY, the use of intensified preconditioning regimens containing FA/CA was significantly increased the risk of EBV infection. CONCLUSION: EBV infection is a common complication after allo-HSCT. Intensified preconditioning regimens, use of ATG/ATG-F, CMV viremia and grade III to IV aGVHD increase the risk of EBV infection after allo-HSCT.

Anaerobic ammonium oxidation coupled to iron(III) reduction catalyzed by a lithoautotrophic nitrate-reducing iron(II) oxidizing enrichment culture.

The last two decades have seen nitrogen/iron-transforming bacteria at the forefront of new biogeochemical discoveries, such as anaerobic ammonium oxidation coupled to ferric iron reduction (feammox) and lithoautotrophic nitrate-reducing ferrous iron-oxidation (NRFeOx). These emerging findings continue to expand our knowledge of the nitrogen/iron cycle in nature and also highlight the need to re-understand the functional traits of the microorganisms involved. Here, as a proof-of-principle, we report compelling evidence for the capability of an NRFeOx enrichment culture to catalyze the feammox process. Our results demonstrate that the NRFeOx culture predominantly oxidizes NH4+ to nitrogen gas, by reducing both chelated nitrilotriacetic acid (NTA)-Fe(III) and poorly soluble Fe(III)-bearing minerals (γ-FeOOH) at pH 4.0 and 8.0, respectively. In the NRFeOx culture, Fe(II)-oxidizing bacteria of Rhodanobacter and Fe(III)-reducing bacteria of unclassified_Acidobacteriota coexisted. Their relative abundances were dynamically regulated by the supplemented iron sources. Metagenomic analysis revealed that the NRFeOx culture contained a complete set of denitrifying genes along with hao genes for ammonium oxidation. Additionally, numerous genes encoding extracellular electron transport-associated proteins or their homologs were identified, which facilitated the reduction of extracellular iron by this culture. More broadly, this work lightens the unexplored potential of specific microbial groups in driving nitrogen transformation through multiple pathways and highlights the essential role of microbial iron metabolism in the integral biogeochemical nitrogen cycle.

Rapid identification of chemical components and screening of acetylcholinesterase inhibitors from Dalbergia odorifera based on mass defect and diagnostic ion filtering strategy, affinity ultrafiltration, and liquid chromatography-tandem mass spectrometry.

Dalbergia odorifera is a natural product rich in pharmacological ingredients, but the comprehensive characterization and rapid profiling of active components remain a challenge. Thus, an integrated data mining and identification strategy was exploited to efficiently identify the chemical constituents and screen acetylcholinesterase inhibitors (AChEIs) through affinity ultrafiltration and ultra-high-performance liquid chromatography-mass spectrometry (AUF-UHPLC-MS). As a result, polygonal mass defect filtering, diagnostic product ions, and neutral loss rules were created for rapid structural classification and component identification. A total of 140 flavonoids were tentatively characterized, including 41 isoflavonoids, 23 flavanones, 21 isoflavans, 19 flavones and flavonols, 13 neoflavonoids, 11 isoflavanones, seven flavone glycosides, and five chalcones. Subsequently, six natural AChEIs including tectorigenin, fisetin, dalbergin, pterostilbene, isoliquiritigenin, and biochanin A were screened out using AUF-UHPLC-MS and molecular docking. Meanwhile, the AChE inhibitory activities of the six compounds were assessed in vitro, tectorigenin, fisetinand, and dalbergin have moderate inhibitory activity. In conclusion, a novel strategy for systematic characterization and further screening of active compounds in natural products was established, which provides a material basis for quality control of Dalbergia odorifera.

High-Throughput Screening of All-d-Metal Heusler Alloys for Magnetocaloric Applications.

Due to their versatile composition and customizable properties, A2BC Heusler alloys have found applications in magnetic refrigeration, magnetic shape memory effects, permanent magnets, and spintronic devices. The discovery of all-d-metal Heusler alloys with improved mechanical properties compared to those containing main group elements presents an opportunity to engineer Heusler alloys for energy-related applications. Using high-throughput density-functional theory calculations, we screened magnetic all-d-metal Heusler compounds and identified 686 (meta)stable compounds. Our detailed analysis revealed that the inverse Heusler structure is preferred when the electronegativity difference between the A and B/C atoms is small, contrary to conventional Heusler alloys. Additionally, our calculations of Pugh ratios and Cauchy pressures demonstrated that ductile and metallic bonding are widespread in all-d-metal Heuslers, supporting their enhanced mechanical behavior. We identified 49 compounds with a double-well energy surface based on Bain path calculations and magnetic ground states, indicating their potential as candidates for magnetocaloric and shape memory applications. Furthermore, by calculating the free energies, we propose that 11 compounds exhibit structural phase transitions and suggest isostructural substitutions to enhance the magnetocaloric effect.

TAR RNA selective targeting ruthenium(II) complexes as HIV-1 reverse transcriptase inhibitors: On exploring structure-activity relationships of multiple positions.

HIV-1 reverse transcriptase (RT) inhibitors play a crucial role in the treatment of HIV by preventing the activity of the enzyme responsible for the replication of the virus. The HIV-1 Tat protein binds to transactivation response (TAR) RNA and recruits host factors to stimulate HIV-1 transcription. We have created a small library consisting of 4 × 6 polypyridyl Ru(II) complexes that selectively bind to TAR RNA, with targeting groups specific to HIV-1 TAR RNA. The molecule design was conducted by introducing hydroxyl or methoxy groups into an established potent TAR binder. The potential TAR binding ability was analysis from nature charge population and electrostatic potential by quantum chemistry calculations. Key modifications were found to be R1 and R3 groups. The most potent and selective TAR RNA binder was a3 with R1 = OH, R2 = H and R3 = Me. Through molecular recognition of hydrogen bonds and electrostatic attraction, they were able to firmly and selectively bind HIV-1 TAR RNA. Furthermore, they efficiently obstructed the contact between TAR RNA and Tat protein, and inhibited the reverse transcription activity of HIV-1 RT. The polypyridyl Ru(II) complexes were chemical and photo-stable, and sensitive and selective spectroscopic responses to TAR RNA. They exhibited little toxicity towards normal cells. Hence, this study might offer significant drug design approaches for researching AIDS and other illnesses associated with RT, including HCV, EBOV, and SARS-CoV-2. Moreover, it could contribute to fundamental research on the interactions of inorganic transition metal complexes with biomolecules.

Inhibitors of APE1 redox and ATM synergistically sensitize osteosarcoma cells to ionizing radiation by inducing ferroptosis.

The resistance of osteosarcoma (OS) to ionizing radiation (IR) is an obstacle for effective patient treatment. Apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/Ref-1) is a multifunctional protein with DNA repair and reduction/oxidation (redox) activities. We previously revealed the role of APE1 in OS radioresistance; however, whether the redox activity of APE1 is involved in OS radioresistance is unclear. APE1 regulates the activation of ataxia-telangiectasia mutated (ATM), an initiator of DNA damage response that mediates radioresistance in other cancers. The role of APE1 redox activity and ATM activation in OS radioresistance is unknown. Our study revealed that IR increased APE1 expression and ATM activation in OS cells, and APE1 directly regulated ATM activation by its redox activity. The combined use of an APE1 redox inhibitor and ATM inhibitor effectively sensitized OS cells to IR in vitro and in vivo. Mechanistically, the increased radiosensitization of OS cells by the combined use of the two inhibitors was mediated by increased ferroptosis. Co-treatment with the two inhibitors significantly decreased expression of the common targeted transcription factor P53 compared with single inhibitor treatment. Collectively, APE1 redox activity, ATM activation and their crosstalk play important roles in the resistance of OS to irradiation. Synergetic inhibition of APE1 redox activity and ATM activation sensitized OS cells to IR by inducing ferroptosis, which provides a promising strategy for OS radiotherapy.