Engeletin alleviates depressive-like behaviours by modulating microglial polarization via the LCN2/CXCL10 signalling pathway.

Microglial polarization and associated inflammatory activity are the key mediators of depression pathogenesis. The natural Smilax glabra rhizomilax derivative engeletin has been reported to exhibit robust anti-inflammatory activity, but no studies to date have examined the mechanisms through which it can treat depressive symptoms. We showed that treatment for 21 days with engeletin significantly alleviated depressive-like behaviours in chronic stress social defeat stress (CSDS) model mice. T1-weighted imaging (T1WI), T2-weighted imaging (T2WI) imaging revealed no significant differences between groups, but the bilateral prefrontal cortex of CSDS mice exhibited significant increases in apparent diffusion coefficient and T2 values relative to normal control mice, with a corresponding reduction in fractional anisotropy, while engeletin reversed all of these changes. CSDS resulted in higher levels of IL-1ß, IL-6, and TNF-a production, enhanced microglial activation, and greater M1 polarization with a concomitant decrease in M2 polarization in the mPFC, whereas engeletin treatment effectively abrogated these CSDS-related pathological changes. Engeletin was further found to suppress the LCN2/C-X-C motif chemokine ligand 10 (CXCL10) signalling axis such that adeno-associated virus-induced LCN2 overexpression ablated the antidepressant effects of engeletin and reversed its beneficial effects on the M1/M2 polarization of microglia. In conclusion, engeletin can alleviate CSDS-induced depressive-like behaviours by regulating the LCN2/CXCL10 pathway and thereby altering the polarization of microglia. These data suggest that the antidepressant effects of engeletin are correlated with the polarization of microglia, highlighting a potential avenue for future design of antidepressant strategies that specifically target the microglia.

SLMO2 is a potential prognostic and immunological biomarker in human pan-cancer.

SLMO2 is a lipid transporter that transports phosphatidylserine to the interior of mitochondria, also known as PRELID3B, which plays an important role in lipid metabolism. It has also been reported to be involved in the growth process of breast and lung tumors. However, its functions and underlying mechanisms in cancer progress remain elusive, and the potential as pan-cancer biomarker and therapeutic target remains unexplored. Using the TCGA project and GEO database, we performed pan-cancer analysis of SLMO2, which including the expression pattern, prognostic value, mutation landscape, methylation modification, protein-protein interaction network and the relationship between SLMO2 expression and immune infiltration. KEGG enrichment analysis was also performed to predict function and relevant cellular pathways of SLMO2. In addition, proliferation and migration assays were performed to detect the proliferation and metastasis capacity of breast cancer and lung cancer cells. In our study, we found that SLMO2 was overexpressed in pan-cancer and the elevated expression of SLMO2 was correlated with poorer prognosis. SLMO2 mutations were distributed in a variety of tumors and correlated with prognosis. Promoter methylation analysis showed that SLMO2 methylation levels were lower in most tumors compared with normal tissues, while a few tumors showed increased methylation levels of SLMO2. SLMO2 expression was also positively correlated with immune infiltration of MDSCs. Further pathway enrichment analysis indicated that SLMO2 was involved in regulating of cytoplasmic transport and other oncogenic processes. In vitro experiments have shown that SLMO2 promotes the proliferation and migration of breast cancer and lung cancer cells. In conclusion, our findings suggested that SLMO2 was a potential prognostic and immunological marker in pan-cancer. This study suggested a potential strategy for targeting SLMO2 to treat tumors, including manipulating tumor growth or the tumor microenvironment, especially the infiltration of MDSC.

Music-oriented auditory attention detection from electroencephalogram.

Music-oriented auditory attention detection (AAD) aims at determining which instrument in polyphonic music a listener is paying attention to by analyzing the listener's electroencephalogram (EEG). However, the existing linear models cannot effectively mimic the nonlinearity of the human brain, resulting in limited performance. Thus, a nonlinear music-oriented AAD model is proposed in this paper. Firstly, an auditory feature and a musical feature are fused to represent musical sources precisely and comprehensively. Secondly, the EEG is enhanced if music stimuli are presented in stereo. Thirdly, a neural network architecture is constructed to capture nonlinear and dynamic interactions between the EEG and auditory stimuli. Finally, the musical source most similar to the EEG in the common embedding space is identified as the attended one. Experimental results demonstrate that the proposed model outperforms all baseline models. On 1-s decision windows, it reaches accuracies of 92.6% and 81.7% under mono duo and trio stimuli, respectively. Additionally, it can be easily extended to speech-oriented AAD. This work can open up new possibilities for studies on both brain neural activity decoding and music information retrieval.

NSC-derived exosomes enhance therapeutic effects of NSC transplantation on cerebral ischemia in mice.

Transplantation of neural stem cells (NSCs) has been proved to promote functional rehabilitation of brain lesions including ischemic stroke. However, the therapeutic effects of NSC transplantation are limited by the low survival and differentiation rates of NSCs due to the harsh environment in the brain after ischemic stroke. Here, we employed NSCs derived from human induced pluripotent stem cells together with exosomes extracted from NSCs to treat cerebral ischemia induced by middle cerebral artery occlusion/reperfusion in mice. The results showed that NSC-derived exosomes significantly reduced the inflammatory response, alleviated oxidative stress after NSC transplantation, and facilitated NSCs differentiation in vivo. The combination of NSCs with exosomes ameliorated the injury of brain tissue including cerebral infarction, neuronal death, and glial scarring, and promoted the recovery of motor function. To explore the underlying mechanisms, we analyzed the miRNA profiles of NSC-derived exosomes and the potential downstream genes. Our study provided the rationale for the clinical application of NSC-derived exosomes as a supportive adjuvant for NSC transplantation after stroke.

Magnetic Targeting Nanocarriers Combined with Focusing Ultrasound for Enhanced Intracerebral Hemorrhage Therapy.

Intracerebral hemorrhage (ICH) remains a significant cause of morbidity and mortality around the world, and surgery is still the most direct and effective way to remove ICH. However, the potential risks brought by surgery, such as normal brain tissue damage, post-operative infection, and difficulty in removing deep hematoma, are still the main problems in the surgical treatment of ICH. Activation of the peroxisome proliferator-activated receptor gamma (PPARγ) is reported to show a good therapeutic effect in hematoma clearance. Herein, a magnetic targeting nanocarrier loaded with a PPARγ agonist (15d-PGJ2-MNPs) is synthesized, which could be magnetically targeted and enriched in the area of the hematoma after intravenous injection. Subsequent application of focusing ultrasound (FUS) could enhance drug diffusion, which activates the PPARγ receptors on macrophages around the hematoma for better hematoma clearance. The 15d-PGJ2-MNP treatment alleviates brain injury, accelerates hematoma clearance, attenuates neuroinflammation, reduces brain edema and significantly improves the deficits in sensory and motor function and spatial learning ability in the ICH mouse model. This work proposes an effective magnetic targeting plus FUS method to treat ICH, highlighting its great potential in the treatment of hemorrhagic stroke.

Effect of Phosphorus Content on Magnetic and Mechanical Properties of Non-Oriented Electrical Steel.

The effect of target phosphorus (P) content on the precipitates, microstructure, texture, magnetic properties, and mechanical properties of low-carbon (C) and low-silicon (Si) non-oriented electrical steel (NOES) was investigated and the influence mechanism was clarified. The results indicate that the precipitates in the steels are mainly aluminum (Al)-manganese (Mn)-Si-bearing complex nitrides ((Al,Si,Mn)xNy) and P-bearing complex nitrides ((Al,Si,Mn)xNy-P). Increasing target phosphorus content in the steels decreases (Al,Si,Mn)xNy, and increases (Al,Si,Mn)xNy-P. The number density of the precipitates is the lowest, and the average size of the precipitates and grain size of the finished steel is the largest in the samples with target P content at the 0.14% level (0.14%P-targeted). The average grain size and microstructure homogeneity of the steels are influenced by the addition of phosphorus. The content of the {111}<112> component decreases, and the favorable texture increases after phosphorus is added to the steel. The magnetic induction of the steel is improved. Grain refinement and microstructure inhomogeneity lead to an iron loss increase after target phosphorus content increases in the steel. The best magnetic induction B50 is 1.765 T in the 0.14%P-targeted samples. The tensile strength and yield strength are improved owing to solid solution strengthening and the grain refinement effect of phosphorus added to the steels.

Titanium Sulfide Nanosheets Serve as Cascade Bioreactors for H2 S-Mediated Programmed Gas-Sonodynamic Cancer Therapy.

Gas-mediated sonodynamic therapy (SDT) has the potential to become an effective strategy to improve the therapeutic outcome and survival rate of cancer patients. Herein, titanium sulfide nanosheets (TiSX NSs) are prepared as cascade bioreactors for sequential gas-sonodynamic cancer therapy. TiSX NSs themselves as hydrogen sulfide (H2 S) donors can burst release H2 S gas. Following H2 S generation, TiSX NSs are gradually degraded to become S-defective and partly oxidized into TiOX on their surface, which endows TiSX NSs with high sonodynamic properties under ultrasound (US) irradiation. In vitro and in vivo experiments show the excellent therapeutic effects of TiSX NSs. In detail, large amounts of H2 S gas and reactive oxygen species (ROS) can simultaneously inhibit mitochondrial respiration and ATP synthesis, leading to cancer cell apoptosis. Of note, H2 S gas also plays important roles in modulating and activating the immune system to effectively inhibit pulmonary metastasis. Finally, the metabolizable TiSX NSs are excreted out of the body without inducing any significant long-term toxicity. Collectively, this work establishes a cascade bioreactor of TiSX NSs with satisfactory H2 S release ability and excellent ROS generation properties under US irradiation for programmed gas-sonodynamic cancer therapy.

USP5 promotes breast cancer cell proliferation and metastasis by stabilizing HIF2α.

Hypoxia-inducible factor 2α (HIF2α) plays a pivotal role in breast tumor growth and metastasis. However, the regulatory mechanisms of HIF2α protein stability remain poorly understood. The precise role of the deubiquitinase (DUB) ubiquitin-specific peptidase 5 (USP5) in breast cancer and the underlying mechanism remains largely unknown. Here, we identified USP5 as a novel DUB for HIF2α. Physically, USP5 interacts with HIF2α and protects HIF2α from ubiquitin-proteasome degradation, thereby promoting the transcription of HIF2α target genes, such as SLC2A1, PLOD2, P4HA1, and VEGFA. USP5 ablation impairs breast cancer cells proliferation, colony formation, migration, and invasion. Moreover, USP5 is highly expressed in breast cancer, and the protein levels of USP5 are positively correlated with HIF2α protein levels in human breast cancer tissues. Importantly, high levels of USP5 leads to poor clinical outcome in patients with breast cancer. Collectively, USP5 stabilizes HIF2α through its DUB activity and provides a potential therapeutic target for breast cancer.

Micro Characterization of Hot-Rolled Plate of Nb-Bearing Grain-Oriented Silicon Steel.

In this study, niobium was added into grain-oriented silicon steels, four Nb-bearing hot-rolled bands with Nb content range from 0-0.025 wt% were prepared and a detailed study of the micro characterization (microstructure, texture and precipitates) of hot-rolled bands was carried out by various analysis methods, such as EBSD and TEM. The results indicate that the precipitates in Nb-free steel are MnS and AlN; however, in the Nb-bearing steel they are MnS, AlN and Nb(C, N). The precipitates are finer and more dispersed in Nb-bearing steel, and a stronger pining force was obtained, which contributes to the finer microstructure and less recrystallization fractions of the hot-rolled bands. A larger volume fraction and stronger intensity of Goss texture is presented in steel with 0.025 wt% Nb due to the effective inhibiting effect. However, it has little effect on the changes of microstructure and texture when the Nb content is more than 0.009 wt%.

c-Myc-activated intronic miR-210 and lncRNA MIR210HG synergistically promote the metastasis of gastric cancer.

The relationship between microRNA (miRNA) and hosting long non-coding RNA (lncRNA) remains unclear. Here, the expression levels of microRNA-210 (miR-210) and hosting lncRNA MIR210HG are significantly increased and positively correlated in gastric cancer (GC). Gain- and loss-of-function studies demonstrate that miR-210 and MIR210HG synergistically promote the migration and invasion of GC cells in vitro. Furthermore, GC sublines simultaneously expressing miR-210 and MIR210HG display synergistic promotion of lung metastasis in vivo. Mechanistically, MIR210HG interacts with DExH-box helicase 9 (DHX9) to increase DHX9/c-Jun complex's occupancy on the promoter of matrix metallopeptidases (MMPs), and thus promotes migration and invasion of GC cells. Additionally, miR-210 directly suppresses the expression of dopamine receptor D5 (DRD5), serine/threonine kinase 24 (STK24) and MAX network transcriptional repressor (MNT), resulting in enhanced migration and invasion. Finally, MYC proto-oncogene (c-Myc) transactivates miR-210 and MIR210HG. Overexpression of miR-210 or/and MIR210HG can rescue the inhibitory effect on the migration and invasion by silencing c-Myc. Moreover, c-Myc inhibitor significantly decreases lung metastasis of GC in vivo. Collectively, our findings identify a novel mechanism, by which c-Myc-activated miR-210 and MIR210HG synergistically promote the metastasis of GC.

Titanium carbide nanosheets with defect structure for photothermal-enhanced sonodynamic therapy.

Sonodynamic therapy (SDT) has attracted widespread interest in biomedicine, owing to its novel and noninvasive therapeutic method triggered by ultrasound (US). Herein, the Ti3C2 MXene nanosheets (Ti3C2 NSs) are developed as good sonosensitizers via a two-step method of chemical exfoliation and high-temperature treatment. With the high-temperature treatment, the oxygen defect of Ti3C2 MXene nanosheets (H-Ti3C2 NSs) is greatly increased. Therefore, the electron (e-) and hole (h+) generated by US can be separated faster due to the improved degree of oxidation, and then the recombination of e--h+ can be prevented with the abundant oxygen defect under US irradiation, which induced the sonodynamic efficiency greatly to improve around 3.7-fold compared with Ti3C2 NSs without high-temperature treatment. After PEGylation, the H-Ti3C2-PEG NSs show good stability and biocompatibility. In vitro studies exhibit that the inherent property of mild photothermal effect can promote the endocytosis of H-Ti3C2-PEG NSs, which can improve the SDT efficacy. In vivo studies further display that the increased blood supply by the mild photothermal effect can significantly relieve hypoxia in the tumor microenvironment, showing photothermal therapy (PTT) enhanced SDT. Most importantly, the H-Ti3C2-PEG NSs can be biodegraded and excreted out of the body, showing no significant long-term toxicity. Our work develops the defective H-Ti3C2 NSs as high-efficiency and safe sonosensitizers for photothermal-enhanced SDT of cancer, extending the biomedical application of MXene-based nanoplatforms.

PPP1R14B Is a Prognostic and Immunological Biomarker in Pan-Cancer.

Recent studies have shown that PPP1R14B was highly expressed in tumor tissues and patients with high expression of PPP1R14B had poor survival rates. However, the function and mechanisms of PPP1R14B in tumor progression remain ill defined. There was also lack of pan-cancer evidence for the relationship between PPP1R14B and various tumor types based on abundant clinical data. We used the TCGA project and GEO databases to perform pan-cancer analysis of PPP1R14B, including expression differences, correlations between expression levels and survival, genetic alteration, immune infiltration, and relevant cellular pathways, to investigate the functions and potential mechanisms of PPP1R14B in the pathogenesis or clinical prognosis of different cancers. Herein, we found that PPP1R14B was involved in the prognosis of pan-cancer and closely related to immune infiltration. Increased PPP1R14B expression correlated with poor prognosis and increased immune infiltration levels in myeloid-derived suppressor cells (MDSCs). Our studies suggest that PPP1R14B can be used as a prognostic biomarker for pan-cancer. Our findings may provide an antitumor strategy targeting PPP1R14B, including manipulation of tumor cell growth or the tumor microenvironment, especially myeloid-derived suppressor cell infiltration.

IL-27 signalling promotes adipocyte thermogenesis and energy expenditure.

Thermogenesis in brown and beige adipose tissue has important roles in maintaining body temperature and countering the development of metabolic disorders such as obesity and type 2 diabetes1,2. Although much is known about commitment and activation of brown and beige adipose tissue, its multiple and abundant immunological factors have not been well characterized3-6. Here we define a critical role of IL-27-IL-27Rα signalling in improving thermogenesis, protecting against diet-induced obesity and ameliorating insulin resistance. Mechanistic studies demonstrate that IL-27 directly targets adipocytes, activating p38 MAPK-PGC-1α signalling and stimulating the production of UCP1. Notably, therapeutic administration of IL-27 ameliorated metabolic morbidities in well-established mouse models of obesity. Consistently, individuals with obesity show significantly decreased levels of serum IL-27, which can be restored after bariatric surgery. Collectively, these findings show that IL-27 has an important role in orchestrating metabolic programs, and is a highly promising target for anti-obesity immunotherapy.

First report of Colletotrichum fioriniae causing anthracnose on mu oil tree in China.

Mu oil tree (Vernicia montana) is an economically important woody oil plant, which is widely distributed in southern China. In mid-May 2020, a leaf spot disease was observed on the leaves of mu oil tree in Taihe County in Jiangxi Province, China (26°55'25.55″N, 114°49'5.85″E). The disease incidence was estimated to be above 40%. Initial symptoms were circular red-brown spots which were 1-2 mm in diameter, then enlarged with red-brown center. In later stages, the spots coalesced and formed large patches, and subsequently red-brown centers of lesions gradually dried and fell out, forming a "shot hole" appearance. To identify the pathogen, diseased leaves were collected from Taihe County. Leaf tissues (5 × 5 mm) were cut from the margins of typical symptomatic lesions, surface- sterilized in 75% ethanol for 30 seconds and 3% sodium hypochlorite for 60 seconds, then rinsed with sterile distilled water three times. Leaf pieces were placed on potato dextrose agar (PDA; 1.5%, Difco-BD Diagnostics) and incubated at 25 °C in the dark. Pure cultures were obtained from individual conidia by recovering single spores. On PDA, colonies were initially white and cottony. The mycelia then became pinkish to deep-pink with time at the center on the front side and pink on the reverse side. Colonies produced pale orange conidial masses after 9 days. Conidia were fusiform with acute ends, smooth-walled, hyaline, and measured 3.6-5.5 × 8.1-14.5 µm (4.5 ± 0.5 × 10.6 ± 1.0 µm, n = 100). The morphological characteristics of the isolate matched the descriptions of Colletotrichum acutatum complex (Damm et al. 2012). For molecular identification, the internal transcribed spacer (ITS) region, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), chitin synthase (CHS-1), beta-tubulin 2 (TUB2), and actin (ACT) were sequenced using the primers ITS1/ITS4, GDF/GDR, CHS-79F/CHS-345R, T1/Bt2b, ACT-512F/ACT-783R, respectively (Weir et al. 2012). The obtained sequences were deposited into the GenBank [accession nos. MW584317 (ITS); MW656269 (GAPDH); MW656270 (TUB2); MW656268 (CHS-1); MW656267 (ACT)]. All the sequences showed 94 to 100% similarity with those of C. fioriniae. A neighbor-joining phylogenetic tree was generated by combining all the sequenced loci using MEGA7.0 (Kumar et al. 2016). The isolate TH-M4 clustered with C. fioriniae, having 99% bootstrap support. Base on the morphology and multi-gene phylogeny, isolate TH-M4 was identified as C. fioriniae (Damm et al. 2012). To confirm pathogenicity, 20 healthy leaves of 10 mu oil trees (3-year-old) grown outdoors were inoculated with a drop of spore suspension (106 conidia per mL) of the isolate TH-M4 in September 2020. Another 10 plants were inoculated with sterile water as the control. The leaves were wounded with a sterile toothpick. All the inoculated leaves were covered with black plastic bags to maintain humidity for 2 days. The pathogenicity test was repeated twice. The resulting symptoms were similar to those on the original infected plants, whereas the control leaves remained asymptomatic. The same fungus was re-isolated from the lesions on the inoculated plant, fulfilling Koch's postulates. C. fioriniae has been recorded as anthracnose pathogen on Mahonia aquifolium (Garibaldi et al. 2020), Paeonia lactiflora (Park et al. 2020), Solanum melongena (Xu et al. 2020), and Juglans regia (Varjas et al. 2020). To our knowledge, this is the first report of C. fioriniae associated with leaf spot disease on mu oil tree in China. This study provided crucial information for epidemiologic studies and appropriate control strategies for this oil plant disease.

CFTR is a negative regulator of γδ T cell IFN-γ production and antitumor immunity.

CFTR, a chloride channel and ion channel regulator studied mostly in epithelial cells, has been reported to participate in immune regulation and likely affect the risk of cancer development. However, little is known about the effects of CFTR on the differentiation and function of γδ T cells. In this study, we observed that CFTR was functionally expressed on the cell surface of γδ T cells. Genetic deletion and pharmacological inhibition of CFTR both increased IFN-γ release by peripheral γδ T cells and potentiated the cytolytic activity of these cells against tumor cells both in vitro and in vivo. Interestingly, the molecular mechanisms underlying the regulation of γδ T cell IFN-γ production by CFTR were either TCR dependent or related to Ca2+ influx. CFTR was recruited to TCR immunological synapses and attenuated Lck-P38 MAPK-c-Jun signaling. In addition, CFTR was found to modulate TCR-induced Ca2+ influx and membrane potential (Vm)-induced Ca2+ influx and subsequently regulate the calcineurin-NFATc1 signaling pathway in γδ T cells. Thus, CFTR serves as a negative regulator of IFN-γ production in γδ T cells and the function of these cells in antitumor immunity. Our investigation suggests that modification of the CFTR activity of γδ T cells may be a potential immunotherapeutic strategy for cancer.

The multifaceted functions of RNA helicases in the adaptive cellular response to hypoxia: From mechanisms to therapeutics.

Hypoxia is a hallmark of cancer. Hypoxia-inducible factor (HIF), a master player for sensing and adapting to hypoxia, profoundly influences genome instability, tumor progression and metastasis, metabolic reprogramming, and resistance to chemotherapies and radiotherapies. High levels and activity of HIF result in poor clinical outcomes in cancer patients. Thus, HIFs provide ideal therapeutic targets for cancers. However, HIF biology is sophisticated, and currently available HIF inhibitors have limited clinical utility owing to their low efficacy or side effects. RNA helicases, which are master players in cellular RNA metabolism, are usually highly expressed in tumors to meet the increased oncoprotein biosynthesis demand. Intriguingly, recent findings provide convincing evidence that RNA helicases are crucial for the adaptive cellular response to hypoxia via a mutual regulation with HIFs. More importantly, some RNA helicase inhibitors may suppress HIF signaling by blocking the translation of HIF-responsive genes. Therefore, RNA helicase inhibitors may work synergistically with HIF inhibitors in cancer to improve treatment efficacy. In this review, we discuss current knowledge of how cells sense and adapt to hypoxia through HIFs. However, our primary focus is on the multiple functions of RNA helicases in the adaptive response to hypoxia. We also highlight how these hypoxia-related RNA helicases can be exploited for anti-cancer therapeutics.

Influence of Nb Content on Precipitation, Grain Microstructure, Texture and Magnetic Properties of Grain-Oriented Silicon Steel.

The effects of Nb content on precipitation, microstructure, texture and magnetic properties of primary recrystallized grain-oriented silicon steel were investigated by various methods. The results show that the precipitates in primary recrystallized sheets are mainly MnS, Nb(C,N), composite precipitates of MnS and AlN, and composite precipitates of Nb(C,N) and AlN. Adding niobium could refine the primary recrystallized microstructure. The steel with 0.009 wt% Nb possesses the finest and the most dispersed precipitates, which contributes to the finest primary recrystallized microstructure due to the strong pinning force. Adding niobium is beneficial to obtain large volume fraction favorable texture for grain-oriented silicon steel, and the effect of Nb addition is not obvious when the content is higher than 0.009 wt%. After final annealing, the steel with 0.009 wt% Nb shows the best magnetic properties, B800 = 1.872 T, P1.7/50 = 1.25 W/kg.

Mechanism of pitting corrosion induced by inclusions in Al-Ti-Mg deoxidized high strength pipeline steel.

In order to reveal the mechanism of galvanic pitting corrosion initiation induced by typical complex inclusions in Al-Ti-Mg deoxidized high strength pipeline steel, first-principles calculations, combining with immersion tests, scanning electron microscopy was used to study the correlation between electronic work function and galvanic corrosion of Al-Ti-Mg killed steel. The results show that MnS inclusions act as anodes in the electrochemical environment, preferentially corroding and dissolving; MgAl2O4 and Al2O3 inclusions act as cathodes, leading to the corrosion of Fe matrix; different end planes of MgTiO3 and MgTi2O4 act as both anodes and cathodes, but they have little effect on pitting corrosion. Microcrevices on the MgTiO3 and MgTi2O4 inclusions boundary are the main cause of matrix dissolution.

Cell-cycle-dependent phosphorylation of RRM1 ensures efficient DNA replication and regulates cancer vulnerability to ATR inhibition.

Ribonucleotide reductase (RNR) catalyzes the rate-limiting step of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs) building blocks for DNA synthesis, and is a well-recognized target for cancer therapy. RNR is a heterotetramer consisting of two large RRM1 subunits and two small RRM2 subunits. RNR activity is greatly stimulated by transcriptional activation of RRM2 during S/G2 phase to ensure adequate dNTP supply for DNA replication. However, little is known about the cell-cycle-dependent regulation of RNR activity through RRM1. Here, we report that RRM1 is phosphorylated at Ser 559 by CDK2/cyclin A during S/G2 phase. And this S559 phosphorylation of RRM1enhances RNR enzymatic activity and is required for maintaining sufficient dNTPs during normal DNA replication. Defective RRM1 S559 phosphorylation causes DNA replication stress, double-strand break, and genomic instability. Moreover, combined targeting of RRM1 S559 phosphorylation and ATR triggers lethal replication stress and profound antitumor effects. Thus, this posttranslational phosphorylation of RRM1 provides an alternative mechanism to finely regulating RNR and therapeutic opportunities for cancer treatment.