Erratum: Author correction to 'FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis' [Acta Pharm Sin B 14 (2024) 1605-1623].

[This corrects the article DOI: 10.1016/j.apsb.2023.12.012.].

Bismuth Chelate-Mediated Digital Subtraction Angiography.

Digital subtraction angiography (DSA) is considered the "gold standard" for the diagnosis of vascular diseases. However, the contrast agents used in DSA are limited to iodine-based small molecules, which are unsuitable for patients with contraindications. Here, we propose iodine-free DSA utilizing a bismuth chelate, Bi-DTPA Dimeglumine, for vascular visualization for the first time. Bi-DTPA Dimeglumine possesses a simple synthesis process without the need for purification, large-scale production ability (over 200 g in the lab), superior X-ray imaging capability, renal clearance capacity, and good biocompatibility. Bi-DTPA-enhanced DSA can clearly display the arteries of the rabbit's head and lower limbs, with a minimum vascular resolution of 0.5 mm. The displayed integrity of terminal vessels by Bi-DTPA-enhanced DSA is superior to that of iopromide-enhanced DSA. In a rabbit model of thrombotic disease, Bi-DTPA Dimeglumine-enhanced DSA enables the detection of embolism and subsequent reevaluation of vascular conditions after recanalization therapy. Our proposed iodine-free DSA provides a promising and universal approach for diagnosing vascular diseases. This article is protected by copyright. All rights reserved.

Three sympatric host nestlings eavesdrop on cuckoo nestling distress calls.

In predator-prey interactions, the prey faces extreme challenges from predation, which drives the evolution of defense or anti-predator mechanisms. Compared with adult birds, nestlings are more vulnerable but not helpless. However, data on whether nestlings eavesdrop on the danger signals transmitted by other prey nestlings and the mechanisms of eavesdropping remain limited. In brood parasitism, common cuckoo (Cuculus canorus) nestlings, raised by host adults who are not closely related, offer an instructive system for studying the transmission and recognition of danger signals among nestlings of different species that share special relationships. We played back the distress calls of common cuckoo nestlings to nestlings of three sympatric host species (the oriental reed warbler Acrocephalus orientalis, which is a primary host of the common cuckoo, the reed parrotbill Paradoxornis heudei, an occasional host, and the vinous-throated parrotbill Sinosuthora webbiana, which is not parasitized in the study area) to investigate whether the host nestlings reduced their begging behavior. We also quantified the degree of inhibition toward begging behavior for these nestlings. The results revealed that, in response to the distress calls, the three sympatric host species markedly suppressed their begging behavior. This response can likely be attributed to the innate response of host nestlings caused by the general characteristics of distress calls, rather than the acoustic similarity and phylogenetic relationship between host nestlings and cuckoo nestlings. Furthermore, we observed that upon hearing the distress calls of cuckoo nestlings, the oriental reed warbler nestlings exhibited the greatest reduction in the total number of calls compared to the other two host species, potentially owing to stronger predation and parasitic pressures. This study suggests that host nestlings can detect danger signals emitted by parasitic nestlings; however, further investigation is needed to determine whether they can respond to distress calls from unfamiliar nestlings in different regions.

Targeting the smooth muscle cell KEAP1-Nrf2-STING axis with pterostilbene attenuates abdominal aortic aneurysm.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a life-threatening aortic disease, and to date, there are currently no effective pharmacological treatments to address this condition. Activation of cytosolic DNA sensing adaptor stimulator of interferon genes (STING) signaling is a crucial mechanism in AAA formation. PURPOSE: This study investigated pterostilbene (Pt), a naturally occurring polyphenol and resveratrol analogue, as a STING inhibitor for preventing AAA. METHODS: We evaluated the effect of Pt on AAA formation in angiotensin II (AngII)-infused apolipoprotein E-deficient (ApoE-/-) mice. We used histological analysis, MMP activity measurement, western blot, and immunohistochemistry to detect AAA formation and development. We applied RNA sequencing, molecular docking, cellular thermal shift assay (CETSA) and functional studies to dissect the molecular mechanism of Pt-regulating KEAP1-Nrf2-STING signaling. We conditionally knocked down Nrf2 in vascular smooth muscle cells (VSMCs) in vivo to investigate its role in Pt-mediated protective effects on AAA. RESULTS: Pt effectively blocked the formation of AAA in AngII-infused ApoE-/- mice. Whole transcriptome sequencing analysis revealed that nuclear factor erythroid 2-related factor 2 (Nrf2) and STING pathway in VSMCs were linked to the anti-AAA effects of pterostilbene. Mechanistically, Pt upregulated Nrf2 target genes (e.g., HO-1 and NQO1) through activation of the KEAP1/Nrf2 signaling, which restricted the immunostimulatory axis of mtDNA-STING-TBK1-NF-κB, thereby alleviating VSMC inflammation and preserving the VSMC contractile phenotype. Subsequently, molecular docking and CETSA revealed a binding mode between Pt and KEAP1/Nrf2. Intriguingly, the inhibitory effect of Pt on STING signaling and the protective role of Pt in AAA were largely abrogated by VSMC-specific Nrf2 knockdown in mice. CONCLUSION: Collectively, naturally derived Pt shows promising efficacy for the treatment of AAA by targeting the KEAP1-Nrf2-STING axis in VSMCs.

Petroleum ether extract of Schisandra sphenanthera prevents hyperglycemia and insulin resistance in association with modulation of sweet taste receptors and gut microbiota in T2DM rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra sphenanthera (Schisandra sphenanthera Rehd. et Wils.) is the dried mature fruit of Schisandra sphenanthera, a plant in the Magnoliaceae family. It was used in the treatment of diabetes mellitus in the Jade Fluid Decoction and the Xiaoke pills, which were recorded in ancient books. However, its mechanism of action in the treatment of type 2 diabetes mellitus (T2DM) was unclear and needs further study. AIM OF THE STUDY: This research aimed to investigate the chemical composition and lignan content of Schisandra sphenanthera petroleum ether parts (SPEP) and to evaluate the effects of SPEP on sweet taste receptors (STRs) and intestinal flora in rats on a high-fat diet (HFD). Additionally, the relationships between SPEP and hyperglycemia and insulin resistance were examined. MATERIALS AND METHODS: GC-MS was used to determine the chemical composition of SPEP, and HPLC was used to determine the lignin content. A combination of the HFD and the administration of streptozotocin (STZ) was employed to generate a rat model of T2DM. Petroleum ether extracts from Schisandra sphenanthera were used as the focus of the research to evaluate the effects of these extracts on the glucolipid metabolism of T2DM rats, as well as the underlying mechanisms. RESULTS: Analysis of the GC-MS spectrum of SESP revealed a total of 58 compounds. HPLC analysis revealed that SPEP had the highest concentration of Schisandrin A and the lowest concentration of Schisandrol A. The drug administration intervention resulted in a significant decrease in body weight and pancreatic weight of diabetic rats compared to the Normal group. When compared to the Model group, the body weight of rats in the drug administration group and the Metformin group had a more moderate decrease, while the pancreatic weight and pancreatic-to-body ratio increased. The Model group shown significant increases in FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, and NEFA, as well as significant decreases in HDL-C and SOD, when compared to the Normal group (P < 0.05). The administration of each group was found to be significantly effective in decreasing FBG, OGTT, GHb, TC, TG, LDL-C, ALT, AST, MDA, FINS, NEFA, while increasing HDL-C and SOD when compared to the Model group. The application of SPEP had a positive impact on hepatocyte swelling, hepatocyte degeneration, and necrosis, as well as the morphological structure of pancreatic islet cells. Furthermore, the protein expression levels of T1R2, TRPM5 and GLP-1 in the small intestine of the Model group were reduced. After a period of six weeks, the protein expression levels began to align more closely with those of the Normal group of rats. Analysis of 16S rRNA sequencing revealed that the intestinal microbiota of diabetic rats was significantly disrupted, with a decrease in the abundance of the Firmicutes phylum and an increase in the abundance of the Bacteroidetes phylum. Furthermore, the composition of the dominant genus was distinct from that of the control group. After the drug intervention, the microbiota of diabetic rats was significantly altered, exhibiting a higher abundance and diversity, as well as a significant enrichment of the community. The SPEP treatment resulted in a significant increase in acetic acid, propionic acid, and butyric acid. CONCLUSIONS: The findings of this research indicated that SPEP could be effective in treating T2DM through the regulation of STRs, the adjustment of disturbed metabolite levels, and the alteration of intestinal flora.

Multiple Synergistic Effects of the Microglia Membrane-Bionic Nanoplatform on Mediate Tumor Microenvironment Remodeling to Amplify Glioblastoma Immunotherapy.

Glioblastoma (GBM) is a lethal brain tumor with high levels of malignancy. Most chemotherapy agents show serious systemic cytotoxicity and restricted delivery effectiveness due to the impediments of the blood-brain barrier (BBB). Immunotherapy has developed great potential for aggressive tumor treatments. Disappointingly, its efficacy against GBM is hindered by the immunosuppressive tumor microenvironment (TME) and BBB. Herein, a multiple synergistic immunotherapeutic strategy against GBM was developed based on the nanomaterial-biology interaction. We have demonstrated that this BM@MnP-BSA-aPD-1 can transverse the BBB and target the TME, resulting in amplified synergetic effects of metalloimmunotherapy and photothermal immunotherapy (PTT). The journey of this nanoformulation within the TME contributed to the activation of the stimulator of the interferon gene pathway, the initiation of the immunogenic cell death effect, and the inhibition of the programmed cell death-1/programmed cell death ligand 1 (PD-1/PD-L1) signaling axis. This nanomedicine revitalizes the immunosuppressive TME and evokes the cascade effect of antitumor immunity. Therefore, the combination of BM@MnP-BSA-aPD-1 and PTT without chemotherapeutics presents favorable benefits in anti-GBM immunotherapy and exhibits immense potential for clinical translational applications.

Vascular endothelial cells-derived exosomes synergize with curcumin to prevent osteoporosis development.

Osteoporosis has gradually become a major public health problem. Further elucidation of the pathophysiological mechanisms that induce osteoporosis and identification of more effective therapeutic targets will have important clinical significance. Experiments in vitro on bone marrow stem cells (BMSCs) subjected to osteogenic and adipogenic differentiation and in vivo on surgical bilateral ovariectomy (OVX) mouse models revealed that exosomes of vascular endothelial cells (EC-EXOs) can promote osteogenic differentiation of BMSCs and inhibit BMSC adipogenic differentiation through miR-3p-975_4191. Both miR-3p-975_4191 and curcumin can target tumor necrosis factor (TNF) and act synergistically to regulate BMSCs fate differentiation and delay the progression of osteoporosis. Our findings suggest that EC-EXOs may exert a synergistic effect with curcumin in reversing the progression of osteoporosis by targeting TNF via miR-3p-975_4191. Our study may provide therapeutic options and potential therapeutic targets for osteoporosis and thus has important clinical implications.

Cytosolic DNA initiates a vicious circle of aging-related endothelial inflammation and mitochondrial dysfunction via STING: the inhibitory effect of Cilostazol.

Endothelial senescence, aging-related inflammation, and mitochondrial dysfunction are prominent features of vascular aging and contribute to the development of aging-associated vascular disease. Accumulating evidence indicates that DNA damage occurs in aging vascular cells, especially in endothelial cells (ECs). However, the mechanism of EC senescence has not been completely elucidated, and so far, there is no specific drug in the clinic to treat EC senescence and vascular aging. Here we show that various aging stimuli induce nuclear DNA and mitochondrial damage in ECs, thus facilitating the release of cytoplasmic free DNA (cfDNA), which activates the DNA-sensing adapter protein STING. STING activation led to a senescence-associated secretory phenotype (SASP), thereby releasing pro-aging cytokines and cfDNA to further exacerbate mitochondrial damage and EC senescence, thus forming a vicious circle, all of which can be suppressed by STING knockdown or inhibition. Using next-generation RNA sequencing, we demonstrate that STING activation stimulates, whereas STING inhibition disrupts pathways associated with cell senescence and SASP. In vivo studies unravel that endothelial-specific Sting deficiency alleviates aging-related endothelial inflammation and mitochondrial dysfunction and prevents the development of atherosclerosis in mice. By screening FDA-approved vasoprotective drugs, we identified Cilostazol as a new STING inhibitor that attenuates aging-related endothelial inflammation both in vitro and in vivo. We demonstrated that Cilostazol significantly inhibited STING translocation from the ER to the Golgi apparatus during STING activation by targeting S162 and S243 residues of STING. These results disclose the deleterious effects of a cfDNA-STING-SASP-cfDNA vicious circle on EC senescence and atherogenesis and suggest that the STING pathway is a promising therapeutic target for vascular aging-related diseases. A proposed model illustrates the central role of STING in mediating a vicious circle of cfDNA-STING-SASP-cfDNA to aggravate age-related endothelial inflammation and mitochondrial damage.

The effect of vitamin D status on the occurrence of Kawasaki Disease: a meta-analysis.

AIM: The relationship between vitamin D status and Kawasaki Disease (KD), as well as coronary artery lesion (CAL), has yet to be established. METHODS: A meta-analysis was conducted to assess the correlation between vitamin D status and KD, as well as the impact of vitamin D status on the progression of KD into CAL. RESULTS: The meta-analysis revealed a consistent and significant association between serum 25(OH)D level and the occurrence KD (studies N = 22; z = -3.51, P < 0.001). Patients with KD had markedly lower levels of vitamin D than healthy controls (SMD: -1.30 ng/mL, 95%CI: -2.05 to -0.55 ng/mL). CONCLUSION: The study provided evidence supporting a significant association between lower serum vitamin D levels and the occurrence of KD, particularly within the Chinese population. However, the findings did not suggest a direct impact of vitamin D on the development of CAL in KD patients.

Ultrasmall catechol-PEG-anchored ferrite nanoparticles for highly sensitive magnetic resonance angiography.

Highly sensitive iron oxide nanoparticles with stable, safe and efficient surface functionalization, as potential substitutes for gadolinium-based contrast agents (GBCAs) with increasing biosafety concerns, exhibit great potential for high-performance magnetic resonance angiography (MRA). Herein, we developed ultrasmall catechol-PEG-anchored ferrite nanoparticles (PEG-UMFNPs) for highly sensitive MRA. The obtained nanoprobe has a high T1 relaxivity value (7.2 mM-1 s-1) due to its ultrasmall size and Mn doping. It has a suitable hydrodynamic size of 20 nm, which prevents rapid vascular extravasation and renal clearance and prolongs its blood circulation time. In vivo MRA at 3.0 T using the nanoprobe shows that the arteries and veins of rats, even blood vessels as small as 0.32 mm, are distinctly visible, and the contrast enhancement can last for at least 1 h. In addition, due to the outstanding contrast enhancement and long circulation time, the stenosis and recanalization process of the rat's carotid artery can be continuously monitored with a single injection of the nanoprobe. Our study indicates that PEG-UMFNPs are outstanding MR imaging nanoprobes that can be used to diagnose vascular diseases without the biosafety issues of GBCAs.

Bispecific CAR T cell therapy targeting BCMA and CD19 in relapsed/refractory multiple myeloma: a phase I/II trial.

Despite the high therapeutic response achieved with B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapy in relapsed and refractory multiple myeloma (R/R MM), primary resistance and relapse exist with single-target immunotherapy. Here, we design bispecific BC19 CAR T cells targeting BCMA/CD19 and evaluate antimyeloma activity in vitro and in vivo. Preclinical results indicate that BC19 CAR specifically recognize target antigens, and BC19 CAR T cells mediate selective killing of BCMA or CD19-positive cancer cells. BC19 CAR T cells also exhibit potent antigen-specific anti-tumor activity in xenograft mouse models. We conduct an open-label, single-arm, phase I/II study of BC19 CAR T cells in 50 patients with R/R MM (ChiCTR2000033567). The primary endpoint was safety. BC19 CAR T cells are well tolerated with grade 3 or higher cytokine release syndrome in 8% of patients and grade 1 neurotoxic events in 4% of patients, which meet the pre-specified primary endpoint. Secondary endpoints include overall response rate (92%), median progression-free survival (19.7 months), median overall survival (19.7 months) and median duration of response (not reached). Our study demonstrates that bispecific BC19 CAR T cells are feasible, safe and effective in treating patients with R/R MM.

FGF4 protects the liver from immune-mediated injury by activating CaMKKß-PINK1 signal pathway to inhibit hepatocellular apoptosis.

Immune-mediated liver injury (ILI) is a condition where an aberrant immune response due to various triggers causes the destruction of hepatocytes. Fibroblast growth factor 4 (FGF4) was recently identified as a hepatoprotective cytokine; however, its role in ILI remains unclear. In patients with autoimmune hepatitis (type of ILI) and mouse models of concanavalin A (ConA)- or S-100-induced ILI, we observed a biphasic pattern in hepatic FGF4 expression, characterized by an initial increase followed by a return to basal levels. Hepatic FGF4 deficiency activated the mitochondria-associated intrinsic apoptotic pathway, aggravating hepatocellular apoptosis. This led to intrahepatic immune hyper-reactivity, inflammation accentuation, and subsequent liver injury in both ILI models. Conversely, administration of recombinant FGF4 reduced hepatocellular apoptosis and rectified immune imbalance, thereby mitigating liver damage. The beneficial effects of FGF4 were mediated by hepatocellular FGF receptor 4, which activated the Ca2+/calmodulin-dependent protein kinasekinase 2 (CaMKKß) and its downstream phosphatase and tensin homologue-induced putative kinase 1 (PINK1)-dependent B-cell lymphoma 2-like protein 1-isoform L (Bcl-XL) signalling axis in the mitochondria. Hence, FGF4 serves as an early response factor and plays a protective role against ILI, suggesting a therapeutic potential of FGF4 and its analogue for treating clinical immune disorder-related liver injuries.

Characterization of the powdery mildew resistance locus in wheat breeding line Jimai 809 and its breeding application.

Powdery mildew, caused by Blumeria graminis f. sp. tritici (Bgt), is a severe disease that affects the yield and quality of wheat. Popularization of resistant cultivars in production is the preferred strategy to control this disease. In the present study, the Chinese wheat breeding line Jimai 809 showed excellent agronomic performance and high resistance to powdery mildew at the whole growth stage. To dissect the genetic basis for this resistance, Jimai 809 was crossed with the susceptible wheat cultivar Junda 159 to produce segregation populations. Genetic analysis showed that a single dominant gene, temporarily designated PmJM809, conferred the resistance to different Bgt isolates. PmJM809 was then mapped on the chromosome arm 2BL and flanked by the markers CISSR02g-1 and CIT02g-13 with genetic distances 0.4 and 0.8 cM, respectively, corresponding to a physical interval of 704.12-708.24 Mb. PmJM809 differed from the reported Pm genes on chromosome arm 2BL in origin, resistance spectrum, physical position and/or genetic diversity of the mapping interval, also suggesting PmJM809 was located on a complex interval with multiple resistance genes. To analyze and screen the candidate gene(s) of PmJM809, six genes related to disease resistance in the candidate interval were evaluated their expression patterns using an additional set of wheat samples and time-course analysis post-inoculation of the Bgt isolate E09. As a result, four genes were speculated as the key candidate or regulatory genes. Considering its comprehensive agronomic traits and resistance findings, PmJM809 was expected to be a valuable gene resource in wheat disease resistance breeding. To efficiently transfer PmJM809 into different genetic backgrounds, 13 of 19 closely linked markers were confirmed to be suitable for marker-assisted selection. Using these markers, a series of wheat breeding lines with harmonious disease resistance and agronomic performance were selected from the crosses of Jimai 809 and several susceptible cultivars. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01467-8.

The cytoplasmic sensor, the AIM2 inflammasome: A precise therapeutic target in vascular and metabolic diseases.

Cardio-cerebrovascular diseases encompass pathological changes in the heart, brain and vascular system, which pose a great threat to health and well-being worldwide. Moreover, metabolic diseases contribute to and exacerbate the impact of vascular diseases. Inflammation is a complex process that protects against noxious stimuli but is also dysregulated in numerous so-called inflammatory diseases, one of which is atherosclerosis. Inflammation involves multiple organ systems and a complex cascade of molecular and cellular events. Numerous studies have shown that inflammation plays a vital role in cardio-cerebrovascular diseases and metabolic diseases. The absent in melanoma 2 (AIM2) inflammasome detects and is subsequently activated by double-stranded DNA in damaged cells and pathogens. With the assistance of the mature effector molecule caspase-1, the AIM2 inflammasome performs crucial biological functions that underpin its involvement in cardio-cerebrovascular diseases and related metabolic diseases: The production of interleukin-1 beta (IL-1ß), interleukin-18 (IL-18) and N-terminal pore-forming Gasdermin D fragment (GSDMD-N) mediates a series of inflammatory responses and programmed cell death (pyroptosis and PANoptosis). Currently, several agents have been reported to inhibit the activity of the AIM2 inflammasome and have the potential to be evaluated for use in clinical settings. In this review, we systemically elucidate the assembly, biological functions, regulation and mechanisms of the AIM2 inflammasome in cardio-cerebrovascular diseases and related metabolic diseases and outline the inhibitory agents of the AIM2 inflammasome as potential therapeutic drugs.

YY1 Contributes to the Inflammatory Responses of Mycobacterium tuberculosis-Infected Macrophages Through Transcription Activation-Mediated Upregulation TLR4.

Tuberculosis (TB) is a chronic respiratory infectious disease and is induced by Mycobacterium tuberculosis (M.tb) infection. Macrophages serve as the cellular home in immunoreaction against M.tb infection, which is tightly regulated through Toll-like receptor 4 (TLR4) expression. Therefore, this study is designed to explore the role and mechanism of TLR4 in mycobacterial injury in human macrophages (THP-1 cells) after M.tb infection. Cell proliferation and apoptosis were assessed using MTT, EdU, and flow cytometry assays. ELISA kits were utilized to assess the levels of Interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor α (TNF-α). The binding between Yin-Yang-1 (YY1) and TLR4 promoter was predicted by JASPAR and verified using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. M.tb infection might repress THP-1 cell proliferation, and induce cell apoptosis and inflammatory response in a multiplicity of infection (MOI)-dependent manner. Moreover, M.tb infection increased the expression of TLR4 in HTP-1 cells in an MOI-dependent way, and its downregulation might overturn M.tb infection-mediated HTP-1 cell damage and inflammatory response. At the molecular level, YY1 was a transcription factor of TLR4 and promoted TLR4 transcription via binding to its promoter region. Besides, YY1 might activate the NF-kB signaling pathway via regulating TLR4. Meanwhile, TLR4 inhibitor BAY11-7082 might overturn the repression effect of TLR4 on M.tb-infected HTP-1 cell damage. YY1-activated TLR4 might aggravate mycobacterial injury in human macrophages after M.tb infection by the NF-kB pathway, providing a promising therapeutic target for TB treatment.

Mechanism of AGT-Mediated Repair of dG-dC Cross-Links in the Drug Resistance to Chloroethylnitrosoureas: Molecular Docking, MD Simulation, and ONIOM (QM/MM) Investigation.

Chloroethylnitrosoureas (CENUs) are important chemotherapies applied in the treatment of cancer. They exert anticancer activity by inducing DNA interstrand cross-links (ICLs) via the formation of two O6-alkylguanine intermediates, O6-chloroethylguanine (O6-ClEtG) and N1,O6-ethanoguanine (N1,O6-EtG). However, O6-alkylguanine-DNA alkyltransferase (AGT), a DNA-repair enzyme, can restore the O6-alkylguanine damages and thereby obstruct the formation of ICLs (dG-dC cross-link). In this study, the inhibitory mechanism of ICL formation was investigated to elucidate the drug resistance of CENUs mediated by AGT in detail. Based on the structures of the substrate-enzyme complexes obtained from docking and MD simulations, two ONIOM (QM/MM) models with different sizes of the QM region were constructed. The model with a larger QM region, which included the substrate (O6-ClEtG or N1,O6-EtG), a water molecule, and five residues (Tyr114, Cys145, His146, Lys165, and Glu172) in the active pocket of AGT, accurately described the repairing reaction and generated the results coinciding with the experimental outcomes. The repair process consists of two sequential steps: hydrogen transfer to form a thiolate anion on Cys145 and alkyl transfer from the O6 site of guanine (the rate-limiting step). The repair of N1,O6-EtG was more favorable than that of O6-ClEtG from both kinetics and thermodynamics aspects. Moreover, the comparison of the repairing process with the formation of dG-dC cross-link and the inhibition of AGT by O6-benzylguanine (O6-BG) showed that the presence of AGT could effectively interrupt the formation of ICLs leading to drug resistance, and the inhibition of AGT by O6-BG that was energetically more favorable than the repair of O6-ClEtG could not prevent the repair of N1,O6-EtG. Therefore, it is necessary to completely eliminate AGT activity before CENUs medication to enhance the chemotherapeutic effectiveness. This work provides reasonable explanations for the supposed mechanism of AGT-mediated drug resistance of CENUs and will assist in the development of novel CENU chemotherapies and their medication strategies.

Characterization of tomato autophagy-related SlCOST family genes.

Autophagy is a eukaryote-specific cellular process that can engulf unwanted targets with double-membrane autophagosomes and subject them to the vacuole or lysosome for breaking down and recycling, playing dual roles in plant growth and environmental adaptions. However, perception of specific environmental signals for autophagy induction is largely unknown, limiting its application in agricultural usage. Identification of plant-unique DUF641 family COST1 (Constitutively Stressed 1) protein directly links drought perception and autophagy induction, shedding light on manipulating autophagy for breeding stress tolerant crops. In this study, we performed a genome-wide analysis of DUF641/COST family in tomato, and identified five SlCOST genes SlCOST1, -2, -3, -4, and -5. SlCOST genes show both overlapping and distinct expression patterns in plant growth and stress responding. In addition, SlCOST1, -3, -4, -5 proteins demonstrate co-localization with autophagy adaptor protein ATG8e, and all five SlCOST proteins show interactions ATG8e in planta. However, only SlCOST1, the closest ortholog of Arabidopsis AtCOST1, can restore cost1 mutant to WT level, suggesting conserved role of COST1 and functional diversification of SlCOST family in tomato. Our study provides clues for future investigation of autophagy-related COST family and its promising implementations in breeding crops with robust environmental plasticity.

Evaluation and identification of powdery mildew-resistant genes in 137 wheat relatives.

Powdery mildew is one of the most severe diseases affecting wheat yield and quality and is caused by Blumeria graminis f. sp. tritici (Bgt). Host resistance is the preferred strategy to prevent this disease. However, the narrow genetic basis of common wheat has increased the demand for diversified germplasm resources against powdery mildew. Wheat relatives, especially the secondary gene pool of common wheat, are important gene donors in the genetic improvement of common wheat because of its abundant genetic variation and close kinship with wheat. In this study, a series of 137 wheat relatives, including 53 Triticum monococcum L. (2n = 2x = 14, AA), 6 T. urartu Thumanjan ex Gandilyan (2n = 2x = 14, AA), 9 T. timopheevii Zhuk. (2n = 4x = 28, AAGG), 66 T. aestivum subsp. spelta (2n = 6x = 42, AABBDD), and 3 Aegilops speltoides (2n = 2x = 14, SS) were systematically evaluated for their powdery mildew resistance and composition of Pm genes. Out of 137 (60.58%) accessions, 83 were resistant to Bgt isolate E09 at the seedling stage, and 116 of 137 (84.67%) wheat relatives were resistant to the mixture of Bgt isolates at the adult stage. This indicates that these accessions show a high level of resistance to powdery mildew. Some 31 markers for 23 known Pm genes were used to test these 137 accessions, and, in the results, only Pm2, Pm4, Pm6, Pm58, and Pm68 were detected. Among them, three Pm4 alleles (Pm4a, Pm4b, and Pm4f) were identified in 4 T. subsp. spelta accessions. q-RT PCR further confirmed that Pm4 alleles played a role in disease resistance in these four accessions. The phylogenetic tree showed that the kinship of Pm4 was close to Pm24 and Sr62. This study not only provides reference information and valuable germplasm resources for breeding new wheat varieties with disease resistance but also lays a foundation for enriching the genetic basis of wheat resistance to powdery mildew.

The relationship between cumulative ecological risk and health risk behaviors among Chinese adolescents.

OBJECTIVES: To explore the relationship between cumulative ecological risk and individual risky behavior and multiple forms of aggregated behaviors among adolescents, and examine the gender differences. METHODS: A large-scale, nationally representative, and students-based investigation was conducted in rural and urban areas of eight provinces in China from October to December 2021. A total of 22 868 adolescents with an average age of 14.64 years completely standardized questionnaire in which the sociodemographic characteristics, socio-ecological risk factors and risky behaviors were used to analyze. RESULTS: Of included students, 48.4% encountered the high level of social-ecological risk. The prevalence of breakfast intake not daily, alcohol use (AU), smoking, physical inactivity, prolonged screen time (ST) on weekdays and weekends, suicidal ideation, suicidal plan, suicidal attempt, and non-suicidal self-injury (NSSI) was 41.0%, 11.9%, 3.4%, 61.9%, 15.1%, 51.1%, 27.7%, 13.9%, 6.5% and 27.0% respectively. 22.2% of participants engaged in high-risk behaviors. All were significantly influences of increased cumulative ecological risk on individual behavior and low-risk clustering behaviors separately. The odds ratio of breakfast intake not daily, AU, smoking, physical inactivity, prolonged ST in weekday and weekend, suicidal ideation, suicidal plan, suicidal attempt, and NSSI for the adjusted model in low versus high level of cumulative ecological risk was respectively significant in both boy and girls, and the ratio of odds ratios (ROR) was separately 0.95 (p = 0.228), 0.67 (p < 0.001), 0.44 (p < 0.001), 0.60 (p < 0.001), 0.78 (p = 0.001), 0.83 (p = 0.001), 0.80 (p = 0.001), 0.83 (p = 0.022), 0.71 (p = 0.005), 0.75 (p = 0.001). Girls encountering a high level of cumulative ecological risk were more likely to engage in multiple forms of clustering risky behaviors than boys (RORs: 0.77, p = 0.001). CONCLUSIONS: Research and effective inventions at the social-ecological environment, based on the view of cumulative risk, are needed to promote the healthy development of behaviors in adolescence, and pay more attention to decreasing the occurrence of risky behaviours in girls than boys.