Multi-Omics profiling identifies aldehyde dehydrogenase 2 as a critical mediator in the crosstalk between Treg-mediated immunosuppression microenvironment and hepatocellular carcinoma.

Dysregulation of the aldehyde dehydrogenase (ALDH) family has been implicated in various pathological conditions, including cancer. However, a systematic evaluation of ALDH alterations and their therapeutic relevance in hepatocellular carcinoma (HCC) remains lacking. Herein, we found that 15 of 19 ALDHs were transcriptionally dysregulated in HCC tissues compared to normal liver tissues. A four gene signature, including ALDH2, ALDH5A1, ALDH6A1, and ALDH8A1, robustly predicted prognosis and defined a high-risk subgroup exhibiting immunosuppressive features like regulatory T cell (Tregs) infiltration. Single-cell profiling revealed selective overexpression of tumor necrosis factor receptor superfamily member 18 (TNFRSF18) on Tregs, upregulated in high-risk HCC patients. We identified ALDH2 as a tumor suppressor in HCC, with three novel phosphorylation sites mediated by protein kinase C zeta that enhanced enzymatic activity. Mechanistically, ALDH2 suppressed Tregs differentiation by inhibiting ß-catenin/TGF-ß1 signaling in HCC. Collectively, our integrated multi-omics analysis defines an ALDH-Tregs-TNFRSF18 axis that contributes to HCC pathogenesis and represents potential therapeutic targets for this aggressive malignancy.

Inhibition of NLRP3 inflammasome by MCC950 under hypoxia alleviates photoreceptor apoptosis via inducing autophagy in Müller glia.

NLRP3 inflammasome activation has emerged as a critical initiator of inflammatory response in ischemic retinopathy. Here, we identified the effect of a potent, selective NLRP3 inhibitor, MCC950, on autophagy and apoptosis under hypoxia. Neonatal mice were exposed to hyperoxia for 5 days to establish oxygen-induced retinopathy (OIR) model. Intravitreal injection of MCC950 was given, and then autophagy and apoptosis markers were assessed. Retinal autophagy, apoptosis, and related pathways were evaluated by western blot, immunofluorescent labeling, transmission electron microscopy, and TUNEL assay. Autophagic activity in Müller glia after NLRP3 inflammasome inhibition, together with its influence on photoreceptor death, was studied using western blot, immunofluorescence staining, mRFP-GFP-LC3 adenovirus transfection, cell viability, proliferation, and apoptosis assays. Results showed that activation of NLRP3 inflammasome in Müller glia was detected in OIR model. MCC950 could improve impaired retinal autophagic flux and attenuate retinal apoptosis while it regulated the retinal AMPK/mTOR/ULK-1 pathway. Suppressed autophagy and depressed proliferation capacity resulting from hypoxia was promoted after MCC950 treatment in Müller glia. Inhibition of AMPK and ULK-1 pathway significantly interfered with the MCC950-induced autophagy activity, indicating MCC950 positively modulated autophagy through AMPK/mTOR/ULK-1 pathway in Müller cells. Furthermore, blockage of autophagy in Müller glia significantly induced apoptosis in the cocultured 661W photoreceptor cells, whereas MCC950 markedly preserved the density of photoreceptor cells. These findings substantiated the therapeutic potential of MCC950 against impaired autophagy and subsequent apoptosis under hypoxia. Such protective effect might involve the modulation of AMPK/mTOR/ULK-1 pathway. Targeting NLRP3 inflammasome in Müller glia could be beneficial for photoreceptor survival under hypoxic conditions.

Recoverable and degradable carboxymethyl chitosan polyelectrolyte hydrogel film for ultra stable encapsulation of curcumin.

Hydrogels have shown great potential for application in food science due to their diverse functionalities. However, most hydrogels inevitably contain toxic chemical cross-linking agent residues, posing serious food safety concerns. In this paper, a curcumin/sodium alginate/carboxymethyl chitosan hydrogels (CSCH) were prepared by self-assembly of two oppositely charged polysaccharides, carboxymethyl chitosan and sodium alginate, to form a three-dimensional network encapsulating curcumin for extending food shelf life. The network structure of the CSCH film confirmed by FTIR, XRD, and XPS was mainly formed by electrostatic interactions. The chemical stability of CSCH network encapsulated curcumin was 4.2 times greater than that of free curcumin, with excellent gas barrier, antimicrobial, antioxidant, and biosafety properties. It was found that CSCH films reduced dehydration, prevented nutrient loss, inhibited microbial growth, and lowered the respiration rate, which effectively maintained the quality of mango and prolonged its shelf-life up to 11 days. Notably, CSCH films possessed the properties of rapid recycling (10 mins) and biodegradability (53 days). This polysaccharide-based hydrogel film provides a viable strategy for the development of green and sustainable food packaging.

YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both in vivo and in vitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis.

DePARylation is critical for S phase progression and cell survival.

Poly(ADP-ribose)ylation or PARylation by PAR polymerase 1 (PARP1) and dePARylation by poly(ADP-ribose) glycohydrolase (PARG) are equally important for the dynamic regulation of DNA damage response. PARG, the most active dePARylation enzyme, is recruited to sites of DNA damage via pADPr-dependent and PCNA-dependent mechanisms. Targeting dePARylation is considered an alternative strategy to overcome PARP inhibitor resistance. However, precisely how dePARylation functions in normal unperturbed cells remains elusive. To address this challenge, we conducted multiple CRISPR screens and revealed that dePARylation of S phase pADPr by PARG is essential for cell viability. Loss of dePARylation activity initially induced S-phase-specific pADPr signaling, which resulted from unligated Okazaki fragments and eventually led to uncontrolled pADPr accumulation and PARP1/2-dependent cytotoxicity. Moreover, we demonstrated that proteins involved in Okazaki fragment ligation and/or base excision repair regulate pADPr signaling and cell death induced by PARG inhibition. In addition, we determined that PARG expression is critical for cellular sensitivity to PARG inhibition. Additionally, we revealed that PARG is essential for cell survival by suppressing pADPr. Collectively, our data not only identify an essential role for PARG in normal proliferating cells but also provide a potential biomarker for the further development of PARG inhibitors in cancer therapy.

[Relationship between gut microbiome and neurodevelopment in early life].

OBJECTIVE: To compare the differences in gut microbiome composition between children with good neurodevelopment and those with delayed neurodevelopment, and to analyze the relationship between gut microbiome and the neurodevelopment status of infants in early life. METHODS: The mothers were included at the Second West China Hospital from November 2020 to April 2021. Their infant stools were collected on day 0 and day 90 after birth, and the follow-up questionnaires at the corresponding time points were completed. Additionally, the Ages and Stages Questionnaires-Third Edition(ASQ-3) were completed by mothers at 12 months of age. The structure and diversity of gut microbiota were examined by 16S rRNA sequencing, and the relationship between gut microbiome and ASQ-3 questionnaire scores in early life was analyzed. RESULTS: According to the ASQ-3 scores, mothers and infants into neurodevelopment good group(G group, n=18) and neurodevelopmental delay group(D group, n=10). Compared with the D group, the relative abundance of the Firmicutes was significantly higher in the G group at day 0(P<0.05), while the level of the Proteobacteria was lower(P<0.05). At day 90 after birth, the relative abundance of the Actinobacteria, Bifidobacteriaceae and Enterococcaceae was significantly higher in the G group(P<0.05). In addition, alpha diversity was not statistically different between the two groups. Spearman's correlation analysis showed that Clostridiaceae of the postnatal day 0 infants was positively correlated with the communication domain score, but negatively associated with gross motor domain score in children at 12 months of age, whereas the relative abundance of Proteobacteria and Enterobacteriaceae of children at postnatal day 90 was negatively associated with communication development, while the relative abundance of Erysipelatoclostridiaceae showed a negative correlation with gross motor domain scores. CONCLUSION: The structure of the gut microbiome in early life between neurodevelopment good and delayed infants, and were associated with the development of communication and gross motor domain in infants at 12 months of age, suggesting that gut microbiome in early life may be related to the level of neurodevelopment in infants.

The potential up-regulation risk of 3' UTR SNP (rs10787760 G > A) for the VAX1 gene is associated with NSCLP in the northwest Chinese population.

AIMS: To investigate the association between single nucleotide polymorphisms (SNPs) in 3'UTR region of VAX1, SYT14 and PAX7 genes and the risk of non-syndromic cleft palate (NSCLP) in a northwest Chinese population. MAIN METHODS: A case-control study was conducted in 406 normal controls and 399 NSCLP patients. Using iMLDRTM genotyping technology, eight SNPs of three genes ((rs10787760, rs7086344 at VAX1), (rs1010113, rs851114, and rs485874 at PAX7), and (rs61820397, rs4609425, rs12133399 at SYT14)) were genotyped to investigate the differences in alleles and genotype distribution frequencies between NSCLP patients and healthy controls. RNA Folding Form software was used to predict RNA secondary structure and expression vectors were constructed to explore the function of the relevant SNP. The effect of SNP polymorphism of gene transcription and translation was assessed using qPCR and Western blot analysis. KEY FINDINGS: Among the eight SNPs of three genes, rs10787760 of VAX1 gene was found to be associated with an increased risk of NSCLP (OR = 1.341, CI = 1.004-1.790) and the GA genotype of rs10787760 increased the risk of cleft lip and/or palate (CL/P) about 1.42 times (p < 0.05), and carrying the A allele might increase the risk of NSCL/P in male (OR = 1.356, 95 % CI = 1.010-1.823). But there was no association observed with cleft palate only (CPO). Cell function experiments revealed that the G to A mutation in rs10787760 up-regulated GFP-VAX1 transcriptional level by 2.39 and 3.13 times in two cell lines respectively, and enhance the protein expression of the VAX1 gene further. RNA secondary structure study showed that the rs10787760 (G > A) had two different secondary structures in 3'UTR region. SIGNIFICANCE: The rs10787760 variant in the 3'UTR region of VAX1 gene is associated with CL/P in northwest Chinese population. We hypothesize that the machanism of it might be caused by the RNA differenct fold in the 3'UTR region caused by the polymorphism of the gene. LEVEL OF EVIDENCE: Original Reports.

Research on the function of CsMYB36 based on an effective hair root transformation system.

The hairy root induction system was used to efficiently investigate gene expression and function in plant root. Cucumber is a significant vegetable crop worldwide, with shallow roots, few lateral roots, and weak root systems, resulting in low nutrient absorption and utilization efficiency. Identifying essential genes related to root development and nutrient absorption is an effective way to improve the growth and development of cucumbers. However, genetic mechanisms underlying cucumber root development have not been explored. Here, we report a novel, rapid, effective hairy root transformation system. Compared to the in vitro cotyledon transformation method, this method shortened the time needed to obtain transgenic roots by 13 days. Furthermore, we combined this root transformation method with CRISPR/Cas9 technology and validated our system by exploring the expression and function of CsMYB36, a pivotal gene associated with root development and nutrient uptake. The hairy root transformation system established in this study provides a powerful method for rapidly identifying essential genes related to root development in cucumber and other horticultural crop species. This advancement holds promise for expediting research on root biology and molecular breeding strategies, contributing to the broader understanding and improvements crop growth and development.

Judging robot ability: How people form implicit and explicit impressions of robot competence.

Robots' proliferation throughout society offers many opportunities and conveniences. However, our ability to effectively employ these machines relies heavily on our perceptions of their competence. In six studies (N = 2,660), participants played a competitive game with a robot to learn about its capabilities. After the learning experience, we measured explicit and implicit competence impressions to investigate how they reflected the learning experience. We observed two distinct dissociations between people's implicit and explicit competence impressions. Firstly, explicit impressions were uniquely sensitive to oddball behaviors. Implicit impressions only incorporated unexpected behaviors when they were moderately prevalent. Secondly, after forming a strong initial impression, explicit, but not implicit, impression updating demonstrated a positivity bias (i.e., an overvaluation of competence information). These findings suggest that the same learning experience with a robot is expressed differently at the implicit versus explicit level. We discuss implications from a social cognitive perspective, and how this work may inform emerging work on psychology toward robots. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

New Carbon Materials for Multifunctional Soft Electronics.

Soft electronics are garnering significant attention due to their wide-ranging applications in artificial skin, health monitoring, human-machine interaction, artificial intelligence, and the Internet of Things. Various soft physical sensors such as mechanical sensors, temperature sensors, and humidity sensors are the fundamental building blocks for soft electronics. While the fast growth and widespread utilization of electronic devices have elevated life quality, the consequential electromagnetic interference (EMI) and radiation pose potential threats to device precision and human health. Another substantial concern pertains to overheating issues that occur during prolonged operation. Therefore, the design of multifunctional soft electronics exhibiting excellent capabilities in sensing, EMI shielding, and thermal management is of paramount importance. Because of the prominent advantages in chemical stability, electrical and thermal conductivity, and easy functionalization, new carbon materials including carbon nanotubes, graphene and its derivatives, graphdiyne, and sustainable natural-biomass-derived carbon are particularly promising candidates for multifunctional soft electronics. This review summarizes the latest advancements in multifunctional soft electronics based on new carbon materials across a range of performance aspects, mainly focusing on the structure or composite design, and fabrication method on the physical signals monitoring, EMI shielding, and thermal management. Furthermore, the device integration strategies and corresponding intriguing applications are highlighted. Finally, this review presents prospects aimed at overcoming current barriers and advancing the development of state-of-the-art multifunctional soft electronics.

Childhood maltreatment and suicidal ideation among Chinese adolescents: Moderated mediation effect of perceived social support and maladaptive cognitive emotion regulation strategies.

BACKGROUND: Although previous studies have shown that childhood maltreatment is a risk factor for adolescent suicidal ideation, less is known about the mediating and moderating mechanisms underlying this association. OBJECTIVE: The current study aimed to investigate the relationship between childhood maltreatment and suicidal ideation among adolescents, as well as the mediating role of maladaptive cognitive emotion regulation strategies (maladaptive CERSs) and the moderating role of perceived social support. METHODS: In a cross-sectional design, 4005 adolescents (Mage = 14.24 years, SD = 1.53; 49.0 % males) completed self-report questionnaires regarding childhood maltreatment, maladaptive CERSs, perceived social support and suicidal ideation, along with their basic information. RESULTS: After controlling for gender, family location, family structure, and depression, childhood maltreatment was positively related to adolescent suicidal ideation, and maladaptive CERSs were found to mediate this association. Moderated mediation analyses revealed that perceived social support buffered the associations between maladaptive CERSs and adolescent suicidal ideation. CONCLUSIONS: The findings assist in understanding the mechanisms of maladaptive CERSs and perceived social support in the relationship between childhood maltreatment and suicidal ideation and can provide new perspectives for researchers designing interventions for suicidal ideation.

Association between dietary patterns and premenstrual disorders: a cross-sectional analysis of 1382 college students in China.

Premenstrual disorders (PMDs) are common among young women and have been linked to metabolic dysfunction. Limited evidence exists regarding the associations between dietary patterns and PMDs. This cross-sectional study involved young female adults recruited from the Care of Premenstrual Emotion (COPE) cohort study in China to examine the relationship between dietary patterns and PMDs in young adulthood. PMDs were assessed using the Calendar of Premenstrual Experiences, and the consumption frequency of 12 common food groups was evaluated using a Food Frequency Questionnaire. We used principal component analysis to identify the dietary patterns and employed logistic regression to investigate the association between dietary pattern adherence and PMDs. The study included 1382 participants, of whom 337 (24.4%) reported having PMDs. Three dietary patterns were identified and named based on regional food preferences: the Traditional North China Diet (TNCD), the Traditional South China Diet (TSCD), and the Lacto-ovo Vegetarian Diet (LVD). The TSCD, characterized by high consumption of rice, red meat, and poultry, showed a significant inverse association with PMDs. This pattern held good for both premenstrual syndrome and premenstrual dysphoric disorder. These findings suggest that targeted dietary modifications could serve as a localized strategy for PMDs prevention.

Live and Heat-Inactivated Streptococcus thermophilus MN-ZLW-002 Mediate the Gut-Brain Axis, Alleviating Cognitive Dysfunction in APP/PS1 Mice.

Research on regulating brain functions with probiotics and postbiotics through the gut-brain axis is attracting attention, offering the possibility of adjuvant therapy for Alzheimer's disease (AD). Three-month-old male APP/PS1 mice were gavaged with live and heat-inactivated S. thermophilus MN-002 for three months. This study demonstrated that live and heat-inactivated S. thermophilus MN-002 improved cognitive dysfunctions in APP/PS1 mice, especially in spatial memory. However, the main effects of live S. thermophilus MN-002 directly altered the intestinal microbiota composition and increased serum IL-1ß and IL-6. Heat-inactivated S. thermophilus MN-002 increased colonic propionic acid levels and enhanced the hippocampus's antioxidant capacity. Furthermore, the changes were more obvious in the high-dose group, such as astrogliosis in the hippocampus. These results indicate that different forms and doses of the same strain, S. thermophilus MN-002, can partly improve cognitive functions in AD model mice via the gut-brain axis.

Temporal Asymmetry of Pleasant and Unpleasant Feelings Among Chinese Adolescents.

Previous studies have shown that anticipation induces more emotions than retrospection, known as temporal emotion asymmetry. However, the majority of previous studies have been confined to Western contexts. Eastern populations tend to emphasize the past more than their Western counterparts and may exhibit distinct forms of temporal emotion asymmetry. Therefore, we conducted an investigation involving Chinese adolescents. Our research encompassed two experiments, investigating Chinese adolescents' temporal emotion asymmetry from a self-perspective (Experiment 1; N = 124) and an other-perspective (Experiment 2; N = 162). Participants were prompted to retrospect and anticipate events that elicited pleasant or unpleasant feelings. The results revealed that, whether from a self-perspective or an other-perspective, retrospection of past positive events elicited greater pleasure than the anticipation of future positive events. However, concerning adverse events, under a self-perspective, anticipation induced more displeasure than retrospection (Experiment 1); under an other-perspective, retrospection induced more displeasure than anticipation (Experiment 2). Our findings provide some support for the construal level theory, fading affect bias, and mobilization-minimization hypothesis of event cognition. Based on these results, retrospection seems to be a potential means for regulating the emotions of Chinese adolescents.

Facing uncertainties: The longitudinal relationship between childhood maltreatment and exploratory behavior.

BACKGROUND: Exploratory behavior, as an essential component of decision-making, is indispensable for maximizing long-term benefits, making it a crucial factor in adolescents' psychological well-being and social adaptation. Despite the established understanding that this adaptive behavior is shaped by early adverse experiences, limited knowledge exists regarding the longitudinal relationship between childhood maltreatment and exploratory behavior. OBJECTIVE: The present study examines whether childhood maltreatment would impede subsequent exploratory behavior, considering the mediating role of uncertainty stress and the moderating role of intolerance of uncertainty. PARTICIPANTS AND SETTING: Participants were 655 adolescents from a longitudinal design with two waves spanning six months (Mage = 15.99, SDage = 0.92, 43.5 % female). METHODS: Correlation analysis and longitudinal moderated mediation effect testing were used to test our hypotheses. RESULTS: Correlation analysis indicated that childhood maltreatment was negatively correlated with exploratory behavior only simultaneously but not longitudinally. After controlling age and gender, childhood maltreatment would accompany higher levels of uncertainty stress, which in turn may act as a driving force behind subsequent exploratory behavior. The heightened intolerance of uncertainty may potentially mitigate the direct link between childhood maltreatment and later exploratory behavior. Furthermore, this trait amplifies the experienced uncertainty stress in individuals who have undergone maltreatment, thereby increasing their inclination toward engaging in subsequent exploratory behavior. CONCLUSIONS: Given the critical role of uncertainty stress, promoting more exploration among these maltreated adolescents requires corresponding cognitive and behavioral interventions to adjust their perception and cognition of uncertainty.

Effectiveness and safety of Moluodan in the treatment of precancerous lesions of gastric cancer: A randomized clinical trial.

OBJECTIVE: To investigate the clinical potential and safety of Moluodan to reverse gastric precancerous lesions. METHODS: Patients aged 18-70 years diagnosed with moderate-to-severe atrophy and/or moderate-to-severe intestinal metaplasia, with or without low-grade dysplasia, and negative for Helicobacter pylori were recruited in this randomized, double-blind, parallel-controlled trial. The primary outcome was the improvement of global histological diagnosis at 1-year follow-up endoscopy using the operative link for gastritis assessment, the operative link for gastric intestinal metaplasia assessment, and the disappearance rate of dysplasia. RESULTS: Between November 3, 2017 and January 27, 2021, 166 subjects were randomly assigned to the Moluodan group, 168 to the folic acid group, 84 to the combination group, and 84 to the high-dose Moluodan group. The improvement in global histological diagnosis was achieved in 60 (39.5%) subjects receiving Moluodan, 59 (37.8%) receiving folic acid, 26 (32.1%) receiving the combined drugs, and 36 (47.4%) receiving high-dose Moluodan. Moluodan was non-inferior to folic acid (95% confidence interval: -9.2 to 12.5; P = 0.02). High-dose Moluodan had a trend for better protective efficacy, though there was no statistical significance. The disappearance rate of dysplasia was 82.8% in the Moluodan group, which was superior to folic acid (53.9%; P = 0.006). No drug-related serious adverse events were observed. CONCLUSIONS: One pack of Moluodan three times daily for 1 year was safe and effective in reversing gastric precancerous lesions, especially dysplasia. Doubling its dose showed a better efficacy trend.

Gasdermin-E-Dependent Non-Canonical Pyroptosis Promotes Drug-Induced Liver Failure by Promoting CPS1 deISGylation and Degradation.

Drug-induced liver injury (DILI) is a significant global health issue that poses high mortality and morbidity risks. One commonly observed cause of DILI is acetaminophen (APAP) overdose. GSDME is an effector protein that induces non-canonical pyroptosis. In this study, the activation of GSDME, but not GSDMD, in the liver tissue of mice and patients with APAP-DILI is reported. Knockout of GSDME, rather than GSDMD, in mice protected them from APAP-DILI. Mice with hepatocyte-specific rescue of GSDME reproduced APAP-induced liver injury. Furthermore, alterations in the immune cell pools observed in APAP-induced DILI, such as the replacement of TIM4+ resident Kupffer cells (KCs) by monocyte-derived KCs, Ly6C+ monocyte infiltration, MerTk+ macrophages depletion, and neutrophil increase, reappeared in mice with hepatocyte-specific rescue of GSDME. Mechanistically, APAP exposure led to a substantial loss of interferon-stimulated gene 15 (ISG15), resulting in deISGylation of carbamoyl phosphate synthetase-1 (CPS1), promoted its degradation via K48-linked ubiquitination, causing ammonia clearance dysfunction. GSDME deletion prevented these effects. Delayed administration of dimethyl-fumarate inhibited GSDME cleavage and alleviated ammonia accumulation, mitigating liver injury. This findings demonstrated a previously uncharacterized role of GSDME in APAP-DILI by promoting pyroptosis and CPS1 deISGylation, suggesting that inhibiting GSDME can be a promising therapeutic option for APAP-DILI.

Iron Oxide Nanoparticles Engineered Macrophage-Derived Exosomes for Targeted Pathological Angiogenesis Therapy.

Engineering exosomes with nanomaterials usually leads to the damage of exosomal membrane and bioactive molecules. Here, pathological angiogenesis targeting exosomes with magnetic imaging, ferroptosis inducing, and immunotherapeutic properties is fabricated using a simple coincubation method with macrophages being the bioreactor. Extremely small iron oxide nanoparticle (ESIONPs) incorporated exosomes (ESIONPs@EXO) are acquired by sorting the secreted exosomes from M1-polarized macrophages induced by ESIONPs. ESIONPs@EXO suppress pathological angiogenesis in vitro and in vivo without toxicity. Furthermore, ESIONPs@EXO target pathological angiogenesis and exhibit an excellent T1-weighted contrast property for magnetic resonance imaging. Mechanistically, ESIONPs@EXO induce ferroptosis and exhibit immunotherapeutic ability toward pathological angiogenesis. These findings demonstrate that a pure biological method engineered ESIONPs@EXO using macrophages shows potential for targeted pathological angiogenesis therapy.

Room-temperature sub-100 nm Néel-type skyrmions in non-stoichiometric van der Waals ferromagnet Fe3-xGaTe2 with ultrafast laser writability.

Realizing room-temperature magnetic skyrmions in two-dimensional van der Waals ferromagnets offers unparalleled prospects for future spintronic applications. However, due to the intrinsic spin fluctuations that suppress atomic long-range magnetic order and the inherent inversion crystal symmetry that excludes the presence of the Dzyaloshinskii-Moriya interaction, achieving room-temperature skyrmions in 2D magnets remains a formidable challenge. In this study, we target room-temperature 2D magnet Fe3GaTe2 and unveil that the introduction of iron-deficient into this compound enables spatial inversion symmetry breaking, thus inducing a significant Dzyaloshinskii-Moriya interaction that brings about room-temperature Néel-type skyrmions with unprecedentedly small size. To further enhance the practical applications of this finding, we employ a homemade in-situ optical Lorentz transmission electron microscopy to demonstrate ultrafast writing of skyrmions in Fe3-xGaTe2 using a single femtosecond laser pulse. Our results manifest the Fe3-xGaTe2 as a promising building block for realizing skyrmion-based magneto-optical functionalities.

Pro-ferroptotic signaling promotes arterial aging via vascular smooth muscle cell senescence.

Senescence of vascular smooth muscle cells (VSMCs) contributes to aging-related cardiovascular diseases by promoting arterial remodelling and stiffness. Ferroptosis is a novel type of regulated cell death associated with lipid oxidation. Here, we show that pro-ferroptosis signaling drives VSMCs senescence to accelerate vascular NAD+ loss, remodelling and aging. Pro-ferroptotic signaling is triggered in senescent VSMCs and arteries of aged mice. Furthermore, the activation of pro-ferroptotic signaling in VSMCs not only induces NAD+ loss and senescence but also promotes the release of a pro-senescent secretome. Pharmacological or genetic inhibition of pro-ferroptosis signaling, ameliorates VSMCs senescence, reduces vascular stiffness and retards the progression of abdominal aortic aneurysm in mice. Mechanistically, we revealed that inhibition of pro-ferroptotic signaling facilitates the nuclear-cytoplasmic shuttling of proliferator-activated receptor-γ and, thereby impeding nuclear receptor coactivator 4-ferrtin complex-centric ferritinophagy. Finally, the activated pro-ferroptotic signaling correlates with arterial stiffness in a human proof-of-concept study. These findings have significant implications for future therapeutic strategies aiming to eliminate vascular ferroptosis in senescence- or aging-associated cardiovascular diseases.