Biomacromolecular carriers based hydrophobic natural products for potential cancer therapy.

Cancer is the second leading cause of death worldwide. It was estimated that 90 % of cancer-related deaths were attributable to the development of multi-drug resistance (MDR) during chemotherapy, which results in ineffective chemotherapy. Hydrophobic natural products plays a pivotal role in the field of cancer therapy, with the potential to reverse MDR in tumor cells, thereby enhancing the efficacy of tumor therapy. However, their targeted delivery is considered a major hurdle in their application. The advent of numerous approaches for encapsulating bioactive ingredients in the nanodelivery systems has improved the stability and targeted delivery of these biomolecules. The manuscript comprehensively analyses the nanodelivery systems of bioactive compounds with potential cancer therapy applications, including liposomes, emulsions, solid lipid nanoparticles (NPs), and polymeric NPs. Then, the advantages and disadvantages of various nanoagents in the treatment of various cancer types are critically discussed. Further, the application of multiple-compbine delivery methods to overcome the limitations of single-delivery have need critically analyzed, which thus could help in the designing nanodrug delivery systems for bioactive compounds in clinical settings. Therefore, the review is timely and important for development of efficient nanodelivery systems involving hydrophobic natural products to improve pharmacokinetic properties for effective cancer treatment.

New insights from bidirectional Mendelian randomization: causal relationships between telomere length and mitochondrial DNA copy number in aging biomarkers.

Mitochondrial DNA (mtDNA) copy number and telomere length (TL) are dynamic factors that have been linked to the aging process in organisms. However, the causal relationship between these variables remains uncertain. In this research, instrumental variables (IVs) related to mtDNA copy number and TL were obtained from publicly available genome-wide association studies (GWAS). Through bidirectional Mendelian randomization (MR) analysis, we examined the potential causal relationship between these factors. The forward analysis, with mtDNA copy number as the exposure and TL as the outcome, did not reveal a significant effect (B=-0.004, P>0.05). On the contrary, upon conducting a reverse analysis, it was found that there exists a positive causal relationship (B=0.054, P<0.05). Sensitivity analyses further confirmed the reliability of these results. The outcomes of this study indicate a one-way positive causal relationship, indicating that telomere shortening in the aging process may lead to a decrease in mtDNA copy number, providing new perspectives on their biological mechanisms.

Fulvic acid-mediated efficient anaerobic digestion for kitchen wastewater: Electrochemical and biochemical mechanisms.

Fulvic acid, prevalent in humus derived from the anaerobic digestion of kitchen wastewater, is crucial in organic matter transformation. However, its effects and underlying mechanisms remain unclear. In this study, the fate of anaerobic digestion of artificial and kitchen wastewater with different fulvic acid contents was investigated. The results showed that 125 mg/L fulvic acid resulted in a 64.02 and 51.72 % increase in methane production in synthetic and kitchen wastewater, respectively. Fulvic acid acted as an electron mediator and increased substrate oxidation by boosting NAD and ATP levels, thereby increasing microbial metabolic rates and ensuring an adequate substrate for methane generation. Isotope analysis suggested that fulvic acid boosts the conversion of volatile fatty acids to methane via the interspecies electron transfer pathway. Gene expression analysis revealed that cytochrome c, FAD, and other electron transport coenzymes were upregulated by fulvic acid, thereby enhancing substrate utilisation and biogas quality. Fulvic acid presented a dual stimulatory and inhibitory effect on anaerobic digestion, with concentrations over 125 mg/L diminishing its positive impact. This dual effect may stem from the properties and concentrations of fulvic acid. This study revealed the effect mechanism of fulvic acid and provided insights into the humus performance in anaerobic digestion.

Characteristics of germline DNA damage response gene mutations in ovarian cancer in Southwest China.

DNA damage response (DDR) pathways are responsible for repairing endogenous or exogenous DNA damage to maintain the stability of the cellular genome, including homologous recombination repair (HRR) pathway, mismatch repair (MMR) pathway, etc. In ovarian cancer, current studies are focused on HRR genes, especially BRCA1/2, and the results show regional and population differences. To characterize germline mutations in DDR genes in ovarian cancer in Southwest China, 432 unselected ovarian cancer patients underwent multi-gene panel testing from October 2016 to October 2020. Overall, deleterious germline mutations in DDR genes were detected in 346 patients (80.1%), and in BRCA1/2 were detected in 126 patients (29.2%). The prevalence of deleterious germline mutations in BRCA2 is higher than in other studies (patients are mainly from Eastern China), and so is the mismatch repair genes. We identified three novel BRCA1/2 mutations, two of which probably deleterious (BRCA1 p.K1622* and BRCA2 p.L2987P). Furthermore, we pointed out that deleterious mutations of FNACD2 and RECQL4 are potential ovarian cancer susceptibility genes and may predispose carriers to ovarian cancer. In conclusion, our study highlights the necessity of comprehensive germline mutation detection of DNA damage response genes in ovarian cancer patients, which is conducive to patient management and genetic counseling.

Self-signal electrochemical identification of circulating tumor DNA employing poly-xanthurenic acid assembled on black phosphorus nanosheets.

A self-signal electrochemical identification interface was prepared for the determination of circulating tumor DNA (ctDNA) in peripheral blood based on poly-xanthurenic acid (PXTA) assembled on black phosphorus nanosheets (BPNSs) acquired through simple ultrasonication method. The BPNSs with large surface area could be integrated with the xanthurenic acid (XTA) monomers by right of physisorption, and hence improved the electropolymerization efficiency and was beneficial to the enlargement of the signal response of PXTA. The assembled PXTA/BPNSs composite with attractive electrochemical activity was adopted as a platform for the recognition of DNA immobilization and hybridization. The probe ssDNA was covalently fixed onto the PXTA/BPNSs composite with plentiful carboxyl groups through the terminate free amines of DNA probes by use of the 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydrosulfosuccinimide cross-linking reaction, accompanied with the decline of the self-signal response. When the hybridization between the probe ssDNA and the target DNA was accomplished, the self-signal response of the composite interface reproduced by virtue of the shaping of helix construction. The determination limit of the assembled DNA identification interface was 2.1 × 10-19 mol/L, and the complementary target DNA concentrations varied from 1.0 × 10-18 mol/L to 1.0 × 10-12 mol/L. The DNA identification platform displayed magnificent sensitivity, specificity and stability, and was efficaciously implemented to the mensuration of ctDNA derived from colorectal cancer.

The dynamics of B-cell reconstitution post allogeneic hematopoietic stem cell transplantation: A real-world study.

BACKGROUND: The immune reconstitution after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is crucial for preventing infections and relapse and enhancing graft-versus-tumor effects. B cells play an important role in humoral immunity and immune regulation, but their reconstitution after allo-HSCT has not been well studied. METHODS: In this study, we analyzed the dynamics of B cells in 252 patients who underwent allo-HSCT for 2 years and assessed the impact of factors on B-cell reconstitution and their correlations with survival outcomes, as well as the development stages of B cells in the bone marrow and the subsets in the peripheral blood. RESULTS: We found that the B-cell reconstitution in the bone marrow was consistent with the peripheral blood (p = 0.232). B-cell reconstitution was delayed by the male gender, age >50, older donor age, the occurrence of chronic and acute graft-versus-host disease, and the infections of fungi and cytomegalovirus. The survival analysis revealed that patients with lower B cells had higher risks of death and relapse. More importantly, we used propensity score matching to obtain the conclusion that post-1-year B-cell reconstitution is better in females. Meanwhile, using mediation analysis, we proposed the age-B cells-survival axis and found that B-cell reconstitution at month 12 posttransplant mediated the effect of age on patient survival (p = 0.013). We also found that younger patients showed more immature B cells in the bone marrow after transplantation (p = 0.037). CONCLUSION: Our findings provide valuable insights for optimizing the management of B-cell reconstitution and improving the efficacy and safety of allo-HSCT.

APE1 inhibition enhances ferroptotic cell death and contributes to hepatocellular carcinoma therapy.

Ferroptosis, a regulated form of cell death triggered by iron-dependent lipid peroxidation, has emerged as a promising therapeutic strategy for cancer treatment, particularly in hepatocellular carcinoma (HCC). However, the mechanisms underlying the regulation of ferroptosis in HCC remain to be unclear. In this study, we have identified a novel regulatory pathway of ferroptosis involving the inhibition of Apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme with dual functions in DNA repair and redox regulation. Our findings demonstrate that inhibition of APE1 leads to the accumulation of lipid peroxidation and enhances ferroptosis in HCC. At the molecular level, the inhibition of APE1 enhances ferroptosis which relies on the redox activity of APE1 through the regulation of the NRF2/SLC7A11/GPX4 axis. We have identified that both genetic and chemical inhibition of APE1 increases AKT oxidation, resulting in an impairment of AKT phosphorylation and activation, which leads to the dephosphorylation and activation of GSK3ß, facilitating the subsequent ubiquitin-proteasome-dependent degradation of NRF2. Consequently, the downregulation of NRF2 suppresses SLC7A11 and GPX4 expression, triggering ferroptosis in HCC cells and providing a potential therapeutic approach for ferroptosis-based therapy in HCC. Overall, our study uncovers a novel role and mechanism of APE1 in the regulation of ferroptosis and highlights the potential of targeting APE1 as a promising therapeutic strategy for HCC and other cancers.

A dynamic nomogram predicting symptomatic pneumonia in patients with lung cancer receiving thoracic radiation.

PURPOSE: The most common and potentially fatal side effect of thoracic radiation therapy is radiation pneumonitis (RP). Due to the lack of effective treatments, predicting radiation pneumonitis is crucial. This study aimed to develop a dynamic nomogram to accurately predict symptomatic pneumonitis (RP ≥ 2) following thoracic radiotherapy for lung cancer patients. METHODS: Data from patients with pathologically diagnosed lung cancer at the Zhongshan People's Hospital Department of Radiotherapy for Thoracic Cancer between January 2017 and June 2022 were retrospectively analyzed. Risk factors for radiation pneumonitis were identified through multivariate logistic regression analysis and utilized to construct a dynamic nomogram. The predictive performance of the nomogram was validated using a bootstrapped concordance index and calibration plots. RESULTS: Age, smoking index, chemotherapy, and whole lung V5/MLD were identified as significant factors contributing to the accurate prediction of symptomatic pneumonitis. A dynamic nomogram for symptomatic pneumonitis was developed using these risk factors. The area under the curve was 0.89(95% confidence interval 0.83-0.95). The nomogram demonstrated a concordance index of 0.89(95% confidence interval 0.82-0.95) and was well calibrated. Furthermore, the threshold values for high- risk and low- risk were determined to be 154 using the receiver operating curve. CONCLUSIONS: The developed dynamic nomogram offers an accurate and convenient tool for clinical application in predicting the risk of symptomatic pneumonitis in patients with lung cancer undergoing thoracic radiation.

Contaminant Organism Growth in Febrile Infants at Low Risk for Invasive Bacterial Infection.

In this multicenter, cross-sectional, secondary analysis of 4042 low-risk febrile infants, nearly 10% had a contaminated culture obtained during their evaluation (4.9% of blood cultures, 5.0% of urine cultures, and 1.8% of cerebrospinal fluid cultures). Our findings have important implications for improving sterile technique and reducing unnecessary cultures.

Continuity corrected score confidence interval for the difference in proportions in paired data.

For paired binary data, the hybrid method and the score method are often recommended for use to calculate the confidence interval for risk difference. These asymptotic intervals do not control the coverage probability. We propose to develop a new score interval with continuity correction to further improve the performance of the existing intervals. The traditional correction value may be too large which leads to a wide interval. For that reason, we propose three different correction values to identify the optimal correction interval with balanced coverage probability and interval width. From simulation studies, we find that a small correction value for the score interval has good performance. In addition, we derive the non-iterative solutions for the developed continuity correction score intervals.

Performance and mechanism of graphene oxide removal from aqueous solutions by calcite: adsorption isotherms, thermodynamics, and kinetics.

The flow of graphene oxide (GO) into natural water systems can adversely affect water environments and ecosystems. In this study, the adsorption effect of calcite on GO under different conditions was studied using calcite as adsorbent. Meanwhile, characterized by a combination of microscopic experiments, including SEM, TEM, XRD, FTIR, Raman, XPS, and AFM, additional research on the performance and the mechanism of GO sorption by calcite was conducted. The findings indicated that the highest adsorption efficiency was observed at a temperature of 303 K, pH 3, a mass of 90 mg of calcite, with an initial concentration of 60 mg L-1 GO, resulting in a 95% adsorption rate. The adsorption isotherm conformed to the model of Langmuir and Temkin, and it is a heat absorption process dominated by monolayer adsorption. The thermodynamic analysis showed that the adsorption was spontaneous and heat-absorbing. The adsorption kinetics conformed to the pseudo-second-order kinetic model, and the sorption procedure is chemisorption. In conclusion, calcite has a good sorption capacity for GO, which can provide a reference for the removal of GO in the aqueous environment.

Orthodontic Practitioners' Knowledge and Education Demand on Clear Aligner Therapy.

OBJECTIVES: Clear aligner therapy (CAT) has been gaining popularity amongst the orthodontic community. No systematic course on CAT has been reported to date. The objectives of this study were to determine practitioners' knowledge and to offer insights for future tailored courses on CAT. METHODS: An online questionnaire was distributed. The questionnaire comprised personal background information, predictability of tooth movement through CAT, and CAT knowledge that practitioners demanded to learn. Four senior expert orthodontists' answers to the predictability of tooth movement through CAT were averaged to be a standard reference. Descriptive statistics, 1-way analysis of variance (ANOVA), principal component analysis, Student t test, and multivariate logistics regression analysis were performed with significance set at P < .05. RESULTS: In total, 190 practitioners participated in this study. As compared to the standard reference, participants overestimated the predictability of difficult-to-be-achived tooth movements (eg, molar mesialisation; P < .0001). Strategy of managing troubleshooting cases and extraction cases ranked the highest CAT knowledge that participants requested to learn. Practice type, number of completed CAT cases, number of undergoing CAT cases, years of practice, education background, and time of using CAT were the influencing factors of the questions regarding the predictability of tooth movement through CAT and CAT knowledge that were demanded to be learned. CONCLUSIONS: The predictability of difficult-to-be-achieved tooth movement through CAT is often overestimated by practitioners with limited clinical experience. Tailored education on CAT, especially managing troubleshooting cases and extraction cases, should be designed for all practitioners.

Race, Ethnicity, Language, and the Treatment of Low-Risk Febrile Infants.

Importance: Febrile infants at low risk of invasive bacterial infections are unlikely to benefit from lumbar puncture, antibiotics, or hospitalization, yet these are commonly performed. It is not known if there are differences in management by race, ethnicity, or language. Objective: To investigate associations between race, ethnicity, and language and additional interventions (lumbar puncture, empirical antibiotics, and hospitalization) in well-appearing febrile infants at low risk of invasive bacterial infection. Design, Setting, and Participants: This was a multicenter retrospective cross-sectional analysis of infants receiving emergency department care between January 1, 2018, and December 31, 2019. Data were analyzed from December 2022 to July 2023. Pediatric emergency departments were determined through the Pediatric Emergency Medicine Collaborative Research Committee. Well-appearing febrile infants aged 29 to 60 days at low risk of invasive bacterial infection based on blood and urine testing were included. Data were available for 9847 infants, and 4042 were included following exclusions for ill appearance, medical history, and diagnosis of a focal infectious source. Exposures: Infant race and ethnicity (non-Hispanic Black, Hispanic, non-Hispanic White, and other race or ethnicity) and language used for medical care (English and language other than English). Main Outcomes and Measures: The primary outcome was receipt of at least 1 of lumbar puncture, empirical antibiotics, or hospitalization. We performed bivariate and multivariable logistic regression with sum contrasts for comparisons. Individual components were assessed as secondary outcomes. Results: Across 34 sites, 4042 infants (median [IQR] age, 45 [38-53] days; 1561 [44.4% of the 3516 without missing sex] female; 612 [15.1%] non-Hispanic Black, 1054 [26.1%] Hispanic, 1741 [43.1%] non-Hispanic White, and 352 [9.1%] other race or ethnicity; 3555 [88.0%] English and 463 [12.0%] language other than English) met inclusion criteria. The primary outcome occurred in 969 infants (24%). Race and ethnicity were not associated with the primary composite outcome. Compared to the grand mean, infants of families that use a language other than English had higher odds of the primary outcome (adjusted odds ratio [aOR]; 1.16; 95% CI, 1.01-1.33). In secondary analyses, Hispanic infants, compared to the grand mean, had lower odds of hospital admission (aOR, 0.76; 95% CI, 0.63-0.93). Compared to the grand mean, infants of families that use a language other than English had higher odds of hospital admission (aOR, 1.08; 95% CI, 1.08-1.46). Conclusions and Relevance: Among low-risk febrile infants, language used for medical care was associated with the use of at least 1 nonindicated intervention, but race and ethnicity were not. Secondary analyses highlight the complex intersectionality of race, ethnicity, language, and health inequity. As inequitable care may be influenced by communication barriers, new guidelines that emphasize patient-centered communication may create disparities if not implemented with specific attention to equity.

The association between social media use and well-being during quarantine period: testing a moderated mediation model.

Objectives: Social media use (SMU) increased dramatically during COVID-19 due to policies such as long-term quarantine. Given that SMU has complex effects on individuals' well-being, this study aimed to explore the relationship between SMU and subjective well-being and the influencing factors in the context of the pandemic in China. Methods: A total of 895 adults (413 males) in different risk areas across China participated in this study. They provided self-reported data on subjective well-being, social media use, adaptive humor, and other demographic variables. Results: It revealed that SMU was positively associated with individual well-being, an effect partially mediated by the score of adaptive humor. Furthermore, the effect of SMU on adaptive humor was moderated by trait optimism, with the effect more robust in high (vs. low) optimistic individuals. Conclusion: This study explored the positive effects of SMU on individuals' well-being, suggesting that individuals may better cope with negative experiences and maintain well-being under quarantine by showing more adaptive humor on social media.

Clinical significance of WT1 in the evaluation of therapeutic effect and prognosis of non-M3 acute myeloid leukemia.

To explore the clinical significance and prognosis of acute myeloid leukemia (AML) patients with WT1 mutations.In total, the clinical data of 269 adult patients with non-M3 AML were considered retrospectively. From these patients, 153 carried WT1 mutation whereas 116 were negative. WT1 mutation positive patients were further divided into WT1 low expression and high expression groups base on the expression level of WT1 by qPCR at diagnosis (cut off: 170500). Survival and therapeutic effect analysis were performed for the above patients with different interfering factors such as co-mutations, the extent of WT1 log reduction and the chemotherapy regimens. Patients with high WT1 expression have higher rate of relapse. We can accurately identify patients with inferior outcomes when we take the following factors into consideration: the WT1 expression level at diagnosis; different prognostic factors including co-mutations (especially NPM1 and FLT3-ITD); the log reduction of WT1 after induction therapy and the risk of stratification. Idarubicin + Cytarabine (IA) regimen could reduce the expression level of WT1 after treatment, and Allo-HSCT played an important role in improving the prognosis of patients with WT1 high expression and patients with WT1 negativity. Among the relapsed patients, there existed a rising trend of WT1-MRD in advance than MFC-MRD and that of patients with continuous complete remission (CR). Different clinical background should be taken into consideration when we judge the prognosis and therapeutic effect of patients with WT1 mutations. In addition, WT1 may be an optional MRD marker, which needs regular monitoring.

Adipose tissue eQTL meta-analysis reveals the contribution of allelic heterogeneity to gene expression regulation and cardiometabolic traits.

Complete characterization of the genetic effects on gene expression is needed to elucidate tissue biology and the etiology of complex traits. Here, we analyzed 2,344 subcutaneous adipose tissue samples and identified 34K conditionally distinct expression quantitative trait locus (eQTL) signals in 18K genes. Over half of eQTL genes exhibited at least two eQTL signals. Compared to primary signals, non-primary signals had lower effect sizes, lower minor allele frequencies, and less promoter enrichment; they corresponded to genes with higher heritability and higher tolerance for loss of function. Colocalization of eQTL with conditionally distinct genome-wide association study signals for 28 cardiometabolic traits identified 3,605 eQTL signals for 1,861 genes. Inclusion of non-primary eQTL signals increased colocalized signals by 46%. Among 30 genes with ≥2 pairs of colocalized signals, 21 showed a mediating gene dosage effect on the trait. Thus, expanded eQTL identification reveals more mechanisms underlying complex traits and improves understanding of the complexity of gene expression regulation.

Metabolomic biomarkers of habitual B vitamin intakes unveil novel differentially methylated positions in the human epigenome.

BACKGROUND: B vitamins such as folate (B9), B6, and B12 are key in one carbon metabolism, which generates methyl donors for DNA methylation. Several studies have linked differential methylation to self-reported intakes of folate and B12, but these estimates can be imprecise, while metabolomic biomarkers can offer an objective assessment of dietary intakes. We explored blood metabolomic biomarkers of folate and vitamins B6 and B12, to carry out epigenome-wide analyses across up to three European cohorts. Associations between self-reported habitual daily B vitamin intakes and 756 metabolites (Metabolon Inc.) were assessed in serum samples from 1064 UK participants from the TwinsUK cohort. The identified B vitamin metabolomic biomarkers were then used in epigenome-wide association tests with fasting blood DNA methylation levels at 430,768 sites from the Infinium HumanMethylation450 BeadChip in blood samples from 2182 European participants from the TwinsUK and KORA cohorts. Candidate signals were explored for metabolite associations with gene expression levels in a subset of the TwinsUK sample (n = 297). Metabolomic biomarker epigenetic associations were also compared with epigenetic associations of self-reported habitual B vitamin intakes in samples from 2294 European participants. RESULTS: Eighteen metabolites were associated with B vitamin intakes after correction for multiple testing (Bonferroni-adj. p < 0.05), of which 7 metabolites were available in both cohorts and tested for epigenome-wide association. Three metabolites - pipecolate (metabolomic biomarker of B6 and folate intakes), pyridoxate (marker of B6 and folate) and docosahexaenoate (DHA, marker of B6) - were associated with 10, 3 and 1 differentially methylated positions (DMPs), respectively. The strongest association was observed between DHA and DMP cg03440556 in the SCD gene (effect = 0.093 ± 0.016, p = 4.07E-09). Pyridoxate, a catabolic product of vitamin B6, was inversely associated with CpG methylation near the SLC1A5 gene promoter region (cg02711608 and cg22304262) and with SLC7A11 (cg06690548), but not with corresponding changes in gene expression levels. The self-reported intake of folate and vitamin B6 had consistent but non-significant associations with the epigenetic signals. CONCLUSION: Metabolomic biomarkers are a valuable approach to investigate the effects of dietary B vitamin intake on the human epigenome.

Upregulated SPAG6 correlates with increased STAT1 and is associated with reduced sensitivity of interferon-α response in BCR::ABL1 negative myeloproliferative neoplasms.

Sperm-associated antigen 6 (SPAG6) has been identified as an oncogene or tumor suppressor in various types of human cancer. However, the role of SPAG6 in BCR::ABL1 negative myeloproliferative neoplasms (MPNs) remains unclear. Herein, we found that SPAG6 was upregulated at the mRNA level in primary MPN cells and MPN-derived leukemia cell lines. The SPAG6 protein was primarily located in the cytoplasm around the nucleus and positively correlated with ß-tubulin expression. In vitro, forced expression of SPAG6 increased cell clone formation and promoted G1 to S cell cycle progression. Downregulation of SPAG6 promoted apoptosis, reduced G1 to S phase transition, and impaired cell proliferation and cytokine release accompanied by downregulated signal transducer and activator of transcription 1 (STAT1) expression. Furthermore, the inhibitory effect of interferon-α (INF-α) on the primary MPN cells with high SPAG6 expression was decreased. Downregulation of SPAG6 enhanced STAT1 induction, thus enhancing the proapoptotic and cell cycle arrest effects of INF-α both in vitro and in vivo. Finally, a decrease in SPAG6 protein expression was noted when the STAT1 signaling was blocked. Chromatin immunoprecipitation assays indicated that STAT1 protein could bind to the SPAG6 promoter, while the dual-luciferase reporter assay indicated that STAT1 could promote the expression of SPAG6. Our results substantiate the relationship between upregulated SPAG6, increased STAT1, and reduced sensitivity to INF-α response in MPN.

Tail engagement of arrestin at the glucagon receptor.

Arrestins have pivotal roles in regulating G protein-coupled receptor (GPCR) signalling by desensitizing G protein activation and mediating receptor internalization1,2. It has been proposed that the arrestin binds to the receptor in two different conformations, 'tail' and 'core', which were suggested to govern distinct processes of receptor signalling and trafficking3,4. However, little structural information is available for the tail engagement of the arrestins. Here we report two structures of the glucagon receptor (GCGR) bound to ß-arrestin 1 (ßarr1) in glucagon-bound and ligand-free states. These structures reveal a receptor tail-engaged binding mode of ßarr1 with many unique features, to our knowledge, not previously observed. Helix VIII, instead of the receptor core, has a major role in accommodating ßarr1 by forming extensive interactions with the central crest of ßarr1. The tail-binding pose is further defined by a close proximity between the ßarr1 C-edge and the receptor helical bundle, and stabilized by a phosphoinositide derivative that bridges ßarr1 with helices I and VIII of GCGR. Lacking any contact with the arrestin, the receptor core is in an inactive state and loosely binds to glucagon. Further functional studies suggest that the tail conformation of GCGR-ßarr governs ßarr recruitment at the plasma membrane and endocytosis of GCGR, and provides a molecular basis for the receptor forming a super-complex simultaneously with G protein and ßarr to promote sustained signalling within endosomes. These findings extend our knowledge about the arrestin-mediated modulation of GPCR functionalities.