Evolution of bitter receptor genes and ontogenetic dietary shift in a frog.

Vertebrate Tas2r taste receptors detect bitter compounds that are potentially poisonous. Previous studies found substantial variation in the number of Tas2r genes across vertebrates, with some frog species carrying the largest number. Peculiar among vertebrates, frogs undergo metamorphosis, often associated with a dietary shift between tadpoles and adults. A possible explanation for the large size of frog Tas2r families could be that distinct sets of Tas2r genes are required for tadpoles and adults, suggesting differential expression of Tas2r genes between tadpoles and adults. To test this hypothesis, we first examined 20 amphibian genomes and found that amphibians generally possess more Tas2r genes than do other vertebrate clades. We next focused on the American bullfrog (Lithobates catesbeianus) to examine the expression of its Tas2r genes in herbivorous tadpoles and insectivorous adult frogs. We report that close to one fifth of its 180 Tas2r genes are differentially expressed (22 genes enriched in adults and 11 in tadpoles). Tuning properties were determined for a subset of differentially expressed genes by a cell-based functional assay, with the adult-enriched Tas2r gene set covering a larger range of ligands compared to the tadpole-enriched subset. These results suggest a role of Tas2r genes in the ontogenetic dietary shift of frogs and potentially initiate a new avenue of ontogenetic analysis of diet-related genes in the animal kingdom.

A modified model for predicting mortality after transjugular intrahepatic portosystemic shunt: A multicentre study.

BACKGROUND AND AIMS: The transjugular intrahepatic portosystemic shunt has controversial survival benefits; thus, patient screening should be performed preoperatively. In this study, we aimed to develop a model to predict post-transjugular intrahepatic portosystemic shunt mortality to aid clinical decision making. METHODS: A total of 811 patients undergoing transjugular intrahepatic portosystemic shunt from five hospitals were divided into the training and external validation data sets. A modified prediction model of post-transjugular intrahepatic portosystemic shunt mortality (ModelMT ) was built after performing logistic regression. To verify the improved performance of ModelMT , we compared it with seven previous models, both in discrimination and calibration. Furthermore, patients were stratified into low-, medium-, high- and extremely high-risk subgroups. RESULTS: ModelMT demonstrated a satisfying predictive efficiency in both discrimination and calibration, with an area under the curve of .875 in the training set and .852 in the validation set. Compared to previous models (ALBI, BILI-PLT, MELD-Na, MOTS, FIPS, MELD, CLIF-C AD), ModelMT showed superior performance in discrimination by statistical difference in the Delong test, net reclassification improvement and integrated discrimination improvement (all p < .050). Similar results were observed in calibration. Low-, medium-, high- and extremely high-risk groups were defined by scores of ≤160, 160-180, 180-200 and >200, respectively. To facilitate future clinical application, we also built an applet for ModelMT . CONCLUSIONS: We successfully developed a predictive model with improved performance to assist in decision making for transjugular intrahepatic portosystemic shunt according to survival benefits.

Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.

BACKGROUND: Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. METHODS: We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. RESULTS: We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. CONCLUSION: Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.

Model containing sarcopenia and visceral adiposity can better predict the prognosis of hepatocellular carcinoma: a multicenter study.

AIM: This study aimed to explore whether the addition of sarcopenia and visceral adiposity could improve the accuracy of model predicting progression-free survival (PFS) in hepatocellular carcinoma (HCC). METHODS: In total, 394 patients with HCC from five hospitals were divided into the training and external validation datasets. Patients were initially treated by liver resection or transarterial chemoembolization. We evaluated adipose and skeletal muscle using preoperative computed tomography imaging and then constructed three predictive models, including metabolic (ModelMA), clinical-imaging (ModelCI), and combined (ModelMA-CI) models. Their discrimination, calibration, and decision curves were compared, to identify the best model. Nomogram and subgroup analysis was performed for the best model. RESULTS: ModelMA-CI containing sarcopenia and visceral adiposity had good discrimination and calibrations (integrate area under the curve for PFS was 0.708 in the training dataset and 0.706 in the validation dataset). ModelMA-CI had better accuracy than ModelCI and ModelMA. The performance of ModelMA-CI was not affected by treatments or disease stages. The high-risk subgroup (scored > 198) had a significantly shorter PFS (p < 0.001) and poorer OS (p < 0.001). CONCLUSIONS: The addition of sarcopenia and visceral adiposity improved accuracy in predicting PFS in HCC, which may provide additional insights in prognosis for HCC in subsequent studies.

Local Adaptation of Bitter Taste and Ecological Speciation in a Wild Mammal.

Sensory systems are attractive evolutionary models to address how organisms adapt to local environments that can cause ecological speciation. However, tests of these evolutionary models have focused on visual, auditory, and olfactory senses. Here, we show local adaptation of bitter taste receptor genes in two neighboring populations of a wild mammal-the blind mole rat Spalax galili-that show ecological speciation in divergent soil environments. We found that basalt-type bitter receptors showed higher response intensity and sensitivity compared with chalk-type ones using both genetic and cell-based functional analyses. Such functional changes could help animals adapted to basalt soil select plants with less bitterness from diverse local foods, whereas a weaker reception to bitter taste may allow consumption of a greater range of plants for animals inhabiting chalk soil with a scarcity of food supply. Our study shows divergent selection on food resources through local adaptation of bitter receptors, and suggests that taste plays an important yet underappreciated role in speciation.

LncRNA-AC006129.1 reactivates a SOCS3-mediated anti-inflammatory response through DNA methylation-mediated CIC downregulation in schizophrenia.

Schizophrenia is a complex genetic disorder, the non-Mendelian features of which are likely complicated by epigenetic factors yet to be elucidated. Here, we performed RNA sequencing of peripheral blood RNA from monozygotic twins discordant for schizophrenia, and identified a schizophrenia-associated upregulated long noncoding RNA (lncRNA, AC006129.1) that participates in the inflammatory response by enhancing SOCS3 and CASP1 expression in schizophrenia patients and further validated this finding in AC006129.1-overexpressing mice showing schizophrenia-related abnormal behaviors. We find that AC006129.1 binds to the promoter region of the transcriptional repressor Capicua (CIC), facilitates the interactions of DNA methyltransferases with the CIC promoter, and promotes DNA methylation-mediated CIC downregulation, thereby ameliorating CIC-induced SOCS3 and CASP1 repression. Derepression of SOCS3 enhances the anti-inflammatory response by inhibiting JAK/STAT-signaling activation. Our findings reveal an epigenetic mechanism with etiological and therapeutic implications for schizophrenia.

Allele-specific DNA methylation maps in monozygotic twins discordant for psychiatric disorders reveal that disease-associated switching at the EIPR1 regulatory loci modulates neural function.

The non-Mendelian features of phenotypic variations within monozygotic twins are likely complicated by environmental modifiers of genetic effects that have yet to be elucidated. Here, we performed methylome and genome analyses of blood DNA from psychiatric disorder-discordant monozygotic twins to study how allele-specific methylation (ASM) mediates phenotypic variations. We identified that thousands of genetic variants with ASM imbalances exhibit phenotypic variation-associated switching at regulatory loci. These ASMs have plausible causal associations with psychiatric disorders through effects on interactions between transcription factors, DNA methylations, and other epigenomic markers and then contribute to dysregulated gene expression, which eventually increases disease susceptibility. Moreover, we also experimentally validated the model that the rs4854158 alternative C allele at an ASM switching regulatory locus of EIPR1 encoding endosome-associated recycling protein-interacting protein 1, is associated with demethylation and higher RNA expression and shows lower TF binding affinities in unaffected controls. An epigenetic ASM switching induces C allele hypermethylation and then recruits repressive Polycomb repressive complex 2 (PRC2), reinforces trimethylation of lysine 27 on histone 3 and inhibits its transcriptional activity, thus leading to downregulation of EIPR1 in schizophrenia. Moreover, disruption of rs4854158 induces gain of EIPR1 function and promotes neural development and vesicle trafficking. Our study provides a powerful framework for identifying regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic variants in mediating psychiatric disorder susceptibility.

Sharing Knowledge to an Entrant for Production Investment Confronting COVID-19: Incentive Alignment and Lose-Lose Dilemma.

Facing the urgent demand of medical devices for COVID-19 treatment, many automakers have recently begun manufacturing ventilators, even though they are inefficient in production and uninformed of demand variability. To help them, some incumbent ventilator manufacturers have chosen to share knowledge, such as production techniques and demand information. Clearly, the incumbent ventilator manufacturers are fulfilling social responsibility, but is their knowledge sharing rewarding, especially when the automakers are entrant rivals? If possible, are win-win situations in the sense of social responsibility and firms' profitability identifiable? In this work, we develop a game-theoretic model in which an incumbent and an entrant ventilator manufacturer engage in two-dimensional competition in production investment and sales volume. We examine the incumbent manufacturer's profitability with and without knowledge sharing by formulating the tradeoffs among supply expansion, intensified competition, and the entrant's production efficiency improvement and demand variance reduction. We identify both "win-win" and "lose-lose" situations for the two competing manufacturers. Specifically, we find that free knowledge could be harmful for the entrant manufacturer, but the incumbent manufacturer benefits from knowledge sharing when market competition is intense, or when market competition is mild but the production investment efficiency varies.

Ceramide synthase 3 affects invasion and metastasis of hepatocellular carcinoma via the SMAD6 gene. / ç¥žç»é °èƒºåˆæˆé ¶3通过SMAD6åŸºå› å½±å“è‚ç»†èƒžç™Œçš„ä¾µè¢­å’Œè½¬ç§».

OBJECTIVES: Patients with hepatocellular carcinoma (HCC) have poor prognosis due to lack of early diagnosis and effective treatment. Therefore, there is an urgent need to better understand the molecular mechanisms associated with HCC and to identify effective targets for early diagnosis and treatment. This study is to explore the expression and biological role of ceramide synthase 3 (CerS3) in HCC. METHODS: A total of 159 pairs of HCC tissues and adjacent non-tumor tissues were obtained from the patients underwent radical resection in Shenzhen People's Hospital, and the total RNA and proteins from HCC tissues and adjacent non-tumor tissues were obtained. The expression of CerS3 protein and mRNA in HCC was detected by immunohistochemistry, Western blotting and real-time PCR. In vitro experiments, Hep3B cells were divided into a control vector group and a CerS3 vector group, and the cells were transfected with retroviral vector containing control cDNA or CerS3 cDNA, respectively. HCCLM3 cells were divided into a normal control shRNA group and a CerS3 shRNA group, and the cells were transfected with lentiviral vectors containing normal control shRNA or CerS3 shRNA, respectively. MTT, EdU, Transwell and scratch method were used to detect cell proliferation, migration and invasion. RNA sequencing was performed to determine the downstream signal of CerS3. RESULTS: Compared with the corresponding adjacent tissues,the mRNA and protein levels of CerS3 were elevated in the HCC tissues, with significant difference (both P<0.05). The Univariate and multivariate analysis showed that the overall survival rate was significantly correlated with the presence of venous invasion (95% CI 1.8-9.2, P<0.01), TNM stage (95% CI 2.3-5.2, P<0.05), poor histological grade (95% CI 1.4-6.8, P<0.05), and CerS3 (95% CI 1.5-3.9, P<0.05). Furthermore, the high CerS3 expression levels in tumor tissues were significantly associated with shorter overall survival rates compared with the low CerS3 expression (P<0.05). Compared with the vector control group, the Hep3B cell viability, EdU positive cells, and migration and invasion cell numbers in the CerS3 vector group were significantly increased (all P<0.05). Compared with the shRNA normal control group, the HCCLM3 cell viability, EdU positive cells, and numbers of migrating and invasive cells in the CerS3 shRNA group were significantly lower (all P<0.05). The RNA sequencing confirmed that the small mothers against decapentaplegic family member 6 (SMAD6) gene as an oncogenic gene could promote the HCC metastasis. CONCLUSIONS: Clinically, the overexpression of CerS3 is closely related to poor clinical features and poor prognosis. Functionally, CerS3 participates in the proliferation, invasion and metastasis of liver cancer cells via activating SMAD6 gene.

Precatalyst-Enabled Selectivity: Enantioselective NiH-Catalyzed anti-Hydrometalative Cyclization of Alkynones to Endo- and Heterocyclic Allylic Alcohols.

A highly enantioselective NiH-catalyzed hydrocyclization of alkynones with unparalleled anti- and endocyclic selectivities is described. The choice of the precatalysts has significant influence in tuning the regio- and enantioselectivity. Using Ni(OTs)2 /Phox as a precatalyst and (EtO)2 MeSiH as a hydride source, an array of enantioenriched O-, N-, and S-containing heterocyclic tertiary allylic alcohols are obtained in 24-81 % yields with 80:20-99:1 er. Mechanistic investigations and synthetic application are also carried out. This study represents an efficient access to a set of allylic alcohols that are unable to access by the state-of-the-art coupling reactions.

Conflict management in a multinational firm's production shifting decisions.

In recent years, many apparel multinational firms (MNFs) have shifted their production from traditional manufacturing bases (e.g., China) to the emerging ones located in Southeast Asia (e.g., Vietnam and Bengal). The interactions among market sizes, MNF's competition with local rival and the global tax rules play key roles in the MNF's decisions. In this paper, we study the preferences of a MNF and its contract manufacturer (CM) over two manufacturing outsourcing structures and investigate whether their objective conflicts can be reconciled. The MNF relies on the CM for production and sells goods in both Chinese and Southeast Asian markets. It is optional for the MNF to use a CM located in China, but has to suffer from the CM's differential prices because of China's partial value-added tax (VAT) refund policy. It is also optional for the MNF to use a CM located in Southeast Asia, resulting in uniform production fee for the goods sold in two markets. The former is traditional outsourcing structure (TS), and the latter is shifted outsourcing structure (SS). Interestingly, we find that, the MNF may first prefer SS, then prefer TS, and back to prefer SS, as the relative market potential between the Southeast Asian market and the Chinese market increases. The CM's preferences may switch twice, too. We identify the opportunities where the preferences of the MNF and the CM are aligned, which are driven by China's partial VAT refund policy.

Tuning the Connectivity, Rigidity, and Functionality of Two-Dimensional Zr-Based Metal-Organic Frameworks.

Presented herein is a group of highly stable Zr-based metal-organic frameworks with bowl-shaped dihydroanthracene-based tetratopic linkers as building blocks. Structural analysis reveals that these frameworks are all two-dimensional but comprise three distinct connectivities of Zr6 nodes. By using the steric hindrance of the nonplanar linker, the connectivity of Zr6 node can be tuned from 8-c to unusual 4-c. Further, through either one-pot synthesis or postsynthetic linker installation strategies, the connectivity of Zr6 node can be tuned from 8-c to 10-c by the insertion of a secondary linear dicarboxylate linker, from which not only the temperature-dependent flexibility of the structure can be effectively controlled with enhanced rigidity and thermal stability but also a scaffold for postsynthetic metalation of Pd(II) catalyst for Heck coupling reaction is offered.

Nonlinear-Optical Behaviors of a Chiral Metal-Organic Framework Comprised of an Unusual Multioriented Double-Helix Structure.

We present here the synthesis of one enantiomeric pair of metal-organic framework materials comprised of a unique multioriented double-helix structure from an achiral spirocenter ligand. Our study clearly shows that the chiral MOF material encompasses concurrently multiple nonlinear-optical functions in the solid state: the noncentrosymmetric structural feature brings the chiral MOF high second-harmonic-generation efficiency; the incorporation of the spirocenter ligand can efficiently produce two-photon-excited photoluminescence with a larger-action cross-sectional value.

Damage-tolerance strategies for nacre tablets.

Nacre, a natural armor, exhibits prominent penetration resistance against predatory attacks. Unraveling its hierarchical toughening mechanisms and damage-tolerance design strategies may provide significant inspiration for the pursuit of high-performance artificial armors. In this work, relationships between the structure and mechanical performance of nacre were investigated. The results show that other than their brick-and-mortar structure, individual nacre tablets significantly contribute to the damage localization of nacre. Affected by intracrystalline organics, the tablets exhibit a unique fracture behavior. The synergistic action of the nanoscale deformation mechanisms increases the energy dissipation efficiency of the tablets and contributes to the preservation of the structural and functional integrity of the shell.

Cathepsin B: The dawn of tumor therapy.

Cathepsin B (CTSB) is a key lysosomal protease that plays a crucial role in the development of cancer. This article elucidates the relationship between CTSB and cancer from the perspectives of its structure, function, and role in tumor growth, migration, invasion, metastasis, angiogenesis and autophagy. Further, we summarized the research progress of cancer treatment related drugs targeting CTSB, as well as the potential and advantages of Traditional Chinese medicine in treating tumors by regulating the expression of CTSB.

Hepatic-associated vascular morphological assessment to predict overt hepatic encephalopathy before TIPS: a multicenter study.

BACKGROUND: To provide patients the chance of accepting curative transjugular intrahepatic portosystemic shunt (TIPS) rather than palliative treatments for portal hypertension-related variceal bleeding and ascites, we aimed to assess hepatic-associated vascular morphological change to improve the predictive accuracy of overt hepatic encephalopathy (HE) risks. METHODS: In this multicenter study, 621 patients undergoing TIPS were subdivided into training (413 cases from 3 hospitals) and external validation datasets (208 cases from another 3 hospitals). In addition to traditional clinical factors, we assessed hepatic-associated vascular morphological changes using maximum diameter (including absolute and ratio values). Three predictive models (clinical, hepatic-associated vascular, and combined) were constructed using logistic regression. Their discrimination and calibration were compared to test the necessity of hepatic-associated vascular assessment and identify the optimal model. Furthermore, to verify the improved performance of ModelC-V, we compared it with four previous models, both in discrimination and calibration. RESULTS: The combined model outperformed the clinical and hepatic-associated vascular models (training: 0.814, 0.754, 0.727; validation: 0.781, 0.679, 0.776; p < 0.050) and had the best calibration. Compared to previous models, ModelC-V showed superior performance in discrimination. The high-, middle-, and low-risk populations displayed significantly different overt HE incidence (p < 0.001). Despite the limited ability of pre-TIPS ammonia to predict overt HE risks, the combined model displayed a satisfactory ability to predict overt HE risks, both in the low- and high-ammonia subgroups. CONCLUSION: Hepatic-associated vascular assessment improved the predictive accuracy of overt HE, ensuring curative chances by TIPS for suitable patients and providing insights for cirrhosis-related studies.

Effects of chemotherapy and immunotherapy on microbial diversity in TME and engineered bacterial-mediated tumor therapy.

Tumor microbiota is a group of microorganisms located in tumor tissues with rich diversity that can promote tumorigenesis and development, and different types of tumors have different tumor microbiotas, which has important implications for tumor research, detection, and clinical treatment. In this review, we examine the diversity of the tumor microbiota, discuss the impact of chemotherapy and immunotherapy on tumor microbiota diversity, and summarize recent advances in the use of genetically engineered bacteria for the treatment of tumors. In addition, we propose key questions that need to be further addressed by the tumor microbiota.

Postprocedural Opioid-Prescribing Practice in Nail Surgery.

BACKGROUND: Ingrown toenails are a common condition requiring outpatient procedures in podiatric medical clinics. To prevent recurrence, chemical matrixectomy is often recommended. Postprocedural pain management is largely based on preferences rather than on a formal guideline. This study aims to explore the postprocedural prescribing behavior among practicing podiatric physicians to foster future guideline and policy development. METHODS: We administered an open, voluntary, anonymous questionnaire via an online survey platform that included a common nail procedure scenario (chemical matrixectomy) and a prescribed demographics section. Podiatric physicians were asked what they would prescribe to manage postprocedural pain. Opioid and nonopioid options were provided. We developed two multiple logistic regression models to identify associations between prescriber characteristics and prescribing opioids after "standard" chemical matrixectomy. RESULTS: Of the 860 podiatrists who completed the survey, 8.7% opted to prescribe an opioid. Hydrocodone was most commonly chosen. A median of 18 opioid pills were prescribed. No prescriber characteristics were associated with prescribing opioids after chemical matrixectomy scenario. There is a large discrepancy and knowledge gap in the literature on the optimal postprocedural pain management for outpatient procedures, including procedures in specialties such as dentistry and dermatology. The median number of opioids prescribed by podiatrists is higher than that by dentists for management of third molar extraction. In contrast, opioid-prescribing behavior among the 8.7% of respondents is similar to dermatologic management of postprocedural pain in Mohs surgery. CONCLUSIONS: Podiatric physicians cannot assume that their prescribing of opioids does not affect the opioid abuse problem in the United States. The presented study serves to be an initiation for procedure-specific opioid prescription benchmarking to foster future guideline and policy development. After nail procedures, opioids should not be routinely prescribed.

Energy metabolism: A critical target of cardiovascular injury.

Cardiovascular diseases are the main killers threatening human health. Many studies have shown that abnormal energy metabolism plays a key role in the occurrence and development of acute and chronic cardiovascular diseases. Regulating cardiac energy metabolism is a frontier topic in the treatment of cardiovascular diseases. However, we are not very clear about the choice of different substrates, the specific mechanism of energy metabolism participating in the course of cardiovascular disease, and how to develop appropriate drugs to regulate energy metabolism to treat cardiovascular disease. Therefore, this paper reviews how energy metabolism participates in cardiovascular pathophysiological processes and potential drugs aimed at interfering energy metabolism.It is expected to provide good suggestions for promoting the clinical prevention and treatment of cardiovascular diseases from the perspective of energy metabolism.

Well-Defined Shell-Sheddable Core-Crosslinked Micelles with pH and Oxidation Dual-Response for On-Demand Drug Delivery.

Micellar-nanocarrier-based drug delivery systems possessing characteristics such as an excellent circulation stability, inhibited premature release and on-demand site-specific release are urgently needed for enhanced therapeutic efficacy. Therefore, a novel kind of shell-sheddable core-crosslinked polymeric micelles with pH and oxidation dual-triggered on-demand drug release behavior was facilely constructed. The multifunctional micelles were self-assembled from a carefully designed amphiphilic triblock PEGylated polyurethane (PEG-acetal-PUBr-acetal-PEG) employing an acid-labile acetal linker at the hydrophilic-hydrophobic interface and pendant reactive bromo-containing polyurethane (PU) as the hydrophobic block, followed by a post-crosslinking via oxidation-cleavable diselenide linkages. These well-defined micelles exhibited an enhanced structural stability against dilution, achieved through the incorporation of diselenide crosslinkers. As expected, they were found to possess dual pH- and oxidation-responsive dissociation behaviors when exposure to acid pH (~5.0) and 50 mM H2O2 conditions, as evidenced using dynamic light-scattering (DLS) and atomic force microscopy (AFM) analyses. An in vitro drug release investigation showed that the drug indomethacin (IND) could be efficiently encapsulated in the micelles, which demonstrated an inhibited premature release compared to the non-crosslinked ones. It is noteworthy that the resulting micelles could efficiently release entrapped drugs at a fast rate in response to either pH or oxidation stimuli. Moreover, the release could be significantly accelerated in the presence of both acid pH and oxidation conditions, relative to a single stimulus, owing to the synergetic degradation of micelles through pH-induced dePEGylation and oxidation-triggered decrosslinking processes. The proposed shell-sheddable core-crosslinked micelles with a pH and oxidation dual-response could be potential candidates as drug carriers for on-demand drug delivery.