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1.
J Cell Biol ; 221(1)2022 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-34813648

RESUMO

Primary cilia transduce diverse signals in embryonic development and adult tissues. Defective ciliogenesis results in a series of human disorders collectively known as ciliopathies. The CP110-CEP97 complex removal from the mother centriole is an early critical step for ciliogenesis, but the underlying mechanism for this step remains largely obscure. Here, we reveal that the linear ubiquitin chain assembly complex (LUBAC) plays an essential role in ciliogenesis by targeting the CP110-CEP97 complex. LUBAC specifically generates linear ubiquitin chains on CP110, which is required for CP110 removal from the mother centriole in ciliogenesis. We further identify that a pre-mRNA splicing factor, PRPF8, at the distal end of the mother centriole acts as the receptor of the linear ubiquitin chains to facilitate CP110 removal at the initial stage of ciliogenesis. Thus, our study reveals a direct mechanism of regulating CP110 removal in ciliogenesis and implicates the E3 ligase LUBAC as a potential therapy target of cilia-associated diseases, including ciliopathies and cancers.

2.
J Colloid Interface Sci ; 607(Pt 2): 1993-2009, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34798708

RESUMO

HYPOTHESIS: Lung surfactant protects lung tissue and reduces the surface tension in the alveoli during respiration. Particulate matter with an aerodynamic diameter of less than 2.5 µm (PM2.5), which invades primely through inhalation, can deposit on and interact with the surfactant layer, leading to changes in the biophysical and morphological properties of the lung surfactant. EXPERIMENTS: Langmuir monolayers of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and clinical surfactant Calsurf were investigated with a PM2.5 model injected into the water subphase, which were characterized by surface pressure-area isotherms, Brewster angle microscopy, atomic force microscopy, fluorescent microscopy, and x-ray photoelectron spectroscopy. The binding between DPPC/Calsurf and PM2.5 was studied using isothermal titration calorimetry. FINDINGS: PM2.5 induced the expansion of the monolayers at low surface pressure (п) and film condensation at high п. Aggregation of PM2.5 mainly occurred at the interface of liquid expanded/liquid condensed (LE/LC) phases. PM2.5 led to slimmer and ramified LC domains on DPPC and the reduction of nano-sized condensed domains on Calsurf. Both DPPC and Calsurf showed fast binding with PM2.5 through complex binding modes attributed to the heterogeneity and amphiphilic property of PM2.5. This study improves the fundamental understanding of PM2.5-lung surfactant interaction and shows useful implications of the toxicity of PM2.5 through respiration process.


Assuntos
1,2-Dipalmitoilfosfatidilcolina , Surfactantes Pulmonares , Produtos Biológicos , Material Particulado , Fosfolipídeos , Propriedades de Superfície , Tensoativos
4.
J Colloid Interface Sci ; 605: 354-363, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34332409

RESUMO

HYPOTHESIS: Organic co-solvents, which are universally employed in adsorption studies of hydrophobic organic chemicals (HOCs), can inhibit HOC adsorption by competing for active sites on the adsorbent. The adsorbent structure can influence co-solvent interference of HOC adsorption; however, this effect remains unclear, leading to an incomplete understanding of the adsorption mechanism. EXPERIMENTS: In this study, dioctyl phthalate (DOP) was used to investigate competitive adsorption on functionalized graphene sheet in a water-methanol co-solvent system through molecular dynamics simulations and quantum chemical calculations. FINDINGS: The simulations showed that the functional groups in the graphene defects had a strong adsorption affinity for methanol. The adsorbed methanol occupied a large number of active sites at the graphene center, thereby weakening DOP adsorption. However, the methanol adsorbed at the graphene edges could not compete with DOP for the active sites. -COOH had the strongest binding affinity for methanol among the functional groups and thus predominantly controlled the interaction between graphene and methanol. This study makes an innovative contribution toward understanding the competitive adsorption of methanol and DOP on functionalized graphene sheet, especially in visualizing the competition for active sites, and provides theoretical guidance for the removal of HOCs and practical application of graphene.


Assuntos
Dietilexilftalato , Grafite , Adsorção , Metanol , Simulação de Dinâmica Molecular , Solventes
5.
Food Chem ; 371: 131388, 2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34808779

RESUMO

In recent years, the safety of copper in drinking water has increasingly been questioned. Copper speciation is an important factor that affects its bioavailability and toxicity; thus, it is critical to investigate the speciation of copper that is ingested from food and drinking water during in vitro digestion. After digestion, water- and food-derived copper formed 60 ± 4% 0.1-1 kDa and 49 ± 6% 10-1,000 kDa copper complexes, respectively. Under simulated fasting drinking water conditions, up to 90 ± 2% 0.1-1 kDa copper complexes formed. In addition, using ion selective electrode analysis, water-derived copper was detected that contained higher Cu2+ concentrations after digestion than those of food-derived copper. These results indicate that water-derived copper forms smaller-sized species and exhibits higher Cu2+ concentrations during digestion than those of food-derived copper, thereby highlighting the importance of reassessing the safety limit for copper in drinking water.


Assuntos
Cobre , Água Potável , Disponibilidade Biológica , Cobre/análise , Digestão
6.
mSystems ; : e0113621, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34726486

RESUMO

Environmental monitoring in public spaces can be used to identify surfaces contaminated by persons with coronavirus disease 2019 (COVID-19) and inform appropriate infection mitigation responses. Research groups have reported detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on surfaces days or weeks after the virus has been deposited, making it difficult to estimate when an infected individual may have shed virus onto a SARS-CoV-2-positive surface, which in turn complicates the process of establishing effective quarantine measures. In this study, we determined that reverse transcription-quantitative PCR (RT-qPCR) detection of viral RNA from heat-inactivated particles experiences minimal decay over 7 days of monitoring on eight out of nine surfaces tested. The properties of the studied surfaces result in RT-qPCR signatures that can be segregated into two material categories, rough and smooth, where smooth surfaces have a lower limit of detection. RT-qPCR signal intensity (average quantification cycle [Cq]) can be correlated with surface viral load using only one linear regression model per material category. The same experiment was performed with untreated viral particles on one surface from each category, with essentially identical results. The stability of RT-qPCR viral signal demonstrates the need to clean monitored surfaces after sampling to establish temporal resolution. Additionally, these findings can be used to minimize the number of materials and time points tested and allow for the use of heat-inactivated viral particles when optimizing environmental monitoring methods. IMPORTANCE Environmental monitoring is an important tool for public health surveillance, particularly in settings with low rates of diagnostic testing. Time between sampling public environments, such as hospitals or schools, and notifying stakeholders of the results should be minimal, allowing decisions to be made toward containing outbreaks of coronavirus disease 2019 (COVID-19). The Safer At School Early Alert program (SASEA) (https://saseasystem.org/), a large-scale environmental monitoring effort in elementary school and child care settings, has processed >13,000 surface samples for SARS-CoV-2, detecting viral signals from 574 samples. However, consecutive detection events necessitated the present study to establish appropriate response practices around persistent viral signals on classroom surfaces. Other research groups and clinical labs developing environmental monitoring methods may need to establish their own correlation between RT-qPCR results and viral load, but this work provides evidence justifying simplified experimental designs, like reduced testing materials and the use of heat-inactivated viral particles.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34745309

RESUMO

Ischemic heart disease is a significant risk factor that threatens human health, and antiplatelet drugs are routinely used to treat cases in clinical settings. Chinese medicine for promoting blood circulation and removing blood stasis (PBCRBSCM) can often be combined with antiplatelet drugs to treat ischemic heart disease. PBCRBSCM can inhibit platelet adhesion, activation, and aggregation; moreover, PBCRBSCM in combination with antiplatelet drugs exerts antiplatelet effects. The mechanism is related to several factors, including the inhibition of platelet activation and aggregation, improvement of the hemodynamic status and coagulation function, and correction of metabolism and inflammation. PBCRBSCM can also regulate the absorption and metabolism of conventional antiplatelet drugs and protect the gastric mucosal epithelial cells against damage induced by conventional antiplatelet drugs. Randomized controlled trials have confirmed that PBCRBSCM preparations and the active ingredients in these preparations can reduce resistance to aspirin and clopidogrel so that the combination of these drugs can exert their antiplatelet effects. In the perioperative treatment of patients with stable angina pectoris, unstable angina pectoris, and acute coronary syndrome undergoing percutaneous coronary intervention therapy, preparations of the active ingredients of PBCRBSCM combined with antiplatelet drugs and other conventional Western medicine treatments have been proven effective. The efficacy and safety of such combinations have also been extensively verified. Considerable progress has been made to understand the antiplatelet mechanism of PBCRBSCM. However, most clinical studies had problems, such as limited sample size and inappropriate research design, which has limited the translational use of PBCRBSCM in antiplatelet therapy. A large-scale, multicenter, randomized controlled study with cardiovascular events as the endpoint is still to be conducted to provide evidence for the combined application of PBCRBSCM and antiplatelet drugs in the prevention and treatment of ischemic heart disease.

8.
Chemosphere ; : 132747, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34728223

RESUMO

The elucidation of interactions between the dissolved black carbon (DBC) in biochar and hydrophobic organic contaminants (HOCs) is crucial for controlling the environmental behavior of HOCs. The complicated chemical structures of DBCs result in diverse interaction mechanisms between DBCs and HOCs, which were driven by different chemical structures in DBCs. In the present study, ten DBCs were extracted from rice straw and corncob biochars and their chemical structures were characterized and analyzed. The binding of phenanthrene (Phen) with DBC were studied through fluorescence quenching experiments. DBCs with low concentration (1 mg C/L) were found to complex with high amounts of Phen per unit mass. No significant difference was found in the amount of the bound Phen per unit amount of DBC when the concentration of DBC increased beyond >5 mg C/L. The dominant mechanisms involved in the binding of Phen by DBCs are speculated to be hydrophobic interactions, π-π electron donor-acceptor (EDA), and chemical partition, which was driven by the fatty carbon chain, aromatic rings, and quinone groups or ester groups, respectively. This study elucidates the interactions between DBC and Phen, which is of great significance for understanding the environmental behavior of HOCs.

9.
Microbiol Spectr ; : e0091321, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34756065

RESUMO

Enterococcus faecium is a clinically important pathogen that can cause significant morbidity and death. In this study, we aimed to develop a machine learning (ML) algorithm-based rapid susceptibility method to distinguish vancomycin-resistant E. faecium (VREfm) and vancomycin-susceptible E. faecium (VSEfm) strains. A predictive model was developed and validated to distinguish VREfm and VSEfm strains by analyzing the matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry (MS) spectra of unique E. faecium isolates from different specimen types. The algorithm used 5,717 mass spectra, including 2,795 VREfm and 2,922 VSEfm mass spectra, and was externally validated with 2,280 mass spectra of isolates (1,222 VREfm and 1,058 VSEfm strains). A random forest-based algorithm demonstrated overall good classification performances for the isolates from the specimens, with mean accuracy, sensitivity, and specificity of 0.78, 0.79, and 0.77, respectively, with 10-fold cross-validation, timewise validation, and external validation. Furthermore, the algorithm provided rapid results, which would allow susceptibility prediction prior to the availability of phenotypic susceptibility results. In conclusion, an ML algorithm designed using mass spectra obtained from the routine workflow may be able to rapidly differentiate VREfm strains from VSEfm strains; however, susceptibility results must be confirmed by routine methods, given the demonstrated performance of the assay. IMPORTANCE A modified binning method was incorporated to cluster MS shifting ions into a set of representative peaks based on a large-scale MS data set of clinical VREfm and VSEfm isolates, including 2,795 VREfm and 2,922 VSEfm isolates. Predictions with the algorithm were significantly more accurate than empirical antibiotic use, the accuracy of which was 0.50, based on the local epidemiology. The algorithm improved the accuracy of antibiotic administration, compared to empirical antibiotic prescription. An ML algorithm designed using MALDI-TOF MS spectra obtained from the routine workflow accurately differentiated VREfm strains from VSEfm strains, especially in blood and sterile body fluid samples, and can be applied to facilitate the rapid and accurate clinical testing of pathogens.

10.
ISA Trans ; 2021 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-34749985

RESUMO

In this paper, we propose a unified and simple trajectory planning-based control strategy for the n-link (n≥2⋂n∈Z) vertical underactuated manipulator (VUM) with an underactuated joint. The proposed method does not need to partition the entire motion space like the traditional methods, and can quickly realize the control objective of swinging the endpoint of the system up from the vertical downward starting position and stabilizing it at the vertical upward ending position. The trajectory planned for each active link includes two stages. The first stage is to make the first active link and passive link reach the intermediate states, and other active links reach the ending states. The second stage is to move the first active link and the passive link to the ending states, while other active links keep at the ending states. Considering the above targets of two stages, the trajectory of each active link is designed and the trajectory parameters are optimized via utilizing the differential evolution algorithm. Then, the tracking controllers and stabilization controllers are designed to track the two-stage trajectories and to stay the endpoint at the ending position. Finally, the numerical simulations are carried out to show the feasibility and superiority of the proposed method.

11.
Nat Commun ; 12(1): 6407, 2021 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-34737287

RESUMO

Colorectal cancer is one of the most common cancers in the world. Although genomic mutations and single nucleotide polymorphisms have been extensively studied, the epigenomic status in colorectal cancer patient tissues remains elusive. Here, together with genomic and transcriptomic analysis, we use ChIP-Seq to profile active enhancers at the genome wide level in colorectal cancer paired patient tissues (tumor and adjacent tissues from the same patients). In total, we sequence 73 pairs of colorectal cancer tissues and generate 147 H3K27ac ChIP-Seq, 144 RNA-Seq, 147 whole genome sequencing and 86 H3K4me3 ChIP-Seq samples. Our analysis identifies 5590 gain and 1100 lost variant enhancer loci in colorectal cancer, and 334 gain and 121 lost variant super enhancer loci. Multiple key transcription factors in colorectal cancer are predicted with motif analysis and core regulatory circuitry analysis. Further experiments verify the function of the super enhancers governing PHF19 and TBC1D16 in regulating colorectal cancer tumorigenesis, and KLF3 is identified as an oncogenic transcription factor in colorectal cancer. Taken together, our work provides an important epigenomic resource and functional factors for epigenetic studies in colorectal cancer.

12.
Neoplasia ; 23(12): 1204-1212, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34735995

RESUMO

BACKGROUND: Metastases are responsible for over 70% of deaths from lung adenocarcinomas. Previous large-scale studies of LUAD mainly focused on primary diseases. We aimed to comprehensively analyze the genomic landscape of metastatic LUADs and elucidate its clinical implications in the context of precision medicine. METHODS: We performed retrospective analyses on targeted sequencing data of 3,743 primary tumors and 934 metastases from 4,480 patients with lung adenocarcinomas, and PD-L1 immunohistochemical data of 1,336 primary tumors and 252 metastases from 1,588 LUAD patients. RESULTS: Metastases generally manifested significantly higher mutational burdens and chromosomal instability than primary lung adenocarcinomas. Clinically actionable alterations, including ALK mutations, ALK and ROS1 fusions, and MET copy number gains, were enriched in metastases, particularly metastases to some specific organs/tissues, such as lymph nodes, liver, and brain. PD-L1 expression decreased as the approximate metastatic distance increased. Additional data of paired primary tumors and metastases to lymph nodes and brain validated patterns of actionable alterations and candidates for metastatic drivers. Two evolutionary modes of metastatic dissemination, common origins and distinct origins, were identified in both types of primary-metastasis pairs. CONCLUSIONS: Our study showed heterogenous patterns of clinically actionable alterations, PD-L1 expressions, metastatic driver candidates, and evolutionary patterns among multiple types of metastases of lung adenocarcinomas, which may advise the planning of treatments and the identification of novel therapeutic targets.

13.
Adv Mater ; : e2106885, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34798686

RESUMO

Improving the enrichment of drugs or theranostic agents within tumors is vital to achieve effective cancer diagnosis and therapy with reduced dosage and damage to normal tissues. In this work, we describe an enzyme-mediated AIEgen intracellular polymerization strategy that can simultaneously promote the accumulation and retention of the AIEgen in the tumor for prolonged imaging and enhanced tumor growth inhibition. We rationally designed an AIEgen-peptide conjugate (D2P1) and cyanobenzothiazole-cysteine (3CBT) that can undergo rapid condensation reaction to form nanoaggregates in tumor cells. Upon tumor-specific cathepsin protease reaction, the cleavage of peptides induces condensate polymerization between the exposed cysteine and 2-cyanobenzothiazole on 3CBT, triggering accumulation of D2P1 into the tumor site, leading to fluorescence light-up. Such enzyme-mediated polymerization of D2P1 and 3CBT alters cellular motility via disrupting actin organization and in turn inhibiting cell proliferation. In addition, due to the built-in intrinsic photosensitization property of the AIEgen, the accumulation of D2P1 could remarkably promote the tumor photodynamic therapy effect in vivo under light irradiation. This study thus represents the enzyme-mediated intracellular polymerization system with high potential to improve the diagnostic and therapeutic outcomes of tumors in vivo. This article is protected by copyright. All rights reserved.

14.
Ann Transl Med ; 9(20): 1556, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34790762

RESUMO

Background: To determine whether preoperative computed tomography (CT) features can be used for the prediction of gastrointestinal stromal tumors (GISTs) with a high Ki-67 proliferation index (Ki-67 PI). Methods: A total of 198 patients with surgically and pathologically proven GISTs were retrospectively included. All GISTs were divided into a low Ki-67 PI group (<10%) and a high Ki-67 PI group (≥10%). All imaging features were blindly interpreted by two radiologists. Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the predictive performance of the imaging features. Results: Imaging features were found to be significantly different between the low and the high Ki-67 PI groups (P<0.05). Wall thickness of necrosis showed the highest predictive ability, with an area under the curve (AUC) of 0.838 [95% confidence interval (CI): 0.627-0.957], followed by necrosis, necrosis degree, hyperenhancement of the overlying mucosa (HYOM), and long diameter (LD) (AUC >0.7, P<0.05). HYOM was the strongest predictive feature for the high Ki-67 PI GISTs group, with an odds ratio (OR) value of 30.037 (95% CI: 5.707-158.106). Conclusions: Imaging features, including the presence of necrosis, high necrosis degree, thick wall of necrosis, and HYOM were significant predictive indicators for the high Ki-67 PI GISTs group.

15.
BMJ Open ; 11(11): e046682, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34794984

RESUMO

OBJECTIVES: Polycyclic aromatic hydrocarbons (PAHs) have been proven to be a risk factor for cardiovascular disease in coke oven workers, and increased plasma viscosity is a signal for higher risk of catching up cardiovascular disease. We want to explore whether the plasma viscosity is affected by the concentration of PAHs. DESIGN: Our study is a cross-sectional dose-response study. SETTING: Participants in this study came from a coke plant in Taiyuan, Shanxi. PARTICIPANTS: We used data of 693 coke oven workers in Taiyuan. PRIMARY AND SECONDARY OUTCOME MEASURES: We assumed that plasma viscosity would increase as the concentration of PAHs metabolites in urine increases. We found that 2-hydroxyfluorene (OHFLU2) and plasma viscosity have a stable linear relationship in different statistical methods. RESULTS: We found that plasma viscosity increased by 1.14 (mPa.s,30/s) for each ng/mL of 2-OHFLU urinary (correlation coefficient range: 0.54-1.74, p<0.05). CONCLUSIONS: The results of this study could provide evidence for coke oven workers to prevent cardiovascular disease by checking whether plasma viscosity is elevated.

16.
J Ultrasound Med ; 2021 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-34837655

RESUMO

OBJECTIVE: This study aimed to investigate the correlation between contrast-enhanced ultrasound (CEUS) features and molecular subtypes of breast cancer (BC). METHODS: A total of 116 patients (116 lesions) with pathologically diagnosed BC who received conventional ultrasound and CEUS before surgery were enrolled in this study. BC molecular subtypes were identified by postoperative pathological and immunohistochemical analysis as Luminal A (LA), Luminal B (LB), HER2 (H2) over-expression, and triple-negative (TN). Qualitative and quantitative CEUS characteristics were analyzed by one-way analysis of variance (continuous variables) or Pearson's χ2 test or Fisher's exact probability method (categorical variables). RESULTS: There were significant differences in enhancement speed and enhancement degree among the four subtypes (P < .05). The area under the curve (AUC), time to peak (TTP), and peak intensity (PI) differed among the four subtypes (P < .05). The AUC of the LA subtype (305.1 ± 188.4) was significantly smaller compared with the H2 (535.7 ± 222.0, P = .007) and TN subtypes (496.6 ± 254.7, P = .019). In addition, TTP was shorter in the H2 subtype (19.8 ± 4.9) compared with the other subtypes, and was significantly shorter than in the LA subtype (26.3 ± 7.2, P = .008) and LB subtype (23.1 ± 6.7, P = .036). The PI of the LA subtype (4.7 ± 2.3) was significantly lower than that of the LB (6.6 ± 2.3, P = .027), H2 (7.4 ± 2.2, P = .005), and TN subtypes (6.9 ± 2.6, P = .014). CONCLUSIONS: CEUS features differed significantly among different molecular subtypes of BC. The enhancement patterns and parameters may be important predictive features of different subtypes of BC.

17.
Mater Horiz ; 8(5): 1454-1460, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34846453

RESUMO

A living therapeutic system based on attenuated Salmonella was developed via metabolic engineering using an aggregation-induced emission (AIE) photosensitizer MA. The engineered bacteria could localize in the tumor tissues and continue to colonize and express exogenous genes. Under light irradiation, the encoded VEGFR2 gene was released and expressed in tumor tissues, which can suppress angiogenesis induced by a T cell-mediated autoimmune response and inhibit tumor growth.

18.
Front Physiol ; 12: 748040, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34819874

RESUMO

Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1-/- mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1-/- adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.

19.
Biomaterials ; : 121261, 2021 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-34815099

RESUMO

Immunogenic cell death (ICD) is a promising strategy in cancer immunotherapy to induce high immunogenicity and activate the immune system. However, its efficacy is counteracted by the concurrent exposure of phosphatidylserine (PS), an immunosuppressive signal on the surface of cancer cells. Here we report the synthesis of a bimetallic metal-organic framework (MOF) nanoparticle containing Gd3+ and Zn2+ (Gd-MOF-5) that can be used as an immunomodulator to downregulate the immunosuppressive PS signal and an ICD inducer to upregulate immunostimulatory signals. Gd3+ inhibits PS externalization via inhibiting the activity of scramblase, an enzyme to transfer PS to the outer leaflet of plasma membrane. Moreover, intracellular Zn2+ overload activates endoplasmic reticulum stress for ICD induction. In combination with an immune checkpoint inhibitor (PD-L1 antibody, denoted as aPDL1), Gd-MOF-5 activated potent immune response and effectively inhibited primary and distal tumor growth in a bilateral 4T1 tumor model. This work presents a new strategy using designed MOF materials to modulate the cell signalling and immunosuppressive microenvironment to improve the outcome of cancer immunotherapy.

20.
IEEE Trans Cybern ; PP2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34818201

RESUMO

For a three-link vertical underactuated manipulator (TVUM) with only one active joint, the control target is to swing up its endpoint from the straight-down equilibrium point (SDEP) and to stabilize the endpoint at the straight-up equilibrium point (SUEP) eventually. Up to now, there are few effective control strategies to achieve the above control target. In this article, we propose an effective control method based on the trajectory optimization to realize the system control target, and the main steps of this article are: 1) a continuous trajectory that consists of two segments with design parameters is planned for the actuated link, along which the actuated link can be swung up from the initial states to the final states; 2) the design parameters are optimized by using the intelligent optimization algorithm to guarantee that the states of the underactuated links are continuous at the junction. In this way, the underactuated links are also moved to their final states with the actuated link simultaneously; 3) a tracking controller is designed by using the sliding-mode method to track the trajectory with optimized design parameters, so the endpoint is swung up from the SDEP to the SUEP directly; and 4) a stabilizing controller is further devised through the LQR method to keep the endpoint being stable at the SUEP. Finally, simulation results show that the proposed control method achieves the swing-up and stable control target of the system, and the control performance of the proposed method is superior than that of the existing control methods through the comparisons.

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