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The design, synthesis, and characterization of two novel nonfullerene acceptors (M8 and M34) based on ladder-type heteroheptacenes with different heterocycles are reported. Replacing the furan heterocycles with the thiophene heterocycles in the heteroheptacene backbone leads to a hypsochromically shifted absorption band and greatly improved carrier transport for the resulting nonfullerene acceptor (M34) although the π-π-stacking distances are barely affected. Bulk-heterojunction polymer solar cells fabricated from M34 and a wide band gap polymer (PM6) as the donor showed a best power conversion efficiency (PCE) of 15.24 % with an open circuit voltage (VOC ) of 0.91â V, much higher than a PCE of 4.21 % and a VOC of 0.83â V for the counterparts based on M8:PM6. These results highlight the importance of key atoms in the construction of high-performance nonfullerene acceptors.
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Expanding the number of nucleotides in DNA increases the information density of functional DNA molecules, creating nanoassemblies that cannot be invaded by natural DNA/RNA in complex biological systems. Here, we show how six-letter GACTZP DNA contributes this property in two parts of a nanoassembly: 1)â in an aptamer evolved from a six-letter DNA library to selectively bind liver cancer cells; and 2)â in a six-letter self-assembling GACTZP nanotrain that carries the drug doxorubicin. The aptamer-nanotrain assembly, charged with doxorubicin, selectively kills liver cancer cells in culture, as the selectivity of the aptamer binding directs doxorubicin into the aptamer-targeted cells. The assembly does not kill untransformed cells that the aptamer does not bind. This architecture, built with an expanded genetic alphabet, is reminiscent of antibodies conjugated to drugs, which presumably act by this mechanism as well, but with the antibody replaced by an aptamer.
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Aptámeros de Nucleótidos/química , ADN/química , Doxorrubicina/uso terapéutico , Neoplasias Hepáticas/tratamiento farmacológico , Línea Celular Tumoral , Doxorrubicina/farmacología , Humanos , Neoplasias Hepáticas/genéticaRESUMEN
This paper focuses on the problem of finding a particular data recommendation strategy based on the user preference and a system expected revenue. To this end, we formulate this problem as an optimization by designing the recommendation mechanism as close to the user behavior as possible with a certain revenue constraint. In fact, the optimal recommendation distribution is the one that is the closest to the utility distribution in the sense of relative entropy and satisfies expected revenue. We show that the optimal recommendation distribution follows the same form as the message importance measure (MIM) if the target revenue is reasonable, i.e., neither too small nor too large. Therefore, the optimal recommendation distribution can be regarded as the normalized MIM, where the parameter, called importance coefficient, presents the concern of the system and switches the attention of the system over data sets with different occurring probability. By adjusting the importance coefficient, our MIM based framework of data recommendation can then be applied to systems with various system requirements and data distributions. Therefore, the obtained results illustrate the physical meaning of MIM from the data recommendation perspective and validate the rationality of MIM in one aspect.
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BACKGROUND: Angiostrongylus cantonensis, an important foodborne parasite, can induce serious eosinophilic meningitis in non-permissive hosts, such as mouse and human. However, the characteristics and mechanisms of the infection are still poorly understood. This study sought to determine the key molecules and its underlying mechanism in inducing brain eosinophilic infiltration caused by Angiostrongylus cantonensis. METHODS: Mathematical models were established for prediction of significantly changing genes and the functional associated protein with RNA-seq data in Angiostrongylus cantonensis infection. The expression level of Chi3l3, the predicted key molecule, was verified using Western blotting and real-time quantitative PCR. Critical cell source of Chi3l3 and its relationship with eosinophils were identified with flow cytometry, immunohistochemistry, and further verified by macrophage depletion using liposomal clodronate. The role of soluble antigens of Angiostrongylus cantonensis in eosinophilic response was identified with mice airway allergy model by intranasal administration of Alternaria alternate. The relationship between Chi3l3 and IL-13 was identified with flow cytometry, Western blotting, and Seahorse Bioscience extracellular flux analyzer. RESULTS: We analyzed the skewed cytokine pattern in brains of Angiostrongylus cantonensis-infected mice and found Chi3l3 to be an important molecule, which increased sharply during the infection. The percentage of inflammatory macrophages, the main source of Chi3l3, also increased, in line with eosinophils percentage in the brain. Network analysis and mathematical modeling predirect a functional association between Chi3l3 and IL-13. Further experiments verified that the soluble antigen of Angiostrongylus cantonensis induce brain eosinophilic meningitis via aggravating a positive feedback loop between IL-13 and Chi3l3. CONCLUSIONS: We present evidences in favor of a key role for macrophave-derived Chi3l3 molecule in the infection of Angiostrongylus cantonensis, which aggravates eosinophilic meningitis induced by Angiostrongylus cantonensis via a IL-13-mediated positive feedback loop. These reported results constitute a starting point for future research of angiostrongyliasis pathogenesis and imply that targeting chitinases and chitinase-like-proteins may be clinically beneficial in Angiostrongylus cantonensis-induced eosinophilic meningitis.
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Angiostrongylus cantonensis , Eosinófilos/metabolismo , Lectinas/metabolismo , Meningitis/metabolismo , Infecciones por Strongylida/metabolismo , beta-N-Acetilhexosaminidasas/metabolismo , Animales , Eosinófilos/inmunología , Femenino , Lectinas/inmunología , Meningitis/inmunología , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Sprague-Dawley , Infecciones por Strongylida/inmunología , beta-N-Acetilhexosaminidasas/inmunologíaRESUMEN
[This corrects the article DOI: 10.1155/2017/3513651.].
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Multi-robot formation control makes prerequisites for a team of robots to execute complex tasks cooperatively, which has been widely applied in both civilian and military scenarios. However, the limited precision of sensors and controllers may inevitably cause position errors in the finally achieved formation, which will affect the tasks undertaken. In this paper, the formation error is analyzed from the viewpoint of information theory. The desired position and the actually achieved position are viewed as two random variables. By calculating the mutual information between them, a lower bound of the formation error is derived. The results provide insights for the estimation of possible formation errors in the multi-robot system, which can assist designers to choose sensors and controllers with proper precision.
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Disease-related biomarkers are objectively measurable molecular signatures of physiological status that can serve as disease indicators or drug targets in clinical diagnosis and therapy, thus acting as a tool in support of personalized medicine. For example, the prostate-specific antigen (PSA) biomarker is now widely used to screen patients for prostate cancer. However, few such biomarkers are currently available, and the process of biomarker identification and validation is prolonged and complicated by inefficient methods of discovery and few reliable analytical platforms. Therefore, in this Perspective, we look at the advanced chemistry of aptamer molecules and their significant role as molecular probes in biomarker studies. As a special class of functional nucleic acids evolved from an iterative technology termed Systematic Evolution of Ligands by Exponential Enrichment (SELEX), these single-stranded oligonucleotides can recognize their respective targets with selectivity and affinity comparable to those of protein antibodies. Because of their fast turnaround time and exceptional chemical properties, aptamer probes can serve as novel molecular tools for biomarker investigations, particularly in assisting identification of new disease-related biomarkers. More importantly, aptamers are able to recognize biomarkers from complex biological environments such as blood serum and cell surfaces, which can provide direct evidence for further clinical applications. This Perspective highlights several major advancements of aptamer-based biomarker discovery strategies and their potential contribution to the practice of precision medicine.
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Biomarcadores , Sondas Moleculares/química , Técnica SELEX de Producción de Aptámeros/métodos , Biomarcadores/sangre , Biomarcadores/química , Humanos , Estructura Molecular , Reacción en Cadena de la Polimerasa , Valor Predictivo de las PruebasRESUMEN
Exosomes are membrane-enclosed extracellular vesicles derived from cells, carrying biomolecules that include proteins and nucleic acids for intercellular communication. Owning to their advantages of size, structure, stability, and biocompatibility, exosomes have been used widely as natural nanocarriers for intracellular delivery of theranostic agents. Meanwhile, surface modifications needed to endow exosomes with additional functionalities remain challenging by their small size and the complexity of their membrane surfaces. Current methods have used genetic engineering and chemical conjugation, but these strategies require complex manipulations and have only limited applications. Herein, we present an aptamer-based DNA nanoassemblies on exosome surfaces. This in situ assembly method is based on molecular recognition between DNA aptamers and their exosome surface markers, as well as DNA hybridization chain reaction initiated by an aptamer-chimeric trigger. It further demonstrated selective assembly on target cell-derived exosomes, but not exosomes derived from nontarget cells. The present work shows that DNA nanostructures can successfully be assembled on a nanosized organelle. This approach is useful for exosome modification and functionalization, which is expected to have broad biomedical and bioanalytical applications.
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Aptámeros de Nucleótidos/química , ADN/química , Exosomas/química , Nanoestructuras/química , Tamaño de la Partícula , Propiedades de SuperficieRESUMEN
BACKGROUND: Potential of liver regeneration after living-donor liver transplantation is closely associated with the recipient's prognosis, whereas exogenous gene might regulate the liver regeneration progress. NM23 is a multifunctional gene, which inhibits tumor metastasis and regulates cell proliferation, differentiation, development, and apoptosis; however, there is little research about NM23 in promoting liver cell proliferation. METHODS: To investigate the effect of NM23-E2 on the liver cell proliferation, the NM23-E2 overexpression vector or negative control vector was transfected into BRL-3A cells and donor liver, respectively. NM23-E2, Cyclin D1, and PCNA expression levels in BRL-3A cells and liver tissues were detected by quantitative real-time polymerase chain reaction and Western blot analysis. Cell Counting Kit-8 was used to detect cell proliferation and flow cytometry for investigating cell cycle. The liver regeneration rate was determined by calculating (regenerated-liver weight of recipient - liver weight of donor/liver weight of donor) × 100%. RESULTS: NM23-E2 overexpression increased the NM23-E2, Cyclin D1, and PCNA levels significantly in BRL-3A cells and liver tissues (P < 0.05). The number of S phase cells was more than that of negative control group, and cell proliferation rate was higher than that of the control group in BRL-3A cells markedly (P < 0.05). Moreover, the liver regeneration rate in the NM23-E2 overexpression group was also higher than that in negative control group on postoperative day 1, day 3, day 5, and day 7. CONCLUSIONS: Overexpression of NM23-E2 can increase Cyclin D1 and PCNA expression, shorten cell cycle, and thereby promoting the proliferation of liver cells and accelerating the regeneration of liver after 40% decreased-size rat liver transplantation.
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Terapia Genética , Regeneración Hepática , Trasplante de Hígado , Nucleósido Difosfato Quinasas NM23/genética , Animales , Ciclo Celular , Línea Celular , Proliferación Celular , Ciclina D1/metabolismo , Lentivirus , Hígado/metabolismo , Masculino , Nucleósido Difosfato Quinasas NM23/metabolismo , Antígeno Nuclear de Célula en Proliferación/metabolismo , Ratas Sprague-DawleyRESUMEN
Exosomes constitute an emerging biomarker for cancer diagnosis because they carry multiple proteins that reflect the origins of parent cells. Assessing exosome surface proteins provides a powerful means of identifying a combination of biomarkers for cancer diagnosis. We report a sensor platform that profiles exosome surface proteins in minutes by the naked eye. The sensor consists of a gold nanoparticle (AuNP) complexed with a panel of aptamers. The complexation of aptamers with AuNPs protects the nanoparticles from aggregating in a high-salt solution. In the presence of exosomes, the non-specific and weaker binding between aptamers and the AuNP is broken, and the specific and stronger binding between exosome surface protein and the aptamer displaces aptamers from the AuNP surface and results in AuNP aggregation. This aggregation results in a color change and generates patterns for the identification of multiple proteins on the exosome surface.
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Aptámeros de Nucleótidos/análisis , Técnicas Biosensibles , Colorimetría/métodos , Exosomas/metabolismo , Nanopartículas del Metal/análisis , Oro/química , Células HeLa , HumanosRESUMEN
Site-selective protein modification is a key step in facilitating protein functionalization and manipulation. To accomplish this, genetically engineered proteins were previously required, but the procedure was laborious, complex, and technically challenging. Herein we report the development of aptamer-based recognition-then-reaction to guide site-selective protein/DNA conjugation in a single step with outstanding selectivity and efficiency. As models, several proteins, including human thrombin, PDGF-BB, Avidin, and His-tagged recombinant protein, were studied, and the results showed excellent selectivity under mild reaction conditions. Taking advantage of aptamers as recognition elements with extraordinary selectivity and affinity, this simple preparation method can tag a protein in a complex milieu. Thus, with the aptamer obtained from cell-SELEX, real-time modification of live-cell membrane proteins can be achieved in one step without any pre-treatment.
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Proteínas/metabolismo , Aptámeros de Nucleótidos/metabolismo , Membrana Celular/metabolismo , Humanos , Técnica SELEX de Producción de Aptámeros , Trombina/metabolismoRESUMEN
A facile strategy has been developed to synthesize double-shelled Zn(OH)2 nanoflowers (DNFs) at room temperature. The nanoflowers were generated via conversion of Cu2 O nanoparticles (NPs) using ZnCl2 and Na2 S2 O3 by a simple process. Outward diffusion of the Cu(2+) , produced by an oxidation process on the surface of NPs, and the inward diffusion of Zn(2+) by coordination and migration, eventually lead to a hollow cavity in the inner NPs with a double-shelled 3D hollow flower shapes. The thickness of the inner and outer shells is estimated to be about 20â nm, and the thickness of nanopetals is about 7â nm. The nanoflowers have large surface areas and excellent adsorption properties. As a proof of potential applications, the DNFs exhibited an excellent ability to remove organic molecules from aqueous solutions.
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NEW FINDINGS: What is the central question of this study? Duodenal ulcer is a common disease. A sex-based difference in the incidence of duodenal ulcer has long been observed clinically, but the cause is unclear. What is the main finding and its importance? Duodenal mucosal bicarbonate secretion is the most important protective factor in duodenal mucosa against acid-induced damage. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion. We demonstrate that endogenous oestrogen upregulates the expression levels and functional activities of duodenal mucosal CFTR and SLC26A6, which contributes to the sex difference in the prevalence of duodenal ulcer. The incidence of duodenal ulcer is markedly lower in women than men, but the cause of the sex difference is not clear. The cystic fibrosis transmembrane conductance regulator (CFTR) and the solute-linked carrier 26 gene family A6 (SLC26A6) are two key bicarbonate transport proteins that mediate duodenal mucosal bicarbonate secretion, which is an important protective factor against acid-induced duodenal injury. The aim of this study was to investigate the effect of oestrogen on the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa. We found that the expression levels of duodenal CFTR and SLC26A6 were markedly higher in young (20- to 30-year-old) women than in young men and old (60- to 70-year-old) women and men. The expression levels of CFTR and SLC26A6 in young women were markedly higher in preovulatory phases than in premenstrual phases, which was consistent with the changes of serum estradiol concentrations. Further results showed that duodenal CFTR and SLC26A6 expression levels in female mice were markedly decreased after ovariectomy, and supplementation with estradiol reversed the changes in CFTR and SLC26A6. 17ß-Estradiol increased CFTR and SLC26A6 expression levels of human duodenocytes in experiments in vitro. Functional experiments showed that basal and forskolin- and prostaglandin E2 -stimulated duodenal bicarbonate secretion in ovariectomized mice was markedly decreased and, likewise, supplementation with 17ß-estradiol reversed the changes. In conclusion, endogenous oestrogen upregulates the expressions and functional activities of CFTR and SLC26A6 in duodenal mucosa, which could contribute to protection of the duodenum and explain the sex difference in the prevalence of duodenal ulcer.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Duodeno/efectos de los fármacos , Estrógenos/farmacología , Mucosa Intestinal/efectos de los fármacos , Proteínas de Transporte de Membrana/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Adulto , Anciano , Animales , Bicarbonatos/metabolismo , Colforsina/metabolismo , Úlcera Duodenal/tratamiento farmacológico , Úlcera Duodenal/metabolismo , Duodeno/metabolismo , Estradiol/metabolismo , Femenino , Humanos , Mucosa Intestinal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Caracteres Sexuales , Transportadores de Sulfato , Adulto JovenRESUMEN
Laboratory inâ vitro evolution (LIVE) might deliver DNA aptamers that bind proteins expressed on the surface of cells. In this work, we used cell engineering to place glypicanâ 3 (GPC3), a possible marker for liver cancer theranostics, on the surface of a liver cell line. Libraries were then built from a six-letter genetic alphabet containing the standard nucleobases and two added nucleobases (2-amino-8H-imidazo[1,2-a][1,3,5]triazin-4-one and 6-amino-5-nitropyridin-2-one), Watson-Crick complements from an artificially expanded genetic information system (AEGIS). With counterselection against non-engineered cells, eight AEGIS-containing aptamers were recovered. Five bound selectively to GPC3-overexpressing cells. This selection-counterselection scheme had acceptable statistics, notwithstanding the possibility that cells engineered to overexpress GPC3 might also express different off-target proteins. This is the first example of such a combination.
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Aptámeros de Nucleótidos/metabolismo , Glipicanos/metabolismo , Animales , Aptámeros de Nucleótidos/química , Secuencia de Bases , Ingeniería Celular , Línea Celular , Técnicas de Laboratorio Clínico , Citometría de Flujo , Glipicanos/química , Glipicanos/genética , Humanos , Ratones , Unión ProteicaRESUMEN
Series multivariable coupled system is a typical controlled object in process control industry. The interaction of various state variables between multiple inputs and outputs in the system forms a complex series multivariable coupled structure. This coupled structure makes the control of a controlled object in the system affect the controlled object in the upper and lower control loop. As a result, it is difficult to control one or more control loops in the system without changing the state of other links in the system. In this paper, a cooperative control method for series multivariable coupled system is proposed. A decoupling controller is designed to remove the coupling effect caused by the interaction between stages, and the system is decoupled into several independent control loops. Differential leading PI (proportional-integral) error compensation method is introduced to ensure the following performance of the controller without static error. The proposed cooperative control method satisfies the Lyapunov stability, and has been successfully applied in the simulation experiment of cascade pumping station system of Beijing East-to-West water transfer project. The proposed method reduces the difficulty to controlling the water level of forebay of each pumping station and ensures the efficient operation of the cascade pumping station system.
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Proton conductors are typically developed by doping to introduce structural defects such as oxygen vacancies to facilitate ionic transport through structural bulk conduction mechanism. In this study, we present a novel electrochemical proton injection method via an in situ fuel cell process, demonstrating proton conduction in europium oxide (Eu2O3) through a surficial conduction mechanism for the first time. By tuning Eu2O3 into a protonated form, H-Eu2O3, we achieved an exceptionally high proton conductivity of 0.16 S cm-1. Distribution of relaxation time (DRT) analysis was employed to investigate the proton transport behavior and reveal the significant contribution of surface proton transport to the overall conductivity of Eu2O3. Remarkably, H-Eu2O3 exhibited a low activation energy for ionic transport, comparable to the best ceramic electrolytes available. The proton-coupled electron transfer (PCET) mechanism describes this novel surficial proton conduction mechanism. These findings provide new possibilities for developing advanced proton conductors with improved performance.
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Fetal growth restriction (FGR) is a major cause of premature and low-weight births, which increases the risk of necrotizing enterocolitis (NEC); however, the association remains unclear. We report a close correlation between placental polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) and NEC. Newborns with previous FGR exhibited intestinal inflammation and more severe NEC symptoms than healthy newborns. Placental PMN-MDSCs are vital regulators of fetal development and neonatal gut inflammation. Placental single-cell transcriptomics revealed that PMN-MDSCs populations and olfactomedin-4 gene (Olfm4) expression levels were significantly increased in PMN-MDSCs in later pregnancy compared to those in early pregnancy and non-pregnant females. Female mice lacking Olfm4 in myeloid cells mated with wild-type males showed FGR during pregnancy, with a decreased placental PMN-MDSCs population and expression of growth-promoting factors (GPFs) from placental PMN-MDSCs. Galectin-3 (Gal-3) stimulated the OLFM4-mediated secretion of GPFs by placental PMN-MDSCs. Moreover, GPF regulation via OLFM4 in placental PMN-MDSCs was mediated via hypoxia inducible factor-1α (HIF-1α). Notably, the offspring of mothers lacking Olfm4 exhibited intestinal inflammation and were susceptible to NEC. Additionally, OLFM4 expression decreased in placental PMN-MDSCs from pregnancies with FGR and was negatively correlated with neonatal morbidity. These results revealed that placental PMN-MDSCs contributed to fetal development and ameliorate newborn intestinal inflammation.
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Retardo del Crecimiento Fetal , Células Supresoras de Origen Mieloide , Placenta , Animales , Femenino , Embarazo , Humanos , Placenta/inmunología , Placenta/metabolismo , Recién Nacido , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Retardo del Crecimiento Fetal/inmunología , Ratones , Ratones Noqueados , Enterocolitis Necrotizante/inmunología , Enterocolitis Necrotizante/metabolismo , Factor Estimulante de Colonias de Granulocitos/metabolismo , Factor Estimulante de Colonias de Granulocitos/genética , Ratones Endogámicos C57BL , Masculino , Galectinas/metabolismo , Galectinas/genética , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/genética , Intestinos/inmunología , Intestinos/patologíaRESUMEN
The survival and suppressive function of regulatory T (Treg) cells rely on various intracellular metabolic and physiological processes. Our study demonstrates that Vps34 plays a critical role in maintaining Treg cell homeostasis and function by regulating cellular metabolic activities. Disruption of Vps34 in Treg cells leads to spontaneous fatal systemic autoimmune disorder and multi-tissue inflammatory damage, accompanied by a reduction in the number of Treg cells, particularly eTreg cells with highly immunosuppressive activity. Mechanistically, the poor survival of Vps34-deficient Treg cells is attributed to impaired endocytosis, intracellular vesicular trafficking and autophagosome formation, which further results in enhanced mitochondrial respiration and excessive ROS production. Removal of excessive ROS can effectively rescue the death of Vps34-deficient Treg cells. Functionally, acute deletion of Vps34 within established Treg cells enhances anti-tumor immunity in a malignant melanoma model by boosting T-cell-mediated anti-tumor activity. Overall, our results underscore the pivotal role played by Vps34 in orchestrating Treg cell homeostasis and function towards establishing immune homeostasis and tolerance.
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This experiment aimed to investigate the effects of the chitosan (CTS) and water-soluble chitosan (WSC) microspheres on plasma lipids in male Sprague-Dawley rats fed with high-fat diets. CTS microspheres and WSC microspheres were prepared by the spray-drying technique. Scanning electron microscopy (SEM) micrographs showed that the microspheres were nearly spherical in shape. The mean size of CTS microspheres was 4.07 µm (varying from 1.50 to 7.21 µm) and of WSC microspheres was 2.00 µm (varying from 0.85 to 3.58 µm). The rats were classified into eight groups (n = 8) and were fed with high-fat diets for two weeks to establish the hyperlipidemic condition and were then treated with CTS microspheres and WSC microspheres, CTS and WSC for four weeks. The results showed that CTS and WSC microspheres reduced blood lipids and plasma viscosity and increased the serum superoxide dismutase (SOD) levels significantly. This study is the first report of the lipid-lowering effects of CTS and WSC microspheres. CTS and WSC microspheres were found to be more effective in improving hyperlipidemia in rats than common CTS and WSC.