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Tumor-targeting Abs can be used to initiate an antitumor immune program, which appears essential to achieve a long-term durable clinical response to cancer. We previously identified an anti-complement factor H (CFH) autoantibody associated with patients with early-stage non-small cell lung cancer. We cloned from their peripheral B cells an mAb, GT103, that specifically recognizes CFH on tumor cells. Although the underlying mechanisms are not well defined, GT103 targets a conformationally distinct CFH epitope that is created when CFH is associated with tumor cells, kills tumor cells in vitro, and has potent antitumor activity in vivo. In the effort to better understand how an Ab targeting a tumor epitope can promote an effective antitumor immune response, we used the syngeneic CMT167 lung tumor C57BL/6 mouse model, and we found that murinized GT103 (mGT103) activates complement and enhances antitumor immunity through multiple pathways. It creates a favorable tumor microenvironment by decreasing immunosuppressive regulatory T cells and myeloid-derived suppressor cells, enhances Ag-specific effector T cells, and has an additive antitumor effect with anti-PD-L1 mAb. Furthermore, the immune landscape of tumors from early-stage patients expressing the anti-CFH autoantibody is associated with an immunologically active tumor microenvironment. More broadly, our results using an mAb cloned from autoantibody-expressing B cells provides novel, to our knowledge, mechanistic insights into how a tumor-specific, complement-activating Ab can generate an immune program to kill tumor cells and inhibit tumor growth.
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Activación de Complemento , Ratones Endogámicos C57BL , Animales , Ratones , Humanos , Activación de Complemento/inmunología , Línea Celular Tumoral , Factor H de Complemento/inmunología , Microambiente Tumoral/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/terapia , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/terapia , Femenino , Linfocitos T Reguladores/inmunologíaRESUMEN
PURPOSE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting. METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses. RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44]. CONCLUSION: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Terapia Neoadyuvante/efectos adversos , Modelos de Riesgos Proporcionales , Receptor ErbB-2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , PronósticoRESUMEN
The limited pattern area of periodic nanostructures limits the development of practical devices. This study introduces an X-ray interference lithography (XIL) stitching technique to fabricate a large-area (1.5â cm × 1.5â cm) two-dimensional photonic crystal (PhC) on the YAG: Ce scintillator, which functions as an encoder in a high numerical aperture optical encoding imaging system to effectively capture high-frequency information. An X-ray imaging experiment revealed a substantial 7.64â dB improvement in the signal-to-noise ratio (SNR) across a large field of view (2.6â mm × 2.6 mm) and achieved comparable or superior image quality with half the exposure dose. These findings have significant implications for advancing practical applications of X-ray imaging.
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A unique feature of the cytokine storm in coronavirus disease 2019 (COVID-19) is the dramatic elevation of interleukin 10 (IL-10). This was thought to be a negative feedback mechanism to suppress inflammation. However, several lines of clinical evidence suggest that dramatic early proinflammatory IL-10 elevation may play a pathological role in COVID-19 severity.
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COVID-19/inmunología , Síndrome de Liberación de Citoquinas/inmunología , Interleucina-10/inmunología , SARS-CoV-2/inmunología , COVID-19/epidemiología , COVID-19/virología , Síndrome de Liberación de Citoquinas/metabolismo , Epidemias , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-10/metabolismo , Linfocitos/inmunología , Linfocitos/metabolismo , Modelos Inmunológicos , SARS-CoV-2/fisiología , Índice de Severidad de la EnfermedadRESUMEN
Converting CO2 into valuable chemicals via sustainable energy sources is indispensable for human development. Photothermal catalysis combines the high selectivity of photocatalysis and the high yield of thermal catalysis, which is promising for CO2 reduction. However, the present photothermal catalysts suffer from low activity due to their poor light absorption ability and fast recombination of photogenerated electrons and holes. Here, a TiO2@Bi2WO6 heterojunction photocatalyst featuring a hierarchical hollow structure was prepared by an in situ growth method. The visible light absorption and photothermal effect of the TiO2@Bi2WO6 photocatalyst is promoted by a hierarchical hollow structure, while the recombination phenomenon is significantly mitigated due to the construction of the heterojunction interface and the existence of excited Bi(3-x)+ sites. Such a catalyst exhibits excellent photothermal performance with a CO yield of 43.7 µmol h-1 g-1, which is 15 and 4.7 times higher than that of pure Bi2WO6 and that of physically mixed TiO2/Bi2WO6, respectively. An in situ study shows that the pathway for the transformation of CO2 into CO over our TiO2@Bi2WO6 proceeds via two important intermediates, including COO- and COOH-. Our work provides a new idea of excited states for the design and synthesis of highly efficient photothermal catalysts for CO2 conversion.
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Bcl2l1 (Bcl-XL) belongs to the Bcl-2 family, Bcl2 and Bcl2-XL are major anti-apoptotic proteins, and the apoptosis of osteoblasts is a key event for bone homeostasis. As the functions of Bcl2l1 in osteoblasts and bone homeostasis remain unclear, we generated osteoblast-specific Bcl2l1-deficient (Bcl2l1fl/flCre) mice using 2.3-kb Col1a1 Cre. Trabecular bone volume and the trabecular number were lower in Bcl2l1fl/flCre mice of both sexes than in Bcl2l1fl/fl mice. In bone histomorphometric analysis, osteoclast parameters were increased in Bcl2l1fl/flCre mice, whereas osteoblast parameters and the bone formation rate were similar to those in Bcl2l1fl/fl mice. TUNEL-positive osteoblastic cells and serum TRAP5b levels were increased in Bcl2l1fl/flCre mice. The deletion of Bcl2l1 in osteoblasts induced Tnfsf11 expression, whereas the overexpression of Bcl-XL had no effect. In a co-culture of Bcl2l1-deficient primary osteoblasts and wild-type bone-marrow-derived monocyte/macrophage lineage cells, the numbers of multinucleated TRAP-positive cells and resorption pits increased. Furthermore, serum deprivation or the deletion of Bcl2l1 in primary osteoblasts increased apoptosis and ATP levels in the medium. Therefore, the reduction in trabecular bone in Bcl2l1fl/flCre mice may be due to enhanced bone resorption through osteoblast apoptosis and the release of ATP from apoptotic osteoblasts, and Bcl2l1 may inhibit bone resorption by preventing osteoblast apoptosis.
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Resorción Ósea , Osteogénesis , Animales , Femenino , Masculino , Ratones , Adenosina Trifosfato/metabolismo , Apoptosis/genética , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Resorción Ósea/genética , Resorción Ósea/metabolismo , Hueso Esponjoso/metabolismo , Diferenciación Celular , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Wet air oxidation (WAO) is a clean and eco-friendly technology for dyes removal, but the high operating temperature and pressure limit its practical application. In the present work, an electric field-promoting (EF-promoting) catalytic WAO process is developed to degrade dyes under room condition. The oxidation kinetics of four different types of dyes and their degradation pathways are studied. A kinetic model is constructed by including the exogenous electric field into the Langmuir-Hinshelwood-Hougen-Watson (LHHW) mechanism framework, and quantitative structure-activity relationship (QSAR) analysis is conducted to correlate the kinetic parameters to the physicochemical properties of the dyes. A negative linear relationship is found between the adsorption equilibrium constants of the dyes and their first ionization energies, and their surface reaction rate constants are positively linearly associated to Esum (ELUMO + EHOMO). The degradation pathways of the different dyes are proposed according to the degradation intermediates and the activities of the atoms within the dye molecules. The heteroatoms N and S, and the atom C connecting the aromatic rings are identified as the susceptible sites upon the electrophilic attack of O2. Bond cleavage at these sites gives rise to aromatic fragments which are eventually mineralized via carboxyl acids. The results of this work is helpful for guiding the design and operation of the EF-promoting catalytic WAO process into the treatment of various dye wastewaters.
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Colorantes , Contaminantes Químicos del Agua , Cinética , Colorantes/química , Oxidación-Reducción , Aguas Residuales , Catálisis , Contaminantes Químicos del Agua/químicaRESUMEN
The adaptor protein Bcl10 is a critically important mediator of T cell receptor (TCR)-to-NF-κB signaling. Bcl10 degradation is a poorly understood biological phenomenon suggested to reduce TCR activation of NF-κB. Here we have shown that TCR engagement triggers the degradation of Bcl10 in primary effector T cells but not in naive T cells. TCR engagement promoted K63 polyubiquitination of Bcl10, causing Bcl10 association with the autophagy adaptor p62. Paradoxically, p62 binding was required for both Bcl10 signaling to NF-κB and gradual degradation of Bcl10 by autophagy. Bcl10 autophagy was highly selective, as shown by the fact that it spared Malt1, a direct Bcl10 binding partner. Blockade of Bcl10 autophagy enhanced TCR activation of NF-κB. Together, these data demonstrate that selective autophagy of Bcl10 is a pathway-intrinsic homeostatic mechanism that modulates TCR signaling to NF-κB in effector T cells. This homeostatic process may protect T cells from adverse consequences of unrestrained NF-κB activation, such as cellular senescence.
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Proteínas Adaptadoras Transductoras de Señales/fisiología , Autofagia/fisiología , FN-kappa B/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Relacionadas con la Autofagia , Proteína 10 de la LLC-Linfoma de Células B , Caspasas/fisiología , Diferenciación Celular , Citosol/inmunología , Citosol/ultraestructura , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Proteínas de Choque Térmico/biosíntesis , Proteínas de Choque Térmico/genética , Proteínas de Choque Térmico/fisiología , Homeostasis , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Microscopía Confocal , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , Proteínas de Neoplasias/fisiología , Fagosomas/fisiología , Fagosomas/ultraestructura , Mapeo de Interacción de Proteínas , Proteína Sequestosoma-1 , Transducción de Señal/genética , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/ultraestructura , Células Th2/inmunología , Células Th2/ultraestructura , Enzimas Ubiquitina-Conjugadoras/fisiologíaRESUMEN
BACKGROUND: Postzygote isolation is an important part of species isolation, especially for fish, and it can be divided into two aspects: genetic isolation and ecological isolation. With the increase in parental genetic distance, the intensity of genetic isolation between them also increases. Will the increase in parental ecological niche differences also lead to the increase in ecological isolation intensity between them? This question is difficult to answer based on the current literature due to the lack of hybridization cases of contrasting ecological niche parents. RESULTS: Cyprinid fish parents (Schizothorax wangchiachii and Percocypris pingi) with contrasting ecological niches (herbivorous and carnivorous) and their F1 hybrids were used as research objects. Fish and periphytic algae were selected as food corresponding to different parental resources. The foraging-related traits of these hybrids are generally the same between parents; however, the intermediate foraging traits of hybrids did not result in intermediate foraging performance for parental resources, and these hybrids could hardly forage for parental resources. The poor foraging performance of these hybrids for parental resources was caused not only by the decline in the foraging ability of these hybrids but, more importantly, by the decrease in foraging activity. Interestingly, these hybrids initially showed a high interest in foraging small fishes; however, after the first successful capture, these hybrids had difficulty ingesting fish and spit them out, which led to the subsequent decrease in foraging activity. We designed a series of experiments to explore the mechanism of the fish spitting of these hybrids, excluding the taste and the size of prey, and found that the decrease in their pharyngeal tooth puncture ability may be the reason. CONCLUSIONS: This study was the first to demonstrate that these parents with contrasting ecological niches will produce great postzygotic ecological isolation for parental resources. The poor foraging performance of these hybrids for parental resources is mainly due to the decrease in foraging activity. Interestingly, these hybrids have obvious fish-spitting behaviour, which is a typical example of the incompatibility between intermediate traits and genetic behaviors.
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Tumor-associated antigens (TAAs) have been tested in various clinical trials in cancer treatment but the patterns of specific T cell response to personalized TAA immunization remains to be fully understood. We report antigen-specific T cell responses in patients immunized with dendritic cell vaccines pulsed with personalized TAA panels. Tumor samples from patients were first analyzed to identify overexpressed TAAs. Autologous DCs were then transfected with pre-manufactured mRNAs encoding the full-length TAAs, overexpressed in the patients' tumors. Patients with glioblastoma multiforme (GBM) or advanced lung cancer received DC vaccines transfected with personalized TAA panels, in combination with low-dose cyclophosphamide, poly I:C, imiquimod and anti-PD-1 antibody. Antigen-specific T cell responses were measured. Safety and efficacy were evaluated. A total of ten patients were treated with DC vaccines transfected with personalized TAA panels containing 3-13 different TAAs. Among the seven patients tested for anti-TAA T cell responses, most of the TAAs induced antigen-specific CD4+ and/or CD8+ T cell responses, regardless of their expression levels in the tumor tissues. No Grade III/IV adverse events were observed among these patients. Furthermore, the treated patients were associated with favorable overall survival when compared to patients who received standard treatment in the same institution. Personalized TAA immunization-induced-specific CD4+ and CD8+ T cell responses without obvious autoimmune adverse events and was associated with favorable overall survival. These results support further studies on DC immunization with personalized TAA panels for combined immunotherapeutic regimens in solid tumor patients.Trial registration ClinicalTrials.gov, NCT02709616 (March, 2016), NCT02808364 (June 2016), NCT02808416 (June, 2016).
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Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Células Dendríticas/inmunología , Glioblastoma/terapia , Neoplasias Pulmonares/terapia , Medicina de Precisión , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/inmunología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Estudios de Seguimiento , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Glioblastoma/inmunología , Glioblastoma/patología , Humanos , Inmunización , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Pronóstico , Tasa de SupervivenciaRESUMEN
BACKGROUND: Mandibulofacial dysostosis with microcephaly (MFDM) is characteristic of multiple skeletal anomalies comprising craniofacial anomalies/dysplasia, microcephaly, dysplastic ears, choanal atresia, and short stature. Heterozygous loss of function variants of EFTUD2 was previously reported in MFDM; however, the mechanism underlying EFTUD2-associated skeletal dysplasia remains unclear. RESULTS: We identified a novel frameshift variant of EFTUD2 (c.1030_1031delTG, p.Trp344fs*2) in an MFDM Chinese patient with craniofacial dysmorphism including ear canal structures and microcephaly, mild intellectual disability, and developmental delay. We generated a zebrafish model of eftud2 deficiency, and a consistent phenotype consisting of mandibular bone dysplasia and otolith loss was observed. We also showed that EFTUD2 deficiency significantly inhibited proliferation, differentiation, and maturation in human calvarial osteoblast (HCO) and human articular chondrocyte (HC-a) cells. RNA-Seq analysis uncovered activated TP53 signaling with increased phosphorylation of the TP53 protein and upregulation of five TP53 downstream target genes (FAS, STEAP3, CASP3, P21, and SESN1) both in HCO and in eftud2-/- zebrafish. Additionally, inhibition of p53 by morpholino significantly reduced the mortality of eftud2-/- larvae. CONCLUSIONS: Our results confirm a novel de novo variant of the EFTUD2 gene and suggest that EFTUD2 may participate in the maturation and differentiation of osteoblasts and chondrocytes, possibly via activation of the TP53 signaling pathway. Thus, mutations in this gene may lead to skeletal anomalies in vertebrates.
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Diferenciación Celular , Condrocitos/patología , Osteoblastos/patología , Factores de Elongación de Péptidos/deficiencia , Factores de Elongación de Péptidos/genética , Ribonucleoproteína Nuclear Pequeña U5/deficiencia , Ribonucleoproteína Nuclear Pequeña U5/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/metabolismo , Animales , Secuencia de Bases , Huesos/embriología , Huesos/patología , Cartílago/embriología , Cartílago/patología , Línea Celular , Preescolar , Condrocitos/metabolismo , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Mutación/genética , Osteoblastos/metabolismo , Linaje , Factores de Elongación de Péptidos/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ribonucleoproteína Nuclear Pequeña U5/metabolismo , Factores de Tiempo , Pez CebraRESUMEN
Mouse strains with specific deficiency of given hematopoietic lineages provide invaluable tools for understanding blood cell function in health and disease. Whereas neutrophils are dominant leukocytes in humans and mice, there are no widely useful genetic models of neutrophil deficiency in mice. In this study, we show that myeloid-specific deletion of the Mcl-1 antiapoptotic protein in Lyz2 Cre/Cre Mcl1 flox/flox (Mcl1 ΔMyelo) mice leads to dramatic reduction of circulating and tissue neutrophil counts without affecting circulating lymphocyte, monocyte, or eosinophil numbers. Surprisingly, Mcl1 ΔMyelo mice appeared normally, and their survival was mostly normal both under specific pathogen-free and conventional housing conditions. Mcl1 ΔMyelo mice were also able to breed in homozygous form, making them highly useful for in vivo experimental studies. The functional relevance of neutropenia was confirmed by the complete protection of Mcl1 ΔMyelo mice from arthritis development in the K/B×N serum-transfer model and from skin inflammation in an autoantibody-induced mouse model of epidermolysis bullosa acquisita. Mcl1 ΔMyelo mice were also highly susceptible to systemic Staphylococcus aureus or Candida albicans infection, due to defective clearance of the invading pathogens. Although neutrophil-specific deletion of Mcl-1 in MRP8-CreMcl1 flox/flox (Mcl1 ΔPMN) mice also led to severe neutropenia, those mice showed an overt wasting phenotype and strongly reduced survival and breeding, limiting their use as an experimental model of neutrophil deficiency. Taken together, our results with the Mcl1 ΔMyelo mice indicate that severe neutropenia does not abrogate the viability and fertility of mice, and they provide a useful genetic mouse model for the analysis of the role of neutrophils in health and disease.
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Artritis/genética , Candida albicans/fisiología , Candidiasis/genética , Epidermólisis Ampollosa Adquirida/genética , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/metabolismo , Neutropenia/genética , Neutrófilos/fisiología , Infecciones Estafilocócicas/genética , Staphylococcus aureus/fisiología , Animales , Modelos Animales de Enfermedad , Fertilidad/genética , Homocigoto , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína 1 de la Secuencia de Leucemia de Células Mieloides/genéticaRESUMEN
Owing to its high-fault tolerance and scalability, the consensus-based paradigm has attracted immense popularity for distributed state estimation. If a target is neither observed by a certain node nor by its neighbors, this node is naive about the target. Some existing algorithms have considered the presence of naive nodes, but it takes sufficient consensus iterations for these algorithms to achieve a satisfactory performance. In practical applications, because of constrained energy and communication resources, only a limited number of iterations are allowed and thus the performance of these algorithms will be deteriorated. By fusing the measurements as well as the prior estimates of each node and its neighbors, a local optimal estimate is obtained based on the proposed distributed local maximum a posterior (MAP) estimator. With some approximations of the cross-covariance matrices and a consensus protocol incorporated into the estimation framework, a novel distributed hybrid information weighted consensus filter (DHIWCF) is proposed. Then, theoretical analysis on the guaranteed stability of the proposed DHIWCF is performed. Finally, the effectiveness and superiority of the proposed DHIWCF is evaluated. Simulation results indicate that the proposed DHIWCF can achieve an acceptable estimation performance even with a single consensus iteration.
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An understanding of the interaction between the antibody and its targeted antigen and knowing of the epitopes are critical for the development of monoclonal antibody drugs. Complement factor H (CFH) is implied to play a role in tumor growth and metastasis. An autoantibody to CHF is associated with anti-tumor cell activity. The interaction of a human monoclonal antibody Ab42 that was isolated from a cancer patient with CFH polypeptide (pCFH) antigen was analyzed by molecular docking, molecular dynamics (MD) simulation, free energy calculation, and computational alanine scanning (CAS). Experimental alanine scanning (EAS) was then carried out to verify the results of the theoretical calculation. Our results demonstrated that the Ab42 antibody interacts with pCFH by hydrogen bonds through the Tyr315, Ser100, Gly33, and Tyr53 residues on the complementarity-determining regions (CDRs), respectively, with the amino acid residues of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448 on the pCFH antigen. In conclusion, this study has explored the mechanism of interaction between Ab42 antibody and its targeted antigen by both theoretical and experimental analysis. Our results have important theoretical significance for the design and development of relevant antibody drugs.
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Anticuerpos Monoclonales/inmunología , Péptidos/inmunología , Anticuerpos Monoclonales/química , Reacciones Antígeno-Anticuerpo , Autoanticuerpos/química , Autoanticuerpos/inmunología , Factor H de Complemento/química , Factor H de Complemento/inmunología , Regiones Determinantes de Complementariedad/química , Regiones Determinantes de Complementariedad/inmunología , Epítopos/química , Epítopos/inmunología , Humanos , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Neoplasias/inmunología , Péptidos/química , Conformación ProteicaRESUMEN
The Odontobutidae is a group of freshwater sleepers endemic to East and Southeast Asia. The composition of the Odontobutidae is controversial and the systematics position of some species (e.g. Philypnus chalmersi) remains unknown. Phylogenetic relationship among the odontobutids has never been really tested due to the lack of informative morphological characters, and that molecular data have not been collected in many species. Here, we sampled 41 specimens, representing all known genera of the Odontobutidae except the Laotian genus Terateleotris, in addition to a disputable odontobutid species, Philypnus chalmersi and 14 outgroups (six families). We collected sequence data of 4434 single-copy nuclear coding loci using gene capture and Illumina sequencing. A robust phylogeny of the odontobutids and outgroups was built, confirming that the Odontobutidae is monophyletic and sister to the Rhyacichthyidae. We verified that Neodontobutis, Sineleotris and Philypnus chalmersi are members of the Odontobutidae based on the resulting phylogeny as well as patterns of pectoral girdle examined by X-ray microtomography. We proposed a new genus Microdous for Philypnus chalmersi based on the new morphological and molecular evidences. The family of the Odontobutidae can be divided into two clades: Microdous (=Philypnus) sister to a group consisting of Micropercops and Sineleotris, and Odontobutis sister to a group unifying Perccottus and Neodontobutis. Divergence time among the odontobutids was estimated based on 100 most clock-like loci and three fossil calibration points using BEAST. Ancestral range of the family was reconstructed using Reconstruct Ancestral States in Phylogenies (RASP) and BioGeoBEARS. The results suggest that the common ancestor of the odontobutids originated around 30.8â¯Ma (20.7-42.0â¯Ma, 95% HPDs) in South China. Orogeny, climatic change and river capture might account for diversification and current distribution of the odontobutids.
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Agua Dulce , Perciformes/clasificación , Filogenia , Animales , Huesos/anatomía & histología , Calibración , China , Fósiles , Funciones de Verosimilitud , Perciformes/anatomía & histología , Filogeografía , Análisis de Secuencia de ADN , Especificidad de la Especie , Factores de TiempoRESUMEN
Microwave I/Q down-converters are frequently used in image-reject super heterodyne receivers, zero intermediate frequency (zero-IF) receivers, and phase/frequency discriminators. However, due to the electronic bottleneck, conventional microwave I/Q mixers face a serious bandwidth limitation, I/Q imbalance, and even-order distortion. In this paper, photonic microwave fundamental and sub-harmonic I/Q down-converters are presented using a polarization division multiplexing dual-parallel Mach-Zehnder modulator (PDM-DPMZM). Thanks to all-optical manipulation, the proposed system features an ultra-wide operating band (7-40 GHz in the fundamental I/Q down-converter, and 10-40 GHz in the sub-harmonic I/Q down-converter) and an excellent I/Q balance (maximum 0.7 dB power imbalance and 1 degree phase imbalance). The conversion gain, noise figure (NF), even-order distortion, and spurious free dynamic range (SFDR) are also improved by LO power optimization and balanced detection. Using the proposed system, a high image rejection ratio is demonstrated for a super heterodyne receiver, and good EVMs over a wide RF power range is demonstrated for a zero-IF receiver. The proposed broadband photonic microwave fundamental and sub-harmonic I/Q down-converters may find potential applications in multi-band satellite, ultra-wideband radar and frequency-agile electronic warfare systems.
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The geostationary remote sensing satellite has the capability of wide scanning, persistent observation and operational response, and has tremendous potential for maritime target surveillance. The GF-4 satellite is the first geostationary orbit (GEO) optical remote sensing satellite with medium resolution in China. In this paper, a novel ship-tracking method in GF-4 satellite sequential imagery is proposed. The algorithm has three stages. First, a local visual saliency map based on local peak signal-to-noise ratio (PSNR) is used to detect ships in a single frame of GF-4 satellite sequential images. Second, the accuracy positioning of each potential target is realized by a dynamic correction using the rational polynomial coefficients (RPCs) and automatic identification system (AIS) data of ships. Finally, an improved multiple hypotheses tracking (MHT) algorithm with amplitude information is used to track ships by further removing the false targets, and to estimate ships’ motion parameters. The algorithm has been tested using GF-4 sequential images and AIS data. The results of the experiment demonstrate that the algorithm achieves good tracking performance in GF-4 satellite sequential images and estimates the motion information of ships accurately.
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Networked multiple sensors are used to solve the problem of maneuvering target tracking. To avoid the linearization of nonlinear dynamic functions, and to obtain more accurate estimates for maneuvering targets, a novel adaptive information-weighted consensus filter for maneuvering target tracking is proposed. The pseudo measurement matrix is computed with unscented transform to utilize the information form of measurements, which is necessary for consensus iterations. To improve the maneuvering target tracking accuracy and get a unified estimation in each sensor node across the entire network, the adaptive current statistical model is exploited to update the estimate, and the information-weighted consensus protocol is applied among neighboring nodes for each dynamic model. Based on posterior probabilities of multiple models, the final estimate of each sensor is acquired with weighted combination of model-conditioned estimates. Experimental results illustrate the superior performance of the proposed algorithm with respect tracking accuracy and agreement of estimates in the whole network.