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A typical magnetometer-based measurement-while-drilling (MWD) system determines the azimuth of the bottom hole assembly during the drilling process by employing triaxial accelerometers and magnetometers. The geomagnetic azimuth solution is susceptible to magnetic interference, especially strong magnetic interference and so a rotary norm constraint filtering (RNCF) method for azimuth estimation, designed to support a gyroscope-aided magnetometer-based MWD system, is proposed. First, a new magnetic dynamical system, one whose output is observed by the magnetometers triad, is designed based on the Coriolis equation of the desired geomagnetic vector. Second, given that the norm of the non-interfered geomagnetic vector can be approximated as a constant during a short-term drilling process, a norm constraint procedure is introduced to the Kalman filter. This is achieved by the normalization of the geomagnetic part of the state vector of the dynamical system and is undertaken in order to obtain a precise geomagnetic component. Simulation and actual drilling experiments show that the proposed RNCF method can effectively improve the azimuth measurement precision with 98.5% over the typical geomagnetic solution and 37.1% over the KF in a RMSE sense when being strong magnetic interference environment.
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Myostatin (MSTN) is a major gene target for skeletal muscle overgrowth in animals. We hypothesized that deletion of the entire mature peptide encoded by MSTN in pigs would knock out its bioactive form and accordingly stimulate skeletal muscle overgrowth. Thus, we engineered two pairs of single-guide RNAs (sgRNAs) to target exons 1 and 3 of MSTN in primary fetal fibroblasts of Taoyuan black pigs. We found that sgRNAs targeting exon 3, which encodes the mature peptide, had higher biallelic null mutation efficiency than those targeting exon 1. Somatic cell nuclear transfer was conducted using the exon 3 mutation cells as donor cells to generate five cloned MSTN null piglets (MSTN-/-). Growth testing revealed that both the growth rate and average daily weight gain of MST-/- pigs were greater than those of wild-type (MSTN+/+) pigs. Slaughter data demonstrated that the lean ratio of MSTN-/- pigs was 11.3% higher (P < 0.01) while the back-fat thickness was 17.33% lower (P < 0.01) than those of MSTN+/+ pigs. Haematoxylin-eosin staining indicated that the increased leanness of MSTN-/- pigs resulted from muscle fibre hyperplasia rather than hypertrophy.HE staining showed markedly decreased adipocyte size in MSTN-/- pigs. We also critically examined the off-target and random integration by resequencing, which showed that the founder MSTN-/- pigs contained no non-target mutations or exogenous plasmid elements. This study is the first to report the successful knock out of the mature MSTN peptide using dual sgRNA-mediated deletion, leading to the most prominent alteration of meat production traits in pigs published thus far. This new strategy is expected to have a wide impact on genetic improvements in food animals.
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Miostatina , ARN Guía de Sistemas CRISPR-Cas , Animales , Porcinos , Técnicas de Inactivación de Genes , Miostatina/genética , Hiperplasia/genética , Hiperplasia/patología , Fibras Musculares Esqueléticas , Músculo Esquelético/patología , AdipocitosRESUMEN
BACKGROUND: Non-small cell lung carcinoma (NSCLC) is one of the most common human cancers, comprising approximately 80-85% of all lung carcinomas. An estimated incidence of NSCLC is approximately 2 million new cases per year worldwide. RESULTS: In recent decade, the treatment of NSCLC has made breakthrough progress owing to a large number of targeted therapies which were approved for clinical use. Epidemiology, genetic susceptibility, and molecular profiles in patients are likely to play an important factor in response rates and survival benefits to these targeted treatments and thus warrant further investigation on ethnic differences in NSCLC. In this study, a total number of 1500 Chinese patient samples,1000 formalin fixed paraffin-embedded (FFPE) and 500 blood samples, from patients with NSCLC were analyzed by targeted sequencing to explore mutational landscape in ethnic groups associated with China. CONCLUSIONS: Overall, the data presented here provide a comprehensive analysis of NSCLC mutational landscape in Chinese patients and findings are discussed in the context of similar studies on different ethnic groups.
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Carcinoma de Pulmón de Células no Pequeñas/genética , Secuenciación del Exoma , Exoma/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/epidemiología , Carcinoma de Pulmón de Células no Pequeñas/patología , China/epidemiología , Estudios de Cohortes , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Masculino , Persona de Mediana Edad , Mutación/genéticaRESUMEN
Puffballs are a class of fungi widely distributed worldwide and associated with various bioactivities. This research mainly showed the antitumor bioactivity of extracts from Calvatia lilacina (CL), which is a common variety of puffballs. NMR and high-performance liquid chromatography methods are used to characterize the extracts. Results showed that CL extracts obtained with petroleum ether, ethyl acetate, ethanol, and water elicited obvious inhibitory effects on the proliferation of A549, Caco-2, and MDA-MB-231. Among these extracts, petroleum ether extract demonstrated the highest performance. This extract was then separated into seven sub-fractions (SFs). Three of these SFs (3#, 6#, and 7#) induces a decrease in the viability of MDA-MB-231 cells in which 7# SF exhibited the highest cytotoxicity, where the major component was found to be ergosta-7,22-dien-3-one. Further tests revealed that 7# SF from petroleum ether extract could trigger severe cell death in human breast cancer cells (MDA-MB-231) by activating the apoptotic pathway dependent on mitochondrial reactive oxygen species and caspase activation. All these results in combination indicate that the mechanism of extract-potentiated apoptosis associates closely with ROS-dependent mitochondrial dysfunction events which further induces mitochondria-mediated intrinsic cytochrome C-caspase-related pathway of apoptosis.Supplemental data for this article is available online at https://doi.org/10.1080/01635581.2021.1936576.
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Agaricales , Neoplasias de la Mama , Apoptosis , Neoplasias de la Mama/patología , Células CACO-2 , Caspasas/metabolismo , Muerte Celular , Línea Celular Tumoral , Proliferación Celular , Femenino , Humanos , Potencial de la Membrana Mitocondrial , Mitocondrias , Extractos Vegetales/química , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Crizotinib and alectinib are the 2 most commonly used anaplastic lymphoma kinase (ALK) inhibitors for ALK-positive non-small cell lung cancer (NSCLC). We compared their antitumor efficacies and adverse effects based on a pooled analysis of the ALEX, ALESIA, and J-ALEX clinical trials. METHODS: Seven databases were searched for eligible articles. The primary endpoints included overall survival (OS), progression-free survival (PFS), central nervous system (CNS)-PFS, drug responses, and adverse effects (AEs). RESULTS: Seven articles on 3 randomized controlled clinical trials (ALEX, ALESIA, and J-ALEX) that included 697 patients were included. Compared with crizotinib, alectinib exhibited superior efficacy in PFS (HR [hazard ratio]: 0.35 [0.25-0.49], p < 0.00001), OS (HR: 0.66 [0.47-0.92], p = 0.02), CNS-PFS (HR: 0.17 [0.11-0.24], p < 0.00001), duration of response (HR: 0.31 [0.23-0.42], p < 0.00001), objective response rate (risk ratio [RR]: 0.87 [0.80-0.94], p = 0.0003), partial response (RR: 0.88 [0.81-0.96], p = 0.004), and grade 3-5 AEs (RR: 1.43 [1.09-1.87], p = 0.009). Additionally, compared with crizotinib, alectinib exhibited a survival advantage that increased with its prolongation of survival time. The disease control rate, complete response, and total AEs were comparable between the 2 groups. The crizotinib group reported higher rates of constipation, nausea, diarrhea, vomiting, peripheral edema, dysgeusia, visual impairment, and levels of alanine aminotransferase and aspartate aminotransferase as well as greater decreases in appetite and neutrophil count. CONCLUSIONS: In both antitumor efficacy and safety, alectinib appears to be superior to crizotinib for the treatment of ALK-positive NSCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico , Carbazoles , Crizotinib/efectos adversos , Humanos , Piperidinas , Inhibidores de Proteínas Quinasas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
The spatio-temporal expression patterns of RNA and comparisons between different developmental stages have been one of the useful techniques for studying animal physiology and functional gene regulations. A Chinese indigenous breed Ningxiang pig is known for its quality meat production, disease resistance and slow growth performances in pig industry. To gain a better understanding of pig immunity and disease resistance, we comprehensively analyzed the whole transcriptome of the spleens from three important developmental nodes of Ningxiang pig at 30, 90 and 210 days of age. By three ways of comparisons (30vs 90 days, 30 vs 210 days and 90 vs 210 days), a total of 364to 865 differentially expressed mRNAs, 37 to 98 differentially expressed miRNAs,220 to 278 lncRNAs, and 96 to 113 circRNAs were identified. Further analysis of expression patterns, potential function and interactions with miRNAs identified the potential non-coding RNAs related to immunomodulation such as ssc-miRNA-150, ssc-miRNA-497, MSTRG24160, MSTRG18646. The results revealed that miRNAs and circRNAs may have evolved to regulate a large set of biological processes of spleen function in Ningxiang pigs, and circRNAs play a role of miRNA sponges. The results from study is the first report of whole transcriptome analysis of Ningxiang pig spleen and provide new insights into the expression changes of RNAs during the spleen development, which contribute to the phenotypic formation of immunity and disease resistancesin Chinese indigenous pig breeds.
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MicroARNs , ARN Largo no Codificante , Animales , China , Perfilación de la Expresión Génica , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Bazo/metabolismo , Porcinos/genética , TranscriptomaRESUMEN
Ku-band drive amplification and a 7-bit true-time-delay (TTD) function were realized as a part of a LTCC-based T/R module to increase integration. The 8-channel T/R module was fabricated and its key characteristics were measured, including a 3-bit (1/2/4 λ) TTD, 4-bit (0.25/0.5/1/2 λ) TTD, receive gain, noise figure and output power. The 8-channel T/R module can be further adopted to increase bandwidth and scanning angle of phased arrays without beam squint.
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Aimed at improving the navigation accuracy of the fixed-wing UAVs in GNSS-denied environments, this paper proposes an algorithm of nongravitational acceleration estimation based on airspeed and IMU sensors, which use a differential tracker (TD) model to further supplement the effect of linear acceleration for UAVs under dynamic flight. We further establish the mapping relationship between vehicle nongravitational acceleration and the vehicle attitude misalignment angle and transform it into the attitude angle rate deviation through the nonlinear complementary filtering model for real-time compensation. It can improve attitude estimation precision significantly for vehicles in dynamic conditions. Furthermore, a lightweight complementary filter is used to improve the accuracy of vehicle velocity estimation based on airspeed, and a barometer is fused on the height channel to achieve the accurate tracking of height and the lift rate. The algorithm is actually deployed on low-cost fixed-wing UAVs and is compared with ACF, EKF, and NCF by using real flight data. The position error within 30 s (about 600 m flying) in the horizontal channel flight is less than 30 m, the error within 90 s (about 1800 m flying) is less than 50 m, and the average error of the height channel is 0.5 m. The simulation and experimental tests show that this algorithm can provide UAVs with good attitude, speed, and position calculation accuracy under UAV maneuvering environments.
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BACKGROUND: To evaluate the antimicrobial and microbicidel activity of B. radicata fermentation broth, the broth was purified by DEAE-cellulose and sephadex LC-20 column. The compounds were submitted to spectral analyses (HPLC, FT-IR, 1D and 2D NMR etc.). RESULTS: The purified compounds were identified as the Griseococcin(s) which were naphthoquinone derivatives, the Chemical formula and MW of Griseococcin (1) was determined as C37O10H43N and 661 Da. only Griseococcin (1) has good antimicrobial activity among the Griseococcin(s). The zone of inhibition (ZOI), minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) or minimum fungicidal concentration (MFC) of Griseococcin (1) were used to investigate the antimicrobial activity. Antifungal activity of Griseococcin (1) was significant, especially for main pathogenic fungus Trichophyton rubrum and Trichophyton mentagrophytes, MFC/MIC of Griseococcin (1) was 1, while MFC/MIC of postive control was greater than 4, the fungicidal effect of Griseococcin (1) was better than that of positive control. CONCLUSIONS: In this paper, the secondary metabolite compound Griseococcin (1) from B. radicata was purified. The purified compound can restrain main pathogens (T. rubrum and T. mentagrophytes) leading to tinea pedis. The antifungal activity of Griseococcin (1) was similar to that of the positive control and the fungicidal effect of Griseococcin (1) was better than that of positive control, it might be suitable for pharmaceutical industries.
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Agaricales/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Agaricales/metabolismo , Antibacterianos/química , Antifúngicos/aislamiento & purificación , Arthrodermataceae/efectos de los fármacos , Bacterias/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos , Fermentación , Hongos/efectos de los fármacos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Metabolismo Secundario , Espectroscopía Infrarroja por Transformada de FourierRESUMEN
The expression of Notch1 plays an important role in the occurrence and development of various tumors. Previous studies have shown that Notch1 plays a negative regulatory role in response to radiation-induced DNA damage responses. It also has been reported that Notch1 was highly expressed in cervical cancer. It is well known that the first-line chemotherapy drug for treating cervical cancer, cisplatin, targets double-stranded DNA and induces apoptosis in the cells. However, the tolerability of cisplatin is an issue to overcome in the treatment of cervical cancer. Cisplatin has been reported to induce the up-regulation of Notch1 intracellular domain (NICD) through the γ-proteolytic enzyme complex, a complex that mediates Notch1 activation. Therefore, whether Notch1 is highly expressed in the cells or cisplatin induced high expression of NICD in cervical cancer has not been specifically discussed in these studies. More importantly, whether the inhibition of Notch1 activation would enhance DNA damage induced by cisplatin and/or cellular apoptosis mediated via ATM/CHK2/P53 pathway has not been reported in cervical cancer. In this study, we observed an enhanced DNA damage and cellular apoptosis via the ATM/CHK2/P53 pathway(s) in HeLa and SiHa cells treated with cisplatin combined with DAPT of Notch1 inhibitor. Our findings provide an alternative therapeutic strategy for the treatment of cervical cancer in the clinic.
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Proliferación Celular/efectos de los fármacos , Cisplatino/farmacología , Receptor Notch1/genética , Neoplasias del Cuello Uterino/tratamiento farmacológico , Apoptosis/efectos de los fármacos , Proteínas de la Ataxia Telangiectasia Mutada/genética , Quinasa de Punto de Control 2/genética , Cisplatino/efectos adversos , Daño del ADN/efectos de los fármacos , Daño del ADN/genética , Diaminas/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Células HeLa , Humanos , Receptor Notch1/antagonistas & inhibidores , Tiazoles/farmacología , Proteína p53 Supresora de Tumor/genética , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
Fly maggot meal has been regarded as one of the substitutes of fish meal and soybean meal in pig feed. However, its effects on pig growth performance and faecal micro-organism remain unclear. The purpose of this study was to investigate the effect of dietary fly maggot meal on fattening performance, plasma indices related to gut hormones, immunity and faecal microbial communities composition of finishing pigs. A total of 40 Ningxiang fattening pigs were randomly allocated to two dietary treatments and pigs in each group were arranged by control group (CK) diet or 8% maggot meal group (MMG) diet for 45 days respectively. Growth performance, indices of gut hormones and immunity in plasma were evaluated. Microbiota composition in faeces was determined using 16S rDNA Amplicon Sequencing. The results showed that dietary MMG did not affect gut hormones and immune proteins in the trial compared with CK group (p > .05). However, dietary MMG significantly increased average daily gain (ADG). The population of the Firmicutes in MMG treatment was increased, while the percentage of the Bacteroidetes was decreased (p < .05). In particular, the number of Clostridiales related to hydrolyzed sugar and protein were increased (p < .05). It can inhibit the growth of harmful intestinal bacteria, promote the proliferation of beneficial bacteria and effectively improve the ability of digestion and absorption of nutrients. In conclusion, a diet containing 8% MMG changed the proportion of intestinal micro-organisms in finishing pigs, especially the higher richness of Firmicutes, and promoted the fattening ability of pigs to a certain extent. These changes should benefit finishing pig production during fattening period.
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Alimentación Animal , Microbioma Gastrointestinal , Alimentación Animal/análisis , Animales , Dieta/veterinaria , Larva , Glycine max , PorcinosRESUMEN
As granular particles in a packing are athermal, their self-assembly has to be realized with the input of energy via walls. But different manners of energy input, e.g., through tapping or shearing walls, have not been discriminated previously. We address this problem in the self-assembly of identical granular spheres in prism-like containers subjected to one-dimensional (1D) vertical vibration by numerical simulations. The edge lengths or diameter of the containers are the integer multiples of the particle diameter. When energy is input with the vibration, the particles can self-assemble into mainly mixed FCC (face-centred-cubic) and HCP (hexagonal-close-packed) structures from the bottom wall and/or the side walls. According to different movements of the walls, the shear-induced and tap-induced self-assemblies are distinguished. These two self-assembly modes can emerge solely or simultaneously, with different but overlapping regions in the vibration amplitude and frequency phase diagram. The structures of the self-assembly from the two modes also present different features, suggesting different formation mechanisms. Moreover, it is found that the close-packed planes of the ordered clusters formed from different walls are often misaligned, leading to conflicts in the self-assembly of the whole system. These findings are helpful for both the understanding and controlling of the self-assembly of granular particles and other similar athermal and low-thermal systems.
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High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Conversely, in HPV-18-transformed HeLa cervical carcinoma cells, inhibition of O-GlcNAc with a low concentration of a chemical inhibitor impaired the transformed phenotypes in vitro. We showed that E6 elevated c-MYC via increased protein stability attributable to O-GlcNAcylation on Thr58. Reduction of HPV-mediated cell viability by a high concentration of O-GlcNAc inhibitor was partially rescued by elevated c-MYC. Finally, knockdown of OGT or O-GlcNAc inhibition in HeLa cells or in TC-1 cells, a mouse cell line transformed by HPV16 E6/E7 and activated K-RAS, reduced c-MYC and suppressed tumorigenesis and metastasis. Thus, we have uncovered a mechanism for HPV oncoprotein-mediated transformation. These findings may eventually aid in the development of effective therapeutics for HPV-associated malignancies by targeting aberrant O-GlcNAc.
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Carcinogénesis , N-Acetilglucosaminiltransferasas/fisiología , Proteínas Oncogénicas Virales/fisiología , Proteínas Represoras/fisiología , Neoplasias del Cuello Uterino/etiología , Animales , Línea Celular Tumoral , Femenino , Genes myc , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas E7 de Papillomavirus/fisiología , Neoplasias del Cuello Uterino/virologíaRESUMEN
The self-assembly of uniform granular spheres is related to the fundamentals of granular matter such as the transitions of phases, order/disorder and jamming states. This paper presents a DEM (discrete element method) study of the continuous self-assembly of uniform granular spheres from random close packing (RCP) to partially and nearly fully ordered packings under one-dimensional (1D) sinusoidal vibration without other interventions. The effects of the vibration amplitude and frequency are investigated in a wide range. The structures of the packings are characterized in terms of packing fraction and other microscopic structural parameters, including the coordination number, bond-orientational orders, and, in particular, ordered clusters, by adaptive common neighbor analysis (a-CNA). It is shown that 1D vibrations can also lead to the self-assembly of uniform granular spheres with packing fractions exceeding the RCP limit, and FCC (face centered cubic) and HCP (hexagonal close packed) structures coexist in the self-assembled packings while their total fraction can reach nearly 100%. The structures of these packings can be better correlated with the vibration velocity amplitude rather than the commonly used vibration intensity. The dynamics of such self-assembly is also preliminarily analyzed. Our study not only presents the conditions for the self-assembly of uniform granular spheres under 1D vibration, but also characterizes the order-disorder transitions during the process, which can improve our understanding of the fundamentals of granular materials and jamming states.
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Electronic appliances and ferromagnetic materials can be easily found in any building in urban environment. A steady magnetic environment and a pure value of geomagnetic field for calculating the heading of the smartphone in case of pedestrian walking indoors is hard to obtain. Therefore, an independent inertial heading correction algorithm without involving magnetic field but only making full use of the embedded Micro-Electro-Mechanical System (MEMS) Inertial measurement unit (IMU) device in the smartphone is presented in this paper. Aiming at the strict navigation requirements of pedestrian smartphone positioning, the algorithm focused in this paper consists of Gravity Assisted (GA) and Middle Time Simulated-Zero Velocity Update (MTS-ZUPT) methods. With the help of GA method, the different using-mode of the smartphone can be judged based on the data from the gravity sensor of smartphone. Since there is no zero-velocity status for handheld smartphone, the MTS-ZUPT algorithm is proposed based on the idea of Zero Velocity Update (ZUPT) algorithm. A Kalman Filtering algorithm is used to restrain the heading divergence at the middle moment of two steps. The walking experimental results indicate that the MTS-ZUPT algorithm can effectively restrain the heading error diffusion without the assistance of geomagnetic heading. When the MTS-ZUPT method was integrated with GA method, the smartphone navigation system can autonomously judge the using-mode and compensate the heading errors. The pedestrian positioning accuracy is significantly improved and the walking error is only 1.4% to 2.0% of the walking distance in using-mode experiments of the smartphone.
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Activation of death receptor-5 (DR5) leads to the formation of death inducing signaling complex (DISC) for apoptotic signaling. Targeting DR5 to induce breast cancer apoptosis is a promising strategy to circumvent drug resistance and present a target for breast cancer treatment. Calmodulin (CaM) has been shown to regulate DR5-mediated apoptotic signaling, however, its mechanism remains unknown. In this study, we characterized CaM and DR5 interactions in breast cancer cells with integrated experimental and computational approaches. Results show that CaM directly binds to DR5 in a calcium dependent manner in breast cancer cells. The direct interaction of CaM with DR5 is localized at DR5 death domain. We have predicted and verified the CaM-binding site in DR5 being (354)WEPLMRKLGL(363) that is located at the α2 helix and the loop between α2 helix and α3 helix of DR5 DD. The residues of Trp-354, Arg-359, Glu-355, Leu-363, and Glu-367 in DR5 death domain that are important for DR5 recruitment of FADD and caspase-8 for DISC formation to signal apoptosis also play an important role for CaM-DR5 binding. The changed electrostatic potential distribution in the CaM-binding site in DR5 DD by the point mutations of W354A, E355K, R359A, L363N, or E367K in DR5 DD could directly contribute to the experimentally observed decreased CaM-DR5 binding by the point mutations of the key residues in DR5 DD. Results from this study provide a key step for the further investigation of the role of CaM-DR5 binding in DR5-mediated DISC formation for apoptosis in breast cancer cells.
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Calcio/metabolismo , Calmodulina/metabolismo , Receptores de Estrógenos/metabolismo , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/metabolismo , Secuencia de Aminoácidos , Apoptosis/genética , Sitios de Unión/genética , Western Blotting , Calmodulina/química , Línea Celular Tumoral , Biología Computacional/métodos , Femenino , Humanos , Modelos Moleculares , Mutación , Unión Proteica , Dominios Proteicos , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/química , Receptores del Ligando Inductor de Apoptosis Relacionado con TNF/genética , Transducción de Señal/genética , Electricidad Estática , Integración de Sistemas , Neoplasias de la Mama Triple Negativas/metabolismo , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
BACKGROUND: In order to improve therapy for head and neck squamous cell carcinoma (HNSCC), biomarkers associated with local and/or distant tumor relapses and cancer drug resistance are urgently needed. This study identified a potential biomarker, Bcl-2 associated athanogene-1 (BAG-1), that is implicated in HNSCC insensitive to cisplatin and tumor progression. METHODS: Primary and advanced (relapsed from parental) University of Michigan squamous cell carcinoma cell lines were tested for sensitivity to cisplatin and gene expression profiles were compared between primary (cisplatin sensitive) and the relapsed (cisplatin resistant) cell lines by using Agilent microarrays. Additionally, differentially expressed genes phosphorylated AKT, and BAG-1, and BCL-xL were evaluated for expression using HNSCC tissue arrays. RESULTS: Advanced HNSCC cells revealed resistant to cisplatin accompanied by increased expression of BAG-1 protein. siRNA knockdown of BAG-1 expression resulted in significant improvement of HNSCC sensitivity to cisplatin. BAG-1 expression enhanced stability of BCL-xL and conferred cisplatin resistant to the HNSCC cells. In addition, high levels of expression of phosphorylated AKT, BAG-1, and BCL-xL were observed in advanced HNSCC compared to in that of primary HNSCC. CONCLUSION: Increased expression of BAG-1 was associated with cisplatin resistance and tumor progression in HNSCC patients and warrants further validation in larger independent studies. Over expression of BAG-1 may be a biomarker for cisplatin resistance in patients with primary or recurrent HNSCCs and targeting BAG-1 could be helpful in overcoming cisplatin resistance.
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Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Cisplatino/uso terapéutico , Proteínas de Unión al ADN/metabolismo , Resistencia a Antineoplásicos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Factores de Transcripción/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Cisplatino/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Reproducibilidad de los Resultados , Transducción de Señal/efectos de los fármacos , Carcinoma de Células Escamosas de Cabeza y Cuello , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Prolonged or excessive ß-adrenergic activation leads to cardiac myocyte loss and heart dysfunction; however, the underlying cellular mechanisms are still unclear. Therefore, we first confirmed the effect of isoproterenol (ISO), a ß-adrenergic receptor agonist, on cardiac toxicity using TUNEL and caspase activity assays in cultured rat cardiomyocytes. ISO treatment significantly increased cardiomyocyte apoptosis. Persistent ISO stimulation of cardiomyocytes also increased the expression of CYP4A3, a major CYP450 ω-hydroxylase that produces 20-hydroxyeicosatetraenoic acid (20-HETE) in a time-dependent manner. Next, we examined the effect of ISO and 20-HETE on cardiomyocyte apoptosis using annexin V and propidium iodide staining. Treatment with either 20-HETE or ISO significantly increased cardiomyocyte apoptosis, and inhibition of 20-HETE production using 17-ODYA, a CYP450 ω-hydroxylase inhibitor, dramatically attenuated ISO-induced cardiomyocyte apoptosis. To determine the apoptotic pathway involved, the mitochondrial membrane potential (ΔΨm) was measured by detecting the ratio of JC-1 green/red emission intensity. The results demonstrated that 17-ODYA significantly abolished ISO-induced disruption of ΔΨm and that 20-HETE alone induced a marked disruptive effect on ΔΨm in cardiomyocytes. In addition, 20-HETE-induced disruption of ΔΨm and apoptosis was significantly attenuated by KN93, a CaMKII inhibitor. Taken together, these results demonstrate that 20-HETE treatment induces significant apoptosis via mitochondrial-dependent pathways, and that inhibition of 20-HETE production using 17-ODYA attenuates ISO-induced cardiomyocyte apoptosis.
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Agonistas Adrenérgicos beta/farmacología , Citocromo P-450 CYP4A/fisiología , Miocitos Cardíacos/fisiología , Receptores Adrenérgicos beta/fisiología , Animales , Animales Recién Nacidos , Células Cultivadas , Miocitos Cardíacos/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
BeiDou system navigation messages are modulated with a secondary NH (Neumann-Hoffman) code of 1 kbps, where frequent bit transitions limit the coherent integration time to 1 millisecond. Therefore, a bit synchronization algorithm is necessary to obtain bit edges and NH code phases. In order to realize bit synchronization for BeiDou weak signals with large frequency deviation, a bit synchronization algorithm based on differential coherent and maximum likelihood is proposed. Firstly, a differential coherent approach is used to remove the effect of frequency deviation, and the differential delay time is set to be a multiple of bit cycle to remove the influence of NH code. Secondly, the maximum likelihood function detection is used to improve the detection probability of weak signals. Finally, Monte Carlo simulations are conducted to analyze the detection performance of the proposed algorithm compared with a traditional algorithm under the CN0s of 20~40 dB-Hz and different frequency deviations. The results show that the proposed algorithm outperforms the traditional method with a frequency deviation of 50 Hz. This algorithm can remove the effect of BeiDou NH code effectively and weaken the influence of frequency deviation. To confirm the feasibility of the proposed algorithm, real data tests are conducted. The proposed algorithm is suitable for BeiDou weak signal bit synchronization with large frequency deviation.
RESUMEN
An integrated navigation system coupled with additional sensors can be used in the Micro Unmanned Aerial Vehicle (MUAV) applications because the multi-sensor information is redundant and complementary, which can markedly improve the system accuracy. How to deal with the information gathered from different sensors efficiently is an important problem. The fact that different sensors provide measurements asynchronously may complicate the processing of these measurements. In addition, the output signals of some sensors appear to have a non-linear character. In order to incorporate these measurements and calculate a navigation solution in real time, the multi-sensor fusion algorithm based on factor graph is proposed. The global optimum solution is factorized according to the chain structure of the factor graph, which allows for a more general form of the conditional probability density. It can convert the fusion matter into connecting factors defined by these measurements to the graph without considering the relationship between the sensor update frequency and the fusion period. An experimental MUAV system has been built and some experiments have been performed to prove the effectiveness of the proposed method.