FOXM1 recruits nuclear Aurora kinase A (AURKA) to participate in a positive feedback loop essential for the self-renewal of breast cancer stem cells

Substantial evidence suggests that breast cancer initiation, recurrence and drug resistance is supported by breast cancer stem cells (BCSCs). Recently, we reported a novel role of Aurora kinase A (AURKA) in BCSCs, as a transactivating co-factor in the induction of the c-Myc oncoprotein. However, the mode of action and transcriptional network of nuclear AURKA in BCSCs remain unknown. Here, we report that nuclear AURKA can be recruited by FOXM1 as a co-factor to transactivate FOXM1-target genes in a kinase-independent manner. In addition, we show that AURKA and FOXM1 participate in a tightly coupled positive feedback loop to enhance BCSC phenotype. Indeed, kinase-dead AURKA can effectively transactivate the FOXM1 promoter through a Forkhead response element (FKHR), while FOXM1 can activate AURKA expression at the transcriptional level in a similar manner. Consistently, breast cancer patient samples portrayed a strong and significant correlation between the expression levels of FOXM1 and AURKA. Moreover, both FOXM1 and AURKA were essential for maintaining the BCSC population. Finally, we demonstrated that the Aurora kinase A inhibitor AKI603 and FOXM1 inhibitor thiostrepton acted synergistically to inhibit cytoplasmic Aurora kinase A activity and disrupt the nuclear AURKA/FOXM1 positive feedback loop respectively, resulting in a more effective inhibition of the tumorigenicity and self-renewal ability of BCSCs. Collectively, our study uncovers a previously unknown tightly coupled positive feedback signalling loop between AURKA and FOXM1, crucial for BCSC self-renewal. Remarkably, our data reveals a novel potential therapeutic strategy for targeting both the cytoplasmic and nuclear AURKA function to effectively eliminate BCSCs, so as to overcome both breast cancer and drug resistance

Desain dan Uji Coba Lembar Kerja Peserta Didik (Lkpd) Berbasis Sets (Science, Environment, Technology, And Society) pada Materi Koloid

This research aimed at knowing the level of validity and practicality students workbook SETS (Science, Environment, Technology and Society) Based on Colloid Lesson. It was a Research and Development (R&D) Method with 4-D Model. It was administered at State Senior High School 1 East Kampar.  Subject of this research were  Media design expert, Learning material expert, Chemistry teacher and Fifteenth studenst. Object of this research were SETS (Science, Environment, Technology and Society) Based on Colloid Lesson. the Instrument of collecting the data were questionnaire of validity test by the experts and questionnaire of practicality test by taecher and students.  student workbook was appropriate, if it was valid and practice aspect qualify.The validity and practicality could be seen from the result of validity and practicality using sheet of  validity and practicalisation. student workbook  resulting was tested with the validity level was 88.125% (Very valid)and practice was 90.4% (Very practice). The research result indentify that Student Workbook was tested, it appropriate to be an additional teaching teacher at school. Keywords : Student Workbook, SETS, Colloi

Functionally graded plate fracture analysis using the field boundary element method

This paper describes the Field Boundary Element Method (FBEM) applied to the fracture analysis of a 2D rectangular plate made of Functionally Graded Material (FGM) to calculate Mode I Stress Intensity Factor (SIF). The case study of this Field Boundary Element Method is the transversely isotropic plane plate. Its material presents an exponential variation of the elasticity tensor depending on a scalar function of position, i.e., the elastic tensor results from multiplying a scalar function by a constant taken as a reference. Several examples using a parametric representation of the structural response show the suitability of the method that constitutes a Stress Intensity Factor evaluation of Functionally Graded Materials plane plates even in the case of more complex geometries

Regulation of PERK expression by FOXO3: a vulnerability of drug-resistant cancer cells

The major impediment to effective cancer therapy has been the development of drug resistance. The tumour suppressive transcription factor FOXO3 promotes cell cycle arrest, senescence and cell death, and mediates the cytotoxic and cytostatic functions of cancer therapeutics. In consequence, FOXO3 is often downregulated as an adaptive response in cancer and particularly in chemotherapeutic drug-resistant cells. Consistently, we find that FOXO3 expression is attenuated in the drug-resistant MCF-7-EpiR and MCF-7-TaxR compared to the parental MCF-7 breast cancer cells. Using ChIP, short-interfering RNA (siRNA) knockdown, and overexpression assays as well as Foxo1/3/4−/− MEFs, we establish the endoplasmic reticulum (ER)-stress defence modulator PERK (eIF2AK3) as a direct downstream transcriptional target of FOXO3. In agreement, there is also a positive correlation between FOXO3 and PERK expression at the protein and RNA levels in breast cancer patient samples. We uncover that PERK expression is downregulated but its activity constitutively elevated in the drug-resistant cells. With this in mind, we exploit this adaptive response of low FOXO3 and PERK expression, and high PERK activity in drug-resistant breast cancer cells and show that these drug-resistant cells are specifically sensitive to PERK inhibition. In support of this finding, we show that ectopic overexpression of FOXO3 can reduce the sensitivity of the resistant cells to the PERK inhibitor GSK2606414, while the Foxo1/3/4−/− MEFs expressing lower levels of PERK are more sensitive to PERK inhibition compared to wild-type MEFs. PERK inhibitor-titration and -time course experiments showed that the drug-resistant cells, which express lower expression and higher activity levels of PERK, are more sensitive to the increasing concentrations of PERK inhibitor compared to parental MCF-7 cells. Our present work thus reveals a chemotherapeutic drug-resistant cancer cell vulnerability in PERK and suggests PERK as a potential target for cancer therapy, specifically in the context of drug-resistant cancers

NSHT: New Smart Hybrid Transducer for Structural and Geotechnical Applications

This work describes the application of a new transducer prototype for continuous monitoring in both the structural and geotechnical fields. The transducer is synthetically constituted by a wire of optical fiber embedded between two fiber tapes (fiberglass or carbon fiber) and glued by a matrix of polyester resin. The fiber optical wire ends have been connected to a control unit whose detection system is based on Brillouin optical time-domain frequency analysis. Three laboratory tests were carried out to evaluate the sensor's reliability and accuracy. In each experiment, the transducer was applied to a sample of inclinometer casing sets in different configurations and with different constraint conditions. The experimental collected data were compared with theoretical models and with data obtained from the use of different measuring instruments to perform validation and calibration of the transducer at the same time. Several diagrams can compare the transducer and highlight its suitability for the monitoring and maintenance of structures. The characteristic of the transducer suggests its use as a mixed system for reinforcing and monitoring, especially in the lifetime maintenance of critical infrastructures such as transportation and service networks, and historical heritag

Mechanistic Modeling of Microtopographic Impacts on CO2 and CH4 Fluxes in an Alaskan Tundra Ecosystem Using the CLM-Microbe Model

Spatial heterogeneities in soil hydrology have been confirmed as a key control on CO2 and CH4 fluxes in the Arctic tundra ecosystem. In this study, we applied a mechanistic ecosystem model, CLM-Microbe, to examine the microtopographic impacts on CO2 and CH4 fluxes across seven landscape types in Utqiaġvik, Alaska: trough, low-centered polygon (LCP) center, LCP transition, LCP rim, high-centered polygon (HCP) center, HCP transition, and HCP rim. We first validated the CLM-Microbe model against static-chamber measured CO2 and CH4 fluxes in 2013 for three landscape types: trough, LCP center, and LCP rim. Model application showed that low-elevation and thus wetter landscape types (i.e., trough, transitions, and LCP center) had larger CH4 emissions rates with greater seasonal variations than high-elevation and drier landscape types (rims and HCP center). Sensitivity analysis indicated that substrate availability for methanogenesis (acetate, CO2 + H2) is the most important factor determining CH4 emission, and vegetation physiological properties largely affect the net ecosystem carbon exchange and ecosystem respiration in Arctic tundra ecosystems. Modeled CH4 emissions for different microtopographic features were upscaled to the eddy covariance (EC) domain with an area-weighted approach before validation against EC-measured CH4 fluxes. The model underestimated the EC-measured CH4 flux by 20% and 25% at daily and hourly time steps, suggesting the importance of the time step in reporting CH4 flux. The strong microtopographic impacts on CO2 and CH4 fluxes call for a model-data integration framework for better understanding and predicting carbon flux in the highly heterogeneous Arctic landscape