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LACTB is identified as a tumor suppressor in several tumors. However, preliminary study reveals that LACTB is overexpressed in osteosarcoma and indicates poor prognosis. Two missense mutations (rs34317102 and rs2729835) exist simultaneously in 92.31% of osteosarcoma patients and cause M5L and R469K double mutations in LACTB, suggesting the biologic function of LACTB protein may be altered in osteosarcoma. Moreover, LACTBM5L+R469K overexpression can promote malignant progression in different tumors, which suggests that the M5L and R469K mutations confer oncogene-like functions to LACTB. Mechanistically, LACTBM5L+R469K not only reduces the wild type p53 via enhancing PSMB7 catalytic activity, but also protects p53R156P protein from lysosomal degradation, which suggesting LACTBM5L+R469K is a dual-regulator for wt-p53 and mutant p53, and derive oncogene-like functions. More importantly, clavulanate potassium, a bacterial ß-lactamase inhibitor, can inhibit osteosarcoma proliferation and sensitize osteosarcoma to cisplatin by binding and blocking LACTBM5L+R469K. These findings revealed that the M5L and R469K double mutations can diminish the tumor suppressive ability of wild type LACTB and provide oncogene-like functions to LACTB. Inhibiting LACTBM5L+R469K can suppress the progression of osteosarcoma harbouring wild-type or mutant p53. Clavulanate potassium is a promising drug by targeting LACTBM5L+R469K-p53 pathway for the treatment of osteosarcoma patients.
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Along with the development of speech and language technologies, the market for speech-enabled human-robot interactions (HRI) has grown in recent years. However, it is found that people feel their conversational interactions with such robots are far from satisfactory. One of the reasons is the habitability gap, where the usability of a speech-enabled agent drops when its flexibility increases. For social robots, such flexibility is reflected in the diverse choice of robots' appearances, sounds and behaviours, which shape a robot's 'affordance'. Whilst designers or users have enjoyed the freedom of constructing a social robot by integrating off-the-shelf technologies, such freedom comes at a potential cost: the users' perceptions and satisfaction. Designing appropriate affordances is essential for the quality of HRI. It is hypothesised that a social robot with aligned affordances could create an appropriate perception of the robot and increase users' satisfaction when speaking with it. Given that previous studies of affordance alignment mainly focus on one interface's characteristics and face-voice match, we aim to deepen our understanding of affordance alignment with a robot's behaviours and use cases. In particular, we investigate how a robot's affordances affect users' perceptions in different types of use cases. For this purpose, we conducted an exploratory experiment that included three different affordance settings (adult-like, child-like, and robot-like) and three use cases (informative, emotional, and hybrid). Participants were invited to talk to social robots in person. A mixed-methods approach was employed for quantitative and qualitative analysis of 156 interaction samples. The results show that static affordance (face and voice) has a statistically significant effect on the perceived warmth of the first impression; use cases affect people's perceptions more on perceived competence and warmth before and after interactions. In addition, it shows the importance of aligning static affordance with behavioural affordance. General design principles of behavioural affordances are proposed. We anticipate that our empirical evidence will provide a clearer guideline for speech-enabled social robots' affordance design. It will be a starting point for more sophisticated design guidelines. For example, personalised affordance design for individual or group users in different contexts.
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BACKGROUND: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment. METHODS: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated. RESULTS: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors. CONCLUSIONS: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.
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Neoplasias Ósseas , Neoplasias Pulmonares , Osteossarcoma , Humanos , Prognóstico , Estudos Retrospectivos , Osteossarcoma/genética , Neoplasias Pulmonares/genética , Neoplasias Ósseas/genética , Biomarcadores , beta-Lactamases , Proteínas de Membrana , Proteínas Mitocondriais , Proteínas Repressoras , Fatores de Transcrição Forkhead , Fatores de Processamento de Serina-ArgininaRESUMO
This paper summarizes the structure and findings from the first Workshop on Troubles and Failures in Conversations between Humans and Robots. The workshop was organized to bring together a small, interdisciplinary group of researchers working on miscommunication from two complementary perspectives. One group of technology-oriented researchers was made up of roboticists, Human-Robot Interaction (HRI) researchers and dialogue system experts. The second group involved experts from conversation analysis, cognitive science, and linguistics. Uniting both groups of researchers is the belief that communication failures between humans and machines need to be taken seriously and that a systematic analysis of such failures may open fruitful avenues in research beyond current practices to improve such systems, including both speech-centric and multimodal interfaces. This workshop represents a starting point for this endeavour. The aim of the workshop was threefold: Firstly, to establish an interdisciplinary network of researchers that share a common interest in investigating communicative failures with a particular view towards robotic speech interfaces; secondly, to gain a partial overview of the "failure landscape" as experienced by roboticists and HRI researchers; and thirdly, to determine the potential for creating a robotic benchmark scenario for testing future speech interfaces with respect to the identified failures. The present article summarizes both the "failure landscape" surveyed during the workshop as well as the outcomes of the attempt to define a benchmark scenario.
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Along with the development of speech and language technologies and growing market interest, social robots have attracted more academic and commercial attention in recent decades. Their multimodal embodiment offers a broad range of possibilities, which have gained importance in the education sector. It has also led to a new technology-based field of language education: robot-assisted language learning (RALL). RALL has developed rapidly in second language learning, especially driven by the need to compensate for the shortage of first-language tutors. There are many implementation cases and studies of social robots, from early government-led attempts in Japan and South Korea to increasing research interests in Europe and worldwide. Compared with RALL used for English as a foreign language (EFL), however, there are fewer studies on applying RALL for teaching Chinese as a foreign language (CFL). One potential reason is that RALL is not well-known in the CFL field. This scope review paper attempts to fill this gap by addressing the balance between classroom implementation and research frontiers of social robots. The review first introduces the technical tool used in RALL, namely the social robot, at a high level. It then presents a historical overview of the real-life implementation of social robots in language classrooms in East Asia and Europe. It then provides a summary of the evaluation of RALL from the perspectives of L2 learners, teachers and technology developers. The overall goal of this paper is to gain insights into RALL's potential and challenges and identify a rich set of open research questions for applying RALL to CFL. It is hoped that the review may inform interdisciplinary analysis and practice for scientific research and front-line teaching in future.
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Background: Seasonal pollen is a common cause of allergic respiratory disease. In the United States, pollen monitoring occurs via manual counting, a method which is both labor-intensive and has a considerable time delay. In this paper, we report the field-testing results of a new, automated, real-time pollen imaging sensor in Atlanta, GA. Methods: We first compared the pollen concentrations measured by an automated real-time pollen sensor (APS-300, Pollen Sense LLC) collocated with a Rotorod M40 sampler in 2020 at an allergy clinic in northwest Atlanta. An internal consistency assessment was then conducted with two collocated APS-300 sensors in downtown Atlanta during the 2021 pollen season. We also investigated the spatial heterogeneity of pollen concentrations using the APS-300 measurements. Results: Overall, the daily pollen concentrations reported by the APS-300 and the Rotorod M40 sampler with manual counting were strongly correlated (r = 0.85) during the peak pollen season. The APS-300 reported fewer tree pollen taxa, resulting in a slight underestimation of total pollen counts. Both the APS-300 and Rotorod M40 reported Quercus (Oak) and Pinus (Pine) as dominant pollen taxa during the peak tree pollen season. Pollen concentrations reported by APS-300 in the summer and fall were less accurate. The daily total and speciated pollen concentrations reported by two collocated APS-300 sensors were highly correlated (r = 0.93-0.99). Pollen concentrations showed substantial spatial and temporal heterogeneity in terms of peak levels at three locations in Atlanta. Conclusions: The APS-300 sensor was able to provide internally consistent, real-time pollen concentrations that are strongly correlated with the current gold-standard measurements during the peak pollen season. When compared with manual counting approaches, the fully automated sensor has the significant advantage of being mobile with the ability to provide real-time pollen data. However, the sensor's weed and grass pollen identification algorithms require further improvement.
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Pólen , Quercus , Alérgenos , Automação , Estações do AnoRESUMO
Chitosan (CS) electrospun nanofiber (ENF) membranes were modified with fucoidan (Fu) and CuS NPs through polyelectrolyte complexation and genipin (GP)-involved cross-linking reaction. The formation of Fu/CS complex and cross-linking of CS with GP increased the acid resistance and reduced the swelling rate of CS ENF, while the covalent conjugation of CuS NPs provided CS ENF with durable Fenton-like catalytic activity. The CuS@ENF composite (ENFC) effectively adsorbed H2O2 and near-infrared (NIR) light, enabling it to kill bacteria by photothermal and photocatalytic bactericidal effects. Fu and copper ions were able to release from the ENFC in a pH-dependent manner, and promoted the alkaline phosphatase activity of osteoblast cells and capillary tube formation of endothelial cells. This study provides a new approach to modify CS ENF with antibacterial and osteoblast differentiation activities, which may be available for bone infection prevention and tissue regeneration.
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Quitosana , Nanofibras , Antibacterianos/farmacologia , Quitosana/farmacologia , Cobre , Células Endoteliais , Peróxido de Hidrogênio , Polissacarídeos , Engenharia TecidualRESUMO
OS (Osteosarcoma) is the most common malignant tumor in adolescents, and lung metastasis limits its therapeutic outcome. The present study aimed to establish a highly metastatic human OS cell line directly from lung metastases and characterize its biological functions. In this study, epithelioid tumor cells with large nucleo-cytoplasmic ratio and abundant organelles were obtained by the tissue mass adherent and repeated digestion adherent method and named ZOSL-1 cells. ZOSL-1 cells had the potential to proliferate in vitro with a doubling time of 39.28 ± 3.04 h and migrate with or without a matrix. ZOSL-1 cells were tumorigenic in vivo, and had the ability to develop lung metastasis after intratibial injection. ZOSL-1 cells expressed the osteogenic-related genes osteocalcin and osteopontin. In addition, the expression of ZOSL-1 in Fas cell surface death receptor (FAS), CD44 molecule (CD44), GNAS complex locus (GNAS), scavenger receptor class B member 1 (SCARB1), C-X-C motif chemokine receptor 4 (CXCR4), cadherin 11 (CDH11), neurofibromin 2 (NF2) and ezrin (EZR) genes may be related to its transfer efficiency. Taken together, these results indicated the high metastatic capability and important biological functions of ZOSL-1 cells. ZOSL-1 establishment provided a relevant model for the study of osteosarcoma lung metastasis.
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Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. Although activator of HSP90 ATPase activity 1 (AHA1) is reported to be a potential oncogene, its role in osteosarcoma progression remains largely unclear. Since metabolism reprogramming is involved in tumorigenesis and cancer metastasis, the relationship between AHA1 and cancer metabolism is unknown. In this study, we found that AHA1 is significantly overexpressed in osteosarcoma and related to the prognosis of osteosarcoma patients. AHA1 promotes the growth and metastasis of osteosarcoma both in vitro and in vivo. Mechanistically, AHA1 upregulates the metabolic activity to meet cellular bioenergetic needs in osteosarcoma. Notably, we identified that isocitrate dehydrogenase 1 (IDH1) is a novel client protein of Hsp90-AHA1. Furthermore, the IDH1 protein level was positively correlated with AHA1 in osteosarcoma. And IDH1 overexpression could partially reverse the effect of AHA1 knockdown on cell growth and migration of osteosarcoma. Moreover, high IDH1 level was also associated with poor prognosis of osteosarcoma patients. This study demonstrates that AHA1 positively regulates IDH1 and metabolic activity to promote osteosarcoma growth and metastasis, which provides novel prognostic biomarkers and promising therapeutic targets for osteosarcoma patients.
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Neoplasias Ósseas/enzimologia , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Isocitrato Desidrogenase/biossíntese , Chaperonas Moleculares/biossíntese , Proteínas de Neoplasias/metabolismo , Osteossarcoma/enzimologia , Regulação para Cima , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Isocitrato Desidrogenase/genética , Camundongos Endogâmicos BALB C , Camundongos Nus , Chaperonas Moleculares/genética , Proteínas de Neoplasias/genética , Osteossarcoma/genética , Osteossarcoma/patologiaRESUMO
Lung cancer is a leading cause of cancer-related death worldwide. In this study, we used lung adenocarcinoma cells as a model, as lung adenocarcinoma has the highest mortality rate among all lung cancers. For the past few years, medical treatments or lung cancer have been limited because of chemotherapy resistance. Therefore, understanding the pathogenesis of the development of drug resistance in lung cancer is urgent. Gemcitabine is widely prescribed in the chemotherapeutic treatment of lung cancers. In this study, we developed gemcitabine-resistant lung adenocarcinoma cells (A549-GR) from the A549 cell line. The results showed that apoptotic protein expression and reactive oxygen species (ROS) generation were reduced in A549-GR cells compared to A549 cells. Interestingly, we found that signal transducer and activator of transcription 3 (STAT3) translocated to the nucleus and mitochondria to affect the apoptotic pathway and ROS generation, respectively. Furthermore, treatment with STAT3 small interfering RNA diminished the increase in ROS production, proliferation and antiapoptotic proteins in A549-GR cells. Taken together, the study demonstrated that STAT3 acts as an essential regulator and moderates apoptosis through two major mechanisms to induce gemcitabine resistance in cells; and these findings provide a potential target for the treatment of gemcitabine-resistant lung cancer.
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Apoptose , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/metabolismo , Mitocôndrias/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/metabolismo , Células A549 , Apoptose/efeitos dos fármacos , Apoptose/genética , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Citosol/metabolismo , Desoxicitidina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/patologia , MicroRNAs/genética , MicroRNAs/metabolismo , Mitocôndrias/efeitos dos fármacos , Modelos Biológicos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , GencitabinaRESUMO
We study the variation of tropospheric NO2 vertical column densities (TropNO2VCDs) over East China during the 2005-2020 lunar new year (LNY) holiday seasons to understand factors on the reduction of tropospheric NO2 during the outbreak of COVID-19 in East China using Ozone Monitoring Instrument (OMI) and TROPOspheric Monitoring Instrument (TROPOMI) observations. TropNO2VCDs from OMI and TROPOMI reveal sharp reductions of 33%-72% during 2020 LNY holiday season and the co-occurring outbreak of COVID-19 relative to the climatological mean of 2005-2019 LNY holiday seasons, and 22%-67% reduction relative to the 2019 LNY holiday season. These reductions of TropNO2VCD occur majorly over highly polluted metropolitan areas with condensed industrial and transportation emission sources. COVID-19 control measures including lockdowns and shelter-in-place regulations are the primary reason for these tropospheric NO2 reductions over most areas of East China in 2020 LNY holiday season relative to the 2019 LNY holiday season, as COVID-19 control measures may explain ~87%-90% of tropospheric NO2 reduction in Wuhan as well as ~62%-89% in Beijing, Yangtze River Delta (YRD) and Sichuan Basin areas. The clean air regulation of China also contributes significantly to reductions of tropospheric NO2 simultaneously and is the primary factor in the Pearl River Delta (PRD) area, by explaining ~56%-63% of the tropospheric NO2 reduction there.
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Poluentes Atmosféricos/análise , Infecções por Coronavirus , Ozônio/análise , Pandemias , Pneumonia Viral , Pequim , Betacoronavirus , COVID-19 , China/epidemiologia , Monitoramento Ambiental , Humanos , Dióxido de Nitrogênio/análise , SARS-CoV-2 , Estações do AnoRESUMO
To measure large external forces exerted on a loading platform, a novel three-dimensional force sensor is developed in this paper. The proposed sensor was designed with a parallel mechanism with three degrees of freedom. Kinematic analysis of this sensor was performed. Due to its structural characteristics, the working principle of the sensor was analyzed using a Jacobian matrix. The sensitivity diversity index and measuring capability were both calculated. The analysis showed that the proposed sensor is more suitable for measuring large forces than existing strain sensors. In addition, compared with existing strain sensors, this sensor is more suitable for measuring forces along the x and y axes. By changing the stiffness coefficients of the springs, the proposed sensor has reconfigurability. This sensor can change its measuring capability to meet different requirements. Next, the mode shapes and natural frequencies of the proposed sensor were performed. Finally, based on these performance indices, the design variables were optimized using a Multi-Objective Genetic Algorithm.
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This study first investigates the anti-metastatic effect of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone) on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced MMPs and u-PA expressions in human lung cancer cells, A549. First, the result demonstrated plumbagin could inhibit TPA induced the abilities of the adhesion, invasion, and migration by cell-matrix adhesion assay and Boyden chamber assay. Data also showed plumbagin could inhibit the activation of extracellular signal-regulated kinase 1 and 2 (ERK1/2) involved in the down-regulating enzyme activities, protein and messenger RNA levels of matrix metalloproteinase-2 (MMP-2), and urokinase-type plasminogen activator (u-PA) induced by TPA. Next, plumbagin also strongly inhibited TPA-induced phosphorylation and degradation of inhibitor of kappaBalpha (IkappaBalpha), and the nuclear levels of nuclear factor kappa B (NF-kappaB), c-Fos, and c-Jun. Also, a dose-dependent inhibition on the binding abilities of NF-kappaB and activator protein-1 (AP-1) by plumbagin treatment was further observed. Further, the treatment of specific inhibitor for ERK (U0126) to A549 cells could inhibit TPA-induced MMP-2 and u-PA expressions along with an inhibition on cell invasion and migration. Presented data reveals that plumbagin is a novel, effective, anti-metastatic agent that functions by down-regulating MMP-2 and u-PA gene expressions.