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Visual reinforcement learning is important in various practical applications, such as video games, robotic manipulation, and autonomous navigation. However, a major challenge in visual reinforcement learning is the generalization to unseen environments, that is, how agents manage environments with previously unseen backgrounds. This issue is triggered mainly by the high unpredictability inherent in high-dimensional observation space. To deal with this problem, techniques including domain randomization and data augmentation have been explored; nevertheless, these methods still cannot attain a satisfactory result. This paper proposes a new method named Internal States Simulation Auxiliary (ISSA), which uses internal states to improve generalization in visual reinforcement learning tasks. Our method contains two agents, a teacher agent and a student agent: the teacher agent has the ability to directly access the environment's internal states and is used to facilitate the student agent's training; the student agent receives initial guidance from the teacher agent and subsequently continues to learn independently. From another perspective, our method can be divided into two phases, the transfer learning phase and traditional visual reinforcement learning phase. In the first phase, the teacher agent interacts with environments and imparts knowledge to the vision-based student agent. With the guidance of the teacher agent, the student agent is able to discover more effective visual representations that address the high unpredictability of high-dimensional observation space. In the next phase, the student agent autonomously learns from the visual information in the environment, and ultimately, it becomes a vision-based reinforcement learning agent with enhanced generalization. The effectiveness of our method is evaluated using the DMControl Generalization Benchmark and the DrawerWorld with texture distortions. Preliminary results indicate that our method significantly improves generalization ability and performance in complex continuous control tasks.
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Ammonia (NH3) is an irritating and harmful gas that affects cell apoptosis and autophagy. Sirtuin 5 (SIRT5) has multiple enzymatic activities and regulates NH3-induced autophagy in tumor cells. In order to determine whether SIRT5 regulates NH3-induced bovine mammary epithelial cell apoptosis and autophagy, cells with SIRT5 overexpression or knockdown were generated and in addition, bovine mammary epithelial cells were treated with SIRT5 inhibitors. The results showed that SIRT5 overexpression reduced the content of NH3 and glutamate in cells by inhibiting glutaminase activity in glutamine metabolism, and reduced the ratio of ADP/ATP. The results in the SIRT5 knockdown and inhibitor groups were comparable, including increased content of NH3 and glutamate in cells by activating glutaminase activity, and an elevated ratio of ADP/ATP. It was further confirmed that SIRT5 inhibited the apoptosis and autophagy of bovine mammary epithelial cells through reverse transcription-quantitative PCR, western blot, flow cytometry with Annexin V FITC/PI staining and transmission electron microscopy. In addition, it was also found that the addition of LY294002 or Rapamycin inhibited the PI3K/Akt or mTOR kinase signal, decreasing the apoptosis and autophagy activities of bovine mammary epithelial cells induced by SIRT5-inhibited NH3. In summary, the PI3K/Akt/mTOR signal involved in NH3-induced cell autophagy and apoptosis relies on the regulation of SIRT5. This study provides a new theory for the use of NH3 to regulate bovine mammary epithelial cell apoptosis and autophagy, and provides guidance for improving the health and production performance of dairy cows.
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Background: Despite the availability of a considerable number of studies on transitional care, few qualitative studies have synthesized physicians' perspectives on PICU-to-ward transition to develop a comprehensive transitional care curriculum. The aim of this study is to explore physicians' perceptions and management of the transition of critically ill children from the PICU to the general ward, with the aim of providing an evidence-based curriculum. Methods: A qualitative study was conducted between July and August 2022. The study involved semi-structured interviews with 11 participants, and data analysis was carried out using NVivo 12.0 software through thematic analysis method. Results: Based on the data analysis, three main themes were identified: recognition of professional roles during transition, difficulties during implementation transitional care and suggestions for improving transitional care. Conclusion: The insights of doctors can be valuable in improving transitional care for critically ill children during PICU-to-Ward transition and in developing relevant curricula. It is essential to introduce standardized clinical pathways and strengthen curricula on critical elements, including communication and follow-up.
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Tongue squamous cell carcinoma (TSCC) is prevailing malignancy in the oral and maxillofacial region, characterized by its high frequency. LncRNA CCAT1 can promote tumorigenesis and progression in many cancers. Here, we investigated the regulatory mechanism by which CCAT1 influences growth and metastasis of TSCC. Levels of CCAT1, WTAP, TRIM46, PHLPP2, AKT, p-AKT, and Ki67 in TSCC tissues and cells were assessed utilizing qRT-PCR, Western blot and IHC. Cell proliferation, migration, and invasion were evaluated utilizing CCK8, colony formation, wound healing and transwell assays. Subcellular localization of CCAT1 was detected utilizing FISH assay. m6A level of CCAT1 was assessed using MeRIP. RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull down elucidated binding relationship between molecules. Nude mouse tumorigenesis experiments were used to verify the TSCC regulatory function of CCAT1 in vivo. Metastatic pulmonary nodules were observed utilizing hematoxylin and eosin (HE) staining. CCAT1 silencing repressed TSCC cell proliferation, migration and invasion. Expression of CCAT1 was enhanced through N6-methyladenosine (m6A) modification of its RNA, facilitated by WTAP. Moreover, IGF2BP1 up-regulated CCAT1 expression by stabilizing its RNA transcript. CCAT1 bond to PHLPP2, inducing its ubiquitination and activating AKT signaling. CCAT1 mediated the ubiquitination and degradation of PHLPP2 by TRIM46, thereby promoting TSCC growth and metastasis. CCAT1/TRIM46/PHLPP2 axis regulated proliferation and invasion of TSCC cells, implying that CCAT1 would be a novel therapeutic target for TSCC patients.
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BACKGROUND: DNA damage and oxidative stress induced by chemotherapy are important factors in the onset of premature ovarian insufficiency (POI). Studies have shown that mitochondria derived from mesenchymal stem cells (MSC-Mito) are beneficial for age-related diseases, but their efficacy alone is limited. Pyrroloquinoline quinone (PQQ) is a potent antioxidant with significant antiaging and fertility enhancement effects. This study aimed to investigate the therapeutic effect of MSC-Mito in combination with PQQ on POI and the underlying mechanisms involved. METHODS: A POI animal model was established in C57BL/6J mice by cyclophosphamide and busulfan. The effects of MSC-Mito and PQQ administration on the estrous cycle, ovarian pathological damage, sex hormone secretion, and oxidative stress in mice were evaluated using methods such as vaginal smears and ELISAs. Western blotting and immunohistochemistry were used to assess the expression of SIRT1, PGC-1α, and ATM/p53 pathway proteins in ovarian tissues. A cell model was constructed using KGN cells treated with phosphoramide mustard to investigate DNA damage and apoptosis through comet assays and flow cytometry. SIRT1 siRNA was transfected into KGN cells to further explore the role of the SIRT1/ATM/p53 pathway in combination therapy with MSC-Mito and PQQ for POI. RESULTS: The combined treatment of MSC-Mito and PQQ significantly restored ovarian function and antioxidant capacity in mice with POI. This treatment also reduced the loss of follicles at various stages, improving the disrupted estrous cycle. In vitro experiments demonstrated that PQQ facilitated the proliferation of MitoTracker-labelled MSC-Mito, synergistically restoring mitochondrial function and inhibiting oxidative stress in combination with MSC-Mito. Both in vivo and in vitro, the combination of MSC-Mito and PQQ increased mitochondrial biogenesis mediated by SIRT1 and PGC-1α while inhibiting the activation of ATM and p53, consequently reducing DNA damage-mediated cell apoptosis. Furthermore, pretreatment of KGN cells with SIRT1 siRNA reversed nearly all the aforementioned changes induced by the combined treatment. CONCLUSIONS: Our research findings indicate that PQQ facilitates MSC-Mito proliferation and, in combination with MSC-Mito, ameliorates chemotherapy-induced POI through the SIRT1/ATM/p53 signaling pathway.
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Células Madre Mesenquimatosas , Insuficiencia Ovárica Primaria , Animales , Femenino , Humanos , Ratones , Antioxidantes/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Células Madre Mesenquimatosas/metabolismo , Ratones Endogámicos C57BL , Mitocondrias/metabolismo , Cofactor PQQ/farmacología , Insuficiencia Ovárica Primaria/patología , ARN Interferente Pequeño/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
BACKGROUND: Eukaryotic Initiation Factor 3C (EIF3C) represents a pivotal translational initiation factor in eukaryotes and has been shown to facilitate the progression of various neoplasms. However, its mechanistic role in ovarian cancer remains elusive. METHODS: In this research, the expression of EIF3C in ovarian cancer tissues was investigated using immunohistochemistry. In addition, the assessments were made on changes in cellular proliferation, invasion, and apoptotic abilities by reducing the expression of EIF3C in ovarian cancer cells. By utilizing microarray analysis, a comparison was performed between the downregulated EIF3C group and the control group of ovarian cancer cells, revealing the genes that were expressed differently. Furthermore, the signalling pathways associated with cellular proliferation were validated. The functional role of EIF3C in vivo was investigated using a xenograft tumour model. RESULTS: The immunohistochemical analysis showed that elevated levels of EIF3C are linked to a negative prognosis in patients with ovarian cancer. Suppression of EIF3C greatly hindered the growth and spread of SK-OV-3 and HO-8910 cells while enhancing cellular programmed cell death. Following KEGG and GSEA enrichment analyses of differentially expressed genes, the p53 signalling pathway was found to be associated with EIF3C. Suppression of EIF3C resulted in the upregulation of the p53 signalling pathway, leading to the inhibition of cell proliferation and invasion and the promotion of apoptosis. In vivo experiments demonstrated that EIF3C knockdown suppressed the growth of subcutaneous tumours in nude mice. CONCLUSION: There is a correlation between overexpression of EIF3C in tumour tissues of ovarian cancer patients and this is associated with a poorer prognosis. By influencing the p53 signaling pathway, EIF3C facilitates the growth and infiltration of cells in ovarian cancer.
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The erratic, intermittent, and unpredictable nature of sweat production, resulting from physiological or psychological fluctuations, poses intricacies to consistently and accurately sample and evaluate sweat biomarkers. Skin-interfaced microfluidic devices that rely on colorimetric mechanisms for semi-quantitative detection are particularly susceptible to these inaccuracies due to variations in sweat secretion rate or instantaneous volume. This work introduces a skin-interfaced colorimetric bifluidic sweat device with two synchronous channels to quantify sweat rate and biomarkers in real-time, even during uncertain sweat activities. In the proposed bifluidic-distance metric approach, with one channel to measure sweat rate and quantify collected sweat volume, the other channel can provide an accurate analysis of the biomarkers based on the collected sweat volume. The closed channel design also reduces evaporation and resists contamination from the external environment. The feasibility of the device is highlighted in a proof-of-the-concept demonstration to analyze sweat chloride for evaluating hydration status and sweat glucose for assessing glucose levels. The low-cost yet highly accurate device provides opportunities for clinical sweat analysis and disease screening in remote and low-resource settings. The developed device platform can be facilely adapted for the other biomarkers when corresponding colorimetric reagents are exploited.
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Piel , Sudor , Sudor/química , Piel/química , Biomarcadores/análisis , Dispositivos Laboratorio en un Chip , Glucosa/análisisRESUMEN
Non-electronic wearables that utilize skin-interfaced microfluidic technology have revolutionized the collection and analysis of human sweat, providing valuable biochemical information and indicating body hydration status. However, existing microfluidic devices often require constant monitoring of data during sweat assessment, thereby impeding the user experience and potentially missing anomalous physiological events, such as excessive sweating. Moreover, the complex manufacturing process hampers the scalability and large-scale production of such devices. Herein, we present a self-feedback microfluidic device with a unique dehydration reminder through a cost-effective "CAD-to-3D device" approach. It incorporates two independent systems for sweat collection and thermal feedback, including serpentine microchannels, reservoirs, petal-like bursting valves and heating chambers. The device operates by sequentially collecting sweat in the channels and reservoirs, and then activating thermal stimulators in the heating chambers through breaking the valves, initiating a chemical exothermic reaction. Human trials validate that the devices effectively alert users to potential dehydration by inducing skin thermal sensations triggered by sweat sampling. The proposed device offers facile scalability and customizable fabrication, and holds promise for managing hydration strategies in real-world scenarios, benefiting individuals engaged in sporting activities or exposed to high-temperature settings.
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Técnicas Biosensibles , Sudor , Humanos , Sudoración , Microfluídica , Retroalimentación , Deshidratación , Dispositivos Laboratorio en un ChipRESUMEN
BACKGROUND: The Makorin ring finger protein 1 (MKRN1) gene, also called RNF61, is located on the long arm of chromosome 7 and is a member of the RING finger protein family. The E3 ubiquitin ligase MKRN1 is closely linked to tumour development, but the exact mechanism needs to be elucidated. In this study, we aimed to investigate the specific mechanism and role of MKRN1 in colorectal cancer (CRC) development. METHODS: MKRN1 expression in CRC was analysed using the Cancer Cell Line Encyclopaedia and the Cancer Genome Atlas (TCGA) databases. Rectal tumour tissues were frozen to explore the MKRN1 expression in CRC and its clinical significance. The impact of MKRN1 on CRC cell proliferation and migration was observed using CCK8, colony formation, wound healing, and transwell assays. A combination of MKRN1 quantitative proteomics, ubiquitination modification omics analysis, and a string of in vitro and in vivo experiments revealed the potential mechanisms by which MKRN1 regulates CRC metastasis. RESULTS: MKRN1 expression was significantly elevated in CRC tissues compared to paracancerous tissues and was positively linked with prognosis (P < 0.01). MKRN1 downregulation inhibits CRC cell proliferation, migration, and invasion. Conversely, MKRN1 overexpression promotes the proliferation, migration, and invasion of CRC cells. Mechanistically, MKRN1 induces epithelial-mesenchymal transition (EMT) in CRC cells via ubiquitination and degradation of Smad nuclear-interacting protein 1 (SNIP1). Furthermore, SNIP1 inhibits transforming growth factor-ß (TGF-ß) signalling, and MKRN1 promotes TGF-ß signalling by degrading SNIP1 to induce EMT in CRC cells. Finally, using conditional knockout mice, intestinal lesions and metastatic liver microlesions were greatly reduced in the intestinal knockout MKRN1 group compared to that in the control group. CONCLUSIONS: High MKRN1 levels promote TGF-ß signalling through ubiquitination and degradation of SNIP1, thereby facilitating CRC metastasis, and supporting MKRN1 as a CRC pro-cancer factor. The MKRN1/SNIP1/TGF-ß axis may be a potential therapeutic target in CRC.
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Neoplasias Colorrectales , Proteínas de Unión al ARN , Ribonucleoproteínas , Animales , Ratones , Línea Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Proteolisis , Humanos , Ribonucleoproteínas/metabolismo , Proteínas de Unión al ARN/genética , Factor de Crecimiento Transformador beta/metabolismo , Transducción de SeñalRESUMEN
OBJECTIVE: Childhood is the prime age for epilepsy onset. Adults in the family of affected children often become caregivers. Providing care for children with epilepsy may affect the caregivers' quality of life. There is a paucity of literature reviewing the experiences of caregivers of children with epilepsy. Therefore, we summarised the best available evidence exploring caregivers' experiences in caring for children with epilepsy. METHOD: Published papers in PubMed, CINAHL, Embase, Cochrane Library, Web of Science, Scopus, and PsycINFO databases were identified by two researchers. All search results were imported into EndNote X20. Two reviewers independently extracted the data using Microsoft Excel. The Critical Appraisal Skill Program systematic review checklist was used to evaluate the quality of the included articles. Data of the included studies were extracted by two independent reviewers using a standardised form. These findings were synthesised using a meta-aggregative approach. RESULTS: A total of 12 studies were included in this meta-synthesis. In total, 260 findings were identified. These findings were aggregated into 13 categories, which were synthesised into four main themes: (i) burden experienced by caregivers, (ii) challenges experienced by caregivers, (iii) lack of social support, and (iv) adaptation to disease conditions. SIGNIFICANCE: The synthesised studies present multiple perspectives on the burdens and challenges encountered by caregivers of children with epilepsy. Caregivers require support from a variety of sources, not only from their families but also society at large. Providing care to children with epilepsy is a dynamic experience for caregivers.
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Cuidadores , Epilepsia , Adulto , Niño , Humanos , Calidad de Vida , Investigación Cualitativa , Apoyo Social , Epilepsia/terapiaRESUMEN
Monitoring sweat rate is vital for estimating sweat loss and accurately measuring biomarkers of interest. Although various optical or electrical sensors have been developed to monitor the sensible sweat rate, the quantification of the insensible sweat rate that is directly related to body thermoregulation and skin barrier functions still remains a challenge. This work introduces a superhydrophobic sweat sensor based on a polyacrylate sodium/MXene composite sandwiched between two superhydrophobic textile layers to continuously measure sweat vapor from insensible sweat with high sensitivity and rapid response. The superhydrophobic textile on a holey thin substrate with reduced stiffness and excellent breathability allows the permeation of sweat vapor, while preventing the sensor from being affected by the external water droplets and internal sensible sweat. Integrating the insensible sweat sensor with a flexible wireless communication and powering module further yields a standalone sensing system to continuously monitor insensible sweat rates at different body locations for diverse application scenarios. Proof-of-concept demonstrations on human subjects showcase the feasibility to continuously evaluate the body's thermoregulation and skin barrier functions for the assessment of thermal comfort, disease conditions, and nervous system activity. The results presented in this work also provide a low-cost device platform to detect other health-relevant biomarkers in the sweat (vapor) as the next-generation sweat sensor for smart healthcare and personalized medicine.
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Técnicas Biosensibles , Sudor , Humanos , Sudor/química , Regulación de la Temperatura Corporal , Biomarcadores/análisis , Interacciones Hidrofóbicas e HidrofílicasRESUMEN
AIM: We aim to explore the experiences of nursing staff in paediatric intensive care units (PICUs) and wards when transporting and caring for patients being discharged from PICU. BACKGROUND: PICU discharge is a challenging and complex procedure with risks and complications for patients. Nursing staff in PICU and paediatric wards play a pivotal role in the transition and are responsible for the quality of care, but their perspectives have rarely been explored. METHODS: Focus groups were conducted between December 2021 and January 2022 with purposively sampled PICU nurses and ward nurses. Four focus groups were formed, and data were analysed using qualitative content analysis. RESULTS: The overarching themes were as follows: communication during handover, attitudes towards follow-up, a challenging transition for nurses and parents and suggestions for optimizing transitional procedure. CONCLUSION: Our findings provide nurses' insights and knowledge regarding the transition of patients from the PICU to the ward. Nursing strategies including the use of liaison nurses and critical training for ward nurses were considered essential to maintaining competence during transition. A well-structured handover checklist as well as interdisciplinary cooperation and transitional care units are important for the patient's quality of care. IMPLICATION FOR NURSING MANAGEMENT: Communication, cooperation, planning and professional care are vital during the transition process. Nurse managers should work to develop collaborative approaches to facilitate safe patient transition.
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Enfermería de Cuidados Críticos , Personal de Enfermería en Hospital , Cuidado de Transición , Humanos , Niño , Grupos Focales , Habitaciones de Pacientes , Unidades de Cuidado Intensivo Pediátrico , Unidades de Cuidados IntensivosRESUMEN
The E3 ubiquitin ligase is an important regulator of cell signaling and proteostasis and is tightly controlled in many diseases, including cancer. Our study aimed to investigate the biological role of the E3 ubiquitin ligase CBLC in breast cancer and elucidate the specific mechanistic network underlying CBLC-mediated target substrate degradation, cell proliferation and metastasis. Here, we showed that CBLC expression was higher in breast cancer tissues and cells than that in normal tissues and cells. Higher expression of CBLC predicted a better prognosis for breast cancer patients. CBLC inhibited the proliferation, migration and invasion of breast cancer cells. Co-IP and immunofluorescence co-localization assays demonstrated that CBLC interacted with CTTN in the cytoplasm. CBLC promoted the degradation of CTTN through the ubiquitin-proteasome pathway without affecting its mRNA level. The inhibitory effect of CBLC on breast cancer cell proliferation, migration and invasion could partly be reversed by CTTN. Taken together, our study clarified the biological role of CBLC as a tumor suppressor and discovered its functional substrate, providing a molecular basis for CBLC/CTTN as a potential therapeutic target in breast cancer.
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Neoplasias de la Mama , Cortactina , Proteínas Proto-Oncogénicas c-cbl , Femenino , Humanos , Neoplasias de la Mama/patología , Línea Celular Tumoral , Proliferación Celular/genética , Cortactina/genética , Cortactina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitinación , Proteínas Proto-Oncogénicas c-cbl/genéticaRESUMEN
A new Co-catalyzed sequential C-C and C-F activation of gem-difluorinated cyclopropanes (gem-FCPs) to form nucleophilic fluoroallylcobalt, followed by addition to aldehydes, is reported. The protocol features the regioselective cleavage of dual chemical bonds of readily available gem-FCPs to prepare easily separable linear (Z)- and (E)-fluorinated homoallylic alcohols with a broad scope. This discovery established a new strategy for the efficient transformation of gem-FCPs as well as the synthesis of challenging fluorinated homoallylic alcohols.
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Ovarian cancer is one of the most fatal gynecologic cancer types, and its heterogeneity in the microenvironment limited the efficacy of the current treatment. In this study, we aimed at building a risk score to predict patient survival based on the amino acid metabolic genes and TCGA RNA-seq dataset (n = 376). We first used univariate analysis and PCA to select and test the survival-related genes, and the LASSO regression was applied to build the risk score signature with prediction accuracy estimation by survival analysis and ROC. We then conducted GSEA and GSVA to investigate the biological roles of the signature and run ESTIMATE and 4 different immunocyte infiltration algorithms to investigate the immunological diversity between the risk groups. Furthermore, the immune checkpoint expression was compared. We finally explored the cMap and PRISM database to screen out sensitive drugs for high-risk patients and analyzed the oncogenic role of TPH1 by clone formation and transwell migration assays. As a result, the risk score predicted patients' survival and stage with high accuracy. We found that the signature mainly affected the extracellular activities and cancer immunity by functional enrichment. We further discovered that the high-risk OV harbored a high level of stromal cell infiltration and was associated with highly infiltrated fibroblasts and decreased CD8+ T cells. The immune checkpoint analyses showed that TGFB1 and CD276 were upregulated. Finally, we screened out 4 PRISM drugs with lower IC50 in the high-risk group and validated the oncogenic role of TPH1 in OV cancers. We believe this research offered a novel understanding of the interplay between amino acid metabolism and immunity in OV and will benefit patients with better prognostic management and therapeutic strategy development.
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Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy. EOC control remains difficult, and EOC patients show poor prognosis regarding metastasis and chemotherapy resistance. The aim of this study was to estimate the effect of CXCR4 knockdown-mediated reduction of cancer stem cells (CSCs) and epithelial-mesenchymal transition (EMT) stemness and enhancement of chemotherapy sensitivity in EOC. Mechanisms contributing to these effects were also explored. Our data showed distinct contribution of CXCR4 overexpression by dependent PI3K/Akt/mTOR signaling pathway in EOC development. CXCR4 knockdown resulted in a reduction in CSCs and EMT formation and enhancement of chemotherapy sensitivity in tumor cells, which was further advanced by blocking CXCR4-PI3K/Akt/mTOR signaling. This study also documented the critical role of silencing CXCR4 in sensitizing ovarian CSCs to chemotherapy. Thus, targeting CXCR4 to suppress EOC progression, specifically in combination with paclitaxel (PTX) treatment, may have clinical application value.