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Sepsis-associated encephalopathy (SAE) manifests clinically in hyperneuroinflammation. Pyroptosis, which can induce an inflammatory cascade response, has been considered to be a causative factor of SAE. Evidence has shown that the bromo- and extraterminal (BET) proteins (including BRD2, BRD3, BRD4 and BRDT) inhibitor JQ1 can inhibit inflammation and suppress pyroptosis in various diseases. Therefore, we examined the effect of JQ1 on inflammasome-induced pyroptosis in the hippocampus in a mouse model of sepsis induced by lipopolysaccharide (LPS) injection. The results showed that JQ1 treatment alleviated sepsis-related symptoms, protected the blood–brain barrier (BBB), as indicated by upregulated expression of the tight junction proteins occludin and ZO-1, and remarkably rescued neuronal damage in SAE mice. Mechanistically, we demonstrated that JQ1 intervention inhibited the expression of BRD proteins and decreased the expression of inflammasomes by blocking nuclear factor kappa B (NFκB) signalling, attenuating the canonical pyroptosis (mediated by cleaved-Caspase1/11) pathway and the release of proinflammatory factors in the hippocampus of septic mice. Interestingly, we also found that JQ1 selectively suppressed the activation of hippocampal microglia in SAE mice. Thus, JQ1 protected the hippocampal BBB and neuronal damage through the attenuation of neuroinflammation by inhibiting the inflammasome-dependent canonical pyroptosis pathway induced by LPS injection in mice, and JQ1 may be a promising target for the prevention of SAE.

Fang Wei,1 Qiuyue Wang,1 Hang Liu,1 Xuejing Yang,1 Wenyu Cao,1 Weiman Zhao,1 Yingying Li,1 Lijie Zheng,1 Tao Ma,1,2 Qingqing Wang1– 3 1School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China; 2Engineering Research Center for Biochemical Pharmaceuticals of Anhui Province, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China; 3Bengbu BBCA Medical Science Co., Ltd., Bengbu, Anhui Province, 233030, People’s Republic of ChinaCorrespondence: Qingqing Wang; Tao Ma, School of Pharmacy, Bengbu Medical College, Bengbu, Anhui Province, 233030, People’s Republic of China, Tel +86 15605528300 ; +86 13855266592, Email qingqingwang@bbmc.edu.cn; matao1992@foxmail.comIntroduction: Methotrexate (MTX) is the first-line drug for the treatment of rheumatoid arthritis (RA) in several countries. However, MTX has an extremely low solubility in water, and the side effects caused by its delivery mode restrict its curative effect. In this study, we designed a dissolving microneedles array (DMNA) containing MTX nanocrystals (MTX-NCs) (MTX-NC@DMNA) to improve the treatment of RA. DMNA-based drug delivery combines the advantages of patient compliance with the use of transdermal drug delivery systems and high-efficiency injection administration; thus, it can mitigate the side effects that result from current administration routes. Carrier-free and surfactant-free MTX-NCs were prepared to overcome bioavailability limitations and poor drug loading problems.Methods: The MTX-NCs prepared by reverse solvent precipitation method was encapsulated in the DMNA. The morphology, mechanical properties, safety, stability and in vivo dissolution were evaluated, and its pharmacodynamic characteristics were assessed in a rat model of RA.Results: The particle size of the MTX-NCs was 148.1 ± 10.1 nm. The MTX-NC@DMNA were found to be rigid enough to penetrate the skin and deliver the drug successfully. The results indicated effective skin recovery after removal of the DMNA. It was found that the MTX-NC@DMNA significantly reduced foot swelling in the rats and regulated the balance in the levels of related cytokines. It also reduced pathological damage to the synovium, joint, and cartilage, and effectively alleviated organ injury in the rats.Conclusion: Transdermal administration of MTX-NC@DMNA may be an effective approach for treating RA.Graphical Abstract: Keywords: nanocrystals, inflammation, dissolving microneedles array, transdermal, rheumatoid arthritis

Background Neuroinflammation is considered as a key mediator of depression. Therefore, understanding the pathophysiological mechanisms by which neuroinflammation and depression are linked can benefit novel therapies. Gonadotropin-releasing hormone (GnRH) is at the head of the neuroendocrine reproductive axis. However, the non-reproductive functions of GnRH expressed in various tissues, including hippocampus, are still not known. Methods We combined viral tool, neuropharmacology, and behavioral tests in male mice to test whether GnRH affects neuroinflammation that mediates LPS induced depression-like behavior. Results Both systemic treatment with GnRH agonist and over-expression of endogenous hippocampal GnRH via viral tool abolished the depression-like behavior after LPS challenges in mice. Conversely, antagonizing GnRHR by drug treatment or by hippocampal GnRHR knockdown could block the antidepressant- effect of GnRH agonist. Interestingly, we found that the peripheral GnRH treatment prevented the microglia activation mediated inflammation in the hippocampus of mice. Conclusion We propose that, at least in the hippocampus, GnRH appears to act on GnRHR to regulate higher order non-reproductive functions associated with the microglia mediated neuroinflammation. These findings also provide insights into the function and cross-talk of GnRH, a known neuropeptide hormone, in neuro-immune response.

The DNA toehold mediated strand displacement reaction is one of the semi-synthetic biology technologies for next-generation computers. In this article, we present a framework for a novel nonlinear neural network based on an engineered biochemical circuit, which is constructed by several reaction modules including catalysis, degradation and adjustment reaction modules. The proposed neural network possesses an architecture that is similar to that of an error back propagation neural network, and is built of an input layer, hidden layer and output layer. As a proof of concept, we utilize this nonlinear neural network based on an analog DNA toehold mediated strand displacement reaction circuit to learn the standard quadratic form function and analyze the robustness of the nonlinear neural network toward DNA strand concentration detection, DNA strand displacement reaction rate and noise. Unlike in error back propagation neural networks, the adaptive behavior of this DNA molecular neural network system endows it with supervised learning capability. This investigation will highlight the potential of analog DNA displacement reaction circuits for implementing artificial intelligence.

Research on the macroscopic phenomenological constitutive model of Haynes 230, which is frequently used as an aero engine combustor liner material, still has important engineering significance. Based on a proposed model for isothermal fatigue and fatigue-creep, a constitutive model is developed which can simulate the thermomechanical fatigue-creep and pure creep behaviors. The results of simulation and experiment are in good agreement with each other under thermomechanical fatigue-creep loads for the hysteresis loops at half-life, the stress amplitude and the mean stress evolution, or the stress relaxation during dwell time. Good results are also obtained in the case of pure creep. Meanwhile, the simulation of isothermal fatigue and fatigue-creep also maintains high accuracy. The main contribution of this paper is to propose a robust unified constitutive model that has the adaptability to a wide range of temperature variations and is suitable for various types of fatigue-creep interaction loads.

Social behavior is essential for the well-being and survival of individuals. However, social isolation is a serious public health issue, especially during the COVID-19 pandemic, affecting a significant number of people worldwide, and can lead to serious psychological crises. Microglia, innate immune cells in the brain, are strongly implicated in the development of psychiatry. Although many microglial inhibitors have been used to treat depression, there is no literature report on pexidartinib (PLX3397) and social isolation. Herein, we adopted PLX3397 to investigate the role of microglia in the modulation of social isolation. Our results found that social isolation during adolescence caused depressive-like, but not anxiety-like behavior in mice in adulthood, with enhanced expression of the microglial marker Iba1 in the hippocampus. In addition, treatment with PLX3397 reduced the expression of the microglial marker Iba1, decreased the mRNA expression of IL-1β, increased the mRNA expression of Arg1, elevated the protein levels of DCX and GluR1 and restored the dendritic spine branches and density, ultimately mitigating depressive-like behavior in mice. These findings suggest that inhibition of microglia in the hippocampus could ameliorate mood disorders in mice, providing a new perspective for the treatment of psychiatric disorders such as depression.

Pyroptosis, a newly discovered proinflammatory programmed cell death, is involved in the regulation of cognitive dysfunction, such as Alzheimer's disease. Exploring potential drug targets that prevent pyroptotic procedures might benefit the development of a cure for these diseases. In the present study, we explored whether the transient receptor potential vanilloid 4 (TRPV4) blocker HC067047 and knockdown of TRPV4 in the hippocampus could improve cognitive behavior through the inhibition of pyroptosis in a mouse model developed using systemic administration of lipopolysaccharide (LPS). We found that systemic administration of HC067047 or knockdown of hippocampal TRPV4 prevented the activation of canonical and noncanonical pyroptosis in the hippocampus of LPS-treated mice. Consistent with the inhibition of the hippocampal pyroptosis pathway, a knockdown of hippocampal TRPV4 lowered expression of TNF-α, IL-1β, IL-18, and IL-6. Furthermore, we verified that the main pyroptosis cell type might be a neuron, indicated by reduced neuronal marker expression. Mechanically, we also found that knockdown of hippocampal TRPV4 might inhibit phosphorylation of CamkⅡα which results in NFκb mediated inflammasome reduction in the hippocampus of LPS-treated mice. More interestingly, mice intraperitoneally injected with HC067047 or the hippocampus injected with TRPV4 shRNA showed improved cognitive behavior, as indicated by the enhanced discrimination ratio in the NORT, NOPT, and SNPT. Collectively, we consider that HC067047 might be a small molecular drug that prevents pyroptosis, and TRPV4 could be an effective therapeutic target for preventing pyroptosis-induced cognitive dysfunction.

Betaine rich in beet is used as an important source of human nutrition. Here this study aims to explore whether betaine supplementation can protect against acute sever ulcerative colitis (ASUC) and the underlying mechanism METHODS AND RESULTS: ASUC model is induced by dextran sulfate sodium (DSS), and effects of betaine as a methyl donor on ASUC are evaluated. Betaine mitigates the changes, for example, elevated DAI, weight loss, spleen enlargement, colon shortening, and disordered colonic mucosa. The protective effects of betaine on colonic barrier integrity in ASUC are then verified through examining tight junction proteins by western blot and immunofluorescence. Spectrophotometry method and western blot confirm that betaine can decrease levels of oxidative markers (MDA, MPO, NOS, and COX2), and promote expressions of antioxidant proteins (GSH, NRF2, CAT, and SOD1). Further, betaine prevents colonic inflammatory pyroptosis by blocking expressions of NLRP3 inflammasome complex (NLRP3, ASC, and cleaved-caspase 1), N terminal-GSDMD, and release of relevant inflammatory factors.Betaine inhibits colonic oxidative stress induced inflammatory pyroptosis to alleviate ASUC, which shows therapeutic potential against colitis and other acute inflammatory disorder.

Chronic pain is a common disease that severely disrupts the quality of life. Persistent neuroinflammation and central sensitization play important roles in its pathogenesis. Caspase-11 is a critical modulator of inflammation of central nervous system. However, its role in chronic pain remains elusive. In this study, chronic pain and acute pain were induced via injecting complete Freund's adjuvant (CFA) and 5% formalin into the plantar of the right hind paw of wild-type (WT) and Caspase-11 deficient (Caspase-11

Osteoarthritis (OA) is a prevalent degenerative disease that has a significant impact on patients' lives. Celecoxib (CXB) is now primarily used to treat OA with oral dosing. CXB's limited water solubility, on the other hand, restricts its therapeutic application. We developed a delivery system of dissolving microneedles (DMNs) loaded with CXB-nanocrystals (CXB-NCs) for the treatment of OA. Oral administration's inefficiency and injectable administration's poor compliance might be solved using DMNs. Furthermore, carrier-free NCs may dramatically increase the dissolution of drugs with poorly water-solubility, as well as the drug load of DMNs. Antisolvent precipitation was used to make CXB-NCs. CXB-NC@DMNs were prepared by mixing CXB-NCs with hyaluronic acid (HA) that had high mechanical qualities and could permeate the skin efficiently in vitro. The therapeutic effect of oral CXB-NCs was substantially better than that of the same dose of oral CXB in an in vivo pharmacodynamic trial, demonstrating that the preparation of CXB into NCs might greatly increase CXB bioavailability. Furthermore, we discovered that DMNs loaded with low-dose CXB-NCs had similar or even better efficacy than the oral CXB-NCs group. The findings suggested that CXB-NC@DMNs may be a very efficient and promising drug delivery strategy in the treatment of OA.

Emodin is the main toxic component in Chinese medicinal herbs such as rhubarb. Our previous studies demonstrated that genetic polymorphisms of UDP-glucuronosyltransferase 2B7 (UGT2B7) had an effect on the glucuronidation and detoxification of emodin. This study aimed to reveal the transcriptional regulation mechanism of UGT2B7 on emodin glucuronidation and its effect on toxicity. Emodin glucuronic activity and genome and transcriptome data were obtained from 36 clinical human kidney tissues. The genome-wide association studies (GWAS) identified that four single nucleotide polymorphisms (SNPs) (rs6093966, rs2868094, rs2071197, and rs6073433), which were located on the hepatocyte nuclear factor 4α (HNF4A) gene, were significantly associated with the emodin glucuronidation (p < 0.05). Notably, rs2071197 was significantly associated with the gene expression of HNF4A and UGT2B7 and the glucuronidation of emodin. The gene expression of HNF4A showed a high correlation with UGT2B7 (R2 = 0.721, p = 5.83 × 10-11). The luciferase activity was increased 7.68-fold in 293T cells and 2.03-fold in HepG2 cells, confirming a significant transcriptional activation of UGT2B7 promoter by HNF4A. The knockdown of HNF4A in HepG2 cells (36.6%) led to a significant decrease of UGT2B7 (19.8%) and higher cytotoxicity (p < 0.05). The overexpression of HNF4A in HepG2 cells (31.2%) led to a significant increase of UGT2B7 (24.4%) and improved cell viability (p < 0.05). Besides, HNF4A and UGT2B7 were both decreased in HepG2 cells and rats after treatment with emodin. In conclusion, emodin used long term or in high doses could inhibit the expression of HNF4A, thereby reducing the expression of UGT2B7 and causing hepatotoxicity.

Associative Classification (AC) is envisioned as one of the most attractive classification approaches to facilitate managers for prediction and decision making in a highly accurate and easily interpretable way. The most of existing AC algorithms mainly focus on the two static metrics of association rules: support and confidence. However, in this paper, we identify a potential limitation of the confidence and further point out these AC algorithms merely consider the explicit expression of classification information and knowledge of Class Association Rules (CARs) and neglect the implicit expression of classification information and knowledge of CARs. And even the explicit expression of classification information and knowledge of CARs is equivalent, the implicit expression of classification information and knowledge of them may be different. Thus, these CARs will cause different influence on prediction or decision-making in terms of the interpretability and rationality of classification, and will result in predictive bias or decision-making bias in practice. In response to this drawback, we introduce the notion of information entropy and propose an innovative approach for associative classification based on information entropy of frequent attribute set, named EAC. Different from the existing schemes, the proposed EAC algorithm enjoys the following promising merits: (1) lower predictive bias or decision-making bias by levering the information entropy of frequent attribute set; (2) better interpretability and rationality by setting higher support threshold; (3) setting global optimum parameter dynamically through repeated trials with reducing the dimension of data sets. Experiments on 20 well-known benchmark data sets demonstrate that our EAC approach is highly competitive to other state-of-the-art AC algorithms in terms of predictive bias or decision-making bias, interpretability, and efficiency, which can be used to construct a new classifier efficiently and effectively in many realistic scenarios.

Background PARP inhibitors have been the most promising target drugs with widely proven benefits among ovarian cancer patients. Although platinum-response, HR-related genes, or HRD genomic scar detection are acceptably used in assessment of Olaparib response, there are still evident limitations in the present approaches. Therefore, we aim to investigate more accurate approaches to predict Olaparib sensitivity and effective synergistic treatment strategies. Methods We probed two databases (TCGA and Qilu Hospital) in order to quest novel miRNAs associated with platinum-sensitivity or HR-related genes. Cellular experiments in vitro or in vivo and PDX models were utilized to validate their role in tumor suppression and Olaparib sensitizing. Furthermore, HR gene mutation was analyzed through WES to explore the relation between HR gene mutation and Olaparib response. Results High miR-509-3 expression indicated better response to platinum and longer progression-free and overall survival in two independent ovarian cancer patient cohorts (high vs. low miR-509-3 expression; PFS: TCGA P P P P P P P Conclusions MiR-509-3 can sensitize ovarian cancer cells to Olaparib by impeding HR, which makes it a potential target in PARPi synergistic treatment. HR core gene analysis and RAD51 functional detection are prospectively feasible in prediction of PARPi response.

INTRODUCTION MicroRNAs (miRNAs) have been demonstrated to be involved in the pathogenesis of various human cancers. However, the role of microRNA-519a (miR-519a) in gastric cancer (GC) remains unclear. This study aimed to investigate the clinical value and biological function of miR-519a in GC. METHODS The expression of miR-519a in GC tissues and cell lines was estimated by quantitative real-time polymerase chain reaction. Survival analysis for GC patients was performed using the Kaplan-Meier method. Cox regression analysis was used to confirm the prognostic value of miR-519a. The biological function and potential targets of miR-519a in GC progression were assessed using cell experiments. RESULTS In this study, we found that miR-519a was an important tumor suppressor with downregulated expression in GC tissues and cells compared with that in normal controls (all p < 0.05). MiR-519a expression was inversely correlated with differentiation, lymph node metastasis, and the TNM stage of patients. Decreased miR-519a expression was associated with the poor overall survival of GC patients (log-rank p = 0.002) and served as an independent prognostic biomarker for the patients. The in vitro analyses indicated that miR-519a overexpression in GC cells resulted in inhibited cell proliferation, migration, and invasion, and IGFBP1 was determined to be a direct target of miR-519a. CONCLUSION All the data in the present study revealed that the downregulated expression of miR-519a predicts the poor prognosis of GC and is involved in the regulation of GC progression. We consider that miR-519a may be a candidate therapeutic target for GC treatment.

Sepsis-associated encephalopathy (SAE) is manifested clinically in hyperneuroinflammation and associated with increased morbidity worldwide. Pyroptosis, a novel programmed cell death, has been considered as a causative factor of SAE. Bromodomain-containing protein 4 (BRD4) is a member of the Bromo and Extra-Terminal (BET) family, and promotes inflammatory response in various diseases. Thereby, we examined the effect of JQ1, which is a specific selective inhibitor of BRD4, on the inflammasome-induced pyroptosis of hippocampus in sepsis mice model induced by lipopolysaccharide (LPS) treatment. And we found that JQ1 treatment inhibited the phosphorylation of BRD4, alleviated weight loss and splenomegaly, as well as decreased the serum levels of procalcitonin (PCT) and D-lactate dehydrogenase (D-LDH) induced by LPS injection. Moreover, JQ1 administration decreased the expression of nod-like receptor family protein 1 (NLRP1) or 3 (NLRP3) or the absent in melanoma 2 (Aim2) inflammasomes by blocking nuclear factor kappa B (NFκB) signaling in the hippocampus of sepsis mice. Interestingly, we found that JQ1 selectively attenuated the canonical pyroptosis pathway in SAE mice, indicating by reduced expression of Caspase-1, Caspase-11, gasdermin D (GSDMD) and gasdermin A (GSDMA). JQ1 intervention also suppressed the activation of hippocampal microglia and the release of pro-inflammatory factors, such as IL-1β, IL-18 and IL-6 in SAE mice. In addition, JQ1 treatment protected blood brain barrier (BBB) by up-regulated the expression of tight junction protein occludin and ZO-1 in SAE mice. Furthermore, JQ1 administration remarkably rescued neuronal damage in SAE mice, as enhanced expression of hippocampal NeuN and Doublecortin (DCX). Thus, the protective effects of BRD4 inhibitor JQ1 on SAE were verified in neurons via the inhibition of canonical pyroptosis induced inflammation.

Tumor immunotherapy has attracted more and more attention nowadays, and multiple clinical trials have confirmed its effect in a variety of solid tumors. Immune checkpoint inhibitors (ICIs), cancer vaccines, adoptive cell transfer (ACT), and lymphocyte-promoting cytokines are the main immunotherapy methods. Endometrial cancer (EC) is one of the most frequent tumors in women and the prognosis of recurrent or metastatic EC is poor. Since molecular classification has been applied to EC, immunotherapy for different EC subtypes (especially POLE and MSI-H) has gradually attracted attention. In this review, we focus on the expression and molecular basis of the main biomarkers in the immunotherapy of EC firstly, as well as their clinical application significance and limitations. Blocking tumor immune checkpoints is one of the most effective strategies for cancer treatment in recent years, and has now become the focus in the field of tumor research and treatment. We summarized clinical date of planned and ongoing clinical trials and introduced other common immunotherapy methods in EC, such as cancer vaccine and ACT. Hormone aberrations, metabolic syndrome (MetS) and p53 mutant and that affect the immunotherapy of endometrial cancer will also be discussed in this review.

Continuous domestic respiration monitoring provides vital information for diagnosing assorted diseases. In this paper, we introduce RESPTRACKER, the first continuous, multiple-person respiration tracking system in domestic settings using acoustic-based COTS devices. RESPTRACKER uses a two-stage algorithm to separate and recombine respiration signals from multiple paths in a short period so that it can track the respiration rate of multiple moving subjects. Our experimental results show that our two-stage algorithm can distinguish the respiration of at least four subjects at a distance of three meters.

Additional file 7: Table S2. Cox regression analysis of TCGA cohort adjusting for FIGO stage, residual tumor size and age at diagnosis.

Additional file 9: Table S4. Correlation between miR-509-3 expression and clinical features in Qilu hospital cohort.

Uterine leiomyosarcoma (ULMS) is the most lethal gynecologic malignancy with few therapeutic options. Chemoresistance prevails as a major hurdle in treating this malignancy, yet the mechanism of chemoresistance remains largely unclear. In this study, we certified MELK as a poor prognostic marker through bioinformatic analysis of the GEO database. Cellular experiments in vitro revealed that MELK played an essential role in ULMS cells' chemoresistance and that a high expression of MELK could lead to doxorubicin resistance. mRNA profiling uncovered the pathways that MELK was involved in which led to doxorubicin resistance. MELK was found to affect ULMS cells' chemoresistance through an anti-apoptotic mechanism via the JAK2/STAT3 pathway. miRNA profiling also revealed that upregulated MELK could induce the decrease of miRNA-34a (regulated by JAK2/STAT3 pathway). We detected that MELK overexpression could induce M2 macrophage polarization via the miR-34a/JAK2/STAT3 pathway, contributing to doxorubicin chemoresistance in the tumor microenvironment. OTSSP167, a MELK inhibitor, may increase ULMS sensitivity to doxorubicin. Our investigation could propose novel targets for early diagnosis and precision therapy in ULMS patients.

Four new chromene derivatives, pestalotiochromenoic acids A − D (1, 2, 4, and 5), and two new chromone derivatives, pestalotiochromones A and B (6 and 7), were obtained from the marine alga-derived fungus Pestalotiopsis neglecta SCSIO41403, as well as a reported derivate named piperochromenoic acid (3) with its configuration determined for the first time. Their structures were determined by detailed nuclear magnetic resonance (NMR) and mass spectroscopic analyses, while the absolute configurations were established by theoretical NMR and electronic circular dichroism (ECD) calculation, including Mo2(OAc)4-induced ECD experiments. Those chromene and chromone derivatives displayed weak cytotoxicity, but showed obvious liver X receptors (LXRs) modulatory activities, by in vitro tests on the expression of LXRα, LXRβ and their target gene ABCA1, as well as in silico docking analysis. Moreover, the high binding affinities between pestalotiochromone A (6) and LXRα, revealed by surface plasmon resonance (SPR) with the dissociation equilibrium constant (KD) value of 6.2 μM, demonstrated 6 could act as a new potential LXR agonist.

e17568 Background: Stratifying endometrial carcinoma (EC) based on molecular profiling is of importance. While, spectrum of molecular subtypes of EC in Chinese population needs to be elucidated. Conventional approaches involve methodologies including Sanger sequencing as well as immunohistochemistry which is highly dependent on experience of pathologists. This study is of first time to display clinical and pathological characters of molecular subtypes of EC which were defined by a simplified NGS panel in Chinese population. Methods: Paraffin-embedded tissues of 135 consented EC patients were retrospectively collected from Qilu Hospital, Shandong Province, China. Genomic DNA was extracted and subjected to a simplified panel covering POLE, TP53 as well as 55 MSI loci for massive parallel sequencing. Mutations annotated as Tier I, II were applied for subtyping. MSI was defined as instability in 22 or more microsatellite loci. Subtypes were stratified as POLE, MSI, TP53-wt or TP53-mut group. Correlations of clinicopathological characters as well as prognosis were further conducted. Results: Histology of collected samples were mostly Endometrioid EC (EEC, 93.33%). Most of samples were at stage I (80%). The fractions of POLE (n=10), MSI (n=29), TP53-wt (n=84) and TP53-mut (n=12) group were 7.41%, 21.48%, 62.22%, and 8.89%, respectively. POLE group was associated with earlier stage (Stage I, 90%), EEC (80%) and less lympho-vascular space invasion (LVSI) (10%). TP53-mutant subtype was correlated to later stage (Stage II-IV, 41.67%), higher grade (G2+G3, 83.33%), serous histology (25%) and higher rate of LVSI (25%). The median follow-up was 74 (1.5-122) months. The 8-year overall (OS) and disease-specific survival (DSS) rate were 100% in POLE group, while only 58.3% and 75% in TP53 mutant cases (P

A unified viscoplastic constitutive model with wide temperature adaptability is developed based on the basic framework of the Chaboche type model to capture the intricate cyclic viscoplastic behaviors of Haynes 230 subjected to isothermal low-cycle fatigue and fatigue-creep loads. By introducing effective aging time into drag stress in the hyperbolic sine viscosity function, the critical value of back stress and the additional hardening model, a rate-dependent model based on the dimensionless concentration of solute atoms or precipitates is further improved to realize simulation of dynamic strain aging effects. A multistage evolutionary approach to determining asymptotic value of back stress influenced by strain range and cumulative plastic strain is proposed to respond to cyclic hardening or softening evolved differently with the variation of temperature. For the fatigue-creep interaction, a rate or time dependent directional hardening cumulative model combined with the existing mean stress model is established. After the multi-step material parameter determination method is given, the capabilities of the proposed model are fully validated to accurately depict the mechanical behaviors of Haynes 230 for five representative temperatures.

Measurements of the excitation power-dependence and temperature-dependence photoluminescence (PL) are performed to investigate the emission mechanisms of InGaN/GaN quantum wells (QWs) in laser diode structures. The PL spectral peak is blueshifted with increasing temperature over a certain temperature range. It is found that the blueshift range was larger when the PL excitation power is smaller. This particular behavior indicates that carriers are thermally activated from localized states and partially screen the piezoelectric field present in the QWs. The small blueshift range corresponds to a weak quantum-confined Stark effect (QCSE) and a relatively high internal quantum efficiency (IQE) of the QWs.

Two ultraviolet InGaN/GaN light emitting diodes (LEDs) with and without InGaN underlying layer beneath the multiple quantum wells (MQWs) were grown by metal-organic vapor phase epitaxy. Based on the photoluminescence excitation measurements, it was found that the Stokes shift of the sample with a 10-nm-thick In0.1Ga0.9N underlying layer was about 64 meV, which was smaller than that of the reference sample without InGaN underlying layer, indicating a reduced quantum-confined Stark effect (QCSE) due to the decrease of the piezoelectric polarization field in the MQWs. In addition, by fitting the photon energy dependence of carrier lifetime values, the radiative recombination lifetime of the sample with and without InGaN underlying layer were obtained about 1.22 and 1.58 ns at 10 K, respectively. The shorter carrier lifetime also confirmed that the QCSE in the MQWs was weakened after inserting the InGaN underlying layer. In addition, although the depth of carrier localization in the sample with InGaN underlying layer became smaller, the nonradiative recombination centers (NRCs) inside it decreased, and thus suppressed the nonradiative recombination process significantly according to the electroluminescence measurement results. Compared to the reference sample, the efficiency droop behavior was delayed in the sample with InGaN underlying layer and the droop effect was also effectively alleviated. Therefore, the enhanced light-emission efficiency of ultraviolet InGaN/GaN MQW LEDs could be attributed to the decrease of QCSE and NRCs.

Medical Informatics is the scientific field that deals with the storage, retrieval and optimal use of information and data in medicine. It is often called healthcare informatics or biomedicai informatics, and forms part of the wider domain of eHealth. The end objective of biomedicai informatics is the coalescing of data, knowledge, and the tools necessary to apply that data and knowledge in the decision-making process, at the time and place that a decision needs to be made. Ubiquitous healthcare is an emerging field of technology that uses a large number of environmental and patient sensors and actuators to monitor and improve patients' physical and mental condition. Biofeedback is a training technique in which people are taught to improve their health and performance by using signals from their own bodies. Based on above, we pick up electrical signals from the brain(EEG) and translates the signals into a form that people can detect, by which we improve the brain function and mental condition. Moreover, a scenario of ubiquitous mental healthcare system has been established.

Web browsers have become the most popular interactive interfaces ever developed and widely deployed in the computing history. Through links embedded in a web page, a user can browse virtually any digital resources in the world. Although these links are naturally interconnected and hierarchical, the browsing model is typically in linear and at any point of time only one-level of information can easily displayed in the whole hierarchy. For example, to browse a book, first the top-level information (say, table of contents) is downloaded and displayed. Click a chapter link to a specific chapter (the next-level information). Click back button to go back to the top-level. Click another chapter link to go to the next level of information. Click back button to go back to the top-level and so on. This paper describes a multi-level web surfing system that allows a user to display multi-level of information and browse at any level without losing the information of the current level. With the system, a user can select either a hint window displaying the extracts of a linked page when the mouse is over a link or a pop window showing the linked page when the mouse is over a link without clicking it.

The electroluminescence (EL) and photoluminescence (PL) spectra of InGaN/GaN multiple quantum wells (MQWs) with a prestrained InGaN interlayer in a laser diode structure are investigated. When the injection current increases from 5 mA to 50 mA, the blueshift of the EL emission peak is 1 meV for the prestrained sample and 23 meV for a control sample with the conventional structure. Also, the internal quantum efficiency and the EL intensity at the injection current of 20 mA are increased by 71% and 65% respectively by inserting the prestrained InGaN interlayer. The reduced blueshift and the enhanced emission are attributed mainly to the reduced quantum-confined Stark effect (QCSE) in the prestrained sample. Such attributions are supported by the theoretical simulation results, which reveal the smaller piezoelectric field and the enhanced overlap of electron and hole wave functions in the prestrained sample. Therefore, the prestrained InGaN interlayer contributes to strain relaxation in the MQW layer and enhancement of light emission due to the reduction of QCSE.