Effect of pH on the soybean whey protein-gum arabic emulsion delivery systems for curcumin: Emulsifying, stability, and digestive properties.

A novel curcumin (CUR) delivery system was developed using soybean whey protein (SWP)-based emulsions, enhanced by pH-adjustment and gum arabic (GA) modification. Modulating electrostatic interactions between SWP and GA at oil/water interface, pH provides favorable charging conditions for stable distribution between droplets. GA facilitated the SWP form a stable interfacial layer that significantly enhanced the emulsifying properties and CUR encapsulation efficiency of the system at pH 6.0, which were 90.15 ± 0.67%, 870.53 ± 3.22 m2/g and 2157.62 ± 115.31%, respectively. Duncan's test revealed significant improvements in thermal, UV, oxidative, and storage stabilities of CUR (P < 0.05). At pH 6.0, GA effectively protected CUR by inhibiting SWP degradation during gastric digestion and promoting the release of CUR by decreasing steric hindrance with oil droplets during intestinal digestion, achieving the highest CUR bioaccessibility (69.12% ± 0.28%) based on Duncan's test. The SWP-GA-CUR emulsion delivery system would be a novel carrier for nutrients.

ErbB3 is required for hyperaminoacidemia-induced pancreatic α cell hyperplasia.

Blood amino acid levels are maintained in a narrow physiological range. The pancreatic α cells have emerged as the primary aminoacidemia regulator through glucagon secretion to promote hepatic amino acid catabolism. Interruption of glucagon signaling disrupts the liver-α cells axis leading to hyperaminoacidemia, which triggers a compensatory rise in glucagon secretion and α cell hyperplasia. The mechanisms of hyperaminoacidemia-induced α cell hyperplasia remain incompletely understood. Using a mouse α cell line and in vivo studies in zebrafish and mice, we found that hyperaminoacidemia-induced α cell hyperplasia requires ErbB3 signaling. In addition to mechanistic target of rapamycin complex 1, another ErbB3 downstream effector signal transducer and activator of transcription 3 also plays a role in α cell hyperplasia. Mechanistically, ErbB3 may partner with ErbB2 to stimulate cyclin D2 and suppress p27 via mechanistic target of rapamycin complex 1 and signal transducer and activator of transcription 3. Our study identifies ErbB3 as a new regulator for hyperaminoacidemia-induced α cell proliferation and a critical component of the liver-α cells axis that regulates aminoacidemia.

The Activity of YCA1 Metacaspase Is Regulated by Reactive Sulfane Sulfur via Persulfidation in Saccharomyces cerevisiae.

YCA1, the only metacaspase in Saccharomyces cerevisiae, plays important roles in the regulation of chronological lifespan, apoptosis, and cytokinesis. YCA1 has protein hydrolase activity and functions by cleaving itself and target proteins. However, there are few reports about the regulation of YCA1 activity. In this study, we observed that reactive sulfane sulfur (RSS) can inhibit the activity of YCA1. In vitro experiments demonstrated that RSS reacted with the Cys276 of YCA1, the residue central to its protein hydrolase activity, to form a persulfidation modification (protein-SSH). This modification inhibited both its self-cleavage and the cleavage of its substrate protein, BIR1. To investigate further, we constructed a low-endogenous-RSS mutant of S. cerevisiae, BY4742 Δcys3, in which the RSS-producing enzyme cystathionine-γ-lyase (CYS3) was knocked out. The activity of YCA1 was significantly increased by the deletion of CYS3. Moreover, increased YCA1 activity led to reduced chronological lifespan (CLS) and CLS-driven apoptosis. This study unveils the first endogenous factor that regulates YCA1 activity, introduces a novel mechanism of how yeast cells regulate chronological lifespan, and broadens our understanding of the multifaceted roles played by RSS.

Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.

Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates.

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells. The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2, resulting in conversion of Bcl-2 from a survival to killer. As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy, targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics. Here, we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway. In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer (TNBC) and MCF-7/LCC2 tamoxifen-resistant breast cancer (TAMR) in a Nur77-dependent manner. Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria, resulting in mitochondria-related apoptosis. Interestingly, XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates. Together, our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

Endocytic activation and exosomal secretion of matriptase stimulate the second wave of EGF signaling to promote skin and breast cancer invasion.

The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic tumor microenvironment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks the activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibits pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy.

Dexmedetomidine adjunct to ropivacaine for ultrasound-guided transversus abdominis plane block for open inguinal hernia repair in the older adults: A randomised clinical trial.

OBJECTIVE: The aim of this study was to evaluate the effect of adding dexmedetomidine to ropivacaine on pain relief and quality of recovery in older patients undergoing open inguinal hernia repair surgeries. METHODS: This was a prospective and randomised clinical trial of 102 patients aged over 65 years who received an ultrasound-guided transversus open mesh herniorrhaphy abdominis plane (TAP) block with either 0.375% ropivacaine 20 ml (Group R, n = 47) or 0.375% ropivacaine combined with 1 µg/kg dexmedetomidine 20 ml (Group RD, n = 45) in the pre-anaesthesia care unit before elective open inguinal hernia surgeries. The primary outcome measure was Visual Analogue Scale (VAS) pain scores at rest and on movement at 2, 4, 8, 12 and 24 h and at 1 and 3 months' postoperatively. The secondary outcome measures were the incidence of post-operative delirium (POD), nausea and vomiting and the occurrence of side effects or complications on post-operative day 1. RESULTS: Group RD had lower VAS scores at rest and on movement at 8 and 12 h postoperatively and a lower incidence of POD on the post-operative day 1 than Group R. Transient bradycardia was more frequent in Group RD than in Group R, and side effects or post-operative complications were reported in either group. CONCLUSION: The addition of dexmedetomidine to ropivacaine in a TAP block enhances postoperative analgesia during hospitalisation and improves the quality of recovery without affecting chronic pain in older patients undergoing open inguinal hernia repair surgery.

Precise delivery of celastrol by PEGylated aptamer dendrimer nanoconjugates for enormous therapeutic effect via superior intratumor penetration over antibody counterparts.

Antibody-coated nanoparticles have been reported to have the extremely low delivery efficiency in solid tumors in preclinical trials. Though aptamers were considered to be superior over antibodies in cancer theranostics, whether PEGylated aptamer nanoparticles are better than antibody nanoparticles in improving delivery specificity and penetration efficiency of chemotherapeutics is still unknown. Here, we conjugate celastrol, a natural product with anti-tumor effect, onto PEGylated EpCAM aptamer or antibody dendrimers to obtain two nanoconjugates, and for the first time, conduct a comprehensive study to compare their performance in delivery specificity, intratumoral penetration ability and therapeutic outcomes. Our results showed that compared to antibody counterparts, PEGylated aptamer nanoconjugates exhibited the enhanced accumulation and retention specificities at tumor sites and the stronger intratumoral penetration capabilities by reducing the macrophage reservoir effects in solid tumors. When delivered celastrol to a colorectal xenograft tumor mice model by PEGylated aptamer dendrimers, 20 % of enhanced therapeutic efficiency was achieved compared to that by antibody-modified ones. Moreover, celastrol at 2 mg/kg delivered by PEGylated aptamer dendrimers showed the prominent anticancer efficiency (nearly 92 %) but without obvious side effects. These data firstly provide the proof-of-concept implementation that PEGylated aptamer nanoconjugates will display the great potential in the effective and safe cancer treatment with regard to the superiority over antibody ones in penetration abilities.

[Stapled anoplin peptide combined with photothermal therapy enhances oncolytic immunotherapy of triple-negative breast cancer].

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

Visible-Light-Driven [2 + 2] Photocycloaddition for Constructing Dimers of N,N'-Diacyl-1,4-dihydropyrazines: Experimental and Theoretical Investigation.

In this study, the visible-light-driven [2 + 2] photocycloaddition of 1,4-dihydropyrazines in solution was reported. The N,N'-diacyl-1,4-dihydropyrazines with different substituents showed completely different reactivity under the irradiation of a 430 nm blue light-emitting diode (LED) lamp. N,N'-Diacetyl-1,4-dihydropyrazine and N,N'-dipropionyl-1,4-dihydropyrazine were the only compounds capable of undergoing a [2 + 2] photocycloaddition reaction, yielding syn-dimers and cage-dimers (known as 3,6,9,12-tetraazatetraasteranes) with overall yields of 76 and 83%, correspondingly. The substituent-reactivity effect on [2 + 2] photocycloaddition of N,N'-diacyl-1,4-dihydropyrazines was investigated by density functional theory calculations. The results show that the substituents have little influence on Gibbs free energy for the [2 + 2] photocycloaddition and mainly affect the excited energy, reaction sites, and the triplet excited-state structures of 1,4-dihydropyrazines, which are closely related to whether the reaction occurs. The results offer insights into the photochemical reactivity of 1,4-dihydropyrazines and an approach for constructing dimers of N,N'-diacyl-1,4-dihydropyrazines through a solution-based visible-light-driven [2 + 2] photocycloaddition, especially for the construction of 3,6,9,12-tetraazatetraasteranes. Compared with the solid-state [2 + 2] photocycloaddition of 1,4-dihydropyrazine, this photocycloaddition will be an efficient and environmentally friendly method for synthesizing tetraazatetraasteranes with the advantages of milder reaction conditions, simple operation, adjustable reaction amounts by omitting the cocrystal growth step, etc.

Nuclear receptor RXRα binds the precursor of miR-103 to inhibit its maturation.

BACKGROUND: The maturation of microRNAs (miRNAs) successively undergoes Drosha, Dicer, and Argonaute -mediated processing, however, the intricate regulations of the individual miRNA maturation are largely unknown. Retinoid x receptor alpha (RXRα) belongs to nuclear receptors that regulate gene transcription by binding to DNA elements, however, whether RXRα binds to miRNAs to exert physiological functions is not known. RESULTS: In this work, we found that RXRα directly binds to the precursor of miR-103 (pre-miR-103a-2) via its DNA-binding domain with a preferred binding sequence of AGGUCA. The binding of RXRα inhibits the processing of miR-103 maturation from pre-miR-103a-2. Mechanistically, RXRα prevents the nuclear export of pre-miR-103a-2 for further processing by inhibiting the association of exportin-5 with pre-miR-103a-2. Pathophysiologically, the negative effect of RXRα on miR-103 maturation correlates to the positive effects of RXRα on the expression of Dicer, a target of miR-103, and on the inhibition of breast cancer. CONCLUSIONS: Our findings unravel an unexpected role of transcription factor RXRα in specific miRNA maturation at post-transcriptional level through pre-miRNA binding, and present a mechanistic insight regarding RXRα role in breast cancer progression.

Chemoselective [2 + 2]/[3 + 2] Photocycloaddition of 1,4-Dihydropyridines: Experimental and Theoretical Investigation.

The photocycloaddition of 1,4-dihydropyridines (1,4-DHPs) is a main approach to synthesize structurally complex compounds, which are important intermediates for the preparation of cage compounds, such as 3,9-diazatetraasterane, 3,6-diazatetraasterane, 3,9-diazatetracyclododecane, and 6,12-diazaterakishomocubanes. The acquisition of different cage compounds depended on the chemoselectivity, which is mainly caused by the reaction conditions and structural characteristics of 1,4-DHPs. This study aimed to investigate the effect of the structural characteristics on chemoselectivity in [2 + 2]/[3 + 2] photocycloaddition of 1,4-DHPs. The photocycloadditions were conducted on the 1,4-diaryl-1,4-dihydropyridine-3-carboxylic ester with steric hindrance groups at the C3 position or chirality at the C4 position irradiated by a 430 nm blue LED lamp. When the 1,4-DHPs contained high steric hindrance groups at the C3 position, [2 + 2] photocycloaddition was the main reaction, resulting in 3,9-diazatetraasteranes with a yield of 57%. Conversely, when the 1,4-DHPs were resolved to a chiral isomer, the main reaction was [3 + 2] photocycloaddition, producing 6,12-diazaterakishomocubanes with a yield of 87%. To investigate the chemoselectivity and understand the photocycloaddition of 1,4-DHPs, density functional theory (DFT) and time-dependent DFT (TDDFT) calculations were performed at the B3LYP-D3/def-SVP//M06-2X-D3/def2-TZVP level. The steric hindrance and excitation energy modulated by substituents at the C3 position and chiral carbon at the C4 position were crucial for the chemoselectivity in [2 + 2]/[3 + 2] photocycloaddition of 1,4-DHPs.

Acid-Responsive Macroporous Silica Nanoparticles for Bcl-2-Functional-Converting Peptide Release and Synergism with Celastrol for Enhanced Therapy against Resistant Cancer.

Combination of chemotherapeutics with polypeptide/protein drugs has been demonstrated to be an effective approach for treatment against cancer multidrug resistance. However, due to the low biostability and weak cell penetrating ability of biomacromolecules, intracellular delivery and release of biomacromolecules in a spatiotemporally controllable manner in target sites in vivo face great challenges, and synergistic effects will not be achieved as expected just by simple drug combination. Here, we conceived an inspired strategy to combat the drug-resistant tumors by fabricating multiarm PEG-gated large pore-sized mesoporous silica nanoparticles for the Bcl-2-functional-converting peptide (denoted as N9@M-CA∼8P) payload and controlled release and realizing synergistic effects with celastrol integration at a low dosage as a curative sensitizer. Our results demonstrated that the N9 peptide could be pH-responsively released from the macropores of the M-CA∼8P nanosystem both in simulated physiological environments and in cancer cells and at tumor sites. Biosafe and enhanced therapeutic outcomes (90% tumor inhibition) were obtained by combination of the N9@M-CA∼8P nanosystem with celastrol coordinatively inducing mitochondrion-mediated cell apoptosis in resistant cancer cell lines and in the corresponding xenografted mice models. Overall, this study provides convincing evidence for effective and safe resistant cancer treatment through a stimulus-responsive biomacromolecule nanosystem combined with a low dosage of a natural compound.

Effects of Li+ conduction on the capacity utilization of cathodes in all-solid-state lithium batteries.

Li+ conduction in all-solid-state lithium batteries is limited compared with that in lithium-ion batteries based on liquid electrolytes because of the lack of an infiltrative network for Li+ transportation. Especially for the cathode, the practically available capacity is constrained due to the limited Li+ diffusivity. In this study, all-solid-state thin-film lithium batteries based on LiCoO2 thin films with varying thicknesses were fabricated and tested. To guide the cathode material development and cell design of all-solid-state lithium batteries, a one-dimensional model was utilized to explore the characteristic size for a cathode with varying Li+ diffusivity that would not constrain the available capacity. The results indicated that the available capacity of cathode materials was only 65.6% of the expected value when the area capacity was as high as 1.2 mAh/cm2. The uneven Li distribution in cathode thin films owing to the restricted Li+ diffusivity was revealed. The characteristic size for a cathode with varying Li+ diffusivity that would not constrain the available capacity was explored to guide the cathode material development and cell design of all-solid-state lithium batteries.

Clinical study of rhGM-CSF for the treatment of pulmonary exogenous acute respiratory distress syndrome by modulating alveolar macrophage subtypes: A randomized controlled trial.

BACKGROUND: By modulating the oxygen partial pressure of alveolar epithelial cells, the granulocyte-macrophage colony-stimulating factor (GM-CSF) can stimulate and enhance the innate immune response in the lungs. This study aimed to investigate the therapeutic efficacy of rhGM-CSF in patients suffering from extrapulmonary-induced acute respiratory distress syndrome (ARDS). METHODS: A randomized, double-blind, placebo-controlled clinical trial was conducted between February 2018 to July 2019, in which 66 sepsis patients with ARDS were recruited. The study randomly allocated the patients into 2 groups: an experimental group (34 cases receiving rhGM-CSF) and a control group (32 cases receiving placebo). The changes in lung function were assessed using the scores of PaO2/FIO2 ratio, acute physiology and chronic health evaluation II, sequential organ failure assessment, and lung injury. Additionally, the study analyzed the levels of inflammatory cells, HLA-DR (%), high mobility group protein B1 (HMGB-1) (ng/mL), tumor necrosis factor-alpha (pg/mL), IL-6 (pg/mL), and GM-CSF (pg/mL) in both blood and bronchoalveolar lavage fluid. RESULTS: The study results revealed that the experimental group significantly enhanced their pulmonary function compared to the control group. Moreover, the experimental group demonstrated higher levels of inflammatory cells and HLA-DR, whereas levels of HMGB-1 and tumor necrosis factor-alpha were lower in blood (P < .05, respectively). In addition, the experimental group displayed a higher alternatively activated cell ratio and GM-CSF levels in bronchoalveolar lavage fluid (both P < .05); while HMGB-1 levels were significantly reduced (P < .05). However, no notable difference observed in mortality between the 2 groups (P > .05). CONCLUSIONS: Administering rhGM-CSF to ARDS patients improves lung function and decreases blood inflammation. Nonetheless, while this treatment demonstrates efficacy in reducing these parameters, it does not significantly impact the incidence of ventilator-associated pneumonia or 28-day mortality in ARDS patients.

A Single Preoperative Dose of S-Ketamine Has No Beneficial Effect on Chronic Postsurgical Pain in Patients Undergoing Video-Assisted Thoracoscopic Surgical Lung Lesion Resection: A Prospective Randomized Controlled Study.

OBJECTIVES: To evaluate the efficacy of a single preoperative dose of S-ketamine for chronic postsurgical pain (CPSP) in patients undergoing video-assisted thoracoscopic surgical lung lesion resection (VATS). DESIGN: A prospective randomized, double-blind controlled study. SETTING: Patients were enrolled from March 17, 2021, to November 18, 2021, at a single tertiary academic hospital. PARTICIPANTS: Patients were 18-to-65 years of age and undergoing VATS. INTERVENTIONS: The experiment was divided into an S-ketamine group (0.5 mg/kg intravenous injection before anesthesia induction) or a placebo group (the same volume of normal saline). MEASUREMENTS AND MAIN RESULTS: The primary endpoint was the incidence of CPSP and its neuropathic component. The secondary endpoints included acute postoperative pain, the use of postoperative analgesics, anxiety and sleep quality scores, and the occurrence of adverse effects. There were no significant differences between the 2 groups in the incidences of CPSP, neuropathic pain, acute postoperative pain, and postoperative use of analgesics. The sleep quality scores on the first postoperative day differed significantly between the groups (47.45 ± 27.58 v . 52.97 ± 27.57, p = 0.049), but not the anxiety scores. In addition, adverse effects were similar between the 2 groups. CONCLUSIONS: A single preoperative dose of S-ketamine in patients who underwent VATS had no significant effect on acute and chronic postoperative pain or the consumption of analgesics after surgery. A single preoperative dose of S-ketamine could improve sleep on the first day after surgery, whereas it had no significant effect on anxiety levels.

Nur77 Serves as a Potential Prognostic Biomarker That Correlates with Immune Infiltration and May Act as a Good Target for Prostate adenocarcinoma.

Prostate adenocarcinoma (PRAD) is the most frequent malignancy, and is the second leading cause of death due to cancer in men. Thus, new prognostic biomarkers and drug targets for PRAD are urgently needed. As we know, nuclear receptor Nur77 is important in cancer development and changes in the tumor microenvironment; whereas, the function of Nur77 in PRAD remains to be elucidated. The TCGA database was used to explore the Nur77 expression and its role in the prognosis of PRAD. It was shown that Nur77 was down regulated in PRAD, and low Nur77 expression was correlated with advanced clinical pathologic characteristics (high grade, histological type, age) and poor prognosis. Furthermore, key genes screening was examined by univariate Cox analysis and Kaplan-Meier survival. Additionally, Nur77 was closely related to immune infiltration and some anti-tumor immune functions. The differentially expressed genes (DEGs) were presented by protein-protein interaction (PPI) network analysis. Therefore, the expression level of Nur77 might help predict the survival of PRAD cases, which presents a new insight and a new target for the treatment of PRAD. In vitro experiments verified that natural product malayoside targeting Nur77 exhibited significant therapeutic effects on PRAD and largely induced cell apoptosis by up-regulating the expression of Nur77 and its mitochondrial localization. Taken together, Nur77 is a prognostic biomarker for patients with PRAD, which may refresh the profound understanding of PRAD individualized treatment.

Mining attention distribution paradigm: Discover gaze patterns and their association rules behind the visual image.

BACKGROUND AND OBJECTIVE: Attention allocation reflects the way of humans filtering and organizing the information. On one hand, different task scenarios seriously affect human's rule of attention distribution, on the other hand, visual attention reflecting the cognitive and psychological process. Most of the previous studies on visual attention allocation are based on cognitive models, predicted models, or statistical analysis of eye movement data or visual images, however, these methods are inadequate to provide an inside view of gaze behavior to reveal the attention distribution pattern within scenario context. Moreover, they seldom study the association rules of these patterns. Therefore, we adopted the big data mining approach to discover the paradigm of visual attention distribution. METHODS: We applied the data mining method to extract the gaze patterns to discover the regularities of attention distribution behavior within the scenario context. The proposed method consists of three components, tasks scenario segmented and clustered, gaze pattern mining, and association rule of frequent pattern mining. RESULTS: The proposed approach is tested on the operation platform. The complex operation task is simultaneously segmented and clustered with the TICC-based method and evaluated by the BCI index. The operator's eye movement frequent patterns and their association rule are discovered. The results demonstrate that our method can associate the eye-tracking data with the task-oriented scene data. DISCUSSION: The proposed method provides the benefits of being able to explicitly express and quantitatively analyze people's visual attention patterns. The proposed method can not only be applied in the field of aerospace medicine and aviation psychology, but also can likely be applied to computer-aided diagnosis and follow-up tool for neurological disease and cognitive impairment related disease, such as ADHD (Attention Deficit Hyperactivity Disorder), neglect syndrome, social attention differences in ASD (Autism spectrum disorder).

Towards pilot's situation awareness enhancement: A framework of adaptive interaction system and its realization.

Adaptive interaction system in flight control always aims to enhance the pilot's situation awareness (SA) to achieve human-in-the-loop control. Most adaptive interaction systems are always activated according to the pilot's current workload state. However, the pilot may already lose important information during a high workload, and thus the corresponding reaction of the adaptive interaction system would lag. Moreover, most adaptive interaction systems adopt the expert's knowledge as a reference to generate information. Still, the tacit knowledge that reveals the information interrelationship is seldom studied, despite being the foundation of the interactive information display. To solve the above problems, we proposed an adaptive interaction system architecture with three subsystems. Firstly, we developed a workload level prediction subsystem, where physiological parameters are used to predict future workload levels, thus avoiding interaction system lag; Secondly, we developed a tacit expert knowledge mining subsystem to discover the interrelationship hidden in the expert's perceived information, which will guide the interactive information interface. Thirdly, we developed a tips information inference subsystem to provide the lost SA information based on expert knowledge and the pilot's online perceived information. The effectiveness of the proposed system is verified via a comparative experiment utilizing the control interface of a remotely piloted aircraft.