Hypoxia inducible factors regulate infectious SARS-CoV-2, epithelial damage and respiratory symptoms in a hamster COVID-19 model.

Understanding the host pathways that define susceptibility to Severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) infection and disease are essential for the design of new therapies. Oxygen levels in the microenvironment define the transcriptional landscape, however the influence of hypoxia on virus replication and disease in animal models is not well understood. In this study, we identify a role for the hypoxic inducible factor (HIF) signalling axis to inhibit SARS-CoV-2 infection, epithelial damage and respiratory symptoms in the Syrian hamster model. Pharmacological activation of HIF with the prolyl-hydroxylase inhibitor FG-4592 significantly reduced infectious virus in the upper and lower respiratory tract. Nasal and lung epithelia showed a reduction in SARS-CoV-2 RNA and nucleocapsid expression in treated animals. Transcriptomic and pathological analysis showed reduced epithelial damage and increased expression of ciliated cells. Our study provides new insights on the intrinsic antiviral properties of the HIF signalling pathway in SARS-CoV-2 replication that may be applicable to other respiratory pathogens and identifies new therapeutic opportunities.

Caspase-3-Triggered Intracellular Gadolinium Nanoparticle Formation for T1-Weighted Magnetic Resonance Imaging of Apoptosis In Vivo.

Apoptosis, with a hallmark of upregulated protease Caspase-3, has been frequently imaged with various probes to reveal the therapeutic efficiencies of different drugs. However, activatable molecular probes with programmable self-assembling behaviors that enable enhanced T1-weighted magnetic resonance imaging (MRI) of apoptosis remain scarce. Herein, taking advantage of a CBT-Cys click reaction, we rationally designed a Caspase-3-activatable self-assembling probe Ac-Asp-Glu-Val-Asp-Cys(StBu)-Lys(DOTA(Gd))-CBT (DEVDCS-Gd-CBT) for apoptosis imaging in vivo. After Caspase-3 cleavage in apoptotic cells, DEVDCS-Gd-CBT underwent CBT-Cys click reaction to form a cyclic dimer, which self-assembled into Gd nanoparticles. With this probe, enhanced T1-weighted MR images of apoptosis were achieved at low magnetic fields in vitro, in cis-dichlorodiamineplatinum-induced apoptotic cells and in tail-amputation-simulated apoptotic zebrafish. We anticipate that the smart probe DEVDCS-Gd-CBT could be applied for T1-weighted MRI of apoptosis-related diseases in the clinic in the future.

ß-Glucuronidase-Activated Bioluminescence Probe for In Vivo Tumor Imaging.

ß-Glucuronidase (GLU) is a hallmark enzyme for many malignant tumors, but bioluminescence (BL) probes that enable GLU imaging in vivo have not been reported. Herein, we rationally designed the BL probe Glc-Luc to address this issue. In vitro results demonstrated the specific responsiveness of Glc-Luc toward GLU with a calculated catalytic efficiency (kcat/Km) of 0.0109 µM-1 min-1 and a limit of detection (LOD) of 1.39 U/mL. Moreover, Glc-Luc rendered 3.1-fold and 15.9-fold higher BL intensities over the control groups in cell lysates and tumor-bearing mice, respectively. We anticipate that Glc-Luc could be further applied for the sensitive diagnosis of GLU-related diseases.

Tandem Guest-Host-Receptor Recognitions Precisely Guide Ciprofloxacin to Eliminate Intracellular Staphylococcus aureus.

Staphylococcus aureus (S. aureus) is able to hide within host cells to escape immune clearance and antibiotic action, causing life-threatening infections. To boost the therapeutic efficacy of antibiotics, new intracellular delivery approaches are urgently needed. Herein, by rational design of an adamantane (Ada)-containing antibiotic-peptide precursor Ada-Gly-Tyr-Val-Ala-Asp-Cys(StBu)-Lys(Ciprofloxacin)-CBT (Cip-CBT-Ada), we propose a strategy of tandem guest-host-receptor recognitions to precisely guide ciprofloxacin to eliminate intracellular S. aureus. Via guest-host recognition, Cip-CBT-Ada is decorated with a ß-cyclodextrin-heptamannoside (CD-M) derivative to yield Cip-CBT-Ada/CD-M, which is able to target mannose receptor-overexpressing macrophages via multivalent ligand-receptor recognition. After uptake, Cip-CBT-Ada/CD-M undergoes caspase-1 (an overexpressed enzyme during S. aureus infection)-initiated CBT-Cys click reaction to self-assemble into ciprofloxacin nanoparticle Nano-Cip. In vitro and in vivo experiments demonstrate that, compared with ciprofloxacin or Cip-CBT-Ada, Cip-CBT-Ada/CD-M shows superior intracellular bacteria elimination and inflammation alleviation efficiency in S. aureus-infected RAW264.7 cells and mouse infection models, respectively. This work provides a supramolecular platform of tandem guest-host-receptor recognitions to precisely guide antibiotics to eliminate intracellular S. aureus infection efficiently.

Maladaptive metacognitive beliefs mediated the effect of intolerance of uncertainty on depression.

Both elevated intolerance of uncertainty (IU) and maladaptive metacognitive beliefs (MBs) were associated with depression. However, the relationship between MBs and IU in clinical depression is unclear. The current study aimed to investigate the putative impairment of MBs and IU in major depressive disorder (MDD) and explore the relationship between these two factors with depressive symptoms. Metacognition Questionnaire-30 Items (MCQ-30), Intolerance of Uncertainty Scale-Short Form (IUS-12) and clinical rating scales were administered to 53 patients with MDD and 56 healthy controls (HCs). Stepwise regressions were performed to explore independent contributions of MBs and IU on depression. Mediation analysis was used to examine associations among variables. Patients with MDD reported higher IUS-12 and MCQ-30 scores than HCs. Stepwise regressions revealed a unique contribution of negative MBs concerning the consequences of not controlling thoughts (MCQ-NC) on depression symptoms while controlling the effects of age, gender, anxiety symptoms and IU. MCQ-NC and negative MBs concerning the uncontrollability and danger of negative thinking (MCQ-NEG) completely mediated the effects of IU on depression and anxiety symptoms. Our results provided clear evidence that maladaptive negative MBs are directly associated with depression symptoms, and mediated the effect of IU on depression and anxiety symptoms, suggesting that IU and MBs influence clinical symptoms in a hierarchical manner.

Covalently Conjugated Hydrogelators for Imaging and Therapeutic Applications.

In recent years, research on supramolecular hydrogels for biomedical applications developed rapidly by covalently conjugating their hydrogelators with functional moieties including therapeutic agents and imaging probes. Such conjugation can not only endow hydrogels with specific functions but also enhance the performance of the functional moieties. Therefore, these evolutionary conjugates may create a great leap for the application of supramolecular hydrogels in clinical scenarios, especially in a bioimaging or a sustained drug release system. In order to draw inspiration from the rapid advancement in this field and establish cornerstones for innovative exploration in the follow-up research, herein, we review the recent advances of the covalently conjugated hydrogelators and their biomedical applications in imaging and therapies. Besides, we provide our views on the remaining challenges and a perspective on future trends of conjugated hydrogelators.

Palladium Nanosheets as Safe Radiosensitizers for Radiotherapy.

Many noble metal-based nanoparticles have emerged for applications in cancer radiotherapy in recent years, but few investigations have been carried out for palladium nanoparticles. Herein, palladium nanosheets (Pd NSs), which possess a sheetlike morphology with a diameter of ∼14 nm and a thickness of ∼2 nm, were utilized as a sensitizer to improve the performance of radiotherapy. It was found that Pd NSs alone did not decrease the cell viability after treatment for as long as 130 h, suggesting the excellent cytocompatibility of the nanoagents. However, the viability of cancer cells treated with X-ray irradiation became lower, and the viability became even lower if the cells were co-treated with X-ray and Pd NSs, indicating the radiosensitization effect of Pd NSs. Additionally, compared with X-ray irradiation, the combined treatment of Pd NSs and X-ray irradiation induced the generation of more DNA double-stranded breaks and reactive oxygen species within cancer cells, which eventually caused elevated cell apoptosis. Moreover, in vivo experiments also verified the radiosensitization effect and the favorable biocompatibility of Pd NSs, indicating their potential for acquiring satisfactory in vivo radiotherapeutic effect at lower X-ray doses. It is believed that the present research will open new avenues for the application of noble metal-based nanoparticles in radiosensitization.

Comparison Of Cimicifuga foetida extract and different hormone therapies regarding in causing breast pain in early postmenopausal women.

This study aimed to compare the influence between Cimicifuga foetida extract and different hormone therapies on breast pain in early postmenopausal women. A prospective, randomized, controlled clinical trial was conducted among 96 early postmenopausal women. Participants were randomly assigned to three groups: group A received 1 mg/day estradiol valerate plus 4 mg/day medroxyprogesterone acetate on days 19-30; group B received 1 mg/day estradiol valerate plus 100 mg/day micronized progesterone on days 19-30; group C received C. foetida extract, 1talet (contains 33.3 mg extract), t.i.d. Breast pain diary and numerical rating scale was used to access the breast pain. For 6 months' treatment, the total incidence of breast pain in group A and B was significantly higher than that in group C (p < .05). The duration (day) of breast pain in each month decreased over time in group A and B while it was continuously low and without significant change in group C (p > .05). The intensity of breast pain was mild in most participants and did not differ among three groups (p > .05). During treatment of early postmenopausal women with C. foetida extract for 6 months, the incidence and duration of breast pain were lower than upon treatment with E2 plus cyclic MPA or m-P and did not change over time.

PHD2 inactivation in Type I cells drives HIF-2α-dependent multilineage hyperplasia and the formation of paraganglioma-like carotid bodies.

KEY POINTS: The carotid body is a peripheral arterial chemoreceptor that regulates ventilation in response to both acute and sustained hypoxia. Type I cells in this organ respond to low oxygen both acutely by depolarization and dense core vesicle secretion and, over the longer term, via cellular proliferation and enhanced ventilatory responses. Using lineage analysis, the present study shows that the Type I cell lineage itself proliferates and expands in response to sustained hypoxia. Inactivation of HIF-2α in Type I cells impairs the ventilatory, proliferative and cell intrinsic (dense core vesicle) responses to hypoxia. Inactivation of PHD2 in Type I cells induces multilineage hyperplasia and ultrastructural changes in dense core vesicles to form paraganglioma-like carotid bodies. These changes, similar to those observed in hypoxia, are dependent on HIF-2α. Taken together, these findings demonstrate a key role for the PHD2-HIF-2α couple in Type I cells with respect to the oxygen sensing functions of the carotid body. ABSTRACT: The carotid body is a peripheral chemoreceptor that plays a central role in mammalian oxygen homeostasis. In response to sustained hypoxia, it manifests a rapid cellular proliferation and an associated increase in responsiveness to hypoxia. Understanding the cellular and molecular mechanisms underlying these processes is of interest both to specialized chemoreceptive functions of that organ and, potentially, to the general physiology and pathophysiology of cellular hypoxia. We have combined cell lineage tracing technology and conditionally inactivated alleles in recombinant mice to examine the role of components of the HIF hydroxylase pathway in specific cell types within the carotid body. We show that exposure to sustained hypoxia (10% oxygen) drives rapid expansion of the Type I, tyrosine hydroxylase expressing cell lineage, with little transdifferentiation to (or from) that lineage. Inactivation of a specific HIF isoform, HIF-2α, in the Type I cells was associated with a greatly reduced proliferation of Type I cells and hypoxic ventilatory responses, with ultrastructural evidence of an abnormality in the action of hypoxia on dense core secretory vesicles. We also show that inactivation of the principal HIF prolyl hydroxylase PHD2 within the Type I cell lineage is sufficient to cause multilineage expansion of the carotid body, with characteristics resembling paragangliomas. These morphological changes were dependent on the integrity of HIF-2α. These findings implicate specific components of the HIF hydroxylase pathway (PHD2 and HIF-2α) within Type I cells of the carotid body with respect to the oxygen sensing and adaptive functions of that organ.

c-myc Gene Copy Number Variation in Cervical Exfoliated Cells Detected on Fluorescence in situ Hybridization for Cervical Cancer Screening.

PURPOSE: This study assessed the clinical significance of c-myc gene copy number gain detected by fluorescence in situ hybridization (FISH) in the prediction of cervical intraepithelial neoplasia (CIN) progression. METHODS: We retrospectively investigated 140 Thinprep cytologic test (TCT) specimens that were histopathologically diagnosed with various stages of cervical neoplasia or malignancy. The specimens were subjected to TCT, human papillomavirus (HPV) testing, and FISH analysis with a c-myc-specific probe. The diagnostic reliability of these methods in determining progression was assessed according to sensitivity, specificity, and κ coefficients. RESULTS: The gene copy number gain of c-myc was significantly higher in the cervical lesion of advanced histologic grade (p < 0.001). For CIN2+ lesions, the sensitivities of TCT, HPV DNA testing, and FISH analysis were 72.3, 92.1, and 64.5%, respectively; the specificities were 81.3, 57.8, and 93.8%, respectively (p < 0.001). The κ coefficients between the c-myc gene test and either the TCT or the HPV DNA test were 0.538 and 0.399, respectively (p < 0.001). CONCLUSIONS: FISH analysis of the c-myc oncogene could be a useful adjunct screening method for the early diagnosis of high-grade cervical lesions. Moreover, c-myc may be a new molecular biomarker for the early diagnosis of cervical lesion progression.

NAADP mobilizes calcium from acidic organelles through two-pore channels.

Ca(2+) mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP(3)), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP(3) and cyclic ADP ribose cause the release of Ca(2+) from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP(3) and ryanodine receptors (InsP(3)Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca(2+) from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related stores that is subsequently amplified by Ca(2+)-induced Ca(2+) release by InsP(3)Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca(2+) stores or by blocking InsP(3)Rs. Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organelles, which can trigger further Ca(2+) signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca(2+) signals in animal cells, and will advance our understanding of the physiological role of NAADP.

Atg4B and Cathepsin B-Triggered in Situ Luciferin Formation for Precise Cancer Autophagy Bioluminescence Imaging.

Autophagy plays a crucial role in tumorigenesis and progression, but current approaches to visualize it in vivo show limited precision due to their single-analyte-responsive mode. Hence, by simultaneously employing dual autophagy enzymes Atg4B and cathepsin B to trigger the in situ formation of luciferin, we herein propose a strategy for precise autophagy bioluminescence imaging. An Atg4B-responsive peptide Ac-Thr-Phe-Gly-d-Cys (TFGC) and a cathepsin B-activatable compound Ac-Lys-Gly-Arg-Arg-CBT (KGRR-CBT) were rationally designed. During tumor autophagy, these two compounds were uptaken by cancer cells and cleaved by their corresponding enzymes to yield d-cysteine and 2-cyano-6-aminobenzothiazole, respectively, which underwent a CBT-Cys click reaction to yield d-aminoluciferin, turning the bioluminescence "on". The responsiveness of these two compounds toward the two enzymes was tested in vitro, and the ability to turn bioluminescence "on" was validated in living cancer cells and in vivo. We anticipate that our precise autophagy imaging strategy could be further applied for the diagnosis of autophagy-related diseases in the near future.

Brain structural alterations in internet gaming disorder: Focus on the mesocorticolimbic dopaminergic system.

AIMS: This study aimed to identify gray/white matter volume (GMV/WMV) alterations in Internet Gaming Disorder (IGD), with a special focus on the subregions of the mesocorticolimbic dopaminergic system and their clinical association. RESULTS: Compared with healthy controls, IGDs showed bigger GMV in the bilateral caudate and the left nucleus accumbens (NAc), and bigger WMV in the inferior parietal lobule. The comparison of regions of interest (ROI) confirmed increased GMV in the bilateral caudate (including the dorsal anterior, body, and tail) and the left core of NAc in IGD, but no significant WMV alterations in the mesocorticolimbic dopaminergic system. GMVs in the left lateral orbital gyrus of orbitofrontal cortex (OFC) were associated with craving for games, while GMVs in the left anterior insula, right NAc, right caudate, and right OFC were associated with self-control in IGD. CONCLUSIONS: IGD was accompanied by changed GMV, but not WMV, in the mesocorticolimbic dopaminergic system. GMV in the mesocorticolimbic dopaminergic system may contribute to impaired self-control and craving in IGD.

Enhanced Pavlovian-to-instrumental transfer in internet gaming disorder.

Background and aims: The Pavlovian-to-instrumental transfer (PIT) effect is a phenomenon that Pavlovian conditioned cues that could influence one's instrumental behavior. In several substance and behavioral addictions, such as tobacco use disorder and gambling disorder, addiction-related cues could promote independently trained instrumental drug-seeking/drug-taking behaviors, indicating a specific PIT effect. However, it is unclear whether Internet gaming disorder (IGD) would show a similar change in PIT effects as other addictions. The study aimed to explore the specific PIT effects in IGD. Methods: We administrated a PIT task to individuals with IGD (n = 40) and matched health controls (HCs, n = 50), and compared the magnitude of specific PIT effects between the two groups. The severity of the IGD symptoms was assessed by the Chinese version 9-item Internet Gaming Disorder Scale (IGDS) and the Internet Addiction Test (IAT). Results: We found that: (1) related to the HCs group, the IGD group showed enhanced specific PITgame effects, where gaming-related cues lead to an increased choice rate of gaming-related responses; (2) in the IGD group, the magnitude of specific PITgame effects were positively correlated with IAT scores (rho = 0.39, p = 0.014). Discussion and Conclusions: Individuals with IGD showed enhanced specific PIT effects related to HCs, which were associated with the severity of addictive symptoms. Our results highlighted the incentive salience of gaming-related cues in IGD.

An evolutionary game analysis of supervision behavior in public-private partnership projects: Insights from prospect theory and mental accounting.

Effective supervision is one of the important ways to ensure the smooth implementation of Public-Private Partnership (PPP) projects. To understand the characteristics of the decision-making behavior of the public and private sectors in the supervision of PPP projects and the influencing mechanisms of some factors, we combine prospect theory and mental accounting theory into the evolutionary game analysis. First, we use prospect theory to reflect the behavioral characteristics of game players when making decisions and classify the value function into a valence account and a cost account according to the mental accounting theory. Accordingly, we construct a payoff matrix based on prospect theory and mental accounting theory, and the system's equilibrium state is analyzed. Then, based on numerical simulations, the influence of different parameters on the behavior of the public and private sectors is analyzed, and management suggestions for practical reference are put forward based on the simulation results. The results show that the greater the perceived cost of active behavior for the public and private sectors, the less likely they will take active behavior. Secondly, there is insufficient incentive for the private sector to fulfill contracts when the penalties for its opportunistic behavior are minor. Thirdly, increasing the cost reference points and decreasing the valence reference points will promote the public and private sectors to adopt active behavior. Fourth, the public sector and the private sector are more inclined to take active behavior when they need to bear more significant risk losses. This study provides new ideas for the analysis of the game players' decision-making behaviors in the supervision of PPP projects and delivers a decision-making reference for reasonable supervision.

The effect of courage on stress: The mediating mechanism of behavioral inhibition and behavioral activation in high-risk occupations.

Employees in high-risk occupations are exposed to tremendous work acute stress or prolonged stress disorders that are likely to undermine the health and organizational effectiveness. Based on positive psychology, courage which refers to behavioral approach despite the experience of fear could buffer the negative effects on stress. However, there is little known about the mechanisms by which courage decreases the risk of stress. Motivational systems may play an underlying role in this process, as behavioral inhibition system (BIS) is inhibited and behavioral activation system (BAS) is evoked by risk or threat. The current study aimed to examine the mediating effects of behavioral inhibition and activation on the relationship between courage and stress in the high-risk occupations. This study recruited 1,761 high-risk employees aged from 18 to 27 (M = 19.32; SD = 4.14) with a cluster sampling method who completed Courage Measure (CM), the BIS/BAS Scales and the Psychological Stress Evaluation Test (PSET). The correlation and mediation analyses examined the inter-variable correlations as well as the underlying mechanism between courage and stress. The results support the hypothesis and reveal that the behavioral inhibition mediates the association between courage and stress (B indirect = -0.02, p < 0. 01, 95%CI = -0.03 to -0.003). The behavioral activation of fun seeking mediates the association between courage and stress as well (B indirect = -0.04, p < 0. 01, 95%CI = -0.058 to -0.029). These findings suggest that behavioral inhibition and activation of fun seeking play imperative mechanism underpinning the buffering effect of courage on stress. Other theoretical and applied implications for desensitizing stress in the high-risk occupations are discussed.

Character strengths as protective factors against behavior problems in early adolescent.

Character strengths could effectively prevent negative psychological outcomes in adults. However, there was little research conducted among early adolescents. The present study aimed to explore character strengths that were independently related to fewer behavior problems in early adolescents. In total, 521 early adolescents (mean age 10.92 ± 0.04, range 10-12 years) were recruited from primary schools in Sichuan, China. Character strengths were measured using the Values in Action Inventory of Strengths for Youth (VIA-Youth). Behavior problems were measured using the Conners Parent Symptom Questionnaire (PSQ). The results showed that behavior problems were negatively correlated with character strengths (r = -0.14 to -0.3, p < 0.05 Bonferroni corrected). Character strengths explained a significant proportion of additional variance (14-22%) in five types of behavior problems after controlling the effect of demographic factors (residence, left-behind experiences, maternal education level). Moreover, several specific character strengths showed an independent contribution (ß = -0.34 to -0.14 for self-regulation, perseverance, zest, humility, and leadership; ß = 0.21 to 0.34, for hope; all p < 0.05) to behavior problems. Our study revealed that character strengths were protective factors against behavior problems in early adolescents.

Direct chemical editing of Gram-positive bacterial cell walls via an enzyme-catalyzed oxidative coupling reaction.

Chemically manipulating bacterial surface structures, a cutting-edge research direction in the biomedical field, predominantly relies on metabolic labeling by now. However, this method may involve daunting precursor synthesis and only labels nascent surface structures. Here, we report a facile and rapid modification strategy based on a tyrosinase-catalyzed oxidative coupling reaction (TyOCR) for bacterial surface engineering. This strategy employs phenol-tagged small molecules and tyrosinase to initiate direct chemical modification of Gram-positive bacterial cell walls with high labeling efficiency, while Gram-negative bacteria are inert to this modification due to the hindrance of an outer membrane. By using the biotin‒avidin system, we further present the selective deposition of various materials, including photosensitizer, magnetic nanoparticle, and horseradish peroxidase, on Gram-positive bacterial surfaces, and realize the purification/isolation/enrichment and naked-eye detection of bacterial strains. This work demonstrates that TyOCR is a promising strategy for engineering live bacterial cells.

Enzymatic Nanosphere-to-Nanofiber Transition and Autophagy Inducer Release Promote Tumor Chemotherapy.

Chemotherapy has remained an effective and predominant cancer treatment for the past decades, but is hampered by its low response rate and severe systemic toxicity. Combination chemotherapies are proposed to address these issues, yet their therapeutic outcomes are still far from satisfactory. Thus, it is urgent to develop novel strategies to promote tumor chemosensitivity while reducing toxic side effects of chemotherapeutics. Herein, employing a rationally designed peptide conjugate Nap-Phe-Phe-Lys(SA-AZD8055)-Tyr(H2 PO3 )-OH (Nap-AZD-Yp), a novel approach of simultaneous intracellular nanofiber formation and autophagy inducer release is proposed for selectively sensitizing tumor to chemotherapy. Upon sequential catalyses of alkaline phosphatase and carboxylesterase, Nap-AZD-Yp undergoes nanosphere-to-nanofiber transition accompanied by autophagy inducer AZD8055 release in cancer cells. Cell experiments show enhanced endocytosis of anticancer drug doxorubicin and inhibition of cell migration due to the intracellular nanofiber formation. The released AZD8055 further activates excessive autophagy of cancer cells, sensitizing them to chemotherapy. Animal experiment results suggest Nap-AZD-Yp can significantly enhance the therapeutic effects of doxorubicin on tumors while mitigate its toxic adverse effects on normal tissues. It is anticipated that the "smart" concept in this work c be widely employed to develop novel combinational therapies for the treatment of cancers and other diseases in near future.

The Validity of Virtual Courage for Trainees in High-Risk Occupations.

Background: Employees in high-risk occupations are exposed to tremendous work stress that hinders organizational effectiveness and personal mental health. Based on positive psychology, courage can be considered a protective factor that buffers the adverse effect of high-risk surroundings on employees. However, little is known about the way courage is simulated or evaluated in response to safety concerns. Virtual reality (VR) is an accessible tool for courage simulation due to its immersive qualities, presence and interactive features and may provide a promising pathway to achieve a scientific, accurate and ecologically valid evaluation of high-risk employees. Methods: The sample consisted of 51 high-risk employees who were recruited voluntarily. Before and after experiencing the VR courage scenarios, the participants completed the VR features questionnaire, the Physical Courage at Work Scale (PCWS), the Courage Measure (CM), and the Positive and Negative Affect Scale (PANAS). During the process of watching the VR courage scenarios, the participants' heart rate and skin conductance at resting-state baseline and during virtual courage scenarios were recorded through HTC VIVE Pro Eye and BioGraph Infiniti 8. Results: The results support the hypothesis and reveal that the interaction, immersion and presence scores of the scenarios were all significantly higher than the median 4 points. The score for the CM in the posttest was significantly higher than that in the pretest. The scared and afraid scores for the posttest were significantly higher than those for the pretest. The heart rate and skin conductance of each scenario showed an increase compared with the baseline. The Pearson's correlation between physiological indicators and the score of the PCWS was 0.28~0.54. Conclusion: This study developed virtual courage for high-risk occupations based on well-established theory and VR technology. Experimental data revealed that the paradigm conformed to the requirements of VR features and was able to activate fear and evoke the quality of courage. Thus, the virtual courage paradigms have good validity in simulating scenarios for high-risk employees, which might accelerate organizational effectiveness while buffering working stress.