Prenatal inflammation exposure accelerates lung cancer tumorigenesis in offspring mouse: possible links to IRE1α/XBP1-mediated M2-like polarization of TAMs and PD-L1 up-expression.

BACKGROUND: Prenatal inflammation exposure (PIE) can increase the disease susceptibility in offspring such as lung cancer. Our purpose was to investigate the mechanisms of PIE on lung cancer. METHODS: Prenatal BALB/c mice were exposed to lipopolysaccharide (LPS), and then, their offspring were intraperitoneally instilled with urethane to establish the two-stage lung cancer carcinogenesis model. At the 48 weeks of age, the offspring mice were killed and lung tissues were collected for HE, immunohistochemistry, immunofluorescence, and Luminex MAGPIX®-based assays. CD11b + F4/80 + tumor-associated macrophages (TAMs) were sorted out from lung tumor tissues by cell sorting technique. Flow cytometry was employed to evaluate the extent of M2-like polarization of TAMs and PD-L1 expression. RESULTS: The offspring of PIE mice revealed more lung lesion changes, including atypical hyperplasia and intrapulmonary metastases. The number of lung nodules, lung organ index, and PCNA, MMP-9 and Vimentin positive cells in lung tissue of PIE group were higher than those of Control group. The increases of mRNA encoding M2 macrophage markers and cytokines in offspring of prenatal LPS-treated mice confirmed the induced effect of PIE on macrophage polarization. Additionally, PIE treatment increased the percentage of CD163 + CD206 + cells in the sorted TAMs. Importantly, endoplasmic reticulum (ER) stress-markers like GRP78/BIP and CHOP, p-IRE1α and XBP1s, and PD-L1 were up-regulated in TAMs from PIE group. Besides, we also observed that IRE1α inhibitor (KIRA6) reversed the M2-like TAMs polarization and metastasis induced by PIE. CONCLUSIONS: IRE1α/XBP1-mediated M2-like TAMs polarization releases the pro-tumorigenic cytokines and PD-L1 expression, which may be the regulatory mechanism of accelerating lung cancer in offspring of mice undergoing PIE.

High titer production of gastrodin enabled by systematic refactoring of yeast genome and an antisense-transcriptional regulation toolkit.

Gastrodin, a phenolic glycoside, is a prominent component of Gastrodia elata, which is renowned for its sedative, hypnotic, anticonvulsant, and neuroprotective activities. Engineering heterologous production of plant natural products in microbial host represents a safe, cost-effective, and scalable alternative to plant extraction. Here, we present the construction of an engineered Yarrowia lipolytica yeast that achieves a high-titer production of gastrodin. We systematically refactored the yeast genome by enhancing the flux of the shikimate pathway and optimizing the glucosyl transfer system. We introduced more than five dozen of genetic modifications onto the yeast genome, including enzyme screening, alleviation of rate-limiting steps, promoter selection, genomic integration site optimization, downregulation of competing pathways, and elimination of gastrodin degradation. Meanwhile, we developed a Copper-induced Antisense-Transcriptional Regulation (CATR) tool. The developed CATR toolkit achieved dynamic repression and activation of violacein synthesis through the addition of copper in Y. lipolytica. This strategy was further used to dynamically regulate the pyruvate kinase node to effectively redirect glycolytic flux towards the shikimate pathway while maintaining cell growth at proper rate. Taken together, these efforts resulted in 9477.1 mg/L of gastrodin in shaking flaks and 13.4 g/L of gastrodin with a yield of 0.149 g/g glucose in a 5-L bioreactor, highlighting the potential for large-scale and sustainable production of gastrodin from microbial fermentation.

Association between higher triglyceride glucose index and increased risk of osteoarthritis: data from NHANES 2015-2020.

BACKGROUND: The relationship between the triglyceride glucose (TyG) index and osteoarthritis (OA) remains unclear. The objective of this study was to examine potential associations between an elevated TyG index and an increased risk of OA prevalence. METHODS: 3,921 participants with OA from the National Health and Nutrition Examination Survey (2015-2020) were included in this study. Participants were categorized into quartiles based on TyG index, which was determined using the formula: Ln [triglyceride (mg/dL) fasting blood glucose (mg/dL)/2]. Weighted multivariable regression, subgroup analyses, and threshold effect analyses were performed to calculate the independent association between TyG index and OA. RESULTS: A total of 25,514 people were enrolled, with a mean TyG index of 8.48 ± 0.65. The results of multivariable logistic regression analysis after full adjustment showed a significant association between higher TyG index values and an increased risk of OA. Specifically, each incremental unit increase in the TyG index was associated with a 634% higher risk of OA [OR = 7.34; 95% CI: 2.25, 23.93; p = 0.0010]. Based on interaction tests, age, gender, BMI, and smoking status did not significantly affect the relationship between the TyG index and OA, while diabetes showed a stronger positive correlation between the TyG index and OA. CONCLUSION: An increased risk of OA was associated with a higher TyG index. TyG could be a valuable predictor of OA and offer novel perspectives on the assessment and treatment of OA.

Synthesis, biological activity evaluation and mechanism of action of novel bis-isatin derivatives as potential anti-liver cancer agents.

A series of bis-isatin conjugates with lysine linker were synthesized with the aim of probing their antiproliferative potential. All the newly synthesized derivatives (0-100 µM) were first screened against liver cancer cell lines(Huh1, H22, Huh7, Hepa1-6, HepG2, Huh6 and 97H) using CCK-8 assay. Results indicated that the derivative 4d exhibited the most potent activity against Huh1 (IC50 = 17.13 µM) and Huh7(IC50 = 8.265 µM). In vivo anti-tumor study showed that compound 4d effectively inhibited tumor growth in Huh1-induced xenograft mouse model; the anti-tumor effect of compound 4d (15 mg/kg) was comparable with sorafenib (20 mg/kg). H&E staining analysis and routine blood test and blood serum biochemistry examination was performed to confirm the safety of compound 4d in xenograft models. The mechanism of action of 4d on tumor growth inhibition was further investigated by RNA-Seq analysis, which indicates a positive regulation of autophagy signaling pathway, which was further confirmed with key biomarker expression of autophagy after 4d treatment. Our results suggest that the bis-isatin conjugate compound 4d is a promising tumor inhibitory agent for some liver cancer.

Improvement in organic solvent resistance of keratinase BLk by directed evolution.

Keratinase, a vital enzyme in hair degradation, requires enhanced stability for industrial applications in the harsh reaction environment used for keratin hydrolysis. Previous studies have focused on improving keratinase thermostability. In this study, directed evolution was applied to enhance the organic solvent stability of the keratinase BLk from Bacillus licheniformis. Three mutants were identified, exhibiting significant enhanced stability in various solvents, although no similar improvements were observed in terms of thermostability. The identified mutations were located on the enzyme surface. The half-lives of the D41A, A24E, and A24Q mutants increased by 47-, 63-, and 61-fold, respectively, in the presence of 50% (v/v) acetonitrile compared to that of the wild type (WT). Similarly, in the presence of 50% (v/v) acetone, the half-lives of these mutants increased by 22-, 27-, and 27-fold compared to that of the WT enzyme. Notably, the proteolytic activity of all the selected mutants was similar to that of the WT enzyme. Furthermore, molecular dynamics simulation was used to assess the possible reasons for enhanced solvent stability. These results suggest that heightened intramolecular interactions, such as hydrogen bonding and hydrophobic interactions, contribute to improved solvent tolerance. The mutants obtained in this study hold significant potential for industrial applications.

Overexpressed FOXM1 collaborates with MMB to increase WEE1 inhibitor sensitivity in NSCLC.

Background: Non-small cell lung cancer (NSCLC) is a common lung tumor with high mortality. The complex formed by MYB-MuvB complex (MMB) and forkhead box M1 (FOXM1) (MMB-FOXM1) plays a vital role in cell cycle progression to affect the progression of diseases. The role of the FOXM1-MMB complex in Wee1-like protein kinase (WEE1) inhibitor sensitivity in NSCLC keeps unclear. Methods: The reverse transcription quantitative polymerase chain reaction (RT-qPCR) was performed to measure the mRNA levels of FOXM1, LIN54, Replication Protein A (RPA), gammaH2AX (γH2AX) and Cyclin B (CCNB). The western blot was performed to examine the corresponding protein expressions. The Cell Counting Kit-8 (CCK-8) assay was performed to test cell survival. Result: It was demonstrated that after AZD-1775 treatment, the decrease in cell survival mediated by FOXM1 overexpression (P<0.001) could be reversed by LIN54 knockdown (P<0.01) and that cell survival in the control group did not differ obviously from that in the pcDNA3.1-FOXM1+siLIN54 group, indicating that the FOXM1-MMB complex was necessary for WEE1 inhibitor sensitivity. Moreover, the mRNA and protein expression levels of RPA and γH2AX were increased after AZD-1775 treatment and FOXM1 overexpression (P<0.01), suggesting that FOXM1 upregulation enhanced DNA replication stress and DNA damage. Finally, we found that the increases in the mRNA and protein expression levels of CCNB mediated by FOXM1 (P<0.01) could be rescued by silencing LIN54 (P<0.001) and that CCNB expression in the control group did not differ obviously from that in the pcDNA3.1-FOXM1+siLIN54 group. These findings revealed that the FOXM1-MMB complex activated G2/M checkpoints. In our work, it was discovered that FOXM1 overexpression increased DNA replication stress, which increased DNA replication and pressure on the WEE1 checkpoint. On the other hand, FOXM1 can enhance CCNB expression, increase the threshold content of the CCNB/CDK1 complex, facilitate mitosis, and promote WEE1 dephosphorylation. Under these two conditions, sensitivity to the WEE1 inhibitor AZD-1775 is increased, which leads to the accumulation of DNA damage and drives the activation of apoptosis. Conclusions: Overexpressed FOXM1 collaborates with MMB to increase WEE1 inhibitor sensitivity in NSCLC. This discovery might highlight the regulatory function of FOXM1/MMB in the treatment of NSCLC patients.

Antitumor Effects of a Distinct Sonodynamic Nanosystem through Enhanced Induction of Immunogenic Cell Death and Ferroptosis with Modulation of Tumor Microenvironment.

Sonodynamic therapy (SDT) holds great promise to be applied for cancer therapy in clinical settings. However, its poor therapeutic efficacy has limited its applications owing to the apoptosis-resistant mechanism of cancer cells. Moreover, the hypoxic and immunosuppressive tumor microenvironment (TME) also weakens the efficacy of immunotherapy in solid tumors. Therefore, reversing TME remains a formidable challenge. To circumvent these critical issues, we developed an ultrasound-augmented strategy to regulate the TME by utilizing an HMME-based liposomal nanosystem (HB liposomes), which can synergistically promote the induction of ferroptosis/apoptosis/immunogenic cell death (ICD) and initiate the reprograming of TME. The RNA sequencing analysis demonstrated that apoptosis, hypoxia factors, and redox-related pathways were modulated during the treatment with HB liposomes under ultrasound irradiation. The in vivo photoacoustic imaging experiment showed that HB liposomes enhanced oxygen production in the TME, alleviated TME hypoxia, and helped to overcome the hypoxia of the solid tumors, consequently improving the SDT efficiency. More importantly, HB liposomes extensively induced ICD, resulting in enhanced T-cell recruitment and infiltration, which normalizes the immunosuppressive TME and facilitates antitumor immune responses. Meanwhile, the HB liposomal SDT system combined with PD1 immune checkpoint inhibitor achieves superior synergistic cancer inhibition. Both in vitro and in vivo results indicate that the HB liposomes act as a sonodynamic immune adjuvant that is able to induce ferroptosis/apoptosis/ICD via generated lipid-reactive oxide species during the SDT and reprogram TME due to ICD induction. This sonodynamic nanosystem integrating oxygen supply, reactive oxygen species generation, and induction of ferroptosis/apoptosis/ICD is an excellent strategy for effective TME modulation and efficient tumor therapy.

Knocking out central metabolism genes to identify new targets and alternating substrates to improve lipid synthesis in Y. lipolytica.

Introduction: Systematic gene knockout studies may offer us novel insights on cell metabolism and physiology. Specifically, the lipid accumulation mechanism at the molecular or cellular level is yet to be determined in the oleaginous yeast Y. lipolytica. Methods: Herein, we established ten engineered strains with the knockout of important genes involving in central carbon metabolism, NADPH generation, and fatty acid biosynthetic pathways. Results: Our result showed that NADPH sources for lipogenesis include the OxPP pathway, POM cycle, and a trans-mitochondrial isocitrate-α-oxoglutarate NADPH shuttle in Y. lipolytica. Moreover, we found that knockout of mitochondrial NAD+ isocitrate dehydrogenase IDH2 and overexpression of cytosolic NADP+ isocitrate dehydrogenase IDP2 could facilitate lipid synthesis. Besides, we also demonstrated that acetate is a more favorable carbon source for lipid synthesis when glycolysis step is impaired, indicating the evolutionary robustness of Y. lipolytica. Discussion: This systematic investigation of gene deletions and overexpression across various lipogenic pathways would help us better understand lipogenesis and engineer yeast factories to upgrade the lipid biomanufacturing platform.

Rational engineering of a metalloprotease to enhance thermostability and activity.

The rational design of enzymes with enhanced thermostability is efficient. Solvent-tolerant metalloprotease from Pseudomonas aeruginosa PT121 presents high Z-aspartame (Z-APM) synthesis activity, but insufficient thermostability. In this study, we enhanced enzyme thermostability using a rational strategy. Molecular dynamics (MD) simulation was applied to rapidly identify that the D28 and D116 mutations are likely to exhibit increased thermostability, and experimentation verified that the D28N and D116N mutants were more stable than the wild-type (WT) enzyme. In particular, the Tm of the D28N and D116N mutants increased by 6.1 °C and 9.2 °C, respectively, compared with that of the WT enzyme. The half-lives of D28N and D116N at 60 °C were 1.07- and 1.8-fold higher than that of the WT, respectively. Z-APM synthetic activities of the mutants were also improved. The potential mechanism of thermostability enhancement rationalized using MD simulation indicated that increased hydrogen bond interactions and a regional hydration shell were mostly responsible for the thermostability enhancement. Our strategy could be a reference for enzyme engineering, and our mutants offer considerable value in industrial applications.

Biosynthesis of cannabinoid precursor olivetolic acid in genetically engineered Yarrowia lipolytica.

Engineering microbes to produce plant-derived natural products provides an alternate solution to obtain bioactive products. Here we report a systematic approach to sequentially identify the rate-limiting steps and improve the biosynthesis of the cannabinoid precursor olivetolic acid (OLA) in Yarrowia lipolytica. We find that Pseudomonas sp LvaE encoding a short-chain acyl-CoA synthetase can efficiently convert hexanoic acid to hexanoyl-CoA. The co-expression of the acetyl-CoA carboxylase, the pyruvate dehydrogenase bypass, the NADPH-generating malic enzyme, as well as the activation of peroxisomal ß-oxidation pathway and ATP export pathway are effective strategies to redirect carbon flux toward OLA synthesis. Implementation of these strategies led to an 83-fold increase in OLA titer, reaching 9.18 mg/L of OLA in shake flask culture. This work may serve as a baseline for engineering cannabinoids biosynthesis in oleaginous yeast species.

CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin.

BACKGROUND: It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer. METHODS: Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo. RESULTS: Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil. CONCLUSIONS: The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobody-based immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.

LncRNA surfactant associated 1 activates large tumor suppressor kinase 1/Yes-associated protein pathway via modulating hypoxic exosome-delivered miR-4766-5p to inhibit lung adenocarcinoma metastasis.

LncRNA surfactant associated 1 (SFTA1P) exhibits low expression in non-small cell lung cancer (NSCLC) tissues as compared with that in adjacent tissues, and may play a suppressing role in NSCLC. However, the effect and mechanism of SFTA1P on the metastasis of lung adenocarcinoma (LUAD) remain undefined, which are thus investigated in this research. Herein, potential impacts of SFTA1P on LUAD were determined through the Cancer Genome Atlas (TCGA) database and Gene Expression Profiling Interactive Analysis (GEPIA). After knockdown/overexpression of SFTA1P, the metastatic ability of LUAD cells was evaluated by molecular biology experiments (cell counting kit-8 assay, scratch test, Transwell assay and Western blot). The effect of SFTA1P on Yes-associated protein (YAP) nuclear translocation was assessed by Western blot. Hypoxia-induced exosomes were extracted for LUAD metastasis analysis. The targeting relationship of SFTA1P/miR-4766-5p/large tumor suppressor kinase 1 (LATS1) was verified by dual-luciferase reporter assay and molecular biology experiments. Xenograft and lung metastasis models were constructed for in vivo validation. SFTA1P was lowly expressed in LUAD, which was associated with the poor prognosis of patients with LUAD. Up-regulated SFTA1P prevented the metastasis of LUAD cells and the nuclear translocation of YAP. Hypoxia-induced exosomes stimulated LUAD cell metastasis, but inhibited the SFTA1P and LATS1/YAP axes. MiR-4766-5p acted as an intermediate "bridge" for SFTA1P to regulate LATS1. SFTA1P repressed xenograft growth and LUAD cell metastasis. To sum up, SFTA1P activates hypoxic exosome-delivered miR-4766-5p through modulating LATS1/YAP pathway, thereby suppressing LUAD cell metastasis, which may serve as a suitable target for the LUAD therapy.

Photothermal Nanozymatic Nanoparticles Induce Ferroptosis and Apoptosis through Tumor Microenvironment Manipulation for Cancer Therapy.

It is highly desirable to design a single modality that can simultaneously trigger apoptosis and ferroptosis to efficiently eliminate tumor progression. Herein, a nanosystem based on the intrinsic properties of tumor microenvironment (TME) is designed to achieve tumor control through the simultaneous induction of ferroptosis and apoptosis. CuCP molecules are encapsulated in a liposome-based nanosystem to assemble into biocompatible and stable CuCP nanoparticles (CuCP Lipo NPs). This nanosystem intrinsically possesses nanozymatic activity and photothermal characteristics due to the property of Cu atoms and the structure of CuCP Lipo NPs. It is demonstrated that the synergistic strategy increases the intracellular lipid-reactive oxides species, induces the occurrence of ferroptosis and apoptosis, and completely eradicates the tumors in vivo. Proteomics analysis further discloses the key involved proteins (including Tp53, HMOX1, Ptgs2, Tfrc, Slc11a2, Mgst2, Sod1, and several GST family members) and pathways (including apoptosis, ferroptosis, and ROS synthesis). Conclusively, this work develops a strategy based on one nanosystem to synergistically induce ferroptosis and apoptosis in vivo for tumor suppression, which holds great potential in the clinical translation for tumor therapy.

Natural Composition and Biosynthetic Pathways of Alkaloids in Medicinal Dendrobium Species.

Dendrobium is the second biggest genus in the Orchidaceae family, some of which have both ornamental and therapeutic values. Alkaloids are a group of active chemicals found in Dendrobium plants. Dendrobine has emerged specific pharmacological and therapeutic properties. Although Dendrobium alkaloids have been isolated and identified since the 1930s, the composition of alkaloids and their biosynthesis pathways, including metabolic intermediates, alkaloid transporters, concrete genes involved in downstream pathways, and associated gene clusters, have remained unresolved scientific issues. This paper comprehensively reviews currently identified and tentative alkaloids from the aspect of biogenic pathways or metabolic genes uncovered based on the genome annotations. The biosynthesis pathways of each class of alkaloids are highlighted. Moreover, advances of the high-throughput sequencing technologies in the discovery of Dendrobium alkaloid pathways have been addressed. Applications of synthetic biology in large-scale production of alkaloids are also described. This would serve as the basis for further investigation into Dendrobium alkaloids.

Occlusal deviations in adolescents with idiopathic and congenital scoliosis.

Objective: This cross-sectional study aimed to investigate the characteristics of malocclusions in scoliotic patients through clinical examinations. Methods: Fifty-eight patients with idiopathic scoliosis (IS) and 48 patients with congenital scoliosis (CS) participated in the study. A randomly selected group of 152 orthopedically healthy children served as the control group. Standardized orthodontic and orthopedic examination protocols were used to record the occlusal patterns and type of scoliosis. Assessments were made by three experienced orthodontists and a spinal surgery team. The differences in the frequency distribution of occlusal patterns were evaluated by the chi-squared test. Results: In comparison with patients showing IS, patients with CS showed a higher incidence of Cobb angle ≥ 45° (p = 0.020) and included a higher proportion of patients receiving surgical treatments (p < 0.001). The distribution of the Angle Class II subgroup was significantly higher in the IS (p < 0.001) and CS (p = 0.031) groups than in the control group. In comparison with the healthy controls, the CS and IS groups showed significantly higher (p < 0.05) frequencies of asymmetric molar and asymmetric canine relationships, upper and lower middle line deviations, anterior deep overbite, unilateral posterior crossbite, and canted occlusal plane, with the frequencies being especially higher in CS patients and to a lesser extent in IS patients. Conclusions: Patients with scoliosis showed a high frequency of malocclusions, which were most obvious in patients with CS.

General Thermodynamic-Controlled Coating Method to Prepare Janus Mesoporous Nanomotors for Improving Tumor Penetration.

Artificial nanomotors are undergoing significant developments in several biomedical applications. However, current experimental strategies for producing nanomotors still have inherent drawbacks such as the requirement for expensive equipment, strict controlling of experimental conditions, and strenuous processes with several complex procedures. In this study, we describe for the first time a facile single-step thermodynamic-controlled coating method to prepare Janus mesoporous organosilica nanomotors. By controlling the total free energy of organosilica oligomers (G) from a low development level to a high level in the reaction system, the nonspontaneous nucleation on the platinum (Pt) nanosurface and the spontaneous nucleation in a solvent can be controlled, respectively. More importantly, we reveal that the molecular arrangement and contact angle of deposited organosilica on Pt cores vary with the total free energy of organosilica oligomers (G). Different values of θ would change the trend of detachment from Pt for organosilica nucleated cores and carry out diverse coating modes. These are indicated by the morphology evolution of platinum/organosilica hybrids, from naked platinum nanoparticles, evenly distributed organosilica shell/core, nonconcentric to typical Janus nanomotor. The prepared Janus mesoporous nanomotor (JMN) showed typical mesopore structures and active propelling behaviors under H2O2 stimulation. In addition, the JMN modified with hyaluronic acid exhibited excellent biocompatibility and improved tumor penetration under H2O2 stimulation. The successful construction of other nanomotor frameworks based on a gold-templated core proves the perfect applicability of the thermodynamic-coating method for the production of nanomotors. In conclusion, this work establishes a manufacturing methodology for nanomotors and drives nanomotors for promising biomedical applications.

The structural characteristics and influential factors of psychological stress of urban residents in Jiangxi province during the COVID-19 pandemic: cross sectional study.

AIMS: To explore the structural characteristics and influential factors of psychological stress of urban residents in Jiangxi province during the COVID-19 pandemic through a survey of psychological stress, personality traits, family function and life satisfaction. METHODS: By the convenient sampling, 1422 urban residents from Jiangxi province were assessed with Eysenck Personality Questionnaire Short Scale (EPQ-RSC), Psychological Questionnaires for Emergent Events of Public Health (PQEEPH), Family APGAR Scale (APGAR) and Satisfaction With Life Scale (SWLS). The relation among personality traits, psychological stress, family function and life satisfaction during the COVID-19 pandemic was analyzed by using the canonical correlation analysis and the serial mediation model. RESULTS: (1) Among the estimated correlation coefficients, the first two pairs were significant (P < 0.001 in each). (2) In the first pair of canonical variables, the loadings of neuroticism and neurasthenia were the higher (0.94, 0.70). (3) Neuroticism and life satisfaction mediated the relationship between family function and neurasthenia (ß neuroticism = -0.174; 95%CI:-0.224, -0.134; ß life satisfaction = -0.034, 95%CI:-0.012, -0.062), respectively. In addition, serial mediation analyses indicated that the association of family function and neurasthenia is mediated by neuroticism and life satisfaction in a sequential manner (ß = -0.010; 95%CI:-0.020, -0.004). CONCLUSIONS: During the COVID-19 pandemic, neuroticism was closely related to psychological stress of urban residents, especially neurasthenia. In addition, the serial mediating effect of neuroticism and life satisfaction played an important role in the process of family function influencing neurasthenia. These findings contributed to a more comprehensive understanding of the influential factors for psychological stress of urban residents during the COVID-19 pandemic.

Characteristics of fork-shaped fringes formed by off-axis interference of two vortex beams.

Fork-shaped fringes are formed for off-axis interference between two oblique-incident vortex beams. New formulas considering various parameters [such as the angles between two vortex beams and their topological charges (TCs)] are established to describe all kinds of fork-shaped fringes. An improved Mach-Zehnder interferometer is employed to investigate these interference fringes. Experimental measurements are consistent with numerical simulations by using our formulas. Our results broaden the understanding of the off-axis interference between two vortex beams, and can be applied to detect the TCs' sign and value of an unknown vortex beam, especially large-value TCs.

Size-shrinkable and protein kinase Cα-recognizable nanoparticles for deep tumor penetration and cellular internalization.

In the present study, the three functions, including enhanced permeability and retention (EPR) effect, deep penetration within tumor, and receptor-mediated endocytosis, were integrated into a single platform in order to improve antitumor efficiency. A novel nanoparticle (dendrigraft poly-L-lysine@glycyrrhetinic acid@cyclohexane dicarboxylic anhydride@doxorubicin@ hyaluronic acid composite) has been successfully developed and was denoted as DGL-GA-CDA-DOX-HA. The transmission electron microscope (TEM), dynamic light scattering (DLS), polymer dispersity index (PDI), fourier transform infrared spectrometer (FTIR), and zeta potentials were used to characterize the physicochemical properties of the nanoparticles. According to the results of TEM and DLS, the DGL-GA-CDA-DOX-HA nanoparticles could be rapidly degraded with a size shrink from 182.5 nm to 47.7 nm by hyaluronidase (HAase) added in the medium. The loading amount of DOX reached 252.03 ± 36.38 mg/g for DGL-GA-CDA-DOX nanoparticles. When the nanoparticles were in a medium with HAase at pH 5.0, the drug quickly released. However, when the nanoparticles were exposed to a medium without HAase at pH 5.0, or a neutral medium containing HAase, drug release slowed down. The modification of GA on nanoparticles significantly enhanced their affinity and cytotoxicity to hepatocellular carcinoma HepG2 cells. The study showed that the penetrability of DGL-GA-CDA-DOX and DGL-GA-CDA DOX-HA nanoparticles pre-degraded by HAase in vitro multicellular tumor spheroids were always better than that of DGL-GA-CDA-DOX-HA nanoparticles untreated by HAase. The imaging in vivo and ex vivo exhibited that DGL-GA-CDA-DOX-HA nanoparticles could preferentially accumulate in the tumor site. Correspondingly, the DGL-GA-CDA-DOX-HA displayed the preferable antitumor efficiency to other experimental groups in H22 tumor-bearing mice, with a tumor inhibition rate of 71.6%. In short, these results suggested that DGL-GA-CDA-DOX-HA nanoparticles could promote therapeutic effects by modulating particle size and GA receptor-mediated endocytosis.