Thermal Proteome Profiling Reveals Insight to Antiproliferative and Pro-Apoptotic Effects of Lagunamide A in the Modulation of DNA Damage Repair.

Lagunamide A is a biologically active natural product with a yet unidentified molecular mode of action. Cellular studies revealed that lagunamide A is a potent inhibitor of cancer cell proliferation, promotes apoptosis and causes mitochondrial dysfunction. To decipher the cellular mechanism responsible for these effects, we utilized thermal protein profiling (TPP) and identified EYA3 as a stabilized protein in cells upon lagunamide A treatment. EYA3, involved in the DNA damage repair process, was functionally investigated via siRNA based knockdown studies and corresponding effects of lagunamide A on DNA repair were confirmed. Furthermore, we showed that lagunamide A sensitized tumor cells to treatment with the drug doxorubicin highlighting a putative therapeutic strategy.

Measurement of Nanofiber Mechanical Flexural Modes Based on Near-Field Scattering.

We systematically investigated the intrinsic mechanical flexural modes of tapered optical fibers (TOFs) with a high aspect ratio up to 3×10^{4}. Based on the near-field scattering of the hemispherical microfiber tip to the vibrating TOF evanescent field, we detected more than 320 ordered intrinsic mechanical modes through the TOF transmission spectra which was enhanced by 72 dB compared to without near-field scattering. The trend of the vibration amplitude with the mode order was similar to pendulum waves. Our results open a pathway to study the mechanical modes of photonic microstructures-nanostructures that are expected to be used in waveguide QED, cavity optomechanical, and optical sensing.

Angiotensin-I-Converting Enzyme (ACE)-Inhibitory Peptides from the Collagens of Monkfish (Lophius litulon) Swim Bladders: Isolation, Characterization, Molecular Docking Analysis and Activity Evaluation.

The objective of this study was to isolate and characterize collagen and angiotensin-I-converting enzyme (ACE)-inhibitory (ACEi) peptides from the swim bladders of monkfish (Lophius litulon). Therefore, acid-soluble collagen (ASC-M) and pepsin-soluble collagen (PSC-M) with yields of 4.27 ± 0.22% and 9.54 ± 0.51%, respectively, were extracted from monkfish swim bladders using acid and enzyme methods. The ASC-M and PSC-M contained Gly (325.2 and 314.9 residues/1000 residues, respectively) as the major amino acid, but they had low imino acid content (192.5 and 188.6 residues/1000 residues, respectively) in comparison with collagen from calf skins (CSC) (216.6 residues/1000 residues). The sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) patterns and ultraviolet (UV) absorption spectrums of ASC-M and PSC-M illustrated that they were mainly composed of type I collagen. Subsequently, three ACEi peptides were isolated from a PSC-M hydrolysate prepared via a double-enzyme system (alcalase + neutrase) and identified as SEGPK (MHP6), FDGPY (MHP7) and SPGPW (MHP9), with molecular weights of 516.5, 597.6 and 542.6 Da, respectively. SEGPK, FDGPY and SPGPW displayed remarkable anti-ACE activity, with IC50 values of 0.63, 0.94 and 0.71 mg/mL, respectively. Additionally, a molecular docking assay demonstrated that the affinities of SEGPK, FDGPY and SPGPW with ACE were -7.3, -10.9 and -9.4 kcal/mol, respectively. The remarkable ACEi activity of SEGPK, FDGPY and SPGPW was due to their connection with the active pockets and/or sites of ACE via hydrogen bonding, hydrophobic interaction and electrostatic force. Moreover, SEGPK, FDGPY and SPGPW could protect HUVECs by controlling levels of nitric oxide (NO) and endothelin-1 (ET-1). Therefore, this work provides an effective means for the preparation of collagens and novel ACEi peptides from monkfish swim bladders, and the prepared ACEi peptides, including SEGPK, FDGPY and SPGPW, could serve as natural functional components in the development of health care products to control hypertension.

S-allyl-l-cysteine attenuates bleomycin-induced pulmonary fibrosis and inflammation via AKT/NF-κB signaling pathway in mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by inflammation, multifocal fibrotic lesions and excessive collagen deposition with limited therapies. As a major bioactive compound in garlic, S-allyl-l-cysteine (SAC) is a neuroprotective drug candidate to prevent cognitive decline, however, its anti-pulmonary fibrotic activity remains unknown. Here, we investigated whether SAC could attenuate bleomycin (BLM)-induced pulmonary fibrosis and inflammation in mice. Our results showed that SAC dose-dependently reduced the infiltration of inflammatory cells, pulmonary lesions and collagen deposition in BLM treated mice with downregulated mRNA expression levels of fibrotic genes including alpha smooth muscle actin (α-SMA), fibronectin, collagen I and collagen III as well as the protein level of α-SMA. In addition, SAC could also reduce the mRNA expression of inflammatory mediators such as TNF-α and iNOS. Furthermore, higher phosphorylation of AKT and NF-κB p65 in IPF patient samples and murine samples was verified by immunohistochemistry while SAC could decrease the phosphorylation level of AKT and NF-κB p65 in mice stimulated with BLM. These findings, for the first time, indicate that SAC might mediate AKT/NF-κB signaling pathway to inhibit BLM-induced pulmonary fibrosis and support the potential role of SAC as an anti-pulmonary fibrosis agent.

AKT2 Regulates Pulmonary Inflammation and Fibrosis via Modulating Macrophage Activation.

Idiopathic pulmonary fibrosis (IPF) is a highly lethal pathological process that is characterized by inflammation, fibroblast accumulation, and excessive collagen deposition. Although AKT2-mediated signaling pathways modulate inflammatory responses, their role in IPF has not been defined. We report that AKT2 deficiency (Akt2-/-) protected against bleomycin-induced pulmonary fibrosis and inflammation. Adoptive transfer of wild-type macrophages or administration of IL-13 to Akt2-/- mice could restore pulmonary fibrosis. In response to IL-33 treatment, Akt2-/- macrophages displayed decreased production of IL-13 and TGF-ß1 and attenuated phosphorylation of FoxO3a compared with Akt2+/+ macrophages. Furthermore, the expression of IL-13 was increased by small interfering RNA knockdown of FoxO3a or in FoxO3a-deficient macrophages. By evaluating lung sections from pulmonary fibrosis patients, we found that the phosphorylation of AKT2 and FoxO3a was remarkably upregulated. Collectively, these results indicate that AKT2 modulates pulmonary fibrosis through inducing TGF-ß1 and IL-13 production by macrophages, and inhibition of AKT2 may be a potential strategy for treating IPF.

Isoalantolactone suppresses LPS-induced inflammation by inhibiting TRAF6 ubiquitination and alleviates acute lung injury.

Isoalantolactone (IAL) is a sesquiterpene lactone extracted from roots of Inula helenium L and has shown anti-inflammatory effects. In this study we investigated the therapeutic effects of IAL on acute lung injury (ALI) and elucidated the mechanisms underlying its anti-inflammation potential in vitro and in vivo. Treatment with lipopolysaccharide (LPS, 100 ng/mL) drastically stimulated production of inflammatory mediators such as NO, TNF-α, IL-1ß, and IL-6 in mouse bone marrow-derived macrophages (BMDMs), which was dose-dependently suppressed by pretreatment with IAL (2.5, 5, 10, 20 µM). We further revealed that IAL suppressed LPS-induced NF-κB, ERK, and Akt activation. Moreover, the downregulation of non-degradable K63-linked polyubiquitination of TRAF6, an upstream transcription factor of NF-κB, contributed to the anti-inflammatory effects of IAL. ALI was induced in mice by intratracheal injection of LPS (5 mg/kg). Administration of IAL (20 mg/kg, i.p.) significantly suppressed pulmonary pathological changes, neutrophil infiltration, pulmonary permeability, and pro-inflammatory cytokine expression. Our results demonstrate that IAL is a potential therapeutic reagent against inflammation and ALI.

Ginkgo biloba Extract Protects Mesenteric Arterioles of Old Rats via Improving Vessel Elasticity through Akt/FoxO3a Signaling Pathway.

BACKGROUND: Previous studies have shown that Ginkgo biloba extract (GBE) dietary diminished salt-related elevation of blood pressure and ameliorated ischemic diseases. However, whether GBE could improve vascular elasticity to protect mesenteric arterioles of old rats is still elusive. In this study, we aimed to investigate the effects of GBE on vascular elasticity of old rats and its possible underlying mechanism. METHODS: Morphological changes of mesenteric arterioles were observed using hematoxylin and eosin and Verhoeff-Van Gieson staining, and diameters of mesenteric arterioles under various pressure were detected after GBE administration. In addition, phosphorylation level of Akt and FoxO3a proteins from mesenteric arterioles were detected. RESULTS: The results implicated that GBE treatment narrowed endothelial cell gap and increased the curvature of inner elastic membrane with reduced middle layer collagen fiber. Meanwhile, compared with young rats, old rats appeared to have lower vascular elasticity while GBE treatment at 50, 100, and 200 mg/kg dosage through intragastric administration per day for 3 weeks could effectively improve the vascular elasticity under different pressures in a dose-dependent manner. Furthermore, phosphorylation level of Akt and FoxO3a was also reduced in GBE-treated rats. CONCLUSIONS: This is the first report to indicate that GBE might exert protective effect on mesenteric arterioles of old rats via improving vascular elasticity and Akt/FoxO3a signaling pathway might be involved in this action.

Gramicidin inhibits human gastric cancer cell proliferation, cell cycle and induced apoptosis.

BACKGROUND: Gastric cancer is a common malignant tumor with high morbidity and mortality worldwide, which seriously affects human health. Gramicidin is a short peptide antibiotic which could be used for treating infection induced by bacteria or fungi. However, the anti-cancer effect of gramicidin on gastric cancer cells and its underlying mechanism remains largely unknown. RESULTS: Gastric cancer cells SGC-7901, BGC-823 and normal gastric mucosal cells GES-1 were treated with different concentrations of gramicidin respectively. The results of CCK-8 experiment revealed cellular toxicity of gramicidin to cancer cells while cell colony formation assay showed that gramicidin significantly inhibited the proliferation of gastric cancer cells, but had little effect on normal gastric mucosal cells. In addition, the wound healing assay showed that gramicidin inhibited the migration of SGC-7901 cell. Meanwhile, apoptosis and cell cycle analysis revealed that gramicidin induced cell apoptosis with G2/M cell cycle inhibition. Furthermore, western blot analysis demonstrated that gramicidin down-regulated the expression of cyclinD1 and Bcl-2 as well as the FoxO1 phosphorylation. CONCLUSIONS: The current study illustrated the anti-tumor activity of gramicidin on gastric cancer cells, providing a possibility for gramicidin to be applied in clinical practice for the treatment of gastric cancer.

The pomegranate (Punica granatum L.) genome and the genomics of punicalagin biosynthesis.

Pomegranate (Punica granatum L.) is a perennial fruit crop grown since ancient times that has been planted worldwide and is known for its functional metabolites, particularly punicalagins. We have sequenced and assembled the pomegranate genome with 328 Mb anchored into nine pseudo-chromosomes and annotated 29 229 gene models. A Myrtales lineage-specific whole-genome duplication event was detected that occurred in the common ancestor before the divergence of pomegranate and Eucalyptus. Repetitive sequences accounted for 46.1% of the assembled genome. We found that the integument development gene INNER NO OUTER (INO) was under positive selection and potentially contributed to the development of the fleshy outer layer of the seed coat, an edible part of pomegranate fruit. The genes encoding the enzymes for synthesis and degradation of lignin, hemicelluloses and cellulose were also differentially expressed between soft- and hard-seeded varieties, reflecting differences in their accumulation in cultivars differing in seed hardness. Candidate genes for punicalagin biosynthesis were identified and their expression patterns indicated that gallic acid synthesis in tissues could follow different biochemical pathways. The genome sequence of pomegranate provides a valuable resource for the dissection of many biological and biochemical traits and also provides important insights for the acceleration of breeding. Elucidation of the biochemical pathway(s) involved in punicalagin biosynthesis could assist breeding efforts to increase production of this bioactive compound.

CMPD1 inhibited human gastric cancer cell proliferation by inducing apoptosis and G2/M cell cycle arrest.

BACKGROUND: Gastric cancer occupies the fourth highest morbidity rate of cancers worldwide. Clinical therapies of gastric cancer remain limited because of uncertainty of mechanisms and shortness of effective medicine. Thus, new drug candidates for gastric cancer treatment is urgently needed. RESULTS: In this study, CMPD1 as a wildly used MK2 phosphorylation inhibitor was employed to find its impact on gastric cancer cell proliferation, apoptosis and cell cycle using colony formation assay and flow cytometry analysis. Along with its anti-proliferation effect on gastric cancer cell line MKN-45 and SGC7901, CMPD1 also induced massive apoptosis and significant G2/M phase arrest in a time-dependent and dose-dependent manner in MKN-45 cells respectively. Furthermore, Western blot confirmed that the expression of anti-apoptotic proteins Bcl-2 was decreased while BAX, cytochrome c release and cleaved PARP were increased. In addition, oncogene c-Myc was downregulated in response to CMPD1 treatment. CONCLUSIONS: Our results demonstrated that CMPD1 has anti-tumor effect on human gastric cancer cell line MKN-45 possibly via downregulating oncogene c-Myc expression and CMPD1 could be applied as a potential candidate for treating gastric malignancy. To the best of our knowledge, it is the first report of anti-tumor effect of CMPD-1 on human gastric cancer cells.

Delivery of fluorescent-labeled cyclodextrin by liposomes: role of transferrin modification and phosphatidylcholine composition.

Drug-in-CD-in-liposome (DCL) systems which encapsulate the drug/CD inclusion complexes into inner aqueous phase of liposomes have been applied as a novel strategy to improve efficacy of lipophilic antitumor drugs. The aim of this work was to assess the role of transferrin (Tf) modification and phosphatidylcholine (PC) composition on the properties of liposomes containing hydroxypropyl-ß-cyclodextrin (HP-ß-CD). Fluorescence dye, FITC, was conjugated with HP-ß-CD to facilitate the analysis. The resulting FITC-HP-ß-CD was further encapsulated into liposomes and then the liposomes were modified with Tf. The FITC-HP-ß-CD-loaded liposomes with different PC compositions were compared in terms of particle size, zeta potential, FITC content, FITC-HP-ß-CD leakage, phase transition temperature (Tm) and cellular uptake. The apparent partition coefficient values of different PCs were also determined. Compared to PEGylated liposomes, FITC-HP-ß-CD-loaded liposomes modified with Tf had been proved to significantly increase vesicle stability and specific cellular uptake. Moreover, PC composition affected the properties of liposomes. Soybean phosphatidylcholine (SPC) liposomes modified with Tf were found to be more easily internalized into tumor cells than 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) and hydrogenated soybean phosphatidylcholine (HSPC) while Tf density on the liposomal surface was similar. And the lipophilicity of SPC was found to be much higher than DPPC and HSPC. Collectively, by the optimization of PC composition, the development of DCL modified with Tf might represent a potential strategy for the antitumor application of lipophilic drugs.

Enhanced production of L-sorbose in an industrial Gluconobacter oxydans strain by identification of a strong promoter based on proteomics analysis.

Gluconobacter oxydans is capable of rapidly incomplete oxidation of many sugars and alcohols, which means the strain has great potential for industrial purposes. Strong promoters are one of the essential factors that can improve strain performance by overexpression of specific genes. In this study, a pipeline for screening strong promoters by proteomics analysis was established. Based on the procedure, a new strong promoter designated as P B932_2000 was identified in G. oxydans WSH-003. The promoter region was characterized based on known genome sequence information using BPROM. The strength of P B932_2000 was further assessed by analysis of enhanced green fluorescent protein (egfp) expression and comparison with egfp expression by two commonly used strong promoters, P E. coli_tufB and P G. oxydans_tufB . Both quantitative real-time PCR and fluorescence intensities for egfp gene expression showed that P B932_2000 promoter is stronger than the other two. Overexpression of D-sorbitol dehydrogenase (sldh) by P B932_2000 in G. oxydans WSH-003 enhanced the titer and productivity of L-sorbose synthesis from D-sorbitol by 12.0 % and 33.3 %, respectively. These results showed that proteomics analysis is an efficient way to identify strong promoters. The isolated promoter P B932_2000 could further facilitate the metabolic engineering of G. oxydans.

Stepwise metabolic engineering of Gluconobacter oxydans WSH-003 for the direct production of 2-keto-L-gulonic acid from D-sorbitol.

2-Keto-L-gulonic acid (2-KLG), the direct precursor of vitamin C, is currently produced by a two-step fermentation route from D-sorbitol. However, this route involves three bacteria, making the mix-culture system complicated and redundant. Thus, replacement of the conventional two-step fermentation process with a one-step process could be revolutionary in vitamin C industry. In this study, different combinations of five L-sorbose dehydrogenases (SDH) and two L-sorbosone dehydrogenases (SNDH) from Ketogulonicigenium vulgare WSH-001 were introduced into Gluconobacter oxydans WSH-003, an industrial strain used for the conversion of d-sorbitol to L-sorbose. The optimum combination produced 4.9g/L of 2-KLG. In addition, 10 different linker peptides were used for the fusion expression of SDH and SNDH in G. oxydans. The best recombinant strain (G. oxydans/pGUC-k0203-GS-k0095) produced 32.4g/L of 2-KLG after 168h. Furthermore, biosynthesis of pyrroloquinoline quinine (PQQ), a cofactor of those dehydrogenases, was enhanced to improve 2-KLG production. With the stepwise metabolic engineering of G. oxydans, the final 2-KLG production was improved to 39.2g/L, which was 8.0-fold higher than that obtained using independent expression of the dehydrogenases. These results bring us closer to the final one-step industrial-scale production of vitamin C.

Circadian syndrome is associated with the development of chronic kidney disease and rapid decline in kidney function in middle-aged and elder adults: a China nationwide cohort study.

PURPOSE: The correlation between circadian syndrome (CircS) and kidney outcomes is currently supported by limited empirical evidence. Thus, the objective of this study was to determine the potential relationship between CircS and the development of chronic kidney disease (CKD), as well as the rapid decline in renal function. MATERIALS AND METHODS: We utilized data from the 2011 China Health and Retirement Longitudinal Study (CHARLS), which involved 6002 Chinese adults ≥40 years of age. Among these participants, 3670 subsequently had follow-up evaluations in the 2015 survey. The primary outcome was the development of CKD, as defined by an estimated glomerular filtration rates decrease to a level <60 ml/min/1.73 m2, while the secondary outcome was rapid decline in renal function, as defined by an estimated glomerular filtration rates decrease of >5 ml/min/1.73 m2 per year. Multivariable logistic regression analysis was utilized to determine the association between CircS and kidney outcomes. RESULTS: Compared to participants without CircS, those with CircS had a higher risk of CKD in the cross-sectional studies conducted in 2011 (OR, 1.292; 95% CI, 1.053-1.585) and 2015 (OR, 1.860; 95% CI, 1.469-2.355). Participants with CircS in the longitudinal cohort study had a higher risk of progressing to CKD (OR, 3.050; 95% CI, 2.052-4.534) and a rapid decline in renal function (OR, 1.959; 95% CI, 1.433-2.677) after 4 years of follow-up evaluations and adjustment for covariates. Moreover, participants who had CircS with ≥6 CirS components had the highest risk of a rapid decline in renal function (OR, 1.703; 95% CI, 1.054-2.753). CONCLUSION: CirS significantly increased the risk of CKD progression and rapid decline in renal function among middle-aged and elder individuals. Our study findings highlights the importance of recognizing and managing CirC as a preventative strategy for CKD.

Neocarzilin Inhibits Cancer Cell Proliferation via BST-2 Degradation, Resulting in Lipid Raft-Trapped EGFR.

Neocarzilin (NCA) is a natural product exhibiting potent antimigratory as well as antiproliferative effects. While vesicle amine transport protein 1 (VAT-1) was previously shown to inhibit migration upon NCA binding, the molecular mechanisms responsible for impaired proliferation remained elusive. We here introduce a chemical probe closely resembling the structural and stereochemical features of NCA and unravel bone marrow stromal antigen 2 (BST-2) as one of the targets responsible for the antiproliferative effect of NCA in cancer cells. The antiproliferative mechanism of NCA was confirmed in corresponding BST-2 knockout (KO) HeLa cells, which were less sensitive to compound treatment. Vice versa, reconstitution of BST-2 in the KO cells again reduced proliferation upon NCA addition, comparable to that of wild-type (wt) HeLa cells. Whole proteome mass spectrometric (MS) analysis of NCA-treated wt and KO cancer cells revealed regulated pathways and showed reduced levels of BST-2 upon NCA treatment. In-depth analysis of BST-2 levels in response to proteasome and lysosome inhibitors unraveled a lysosomal degradation path upon NCA treatment. As BST-2 mediates the release of epidermal growth factor receptor (EGFR) from lipid rafts to turn on proliferation signaling pathways, reduced BST-2 levels led to attenuated phosphorylation of STAT3. Furthermore, fluorescence microscopy confirmed increased colocalization of EGFR and lipid rafts in the presence of NCA. Overall, NCA represents a versatile anticancer natural product with a unique dual mode of action and unconventional inhibition of proliferation via BST-2 degradation.

Isolated Proteinuria Caused by CUBN Gene Mutations: A Case Report and Review of the Literature.

Mutations in the cubilin (CUBN) gene commonly cause Imerslund-Gräsbeck syndrome, while isolated proteinuria as a result of CUBN variations is rarely reported. The clinical manifestation is mainly chronic isolated proteinuria in the non-nephrotic range. However, findings to date suggest that isolated proteinuria associated with abnormalities in the CUBN gene is benign and does not affect long-term prognosis of kidney function. We identified 2 patients with isolated proteinuria triggered by compound heterozygous CUBN mutations. Renal functions of both patients remained normal over a 10-year follow-up period, supporting the benign nature of proteinuria caused by CUBN gene variations. Two novel mutation sites were detected, expanding the genotypic spectrum of CUBN variations. In addition, etiology, pathogenesis, clinical manifestations, auxiliary examination, and treatment of the condition were reviewed, with the aim of providing further guidance for clinical management.

Cellular and Humoral Responses to Recombinant and Inactivated SARS-CoV-2 Vaccines in CKD Patients: An Observational Study.

BACKGROUND: It remains unclear what B cell and humoral responses are mounted by chronic kidney disease (CKD) patients in response to recombinant and inactivated SARS-CoV-2 vaccines. In this study, we aimed to explore the cellular and humoral responses, and the safety of recombinant and inactivated SARS-CoV-2 vaccines in CKD patients. METHODS: 79 CKD and 420 non-CKD individuals, who completed a full course of vaccination, were enrolled in the study. Adverse events (AEs) were collected via a questionnaire. Cellular and humoral responses were detected at 1, 3, and 6 months, including IgG antibody against the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (anti-RBD-IgG), neutralizing antibodies (NAbs), the positive rate of NAbs and anti-RBD-IgG, RBD-atypical memory B cells (MBCs) (CD3 - CD19 + RBD + CD21 - CD27-), RBD-activated MBCs (CD3 - CD19 + RBD + CD21 - CD27+), RBD-resting MBCs (CD3 - CD19 + RBD + CD21 + CD27+), and RBD-intermediate MBCs (CD3 - CD19 + RBD + CD21 + CD27-). RESULTS: We found no differences in the positivity rates of NAbs (70.89% vs. 79.49%, p = 0.212) and anti-RBD IgG (72.15% vs. 83.33%, p = 0.092) between the CKD and control groups. A total of 22 CKD individuals completed the full follow-up (1, 3, and 6 months). Significant and sustained declines were found at 3 months in anti-RBD IgG (26.64 BAU/mL vs. 9.08 BAU/mL, p < 0.001) and NAbs (161.60 IU/mL vs. 68.45 IU/mL p < 0.001), and at 6 months in anti-RBD IgG (9.08 BAU/mL vs. 5.40 BAU/mL, p = 0.064) and NAbs (68.45 IU/mL vs. 51.03 IU/mL, p = 0.001). Significant differences were identified in MBC subgroups between CKD patients and healthy controls, including RBD-specific atypical MBCs (60.5% vs. 17.9%, p < 0.001), RBD-specific activated MBCs (36.3% vs. 14.8%, p < 0.001), RBD-specific intermediate MBCs (1.24% vs. 42.6%, p < 0.001), and resting MBCs (1.34% vs. 22.4%, p < 0.001). Most AEs in CKD patients were mild (grade 1 and 2) and self-limiting. One patient with CKD presented with a recurrence of nephrotic syndrome after vaccination. CONCLUSIONS: The recombinant and inactivated SARS-CoV-2 vaccine was well-tolerated and showed a good response in the CKD cohort. Our study also revealed differences in MBC subtypes after SARS-CoV-2 vaccination between CKD patients and healthy controls.

Investigation of Adhesion Performance of Wax Based Warm Mix Asphalt with Molecular Dynamics Simulation.

Compared with traditional hot mix asphalt (HMA), wax based warm mix asphalt (WWMA) can be mixed with the aggregate at a lower temperature and achieve the desired compaction. However, the adhesion performance of WWMA on aggregate is uncertain. To evaluate the adhesion performance of asphalt and aggregate, researchers used contact angle test, pull-off test, and ultrasonic washing experiments. However, these tests cannot adequately explain the microscopic mechanism of the interface between asphalt and aggregate. Molecular dynamics (MD) can better explain the adhesion mechanism of asphalt aggregates because they can be simulated at the molecular scale. So, the purpose of this research is to use the MD method to study the adhesion performance between WWMA and aggregate. Two aggregate oxides (CaCO3 and SiO2) models, the matrix asphalt model and WWMA models, were built in Materials Studio (MS) software. The adhesion work of asphalt and aggregate oxides was calculated. With the increase of wax modifier content, the adhesion work of asphalt and aggregate oxides (CaCO3 and SiO2) first increases and then decreases. When the wax modifier is increased to 3 wt%, the adhesion works of the WWMA-SiO2 and WWMA-CaCO3 increase by 31.2% and 14.0%, compared with that of matrix asphalt. In this study, the accuracy of the MD calculation result was verified by the pull-off experiments and the contact angle experiments. WWMA was prepared by a high-shear mixer emulsifier. In the pull-off experiments and the contact angle experiments, the tensile strength and the adhesion work between the aggregate and the asphalt containing 3% wax modifier reaches peak values. These values are 140.7% and 124.9%, compared with those between the aggregate and the matrix asphalt. In addition, the results of the pull-off experiments and the contact angle experiments are in good agreement with that of the MD simulation. Finally, Fourier transform infrared spectroscopy (FTIR) shows that the carbonyl content of WWMA is greater than that of matrix asphalt. It explains well that the wax modifier promotes the adhesion between asphalt and aggregate. This paper provides an important theoretical basis to understand the adhesion performance of WWMA and aggregate.

Schisantherin A induces cell apoptosis through ROS/JNK signaling pathway in human gastric cancer cells.

Gastric cancer is one of the most lethal cancers with unmet clinical treatment and low 5-year survival rate. Schisantherin A is a major compound derived from Fructusschisandrae while its anti-tumor role remains nearly unknown. Here, we reported that schisantherin A had an anti-proliferation effect on gastric cancer cell lines MKN45 and SGC-7901. Schisantherin A induced cell cycle arrest at G2/M phase and cell apoptosis, and inhibited cell migration in gastric cancer MKN45 and SGC7901 cells. Meanwhile, upregulation of cleaved caspase-9, cleaved caspase-3 and cleaved PARP were accompanied with the loss of mitochondrial membrane potential (MMP). Moreover, schisantherin A induced ROS-dependent JNK phosphorylation with higher ROS production. The JNK inhibitor and ROS scavenger NAC rescued the cell apoptosis and cycle inhibition elicited by schisantherin A. Furthermore, the expression level of antioxidant factor Nrf2 was suppressed by schisantherin A. These findings suggest that schisantherin A possesses an anti-tumor activity via activation of ROS/JNK with Nrf2 inhibition, indicating that schisantherin A is a promising chemotherapeutic candidate for gastric cancer.

No Evidence of Re-infection or Person-to-Person Transmission in Cured COVID-19 Patients in Guangzhou, a Retrospective Observational Study.

Objectives: To clarify the clinical characteristics of cured patients with coronavirus disease (COVID-19), and to clarify the re-infection and person-to-person transmission in the cured. Methods: A total of 187 cured COVID-19 patients with antibody test were followed up every 2 weeks in this retrospective observational study. Assessment for general condition, symptoms, epidemiological contact history, polymerase chain reaction (PCR) assay, and antibody tests were performed and recorded. Information from Guangzhou CDC was also screened. Results: There were 33 (17.6%) patients with negative results for IgG and 35 (18.7%) patients with positive results for IgM. The average days of antibody detection from disease onset were 53.0. PCR assay was positive in 10 (5.3%) patients during the follow-up. Neither IgG nor IgM results showed a relationship with PCR test results (all P > 0.05). Neither re-infection nor person-to-person transmission was found in the cured patients. Factors associated with appearance of antibody comprised hospitalization days (OR: 1.06, 95%CI: 1.02-1.11, P = 0.006) and antibiotics treatment (OR: 3.50, 95%CI: 1.40-8.77, P = 0.007). Conclusions: In our study, no evidence of person-to-person transmission was found in cured COVID-19 patients. There seemed to be no re-infection in the cured COVID-19 patients in Guangzhou. These finding suggest that the cured do not cause the spread of disease. Additionally, neither IgG nor IgM can be used to replace the PCR test in cured patients.