COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, ...we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor-locker mechanism. The higher binding free energy in State d of the RBD
.
-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBD
, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBD
-ACE2 binding in the last step of recognition. For RBD
.
, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.
Abstract
Background
The chimeric antigen receptor (CAR)-T therapy has a limited therapeutic effect on solid tumors owing to the limited CAR-T cell infiltration into solid tumors and the inactivation ...of CAR-T cells by the immunosuppressive tumor microenvironment. Macrophage is an important component of the innate and adaptive immunity, and its unique phagocytic function has been explored to construct CAR macrophages (CAR-Ms) against solid tumors. This study aimed to investigate the therapeutic application of CAR-Ms in ovarian cancer.
Methods
In this study, we constructed novel CAR structures, which consisted of humanized anti-HER2 or CD47 scFv, CD8 hinge region and transmembrane domains, as well as the 4-1BB and CD3ζ intracellular domains. We examined the phagocytosis of HER2 CAR-M and CD47 CAR-M on ovarian cancer cells and the promotion of adaptive immunity. Two syngeneic tumor models were used to estimate the in vivo antitumor activity of HER2 CAR-M and CD47 CAR-M.
Results
We constructed CAR-Ms targeting HER2 and CD47 and verified their phagocytic ability to ovarian cancer cells in vivo and in vitro. The constructed CAR-Ms showed antigen-specific phagocytosis of ovarian cancer cells in vitro and could activate CD8
+
cytotoxic T lymphocyte (CTL) to secrete various anti-tumor factors. For the in vivo model, mice with human-like immune systems were used. We found that CAR-Ms enhanced CD8
+
T cell activation, affected tumor-associated macrophage (TAM) phenotype, and led to tumor regression.
Conclusions
We demonstrated the inhibition effect of our constructed novel HER2 CAR-M and CD47 CAR-M on target antigen-positive ovarian cancer in vitro and in vivo, and preliminarily verified that this inhibitory effect is due to phagocytosis, promotion of adaptive immunity and effect on tumor microenvironment.
FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, thereby promoting aerobic glycolysis. Further, FOXM1D interacts with PKM2 and NF‐κB and induces their nuclear translocation via importin ...4. The nuclear PKM2 and NF‐κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis.
Tumor growth, especially in the late stage, requires adequate nutrients and rich vasculature, in which PKM2 plays a convergent role. It has been reported that PKM2, together with FOXM1D, is upregulated in late‐stage colorectal cancer and associated with metastasis; however, their underlying mechanism for promoting tumor progression remains elusive. Herein, we revealed that FOXM1D potentiates PKM2‐mediated glycolysis and angiogenesis through multiple protein–protein interactions. In the presence of FBP, FOXM1D binds to tetrameric PKM2 and assembles a heterooctamer, restraining PKM2 metabolic activity by about a half and thereby promoting aerobic glycolysis. Furthermore, FOXM1D interacts with PKM2 and NF‐κB and induces their nuclear translocation with the assistance of the nuclear transporter importin 4. Once in the nucleus, PKM2 and NF‐κB complexes subsequently augment VEGFA transcription. The increased VEGFA is secreted extracellularly via exosomes, an event potentiated by the interaction of FOXM1 with VPS11, eventually promoting tumor angiogenesis. Based on these findings, our study provides another insight into the role of PKM2 in the regulation of glycolysis and angiogenesis.
This study evaluated the biocontrol effect of isolated epiphytic yeasts (
, and
) against
and
in blueberry fruits and its possible mechanisms. Our findings indicated that the three tested yeasts ...exerted a good biocontrol effect on postharvest diseases in blueberry, and that
was the most effective. In addition, the three tested yeasts could improve the postharvest storage quality of blueberry fruits to some extent.
demonstrated the strongest direct inhibitory effect on pathogens by suppressing spore germination, mycelial growth, and antifungal volatile organic compound (VOC) production.
showed the highest extracellular lytic enzymes activities. It also had better adaptation to low temperature in fruit wounds at 4 °C. The biofilm formation capacity was suggested to be the main action mechanism of
, which rapidly colonized fruit wounds at 20 °C. Several action mechanisms are employed by the superb biocontrol yeasts, while yeast strains possess distinctive characteristics and have substantially different action mechanisms.
Abstract
Background
Benevolent leadership is common in organizations, including hospitals, and is known to have positive effects on employees. Yet, nursing literature lacks sufficient research on its ...relationships with nurses’ behavior.
Methods
In March to April 2022, a cross-sectional study was carried out involving 320 nurses employed across various hospitals in Sichuan Province, China. Benevolent leadership, affective commitment, work engagement, and helping behavior were evaluated using the Benevolent Leadership Scale, Affective Commitment Scale, Work Engagement Scale, and Helping Behavior Questionnaire, respectively. The study employed structural equation model and the bootstrap method to investigate the proposed relationships.
Results
The SEM analysis results indicated a positive association between benevolent leadership and several outcomes among nurses. Specifically, benevolent leadership was found to be positively associated with nurses’ affective commitment (
β =
0.58,
p
< .001), work engagement (
β
= 0.02,
p
< .001), and helping behavior (
β
= 0.17,
p
= .001). Additionally, there was a significant indirect effect between benevolent leadership and nurses’ work engagement through affective commitment (
β =
0.08,
p =
.007) as well as between benevolent leadership and helping behavior through affective commitment (
β =
0.16,
p
< .001).
Conclusions
This study’s findings emphasize the crucial role of benevolent leadership in fostering nurses’ positive attitudes and behaviors in the workplace. Hospital administrators could promote the benevolent leadership of head nurses to enhance nurses’ affective commitment, work engagement, and helping behaviors.
Background Artesunate (ART) has been reported to have an antifibrotic effect in various organs. The underlying mechanism has not been systematically elucidated. We aimed to clarify the effect of ART ...on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in an experimentally infected rodent model and the potential underlying mechanisms. Methods The effect of ART on hepatic stellate cells (HSCs) was assessed using CCK-8 and Annexin V-FITC/PI staining assays. The experimental model of liver fibrosis was established in the Mongolian gerbil model infected with S. japonicum cercariae and then treated with 20 mg/kg or 40 mg/kg ART. The hydroxyproline (Hyp) content, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in liver tissue were measured and histopathological changes of liver tissues were observed. Whole-transcriptome RNA sequencing (RNA-seq) of the liver tissues was performed. Differentially expressed genes (DEGs) were identified using bioinformatic analysis and verified by quantitative PCR (qPCR) and western blot assay. Results ART significantly inhibited the proliferation and induce the apoptosis of HSCs in a dose-dependent manner. In vivo, Hyp content decreased significantly in the ART-H group compared to the model (MOD) group and GPX activity was significantly higher in the ART-H group than in the MOD group. Besides, ART treatment significantly reduced collagen production (p <0.05). A total of 158 DEGs and 44 differentially expressed miRNAs related to ART-induced anti-schistosomiasis liver fibrosis were identified. The qPCR and western blot results of selected DEGs were consistent with the sequencing results. These DEGs were implicated in key pathways such as immune and inflammatory response, integrin-mediated signaling and toll-like receptor signaling pathways. Conclusion ART is effective against liver fibrosis using Mongolian gerbil model induced by S. japonicum infection. We identified host candidate regulators of schistosomiasis-induced liver fibrosis in response to ART through transcriptomics approach.
Bromate, a possible human carcinogen, can be reduced to innocuous bromide by microorganisms. To characterize bromate reducers, microbes were enriched anaerobically from activated sludge by using ...bromate as the sole electron acceptor and different carbon sources as the electron donor. Bacteria that showed significant bromate-reducing activity but not coupled to cell growth were isolated. Two whole genomes of the isolates, namely,
Lac1 and
Glu3, were reconstructed by Illumina and Nanopore sequencing. Transcriptomic analysis suggested that neither the respiratory nitrate reductase, the selenate reductase, nor the dimethylsulfoxide reductase was involved in the bromate reduction process, and strain
Glu3 reduced bromate
a yet undiscovered enzymatic mechanism. The results provide novel phylogenetic insights into bromate-reducing microorganisms and clues in putative genes encoding enzymes related to bromate reduction.
In addition to the classical role as a serum effector system of innate immunity, accumulating evidence suggests that intracellular complement components have indispensable functions in immune ...defense, T cell homeostasis, and tumor cell proliferation and metastasis. Here, we revealed that complement component 3 (C3) is remarkably upregulated in paclitaxel (PTX)-resistant non-small cell lung cancer (NSCLC) cells and that knockdown of C3 promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy. Ectopic C3 decreased PTX-induced apoptosis and induced resistance to PTX treatment in original NSCLC cells. Interestingly, C3b, the activated fragment of C3, was found to translocate into the nucleus and physically associate with the HDAC1/2-containing SIN3A complex to repress the expression of GADD45A, which plays an important role in cell growth inhibition and apoptosis induction. Importantly, C3 downregulated GADD45A by enhancing the binding of the SIN3A complex with the promoter of GADD45A, thus decreasing the H3Ac level to compress chromatin around the GADD45A locus. Subsequently, ectopic GADD45A promoted PTX-induced cell apoptosis, sensitizing resistant cells to PTX therapy, and insufficiency of GADD45A in original cancer cells induced resistance to PTX treatment. These findings identify a previously unknown nucleus location and oncogenic property for C3 in chemotherapy and provide a potential therapeutic opportunity to overcome PTX resistance.
The flow field structure of a rotorcraft is complex; specifically, the rotor tip vortex structure has a great influence on the rotor performance. Therefore, in this paper, the evolution ...characteristics of rotor tip vortices and the dynamic mode decomposition (DMD) of rotor tip vortices in a rotor hovering state are studied. Through a time-resolved particle image velocimetry experiment, a comparative study of the blade tip vortex flow field at a fixed rotation speed (1500 rpm) and a collective pitch of 6° and 9° was performed. The method of DMD is used for the reduced-order analysis of the vorticity field of the blade tip vortex in the hovering state. By this method, these important vortex structures are extracted and discussed; meanwhile, the future flow field is also reconstructed. The results of flow visualization indicate that the trajectory of the blade tip vortex is moving down the axis, while moving toward the hub in the radial direction in the hovering state. The results of DMD analysis show that during the evolution of the blade tip vortex, different modes have different contributions to the rotor as a whole. In addition, the larger the collective pitch, the larger the modal coefficient amplitude and the slower the stabilization speed.
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