Nanomechanical collective vibration of SARS-CoV-2 spike proteins.

The development of effective therapeutics against COVID-19 requires a thorough understanding of the receptor recognition mechanism of the SARS-CoV-2 spike (S) protein. Here the multidomain collective dynamics on the trimer of the spike protein has been analyzed using normal mode analysis (NMA). A common nanomechanical profile was identified in the spike proteins of SARS-CoV-2 and its variants. The profile involves collective vibrations of the receptor-binding domain (RBD) and the N-terminal domain (NTD), which may mediate the physical interaction process. Quantitative analysis of the collective modes suggests a nanomechanical property involving large-scale conformational changes, which explains the difference in receptor binding affinity among different variants. These results support the use of intrinsic global dynamics as a valuable perspective for studying the allosteric and functional mechanisms of the S protein. This approach also provides a low-cost theoretical toolkit for screening potential pathogenic mutations and drug targets.

Comparative analysis of biofilm characterization of probiotic Escherichia coli.

Biofilms are thought to play a vital role in the beneficial effects of probiotic bacteria. However, the structure and function of probiotic biofilms are poorly understood. In this work, biofilms of Escherichia coli (E. coli) Nissle 1917 were investigated and compared with those of pathogenic and opportunistic strains (E. coli MG1655, O157:H7) using crystal violet assay, confocal laser scanning microscopy, scanning electron microscopy and FTIR microspectroscopy. The study revealed significant differences in the morphological structure, chemical composition, and spatial heterogeneity of the biofilm formed by the probiotic E. coli strain. In particular, the probiotic biofilm can secrete unique phospholipid components into the extracellular matrix. These findings provide new information on the morphology, architecture and chemical heterogeneity of probiotic biofilms. This information may help us to understand the beneficial effects of probiotics for various applications.

Protopanaxadiol Targeting Membrane Induces HepG2 Cell Apoptosis Via Raft-like Formation and Tubulation Disruption.

Protopanaxadiol (PPD), which has a molecular structure similar to cholesterol, is a potent anticancer agent that has been proposed to target the lipid membrane for the pharmacological effects. However, the underlying mechanism by which PPD modulates the cell membrane leading to cancer cell death is not be fully understood. In this work, we used single cell infrared spectroscopy, scanning electron microscopy and confocal microscopy to investigate the effects of PPD on human hepatocellular carcinoma (HepG2) cells, focusing on the change in membrane structure. We found that PPD significantly reduced the number of membrane tubules over the course of treatment. Interestingly, the addition of PPD could promote the formation of lipid raft-like domains (PPD rafts) and even restore the domain disruption caused by methyl-beta-cyclodextrin depletion of membrane cholesterol. In addition, PPD pre-treatment may increase the induction effect of FasL, which impairs cell viability, although it does not appear to be beneficial for Fas clustering in the PPD rafts. Collectively, these results highlight a non-classical mechanism by which PPD induces HepG2 apoptosis by directly affecting the physical properties of the cell membrane, providing a novel insight into understanding membrane-targeted therapy.

Vibrational phenomics decoding of the stem cell stepwise aging process at single-cell resolution.

We introduce vibrational spectroscopy to quantitatively measure the phenotypic heterogeneity of senescent stem cells in the aging process at the single cell level. Using an aging model of serially passaged human mesenchymal stem cells (MSCs), we characterized the phenotypic changes of MSCs during different aged stages and discovered a stepwise aging process with several distinct subtypes.

SUN1/2 controls macrophage polarization via modulating nuclear size and stiffness.

Alteration of the size and stiffness of the nucleus triggered by environmental cues are thought to be important for eukaryotic cell fate and function. However, it remains unclear how context-dependent nuclear remodeling occurs and reprograms gene expression. Here we identify the nuclear envelope proteins SUN1/2 as mechano-regulators of the nucleus during M1 polarization of the macrophage. Specifically, we show that LPS treatment decreases the protein levels of SUN1/2 in a CK2-ßTrCP-dependent manner to shrink and soften the nucleus, therefore altering the chromatin accessibility for M1-associated gene expression. Notably, the transmembrane helix of SUN1/2 is solely required and sufficient for the nuclear mechano-remodeling. Consistently, SUN1/2 depletion in macrophages facilitates their phagocytosis, tissue infiltration, and proinflammatory cytokine production, thereby boosting the antitumor immunity in mice. Thus, our study demonstrates that, in response to inflammatory cues, SUN1/2 proteins act as mechano-regulators to remodel the nucleus and chromatin for M1 polarization of the macrophage.

Exercise improves cardiac function and attenuates myocardial inflammation and apoptosis by regulating APJ/STAT3 in mice with stroke.

Stroke can induce cardiac dysfunction without a primary cardiac disease. Exercise can promote the overall rehabilitation of stroke patients and be beneficial for all kinds of heart diseases. However, the mechanisms underlying the protective effects of exercise in stroke-induced cardiac dysfunction are poorly understood. Hence, we aimed to distinguish the different effects of acute and long-term exercise and further study the mechanism of protection against cardiomyopathy caused by stroke. Mice underwent a single acute session or long-term exercise for 30 days, followed by middle cerebral artery occlusion surgery. The expression of apoptosis-related proteins and proinflammatory factors in the heart was evaluated. Then, overexpression of apelin peptide jejunum (APJ) transfected adeno-associated virus type 9 (AAV9) and inhibition of signal transducer and activator of transcription 3 (STAT3) by Stattic were used in stroke mice or hypoxic cardiomyocytes. ML221 were used to inhibit APJ activity in exercise mouse. Thereafter, changes in apoptotic and proinflammatory factors were evaluated. The results demonstrated that chronic exercise prevented myocardial inflammation, apoptosis and cardiac dysfunction after stroke. However, acute exercise did not have similar effects. Exercise maintained the levels of APJ expression and decreased phosphorylated-STAT3 (p-STAT3) activation to protect cardiomyocytes. Moreover, APJ overexpression promoted cardiomyocyte survival and reduced p-STAT3 levels. STAT3 inhibition also reduced apoptosis and proinflammatory factors in mice hearts. Conversely, the protective effect of exercise was eliminated by APJ inhibition. This study showed that exercise can maintain APJ expression and inhibit p-STAT3, thus, conferring protection against myocardial inflammation and apoptosis induced by stroke.

Impact of perceived ease of use, organizational support mechanism, and industry competitive pressure on physicians' use of liver cancer screening technology in medical alliances.

Background: Liver cancer is one of the malignant tumors worldwide, while the prevention and control situation is grim at present, and the diffusion of its early screening technology still faces some challenges. This study aims to investigate the influencing mechanism of perceived ease of use, organizational support mechanism, and industry competitive pressure on hepatic early screening technologies use by physicians, so as to promote the wider use of corresponding technologies. Methods: Under the theoretical guidance of technology-organization-environment framework and mindsponge theory, this study took hepatic contrast-enhanced ultrasound as an example, and conducted a cross-sectional questionnaire by randomly selecting physicians from Fujian and Jiangxi provinces in China with a high and low incidence of liver cancer, respectively. Structural equation modeling was used to determine the correlation among perceived ease of use, organizational support mechanism, and industry competitive pressure, as well as their impact on the physicians' behavior toward contrast-enhanced ultrasound use. Results: The hypothesis model fits well with the data (χ2/df = 1.863, GFI = 0.937, AGFI = 0.908, RMSEA = 0.054, NFI = 0.959, IFI = 0.980, CFI = 0.980). Under technology-organization-environment framework, the perceived ease of use (ß = 0.171, p < 0.05), organizational support mechanism (ß = 0.423, p < 0.01), industry competitive pressure (ß = 0.159, p < 0.05) significantly influenced physicians' use of hepatic contrast-enhanced ultrasound. Besides, perceived ease of use and organizational support mechanism (ß = 0.216, p < 0.01), perceived ease of use and industry competitive pressure (ß = 0.671, p < 0.01), organizational support mechanism and industry competitive pressure (ß = 0.330, p < 0.01) were all associated significantly. Conclusion: From the lens of information processing (mindsponge theory) and technology-organization-environment framework, this study clarified the social and psychological influencing mechanism of perceived ease of use, organizational support mechanism, and industry competitive pressure on physicians' use of hepatic contrast-enhanced ultrasound. The results will directly propose recommendations for expanding hepatic contrast-enhanced ultrasound utilization and indirectly promoting other appropriate and effective health technologies diffusion within the integrated health system.

Hydrogel microenvironment contributes to chemical-induced differentiation of mesenchymal stem cells: single-cell infrared microspectroscopy characterization.

Stem cell microenvironment plays vital roles in directing cell proliferation and differentiation. Due to the tiny biochemical changes in the early stage of stem cell development, technical challenges to characterize the potential effects of environmental signals remain. In this work, we have introduced synchrotron radiation-based Fourier transform infrared microspectroscopy to evaluate the synergistic effects of physical and chemical factors on stem cell differentiation at the single-cell level. By using principal component analysis and cell-cell Euclidean distance calculation, the phenotypic heterogeneity changes during stem cell osteogenesis induced by lithium chloride or Wnt5a protein loaded in the polyvinyl alcohol (PVA) hydrogel were characterized in detail. The results demonstrated that PVA hydrogel could lead to the distinct effects between low-concentration lithium and wnt5a on human mesenchymal stem cells, suggesting a vital role of niche signals in Wnt pathway. These findings highlight the importance of microenvironment to the chemical-induced effects on stem cell differentiation and also provide a label-free, noninvasive method to sensitively identify the niche function in stem cell biology.

Label-free analysis of biofilm phenotypes by infrared micro- and correlation spectroscopy.

The methodology development for deeply describing the complex biofilm phenotypes is an urgent demand for understanding their basic biology and the central clinic relevance. Here, we developed an infrared microspectroscopy-based method for the quantitative evaluation and description of biofilm phenotypic characteristics by calculating the spectral similarity of the infrared data. Using this approach, we revealed the phenotypic variation during the biofilm formation process and biofilm heterogeneity between two E. coli strains. Two-dimensional correlation spectroscopy was further combined to deeply investigate the biochemical component evolution sequences during E. coli biofilm formation and revealed the first-order of the polysaccharide molecules change, expanding new opportunities for infrared microspectroscopy in revealing molecule evolution in the biofilm formation. This novel development offers a label-free optical toolkit for the bioanalytical analysis of biofilm phenotypes but also paves the way for screening the drugs to modulate the structure and ecology of biofilm microbiome.

An antioxidation strategy based on ultra-small nanobubbles without exogenous antioxidants.

Antioxidation is in demand in living systems, as the excessive reactive oxygen species (ROS) in organisms lead to a variety of diseases. The conventional antioxidation strategies are mostly based on the introduction of exogenous antioxidants. However, antioxidants usually have shortcomings of poor stability, non-sustainability, and potential toxicity. Here, we proposed a novel antioxidation strategy based on ultra-small nanobubbles (NBs), in which the gas-liquid interface was employed to enrich and scavenge ROS. It was found that the ultra-small NBs (~ 10 nm) exhibited a strong inhibition on oxidization of extensive substrates by hydroxyl radicals, while the normal NBs (~ 100 nm) worked only for some substrates. Since the gas-water interface of the ultra-small NBs is non-expendable, its antioxidation would be sustainable and its effect be cumulative, which is different to that using reactive nanobubbles to eliminate free radicals as the gases are consumptive and the reaction is unsustainable. Therefore, our antioxidation strategy based on ultra-small NB would provide a new solution for antioxidation in bioscience as well as other fields such as materials, chemical industry, food industry, etc.

Ultrafine FeF3·0.33H2O Nanocrystal-Doped Graphene Aerogel Cathode Materials for Advanced Lithium-Ion Batteries.

FeF3 has been extensively studied as an alternative positive material owing to its superior specific capacity and low cost, but the low conductivity, large volume variation, and slow kinetics seriously hinder its commercialization. Here, we propose the in situ growth of ultrafine FeF3·0.33H2O NPs on a three-dimensional reduced graphene oxide (3D RGO) aerogel with abundant pores by a facile freeze drying process followed by thermal annealing and fluorination. Within the FeF3·0.33H2O/RGO composites, the three-dimensional (3D) RGO aerogel and hierarchical porous structure ensure rapid diffusion of electrons/ions within the cathode, enabling good reversibility of FeF3. Benefiting from these advantages, a superior cycle behavior of 232 mAh g-1 under 0.1C over 100 cycles as well as outstanding rate performance is achieved. These results provide a promising approach for advanced cathode materials for Li-ion batteries.

Single-cell infrared phenomics identifies cell heterogeneity of individual pancreatic islets in mouse model.

Identifying the islet heterogeneity (cell types and the proportion of each subpopulation) and their relevance to function and disease will lead to fundamental information for the prevention and therapies of diabetes. Here, we introduce a single-cell phenotypic essay on the heterogeneity within individual pancreatic islets by using the combination of synchrotron infrared microspectroscopy and quantitative calculation. In a mouse model, the cellular heterogeneities at both the whole pancreas and single intact islet level were identified. The variation of biochemical phenotypes successfully subdivided islet cells into five main groups and quantitatively determined their proportion. These findings not only demonstrate single-cell infrared phenomics as a value complementary technique and strategy for the description of cellular heterogeneity within the pancreatic islets but also provide a quick, label-free optical platform for investigating phenotypic heterogeneity at the small-organelle level with single cell resolution.

Mechanical strain treatment improves nuclear transfer reprogramming efficiency by enhancing chromatin accessibility.

Cellular mechanical properties are considered to be important factors affecting cell fate transitions, but the links between cellular mechanical properties and transition efficiency and chromatin structure remain elusive. Here, we predicted that mechanical strain treatment could induce signatures of cellular dedifferentiation and transdifferentiation, and we validated this prediction by showing that mechanical strain-treated mouse cumulus cells (CCs) exhibit significantly improved somatic cell nuclear transfer (SCNT) reprogramming efficiency. We found that the chromatin accessibility of CCs was globally increased by mechanical strain treatment and that this increase was partially mediated by the induction of the YAP-TEAD interaction. Moreover, using mechanical strain-treated CCs could prevent transcriptional dysregulation in SCNT embryos. Taken together, our study results demonstrated that modulating cell mechanical properties to regulate epigenetic status is a promising approach to facilitate cell fate transition.

pT1-2 gastric cancer with lymph node metastasis predicted by tumor morphologic features on contrast-enhanced computed tomography

PURPOSE: To investigate the value of tumor morphologic features of pT1-2 gastric cancer (GC) on contrast-enhanced computed tomography (CT) in assessing lymph node metastasis (LNM) with reference to histopathological results. METHODS: Eighty-six patients seen from October 2017 to April 2019 with pT1-2 GC proven by histopathology were included. Tumor volume and CT densities were measured in the plain scan and the portal-venous phase (PVP), and the percent enhancement was calculated. The correlations between tumor morphologic features and the N stages were analyzed. The diagnostic capability of tumor volume and enhancement features in predicting the LN status of pT1-2 GCs was further investigated using receiver operating characteristic (ROC) analysis. RESULTS: Tumor volume, CT density in the PVP, and tumor percent enhancement in the PVP correlated significantly with the N stage (rho: 0.307, 0.558, and 0.586, respectively). Tumor volumes were significantly lower in the LNM- group than in the LNM+ group (14.4 mm3 vs. 22.6 mm3, P = 0.004). The differences between the LNM- and LNM+ groups in the CT density in the PVP and the percent enhancement in the PVP were also statistically significant (68.00 HU vs. 87.50 HU, P < 0.001; and 103.06% vs. 179.19%, P < 0.001, respectively). The area under the ROC curves for identifying the LNM+ group was 0.69 for tumor volume and 0.88 for percent enhancement in the PVP, respectively. The percent enhancement in the PVP of 145.2% and tumor volume of 17.4 mL achieved good diagnostic performance in determining LNM+ (sensitivity: 71.4%, 82.1%; specificity: 91.4%, 58.6%; and accuracy: 84.9%, 66.3%, respectively). CONCLUSION: Tumor volume and percent enhancement in the PVP of pT1-2 GC could improve the diagnostic accuracy of LNM and would be helpful in image surveillance of these patients.

Protopanaxadiol manipulates gut microbiota to promote bone marrow hematopoiesis and enhance immunity in cyclophosphamide-induced immunosuppression mice.

Protopanaxadiol (PPD) has potential immunomodulatory effects, but the underlying mechanism remains unclear. Here, we explored the potential roles of gut microbiota in the immunity regulation mechanisms of PPD using a cyclophosphamide (CTX)-induced immunosuppression mouse model. Our results showed that a medium dose of PPD (PPD-M, 50 mg/kg) effectively ameliorated the immunosuppression induced by CTX treatment by promoting bone marrow hematopoiesis, increasing the number of splenic T lymphocytes and regulating the secretion of serum immunoglobulins and cytokines. Meanwhile, PPD-M protected against CTX-induced gut microbiota dysbiosis by increasing the relative abundance of Lactobacillus, Oscillospirales, Turicibacter, Coldextribacter, Lachnospiraceae, Dubosiella, and Alloprevotella and reducing the relative abundance of Escherichia-Shigella. Importantly, PPD-M lost the ability to promote bone marrow hematopoiesis and enhance immunity when the gut microbiota was depleted by broad-spectrum antibiotics. Moreover, PPD-M promoted the production of microbiota-derived immune-enhancing metabolites including cucurbitacin C, l-gulonolactone, ceramide, DG, prostaglandin E2 ethanolamide, palmitoyl glucuronide, 9R,10S-epoxy-stearic acid, and 9'-carboxy-gamma-chromanol. KEGG topology analysis showed that the PPD-M treatment significantly enriched the sphingolipid metabolic pathway with ceramide as a main metabolite. Our findings reveal that PPD enhances immunity by manipulating gut microbiota and has the potential to be used as an immunomodulator in cancer chemotherapy.

Oxygen therapy accelerates apoptosis induced by selenium compounds via regulating Nrf2/MAPK signaling pathway in hepatocellular carcinoma.

Selenium has good antitumor effects in vitro, but the hypoxic microenvironment in solid tumors makes its clinical efficacy unsatisfactory. We hypothesized that the combination with oxygen therapy might improve the treatment efficacy of selenium in hypoxic tumors through the changes of redox environment. In this work, two selenium compounds, Na2SeO3 and CysSeSeCys, were selected to interrogate their therapeutic effects on hepatocellular carcinoma (HCC) under different oxygen levels. In tumor-bearing mice, both selenium compounds significantly inhibited the tumor growth, and combined with oxygen therapy further reduced the tumor volume about 50 %. In vitro HepG2 cell experiments, selenium induced autophagy and delayed apoptosis under hypoxia (1 % O2), while inhibited autophagy and accelerated apoptosis under hyperoxia (60 % O2). We found that, in contrast to hypoxia, the hyperoxic environment facilitated the H2Se, produced by the selenium metabolism in cells, to be rapidly oxidized to generate H2O2, leading to inhibit the expression level of Nrf2 and to increase that of phosphorylation of p38 and MKK4, resulting in inhibiting autophagy and accelerating apoptosis. Once the Nrf2 gene was knocked down, selenium compounds combined with hyperoxia treatment would further activate the MAPK signaling pathway and further increase apoptosis. These findings highlight oxygen can significantly enhance the anti-HCC effect of selenium compounds through regulating the Nrf2 and MAPK signaling pathways, thus providing novel therapeutic strategy for the hypoxic tumors and pave the way for the application of selenium in clinical treatment.

Synchrotron Infrared Microspectroscopy for Stem Cell Research.

Stem cells have shown great potential functions for tissue regeneration and repair because of their unlimited self-renewal and differentiation. Stem cells reside in their niches, making them a hotspot for the development and diagnosis of diseases. Complex interactions between niches and stem cells create the balance between differentiation, self-renewal, maturation, and proliferation. However, the multi-facet applications of stem cells have been challenged since the complicated responses of stem cells to biological processes were explored along with the limitations of current systems or methods. Emerging evidence highlights that synchrotron infrared microspectroscopy, known as synchrotron radiation-based Fourier transform infrared microspectroscopy, has been investigated as a potentially attractive technology with its non-invasive and non-biological probes in stem cell research. With their unique vibration bands, the quantitative mapping of the content and distribution of biomolecules can be detected and characterized in cells or tissues. In this review, we focus on the potential applications of synchrotron infrared microspectroscopy for investigating the differentiation and fate determination of stem cells.

Recent Advances in Solid-Electrolyte Interphase for Li Metal Anode.

Lithium metal batteries (LMBs) are considered to be a substitute for lithium-ion batteries (LIBs) and the next-generation battery with high energy density. However, the commercialization of LMBs is seriously impeded by the uncontrollable growth of dangerous lithium dendrites during long-term cycling. The generation and growth of lithium dendrites are mainly derived from the unstable solid-electrolyte interphase (SEI) layer on the metallic lithium anode. The SEI layer is a key by-product formed on the surface of the lithium metal anode during the electrochemical reactions and has been the barrier to development in this area. An ideal SEI layer should possess electrical insulating, superior mechanical modulus, high electrochemical stability, and excellent Li-ion conductivity, which could improve the structural stability of the electrode upon a long cycling time. This mini-review carefully summarizes the recent developments in the SEI layer for LMBs, and the relationship between SEI layer optimization and electrochemical property is discussed. In addition, further development direction of a stable SEI layer is proposed.

Effects of Organizational Atmosphere and Organizational Practice on Knowledge, Attitude, and Practice Toward Diffusion and Utilization of Hepatic Contrast-Enhanced Ultrasound Among Physicians.

Background: Promoting technology diffusion and utilization is a key measure to address the great disparity in technical capacity within integrated health systems. However, even the effectiveness and appropriateness regarding technology has been widely recognized, its diffusion and utilization are still stagnant. The mechanisms that influence the technology from being recognized to being widely applied in practice remain largely unknown. Purpose: Taking hepatic contrast-enhanced ultrasound (CEUS) as an example, this study aimed to investigate the comprehensive influencing mechanism of organizational atmosphere and organizational practice on the knowledge, attitude, and practice toward diffusion and utilization of hepatic CEUS in the medical alliance. Methods: Based on the integration of organizational ready for change (ORC) and knowledge-attitude-practice (KAP), a structured questionnaire was developed. A multistage random sampling method was applied to investigate physicians who directly use CEUS working at the liver disease-related departments of sampled health institutions. Structural equation modeling (SEM) was used to verify the proposed hypotheses, and determine the relationship between the factors. Results: In total, 292 physicians were included. SEM results demonstrated that knowledge influenced both attitude and practice, while attitude positively predicted practice. Organizational practice and organizational atmosphere associated positively with each other. Organizational atmosphere positively affected the physicians' attitude toward CEUS diffusion and utilization (ß = 0.425, p < 0.001), while organizational practice positively affected corresponding knowledge (ß = 0.423, p < 0.001) and practice (ß = 0.275, p < 0.001). Additionally, there was a partial mediating effect between organizational practice and physicians' CEUS diffusion and utilization behavior. Conclusion: By verifying the influencing mechanism of organizational atmosphere and organizational practice on the physicians' KAP of hepatic CEUS diffusion and utilization, this study benefit tailoring strategies for promoting technology diffusion and utilization within medical alliance. It is recommended to develop an organizational atmosphere of advocating technology innovation, establish organizational support mechanism (SM) with multiple concrete supporting countermeasures, and so on.

Probing terahertz dynamics of multidomain protein in cell-like confinement.

The development of meaningful descriptions of multidomain proteins exhibiting complex inter-domain dynamics modes is a key challenge for understanding their roles in molecular recognition and signalling processes. Here we developed a generally applicable approach for probing the low frequency collective hydration dynamics of multidomain proteins that uses terahertz spectroscopy of a protein molecule confined in a phospholipid reverse micelles environment (named Droplet THz). With the combination of normal mode analysis, we demonstrated the binding of calcium ions modulates the local inter-domain motion of the human coagulant factor VIII protein in a concentration-dependent manner. These findings highlight the Droplet THz as a valuable tool for dissecting the ultrafast dynamics of domain motion in the multidomain proteins and suggest a modulating mechanism of calcium ions on the structural flexibility and function of human coagulant proteins.