Abstract
In a retrospective study of 39 COVID-19 patients and 32 control participants in China, we collected clinical data and examined the expression of endothelial cell adhesion molecules by ...enzyme-linked immunosorbent assays. Serum levels of fractalkine, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular adhesion protein-1 (VAP-1) were elevated in patients with mild disease, dramatically elevated in severe cases, and decreased in the convalescence phase. We conclude the increased expression of endothelial cell adhesion molecules is related to COVID-19 disease severity and may contribute to coagulation dysfunction.
Richly illustrated throughout with actual tissue images, this innovative book shows that the soft-hard tissue junction is best understood in a biomechanical context. The authors describe their ...pioneering experimental methods, providing an essential structure-function framework for computational modelling, and thereby encouraging the development of more realistic, predictive models of this important tissue junction. Covering the three main musculoskeletal junctions of cartilage-bone, disc-vertebra, and ligament/tendon-bone, the relevant soft tissues are examined with respect to both their own inherent structure and their mode of integration with the hard tissue. The soft-hard tissue interface is explored with a focus on structural damage resulting from overloading, and its associated pathologies. Adopting a multiscale approach, ranging in structural resolution from the macro to fibril levels, this is a must-have guide to the field and an ideal resource for researchers seeking new and creative approaches for studying the joint and spine tissues.
Focal adhesion kinase (FAK) relays integrin signaling from outside to inside cells and contributes to cell adhesion and motility. However, the spatiotemporal dynamics of FAK activity in single FAs is ...unclear due to the lack of a robust FAK reporter, which limits our understanding of these essential biological processes. Here we have engineered a genetically encoded FAK activity sensor, dubbed FAK-separation of phases-based activity reporter of kinase (SPARK), which visualizes endogenous FAK activity in living cells and vertebrates. Our work reveals temporal dynamics of FAK activity during FA turnover. Most importantly, our study unveils polarized FAK activity at the distal tip of newly formed single FAs in the leading edge of a migrating cell. By combining FAK-SPARK with DNA tension probes, we show that tensions applied to FAs precede FAK activation and that FAK activity is proportional to the strength of tension. These results suggest tension-induced polarized FAK activity in single FAs, advancing the mechanistic understanding of cell migration.
Tissue adhesion is a severe postoperative complication. Various strategies have been developed to minimize postoperative adhesion, but the clinical efficacy is still far from satisfactory. Herein, we ...present a dual dynamically crosslinked hydrogel to serve as a physical postoperative anti-adhesion barrier. The hydrogel was generated by dynamic chemical oxime bonding from alkoxyamine-terminated Pluronic F127 (AOP127) and oxidized hyaluronic acid (OHA), as well as hydrophobic association of AOP127. Rheological analysis demonstrated that the hydrogel exhibits temperature sensitivity. At 37 °C, it shows much higher modulus and higher stability than the Pluronic F127 hydrogel. Hemolytic assays suggested that the hydrogel undergoes low hemolysis. In addition, it exhibited anti-adhesion to blood cells in blood cell adhesion tests. It also showed an anti-attachment effect to fibroblasts and biocompatibility in vitro cell studies. Macroscopic evaluation and lap-shear tests revealed that the hydrogel has a moderate adhesive capacity to tissue, which is important for self-fixation. A rat model of sidewall defect-bowel abrasion was established to evaluate the anti-adhesion effect in vivo. The gross observation and pathological analysis revealed a significant reduction in postoperative peritoneal adhesion in the AOP127/OHA hydrogel-treated group than those treated with normal saline or Pluronic F127 hydrogel. Hence, the dual dynamically crosslinked hydrogel with self-fixable capacity may be suitable as a physical barrier for postoperative adhesion prevention.
Despite the development of numerous postoperative anti-adhesion barriers, their anti-adhesion efficacy is still limited in clinical trials due to poor tissue adhesion and rapid clearance from injured areas. Herein, we have developed a dual dynamic crosslinked hydrogel, generated by dynamic oxime bonds and hydrophobic interactions. The hydrogel is temperature-sensitive and demonstrates moderate tissue adhesion capacity, which allows for self-fixation when applied to defects. The introduction of dynamic covalent bonds improves the stability of the hydrogel. Moreover, the hydrogel not only displays appropriate hemocompatibility, cytocompatibility and anti-adhesion of blood cells and fibroblasts, but it also effectively contributes to preventing postoperative peritoneal adhesions in vivo. Hence, this dual dynamic crosslinked hydrogel may have potential applications as a physical barrier in clinical practice.
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Protein tyrosine kinase (PTK) activity has been implicated in pro-inflammatory gene expression following tumor necrosis factor-α (TNF-α) or interkeukin-1β (IL-1β) stimulation. However, the identity ...of responsible PTK(s) in cytokine signaling have not been elucidated. To evaluate which PTK is critical to promote the cytokine-induced inflammatory cell adhesion molecule (CAM) expression including VCAM-1, ICAM-1, and E-selectin in human aortic endothelial cells (HAoECs), we have tested pharmacological inhibitors of major PTKs: Src and the focal adhesion kinase (FAK) family kinases - FAK and proline-rich tyrosine kinase (Pyk2). We found that a dual inhibitor of FAK/Pyk2 (PF-271) most effectively reduced all three CAMs upon TNF-α or IL-1β stimulation compared to FAK or Src specific inhibitors (PF-228 or Dasatinib), which inhibited only VCAM-1 expression. In vitro inflammation assays showed PF-271 reduced monocyte attachment and transmigration on HAoECs. Furthermore, FAK/Pyk2 activity was not limited to CAM expression but was also required for expression of various pro-inflammatory molecules including MCP-1 and IP-10. Both TNF-α and IL-1β signaling requires FAK/Pyk2 activity to activate ERK and JNK MAPKs leading to inflammatory gene expression. Knockdown of either FAK or Pyk2 reduced TNF-α-stimulated ERK and JNK activation and CAM expression, suggesting that activation of ERK or JNK is specific through FAK and Pyk2. Finally, FAK/Pyk2 activity is required for VCAM-1 expression and macrophage recruitment to the vessel wall in a carotid ligation model in ApoE-/- mice. Our findings define critical roles of FAK/Pyk2 in mediating inflammatory cytokine signaling and implicate FAK/Pyk2 inhibitors as potential therapeutic agents to treat vascular inflammatory disease such as atherosclerosis.
An aged circulatory environment can activate microglia, reduce neural precursor cell activity and impair cognition in mice. We hypothesized that brain endothelial cells (BECs) mediate at least some ...of these effects. We observe that BECs in the aged mouse hippocampus express an inflammatory transcriptional profile with focal upregulation of vascular cell adhesion molecule 1 (VCAM1), a protein that facilitates vascular-immune cell interactions. Concomitantly, levels of the shed, soluble form of VCAM1 are prominently increased in the plasma of aged humans and mice, and their plasma is sufficient to increase VCAM1 expression in cultured BECs and the hippocampi of young mice. Systemic administration of anti-VCAM1 antibody or genetic ablation of Vcam1 in BECs counteracts the detrimental effects of plasma from aged individuals on young brains and reverses aging aspects, including microglial reactivity and cognitive deficits, in the brains of aged mice. Together, these findings establish brain endothelial VCAM1 at the blood-brain barrier as a possible target to treat age-related neurodegeneration.
This comprehensive work discusses novel biomolecular surfaces that have been engineered to either control or measure cell function at the atomic, molecular, and cellular levels. Each chapter presents ...real results, concepts, and expert perspectives of how cells interact with biomolecular surfaces, with particular emphasis on interactions within complex mechanical environments such as in the cardiovascular system. In addition, the book provides detailed coverage of inflammation and cellular immune response as a useful model for how engineering concepts and tools may be effectively applied to complex systems in biomedicine.
-Accessible to biologists looking for new ways to model their results and engineers interested in biomedical applications -Useful to researchers in biomaterials, inflammation, and vascular biology -Excellent resource for graduate students as a textbook in cell & tissue engineering or cell mechanics courses
Members of the Navajo Nation, who possess a high prevalence of cardiometabolic disease, reside near hundreds of local abandoned uranium mines (AUM), which contribute uranium, arsenic and other metals ...to the soil, water and air. We recently reported that hypertension is associated with mine waste exposures in this population. Inflammation is a major player in the development of numerous vascular ailments. Our previous work establishing that specific transcriptional responses of cultured endothelial cells treated with human serum can reveal relative circulating inflammatory potential in a manner responsive to pollutant exposures, providing a model to assess responses associated with exposure to these waste materials in this population. To investigate a potential link between exposures to AUM and serum inflammatory potential in affected communities, primary human coronary artery endothelial cells were treated for 4 h with serum provided by Navajo study participants (n=145). Endothelial transcriptional responses of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and chemokine ligand 2 (CCL2) were measured. These transcriptional responses were then linked to AUM exposure metrics, including surface area-weighted AUM proximity and estimated oral intake of metals. AUM proximity strongly predicted endothelial transcriptional responses to serum including CCL2, VCAM-1 and ICAM-1 (P<0.0001 for each), whereas annual water intakes of arsenic and uranium did not, even after controlling for all major effect modifiers. Inflammatory potential associated with proximity to AUMs, but not oral intake of specific metals, additionally suggests a role for inhalation exposure as a contributor to cardiovascular disease.
The germinal center (GC) reaction begins with a diverse and expanded group of B cell clones bearing a wide range of antibody affinities. During GC colonization, B cells engage in long-lasting ...interactions with T follicular helper (Tfh) cells, a process that depends on antigen uptake and antigen presentation to the Tfh cells. How long-lasting T-B interactions and B cell clonal expansion are regulated by antigen presentation remains unclear. Here, we use in vivo B cell competition models and intravital imaging to examine the adhesive mechanisms governing B cell selection for GC colonization. We find that intercellular adhesion molecule 1 (ICAM-1) and ICAM-2 on B cells are essential for long-lasting cognate Tfh-B cell interactions and efficient selection of low-affinity B cell clones for proliferative clonal expansion. Thus, B cell ICAMs promote efficient antibody immune response by enhancement of T cell help to cognate B cells.
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