The innate immune system, acting as the first line of host defense, senses and adapts to foreign challenges through complex intracellular and intercellular signaling networks. Endotoxin tolerance and priming elicited by macrophages are classic examples of the complex adaptation of innate immune cells. Upon repetitive exposures to different doses of bacterial endotoxin (lipopolysaccharide) or other stimulants, macrophages show either suppressed or augmented inflammatory responses compared to a single exposure to the stimulant. Endotoxin tolerance and priming are critically involved in both immune homeostasis and the pathogenesis of diverse inflammatory diseases. However, the underlying molecular mechanisms are not well understood. By means of a computational search through the parameter space of a coarse-grained three-node network with a two-stage Metropolis sampling approach, we enumerated all the network topologies that can generate priming or tolerance. We discovered three major mechanisms for priming (pathway synergy, suppressor deactivation, activator induction) and one for tolerance (inhibitor persistence). These results not only explain existing experimental observations, but also reveal intriguing test scenarios for future experimental studies to clarify mechanisms of endotoxin priming and tolerance.
This study predicts the nonlinear response of a cantilevered carbon nanotube(CNT) for biomolecular mass sensing using simple mechanical model analysis. The electrostatically resonating CNT cantilever can measure the frequency shift due to the added mass such as virus, bacterium and various macromolecules on the CNT. The analysis model of the resonating CNT has
The phenotype of tumor-associated macrophages plays an important role in their function of regulating the tumor immune microenvironment. The M1-phenotype macrophages display tumor-killing and immune activating functions. Here we show that the tobacco mosaic virus (TMV), a rod-like plant virus, can polarize macrophages to an M1 phenotype and shape a tumor-suppressive microenvironment. RAW 264.7 cells and bone marrow derived-macrophages (BMDMs) can recognize TMV via Toll-like receptor-4, and then the MAPK and NF-κB signaling pathways are activated, leading to the production of pro-inflammatory factors. Furthermore, the in vivo assessments on a subcutaneous co-injection tumor model show that the TMV-polarized BMDMs shape a tumor-suppressive microenvironment, resulting in remarkable delay of 4T1 tumor growth. Another in vivo assessment on an established tumor model indicates the high tumor-metastasis-inhibiting capacity of TMVpolarized BMDMs. This work suggests a role for this plant virus in macrophage-mediated therapeutic approaches and provides a strategy for tumor immunotherapy.
This paper presents an interactive rendering method for sparse level sets. A GPU-CPU hybrid ray casting approach is developed to perform a surface extraction of a level set embedded in a signed distance field. The sparseness of the data structure is exploited to allow object-order empty-space skipping. The signed distance nature of the dataset is used to naturally provide adaptive sampling which leads to high quality surface reconstruction. Ray surface intersections are rendered as oriented points with smooth normals computed directly from the dataset. Alternative shading methods are possible after the intersections are found, however, we explicitly use only normals as the main purpose is to have this method work interactively with other similarly shaded objects in the same scene.
OBJECTIVE:This study aims to measure the expression of toll-like receptors (TLR) in monocyte-derived dendritic cells (MoDC) from chronic severe hepatitis B (CSHB), to assess the contribution of TLRs in CSHB.
METHODS:Peripheral blood was collected from 40 CSHB patients, 30 chronic hepatitis B (CHB) patients, and 30 healthy individuals who served as healthy controls (HCs). Purified monocytes were isolated by a combination of Histopaque-1.077 and CD14 Microbeads. MoDCs were induced with granulocyte macrophage colony-stimulating factor and interleukin-4 for 6 days from CD14 + monocytes. The expression of TLRs in MoDC was measured using real-time PCR and flow cytometry.
RESULTS:The expressions of TLR-1, -2, -7 were significantly higher in MoDC of CSHB than that of HCs, of which the level of TLR-3 was decreased. Particularly in CSHB patients, the TLR-3 expression was further decreased compared to CHB patients. In nonsurvival CSHB patients, TLR-3 level was significantly decreased, while TLR-2 expression was dramatically increased. Linear correlation analysis demonstrated significant correlations between TLR-3 level and disease severity markers (total bilirubin, prothrombin activity, creatinine, white blood cell count, and maximum volume of ascitic fluid) in individual CSHB patients.
CONCLUSIONS:TLR-2 and TLR-3 may be involved in the pathogenesis of CSHB, and TLR-3 may influence the prognosis of CSHB.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.