Abstract
The integrins and G protein-coupled receptors are both fundamental in cell biology. The cross talk between these two, however, is unclear. Here we show that β
3
integrins negatively regulate ...G protein-coupled signaling by directly inhibiting the Gα
13
-p115RhoGEF interaction. Furthermore, whereas β
3
deficiency or integrin antagonists inhibit integrin-dependent platelet aggregation and exocytosis (granule secretion), they enhance G protein-coupled RhoA activation and integrin-independent secretion. In contrast, a β
3
-derived Gα
13
-binding peptide or Gα
13
knockout inhibits G protein-coupled RhoA activation and both integrin-independent and dependent platelet secretion without affecting primary platelet aggregation. In a mouse model of myocardial ischemia/reperfusion injury in vivo, the β
3
-derived Gα
13
-binding peptide inhibits platelet secretion of granule constituents, which exacerbates inflammation and ischemia/reperfusion injury. These data establish crucial integrin-G protein crosstalk, providing a rationale for therapeutic approaches that inhibit exocytosis in platelets and possibly other cells without adverse effects associated with loss of cell adhesion.
Climate change and associated factors such as global and regional sea-level rise; the upsurge in high-intensity flooding events; and coastal erosion are pulse and press disturbances that threaten to ...increase landslides in coastal regions. Under these circumstances; a rigorous framework is required to evaluate coastal vulnerability in order to plan for future climate change scenarios. A vast majority of coastal vulnerability assessments across the globe are evaluated at the macro level (city scale) but not at the micro level (small town scale); particularly in the United Kingdom (UK). In order to fill this vital research gap; the current study established a coastal vulnerability index termed here as the Micro Town Coastal Vulnerability Index (MTCVI) and then applied it to Barton-on-Sea; which is a small coastal town of the Hampshire region; England; UK. MTCVI was evaluated for Barton-on-Sea coastal vulnerability by integrating both novel and existing parameters. Results suggest that the entire shoreline frontage (2 km) exhibits very high coastal vulnerability and is prone to various coastal hazards such as landslides; erosion; and wave intrusion. This suggests that Barton-on-Sea coastal amenities will require a substantial improvement in shoreline protection measures. In this study; GIS (geographic information system) coastal vulnerability and landslide maps were generated; and these maps can be used by the local authorities; district councils; coastal engineers; and planners to improve and design coastal management strategies under the climate change scenarios. Meanwhile; the methodology used in this study could also be applied to any other suitable location in the world depending on the availability of the data.
The platelet von Willebrand factor (vWF) receptor, glycoprotein Ib-IX (GPIb-IX), mediates platelet adhesion and induces signaling leading to integrin activation. Phosphoinositol 3-kinase (PI3K) is ...important in GPIb-IX–mediated signaling. PI3K–dependent signaling mechanisms, however, are unclear. We show that GPIb-IX–induced platelet aggregation and stable adhesion under flow were impaired in mouse platelets deficient in PI3K effectors, Akt1 and Akt2, and in human platelets treated with an Akt inhibitor, SH-6. Akt1 and Akt2 play important roles in early GPIb-IX signaling independent of Syk, adenosine diphosphate (ADP), or thromboxane A2 (TXA2), in addition to their recognized roles in ADP- and TXA2–dependent secondary amplification pathways. Knockout of Akt1 or Akt2 diminished platelet spreading on vWF but not on immobilized fibrinogen. Thus, Akt1 and Akt2 are both required only in the GPIb-IX–mediated integrin activation (inside-out signaling). In contrast, PI3K inhibitors abolished platelet spreading on both vWF and fibrinogen, indicating a role for PI3K in integrin outside-in signaling distinct from that in GPIb-IX–mediated inside-out signaling. Furthermore, Akt1- or Akt2-deficiency diminished vWF–induced cGMP elevation, and their inhibitory effects on GPIb-IX–dependent platelet adhesion were reversed by exogenous cGMP. Thus, Akt1 and Akt2 mediate GPIb-IX signaling via the cGMP–dependent signaling pathway.
In time-dependent reliability analysis, an upcrossing is defined as the event when a limit-state function reaches its failure region from its safe region. Upcrossings are commonly assumed to be ...independent. The assumption may not be valid for some applications and may result in large errors. In this work, we develop a more accurate method that relaxes the assumption by using joint upcrossing rates. The method extends the existing joint upcrossing rate method to general limit-state functions with both random variables and stochastic processes. The First Order Reliability Method (FORM) is employed to derive the single upcrossing rate and joint upcrossing rate. With both rates, the probability density of the first time to failure can be solved numerically. Then the probability density leads to an easy evaluation of the time-dependent probability of failure. The proposed method is applied to the reliability analysis of a beam and a mechanism, and the results demonstrate a significant improvement in accuracy.
Abstract
Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a ...thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα
13
-mediated integrin “outside-in” signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα
13
knockout inhibited septic thrombosis whereas leukocyte Gα
13
knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα
13
knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage.
Intelligent and Connected Vehicle (ICV) technology is considered to be a solution to improve the traffic performance. Through the information exchange in real-time among the vehicles, the roadside ...infrastructures, and the cloud platform, the sensing of the vehicles can be enhanced. This also enables coordinated driving decisions, which can improve traffic operations, especially at bottleneck locations. This paper addresses the problem of coordinating the vehicles near the bottleneck locations to help the vehicles passing the area quickly and smoothly. A lane advisory algorithm is designed to reduce conflicts by encouraging early lane changes. A coordinated vehicle movement planning algorithm is proposed to achieve a smooth longitudinal reference speed profiles for vehicles in the subject area. The algorithm can open enough headway for vehicles to change the lane and continue their trips. The effectiveness of the algorithm is evaluated using SUMO (Simulation of Urban MObility) as the simulation tool with no communication between vehicles as the benchmark case as well as the case where the vehicular traffic follows the so-called First-in-First-Out (FIFO) principle. The results of the evaluation summarize and indicate that the Coordinated Control Algorithm (CCA) proposed in this paper can improve traffic performance in terms of the average speed, the waiting time, the total travel time, and the traffic flow rate under different levels of service.
Rapid, non-destructive detection of wheat Fusarium head blight (FHB) is an important tool for disease control. Red-edge (RE) is a prominent spectral feature for determining crop conditions with the ...potential to enhance the accuracy of monitoring FHB regionally. This study explored the potential of RE for FHB monitoring based on Sentinel-2 Multispectral Instrument (MSI) data. The novel red-edge head blight index (REHBI) was developed to detect FHB at a regional scale. Hyperspectral data at the canopy scale was integrated to simulate Sentinel-2 multispectral reflectance using the relative spectral response (RSR) function of the sensor. Then, many differential and ratio combinations of Sentinel-2 bands that were sensitive to FHB severity were selected. REHBI was established based on these basic vegetation indexes (VIs), and the model developed from REHBI performed best in monitoring FHB severity (R2 = 0.82, RMSE = 10.1). Additionally, the infected canopies with disease index (DI) values between 10 and 50 were classified as slightly diseased canopies. Ordinary least square (OLS) was used to test the performance of REHBI and two conventional VIs, i.e., OSAVI and RDVI, in monitoring slightly diseased canopies; REHBI outperformed these alternatives (R2 = 0.69, RMSE = 3.6). To approximate real agricultural conditions, Poisson noise was added to the simulated Sentinel-2 multispectral data and generalized performance of VIs was evaluated again; REHBI still had the highest R2 and lowest RMSE values (0.74 and 12.6, respectively). Finally, to validate REHBI's ability to detect FHB infection in agricultural production, it was applied to monitoring FHB in the wheat planting areas of Changfeng and Dingyuan counties from Sentinel-2 imagery. Generally, REHBI performed better in disease monitoring than OSAVI and RDVI. The overall accuracy was up to 78.6%, and the kappa coefficient was 0.51. Experimental results demonstrate that REHBI can be used to monitor FHB.
A variant of somatic nuclear autoantigenic sperm protein (sNASP) was identified from the murine lupus susceptibility locus Sle2c1 by whole exome sequencing (WES). Previous studies have shown that ...mutant sNASP could synergize with the Faslpr mutation in exacerbating autoimmunity and aggravating end-organ inflammation. In the current study, the sNASP mutation was introduced into Sle1.Yaa mice to detect whether it has a synergistic effect with Sle1 or Yaa loci. As expected, compared with Sle1.Yaa mice, Sle1.Yaa.ΔsNASP mice showed enlarged lymph nodes, aggravated renal inflammation, and shortened survival time. The proportions of CD3+ T cells, activated CD19+CD86+ B cells, Th1 cells in the spleen and lymph nodes, and Th17 cells in lymph nodes in Sle1.Yaa.ΔsNASP mice were increased compared to those in Sle1.Yaa mice. The levels of IFN-γ and TNF-α in the serum of Sle1.Yaa.ΔsNASP mice were higher than those of Sle1.Yaa mice. The above results show that mutant sNASP can interact with different lupus susceptibility genes and promote the disease process of systemic lupus erythematosus.
The detection of primary and secondary schools (PSSs) is a meaningful task for composite object detection in remote sensing images (RSIs). As a typical composite object in RSIs, PSSs have diverse ...appearances with complex backgrounds, which makes it difficult to effectively extract their features using the existing deep-learning-based object detection algorithms. Aiming at the challenges of PSSs detection, we propose an end-to-end framework called the attention-guided dense network (ADNet), which can effectively improve the detection accuracy of PSSs. First, a dual attention module (DAM) is designed to enhance the ability in representing complex characteristics and alleviate distractions in the background. Second, a dense feature fusion module (DFFM) is built to promote attention cues flow into low layers, which guides the generation of hierarchical feature representation. Experimental results demonstrate that our proposed method outperforms the state-of-the-art methods and achieves 79.86% average precision. The study proves the effectiveness of our proposed method on PSSs detection.
The world is transitioning to renewable energy, with photovoltaic (PV) solar power being one of the most promising energy sources. Large-scale PV mapping provides the most up-to-date and accurate PV ...geospatial information, which is crucial for planning and constructing PV power plants, optimizing energy structure, and assessing the ecological impact of PVs. However, previous methods of PV extraction relied on simple models and single data sources, which could not accurately obtain PV geospatial information. Therefore, we propose the Filter-Embedded Network (FEPVNet), which embeds high-pass and low-pass filters and Polarized Self-Attention (PSA) into a High-Resolution Network (HRNet) to improve its noise resistance and adaptive feature extraction capabilities, ultimately enhancing the accuracy of PV extraction. We also introduce three data migration strategies by combining Sentinel-2, Google-14, and Google-16 images in varying proportions and transferring the FEPVNet trained on Sentinel-2 images to Gaofen-2 images, which improves the generalization performance of models trained on a single data source for extracting PVs in images of different scales. Our model improvement experiments demonstrate that the Intersection over Union (IoU) of FEPVNet in segmenting China PVs in Sentinel-2 images reaches 88.68%, a 2.37% increase compared to the HRNet. Furthermore, we use FEPVNet and the optimal migration strategy to extract photovoltaics across scales, achieving a precision of 94.37%. In summary, this study proposes the FEPVNet model with adaptive strategies for extracting PVs from multiple image sources, with significant potential for application in large-scale PV mapping.
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