Role of p21-Activated Kinase 4 in Cell Migration

Cell migration is a cellular process that plays a critical role in various physiological and pathological phenomena, including in cancer metastasis. Understanding at a fundamental level how cancer cells migrate and invade will help to delineate potential targets for the directed development of anti-metastatic therapeutic agents. For example, αv integrins are up-regulated or activated in many migratory cells, and are essential to the processes of wound healing, angiogenesis, and metastasis. Similarly, integrin αvβ5, a vitronectin (VN) receptor, is expressed in most patient carcinoma specimens and is functionally involved in growth factor-induced carcinoma cell migration in vitro and metastasis in vivo. However, the mechanisms of integrin αvβ5-mediated cell migration are not fully understood. In this project, we aimed to identify proteins that interact with the cytoplasmic tail of integrin β5, and to study their role in cell motility. Firstly, we employed a yeast two-hybrid screening of a mouse embryo cDNA library and thereby identified six proteins specifically interacting with the human integrin β5 cytoplasmic domain. One of the integrin β5-interacting proteins was p21-activated kinase 4 (PAK4), which, in addition to its direct interaction with the integrin β5 cytoplasmic tail, also appeared to functionally regulate αvβ5-mediated migration of the human MCF-7 breast carcinoma cells. Importantly, engagement of integrin αvβ5 by cell attachment to VN led to a redistribution of PAK4 from the cytosol to dynamic lamellipodial structures where PAK4 colocalized with integrin αvβ5. Functionally, PAK4 induced integrin αvβ5-mediated, but not integrin β1-mediated MCF-7 cell migration, without affecting the cell surface levels of integrin αvβ5. In addition, we found that PAK4 was activated by cell attachment to VN mediated by the PAK4 binding partner integrin αvβ5, and that active PAK4 induced accelerated integrin αvβ5 turn-over within adhesion complexes. Accelerated integrin turn-over was the likely cause of additionally observed PAK4-mediated effects, including inhibited integrin αvβ5 clustering, reduced integrin to F-actin connectivity and perturbed maturation of cell adhesion complexes. These specific outcomes were ultimately associated with reduced cell adhesion capacity and increased cell motility. We thus demonstrate a novel mechanism deployed by cells to tune cell adhesion levels through the auto-inhibitory regulation of integrin-mediated adhesion. Furthermore, we identified a unique PAK4-binding membrane-proximal β5-SERS-motif in the cytoplasmic tail of β5, and demonstrated a key role for this motif in controlling cell adhesion and migration. We mapped the integrin β5-binding within PAK4 and observed that PAK4 binding to integrin β5 was not sufficient to promote cell migration; instead the PAK4 kinase activity was required for PAK4 promotion of cell motility. In fact, PAK4 specifically phosphorylated the integrin β5 subunit at Ser 759 and Ser 762 within the β5-SERS-motif. Importantly, point mutation of these two serine residues abolished PAK4-mediated promotion of cell migration, indicating a functional role for these phosphorylations in cell migration. In conclusion, our results demonstrate that PAK4 interacts with and selectively phosphorylates integrin αvβ5 and thereby promotes αvβ5-mediated cell migration, a functional outcome paralleled by a concurrent decrease in total cellular adhesion to VN. Given our finding that PAK4 is activated by αvβ5 ligation to VN, these results delineate an auto-inhibitory negative feedback loop that is initiated by cell adhesion to VN. Binding of integrin αvβ5 to VN drives translocation and activation of PAK4, leading to phosphorylation of αvβ5 and ultimately the limiting of total adhesion between cells and VN and increased cell migration. Thus, our findings provide a new mechanistic characterization of PAK4’s role in the functional regulation of integrin αvβ5. This knowledge may ultimately be important for understanding vascular permeability, angiogenesis and cancer dissemination

Towards Generative Modeling of Urban Flow through Knowledge-enhanced Denoising Diffusion

Although generative AI has been successful in many areas, its ability to model geospatial data is still underexplored. Urban flow, a typical kind of geospatial data, is critical for a wide range of urban applications. Existing studies mostly focus on predictive modeling of urban flow that predicts the future flow based on historical flow data, which may be unavailable in data-sparse areas or newly planned regions. Some other studies aim to predict OD flow among regions but they fail to model dynamic changes of urban flow over time. In this work, we study a new problem of urban flow generation that generates dynamic urban flow for regions without historical flow data. To capture the effect of multiple factors on urban flow, such as region features and urban environment, we employ diffusion model to generate urban flow for regions under different conditions. We first construct an urban knowledge graph (UKG) to model the urban environment and relationships between regions, based on which we design a knowledge-enhanced spatio-temporal diffusion model (KSTDiff) to generate urban flow for each region. Specifically, to accurately generate urban flow for regions with different flow volumes, we design a novel diffusion process guided by a volume estimator, which is learnable and customized for each region. Moreover, we propose a knowledge-enhanced denoising network to capture the spatio-temporal dependencies of urban flow as well as the impact of urban environment in the denoising process. Extensive experiments on four real-world datasets validate the superiority of our model over state-of-the-art baselines in urban flow generation. Further in-depth studies demonstrate the utility of generated urban flow data and the ability of our model for long-term flow generation and urban flow prediction. Our code is released at: https://github.com/tsinghua-fib-lab/KSTDiff-Urban-flow-generation

Integrin-mediated Cell Attachment Induces a PAK4-dependent Feedback Loop Regulating Cell Adhesion through Modified Integrin αvβ5 Clustering and Turnover

This article presents a novel mechanism deployed by cells to tune cell adhesion levels through the autoinhibitory regulation of integrin adhesion involving the activation of PAK4

TEM and EDS investigation of heterogeneous interfaces in cofired multilayer ceramic capacitors

Abstract The interfacial microstructure and cofiring migration between Ag Á/Pd electrode and Pb-based relaxor ferroelectric ceramics were directly investigated via transmission electron microscope and energy dispersive X-ray spectroscopy (EDS). Different silver migration abilities of 70Ag Á/30Pd and 90Ag Á/10Pd electrodes were confirmed by EDS microanalysis. This difference is generally considered to be responsible for different effects of inside electrode on the reliability of multilayer cofired devices. Further, Pb diffusion and new phase formation near the interface were detected, incorporating interfacial microstructural observation. A good consistency of direct experimental evidence to the following theoretic analyses was well combined in this paper.

All-Inorganic Perovskite Solar Cells With Both High Open-Circuit Voltage and Stability

Metal halide perovskite solar cells based on all-inorganic CsPbBr3 have attracted considerable attentions recently, due to their high open-circuit voltage and good stability. However, the fabrication of CsPbBr3 film is limited by the poor solubility of cesium precursors in organic solvents by the one-step method. Here, we successfully fabricated CsPbBr3 film solar cells by employing colloid nanocrystal. The effects of technique parameters, including purification times, anneal temperatures, and spin-coating times on film morphology, optical spectra, and device performance are investigated in detail. The highest power conversion efficiency of 4.57% has been achieved based on a large open-circuit voltage of 1.45 V and a large short-circuit current of 9.41 mA cm−2. A large open-circuit voltage results from the reduced non-radiative energy loss channels and defect states while a large short-circuit current is related to the high conductivity induced by the removal of organic ligands with the increased nanocrystal electronic coupling. Furthermore, excellent stability in air is disclosed on the unencapsulated device suggesting the enormous potential for developing high open-circuit photovoltaic devices with high stability in future

Roles of TNF-α gene polymorphisms in the occurrence and progress of SARS-Cov infection: A case-control study

<p>Abstract</p> <p>Background</p> <p>Host genetic factors may play a role in the occurrence and progress of SARS-Cov infection. This study was to investigate the relationship between tumor necrosis factor (TNF)-<it>α </it>gene polymorphisms with the occurrence of SARS-CoV infection and its role in prognosis of patients with lung interstitial fibrosis and femoral head osteonecrosis.</p> <p>Methods</p> <p>The association between genetic polymorphisms of <it>TNF-α </it>gene and susceptibility to severe acute respiratory syndromes (SARS) was conducted in a hospital-based case-control study including 75 SARS patients, 41 health care workers and 92 healthy controls. Relationships of TNF-α gene polymorphisms with interstitial lung fibrosis and femoral head osteonecrosis were carried out in two case-case studies in discharged SARS patients. PCR sequencing based typing (PCR-SBT) method was used to determine the polymorphisms of <it>TNF-α </it>gene in locus of the promoter region and univariate logistic analysis was conducted in analyzing the collected data.</p> <p>Results</p> <p>Compared to TT genotype, the CT genotype at the -204 locus was found associated with a protective effect on SARS with OR(95%<it>CI</it>) of 0.95(0.90–0.99). Also, TT genotype, CT and CC were found associated with a risk effect on femoral head necrosis with ORs(95%<it>CI</it>) of 5.33(1.39–20.45) and 5.67(2.74–11.71), respectively and the glucocorticoid adjusted OR of CT was 5.25(95%CI 1.18–23.46) and the combined (CT and CC) genotype OR was 6.0 (95%<it>CI </it>1.60–22.55) at -1031 site of <it>TNF-α </it>gene. At the same time, the -863 AC genotype was manifested as another risk effect associated with femoral head necrosis with OR(95%<it>CI</it>) of 6.42(1.53–26.88) and the adjusted OR was 8.40(95%CI 1.76–40.02) in cured SARS patients compared to CC genotype.</p> <p>Conclusion</p> <p>SNPs of <it>TNF-α </it>gene of promoter region may not associate with SARS-CoV infection. And these SNPs may not affect interstitial lung fibrosis in cured SARS patients. However, the -1031CT/CC and -863 AC genotypes may be risk factors of femoral head necrosis in discharged SARS patients.</p

Experimental comparison of Yb/Al/Ce and Yb/Al/P co-doped fibers on the suppression of transverse mode instability

We presented an experimental comparison of the core-composition difference on the suppression of the photodarkening and transverse mode instability effects. Two core-composition fibers, entailing Yb/Al/Ce and Yb/Al/P co-doped fibers, were fabricated by MCVD process combined with solution doping technique. The parameters of two fibers were almost the same. The PD-induced loss at equilibrium was 3.94 dB/m at 702 nm in Yb/Al/Ce fiber, while it was 0.99 dB/m in Yb/Al/P fiber. To obtain a deeper understanding of the impact of PD on laser performance, a bidirectional pumping fiber amplifier was constructed. Compared with Yb/Al/Ce co-doped fiber, the TMI thresholds of Yb/Al/P co-doped fiber were enhanced in co-pumped and counter-pumped schemes. Meanwhile, the slope efficiency in bidirectional scheme was promoted by 4%. Moreover, the transmittance at 638 nm confirmed the superior PD resistance of Yb/Al/P co-doped fiber. These experimental results pave the way for the further development of high-power fiber lasers

Cold sintering of microwave dielectric ceramics and devices

Microwave (MW) dielectric ceramics are used in numerous electronic components for modern wireless communication systems, including antennas, resonators, capacitors and filters. However, to date, MW ceramics are manufactured by an energy-intensive, conventional high-temperature (> 1000 °C) sintering technology and thus cannot be co-sintered with low melting point and base electrodes (Ag, Al, etc., < 1000 °C), nor directly integrated with polymers (< 200 °C). Cold sintering is able to densify ceramics at < 200 °C via a combination of external pressure and a transient liquid phase, reducing the energy consumed and facilitating greater integration with dissimilar materials. This review outlines the basics of MW ceramics alongside the mechanism of cold sintering. Recent developments in cold sintering of MW ceramics, composites and devices are described, emphasizing new materials and progress towards component/device fabrication. Future prospects and critical issues for advancing cold-sintered MW materials and devices, such as unclear mechanism, low Q × f values and poor mechanical properties, are discussed

Electroceramics for High-Energy Density Capacitors: Current Status and Future Perspectives

Materials exhibiting high energy/power density are currently needed to meet the growing demand of portable electronics, electric vehicles and large-scale energy storage devices. The highest energy densities are achieved for fuel cells, batteries, and supercapacitors, but conventional dielectric capacitors are receiving increased attention for pulsed power applications due to their high power density and their fast charge–discharge speed. The key to high energy density in dielectric capacitors is a large maximum but small remanent (zero in the case of linear dielectrics) polarization and a high electric breakdown strength. Polymer dielectric capacitors offer high power/energy density for applications at room temperature, but above 100 °C they are unreliable and suffer from dielectric breakdown. For high-temperature applications, therefore, dielectric ceramics are the only feasible alternative. Lead-based ceramics such as La-doped lead zirconate titanate exhibit good energy storage properties, but their toxicity raises concern over their use in consumer applications, where capacitors are exclusively lead free. Lead-free compositions with superior power density are thus required. In this paper, we introduce the fundamental principles of energy storage in dielectrics. We discuss key factors to improve energy storage properties such as the control of local structure, phase assemblage, dielectric layer thickness, microstructure, conductivity, and electrical homogeneity through the choice of base systems, dopants, and alloying additions, followed by a comprehensive review of the state-of-the-art. Finally, we comment on the future requirements for new materials in high power/energy density capacitor applications