Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles ...in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA1–7 receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling. This article is part of a Special Issue entitled: Advances in Lysophospholipid Research.
► LPA regulates cytokines and cytokine decoy receptors release in lung epithelial cells. ► LPA regulates cell–cell adherens junction and cell motility. ► LPA induces its biological responses via LPA receptors and intracellular signaling pathways. ► LPA receptors contribute to pathogenesis of lung inflammatory diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
A frequency and beam reconfigurable antenna based on encoded reflectors for Wi-Fi and IoT applications is proposed in this paper. By modifying the traditional Alford antenna, extending the ...transmission line, adding radiation arms, and loading PIN diodes, the frequency reconfigurable function can be realized. Then, the three-layer reflectors are loaded around the antenna. The pattern reconfigurable function of the antenna can be achieved by encoding the operating states of the PIN diodes on the reflectors. The antenna is fed from the bottom via a coaxial transmission line, and the dimension of the antenna is 0.99λ0 × 0.99λ0. The simulated and measured results show that the working frequencies of the antenna can be switched between 1.65, 2, and 2.4 GHz with bandwidths of 2.4%, 4.4%, and 1.2%, gains of 3, 4.5, and 2 dBi, and efficiencies of 48.8%, 75.0%, and 49.6% in directional mode, respectively. The antenna works in omnidirectional radiation mode with a scanning accuracy of 10°, bandwidths of 6.6%, 4.9%, and 0.8%, gains of 0.3, 0.52, and −2.8 dBi, and efficiencies of 73.1%, 74.1%, and 51.9% at 1.65, 2, and 2.4 GHz, respectively, when the PIN diodes are tuned in off states. The antenna proposed in this paper offers several advantages, including a wider frequency band, a broader angular range, and higher precision compared to other frequency and pattern reconfigurable antennas. The antenna can be utilized for Wi-Fi and IoT communication, thereby reducing the number of antennas, enhancing communication quality and accuracy, and improving device integration.
Lysophosphatidic acid receptor 1 (LPA1) belongs to the G protein-coupled receptor family. The ligand for LPA1 is LPA, the simplest lysophospholipid. LPA is considered a growth factor and induces cell ...proliferation, anti-apoptosis, and cell migration. The pro-inflammatory and pro-fibrotic roles of LPA have also been well-demonstrated. Most of the biological functions of LPA are mostly executed through LPA1. The mature form of LPA1 is glycosylated and localized on the plasma membrane. LPA1 is bound to heterotrimetric G proteins and transduces intracellular signaling in response to ligation to LPA. Desensitization of LPA1 negatively regulates LPA1-mediated signaling and the resulting biological functions. Phosphorylation and ubiquitination are well-demonstrated posttranslational modifications of GPCR. In this review, we will discuss our knowledge of LPA1 glycosylation, maturation, and trafficking from the endoplasmic reticulum (ER)/Golgi to the plasma membrane. Moreover, in light of recent findings, we will also discuss molecular regulation of LPA1 internalization and stability.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
OpenMM is a molecular dynamics simulation toolkit with a unique focus on extensibility. It allows users to easily add new features, including forces with novel functional forms, new integration ...algorithms, and new simulation protocols. Those features automatically work on all supported hardware types (including both CPUs and GPUs) and perform well on all of them. In many cases they require minimal coding, just a mathematical description of the desired function. They also require no modification to OpenMM itself and can be distributed independently of OpenMM. This makes it an ideal tool for researchers developing new simulation methods, and also allows those new methods to be immediately available to the larger community.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alpha-helical transmembrane proteins (αTMPs) play essential roles in drug targeting and disease treatments. Due to the challenges of using experimental methods to determine their structure, αTMPs ...have far fewer known structures than soluble proteins. The topology of transmembrane proteins (TMPs) can determine the spatial conformation relative to the membrane, while the secondary structure helps to identify their functional domain. They are highly correlated on αTMPs sequences, and achieving a merge prediction is instructive for further understanding the structure and function of αTMPs. In this study, we implemented a hybrid model combining Deep Learning Neural Networks (DNNs) with a Class Hidden Markov Model (CHMM), namely HDNNtopss. DNNs extract rich contextual features through stacked attention-enhanced Bidirectional Long Short-Term Memory (BiLSTM) networks and Convolutional Neural Networks (CNNs), and CHMM captures state-associative temporal features. The hybrid model not only reasonably considers the probability of the state path but also has a fitting and feature-extraction capability for deep learning, which enables flexible prediction and makes the resulting sequence more biologically meaningful. It outperforms current advanced merge-prediction methods with a Q4 of 0.779 and an MCC of 0.673 on the independent test dataset, which have practical, solid significance. In comparison to advanced prediction methods for topological and secondary structures, it achieves the highest topology prediction with a Q2 of 0.884, which has a strong comprehensive performance. At the same time, we implemented a joint training method, Co-HDNNtopss, and achieved a good performance to provide an important reference for similar hybrid-model training.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
South Asia experienced a weakening of summer monsoon circulation in the past several decades, resulting in rainfall decline in wet regions. In comparison with other tropical ecosystems, quantitative ...assessments of the extent and triggers of vegetation change are lacking in assessing climate‐change impacts over South Asia dominated by crops. Here, we use satellite‐based Normalized Difference Vegetation Index (NDVI) to quantify spatial–temporal changes in vegetation greenness, and find a widespread annual greening trend that stands in contrast to the weakening of summer monsoon circulation particularly over the last decade. We further show that moisture supply is the primary factor limiting vegetation activity during dry season or in dry region, and cloud cover or temperature would become increasingly important in wet region. Enhanced moisture conditions over dry region, coinciding with the decline in monsoon, are mainly responsible for the widespread greening trend. This result thereby cautions the use of a unified monsoon index to predict South Asia's vegetation dynamics. Current climate–carbon models in general correctly reproduce the dominant control of moisture in the temporal characteristics of vegetation productivity. But the model ensemble cannot exactly reproduce the spatial pattern of satellite‐based vegetation change mainly because of biases in climate simulations. The moisture‐induced greening over South Asia, which is likely to persist into the wetter future, has significant implications for regional carbon cycling and maintaining food security.
Spatial distributions of GIMMS NDVI trends over the South Asia during the three periods: 1982–2014 (first row), 1982–2001 (second row), and 2002–2014 (third row). The trends are estimated on the annual (a, d, and g), wet season (b, e, and h), and dry season basis (c, f, and i), respectively. The inset panels show the pixels where NDVI trends are statistically significant at p < .05.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
COVID-19 is the current public health threat all over the world. Unfortunately, there is no specific prevention and treatment strategy for this disease. We aim to explore the potential role of ...angiotensin-converting enzyme 2 (ACE2) in this regard through this literature review. As a crucial enzyme of renin-angiotensin-aldosterone system (RAAS), ACE2 not only mediates the virus entry but also affects the pathophysiological process of virus-induced acute lung injury (ALI), as well as other organs’ damage. As interaction of COVID-19 virus spike and ACE2 is essential for virus infection, COVID-19-specific vaccine based on spike protein, small molecule compound interrupting their interaction, human monoclonal antibody based on receptor-binding domain, and recombinant human ACE2 protein (rhuACE2) have aroused the interests of researchers. Meanwhile, ACE2 could catalyze angiotensin II (Ang II) to form angiotensin 1-7 (Ang 1-7), thus alleviates the harmful effect of Ang II and amplifies the protection effect of Ang1-7. ACE inhibitor and angiotensin II receptor blocker (ARB) have been shown to increase the level of expression of ACE2 and could be potential strategies in protecting lungs, heart, and kidneys. ACE2 plays a very important role in the pathogenesis and pathophysiology of COVID-19 infection. Strategies targeting ACE2 and its ligand, COVID-19 virus spike protein, may provide novel method in the prevention and management of novel coronavirus pneumonia.
The tumor necrosis factor receptor‐associated factor 2 (TRAF2) is a second messenger adaptor protein that plays an essential role in propagating TNF‐α‐mediated signaling pathways. Modulation of TRAF2 ...activity by ubiquitination is well studied; however, the deubiquitinating enzyme (DUB), which regulates TRAF2 stability, has not been identified. Here we reveal USP48 as the first identified DUB to deubiquitinate and stabilize TRAF2 in epithelial cells. Down‐regulation of USP48 increases K48‐linked polyubiquitination of TRAF2 and reduces TRAF2 protein levels. Interestingly, USP48 only targets the TRAF2 related to JNK pathway, not the TRAF2 related to NF‐KB and p38 pathways. USP48 is serine phosphorylated in response to TNF‐α. The phosphorylation is catalyzed by glycogen synthase kinase 3β (GSK3β), ultimately resulting in increases in USP48 DUB activity. Furthermore, we reveal a new biologic function of TRAF2 that contributes to epithelial barrier dysfunction, which is attenuated by knockdown of USP48. Inhibition of TRAF2/JNK pathway increases E (epithelial)‐cadherin expression and enhances epithelial barrier integrity, while knockdown of USP48 attenuates TNF‐α/JNK pathway and increases E‐cadherin expression and cell‐cell junction in epithelial cells. These data, taken together, indicate that USP48 stabilizes TRAF2, which is promoted by GSK3β‐mediated phosphorylation. Further, down‐regulation of USP48 increases E‐cadherin expression and epithelial barrier integrity through reducing TRAF2 stability.—Li, S., Wang, D., Zhao, J., Weathington, N. M., Shang, D., Zhao, Y. The deubiquitinating enzyme USP48 stabilizes TRAF2 and reduces E‐cadherin‐mediated adherens junctions. FASEB J. 32,230‐242 (2018). www.fasebj.org
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a ...variety of human disorders, such as inflammatory diseases and cancers. Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases. Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability, receptor internalization, enzyme activity, and protein-protein interactions. Ubiquitination is tightly regulated by ubiquitin E3 ligases and can be reversed by deubiquitinating enzymes. Recent studies have been focusing on investigating the effect of protein stability in the regulation of cell-cell junctions. Ubiquitination and degradation of cadherins, claudins, and their interacting proteins are implicated in epithelial and endothelial barrier disruption. Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases' biological activities. Taken together these studies, ubiquitination plays a critical role in modulating cell junctions and motility. In this review, we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions, including junction proteins, their interacting proteins, and small Rho GTPases. We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiquitination on human disorders caused by dysfunction of cell junctions.
Pulmonary fibrosis is a fatal and chronic lung disease that is characterized by accumulation of thickened scar in the lungs and impairment of gas exchange. The cases with unknown etiology are ...referred as idiopathic pulmonary fibrosis (IPF). There are currently no effective therapeutics to cure the disease; thus, the investigation of the pathogenesis of IPF is of great importance. Recent studies on bone morphogenic proteins (BMPs) and their receptors have indicated that reduction of BMP signaling in lungs may play a significant role in the development of lung fibrosis. BMPs are members of TGF-β superfamily, and they have been shown to play an anti-fibrotic role in combating TGF-β-mediated pathways. The impact of BMP receptors, in particular BMPR2, on pulmonary fibrosis is growing attraction to researchers. Previous studies on BMPR2 have often focused on pulmonary arterial hypertension (PAH). Given the strong clinical association between PAH and lung fibrosis, understanding BMPs/BMPR2-mediated signaling pathway is important for development of therapeutic strategies to treat IPF. In this review, we comprehensively review recent studies regarding the biological functions of BMPs and their receptors in lungs, especially focusing on their roles in the pathogenesis of pulmonary fibrosis and fibrosis resolution.
•Reduction of BMPs/BMPR2 signaling contributes to the pathogenesis of pulmonary fibrosis.•BMPs/BMPR2 signaling plays an anti-fibrotic role in lung fibroblasts.•The new strategies that activate BMPs/BMPR2 signaling may reduce severity of pulmonary fibrosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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