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Abstract Endothelial cell (EC) barrier disruption and inflammation are the pathological hallmarks of vascular disorders and acute infectious diseases and related conditions, including the coronavirus disease 2019 (COVID-19) and sepsis. Ubiquitination plays a critical role in regulating the stability, intracellular trafficking, and enzymatic activity of proteins and is reversed by deubiquitinating enzymes (DUBs). The role of DUBs in endothelial biology is largely unknown. In this study, we report that USP40, a poorly characterized DUB, prevents EC barrier disruption through reductions in the activation of RhoA and phosphorylation of myosin light chain (MLC) and cofilin. Furthermore, USP40 reduces EC inflammation through the attenuation of NF-ĸB activation, ICAM1 expression, and leukocyte-EC adhesion. We further show that USP40 activity and expression are reduced in response to endotoxin challenge. Global depletion of USP40 and EC-targeted USP40 depletion in mice exacerbated experimental lung injury, whereas lentiviral gene transfer of USP40 protected against endotoxin-induced lung injury. Using an unbiased approach, we discovered that the protective effect of USP40 occurs through the targeting of heat shock protein 90β (HSP90β) for its deubiquitination and inactivation. Together, these data reveal a critical protective role of USP40 in vascular injury, identifying a unique mechanistic pathway that profoundly impacts endothelial function via DUBs.

Anomalous bright spots, called the string of bead-like response, are typical seismic migration profile features in carbonate fractured reservoirs in the Tarim Basin, and they are indicators of high-quality oil and gas reservoirs. Correctly recognizing the correspondence between fractures and the SBLR can contribute to the efficient drilling of target carbonate fractured reservoirs. Physical models can describe fractured reservoirs more directly and efficiently than real situations and have obvious advantages in accurately and quantitatively designing parameters such as dipping angles and the number of layers of fractured reservoirs. Under such a background, according to the real tectonic characteristics of the Tarim Basin, among the main hydrocarbon reservoirs, fractured reservoirs with various parameters were designed and a physical model was constructed according to the real stratigraphic parameters. After seismic data acquisition and processing, the response characteristics of the string of bead-like response were extracted and summarized from seismic migration profiles for all fractured reservoirs, which provided targeted analyses and discussions on the fracture dipping angle, number of fracture layers, overlying stratigraphic influences, and planar attributes of the fractured reservoirs. In general, the larger the fracture dip, the more difficult it is to identify, while the slope of reflection strength and maximum absolute amplitude attributes can be important markers for fractured reservoir identification. The physical modeling study of fractured reservoirs in this paper can provide a basis for the analysis and prediction of carbonate fractured reservoirs in the Tarim Basin.

Prediction of fine particulate matter with particle size less than 2.5 µm (PM2.5) is an important component of atmospheric pollution warning and control management. In this study, we propose a deep learning model, namely, a spatiotemporal weighted neural network (STWNN), to address the challenge of poor long-term PM2.5 prediction in areas with sparse and uneven stations. The model, which is based on convolutional neural network–bidirectional long short-term memory (CNN–Bi-LSTM) and attention mechanisms and uses a geospatial data-driven approach, considers the spatiotemporal heterogeneity effec It is correct.ts of PM2.5. This approach effectively overcomes instability caused by sparse station data in forecasting daily average PM2.5 concentrations over the next week. The effectiveness of the STWNN model was evaluated using the Xinjiang Uygur Autonomous Region as the study area. Experimental results demonstrate that the STWNN exhibits higher performance (RMSE = 10.29, MAE = 6.4, R2 = 0.96, and IA = 0.81) than other models in overall prediction and seasonal clustering. Furthermore, the SHapley Additive exPlanations (SHAP) method was introduced to calculate the contribution and spatiotemporal variation of feature variables after the STWNN prediction model. The SHAP results indicate that the STWNN has significant potential in improving the performance of long-term PM2.5 prediction at the regional station level. Analyzing spatiotemporal differences in key feature variables that influence PM2.5 provides a scientific foundation for long-term pollution control and supports emergency response planning for heavy pollution events.

Background: Trunk volume (Vt) is an essential parameter for estimating forest stand volume, biomass, and carbon sequestration potential. As the dominant tree species in desert riparian forests, Euphrates poplar (Populus euphratica) has a high proportion of irregularly shaped tree trunks along the Tarim River, NW China, where the habitat is very fragile owing to long-term water stress. This causes uncertainty in estimation accuracy as well as technical challenges for forest surveys. Our study aimed to acquire P. euphratica Vt using terrestrial laser scanning (TLS) and to establish a species-specific Vt prediction model. Methods: A total of 240 individual trees were measured by TLS multiple-station in 12 sampling plots in three sections along the lower reaches of the Tarim River. Vt was calculated by a definite integration method using trunk diameters (Di) at every 0.1-m tree height obtained from TLS, and all data were split randomly into two sets: 70% of data were used to estimate the model parameter calibration, and the remaining 30% were used for model validation. Sixteen widely used candidate tree Vt estimation models were fitted to the TLS-measured Vt and tree structural parameter data, including tree height (H), diameter at breast height (DBH), and basal diameter (BD). All model performances were evaluated and compared by the statistical parameters of determination coefficient (R2), root mean square error (RMSE), Bayesian information criterion (BIC), mean prediction error (ME), mean absolute error (MAE), and modeling efficiency (EF), and accordingly the best model was selected. Results: TLS point cloud reflection intensity (RI) has advantageous in the extraction of data from irregular tree trunk structures. The P. euphratica tree Vt values showed obvious differences at the same tree height (H). There was no significant correlation between Vt and H (R2 ​= ​0.11, P ​

Populus euphratica Oliv. (Euphrates poplar), as the dominant tree species of desert riparian forests along the Central Asian inland rivers, plays a critical role in protecting arid land ecosystems. In recent decades, climate change and excessive water resources utilization activities have led to the environmental degradation of desert riparian forests along the Tarim River in northwest China. Understanding the forest stand structure and spatial distribution pattern provide important guidance for monitoring forest dynamics in support of sustainable management. However, few studies have examined how riparian forests stand attributes differ in response to environmental heterogeneity. In this study, terrestrial laser scanning (TLS) was applied to acquire a total of 1648 individual P. euphratica tree’s 3D structure attributes within 18 plots along the upper, middle, and lower reaches of the Tarim River, which included tree height (TH), diameter at breast height (DBH), crown diameter (CD), crown projection area (CPA), stand density index (SDI), age structure ratios, and spatial pattern. The results showed that the average tree segmentation and structure determination accuracies of TLS were 93.2 and 94.6%. From the upper to the lower reaches, the average TH and CD decreased by 3.8 and 0.3 m, while the DBH increased by 4.2 cm. The SDI and CPA exhibited the following order: upper reaches (454 n ha–1, 82.3%) > middle reaches (382 n ha–1, 67.3%) > lower reaches (263 n ha–1, 39.1%), the differences were significant at 0.05 level. The population age structure changed from growing population in the upper reaches to stable population in the middle and a temporarily stable population in the lower reaches. The pair correlation g(r) function determined random distribution pattern in the upper reaches [g(r) = 1.2], an aggregated pattern in the middle [g(r) = 3.1], and lower reaches [g(r) = 9.7]. The decline in groundwater depth and soil moisture increased aggregated distribution pattern (R = 0.67 and 0.56, P < 0.05) of the P. euphratica along the mainstream of Tarim River. The results enrich our understanding of the current development stage of P. euphratica, which is important for optimizing management strategies and realizing the sustainability of floodplain ecosystems.

Summary: miRNAs are versatile regulators of smooth muscle cell (SMC) fate and behavior in vascular development and disease. Targeted loss-of-function studies have established the relevance of specific miRNAs in controlling SMC differentiation or mediating phenotypic modulation. Our goal was to characterize SMC miRNAome and its contribution to transcriptome changes during phenotypic modulation. Small RNA sequencing revealed that dedifferentiation led to the differential expression of over 50 miRNAs in cultured SMC. miRNA/mRNA comparison predicted that over a third of SMC transcript expression was regulated by differentially expressed miRNAs. Our screen identified the miR-200 cluster as highly downregulated during dedifferentiation. miR-200 maintains SMC quiescence and represses proliferation, migration, and neointima formation, in part by targeting Quaking, a central SMC phenotypic switching mediator. Our study unraveled the substantial contribution of miRNAs in regulating the SMC transcriptome and identified the miR-200 cluster as a pro-quiescence mechanism and a potential inhibitor of vascular restenosis.

Necroptosis has emerged as a potential mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Here, we found that markers of necroptosis, including high mobility group box 1 release and phosphorylation of mixed lineage kinase domain-like protein (p-MLKL), were markedly induced in the late stage of cigarette smoking–induced (CS-induced) emphysema in mouse lung tissue as well as in lung epithelial cells and organoids with higher dosage of or more prolonged exposure to cigarette smoking extract (CSE). Apoptotic signals were also detected and maximally induced in the early stage of CS-exposed mice and CSE-treated epithelial cells. Inhibition of apoptosis by Z-VAD, a pan-caspase inhibitor, switched the cellular stress to enhanced necroptosis in lung epithelial cells and organoids treated with CSE. Depletion or inhibition of receptor-interacting protein kinase 3 (RIP3) or MLKL attenuated the CSE-induced cell death, suggesting that necroptosis contributes to CSE-induced cell death. Silencing or inhibition of RIP1 had no protective effect, indicating a RIP1-independent RIP3 activation pathway. CSE-induced necroptosis released more damage-associated molecular patterns and evoked greater engulfment but slower clearance by bone marrow–derived macrophages, leading to enhanced expression of proinflammatory cytokines Tnfα and Il6. Finally, our in vivo data verified that inhibition of necroptosis by RIP3 inhibitor GSK’872 protected mice from CS-induced emphysema and suppressed the lung inflammation. In conclusion, we provide evidence that necroptosis contributes to the pathogenesis of COPD. Targeting RIP3 and its downstream pathway may be an effective therapy for COPD.

Objective The present meta-analysis aimed to determine the relationship between intra-abdominal hypertension (IAH) and an increased prevalence of acute kidney injury (AKI) and identify the associated risk factors in various patient populations, regardless of whether they were admitted to an intensive care unit. Methods We used three databases for the following search terms: “IAH,” “abdominal compartment syndrome,” “AKI,” “acute kidney failure,” and others. The articles retrieved were compared to identify appropriate studies published until 7 May 2020. The main outcome was AKI. Results Six studies with 344 individuals were included. The patients were divided into two main groups: the IAH and non-IAH groups. Compared with patients without IAH, patients with IAH had a higher risk of AKI (odds ratio = 2.57, 95% confidence interval: 1.55–4.26). In the subgroup and meta-regression analyses, body mass index, age, the presence or absence of burns, and cardiac surgery did not affect the risk of AKI. Conclusion IAH was associated with AKI risk, and this association was not influenced by age, body mass index, the presence or absence of burns, or cardiac surgery.

Background: The Single immunoglobin interleukin-1 (IL-1)-related receptor (Sigirr), also known as IL-1R8, has been shown to exhibit broad anti-inflammatory effects against inflammatory diseases including acute lung injury, while molecular regulation of IL-1R8/Sigirr protein stability has not been reported. This study is designed to determine whether stabilization of IL-1R8/Sigirr by a deubiquitinating enzyme (DUB) is sufficient to suppress inflammatory responses and lessen lung inflammation. Methods: A molecular signature of ubiquitination and degradation of IL-1R8/Sigirr was determined using a receptor ligation chase model. The anti-inflammatory effects on USP13 were investigated. USP13 knockout mice were evaluated for stabilization of IL-1R8/Sigirr and disease phenotype in an acute lung injury model. Findings: IL-1R8/Sigirr degradation is mediated by the ubiquitin-proteasome system, through site-specific ubiquitination. This effect was antagonized by the DUB USP13. USP13 levels correlate directly with IL-1R8/Sigirr, and both proteins were reduced in cells and tissue from mice subjected to inflammatory injury by the TLR4 agonist lipopolysaccharide (LPS). Knockdown of USP13 in cells increased IL-1R8/Sigirr poly-ubiquitination and reduced its stability, which enhanced LPS-induced TLR4 signaling and cytokine release. Likewise, USP13-deficient mice were highly susceptible to LPS or Pseudomonas aeruginosa models of inflammatory lung injury. IL-1R8/Sigirr overexpression in cells or by pulmonary viral transduction attenuated the inflammatory phenotype conferred by the USP13−/− genotype. Interpretation: Stabilization of IL-1R8/Sigirr by USP13 describes a novel anti-inflammatory pathway in diseases that could provide a new strategy to modulate immune activation. Fund: This study was supported by the US National Institutes of Health (R01HL131665, HL136294 to Y.Z., R01 GM115389 to J.Z.). Keywords: Deubiquitinating enzyme, Anti-inflammation, Cytokine receptor, Protein stability

There are various methods available which are used to search large chemical databases and to predict the physicochemical properties of molecular structures. Using molecular descriptors for this purpose is the simplest of these methods. The Zagreb indices are amongst the oldest molecular descriptors, and their properties have been extensively studied and applied in QSAR/QSPR studies. The Zagreb coindices were recently introduced, attracting the attention of researchers in mathematical chemistry. In this paper, we study Zagreb indices and several other Zagreb-type indices including the general Randić index, sum-connectivity index, F-index, and Zagreb coindices of R-vertex and edge join of two arbitrary graphs.

Circulant networks form a very important and widely explored class of graphs due to their interesting and wide-range applications in networking, facility location problems, and their symmetric properties. A resolving set is a subset of vertices of a connected graph such that each vertex of the graph is determined uniquely by its distances to that set. A resolving set of the graph that has the minimum cardinality is called the basis of the graph, and the number of elements in the basis is called the metric dimension of the graph. In this paper, the metric dimension is computed for the graph Gn1,k constructed from the circulant graph Cn1,k by subdividing its edges. We have shown that, for k=2, Gn1,k has an unbounded metric dimension, and for k=3 and 4, Gn1,k has a bounded metric dimension.

Lysophosphatidic acid receptor 1 (LPA1) is a druggable target for treating pulmonary inflammatory diseases. However, the molecular regulation of LPA1 stability, a factor that critically impacts its biological activity, remains largely unknown. Here we identify two enzymes that regulate the balance of LPA1 ubiquitination and deubiquitination. Ubiquitin E3 ligase Nedd4L targets LPA1 for its site specific ubiquitination and degradation in the lysosome. Nedd4L negatively regulates LPA-LPA1-mediated cytokine release. The stability of LPA1 is up-regulated by ubiquitin-specific protease 11 (USP11), which deubiquitinates LPA1 and enhances LPA1-mediated pro-inflammatory effects. LPA1 is associated with USP11 in quiescent cells, while LPA treatment triggers LPA1 dis-association with USP11 and in turn binding to Nedd4L. Knockdown or inhibition of USP11 reduces LPA1 stability, levels of LPA1, and LPA1-CD14 interaction complex; thereby diminishing both LPA- and LPS-induced inflammatory responses and lung injury in preclinical murine models. Thus, our findings identify an ubiquitin E3 ligase and a deubiquitinating enzyme responsible for regulation of LPA1 stability and biological activities. This study provides potential targets for the development of anti-inflammatory molecules to lessen lung injury.

Maintenance of pulmonary endothelial barrier integrity is important for reducing severity of lung injury. Lysophosphatidic acid (LPA) regulates cell motility, cytoskeletal rearrangement, and cell growth. Knockdown of LPA receptor 1 (LPA1) has been shown to mitigate lung injury and pulmonary fibrosis. AM966, an LPA1 antagonist exhibiting an antifibrotic property, has been considered to be a future antifibrotic medicine. Here, we report an unexpected effect of AM966, which increases lung endothelial barrier permeability. An electric cell-substrate sensing (ECIS) system was used to measure permeability in human lung microvascular endothelial cells (HLMVECs). AM966 decreased the transendothelial electrical resistance (TEER) value immediately in a dose-dependent manner. VE-cadherin and f-actin double immunostaining reveals that AM966 increases stress fibers and gap formation between endothelial cells. AM966 induced phosphorylation of myosin light chain (MLC) through activation of RhoA/Rho kinase pathway. Unlike LPA treatment, AM966 had no effect on phosphorylation of extracellular signal-regulated kinases (Erk). Further, in LPA1 silencing cells, we observed that AM966-increased lung endothelial permeability as well as phosphorylation of VE-cadherin and focal adhesion kinase (FAK) were attenuated. This study reveals that AM966 induces lung endothelial barrier dysfunction, which is regulated by LPA1-mediated activation of RhoA/MLC and phosphorylation of VE-cadherin.

In this work, we applied a robust and fully air-coupled method to investigate the propagation of the lowest-order antisymmetric Lamb (A0) mode in both a stubbed and an air-drilled phononic-crystal (PC) plate. By measuring simply the radiative acoustic waves of A0 mode close to the plate surface, we observed the band gaps for the stubbed PC plate caused by either the local resonance or the Bragg scattering, in frequency ranges in good agreement with theoretical predictions. We measured then the complete band gap of A0 mode for the air-drilled PC plate, in good agreement with the band structures. Finally, we compared the measurements made using the air-coupled method with those obtained by the laser ultrasonic technique.

Background: Trunk volume (Vt) is an essential parameter for estimating forest stand volume, biomass, and carbon sequestration potential. As the dominant tree species in desert riparian forests, Euphrates poplar (Populus euphratica) has a high proportion of irregularly shaped tree trunks along the Tarim River, NW China, where the habitat is very fragile owing to long-term water stress. This causes uncertainty in estimation accuracy as well as technical challenges for forest surveys. Our study aimed to acquire P. euphratica Vt using terrestrial laser scanning (TLS) and to establish a species-specific Vt prediction model. Methods: A total of 240 individual trees were measured by TLS multiple-station in 12 sampling plots in three sections along the lower reaches of the Tarim River. Vt was calculated by a definite integration method using trunk diameters (Di) at every 0.1-m tree height obtained from TLS, and all data were split randomly into two sets: 70% of data were used to estimate the model parameter calibration, and the remaining 30% were used for model validation. Sixteen widely used candidate tree Vt estimation models were fitted to the TLS-measured Vt and tree structural parameter data, including tree height (H), diameter at breast height (DBH), and basal diameter (BD). All model performances were evaluated and compared by the statistical parameters of determination coefficient (R²), root mean square error (RMSE), Bayesian information criterion (BIC), mean prediction error (ME), mean absolute error (MAE), and modeling efficiency (EF), and accordingly the best model was selected. Results: TLS point cloud reflection intensity (RI) has advantageous in the extraction of data from irregular tree trunk structures. The P. euphratica tree Vt values showed obvious differences at the same tree height (H). There was no significant correlation between Vt and H (R² = 0.11, P < 0.01), which reflected the irregularity of P. euphratica trunk shape in the study area. Among all the models, model (14): Vt = 0:909DBH1:184H0:487BD0:836 (R² = 0.97, RMSE = 0.14) had the best prediction capability for irregularly shaped Vt with the highest R², BIC (-37.96), and EF (0.96), and produced a smaller ME (0.006) and MAE (1.177) compared to other models. The prediction accuracy was 93.18%. Conclusions: TLS point cloud RI has a potential for nondestructively measuring irregularly shaped trunk structures of P. euphratica and developed Vt prediction models. The multivariate models more effectively predicted Vt for irregularly shaped trees compared to one-way and general volume models. [ABSTRACT FROM AUTHOR]

Accurate estimates of forest aboveground biomass (AGB) are essential for global carbon cycle studies and have widely relied on approaches using spectral and structural information of forest canopies extracted from various remote sensing datasets. However, combining the advantages of active and passive data sources to improve estimation accuracy remains challenging. Here, we proposed a new approach for forest AGB modeling based on allometric relationships and using the form of power-law to integrate structural and spectral information. Over 60 km² of drone light detection and ranging (LiDAR) data and 1,370 field plot measurements, covering the four major forest types of China (coniferous forest, sub-tropical broadleaf forest, coniferous and broadleaf-leaved mixed forest, and tropical broadleaf forest), were collected together with Sentinel-2 images to evaluate the proposed approach. The results show that the most universally useful structural and spectral metrics are the average values of canopy height and spectral index rather than their maximum values. Compared with structural attributes used alone, combining structural and spectral information can improve the estimation accuracy of AGB, increasing R² by about 10% and reducing the root mean square error by about 22%; the accuracy of the proposed approach can yield a R² of 0.7 in different forests types. The proposed approach performs the best in coniferous forest, followed by sub-tropical broadleaf forest, coniferous and broadleaf-leaved mixed forest, and then tropical broadleaf forest. Furthermore, the simple linear regression used in the proposed method is less sensitive to sample size and outperforms statistically multivariate machine learning-based regression models such as stepwise multiple regression, artificial neural networks, and Random Forest. The proposed approach may provide an alternative solution to map large-scale forest biomass using space-borne LiDAR and optical images with high accuracy. [ABSTRACT FROM AUTHOR]

Endothelial cell (EC) inflammation is regarded as an important pathogenic feature of many inflammatory diseases, including acute lung injury and sepsis. An increase in EC inflammation results in neutrophil infiltration from the blood to the site of inflammation, further promoting EC permeability. The ubiquitin E3 ligase TRIM21 has been implicated in human disorders; however, the roles of TRIM21 in endothelial dysfunction and acute lung injury have not been reported. Here, we reveal an antiinflammatory property of TRIM21 in a mouse model of acute lung injury and human lung microvascular ECs. Overexpression of TRIM21 by lentiviral vector infection effectively dampened LPS-induced neutrophil infiltration, cytokine release, and edema in mice. TRIM21 inhibited human lung microvascular endothelial cell inflammatory responses as evidenced by attenuation of the NF-kB pathway, release of IL-8, expression of intercellular adhesion molecules, and adhesion of monocytes to ECs. Furthermore, we demonstrated that TRIM21 was predominantly degraded by an increase in its monoubiquitination and lysosomal degradation after inflammatory stimuli. Thus, inhibition of vascular endothelial inflammation by TRIM21 provides a novel therapeutic target to lessen pulmonary inflammation. [ABSTRACT FROM AUTHOR]

Ubiquitin E3 ligases mediate ubiquitination and degradation of intracellular proteins. We have shown that a relatively new Skp, Cullin, F-box (SCF) protein E3 ligase, SCF FBXL19, has an anti-inflammatory effect and controls actin cytoskeleton dynamics via targeting cell membrane receptor and small GTPases for their ubiquitination and degradation, but the molecular regulation of its subunit FBXL19 stability remains unclear. Here we show that FBXL19 degradation is controlled by the balance between its ubiquitination and acetylation. FBXL19 is an unstable protein with a half-life of ~3 h. FBXL19 can be polyubiquitinated, and the proteasome inhibitor MG-132 prolongs FBXL19 half-life, suggesting that FBXL19 degradation is mediated in the ubiquitin-proteasome system. FBXL19 can also be acetylated, and enhancing acetylation of FBXL19 by a deacetylase inhibitor reduces FBXL19 ubiquitination levels. Acetylation-mimic FBXL19 mutant exhibits a longer half-life than wild type. An acetyltransferase CBP catalyzes acetylation of FBXL19. Inhibition or down-regulation of CBP reduces FBXL19 stability, whereas it is increased in CBP-overexpressing cells. Taken together, the data indicate that CBP-mediated acetylation reduces ubiquitination and stabilizes FBXL19. Further, we demonstrate that FBXL19 targets small GTPase Cdc42 for its ubiquitination and degradation, whereas this effect is reversed by inhibition of CBP, suggesting that CBP increases the effect of SCF FBXL19 E3 ligase through acetylation and stabilization of FBXL19. Our study reveals a new molecular model for regulation of SCF E3 ligase function by acetylation and stabilization of its subunit F-box protein. [ABSTRACT FROM AUTHOR]

Understanding the influence of lithology, porosity, permeability, pore structure, fluid content and fluid distribution on the elastic wave properties of porous rocks is of great significance for seismic exploration. However, unlike conventional sandstones, the petrophysical characteristics of tight sandstones are more complex and less understood. To address this problem, we measured ultrasonic velocity in partially saturated tight sandstones under different effective pressures. A new model is proposed, combining the Mavko-Jizba-Gurevich relations and the White model. The proposed model can satisfactorily simulate and explain the saturation dependence and pressure dependence of velocity in tight sandstones. Under low effective pressure, the relationship of P-wave velocity to saturation is pre-dominantly attributed to local (pore scale) fluid flow and inhomogeneous pore-fluid distribution (large scale). At higher effective pressure, local fluid flow gradually decreases, and P-wave velocity gradually shifts from uniform saturation towards patchy saturation. We also find that shear modulus is more sensitive to saturation at low effective pressures. The new model includes wetting ratio, an adjustable parameter that is closely related to the relationship between shear modulus and saturation. [ABSTRACT FROM AUTHOR]

The presence of clay minerals can alter the elastic behaviour of reservoir rocks significantly as the type of clay minerals, their volume and distribution, and their orientation control the shale's intrinsic anisotropic behaviours. Clay minerals are the most abundant materials in shale, and it has been proven extremely difficult to measure the elastic properties of natural shale by means of a single variable (in this case, the type of clay minerals), due to the influences of multiple factors, including water, TOC content and complex mineral compositions. We used quartz, clay (kaolinite, illite and smectite), carbonate and kerogen extract as the primary materials to construct synthetic shale with different clay minerals. Ultrasonic experiments were conducted to investigate the anisotropy of velocity and mechanical properties in dry synthetic and natural shale as a function of confining pressure. Velocities in synthetic shale are sensitive to the type of clay minerals, possibly due to the different structures of the clay minerals. The velocities increase with confining pressure and show higher rate of velocity increase at low pressures, and P-wave velocity is usually more sensitive than S-wave velocity to confining pressure according to our results. Similarly, the dynamic Young's modulus and Poisson's ratio increase with applied pressure, and the results also reveal that E11 is always larger than E33 and 31 is smaller than ν12. Velocity and mechanical anisotropy decrease with increasing stress, and are sensitive to stress and the type of clay minerals. However, the changes of mechanical anisotropy with applied stress are larger compared with the velocity anisotropy, indicating that mechanical properties are more sensitive to the change of rock properties. [ABSTRACT FROM AUTHOR]

Phosphorylation affects ubiquitination, stability, and activity of transcriptional factors, thus regulating various cellular functions. E2F transcriptional factor 1 (E2F1) regulates paternally expressed imprinted gene 10 (Peg10) expression, thereby promoting cell proliferation. However, the effect of E2F1 stability on Peg10 expression and the molecular regulation of E2F1 stability by its phosphorylation have not been well demonstrated. Here, we describe a new pathway in which phosphorylation of E2F1 by GSK3ß increases E2F1 association with the deubiquitinating enzyme, ubiquitin-specific protease 11 (USP11), which removes K63-linked ubiquitin chains thereby preventing E2F1 degradation in the nuclei. Downregulation of USP11 increases E2F1 ubiquitination and reduces E2F1 stability and protein levels, thereby decreasing Peg10 mRNA levels. Physiologically, USP11 depletion suppresses cell proliferation and wound healing in lung epithelial cells, and these effects are reversed by E2F1 and PEG10 overexpression. Thus, our study reveals a new molecular model that phosphorylation promotes substrate stability through increasing its association with a deubiquitinating enzyme. The data suggest that GSK3ß and USP11 act in concert to modulate E2F1 abundance and PEG10 expression in lung epithelial cells to affect cell wound healing. This study provides new therapeutic targets to lessen lung injury by improving lung epithelial cell repair and remodeling after injury. [ABSTRACT FROM AUTHOR]

Anemia is a very common blood disorder that affects the lives of billions of people worldwide. Anemia is caused by the loss of blood, increased destruction of red blood cells (RBCs), or reduced production of RBCs. Erythropoiesis is the complex process of RBC differentiation and maturation, in which protein degradation plays a crucial role. Protein ubiquitination regulates programmed protein degradation, which can be reversed by deubiquitinating enzymes (DUBs); however, the role of DUBs in erythropoiesis has not been well studied. We examined the expression of DUBs during erythropoiesis using an ex vivo human CD34+ hematopoietic progenitor cell culture system. Here we show that ubiquitin-specific protease 50 (USP50) levels are increased during erythropoiesis. USP50 mRNA levels are significantly increased on day 3 and protein levels are elevated on day 9 of erythroid differentiation. Coimmunoprecipitation and proteomics analyses reveal that Ku70, a DNA-binding protein, is associated with USP50. Overexpression of USP50 has no effect on Ku70 mRNA levels, while it reduces Ku70 protein levels by promoting Ku70 degradation, suggesting that USP50 may indirectly regulate Ku70 protein stability. USP50 protein is also not stable. USP50 protein degradation is independent of the proteasomal and the lysosomal degradation systems. This study suggests that DUBs like USP50 may regulate protein stability during erythropoiesis; however, more investigation is warranted. [ABSTRACT FROM AUTHOR]

Effects of quenching process on dielectric, ferroelectric, and piezoelectric properties of 0.71BiFeO3-0.29BaTiO3 ceramics with Mn modification (BF-BT-xmol%Mn) were investigated. The dielectric, ferroelectric, and piezoelectric properties of BF- BT-xmol%Mn were improved by quenching, especially to the BF-BT-0.3 mol% Mn ceramics. The dielectric loss tand of quenched BF-BT-0.3 mol%Mn ceramics was only 0.28 at 500°C, which was half of the slow cooling one. Meanwhile, the remnant polarization Pr of quenched BF-BT-0.3 mol%Mn ceramics increased to 21 lC/cm2. It was notable that the piezoelectric constant d33 of quenched BF-BT-0.3 mol%Mn ceramics reached up to 191 pC/N, while the TC was 530°C, showing excellent compatible properties. The BF-BT-xmol%Mn system ceramics showed to obey the Rayleigh law within suitable field regions. The Rayleigh law results indicated that the extrinsic contributions to the dielectric and piezoelectric responses of quenched BF-BT-xmol%Mn ceramics were larger than the unquenched ceramics. These results presented that the quenched BF-BT-xmol%Mn ceramics were promising candidates for high-temperature piezoelectric devices. [ABSTRACT FROM AUTHOR]

We have built an experimental device and performed seismoelectric physical modelling experiments on sandstone rock models with different geometries. Our aims are (1) to gain insight into the interface response behaviour of rock models with different geometry, (2) to illustrate the amplitude characteristics of the interface responses induced by incident waves and reflections of multiple interfaces and (3) to investigate the polarity reversal of the interface responses generated at different interfaces. For experimental preciseness, we conducted a series of control measurements on sandstone to confirm that we indeed measured the seismoelectric conversion, and gained insight on the influence of the surface wave coseismic signals and the P-wave coseismic signals. The seismoelectric results of wedge model verify that a thin layer structure can enhance the seismoelectric signal. The strength differences between the incident-wave-induced signals and the reflection-induced signals have significant effects on the interpretation of underground structures and interfaces. The incident-wave-induced signals at the lower interface may be neglected easily for its small amplitude, while the reflection-induced signals at the upper interface with a longer traveltime may be regarded as a new event of a lower interface for its large amplitude. Therefore, the depth of interfaces is likely to be misinterpreted. Our experiments show that the polarity reversal of interface responses is affected by receiver positions. For a given interface measured with electrodes at different depths in a borehole, seismoelectric interface responses recorded by electrodes on two sides of an interface have the opposite polarity. For multiple interfaces measured with one electrode, the polarity of the interface responses from the interfaces above the electrode reverses with that from the interfaces below the electrode. The variation characteristics of the polarity reversal can help to correct the polarity variation affected by the electrodes position for the seismoelectric record. Both the amplitude and polarity analysis may contribute to a better interpretation of field seismoelectric records. [ABSTRACT FROM AUTHOR]

Cyclic adenosine monophosphate (cAMP) response element-binding protein (CREB)-binding protein (CBP) is a histone acetyltransferase that plays a pivotal role in the control of histone modification and the expression of cytokine-encoding genes in inflammatory diseases, including sepsis and lung injury. We found that the E3 ubiquitin ligase subunit FBXL19 targeted CBP for site-specific ubiquitylation and proteasomal degradation. The ubiquitylationdependent degradation of CBP reduced the extent of lipopolysaccharide (LPS)-dependent histone acetylation and cytokine release in mouse lung epithelial cells and in a mouse model of sepsis. Furthermore, we demonstrated that the deubiquitylating enzyme USP14 (ubiquitin-specific peptidase 14) stabilized CBP by reducing its ubiquitylation. LPS increased the stability of CBP by reducing the association between CBP and FBXL19 and by activating USP14. Inhibition of USP14 reduced CBP protein abundance and attenuated LPS-stimulated histone acetylation and cytokine release. Together, our findings delineate the molecular mechanisms through which CBP stability is regulated by FBXL19 and USP14, which results in the modulation of chromatin remodeling and the expression of cytokine-encoding genes. [ABSTRACT FROM AUTHOR]

Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skp1/Cullin-1/Fbox (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial cells through lysine 183 as an acceptor site for K48 polyubiquitination. We have identified FBXO17 as an F-box protein subunit that recognizes and mediates GSK3β polyubiquitination. Both endogenous and ectopically expressed FBXO17 associate with GSK3β, and its overexpression leads to decreased protein levels of GSK3β. Silencing FBXO17 gene expression increased the half-life of GSK3β in cells. Furthermore, overexpression of FBXO17 inhibits agonist-induced release of keratinocyte-derived cytokine (KC) and interleukin-6 (IL-6) production by cells. Thus, the SCFFBXO17 E3 ubiquitin ligase complex negatively regulates inflammation by targeting GSK3β in lung epithelia. [ABSTRACT FROM AUTHOR]

We have developed a method of nonstationary sparse reflectivity inversion (NSRI) that directly retrieves the reflectivity series from nonstationary seismic data without the intrinsic instability associated with inverse Q filtering methods. We have investigated the NSRI performance in the presence of input error (e.g., the phase shift and the peak frequency of the wavelet), which determined that NSRI results are reasonable in the case of moderate error. NSRI was then applied to data collected from a laboratory physical model made of highly attenuating media, for which true reflectivities were known, but the wave propagation and the Q filtering mechanism were not. Analysis of data from the physical model, therefore, represented a blind test for evaluating the effectiveness and accuracy of NSRI. The physical model had a specified spatial scale of 1:5000 (relative to the field scale) and an approximate 1:1 velocity scale. Because the Q input is required by NSRI, attenuation of the P-wave was measured in the laboratory at ultrasonic frequencies with a pulse transmission technique and the spectral ratio method. Although multiples, side reflections from the model boundaries, diffractions, and other event types were clearly observed from the raw data, no preprocessing was done to avoid affecting the Q filtering effects. Results from the physical modeling data demonstrated that the derived formula for an attenuated seismogram was correct and estimated Q values were reliable. The functions and advantages of NSRI were confirmed. The Q compensated seismogram generated by NSRI was superior to that generated using gain-limited inverse Q filtering. We have also investigated NSRI's capabilities in analyzing a marine data set from the Gulf of Suez. These examples provided a basis for discussing assumptions and limitations of NSRI. [ABSTRACT FROM AUTHOR]

On seismic migration sections, anomalous bright spots, called the string of beads response (SBR), are common features of carbonate karst reservoirs at the seismic scale in the Tarim Basin, China. To understand the SBR features of different karst caves, which is an important issue for local exploration, we conducted a physical modeling experiment. Within the physical model, we included various single caves with different scales, velocities, shapes, and fluids, as well as multiple caves in different spatial distributions. SBRs of all caves were extracted and summarized from the migration sections. First, we investigated effects of the cave scale, velocity, spatial distribution, shape, and fluids on SBRs. The relative amplitude of SBRs increased with the cave width ranging from 25 to 400 m and decreased with the cave velocity. The SBR split into two new SBRs when the cave height was larger than 100 m. Spatially distributed multiple caves resulted in some special SBRs, such as long SBRs, inclined SBRs, waved SBRs, and chaotic SBRs. The cave shape contribution to SBRs could be neglected in deep strata practically. The relative amplitude of SBRs of caves filled with gas and oil was stronger than those filled with water. Then, we established an interpretation chart of the corresponding relationship between six types of SBRs and their potential caves. Short SBRs were the responses of caves with a height of less than 60 m. Long SBRs corresponded to two kinds of cave units: (1) a single cave with a height between 70 and 100 m and (2) two caves (height less than 60 m) vertically distributed with a small distance (less than 60 m). Chop-shaped SBRs indicated caves with a width of more than 100 m. Inclined SBRs, waved SBRs, and chaotic SBRs corresponded to multiple caves spatially distributed in triangles, rhombuses, and clusters, respectively. [ABSTRACT FROM AUTHOR]

IL-33, a relatively new member of the IL-1 cytokine family, plays a crucial role in allergic inflammation and acute lung injury. Long form ST2 (ST2L), the receptor for IL-33, is expressed on immune effector cells and lung epithelia and plays a critical role in triggering inflammation. We have previously shown that ST2L stability is regulated by the ubiquitin-proteasome system; however, its upstream internalization has not been studied. In this study, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. IL-33 treatment induced ST2L internalization, and an effect was attenuated by inhibition or downregulation of GSK3β. GSK3β was found to interact with ST2L on serine residue 446 in response to IL-33 treatment. GSK3β binding site mutant (ST2LS446A) and phosphorylation site mutant (ST2LS442A) are resistant to IL-33-induced ST2L internalization. We also found that IL-33 activated focal adhesion kinase (FAK). Inhibition of FAK impaired IL-33-induced GSK3β activation and ST2L internalization. Furthermore, inhibition of ST2L internalization enhanced IL-33-induced cytokine release in lung epithelial cells. These results suggest that modulation of the ST2L internalization by FAK/GSK3β might serve as a unique strategy to lessen pulmonary inflammation. [ABSTRACT FROM AUTHOR]

E-cadherin is essential for the integrity of adherens junctions between lung epithelial cells, and the loss of E-cadherin allows cell motility and is thought to promote lung cancer metastasis. While the downregulation of E-cadherin expression has been well characterized and is seen with transforming growth factor-1 (TGF-1) exposure, few studies have focused on E-cadherin upregulation. Here, we show that serum starvation causes increased E-cadherin expression via the activation of c-Src kinase in non-small-cell lung cancer A549 cells. Serum starvation increased E-cadherin protein levels in a time- and dose-dependent manner. E-cadherin mRNA transcripts were unchanged with starvation, while protein translation inhibition with cycloheximide attenuated E-cadherin protein induction by starvation, suggesting that E-cadherin is regulated at the translational level by serum starvation. c-Src is a nonreceptor tyrosine kinase known to regulate protein translation machinery; serum starvation caused early and sustained activation of c-Src in A549 cells followed by Ecadherin upregulation. Furthermore, overexpression of a dominant negative c-Src attenuated the induction of E-cadherin by serum deprivation. Finally, we observed that TGF-1 treatment attenuated the serum activation of c-Src as well as E-cadherin expression when cells were deprived of serum. In conclusion, our data demonstrate that the c-Src kinase is activated by serum starvation to increase Ecadherin expression in A549 cells, and these phenomena are antagonized by TGF-1. These novel observations implicate the c-Src kinase as an upstream inducer of E-cadherin protein translation with serum starvation and TGF-1 diametrically regulating c-Src kinase activity and thus E-cadherin abundance in A549 cells. [ABSTRACT FROM AUTHOR]

Background: Rac3 is a small GTPase multifunctional protein that regulates cell adhesion, migration, and differentiation. It has been considered as an oncogene in breast cancer; however, its role in esophageal cancer and the regulation of its stability have not been studied. F-box proteins are major subunits within the Skp1-Cullin-1-Fbox (SCF) E3 ubiquitin ligases that recognize particular substrates for ubiquitination and proteasomal degradation. Recently, we have shown that SCFFBXL19 targets Rac1 and RhoA, thus regulating Rac1 and RhoA ubiquitination and degradation. Here, we demonstrate the role of FBXL19 in the regulation of Rac3 site-specific ubiquitination and stability. Expression of TGFβ1 is associated with poor prognosis of esophageal cancer. TGFβ1 reduces tumor suppressor, E-cadherin, expression in various epithelial-derived cancers. Here we investigate the role of FBXL19- mediated Rac3 degradation in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Methods: FBXL19-regulated endogenous and over-expressed Rac3 stability were determined by immunoblotting and co-immunoprecipitation. Esophageal cancer cells (OE19 and OE33) were used to investigate TGFβ1-induced E-cadherin down-regulation by Immunoblotting and Immunostaining. Results: Overexpression of FBXL19 decreased endogenous and over-expressed Rac3 expression by interacting and polyubiquitinating Rac3, while down-regulation of FBXL19 suppressed Rac3 degradation. Lysine166 within Rac3 was identified as an ubiquitination acceptor site. The FBXL19 variant with truncation at the N-terminus resulted in an increase in Rac3 degradation; however, the FBXL19 variant with truncation at the C-terminus lost its ability to interact with Rac3 and ubiquitinate Rac3 protein. Further, we found that Rac3 plays a critical role in TGFβ1-induced E-cadherin down-regulation in esophageal cancer cells. Over-expression of FBXL19 attenuated TGFβ1-induced E-cadherin down-regulation and esophageal cancer cells elongation phenotype. Conclusions: Collectively these data unveil that FBXL19 functions as an antagonist of Rac3 by regulating its stability and regulates the TGFβ1-induced E-cadherin down-regulation. This study will provide a new potential therapeutic strategy to regulate TGFβ1 signaling, thus suppressing esophageal tumorigenesis. [ABSTRACT FROM AUTHOR]