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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.