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Abstract Background Pathological neovascularization plays a pivotal role in the onset and progression of tumors and neovascular eye diseases. Despite notable advancements in the development of anti-angiogenic medications that target vascular endothelial growth factor (VEGF) and its receptors (VEGFRs), the occurrence of adverse reactions and drug resistance has somewhat impeded the widespread application of these drugs. Therefore, additional investigations are warranted to explore alternative therapeutic targets. In recent years, owing to the swift advancement of high-throughput sequencing technology, pan-cancer analysis and single-cell sequencing analysis have emerged as pivotal methodologies and focal areas within the domain of omics research, which is of great significance for us to find potential targets related to the regulation of pathological neovascularization. Methods Pan-cancer analysis and scRNA-seq data analysis were employed to forecast the association between Actin filament-associated protein 1 like 1 (AFAP1L1) and the development of tumors and endothelial cells. Tumor xenograft model and ocular pathological neovascularization model were constructed as well as Isolectin B4 (IsoB4) staining and immunofluorescence staining were used to assess the effects of AFAP1L1 on the progression of neoplasms and neovascular eye diseases in vivo. Transwell assay, wound scratch assay, tube forming assay, three-dimensional germination assay, and rhodamine-phalloidin staining were used to evaluate the impact of AFAP1L1 on human umbilical vein endothelial cells (HUVECs) function in vitro; Dual luciferase reporting, qRT-PCR and western blot were used to investigate the upstream and downstream mechanisms of pathological neovascularization mediated by AFAP1L1. Results Our investigation revealed that AFAP1L1 plays a crucial role in promoting the development of various tumors and demonstrates a strong correlation with endothelial cells. Targeted suppression of AFAP1L1 specifically in endothelial cells in vivo proves effective in inhibiting tumor formation and ocular pathological neovascularization. Mechanistically, AFAP1L1 functions as a hypoxia-related regulatory protein that can be activated by HIF-1α. In vitro experiments demonstrated that reducing AFAP1L1 levels can reverse hypoxia-induced excessive angiogenic capacity in HUVECs. The principal mechanism of angiogenesis inhibition entails the regulation of tip cell behavior through the YAP-DLL4-NOTCH axis. Conclusion In conclusion, AFAP1L1, a newly identified hypoxia-related regulatory protein, can be activated by HIF-1α. Inhibiting AFAP1L1 results in the inhibition of angiogenesis by suppressing the germination of endothelial tip cells through the YAP-DLL4-NOTCH axis. This presents a promising therapeutic target to halt the progression of tumors and neovascular eye disease.

Abstract Background The clinical efficiency of routine oxygen therapy is uncertain in patients with acute heart failure (AHF) who do not have hypoxemia. The aim of this study was to investigate the association between oxygen therapy and clinical outcomes in normoxemic patients hospitalized with AHF using real-world data. Methods Normoxemic patients diagnosed with AHF on ICU admission from the electronic ICU (eICU) Collaborative Research Database were included in the current study, in which the study population was divided into the oxygen therapy group and the ambient-air group. Propensity score matching (PSM) was applied to create a balanced covariate distribution between patients receiving supplemental oxygen and those exposed to ambient air. Linear regression and logistic regression models were performed to assess the associations between oxygen therapy and length of stay (LOS), and all-cause in-hospital as well as ICU mortality rates, respectively. A series of sensitivity and subgroup analyses were conducted to further validate the robustness of our findings. Results A total of 2922 normoxemic patients with AHF were finally included in the analysis. Overall, 42.1% (1230/2922) patients were exposed to oxygen therapy, and 57.9% (1692/2922) patients did not receive oxygen therapy (defined as the ambient-air group). After PSM analysis, 1122 pairs of patients were matched: each patient receiving oxygen therapy was matched with a patient without receiving supplemental oxygen. The multivariable logistic model showed that there was no significant interaction between the ambient air and oxygen group for all-cause in-hospital mortality [odds ratio (OR) 1.30; 95% confidence interval (CI) 0.92–1.82; P = 0.138] or ICU mortality (OR 1.39; 95% CI 0.83–2.32; P = 0.206) in the post-PSM cohorts. In addition, linear regression analysis revealed that oxygen therapy was associated with prolonged ICU LOS (OR 1.11; 95% CI 1.06–1.15; P

Summary: In mammals and yeast, tail‐anchored (TA) membrane proteins destined for the post‐translational pathway are safely delivered to the endoplasmic reticulum (ER) membrane by a well‐known targeting factor, TRC40/Get3. In contrast, the underlying mechanism for translocation of TA proteins in plants remains obscure. How this unique eukaryotic membrane‐trafficking system correctly distinguishes different subsets of TA proteins destined for various organelles, including mitochondria, chloroplasts and the ER, is a key question of long standing. Here, we present crystal structures of algal ArsA1 (the Get3 homolog) in a distinct nucleotide‐free open state and bound to adenylyl‐imidodiphosphate. This approximately 80‐kDa protein possesses a monomeric architecture, with two ATPase domains in a single polypeptide chain. It is capable of binding chloroplast (TOC34 and TOC159) and mitochondrial (TOM7) TA proteins based on features of its transmembrane domain as well as the regions immediately before and after the transmembrane domain. Several helices located above the TA‐binding groove comprise the interlocking hook‐like motif implicated by mutational analyses in TA substrate recognition. Our data provide insights into the molecular basis of the highly specific selectivity of interactions of algal ArsA1 with the correct sets of TA substrates before membrane targeting in plant cells. Significance Statement: The molecular and cellular mechanisms responsible for targeting tail‐anchored (TA) proteins in plant cells remain insufficiently understood, despite the likelihood that they play essential roles in metabolic regulation and responses to environmental stress, amongst other processes, in different membrane‐bound organelles during plant growth and development. Here, we propose a model of the TA pathway that is based on structural and biochemical data to explain how these diverse organelle‐targeting signals are appropriately recognized by a targeting factor(s) in plant cells. [ABSTRACT FROM AUTHOR]

Based on the 3-D model, we recently proposed to investigate numerically the performance of the HTS maglev system. The speed-related behavior of this kind of maglev system is further studied in this article. The 3-D model is firstly briefly introduced: the 3-D governing equations are established with current vector potential ( T) as the state variable, and the special anisotropic behavior and the nonlinear E- J characteristic of the HTS were taken into account by an elliptical model and power-law model, respectively. Using a translational symmetry levitation system, which is composed of a rectangular HTS and a permanent magnet guideway (PMG) as an example, the speed-related behavior of the magnetic force in three different cases-i.e., the levitation force (LF) versus gap relation under the vertical movement, the time evolution of the LF, the guidance force (GF) versus lateral displacement relation under the transverse movement-are investigated. The result indicates that, with the increase of the speed, both the LF and GF increase but the rate of increase is reduced and finally saturates when the speed is large enough. We also find that the commonly used speed of 1 mm/s to investigate the magnetic force of the bulk HTS in the experiment is reasonable because both the LF and GF tend to saturate at this speed. For the time evolution study of the LF, although the peak value of the LF is largest when the speed is largest, the LF decay in the relaxed process is most serious, and consequently the final LF at different speeds is almost identical after relaxation. Therefore, the magnetic force cannot be enhanced by simply increasing the speed in the practical application. [ABSTRACT FROM AUTHOR]

In this paper, the 3-D model proposed in Part I of this study is verified in detail on the basis of a levitation/suspension system composed of a rectangular single-domain Y-Ba-Cu-O and a cylindrical Nd-Fe-B magnet or a permanent magnet guideway (PMG) assembled by the Nd-Fe-B magnets. The magnetic forces along the vertical direction perpendicular or the transverse direction parallel to the surface of the PMG(or magnet) were calculated and compared well with the measured data under vertical and transverse displacements. The computed results of the induced current distribution within the Y-Ba-Cu-O domain, as well as the magnetic field profiles in the Y-Ba-Cu-O and its vicinal region, were also presented and discussed. [ABSTRACT FROM AUTHOR]

A magnetic levitation technique with high-Tc superconductor (HTS) has received significant interest for a wide range of applications after its discovery due to its unique inherent stability, which gives a fundamental significance to evaluate the HTS magnetic levitation in both experiment and calculation. To numerically investigate the HTS magnetic levitation, a 3-D model describing the electromagnetic property of the HTS, including its anisotropic behavior, was established by incorporating the current vector potential and Helmholtz's theorem. In addition to the commonly considered nonlinear E--J characteristic in the reported calculation, we introduce an elliptical model to formulate the angular dependence of the critical current density Jc resulting from the anisotropic behavior of the HTS. To numerically resolve the governing equations of the 3-D model, Galerkin's finite-element method and the Crank--Nicolson-θ method were employed to discretize the governing equations in space and time domains, respectively. The obtained algebraic equations were firstly linearized by the Newton--Raphson method, and then an extended format of the incomplete Cholesky-conjugate gradient method was applied to solve the linear algebraic equations. The 3-D model was implemented by a self-written numerical program based on a VC++ platform to calculate the magnetic force of a bulk HTS exposed to applied field generated by a permanent magnet guideway (PMG) assembled by the Nd-F-e-B magnets. In this paper, we present the numerical results of the levitation force of a moving bulk HTS above the PMG with different mesh densities and number of time steps. This presents a preliminary validation of the 3-D model proposed in this paper. [ABSTRACT FROM AUTHOR]

A three-dimensional analytical method is proposed to model the permanent magnet guideway (PMG) involved in the high-temperature superconducting (HTS) maglev vehicle system, and with this analytical method, the non-uniformity of magnetic field along the longitudinal direction of the PMG due to the existent gap between the adjacent permanent magnet (PM) can be taken into account in the simulation of the HTS maglev vehicle system. The analytical expressions for two rectangular PM with different magnetization directions are deduced from the Biot–Savart’s law. The 3D modeling of the PMG is validated from the four aspects, i.e., the comparison of the measurement and calculation value of the magnetic field; the magnetic field contour of the PMG; the comparison of the 3D method results with the 2D method; and the comparison of the results from the present 3D analytical model and previous finite element software. Currently, using the 3D analytical model, we have proposed a 3D method to numerically investigate the HTS magnetic levitation/suspension system with bulk high-temperature superconductor (HTSC). [ABSTRACT FROM AUTHOR]