Axl promotes intracranial aneurysm rupture by regulating macrophage polarization toward M1 via STAT1/HIF-1α.

Background: Macrophage infiltration and polarization are crucial for the pathogenesis of intracranial aneurysm (IA) rupture. Axl, a receptor tyrosine kinase, is involved in inflammation and efferocytosis in multiple organs. Upregulated soluble Axl in cerebrospinal fluid (CSF) and plasma is correlated with intracranial aneurysm rupture. This study aimed to investigate the role of Axl in IA rupture and macrophage polarization. Methods: Male C57BL/6J mice were used to induce IA. The level of Axl from control vessels and unruptured and ruptured IA samples was detected. In addition, the relationship between Axl and macrophages was confirmed. The pathway of Axl-mediated macrophage polarization was explored after IA induction in vivo and in bone marrow-derived macrophages (BMDMs) stimulated by LPS/IFN-γ in vitro. The animals were randomized into three groups and treated intraperitoneally with the vehicle, selective AXL antagonist R428, and recombinant mouse growth arrest-specific 6 (rmGas6) for 21 consecutive days. Then, we evaluated the influence of Axl on IA rupture by administrating R428 to inhibit or rmGas6 to activate the Axl receptor in vivo. Results: Compared with that in normal vessels, Axl expression was significantly upregulated in unruptured IA samples. The ruptured IA tissue exhibited significantly higher expression of Axl than the unruptured IA tissue. Axl and F4/80 were coexpressed in IA tissue and LPS/IFN-γ-stimulated BMDMs. R428 treatment significantly reduced the rate of M1-like macrophage infiltration and IA rupture. In contrast, rmGas6 treatment promoted M1 macrophage infiltration and IA rupture. Mechanistically, R428 inhibited the phosphorylation of Axl and STAT1 and the expression of hypoxia-inducible factor-1α (HIF-1α) and decreased the levels of IL-1ß, NOS2, and MMP9 in LPS/IFN-γ-stimulated BMDMs. rmGas6 promoted the phosphorylation of Axl and STAT1 and the expression of HIF-1α. In addition, STAT1 knockdown abolished Axl-mediated M1 macrophage polarization. Conclusion: The inhibition of Axl reduced macrophage polarization toward the M1 phenotype via the STAT1/HIF-1α signaling pathway and prevented IA rupture in mice. This finding suggests that pharmacological inhibition of Axl might be used to prevent the progression and rupture of IA.

URB2 as an important marker for glioma prognosis and immunotherapy.

Introduction: Glioma is the most common primary brain tumor and primary malignant tumor of the brain in clinical practice. Conventional treatment has not significantly altered the prognosis of patients with glioma. As research into immunotherapy continues, glioma immunotherapy has shown great potential. Methods: The clinical data were acquired from the Chinese Glioma Genome Atlas (CGGA) database and validated by the Gene Expression Omnibus (GEO) database, The Cancer Genome Atlas (TCGA) dataset, Clinical Proteomic Tumor Analysis Consortium (CPTAP) database, and Western blot (WB) analysis. By Cox regression analyses, we examined the association between different variables and overall survival (OS) and its potential as an independent prognostic factor. By constructing a nomogram that incorporates both clinicopathological variables and the expression of URB2, we provide a model for the prediction of prognosis. Moreover, we explored the relationship between immunity and URB2 and elucidated its underlying mechanism of action. Results: Our study shows that URB2 likely plays an oncogenic role in glioma and confirms that URB2 is a prognostic independent risk factor for glioma. Furthermore, we revealed a close relationship between immunity and URB2, which suggests a new approach for the immunotherapy of glioma. Conclusion: URB2 can be used for prognosis prediction and immunotherapy of glioma.

Curcumin alleviates LPS-induced intestinal homeostatic imbalance through reshaping gut microbiota structure and regulating group 3 innate lymphoid cells in chickens.

Gastrointestinal dysfunction is associated with a disturbance of immune homeostasis, changes in the intestinal microbiome, alteration of the composition of the bile acid pool, and dynamic imbalance of group 3 innate lymphoid cells (ILC3s). Curcumin (CUR), a polyphenolic compound isolated from turmeric, has been known to attenuate intestinal inflammation in potential therapies for gastrointestinal diseases. It was hypothesized that CUR could target the gut microbiome to modulate bile acid (BA) metabolism and the function of ILC3s in ameliorating lipopolysaccharide (LPS)-induced imbalance of intestinal homeostasis in chickens. Seven hundred and twenty 1-day-old crossbred chickens were randomly divided into four treatments, namely CON_saline (basal diet + saline control), CUR_saline (basal diet + 300 mg kg-1 curcumin + saline), CON_LPS (basal diet + LPS), and CUR_LPS (basal diet + 300 mg kg-1 curcumin + LPS), each consisting of 6 replicates of 30 birds. On days 14, 17, and 21, the chickens in the CON_LPS and CUR_LPS treatments were intraperitoneally injected with LPS at 0.5 mg per kg BW. Dietary CUR supplementation significantly decreased LPS-induced suppression of growth performance and injury to the intestinal tight junctions and decreased the vulnerability to LPS-induced acute inflammatory response by inhibiting pro-inflammatory (interleukin-1ß and tumor necrosis factor-α) cytokines. CUR reshaped the cecal microbial community and BA metabolism, contributing to regulation of the intestinal mucosal immunity by promoting the anti-inflammatory (interleukin 10, IL-10) cytokines and enhancing the concentrations of primary and secondary BA metabolites (chenodexycholic acid, lithocholic acid). LPS decreased farnesoid X receptor (FXR) and G protein-coupled receptor class C group 5 member A synthesis, which was reversed by CUR administration, along with an increase in interleukin 22 (IL-22) production from ILC3s. Dietary supplementation of CUR increased the prevalence of Butyricicoccus and Enterococcus and enhanced the tricarboxylic acid cycle of intestinal epithelial cells. In addition, curcumin supplementation significantly increased sirtuin 1 and sirtuin 5 transcription and protein expression, which contributes to regulating mitochondrial metabolic and oxidative stress responses to alleviate LPS-induced enteritis. Our findings demonstrated that curcumin played a pivotal role in regulating the structure of the intestinal microbiome for health promotion and the treatment of intestinal dysbiosis. The beneficial effects of CUR may be attributed to the modulation of the BA-FXR pathway and inhibition of inflammation that induces IL-22 secretion by ILC3s in the intestinal lamina propria.

Stent-assisted coiling of acutely ruptured cerebral aneurysm: a multicenter prospective registry study (SAVE).

BACKGROUND: Stent-assisted coiling (SAC) has been reported as a feasible and effective treatment of wide-neck cerebral aneurysms. However, the evidence of SAC of ruptured cerebral aneurysm is lacking. There are no prospective multicenter studies regarding SAC of acutely ruptured aneurysms within 72 hours after subarachnoid hemorrhage. The purpose of the study is to evaluate the safety and efficiency of SAC of acutely ruptured cerebral aneurysms. METHODS: This study is a prospective, multicenter, and observation registry of consecutive patients with acutely ruptured cerebral aneurysms treated with SAC. Acutely ruptured aneurysms were confirmed within 72 h after the onset of the syndrome. This study will enroll at least 300 patients in 7 high-volume tertiary hospitals (more than 150 cerebral aneurysms treated per year). The primary outcomes are treatment-related thromboembolic complications within 30 days of the treatment. The secondary outcomes are any hemorrhagic complications and aneurysm recurrence at 6 months of angiographic follow-up. The clinical outcomes are measured with the Modified Rankin Scale (mRS) at discharge and at the 6 months of follow-up. The favorable outcomes are defined as an mRS of grades 0 and 2. DISCUSSION: We will perform a prospective, multicenter, and observational registry study of consecutive patients with wide-neck acutely ruptured cerebral aneurysms to improve the safety strategy of SAC of acutely ruptured cerebral aneurysms. TRIAL REGISTRATION: Chinese Clinic Trial Registry: ChiCTR2000036972 ; Registration date: Aug 26, 2020.

Prediction of the Weld Pool Stability by Material Flow Behavior of the Perforated Weld Pool.

This article presents the application of a computational fluid dynamics (CFD) finite volume method (FVM) model for a thermo-mechanical coupling simulation of the weld pool used in variable polarity plasma arc welding (VPPAW). Based on the mechanism of the additional pressure produced through self-magnetic arc compression and the jet generated from mechanical plasma arc compression, and considering the influence of arc height and keyhole secondary compression on arc pressure, a three-dimensional transient model of variable polarity plasma arc (VPPA) arc pressure was established. The material flow behaviors of the perforated weld pools were studied. The results show that three kinds of flow behavior existed in the perforation weld pools and it is feasible to predict the weld pool stability by the material flow behaviors of the perforated weld pools. The weld pools can exist stably if the material flow in the bottom of the perforated weld pools can form confluences with moderate flow velocities of 0.45 m/s, 0.55 m/s and 0.60 m/s. The weld pools were cut when the material flowed downward and outward with the maximum velocity of 0.70 m/s, 0.80 m/s. When the maximum material flow velocity was 0.40 m/s, the weld pool collapsed downward under the action of larger gravity. The thermo-mechanical coupling model was verified by the comparison of the simulation and experimental results.

The use of pituitary adenylate cyclase-activating polypeptide in the pre-maturation system improves in vitro developmental competence from small follicles of porcine oocytes.

OBJECTIVE: We investigated how pituitary adenylate cyclase-activating polypeptide (PACAP) affects embryonic development during pre-in vitro maturation (pre-IVM) using porcine oocytes isolated from small follicles. METHODS: We divided the follicles into the experimental groups by size (SF, small follicles; MF, medium follicles) and treated with and without PACAP and cultured for 18 hours (Pre-SF[-]PACAP; without PACAP, Pre-SF[+]PACAP; with PACAP) before undergoing IVM. The gene expression related to extracellular matrix formation (amphiregulin, epiregulin, and hyaluronan synthase 2 [HAS2]) and apoptosis (Bcl-2-associated X [BAX], B-cell lymphoma 2, and cysteine-aspartic acid protease 3) was investigated after maturation. The impact on developmental competence was assessed by the cleavage and blastocyst rate and total cell number of blastocysts in embryos generated from parthenogenesis (PA) and in vitro fertilization (IVF). RESULTS: Cleavage rates in the Pre-SF(+)PACAP after PA were significantly higher than SF and Pre-SF(-)PACAP (p<0.05). The cleavage rates between MF and Pre- SF(+)PACAP groups yielded no notable differences after IVF. Pre-SF(+)PACAP displayed the higher rate of blastocyst formation and greater total cell number than SF and Pre-SF(-)PACAP (p<0.05). Cumulus cells showed significant upregulation of HAS2 mRNA in the Pre-SF(+)PACAP compared to the SF (p<0.05). In comparison to other groups, the Pre-SF(+)PACAP group displayed a downregulation in mRNA expression of BAX in matured oocytes (p<0.05). CONCLUSION: The PACAP treatment during pre-IVM improved the developmental potential of porcine oocytes derived from SF by regulating cumulus expansion and apoptosis of oocytes.

Effect of porcine uterus as ex vivo model of fertilizing ability and gene expression pattern on blastocysts.

The success of in vitro embryo production demonstrates that the oviduct can be bypassed during early embryonic development. Using an ex vivo model of porcine uterus is one of the strategies used to investigate fertilization within the oviductal environment. In this study, in vitro-matured porcine oocytes (MII) were fertilized with 7.5 × 107, 15 × 107, or 30 × 107 sperm cells for 20 min in the oviduct of a porcine uterine ex vivo model. MII oocytes used for in vitro fertilization (IVF) served as control 1; those cultured in the oviduct of the ex vivo model for 20 min before IVF served as control 2. In present study, the penetration rate, polyspermy, and fertilization efficiency, and accumulated reactive oxygen species (ROS) levels in the treatment groups were significantly decreased compared to those in the control 1 group. During embryonic development, the cleavage rates in the treatment groups were significantly lower than those in the control groups. The cleavage rate in the 30 × 107 sperm cell-treated group was higher than that in the 7.5 × 107 sperm cell-treated group. The blastocyst formation rate in control 1 and 2, and 30 × 107 sperm cell-treated groups increased compared to that in the 7.5 and 15 × 107 sperm cell-treated groups. PCNA, HSP70.2, and GLUT1 were upregulated in the treatment groups and POU5F1, BAX, GPX1 were upregulated in the treatment and control 2 groups, compared to the control 1 group. These results suggest that an ex vivo model may decrease the penetration rate and fertilization efficiency by increasing the accumulated ROS levels and inducing the expression of apoptosis- and stress-related genes. However, the model improved the monospermy rate and expression of embryo developmental competence genes. This is the first study that evaluates the effect of an ex vivo model of porcine uterus on fertilization parameters, and the development of porcine embryos.

Improving Mechanical Properties of PVPPA Welded Joints of 7075 Aluminum Alloy by PWHT.

In this study, 7075 aluminum alloy with a thickness of 10 mm was successfully welded with no obvious defects by pulsed variable polarity plasma arc (PVPPA) welding. The mechanical properties of PVPPA welded joints have been researched by post weld heat treatment (PWHT). The results indicate that the heat treatment strongly affects the mechanical properties of the welded joints. The tensile strength and the microhardness of the welded joints gradually improved with the increase of the solution temperature. With the increase of the solution time, the tensile strength, and microhardness first dramatically increased and then decreased slightly. The best tensile strength of 537.5 MPa and the microhardness of 143.7 HV were obtained after 490 °C × 80 min + 120 °C × 24 h, and the strength was nearly 91.2% of that of the parent metal, and increased about 35% compared with as-welded. The improvement of strength and microhardness was mainly due to the precipitation of η' phase.

Lysophosphatidic acid increases in vitro maturation efficiency via uPA-uPAR signaling pathway in cumulus cells.

Lysophosphatidic acid (LPA) is a phospholipid-derived signaling molecule with biological activities, such as stimulating cell proliferation, differentiation and migration. In the present study, we examined the effect of LPA on porcine oocytes during in vitro maturation (IVM) and subsequent embryonic development following parthenogenetic activation (PA) and in vitro fertilization (IVF). During IVM, the maturation medium was supplemented with various concentrations of LPA (0, 10, 30, and 60 µM). After 42 h of IVM, the 30 µM LPA-treated group showed a significant (P <0.05) increase in nuclear maturation and intracellular glutathione (GSH) levels compared with the other groups. The 30 µM LPA-treated group exhibited a significant decrease in intracellular reactive oxygen species (ROS) levels compared with the other groups. In PA, the 30 µM LPA-treated group had significantly higher cleavage (CL) and blastocyst (BL) rates compared with those of the other LPA-treated groups. In IVF, the 30 µM LPA-treated group had significantly higher CL and BL rates than the other LPA-treated groups. The expression of the developmental competence gene (proliferating cell nuclear antigen, PCNA) in the oocytes and cumulus cells of the individuals in the 30 µM LPA-treated group was significantly increased compared with the control group. In addition, the specific expression of urokinase Plasminogen Activator (uPA) and uPA Receptor (uPAR) in cumulus cells was significantly increased in the 30 µM LPA-treated group. The western blotting results revealed that LPA improves the activities of p38 mitogen-activated protein kinase (MAPK) and epidermal growth factor (EGF) by enhanced phosphorylation. In conclusion, treatment with 30 µM LPA during IVM promotes enhances the EGF-EGFR signaling pathway, resulting in cumulus cell expansion. And then, this treatment improves the developmental potential of PA and IVF porcine embryos by enhancing nuclear and cytoplasmic maturation and reducing ROS.

Evolutionary-algorithm-based strategy for computer-assisted structure elucidation.

An evolutionary algorithm (EA) using a graph-based data structure to explore the molecular constitution space is presented. The EA implementation proves to be a promising alternative to deterministic approaches to the problem of computer-assisted structure elucidation (CASE). While not relying on any external database, the EA-guided CASE program SENECA is able to find correct solutions within calculation times comparable to that of other CASE expert systems. The implementation presented here significantly expands the size limit of constitutional optimization problems treatable with evolutionary algorithms by introducing novel efficient graph-based genetic operators. The new EA-based search strategy is discussed including the underlying data structures, component design, parameter optimization, and evolution process control. Typical structure elucidation examples are given to demonstrate the algorithm's performance.

The Chemistry Development Kit (CDK): an open-source Java library for Chemo- and Bioinformatics.

The Chemistry Development Kit (CDK) is a freely available open-source Java library for Structural Chemo- and Bioinformatics. Its architecture and capabilities as well as the development as an open-source project by a team of international collaborators from academic and industrial institutions is described. The CDK provides methods for many common tasks in molecular informatics, including 2D and 3D rendering of chemical structures, I/O routines, SMILES parsing and generation, ring searches, isomorphism checking, structure diagram generation, etc. Application scenarios as well as access information for interested users and potential contributors are given.