A Novel IRAK4 Inhibitor DW18134 Ameliorates Peritonitis and Inflammatory Bowel Disease.

IRAK4 is a critical mediator in NF-κB-regulated inflammatory signaling and has emerged as a promising therapeutic target for the treatment of autoimmune diseases; however, none of its inhibitors have received FDA approval. In this study, we identified a novel small-molecule IRAK4 kinase inhibitor, DW18134, with an IC50 value of 11.2 nM. DW18134 dose-dependently inhibited the phosphorylation of IRAK4 and IKK in primary peritoneal macrophages and RAW264.7 cells, inhibiting the secretion of TNF-α and IL-6 in both cell lines. The in vivo study demonstrated the efficacy of DW18134, significantly attenuating behavioral scores in an LPS-induced peritonitis model. Mechanistically, DW18134 reduced serum TNF-α and IL-6 levels and attenuated inflammatory tissue injury. By directly blocking IRAK4 activation, DW18134 diminished liver macrophage infiltration and the expression of related inflammatory cytokines in peritonitis mice. Additionally, in the DSS-induced colitis model, DW18134 significantly reduced the disease activity index (DAI) and normalized food and water intake and body weight. Furthermore, DW18134 restored intestinal damage and reduced inflammatory cytokine expression in mice by blocking the IRAK4 signaling pathway. Notably, DW18134 protected DSS-threatened intestinal barrier function by upregulating tight junction gene expression. In conclusion, our findings reported a novel IRAK4 inhibitor, DW18134, as a promising candidate for treating inflammatory diseases, including peritonitis and IBD.

miR-29a/b1 Regulates the Luteinizing Hormone Secretion and Affects Mouse Ovulation.

miR-29a/b1 was reportedly involved in the regulation of the reproductive function in female mice, but the underlying molecular mechanisms are not clear. In this study, female mice lacking miR-29a/b1 showed a delay in vaginal opening, irregular estrous cycles, ovulation disorder and subfertility. The level of luteinizing hormone (LH) was significantly lower in plasma but higher in pituitary of mutant mice. However, egg development was normal in mutant mice and the ovulation disorder could be rescued by the superovulation treatment. These results suggested that the LH secretion was impaired in mutant mice. Further studies showed that deficiency of miR-29a/b1 in mice resulted in an abnormal expression of a number of proteins involved in vesicular transport and exocytosis in the pituitary, indicating the mutant mice had insufficient LH secretion. However, the detailed mechanism needs more research.

Experimental Study on Whole Wind Power Structure with Innovative Open-Ended Pile Foundation under Long-Term Horizontal Loading.

The offshore wind energy (OWE) pile foundation is mainly a large diameter open-ended single pile in shallow water, which has to bear long-term horizontal cyclic loads such as wind and waves during OWE project lifetime. Under the complex cyclic loads, the stress and displacement fields of the pile-soil system change continuously, which affects the dynamic characteristics of the pile foundation. Within the service life of the pile foundation, the pile-soil system has irreversible cumulative deformation, which further causes damage to the whole structure. Therefore, it is important to examine the overall dynamic characteristics of wind power foundation under high cycle. In this paper, in the dry sand foundation, taking the Burbo Bank 3.6 MW offshore turbine-foundation structure as the prototype, the horizontal cyclic loading model tests of the wind power pile foundation with the scale of 1:50 were carried out. Considering the factors such as loading frequency and cyclic load ratio, the horizontal dynamic characteristics of the whole OWE pile foundation are studied. The comparison results between the maximum bending moment of pile and the fitting formula are discussed. In conclusion, moment of OWE pile shaft is corresponding to the loading frequency (f = 9 HZ) and loading cycles by fitting formulas. The fatigue damage of the OWE pile does not occurs with low frequencies in high cycles.

Betaine/GABA transporter-1 (BGT-1) deficiency in mouse prevents acute liver failure in vivo and hepatocytes apoptosis in vitro.

Betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT-1 or Slc6a12) is a transporter for the neurotransmitter GABA and osmolyte betaine. To date, most studies on BGT-1 have focused on its functions in the nervous system and renal osmotic homeostasis. Despite its dominant distribution in the liver, the function of BGT-1 in hepatic physiology or disease remains unknown. Here, we report that BGT-1 was significantly downregulated in patients with liver failure as well as in mice with experimental acute liver failure (ALF). Furthermore, mice deficient in BGT-1 showed significant resistance to ALF compared with wild type (WT) mice, manifesting as improved survival rate, reduced alanine transaminase/aspartate aminotransferase levels, better histopathological symptoms and fewer apoptotic cells in the liver. Similarly, in primary hepatocytes, BGT-1 deficiency or treatment with a BGT-1 inhibitor, NNC 05-2090, attenuated TNF-α mediated apoptosis. In addition, BGT-1 deficiency or dosing with NNC 05-2090 stimulated the expression of the anti-apoptotic gene, c-Met in the liver, suggesting the involvement of c-Met in the function on hepatocytes of BGT-1 apoptosis. Our findings suggest BGT-1 is a promising candidate drug target to prevent and treat hepatocyte apoptosis related diseases, such as ALF.

Superplastic Deformation and Dynamic Recrystallization of a Novel Disc Superalloy GH4151.

The superplastic deformation of a hot-extruded GH4151 billet was investigated by means of tensile tests with the strain rates of 10-4 s-1, 5 × 10-4 s-1 and 10-3 s-1 and at temperatures at 1060 °C, 1080 °C and 1100 °C. The superplastic deformation of the GH4151 alloy was reported here for the first time. The results reveal that the uniform fine-grained GH4151 alloy exhibited an excellent superplasticity and high strain rate sensitivity (exceeded 0.5) under all experimental conditions. It was found that the increase of strain rate resulted in an increased average activation energy for superplastic deformation. A maximum elongation of 760.4% was determined at a temperature of 1080 °C and strain rate of 10-3 s-1. The average activation energy under different conditions suggested that the superplastic deformation with 1 × 10-4 s-1 in this experiment is mainly deemed as the grain boundary sliding controlled by grain boundary diffusion. However, with a higher stain rate of 5 × 10-4 s-1 and 1 × 10-3 s-1, the superplastic deformation is considered to be grain boundary sliding controlled by lattice diffusion. Based on the systematically microstructural examination using optical microscope (OM), SEM, electron backscatter diffraction (EBSD) and TEM techniques, the failure and dynamic recrystallization (DRX) nucleation mechanisms were proposed. The dominant nucleation mechanism of dynamic recrystallization (DRX) is the bulging of original grain boundaries, which is the typical feature of discontinuous dynamic recrystallization (DDRX), and continuous dynamic recrystallization (CDRX) is merely an assistant mechanism of DRX. The main contributions of DRX on superplasticity elongation were derived from its grain refinement process.

[Study on the geometric characteristics and distribution of porosities in three-dimensional printed Ti-6Al-4V titanium alloy].

Three dimensional (3D) printing is considered as an advanced manufacturing technology because of its additive nature. Electron beam melting (EBM) is a widely used 3D printing processes for the manufacturing of metal components. However, the products printed via this process generally contain micro porosities which affect mechanical properties, especially the fatigue property. In this paper, two types of EBM printed samples of the Ti-6Al-4V alloy, one with a round cross section and the other with a triangle cross section, were employed to investigate the existence of porosities using computed tomography (CT). Statistical analyses were conducted on the number, volume, shape, and distribution of pores. The results show that small pores (less than 0.000 2 mm 3) account for 80% of all pores in each type of samples. Additionally, to some extent, the shape of sample has influence on the number of micro porosities in EBM made Ti-6Al-4V. The sphericity of the pores is relatively low and is inversely proportional to pore volume. It is found that re-melting on the free surface effectively reduce pore density near the surface. This study may help produce a medical implant with better fatigue resistance.

Brain-Specific SNAP-25 Deletion Leads to Elevated Extracellular Glutamate Level and Schizophrenia-Like Behavior in Mice.

Several studies have associated reduced expression of synaptosomal-associated protein of 25 kDa (SNAP-25) with schizophrenia, yet little is known about its role in the illness. In this paper, a forebrain glutamatergic neuron-specific SNAP-25 knockout mouse model was constructed and studied to explore the possible pathogenetic role of SNAP-25 in schizophrenia. We showed that SNAP-25 conditional knockout (cKO) mice exhibited typical schizophrenia-like phenotype. A significantly elevated extracellular glutamate level was detected in the cerebral cortex of the mouse model. Compared with Ctrls, SNAP-25 was dramatically reduced by about 60% both in cytoplasm and in membrane fractions of cerebral cortex of cKOs, while the other two core members of SNARE complex: Syntaxin-1 (increased ~80%) and Vamp2 (increased ~96%) were significantly increased in cell membrane part. Riluzole, a glutamate release inhibitor, significantly attenuated the locomotor hyperactivity deficits in cKO mice. Our findings provide in vivo functional evidence showing a critical role of SNAP-25 dysfunction on synaptic transmission, which contributes to the developmental of schizophrenia. It is suggested that a SNAP-25 cKO mouse, a valuable model for schizophrenia, could address questions regarding presynaptic alterations that contribute to the etiopathophysiology of SZ and help to consummate the pre- and postsynaptic glutamatergic pathogenesis of the illness.