BRSK2 in pancreatic ß cells promotes hyperinsulinemia-coupled insulin resistance and its genetic variants are associated with human type 2 diabetes.

Brain-specific serine/threonine-protein kinase 2 (BRSK2) plays critical roles in insulin secretion and ß-cell biology. However, whether BRSK2 is associated with human type 2 diabetes mellitus (T2DM) has not been determined. Here, we report that BRSK2 genetic variants are closely related to worsening glucose metabolism due to hyperinsulinemia and insulin resistance in the Chinese population. BRSK2 protein levels are significantly elevated in ß cells from T2DM patients and high-fat diet (HFD)-fed mice due to enhanced protein stability. Mice with inducible ß-cell-specific Brsk2 knockout (ßKO) exhibit normal metabolism with a high potential for insulin secretion under chow-diet conditions. Moreover, ßKO mice are protected from HFD-induced hyperinsulinemia, obesity, insulin resistance, and glucose intolerance. Conversely, gain-of-function BRSK2 in mature ß cells reversibly triggers hyperglycemia due to ß-cell hypersecretion-coupled insulin resistance. Mechanistically, BRSK2 senses lipid signals and induces basal insulin secretion in a kinase-dependent manner. The enhanced basal insulin secretion drives insulin resistance and ß-cell exhaustion and thus the onset of T2DM in mice fed an HFD or with gain-of-function BRSK2 in ß cells. These findings reveal that BRSK2 links hyperinsulinemia to systematic insulin resistance via interplay between ß cells and insulin-sensitive tissues in the populations carrying human genetic variants or under nutrient-overload conditions.

Influence of Electroplated CBN Wheel Wear on Grinding Surface Morphology of Powder Metallurgy Superalloy FGH96.

The electroplated cubic boron nitride (CBN) wheel has perfect precision retention and high-temperature grinding performance, which is widely used in the field of grinding difficult-to-cut materials, such as nickel-based superalloy. However, the research on the influence law and mechanism of grinding surface morphology affected by the wear state of small-size grinding wheel is insufficient, which limits the further promotion and application of electroplated CBN wheel in the field of precision grinding of superalloy materials. Based on the in-depth analysis of the structure of FGH96 turbine disk, and combined with the actual processing requirements, the electroplated CBN wheel was designed, and the abrasive grains size selection experiments and CBN wheel wear experiments were then carried out for the powder metallurgy superalloy FGH96 in turn. The influence law of the abrasive grain size of CBN grinding wheel and the wear state of grinding wheel on the surface morphology was investigated, respectively. The obtained results showed that under the given processing parameters, the surface roughness Ra using 400# and 600# electroplated CBN wheels are around 0.66 µm and 0.53 µm during the normal wear state of grinding wheels, respectively, which can meet the requirement of surface quality less than Ra 0.8 µm in engineering application of turbine disk, and prove the feasibility of small-size CBN wheel grinding FGH96. In addition, the failure form of electroplated CBN wheel is mainly the accumulation and adhesion of abrasive debris, and the crushing and shedding of abrasive grain are hard to appear.

Fractal Characteristics of Chip Morphology and Tool Wear in High-Speed Turning of Iron-Based Super Alloy.

Considering that iron-based super alloy is a kind of difficult-to-cut material, it is easy to produce work hardening and serious tool wear during machining. Therefore, this work aims to explore the chip change characteristics and tool wear mechanism during the processing of iron-based super alloy, calculate the fractal dimensions of chip morphology and tool wear morphology, and use fractals to analyze their change trend. Meanwhile, a new cutting tool with a super ZX coating is used for a high-speed dry turning experiment. The results indicate that the morphology of the chip is saw-tooth, and its color changes gradually, due to the oxidation reaction. The main wear mechanisms of the tool involve abrasive wear, adhesive wear, oxidation wear, coating spalling, microcracking and chipping. The fractal dimension of the tool wear surface and chip is increased with the improvement of cutting speed. This work investigates the fractal characteristics of chip morphology and tool wear morphology. The fractal dimension changes regularly with the change of tool wear, which plays an important role in predicting this tool wear. It is also provides some guidance for the efficient processing of an iron-based super alloy.

Cutting Performance Evaluation of the Coated Tools in High-Speed Milling of AISI 4340 Steel.

The cutting performance of cutting tools in high-speed machining (HSM) is an important factor restricting the machined surface integrity of the workpiece. The HSM of AISI 4340 is carried out by using coated tools with TiN/TiCN/TiAlN multi-coating, TiAlN + TiN coating, TiCN + NbC coating, and AlTiN coating, respectively. The cutting performance evaluation of the coated tools is revealed by the chip morphology, cutting force, cutting temperature, and tool wear. The results show that the serration and shear slip of the chips become more clear with the cutting speed. The lower cutting force and cutting temperature are achieved by the TiN/TiCN/TiAlN multi-coated tool. The flank wear was the dominant wear form in the milling process of AISI 4340. The dominant wear mechanisms of the coated tools include the crater wear, coating chipping, adhesion, abrasion, and diffusion. In general, a TiN/TiCN/TiAlN multi-coated tool is the most suitable tool for high-speed milling of AISI 4340, due to the lower cutting force, the lower cutting temperature, and the high resistance of the element diffusion.

Ets-1 deficiency alleviates nonalcoholic steatohepatitis via weakening TGF-ß1 signaling-mediated hepatocyte apoptosis.

Hepatocyte apoptosis is a hallmark of nonalcoholic steatohepatitis (NASH) and contributes to liver injury, fibrosis, and inflammation. However, the molecular mechanisms underlying excessive hepatocyte apoptosis in NASH remain largely unknown. This study aimed to explore whether and how the v-ets avian erythroblastosis virus E26 oncogene homolog 1 (Ets-1) is involved in diet-induced hepatocyte apoptosis in mice. The study found that the expression level of hepatic Ets-1 was elevated in a NASH mouse model as a result of the activation of transforming growth factor beta1 (TGF-ß1) signaling. In the presence of TGF-ß1, phosphorylated mothers against decapentaplegic homolog 2/3 (p-Smad2/3) translocated to the binding sites of the Ets-1 promoter to upregulate the expression of Ets-1 in primary hepatocytes. In addition, Ets-1 bound directly to phosphorylated Smad3 (p-Smad3), thereby preventing the ubiquitination and proteasomal degradation of p-Smad3 and enhancing the activity of TGF-ß1/Smad3 signaling. Consequently, elevated Ets-1 stimulated TGF-ß1-induced hepatocyte apoptosis. However, Ets-1 knockdown alleviated diet-induced hepatocyte apoptosis and NASH with reduced liver injury, inflammation, and fibrosis. Taken together, Ets-1 had an adverse impact on hepatocyte survival under TGF-ß1 treatment and accelerated the development of NASH in mice.

Fabrication of a Low Adhesive Superhydrophobic Surface on Ti6Al4V Alloys Using TiO2/Ni Composite Electrodeposition.

A superhydrophobic surface with low adhesion and good wear resistance was fabricated on Ti6Al4V substrates via TiO2/Ni composite electrodeposition, and subsequently modified with a fluoroalkylsilane (FAS) film. Scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and optical contact angle measurements were used to characterize the surface morphologies, chemical compositions, and surface wettability. The superhydrophobicity of the as-prepared surface results from the fabrication of a hierarchical structure and the assembly of low-surface energy fluorinated components. The as-prepared surface had a water contact angle as high as 162.6° and a sliding angle close to 1.8°. Scratch and abrasion tests showed that the superhydrophobic coating provided a superior wear resistance and stable mechanical abrasion protection. In addition, the influence of processing conditions, such as working voltage, deposited time, pH value, and TiO2 concentration, was also investigated.

Fabrication of Adhesive Resistance Surface with Low Wettability on Ti6Al4V Alloys by Electro-Brush Plating.

Anti-adhesive Ni coatings with low wettability were successfully fabricated on Ti6Al4V substrates via an electro-brush plating method, and subsequently modified with a fluoroalkylsilane (FAS) film. The surface morphology, chemical compositions, and wettability of the as-prepared coatings were measured using scanning electron microscopy (SEM), X-ray diffractometer (XRD), Fourier transform infrared spectrophotometry (FTIR), and contact angle measurements. The results showed that the surface of Ti6Al4V substrate was endowed with flower-like structures. Each flower-like cluster was constituted by a large number of Ni ions. After surface modification of FAS, the as-prepared Ti6Al4V surface had a water contact angle as high as 151.5°, a sliding angle close to 2.1°, and a solid surface energy as low as 0.97 mJ/m². Potentiodynamic polarization tests showed that the Ni coating could provide a stable corrosion protection. In addition, the effects of processing conditions, such as working voltage, relative velocity, electrolyte concentration, and processing time, were investigated. The mechanism of the adhesive resistance was proposed, and the low wettability of Ti6Al4V surfaces was explained by Cassie⁻Baxter model. As a result, it was necessary to reduce the fraction of the solid⁻liquid interface in order to achieve anti-adhesive surface.

SAD-A, a downstream mediator of GLP-1 signaling, promotes the phosphorylation of Bad S155 to regulate in vitro ß-cell functions.

The incretin hormone GLP-1 reduces ß-cell failure in patients with type 2 diabetes. Previous studies demonstrated that GLP-1 activates SAD-A, a member of the AMPK family, to regulate glucose-stimulated secretion (GSIS), but the underlying mechanisms of SAD-A regulation of ß-cell functions remain poorly understood. Here, we propose that activation of SAD-A by GLP-1 promotes the phosphorylation of Bad S155, which in turn positively affects GSIS and ß-cell survival. Bad therefore appears to be a downstream molecule of a SAD-A pathway that mediates the GLP-1-triggered reduction in ß-cell failure. Knockdown of endogenous SAD-A expression significantly exacerbated in vitro ß-cell dysfunction under lipotoxic conditions and promoted lipotoxicity-induced apoptosis, whereas overexpression of SAD-A inhibited ß-cell apoptosis. SAD-A silencing increased ER stress and inhibited the autophagic flux, which contributed to ß-cell apoptosis. Thus, SAD-A appears to function as a downstream molecule of GLP-1 signaling that results in Bad S155 phosphorylation. This phosphorylation might therefore be involved in the GLP-1-linked protection against ß-cell dysfunction and apoptosis.

Identifying differentially expressed long non-coding RNAs in PBMCs in response to the infection of multidrug-resistant tuberculosis.

PURPOSE: The aim of this paper was to identify differentially expressed long non-coding RNAs (lncRNAs) in peripheral blood mononuclear cells (PBMCs) influenced by the infection of multidrug-resistant tuberculosis (MDR-TB). MATERIALS AND METHODS: IncRNA and mRNA expression profiles in PBMCs derived from healthy controls (HCs) and individuals with MDR-TB and drug-sensitive tuberculosis (DS-TB) were analyzed and compared by microarray assay. Six lncRNAs were randomly selected for validation by using real-time quantitative polymerase chain reaction (RT-qPCR). The biological functions and signaling pathways affected by the differentially expressed mRNAs were investigated by using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway-based approaches. RESULTS: Compared with the HC group, 1,429 lncRNAs (983 mRNAs) and 2,040 lncRNAs (1,407 mRNAs) were identified to be deregulated in the MDR-TB group and in the DS-TB group, respectively, and 1,511 lncRNAs and 1,047 mRNAs were identified to be differentially expressed in both MDR-TB and DS-TB groups. Between the three groups, 22 lncRNAs and 38 mRNAs were found deregulated. Most deregulated lncRNAs were from intergenic regions (~55% of the total), natural antisense to protein-coding loci (~32% of the total), or intronic antisense to protein-coding loci (~5% of the total). Significantly enriched signaling pathways regulated by the deregulated mRNAs were mainly associated with natural killer cell-mediated cytotoxicity, antigen processing and presentation, graft-vs-host disease, the transforming growth factor-ß signaling pathway, and the Hippo signaling pathway. CONCLUSION: This study is the first to report differentially expressed lncRNAs in PBMCs in response to MDR-TB infection. It revealed that some lncRNAs might be associated with regulating host immune response to MDR-TB infection. Further elucidation of the potential of these deregulated lncRNAs in MDR-TB and its reactivation requires further study.

Removal of chloride ion from aqueous solution by ZnAl-NO(3) layered double hydroxides as anion-exchanger.

The layered double hydroxides (LDHs) containing nitrate as the interlayer anion has a high anion-exchange capacity in the presence of appropriate anions. In the light of this, ZnAl-NO(3) LDHs have been employed to remove chloride ion from aqueous solution in a batch mode. The influences of conditions for chloride ion uptake, including dosage of LDHs, pH of aqueous solution, and temperature on anion-exchange have been investigated, respectively. The thermodynamic parameters including Gibbs free energy (DeltaG(0)), standard enthalpy change (DeltaH(0)), and standard entropy change (DeltaS(0)) for the process were calculated using the Langmuir constants. It was found from kinetics test that the pseudo-second order kinetics model could be used to well describe the uptake process. An E(a) value of 10.27 kJ/mol provides evidence the anion-exchange process. The explanation of anion-exchange phenomenon has also been supported by X-ray diffraction and FT-IR spectra.