Differential contributions of G protein- or arrestin subtype-mediated signalling underlie urocortin 3-induced somatostatin secretion in pancreatic δ cells.

BACKGROUND AND PURPOSE: Pancreatic islets are modulated by cross-talk among different cell types and paracrine signalling plays important roles in maintaining glucose homeostasis. Urocortin 3 (UCN3) secreted by pancreatic ß cells activates the CRF2 receptor (CRF2R) and downstream pathways mediated by different G protein or arrestin subtypes in δ cells to cause somatostatin (SST) secretion, and constitutes an important feedback circuit for glucose homeostasis. EXPERIMENTAL APPROACH: Here, we used Arrb1-/-, Arrb2-/-, Gsfl/fl and Gqfl/fl knockout mice, the G11-shRNA-GFPfl/fl lentivirus, as well as functional assays and pharmacological characterization to study how the coupling of Gs, G11 and ß-arrestin1 to CRF2R contributed to UCN3-induced SST secretion in pancreatic δ cells. KEY RESULTS: Our study showed that CRF2R coupled to a panel of G protein and arrestin subtypes in response to UCN3 engagement. While RyR3 phosphorylation by PKA at the S156, S2706 and S4697 sites may underlie the Gs-mediated UCN3- CRF2R axis for SST secretion, the interaction of SYT1 with ß-arrestin1 is also essential for efficient SST secretion downstream of CRF2R. The specific expression of the transcription factor Stat6 may contribute to G11 expression in pancreatic δ cells. Furthermore, we found that different UCN3 concentrations may have distinct effects on glucose homeostasis, and these effects may depend on different CRF2R downstream effectors. CONCLUSIONS AND IMPLICATIONS: Collectively, our results provide a landscape view of signalling mediated by different G protein or arrestin subtypes downstream of paracrine UCN3- CRF2R signalling in pancreatic ß-δ-cell circuits, which may facilitate the understanding of fine-tuned glucose homeostasis networks.

The ages in a self-suspended nanoparticle liquid.

Telomers ionically tethered to nanometer-sized particles yield self-suspended, nanoparticle-laden liquids with unusual dynamical features. By subjecting these suspensions to controlled, modest shear strains, we find that their flow behaviors observed using experiments performed on time scales of tens of seconds can be projected to obtain maps of their dynamical response on geological time scales. That such extraordinarily slow dynamic processes can be uncovered from real-time measurements by simply stretching a system provides a simple but powerful tool for interrogating extremely slow motions in other jammed physical states.

Microstructure and Mechanical Properties of Al-12Si Alloys Fabricated by Ultrasonic-Assisted Laser Metal Deposition.

This paper presents a method of ultrasonic-assisted laser metal deposition of Al-12Si alloy. The effects of the ultrasonic power and remelting treatment on the development of porosity, microstructural evolution, and tensile properties of the deposits were investigated. The results suggested that a combination of an ultrasonic vibration and remelting treatment could prolong the existence of the molten pool and the effect of the ultrasound. Therefore, the density of the samples increased from 95.4% to 99.1% compared to the as-prepared samples. The ultrasonic action in the molten pool could not only increase the density of the samples but also refine the grains and improve the tensile properties of the samples. Metallographic observation showed that the maximum size of the primary α-Al dendrites were refined from 277.5 µm to 87.5 µm. The ultimate tensile strength and elongation of the remelting treatment samples with ultrasonic vibration were ~227 ± 3 MPa and 12.2% ± 1.4%, respectively, which were approximately 1.17 and 1.53 times those of the as-prepared samples, respectively. According to the tensile properties and fracture analysis, the density increase dominated the improvement of the mechanical properties.

A cullin 4B-RING E3 ligase complex fine-tunes pancreatic δ cell paracrine interactions.

Somatostatin secreted by pancreatic δ cells mediates important paracrine interactions in Langerhans islets, including maintenance of glucose metabolism through the control of reciprocal insulin and glucagon secretion. Disruption of this circuit contributes to the development of diabetes. However, the precise mechanisms that control somatostatin secretion from islets remain elusive. Here, we found that a super-complex comprising the cullin 4B-RING E3 ligase (CRL4B) and polycomb repressive complex 2 (PRC2) epigenetically regulates somatostatin secretion in islets. Constitutive ablation of CUL4B, the core component of the CRL4B-PRC2 complex, in δ cells impaired glucose tolerance and decreased insulin secretion through enhanced somatostatin release. Moreover, mechanistic studies showed that the CRL4B-PRC2 complex, under the control of the δ cell-specific transcription factor hematopoietically expressed homeobox (HHEX), determines the levels of intracellular calcium and cAMP through histone posttranslational modifications, thereby altering expression of the Cav1.2 calcium channel and adenylyl cyclase 6 (AC6) and modulating somatostatin secretion. In response to high glucose levels or urocortin 3 (UCN3) stimulation, increased expression of cullin 4B (CUL4B) and the PRC2 subunit histone-lysine N-methyltransferase EZH2 and reciprocal decreases in Cav1.2 and AC6 expression were found to regulate somatostatin secretion. Our results reveal an epigenetic regulatory mechanism of δ cell paracrine interactions in which CRL4B-PRC2 complexes, Cav1.2, and AC6 expression fine-tune somatostatin secretion and facilitate glucose homeostasis in pancreatic islets.

Determination of 6-thioguanine based on localized surface plasmon resonance of gold nanoparticle.

Gold nanoparticles exhibit the optical properties of localized surface plamon resonance (LSPR) and are widely applied to the biosensors. The application of gold nanoparticles to the determination of anticancer drug 6-thioguanine (6-TG) was discussed. The binding of 6-TG molecule to the surface of gold nanoparticles alters the local refractive index in the vicinity of the nanoparticles and results in a shift of the LSPR spectrum. The experimental conditions were examined and optimized. Under the optimal conditions, the ratios of absorbances at two wavelengths are directly proportional to the concentrations of 6-TG. The developed method is simple, rapid, and sensitive. In addition, this method is particularly attractive because organic cosolvents, light-sensitive dyes, and sophisticated instruments are not required. This method was successfully applied to the determination of 6-TG in real samples and the results were satisfactory.

A sensitive localized surface plasmon resonance sensor for determining mercury(II) ion using noble metal nanoparticles as probe.

The noble metal nanoparticles (NPs), including gold nanorods (AuNRs), gold nanospheres (AuNSs) and silver nanoplates (AgNPTs), were synthesized and Tween 20 stabilized NPs (Tween 20-NPs) were used as the probes for determining Hg(2+). Hg(2+) was determined based on the strong affinity between Au (Ag) and Hg. Hg(2+) was reduced to Hg in the presence of sodium borohydride. Hg interacts with the NPs and the diameter of the NPs decreases with the increase of Hg(2+) concentration, which causes the shift in absorption peak of Tween 20-NPs. The peak shifts are linearly related to Hg(2+) concentrations. Compared with AuNSs and AgNPTs, when the AuNRs was used, the sensitivity for determining Hg(2+) was higher. The developed method shows a good selectivity for Hg(2+) and can be applied to the determination of Hg(2+) in water samples.

Determination of the sodium 2-mercaptoethanesulfonate based on surface-enhanced Raman scattering.

Based on the surface-enhanced Raman scattering (SERS) sodium 2-mercaptoethanesulfonate (mesna) was determined using unmodified gold colloid as the probe. The Raman scattering intensity was obviously enhanced in the presence of sodium chloride. The influence of experimental parameters, such as incubation time, sodium chloride concentration and pH value on SERS performance was examined. Under the optimum conditions, the SERS intensity is proportional to the concentration of mesna in the range of 9.0×10(-8) to 9.0×10(-7) mol/L and detection limit (S/N=3) is 1.16×10(-8) mol/L. The corresponding correlation coefficient of the linear equation is 0.996, which indicates that there is a good linear relationship between SERS intensity and mesna concentration. The experimental results indicate that the proposed method is a viable method for determination of mesna. The real samples were analyzed and the results obtained were satisfactory.

Determination of DNA based on localized surface plasmon resonance light scattering using unmodified gold bipyramids.

The DNA was determined based on resonance light scattering (RLS) spectrometry and the localized surface plasmon resonance. The gold bipyramids were used as the probes and synthesized by a seed-mediated method. Cetyltrimethylammonium bromide was used as stabilizing agent. DNA can be bound to the gold bipyramids due to electrostatic interaction and aggregates, which results in a strong enhancement of the RLS intensity. Under the optimal conditions, the intensity of RLS is directly proportional to the concentration of DNA in the range from 0.1 to 2.0 µg mL(-1).