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摘要 背景:2型糖尿病(T2D)以胰岛β细胞功能进行性恶化和胰岛素分泌持续下降为特征。葡萄糖激酶(GCK)促进胰岛β细胞糖酵解的限速步骤, 以获得适当的葡萄糖刺激的胰岛素分泌。多种葡萄糖激酶激活剂(GKA)已经被研发出来并进行了临床测试, 但在T2D进展过程中, 人胰腺GCK表达的动态变化尚未被研究。 方法:我们通过测定11名非糖尿病受试者(ND)、10名空腹血糖受损(IFG)受试者、9名血糖控制良好的2型糖尿病患者和5名血糖控制不佳的2型糖尿病患者胰腺切片中胰岛素细胞或胰高血糖素分泌细胞中GCK的平均免疫反应性来评估GCK的表达。我们还评估了GCK表达与糖尿病患者β细胞适应性未折叠蛋白反应(UPR)之间的关系。 结果:我们没有检测到空腹血糖受损患者胰岛中GCK表达的变化, 但是我们发现β细胞GCK水平在血糖控制良好的T2D (wT2D)中显著增加, 而在血糖控制不佳的T2D (uT2D)中却没有。此外, 在糖尿病患者β细胞中, GCK的表达与适应性UPR (XBP1s和ATF4)以及功能性成熟标记物(UCN3)呈强正相关。 结论:我们的研究表明, GCK的诱导增强了人β细胞的适应性UPR和UCN3, 这可能是T2D进展中的一种适应性机制。这一发现为探索激活β细胞GCK的新分子以及改善T2D的药物治疗提供了理论基础。

Type 2 diabetes (T2D) is characterized by a progressive deterioration of β-cell function with a continuous decline in insulin secretion. Glucokinase (GCK) facilitates the rate-limiting step of glycolysis in pancreatic β-cells, to acquire the proper glucose-stimulated insulin secretion. Multiple glucokinase activators (GKAs) have been developed and clinically tested. However, the dynamic change of human pancreatic GCK expression during T2D progression has not been investigated. We evaluated GCK expression by measuring the average immunoreactivity of GCK in insulin or glucagon cells from pancreatic sections of 11 nondiabetic subjects (ND), 10 subjects with impaired fasting glucose (IFG), 9 with well-controlled T2D (wT2D), and 5 individuals with poorly controlled T2D (uT2D). We also assessed the relationship between GCK expression and adaptive unfolded protein response (UPR) in human diabetic β-cells. We did not detect changes of GCK expression in IFG islets. However, we found β-cell GCK levels were significantly increased in T2D with adequate glucose control (wT2D) but not in T2D with poor glucose control (uT2D). Furthermore, there was a strong positive correlation between GCK expression and adaptive UPR (spliced X-box binding protein 1 [XBP1s] and activating transcription factor 4 [ATF4]), as well as functional maturity marker (urocortin-3 [UCN3]) in human diabetic β-cells. Our study demonstrates that inductions of GCK enhanced adaptive UPR and UCN3 in human β-cells, which might be an adaptive mechanism during T2D progression. This finding provides a rationale for exploring novel molecules that activate β-cell GCK and thereby improve pharmacological treatment of T2D.

背景: 2型糖尿病(T2D)以胰岛β细胞功能进行性恶化和胰岛素分泌持续下降为特征。葡萄糖激酶(GCK)促进胰岛β细胞糖酵解的限速步骤, 以获得适当的葡萄糖刺激的胰岛素分泌。多种葡萄糖激酶激活剂(GKA)已经被研发出来并进行了临床测试, 但在T2D进展过程中, 人胰腺GCK表达的动态变化尚未被研究。 方法: 我们通过测定11名非糖尿病受试者(ND)、10名空腹血糖受损(IFG)受试者、9名血糖控制良好的2型糖尿病患者和5名血糖控制不佳的2型糖尿病患者胰腺切片中胰岛素细胞或胰高血糖素分泌细胞中GCK的平均免疫反应性来评估GCK的表达。我们还评估了GCK表达与糖尿病患者β细胞适应性未折叠蛋白反应(UPR)之间的关系。 结果: 我们没有检测到空腹血糖受损患者胰岛中GCK表达的变化, 但是我们发现β细胞GCK水平在血糖控制良好的T2D (wT2D)中显著增加, 而在血糖控制不佳的T2D (uT2D)中却没有。此外, 在糖尿病患者β细胞中, GCK的表达与适应性UPR (XBP1s和ATF4)以及功能性成熟标记物(UCN3)呈强正相关。 结论: 我们的研究表明, GCK的诱导增强了人β细胞的适应性UPR和UCN3, 这可能是T2D进展中的一种适应性机制。这一发现为探索激活β细胞GCK的新分子以及改善T2D的药物治疗提供了理论基础。

Background Cyclic Nucleotide-Binding Domain (CNBD)-family channels display distinct voltage-sensing properties despite sharing sequence and structural similarity. For example, the human Ether-a-go-go Related Gene (hERG) channel and the Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channel share high amino acid sequence similarity and identical domain structures. hERG conducts outward current and is activated by positive membrane potentials (depolarization), whereas HCN conducts inward current and is activated by negative membrane potentials (hyperpolarization). The structural basis for the “opposite” voltage-sensing properties of hERG and HCN remains unknown. Results We found the voltage-sensing domain (VSD) involves in modulating the gating polarity of hERG. We identified that a long-QT syndrome type 2-related mutation within the VSD, K525N, mediated an inwardly rectifying non-deactivating current, perturbing the channel closure, but sparing the open state and inactivated state. K525N rescued the current of a non-functional mutation in the pore helix region (F627Y) of hERG. K525N&F627Y switched hERG into a hyperpolarization-activated channel. The reactivated inward current induced by hyperpolarization mediated by K525N&F627Y can be inhibited by E-4031 and dofetilide quite well. Moreover, we report an extracellular interaction between the S1 helix and the S5-P region is crucial for modulating the gating polarity. The alanine substitution of several residues in this region (F431A, C566A, I607A, and Y611A) impaired the inward current of K525N&F627Y. Conclusions Our data provide evidence that a potential cooperation mechanism in the extracellular vestibule of the VSD and the PD would determine the gating polarity in hERG.

Lithosphere thinning and destruction in the middle-eastern North China Craton (NCC), a region susceptible to strong earthquakes, is one of the research hotspots in solid earth science. All 42 seismic wide-angle reflection/refraction profiles have been completed in the middle-eastern NCC. We collect all the 2-D profiling results and perform gridding of the velocity and interface depth data, building a 3-D crustal velocity structure model for the middle-eastern NCC, named HBCrust1.0, by using the Kriging interpolation method. Our result shows that the first-arrival times calculated by HBCust1.0 fit well with the observations. The result demonstrates that the upper crust is the main seismogenic layer, and the brittle-ductile transition occurs at depths near interface C (the interface between upper and lower crust). The depth of interface Moho varies beneath the source area of the Tangshan earthquake, and a low-velocity structure is found to extend from the source area to the lower crust. Based on these observations, it can be inferred that stress accumulation responsible for the Tangshan earthquake may have been closely related to the migration and deformation of the mantle materials. Comparisons of the average velocities of the whole crust, the upper and the lower crust show that the average velocity of the lower crust under the central part of the North China Basin (NCB) in the east of the craton is obviously higher than the regional average. This high-velocity probably results from long-term underplating of the mantle magma.

AlGaN‐based deep‐ultraviolet vertical‐cavity surface‐emitting lasers (DUV VCSELs) have shown a great application potential in optical atomic clocks, maskless photolithography, etc. Nevertheless, the uncontrolled cavity length‐induced detuning issue, i.e., the difference between the resonance wavelength and gain peak, severely impairs the device performance. Herein, a DUV‐VCSEL strategy featuring the uniform nanometer‐class control of the cavity length in a 4‐in wafer is proposed in the DUV framework based on GaN templates, which ensures the wafer‐scale removal of sapphire substrates by laser lift‐off, and then provides space for the subsequent deposition of dielectric distributed Bragg reflector (DBR). It is more significant that the strategy brings about a GaN/AlGaN sharp interface with an Al composition difference up to 80%, whereby self‐terminated etching with an ultrahigh selectivity of 100:1 is achieved. The cavity length is hence accurately determined by epitaxy itself instead of the fabrication process, so as to minimize the detuning. As such, 285.6‐nm optically pumped DUV VCSELs with double dielectric DBRs are fabricated, exhibiting a record low threshold of 0.38 MW cm −2 and a narrow linewidth of 0.11 nm. What's more, the lasing wavelength varies within 1.9 nm across the 4‐in wafer, indicating a cavity length variation of only 0.81%.

Songpan-Garze massif is located at the turning position of tectonics from the near west-east direction to the near north-south direction in the northeastern margin of Qinghai-Tibet Plateau, with Zoigê basin in the centre of the massif. In this paper, we build a crustal structure model of Zoigê basin and its surrounding folded orogenic belts using the deep seismic sounding data in this region. We also discuss structures and properties of the basement in Zoigê basin, tectonic relations between Zoigê upland basin and its surrounding folded orogenic belts, crustal deformation and thickening in the northeastern margin of Tibetan Plateau, and decoupling and relaxing processes in the crust. The results indicate that a special “Mesozoic basement” is formed of Triassic rocks with high density (2.65–2.75 g/cm 3 ) and high velocity (5.6 km/s) in Zoigê basin. Songpan-Garze tectonic massif was transformed into two types of tectonic units with different crustal structures, i.e., relatively stable Zoigê upland basin and active folded orogenic belts around the basin, in the course of the crustal material of Tibetan Plateau flowing eastward and obstructed by surrounding stable blocks. The thickening of the crust in the northeastern margin of Tibetan Plateau mainly occurred in the mid and lower crust, and the structure characterized by low velocities and multiple reflectors obviously appears in the folded orogenic belts around Zoigê basin. It implies that the mid and lower crust underwent a strong tectonic deformation in the folded orogenic areas. The thickness of the crust is about 50 km in Zoigê basin and the folded orogenic belts at the both southern and northern sides of Zoigê basin. The “Mountain root” cannot be identified. It is inferred that during the later orogenic period the eastwards flowing deep materials moved clockwise along the relatively relaxing southern side around the eastern tectonic knot under the obstructing of surrounding rigid massifs, and it resulted in the strong stretching action of the folded orogenic belts around Zoigê basin.

The authors processed the seismic refraction Pg-wave travel time data with finite difference tomography method and revealed velocity structure of the upper crust on active block boundaries and deep features of the active faults in western Sichuan Province. The following are the results of our investigation. The upper crust of Yanyuan basin and the Houlong Mountains consists of the superficial low-velocity layer and the deep uniform high-velocity layer, and between the two layers, there is a distinct, and gently west-dipping structural plane. Between model coordinates 180-240 km, P-wave velocity distribution features steeply inclined strip-like structure with strongly non-uniform high and low velocities alternately. Xichang Mesozoic basin between 240 and 300 km consists of a thick low-velocity upper layer and a high-velocity lower layer, where lateral and vertical velocity variations are very strong and the interface between the two layers fluctuates a lot. The Daliang Mountains to the east of the 300 km coordinate is a non-uniform high-velocity zone, with a superficial velocity of approximately 5 km/s. From 130 to 150 km and from 280 to 310 km, there are extremely distinct deep anomalous high-velocity bodies, which are supposed to be related with Permian magmatic activity. The Yanyuan nappe structure is composed of the superficial low-velocity nappe, the gently west-dipping detachment surface and the deep high-velocity basement, with Jinhe-Qinghe fault zone as the nappe front. Mopanshan fault is a west-dipping low-velocity zone, which extends to the top surface of the basement. Anninghe fault and Zemuhe fault are east-dipping, tabular-like, and low-velocity zones, which extend deep into the basement. At a great depth, Daliangshan fault separates into two segments, which are represented by drastic variation of velocity structures in a narrow strip: the west segment dips westward and the east segment dips eastward, both stretching into the basement. The east margin fault of Xichang Mesozoic basin features a strong velocity gradient zone, dipping southwestward and stretching to the top surface of the basement. The west-dipping, tabular-like, and low-velocity zone at the easternmost segment of the profile is a branch of Mabian fault, but the reliability of the supposition still needs to be confirmed by further study. Anninghe, Zemuhe and Daliangshan faults are large active faults stretching deep into the basement, which dominate strong seismic activities of the area. [PUBLICATION ABSTRACT]