Structural and Functional Characterization of the ABCC6 Transporter in Hepatic Cells: Role on PXE,Cancer Therapy and Drug Resistance

Pseudoxanthoma elasticum (PXE) is a complex autosomal recessive disease caused by mutations of ABCC6 transporter and characterized by ectopic mineralization of soft connective tissues. Compared to the other ABC transporters, very few studies are available to explain the structural components and working of a full ABCC6 transporter, which may provide some idea about its physiological role in humans. Some studies suggest that mutations of ABCC6 in the liver lead to a decrease in some circulating factor and indicate that PXE is a metabolic disease. It has been reported that ABCC6 mediates the efflux of ATP, which is hydrolyzed in PPi and AMP; in the extracellular milieu, PPi gives potent anti-mineralization effect, whereas AMP is hydrolyzed to Pi and adenosine which affects some cellular properties by modulating the purinergic pathway. Structural and functional studies have demonstrated that silencing or inhibition of ABCC6 with probenecid changed the expression of several genes and proteins such as NT5E and TNAP, as well as Lamin, and CDK1, which are involved in cell motility and cell cycle. Furthermore, a change in cytoskeleton rearrangement and decreased motility of HepG2 cells makes ABCC6 a potential target for anti-cancer therapy. Collectively, these findings suggested that ABCC6 transporter performs functions that modify both the external and internal compartments of the cells.     

氮含量及固溶温度对21-6-9奥氏体不锈钢组织和硬度的影响

为了探讨氮含量及固溶温度对21-6-9不锈钢组织和硬度的影响,分别在950、1000、1050和1100 ℃对3种不同氮含量的热轧态21-6-9不锈钢进行1 h固溶处理,通过光学显微镜观察其组织结构,结合Thermo-Calc热力学计算对试验钢的微观组织进行分析,并对其进行硬度测试。结果表明,0.20%~0.28%N的21-6-9不锈钢热轧后沿轧制方向析出铁素体,且钢中铁素体经950~1100 ℃固溶处理可消除,当N含量达到0.34%时,试验钢中不再出现铁素体。随着固溶处理温度的升高,21-6-9不锈钢的晶粒组织长大,硬度降低。N含量的增加可显著提高固溶态21-6-9不锈钢的硬度,其增加程度随固溶处理温度的升高而减弱。     

Functional Inactivation of Drosophila GCK Orthologs Causes Genomic Instability and Oxidative Stress in a Fly Model of MODY-2

Maturity-onset diabetes of the young (MODY) type 2 is caused by heterozygous inactivating mutations in the gene encoding glucokinase (GCK), a pivotal enzyme for glucose homeostasis. In the pancreas GCK regulates insulin secretion, while in the liver it promotes glucose utilization and storage. We showed that silencing the Drosophila GCK orthologs Hex-A and Hex-C results in a MODY-2-like hyperglycemia. Targeted knock-down revealed that Hex-A is expressed in insulin producing cells (IPCs) whereas Hex-C is specifically expressed in the fat body. We showed that Hex-A is essential for insulin secretion and it is required for Hex-C expression. Reduced levels of either Hex-A or Hex-C resulted in chromosome aberrations (CABs), together with an increased production of advanced glycation end-products (AGEs) and reactive oxygen species (ROS). This result suggests that CABs, in GCK depleted cells, are likely due to hyperglycemia, which produces oxidative stress through AGE metabolism. In agreement with this hypothesis, treating GCK-depleted larvae with the antioxidant vitamin B6 rescued CABs, whereas the treatment with a B6 inhibitor enhanced genomic instability. Although MODY-2 rarely produces complications, our data revealed the possibility that MODY-2 impacts genome integrity.     

基于设计事理学的儿童情感陪伴玩具研究

目的 从设计事理学视角，探讨儿童情感陪伴玩具的设计方法。方法 通过社会调研结合理论分析，提炼7～12岁城市留守儿童情感陪伴玩具中“事”的各外部因素与内部因素，建立合理的儿童情感陪伴玩具设计模型及评价体系。运用案例分析法，结合儿童情感陪伴玩具设计案例与实践，验证设计事理学在实际儿童情感陪伴玩具设计中的应用价值。结论 探索儿童情感陪伴玩具的设计路径，以Combot——具有情感陪伴与寓教于乐功能的儿童情感陪伴玩具为实践案例，证明了基于设计事理学的儿童情感陪伴玩具设计方法是有效可行的，可有效指导儿童玩具设计，满足父母与孩子的情感需求，促进儿童健康成长。     

Application of artificial neural network method to predict the breakage properties of PGE bearing chromite ore

In the present investigation, systematic grinding experiments were conducted in a laboratory ball mill to determine the breakage properties of low-grade PGE bearing chromite ore. The population balance modeling technique was used to study the breakage parameters such as primary breakage distribution (B_{i, j}) and the specific rates of breakage (S_i). The breakage and selection function values were determined for six feed sizes. The results stated that the breakage follows the first-order grinding kinetics for all the feed sizes. It was observed that the coarser feed sizes exhibit higher selection function values than the finer feed size. Further, an artificial neural network was used to predict breakage characteristics of low-grade PGE bearing chromite ore. The predicted results obtained from the neural network modeling were close to the experimental results with a correlation of determination R² = 0.99 for both product size and selection function.     

High Q×f values of Zn-Ni co-modified LiMg0.9Zn0.1-xNixPO4 microwave dielectric ceramics for 5G/6G LTCC modules

In this work, Zn-Ni co-modified LiMg_0.9Zn_0.1-xNi_xPO₄ (x = 0–0.1) microwave dielectric ceramics were fabricated using a solid state synthesis route. Rietveld refinement of the XRD data revealed that all ceramic samples have formed a single phase with olivine structure. SEM images showed that the samples have a dense microstructure, that agrees with the measured relative density of 97.73 %. Based on the complex chemical bond theory, Raman and infrared reflectance spectra, we postulate that ε_r is mainly affected by the ionic polarizability, lattice and bond energy, while P-O bond plays a decisive role in Q×f and τ_f value. Optimum properties of Q×f ~ 153,500 GHz, ε_r ~ 7.13 and τ_f ~ ?59 ppm/°C were achieved for the composition LiMg_0.9Zn_0.06Ni_0.04PO₄ sintered at 875 ℃ for 2 h. This set of properties makes these ceramics an excellent candidate for LTCC, wave-guide filters and antennas for 5 G/6 G communication applications.     

Effects of the Anti-Tumorigenic Agent AT101 on Human Glioblastoma Cells in the Microenvironmental Glioma Stem Cell Niche

Glioblastoma (GBM) is a barely treatable disease due to its profound chemoresistance. A distinct inter- and intratumoral heterogeneity reflected by specialized microenvironmental niches and different tumor cell subpopulations allows GBMs to evade therapy regimens. Thus, there is an urgent need to develop alternative treatment strategies. A promising candidate for the treatment of GBMs is AT101, the R(-) enantiomer of gossypol. The present study evaluates the effects of AT101, alone or in combination with temozolomide (TMZ), in a microenvironmental glioma stem cell niche model of two GBM cell lines (U251MG and U87MG). AT101 was found to induce strong cytotoxic effects on U251MG and U87MG stem-like cells in comparison to the respective native cells. Moreover, a higher sensitivity against treatment with AT101 was observed upon incubation of native cells with a stem-like cell-conditioned medium. This higher sensitivity was reflected by a specific inhibitory influence on the p-p42/44 signaling pathway. Further, the expression of CXCR7 and the interleukin-6 receptor was significantly regulated upon these stimulatory conditions. Since tumor stem-like cells are known to mediate the development of tumor recurrences and were observed to strongly respond to the AT101 treatment, this might represent a promising approach to prevent the development of GBM recurrences.     

近源成藏——来自鄂尔多斯盆地延长组湖盆东部“边缘”延长组6段原油的地球化学证据

延安以东和以北的鄂尔多斯盆地东北部地区曾被认为位处三叠纪延长组7段（长7段）沉积期古湖盆的"边缘"，一些学者认为该区延长组烃源岩不发育，因而其油藏原油系湖盆中心生成的原油经长距离侧向运移而来；但也有研究认为，包括盆地边缘在内的整个鄂尔多斯盆地致密油藏均为近源成藏。为明确盆地东部地区延长组原油来源，对三叠纪湖盆"东缘"七里村油田的主力油层延长组6段（长6段）原油开展了原油地球化学和油源对比研究。七里村油田长6段原油具有高饱和烃、高饱芳比、低非烃和低沥青质的特征，正构烷烃呈前高单峰型，主峰碳为C₁₉，生物标志化合物分析显示长6段原油为同源成熟原油，生油母质以藻类等低等水生生物为主，混有陆源高等植物，母源沉积环境为偏还原性的淡水湖泊。七里村油田长6段原油与本地区长7段黑色泥页岩和暗色泥岩2种烃源岩均具有明显亲缘关系，而与志丹、富县等湖盆中心地区的长7段烃源岩在族组成、生物标志化合物和稳定碳同位素特征上均存在明显区别。综合分析认为七里村油田长6段原油并非湖盆中心长7段优质烃源岩所生油气经长距离运移而来，而主要为原位长7段烃源岩生成的原油经垂向运移和短距离侧向运移在长6段等储层中聚集成藏，属于近源成藏。     

Role of the HSP70 Co-Chaperone SIL1 in Health and Disease

Cell surface and secreted proteins provide essential functions for multicellular life. They enter the endoplasmic reticulum (ER) lumen co-translationally, where they mature and fold into their complex three-dimensional structures. The ER is populated with a host of molecular chaperones, associated co-factors, and enzymes that assist and stabilize folded states. Together, they ensure that nascent proteins mature properly or, if this process fails, target them for degradation. BiP, the ER HSP70 chaperone, interacts with unfolded client proteins in a nucleotide-dependent manner, which is tightly regulated by eight DnaJ-type proteins and two nucleotide exchange factors (NEFs), SIL1 and GRP170. Loss of SIL1′s function is the leading cause of Marinesco-Sjögren syndrome (MSS), an autosomal recessive, multisystem disorder. The development of animal models has provided insights into SIL1′s functions and MSS-associated pathologies. This review provides an in-depth update on the current understanding of the molecular mechanisms underlying SIL1′s NEF activity and its role in maintaining ER homeostasis and normal physiology. A precise understanding of the underlying molecular mechanisms associated with the loss of SIL1 may allow for the development of new pharmacological approaches to treat MSS.