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.     

北京亦庄半岛幼儿园

正项目地址_中国北京项目面积_8000m~2设计单位_ArkA北京亦庄半岛幼儿园项目是设计团队与半岛教育集团的第二次合作,目标是将蒙特梭利教育理念和建筑设计融为一体,创造出一个更合理的空间和安全的环境,让孩子们能够自由快乐地学习和成长。原有的建筑物是一个开放的空间,整个大空间分作4层。设计团队的首要任务是根据孩子的比例改造空间。在设计时,设计团队加入了许多小房屋的设计,以此让孩子更具有主人感和安全感。对教室的设计是简约的房屋;图书馆则是一个开放空间,在其中央种下一棵树,好似一个乡村小镇的广场;走廊设计成多功能的开放空间,孩子     

Dihydrotanshinone,a Natural Diterpenoid,Preserves Blood-Retinal Barrier Integrity via P2X7 Receptor

Activation of P2X7 signaling, due to high glucose levels, leads to blood retinal barrier (BRB) breakdown, which is a hallmark of diabetic retinopathy (DR). Furthermore, several studies report that high glucose (HG) conditions and the related activation of the P2X7 receptor (P2X7R) lead to the over-expression of pro-inflammatory markers. In order to identify novel P2X7R antagonists, we carried out virtual screening on a focused compound dataset, including indole derivatives and natural compounds such as caffeic acid phenethyl ester derivatives, flavonoids, and diterpenoids. Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring and structural fingerprint clustering of docking poses from virtual screening highlighted that the diterpenoid dihydrotanshinone (DHTS) clustered with the well-known P2X7R antagonist JNJ47965567. A human-based in vitro BRB model made of retinal pericytes, astrocytes, and endothelial cells was used to assess the potential protective effect of DHTS against HG and 2′(3′)-O-(4-Benzoylbenzoyl)adenosine-5′-triphosphate (BzATP), a P2X7R agonist, insult. We found that HG/BzATP exposure generated BRB breakdown by enhancing barrier permeability (trans-endothelial electrical resistance (TEER)) and reducing the levels of ZO-1 and VE-cadherin junction proteins as well as of the Cx-43 mRNA expression levels. Furthermore, HG levels and P2X7R agonist treatment led to increased expression of pro-inflammatory mediators (TLR-4, IL-1β, IL-6, TNF-α, and IL-8) and other molecular markers (P2X7R, VEGF-A, and ICAM-1), along with enhanced production of reactive oxygen species. Treatment with DHTS preserved the BRB integrity from HG/BzATP damage. The protective effects of DHTS were also compared to the validated P2X7R antagonist, JNJ47965567. In conclusion, we provided new findings pointing out the therapeutic potential of DHTS, which is an inhibitor of P2X7R, in terms of preventing and/or counteracting the BRB dysfunctions elicited by HG conditions.     

Milk from cows fed a diet with a high forage:concentrate ratio improves inflammatory state,oxidative stress,and mitochondrial function in rats

Excessive energy intake may evoke complex biochemical processes characterized by inflammation, oxidative stress, and impairment of mitochondrial function that represent the main factors underlying noncommunicable diseases. Because cow milk is widely used for human nutrition and in food industry processing, the nutritional quality of milk is of special interest with respect to human health. In our study, we analyzed milk produced by dairy cows fed a diet characterized by a high forage:concentrate ratio (high forage milk, HFM). In view of the low n-6:n-3 ratio and high content of conjugated linoleic acid of HFM, we studied the effects of this milk on lipid metabolism, inflammation, mitochondrial function, and oxidative stress in a rat model. To this end, we supplemented for 4 wk the diet of male Wistar rats with HFM and with an isocaloric amount (82 kJ, 22 mL/d) of milk obtained from cows fed a diet with low forage:concentrate ratio, and analyzed the metabolic parameters of the animals. Our results indicate that HFM may positively affect lipid metabolism, leptin:adiponectin ratio, inflammation, mitochondrial function, and oxidative stress, providing the first evidence of the beneficial effects of HFM on rat metabolism.     

Recent-onset ecstasy use: Association with deviant behaviors and psychiatric comorbidity.

Background: Despite increases in ecstasy (MDMA) use in the United States, little is known about characteristics linked with recent-onset ecstasy use, especially psychiatric symptoms and deviant behaviors. Aims: To test whether individuals with high levels of other drug use are more likely to be recent-onset ecstasy users; to test whether psychiatric symptoms in adults are associated with recent-onset ecstasy use; to explore the association between recent-onset ecstasy use and concomitant deviant behaviors in adolescents and adults. Methods: Data from the 2001 National Survey on Drug Use and Health. Findings: Recent-onset ecstasy use was significantly more likely to occur among adolescents and adults (18-34 years old) who engaged in deviant behaviors during the past year as compared with those who did not engage in deviant behaviors during the past year. Higher levels of deviancy indicated a higher likelihood of being a recent-onset ecstasy user, and associations were strongest with nonviolent deviant behaviors such as selling illegal drugs and stealing. Associations between deviant behaviors and recent-onset ecstasy use were similar in strength to associations between deviant behaviors and recent-onset cocaine and marijuana use, respectively. Adults who had past-year psychiatric symptoms (both depressive and panic symptoms) were twice as likely to be recent-onset ecstasy users as compared with those without past-year psychiatric symptoms. Greater levels of drug involvement increased the odds of being a recent-onset ecstasy user. Conclusion: Recent-onset ecstasy use seems to be associated with a range of other behavioral problems and may reflect one aspect of a larger problem behavior syndrome. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

300km/h高速铁路PC槽型梁动力试验研究

介绍北方交通大学与比利时鲁汶大学、布鲁塞尔自由大学、比利时铁路公司合作,在巴黎至布鲁塞尔之间高速铁路线上的Antoing大桥进行的二次高速铁路桥梁动力试验。试验桥梁由跨度50m的多跨预应力混凝土简支槽型梁构成,试验中列车速度达265-310km/h。通过现场试验和实验结果分析,得到了桥梁的频率、振型、阻尼等自振特性,以及桥梁在高速列车作用下的动挠度、梁和桥墩的横向和竖向加速度、橡胶支座的相对位移、梁体的动应变等动力响应特性。试验经验和测试结果对于充实高速铁路桥梁动力分析理论、改进数值分析模型、验证计算结果、提高高速铁路桥梁的动力设计水平、保证行车安全,具有重要的意义。     

Doped silicon and NIS junctions for bolometer applications

We discuss the performance, of a normal metal hot electron bolometer (NHEB) that we have measured at 0.3 K. We found that the noise equivalent power was limited by the amplifier noise. To improve the NHEB power response and to make it more robust and reliable we propose to substitute the normal metal with heavily doped silicon. The heavily doped silicon behaves like a metal with lower carrier concentration and has a smaller electron–phonon thermal coupling. We have fabricated superconductor-doped silicon-superconductor contacts (S-Sm-S) and we have used them as thermometers and coolers.