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.     

Assessing organo-clay dispersion in polymer layered silicate nanocomposites: A SAXS approach

A SAXS method for the quantitative assessment of the morphology of polymer layered silicate nanocomposites is proposed. Fitting the SAXS patterns, the number of clay layers, the periodicity of the layers in the tactoids, the thickness of the regions interposed between the clay platelets and their distributions can be measured. A good agreement with TEM data was obtained, avoiding the inconsistencies with microscopical observations often reported in the literature.     

Co- and Ni-exchanged ferrierite: The contribution of synchrotron X-ray diffraction data to siting of TMIs

High-silica zeolites exchanged with transition metal ions (TMIs) are the subject of great interest for their unusual catalytic activity and selectivity. Structural information like coordination and accessibility of TMIs in zeolites are important factors for understanding their catalytic activity. Siting of TMIs in zeolites is typically obtained by spectroscopic (EXAFS, EPR, UV–vis and IR) and computational methods, as in the case of Co-ferrierite. However, some controversy exists in the literature concerning the model for incorporation of bare Co ions in ferrierite. We show here that the results of our synchrotron X-ray powder diffraction studies on Co- and Ni-exchanged ferrierite (Si/Al = 8.5) are in a good agreement with the model of Co siting based on an indirect spectroscopic approach and help to validate this model. By direct structural evidences, a possible explanation for the larger catalytic activity of Co sites in the main channels of ferrierite can be inferred. A combination of data from in situ XRD continuous monitoring of the Co ion migration during calcination and crystal-chemical considerations allows to device a strategy for the design of optimised co-cations containing Co-ferrierite catalysts.     

Neural network systems to reproduce crash behavior of structural components

The use of neural networks as global approximation tool in crashworthiness problems is here investigated. Neural networks are not only asked to return some meaningful indices of the structural behavior but also to reproduce load-time curves during crash phenomena. To contain the number of examples required for the training process, parallel subsystems of small neural networks are designed. Design points for the training process are obtained by explicit finite element analyses performed by PAMCRASH. The settlement of the points in the design domain is defined using a maximum distance concept. The procedure is applied to different typical absorption structures made of aluminum alloy: riveted tubes, honeycomb structures, longitudinal keel beam and intersection elements of helicopter subfloors.     

Tensile and flexural creep rupture tests on partially-damaged concrete specimens

Three series of novel tensile and flexural creep tests on partially-damaged concrete specimens were carried out in order to gain some insight into creep crack growth and failure of strain-softening materials. In the tests, each specimen was initially loaded to a given point in the descending branch and thus had a lower load-carrying capacity than that at the peak-point. Then, the specimen was unloaded and reloaded to sustain a load which was from 70% to 95% of its current load-carrying capacity. Experimental creep curves display a three-stage process, consisting of primary, secondary and tertiary stages, with a decreasing, constant and increasing creep rate, respectively. The secondary stage dominates the whole failure lifetime, whereas both the secondary and tertiary stages are important in terms of creep deformation. Failure life-time seems to be more sensitive to the change of load level in flexural tests rather than in tensile tests. The decrease in load-carrying capacity due to damage tends to result in a shorter failure lifetime and a lower critical load level for creep rupture. The descending branch of the static load-deflection or load-CMOD curve may be used as an envelope criterion for creep fracture.