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.     

Current Status of Angiogenic Cell Therapy and Related Strategies Applied in Critical Limb Ischemia

Critical limb ischemia (CLI) constitutes the most severe form of peripheral arterial disease (PAD), it is characterized by progressive blockade of arterial vessels, commonly correlated to atherosclerosis. Currently, revascularization strategies (bypass grafting, angioplasty) remain the first option for CLI patients, although less than 45% of them are eligible for surgical intervention mainly due to associated comorbidities. Moreover, patients usually require amputation in the short-term. Angiogenic cell therapy has arisen as a promising alternative for these “no-option” patients, with many studies demonstrating the potential of stem cells to enhance revascularization by promoting vessel formation and blood flow recovery in ischemic tissues. Herein, we provide an overview of studies focused on the use of angiogenic cell therapies in CLI in the last years, from approaches testing different cell types in animal/pre-clinical models of CLI, to the clinical trials currently under evaluation. Furthermore, recent alternatives related to stem cell therapies such as the use of secretomes, exosomes, or even microRNA, will be also described.     

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.     

Indoor heterogeneous photochemistry of furfural drives emissions of nitrous acid

People spend approximately 80% of their time indoor, making the understanding of the indoor chemistry an important task for safety. The high surface-area-to-volume ratio characteristic of indoor environments leads the semi-volatile organic compounds (sVOCs) to deposit on the surfaces. Using a long path absorption photometer (LOPAP), this work investigates the formation of nitrous acid (HONO) through the photochemistry of adsorbed nitrate anions and its enhancement by the presence of furfural. Using a high-resolution proton-transfer-reaction time-of-flight mass spectrometer (PTR-TOF-MS), this work also investigates the surface emissions of VOCs from irradiated films of furfural and a mix of furfural and nitrate anions. Among the emitted VOCs, 2(5H)-furanone/2-Butenedial was observed at high concentrations, leading to maleic anhydride formation after UV irradiation. Moreover, the addition of potassium nitrate to the film formed NO_x and HONO concentrations up to 10 ppb, which scales to ca. 4 ppb for realistic indoor conditions. This work helps to understand the high levels of HONO and NO_x measured indoors.     

A Donor–Acceptor Polymer with a Peculiar Negative‐Charge‐“Trapping” Characteristic

Voltammetric and spectrophotometric measurements of poly(3,3″‐dipentoxy‐3′‐dicyanoethenyl‐2,2′:5′,2″‐terthiophene) (polyCN) films, in connection with other experimental evidence, reveal a normal oxidative, but a peculiar reductive behavior consisting of trapping of the negative charge during the cathodic scan. Another interesting property of polyCN films is the tendency to form strong intramolecular and intermolecular associations, probably charge‐transfer (CT) complexes. These properties could account for the fact that the photovoltaic performance does not improve when polyCN is blended with a polythiophene donor.     

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.