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.     

Charge Density Influences C1 Domain Ligand Affinity and Membrane Interactions

The C1 domain, which represents the recognition motif on protein kinase C for the lipophilic second messenger diacylglycerol and its ultrapotent analogues, the phorbol esters, has emerged as a promising therapeutic target for cancer and other indications. Potential target selectivity is markedly enhanced both because binding reflects ternary complex formation between the ligand, C1 domain, and phospholipid, and because binding drives membrane insertion of the C1 domain, permitting aspects of the C1 domain surface outside the binding site, per se, to influence binding energetics. Here, focusing on charged residues identified in atypical C1 domains which contribute to their loss of ligand binding activity, we showed that increasing charge along the rim of the binding cleft of the protein kinase C δ C1 b domain raises the requirement for anionic phospholipids. Correspondingly, it shifts the selectivity of C1 domain translocation to the plasma membrane, which is more negatively charged than internal membranes. This change in localization is most pronounced in the case of more hydrophilic ligands, which provide weaker membrane stabilization than do the more hydrophobic ligands and thus contributes an element to the structure–activity relations for C1 domain ligands. Coexpressing pairs of C1‐containing constructs with differing charges each expressing a distinct fluorescent tag provided a powerful tool to demonstrate the effect of increasing charge in the C1 domain.     

N‐Methyl‐Substituted Fluorescent DAG–Indololactone Isomers Exhibit Dramatic Differences in Membrane Interactions and Biological Activity

N‐methyl‐substituted diacylglycerol–indololactones (DAG–indololactones) are newly synthesized effectors of protein kinase C (PKC) isoforms and exhibit substantial selectivity between RasGRP3 and PKCα. We present a comprehensive analysis of membrane interactions and biological activities of several DAG–indololactones. Translocation and binding activity assays underline significant variations between the PKC translocation characteristics affected by the ligands as compared to their binding activities. In parallel, the fluorescent properties of the ligands were employed for analysis of their membrane association profiles. Specifically, we found that a slight change in the linkage to the indole ring resulted in significant differences in membrane binding and association of the DAG–indololactones with lipid bilayers. Our analysis shows that seemingly small structural modifications of the hydrophobic regions of these biomimetic PKC effectors contribute to pronounced modulation of membrane interactions of the ligands.     

Evidence of Oxygen Ferromagnetism in ZnO Based Materials

Discoveries of room‐temperature ferromagnetism (RTFM) in semiconductors hold great promise in future spintronics technologies. Unfortunately, this ferromagnetism remains poorly understood and the debate concerning the nature, carrier‐mediated versus defect‐mediated, of this ferromagnetism in semiconducting oxides is still open. Here, by using X‐ray absorption (XAS) and X‐ray magnetic circular dichroism (XMCD), it is demonstrated that the oxygen ions have a ferromagnetic response in different ZnO‐based compounds showing RTFM behavior: ZnO nanoparticles capped with organic molecules and ZnO/ZnS heterostructures. These results demonstrate the intrinsic occurrence of RTFM in these systems, and point out that it is not related to the metallic cation but it relays on the conduction band of the semiconductor.     

Utilization of Ultrasonic Measurements for Determining the Variations in Microstructure of Thermally Degraded 2205 Duplex Stainless Steel

The aim of this study is to investigate the changes in attenuation of longitudinal waves and velocity of shear wave modes for assessing variations in the microstructure of thermally degraded 2205 duplex stainless steel samples that were aged isothermally at 700°C and 900°C for different time intervals. The evaluation of material microstructural changes such as phase transformation and second phase precipitation which are related to material properties is of primary importance to ensure quality of components. This paper presents evidence that indicate that the attenuation coefficient of the longitudinal mode is sensitive to gradual microstructural changes produced by the aging treatments. The gradual changes in microstructure are associated with reduction of impact properties. On the other hand, for samples aged at 700°C, the velocity of the fast mode of shear wave show changes at high aging times and does not show changes at early aging times were the materials properties are already degraded.     

Geodesign application for bio-swale design: rule-based approach stormwater management for Ottawa Street North in Hamilton,Ontario

With increases in storm frequency and intensity, municipalities are finding new ways of managing stormwater. Solutions require collaboration across planning disciplines and input from an informed public. This study compares a system of bioswales to existing curb and gutter infrastructure in a post-industrial streetscape of Hamilton, Ontario. Using the geodesign process, a section of Ottawa St. North was modelled to show how green infrastructure can ease the burden on aging, combined sewer systems. Qualitative data was gathered from residents of the neighbourhood through field notes, and quantitative geospatial data through GIS. Parametric modelling was used to generate a design, and scenarios created to show resulting impacts on stormwater run-off. The model was posted online as an interactive presentation, accessible to all stakeholders for review and comment. The results of the study demonstrate powerful new tools that can assist landscape architects in designing, collaborating and communicating stormwater strategies.