Combinatorial Synthesis of Structurally Diverse Triazole-Bridged Flavonoid Dimers and Trimers

Flavonoids are a large family of compounds associated with a broad range of biologically useful properties. In recent years, synthetic compounds that contain two flavonoid units linked together have attracted attention in drug discovery and development projects. Numerous flavonoid dimer systems, incorporating a range of monomers attached via different linkers, have been reported to exhibit interesting bioactivities. From a medicinal chemistry perspective, the 1,2,3-triazole ring system has been identified as a particularly attractive linker moiety in dimeric derivatives (owing to several favourable attributes including proven biological relevance and metabolic stability) and triazole-bridged flavonoid dimers possessing anticancer and antimalarial activities have recently been reported. However, there are relatively few examples of libraries of triazole-bridged flavonoid dimers and the diversity of flavonoid subunits present within these is typically limited. Thus, this compound type arguably remains underexplored within drug discovery. Herein, we report a modular strategy for the synthesis of novel and biologically interesting triazole-bridged flavonoid heterodimers and also very rare heterotrimers from readily available starting materials. Application of this strategy has enabled step-efficient and systematic access to a library of structurally diverse compounds of this sort, with a variety of monomer units belonging to six different structural subclasses of flavonoid successfully incorporated.Cambridge Commonwealth Trust, European Research Council under the European Union’s Seventh Framework Programme (FP7/2007–2013)/ERC grant agreement No. [279337/DOS], AstraZeneca, European Union, Engineering and Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Medical Research Council, Wellcome Trus

A combined computational and experimental investigation of the [2Fe–2S] cluster in biotin synthase

Biotin synthase was the first example of what is now regarded as a distinctive enzyme class within the radical S-adenosylmethionine superfamily, the members of which use Fe/S clusters as the sulphur source in radical sulphur insertion reactions. The crystal structure showed that this enzyme contains a [2Fe–2S] cluster with a highly unusual arginine ligand, besides three normal cysteine ligands. However, the crystal structure is at such a low resolution that neither the exact coordination mode nor the role of this exceptional ligand has been elucidated yet, although it has been shown that it is not essential for enzyme activity. We have used quantum refinement of the crystal structure and combined quantum mechanical and molecular mechanical calculations to explore possible coordination modes and their influences on cluster properties. The investigations show that the protonation state of the arginine ligand has little influence on cluster geometry, so even a positively charged guanidinium moiety would be in close proximity to the iron atom. Nevertheless, the crystallised enzyme most probably contains a deprotonated (neutral) arginine coordinating via the NH group. Furthermore, the Fe···Fe distance seems to be independent of the coordination mode and is in perfect agreement with distances in other structurally characterised [2Fe–2S] clusters. The exceptionally large Fe···Fe distance found in the crystal structure could not be reproduced

Oncogenic LMO3 Collaborates with HEN2 to Enhance Neuroblastoma Cell Growth through Transactivation of Mash1

Expression of Mash1 is dysregulated in human neuroblastoma. We have also reported that LMO3 (LIM-only protein 3) has an oncogenic potential in collaboration with neuronal transcription factor HEN2 in neuroblastoma. However, the precise molecular mechanisms of its transcriptional regulation remain elusive. Here we found that LMO3 forms a complex with HEN2 and acts as an upstream mediator for transcription of Mash1 in neuroblastoma. The high levels of LMO3 or Mash1 mRNA expression were significantly associated with poor prognosis in 100 primary neuroblastomas. The up-regulation of Mash1 remarkably accelerated the proliferation of SH-SY5Y neuroblastoma cells, while siRNA-mediated knockdown of LMO3 induced inhibition of growth of SH-SY5Y cells in association with a significant down-regulation of Mash1. Additionally, overexpression of both LMO3 and HEN2 induced expression of Mash1, suggesting that they might function as a transcriptional activator for Mash1. Luciferase reporter assay demonstrated that the co-expression of LMO3 and HEN2 attenuates HES1 (a negative regulator for Mash1)-dependent reduction of luciferase activity driven by the Mash1 promoter. Chromatin immunoprecipitation assay revealed that LMO3 and HEN2 reduce the amount of HES1 recruited onto putative HES1-binding sites and E-box within the Mash1 promoter. Furthermore, both LMO3 and HEN2 are physically associated with HES1 by immunoprecipitation assay. Thus, our present results suggest that a transcriptional complex of LMO3 and HEN2 may contribute to the genesis and malignant phenotype of neuroblastoma by inhibiting HES1 which suppresses the transactivation of Mash1

Oncogenic Stress Induced by Acute Hyper-Activation of Bcr-Abl Leads to Cell Death upon Induction of Excessive Aerobic Glycolysis

In response to deregulated oncogene activation, mammalian cells activate disposal programs such as programmed cell death. To investigate the mechanisms behind this oncogenic stress response we used Bcr-Abl over-expressing cells cultivated in presence of imatinib. Imatinib deprivation led to rapid induction of Bcr-Abl activity and over-stimulation of PI3K/Akt-, Ras/MAPK-, and JAK/STAT pathways. This resulted in a delayed necrosis-like cell death starting not before 48 hours after imatinib withdrawal. Cell death was preceded by enhanced glycolysis, glutaminolysis, and amino acid metabolism leading to elevated ATP and protein levels. This enhanced metabolism could be linked to induction of cell death as inhibition of glycolysis or glutaminolysis was sufficient to sustain cell viability. Therefore, these data provide first evidence that metabolic changes induced by Bcr-Abl hyper-activation are important mediators of oncogenic stress-induced cell death

A case control study on passive smoking and childhood hospitalization due to respiratory illnesses

Conferenc Theme: Transformation in Hospital Service

3D printed porous methacrylate/silica hybrid scaffold for bone substitution

Inorganic–organic hybrid biomaterials made with star polymer poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate) and silica, which show promising mechanical properties, are 3D printed as bone substitutes for the first time, by direct ink writing of the sol. Three different inorganic:organic ratios of poly(methyl methacrylate-co-3-(trimethoxysilyl)propyl methacrylate)-star-SiO2 hybrid inks are printed with pore channels in the range of 100–200 µm. Mechanical properties of the 3D printed scaffolds fall within the range of trabecular bone, and MC3T3 pre-osteoblast cells are able to adhere to the scaffolds in vitro, regardless of their compositions. Osteogenic and angiogenic properties of the hybrid scaffolds are shown using a rat calvarial defect model. Hybrid scaffolds with 40:60 inorganic:organic composition are able to instigate new vascularized bone formation within its pore channels and polarize macrophages toward M2 phenotype. 3D printing inorganic–organic hybrids with sophisticated polymer structure opens up possibilities to produce novel bone graft materials

A case control study on passive smoking and childhood hospitalization due to respiratory illness

Conferenc Theme: Transformation in Hospital ServicesAbstrac

Expression of LMO4 and outcome in pancreatic ductal adenocarcinoma

Identification of a biomarker of prognosis and response to therapy that can be assessed preoperatively would significantly improve overall outcomes for patients with pancreatic cancer. In this study, patients whose tumours exhibited high LMO4 expression had a significant survival advantage following operative resection, whereas the survival of those patients whose tumours had low or no LMO4 expression was not significantly different when resection was compared with operative biopsy alone

Scanning Probe Microscopy for Industrial Applications: Selected Examples

DAMMER U, Anselmetti D, DREIER M, et al. Scanning Probe Microscopy for Industrial Applications: Selected Examples. Scanning. 1993;15(5):257-264.Some examples are selected to demonstrate the variety of possible scanning probe microscopy application in industry. Magnetic and magnetooptical storage media can be investigated by magnetic force microscopy, whereas a conventional scanning force microscope is used to examine surface features of many different materials, such as technical glasses, photosensitive materials, new superconductors, and biomolecules. Some other examples include the modification as well as the observation of liquid crystal devices, and the impact that scanning probe microscopy has on other techniques such as high precision stepping motors and high quality electron beam sources