Potent γ-secretase inhibitors/modulators interact with amyloid-β fibrils but do not inhibit fibrillation: A high-resolution NMR study

Recently, γ-secretase modulators (GSM) have been shown to interact directly with the amyloid precursor protein (APP) and simultaneously inhibit the activity of the Presenilin domain of γ-secretase. A clear understanding of the molecular recognition pathways by which GSM can target both γ-secretase and Aβ precursor protein can lead to the development of more effective inhibitors. To examine whether this direct interaction with APP affects the downstream Aβ fibril formation, we chose to investigate three different molecules in this study: Sulindac sulfide, Semagacestat and E2012 from the class of generation I GSMs, γ-secretase inhibitors (GSI), and generation II GSM molecules, respectively. Firstly, through NMR based ligand titration, we identified that Sulindac sulfide and Semagacestat interact strongly with Aβ40 monomers, whereas E2012 does not. Secondly, using saturation transfer difference (STD) NMR experiments, we found that all three molecules bind equally well with Aβ40 fibrils. To determine if these interactions with the monomer/fibril lead to a viable inhibition of the fibrillation process, we designed an NMR based time-dependent assay and accurately distinguished the inhibitors from the non-inhibitors within a short period of 12 h. Based on this pre-seeded fibril assay, we conclude that none of these molecules inhibit the ongoing fibrillation, rather ligands such as Semagacestat and E2012 accelerated the rate of aggregation.     

Redistribution of nitrogen in an ecosystem due to long-term fertilization and continuous cropping

Summary When a leguminous crop like cowpea was included in a crop rotation of Ganga 5 maize, CO 7 ragi and CO 2 cowpea, the total nitrogen content in the soil was considerably increased even in the unfertilized plots. The leguminous crop fixed atmospheric nitrogen at the rate of 205 kg N/hectare/year. Potassium did not influence the status whereas phosphorus, over a background of N, improved it. Considerable quantity of N fixed was observed to have been redistributed in the soil which depended on the fertilization pattern.     

Soluble Collagen VI Induces Tyrosine Phosphorylation of Paxillin and Focal Adhesion Kinase and Activates the MAP Kinase Erk2 in Fibroblasts

Signals from the extracellular matrix can modulate cellular differentiation and gene expression. We have shown previously that in contrast to other extracellular matrix molecules pepsin-solubilized collagen VI (CVI) can stimulate DNA synthesis of various mesenchymal cell types, apparently independent of integrin-mediated signal transduction. In order to further elucidate collagen VI-induced signaling events, we exposed mouse 3T3 fibroblasts and human HT1080 fibrosarcoma cells to soluble CVI. CVI induced tyrosine phosphorylation of proteins that associate with focal adhesions, such as paxillin, focal adhesion kinase (FAK), and p130CAS. Furthermore, it activated the mitogen-activated protein kinase, erk2. Kinetic analysis showed that these phosphorylations were transient, reaching a maximum after 5 min for transformed HT1080 cells and 30 min for 3T3 fibroblasts. These effects were partly inhibited by a beta1-integrin function blocking antibody and by single chains of CVI. Our results indicate that soluble fragments of native collagen VI, a ubiquitous component of the interstitial extracellular matrix, can mediate stimulation of DNA synthesis via tyrosine phosphorylation of paxillin, FAK, p130CAS, and erk2 in the absence of classical growth factors. Thus, CVI may serve as a matrix-derived sensor that allows for rapid reconstitution of a tissue defect by activating nearby mesenchymal cells.     

Nutrient uptake by paddy during the main three stages of growth

Summary Uptake of mineral nutrients and production of carbohydrates by paddy during the vegetative, the reproductive, and the ripening stage of growth were determined in a pot experiment.From 59 to 84 per cent of the nutrients present in the ripe plants were absorbed between tillering and flowering. More than 90 per cent of the N and K, 80 per cent of the P and Ca, and 65 per cent of the Mg were absorbed prior to flowering, and the remainder after heading.More than 60 per cent of the carbohydrates present in the ripe stage was produced after flowering.     

Gamma-aminobutyric acid production through GABA shunt by synthetic scaffolds introduction in recombinant <Emphasis Type="Italic">Escherichia coli</Emphasis>

Nylon 4 is a biodegradable polymer which can be produced from the monomer of pyrrolidone. Gammaaminobutyric acid (GABA) is a precursor of pyrrolidone used for the production of bioplastics. In this study, Escherichia coli were engineered to produce gammaaminobutyric acid from glucose via an alternative novel pathway by the introduction of synthetic scaffolds. The GABA pathway constructed contained succinate dehydrogenase, succinate-semialdehyde dehydrogenase and GABA aminotransferase to redirect the Krebs cycle flux to GABA production. By introduction of a synthetic scaffold, production of 0.64 g/L GABA was achieved at 30°C and pH 6.5. Final GABA concentration was increased by 11.3% via the inactivation of competing pathways, and higher initial glucose concentration led to the enhanced final GABA concentration of 1.01 g/L.     

Pixel sensible local band analysis in microscopic chromosome images using CSPA

In chromosome analysis, local band analysis plays the main role to identify the perfect matched chromosome in metaspread images to attain the karyotyping. Literature investigations are narrow in chromosome image band analysis due to the higher complexities. In this paper, Pixel level based Conditional Seed Point Algorithm (CSPA) is proposed. This simulation algorithm separates the weak band region to the strong band region, and the strong band region area evaluated was based on the Region of Seed condition Points. This algorithm works well for different intensity levels and adopts the structural changes to identify the bands in image. This algorithm was simulated in more than 450 individual chromosomes to identify the local bands in the chromosome images and provided the accuracy more than 96%.     

Re-irradiation after stereotactic body radiotherapy for spine metastases from hepatocellular carcinoma: a case report

Modern radiotherapy machines with refinements in planning software and image-guidance apparatuses have made stereotactic body radiotherapy (SBRT) more widely available as an effective tool in the management of spine metastases. In conventional palliative radiotherapy, the aim has traditionally been pain relief and short-term local control. In contrast, SBRT aims to deliver an ablative dose to enhance local control, with a smaller number of fractions while sparing the organs at risk (OAR), especially the spinal cord. Recently, trials have asserted the role of spine SBRT as an effective modality for durable local control, in addition to achieving pain relief. The quality of evidence for spine SBRT data is maturing, while prospective published trials on re-irradiation SBRT in spine remain sparse. The purpose of the present case report is to share the challenges faced while salvaging a dorsal spine metastasis and ablating a new right adrenal metastatic lesion in proximity of the transplanted liver.