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Dysregulation of histone H3 lysine 4 (H3K4) methylation is implicated in the pathogenesis of neurodevelopmental disorders. Lysine-specific demethylase 1 (LSD1) determines the methylation status of H3K4 through flavin adenine dinucleotide (FAD)-mediated histone demethylation. Therefore, LSD1 inhibition in the brain can be a novel therapeutic option for treating these disorders. Positron emission tomography (PET) imaging of LSD1 allows for investigating LSD1 expression levels under normal and disease conditions and validating target engagement of therapeutic LSD1 inhibitors. This study designed and synthesized (2-aminocyclopropyl)phenyl derivatives with irreversible binding to LSD1 as PET imaging agents for LSD1 in the brain. We optimized lipophilicity of the lead compound to minimize the risk of nonspecific binding and identified 1e with high selectivity over monoamine oxidase A and B, which are a family of FAD-dependent enzymes homologous to LSD1. PET imaging in a monkey showed a high uptake of [18F]1e to regions enriched with LSD1, indicating its specific binding to LSD1.

Dysregulation of histone H3 lysine 4 (H3K4) methylation has been implicated in the pathogenesis of several neurodevelopmental disorders. Targeting lysine-specific demethylase 1 (LSD1), an H3K4 demethylase, is therefore a promising approach to treat these disorders. However, LSD1 forms complexes with cofactors including growth factor independent 1B (GFI1B), a critical regulator of hematopoietic differentiation. Known tranylcypromine-based irreversible LSD1 inhibitors bind to coenzyme flavin adenine dinucleotide (FAD) and disrupt the LSD1-GFI1B complex, which is associated with hematotoxicity such as thrombocytopenia, representing a major hurdle in the development of LSD1 inhibitors as therapeutic agents. To discover LSD1 inhibitors with potent epigenetic modulation and lower risk of hematotoxicity, we screened small molecules that enhance H3K4 methylation by the inhibition of LSD1 enzyme activity in primary cultured rat neurons but have little impact on LSD1-GFI1B complex in human TF-1a erythroblasts. Here we report the discovery of a specific inhibitor of LSD1 enzyme activity, T-448 (3-((1S,2R)-2-(cyclobutylamino)cyclopropyl)-N-(5-methyl-1,3,4-thiadiazol-2-yl)benzamide fumarate). T-448 has minimal impact on the LSD1-GFI1B complex and a superior hematological safety profile in mice via the generation of a compact formyl-FAD adduct. T-448 increased brain H3K4 methylation and partially restored learning function in mice with NMDA receptor hypofunction. T-448-type LSD1 inhibitors with improved safety profiles may provide unique therapeutic approaches for central nervous system disorders associated with epigenetic dysregulation.

A three-stage chromatography protocol for the purification of human papillomavirus-like particles (HPV-LPs) from the silkworm-based Bombyx mori nucleopolyhedrovirus bacmid expression system was developed. For host cell DNA separation, anion exchange chromatography was used after screening for a suitable stationary phase. Using the two separation principles of cation exchange chromatography and metal affinity of ceramic hydroxyapatite (CHT) as a second stage, the amount of baculovirus in the sample was reduced to less than the detection limit of qPCR. The CHT separation was optimized with respect to the elution buffer used; 150–600 mM sodium phosphate, pH 7.2, resulted in the highest recovery of HPV-LPs. Using heparin chromatography, it was possible to reduce the sample volume and to thus highly concentrate the target protein during the separation of contaminating proteins. During the second purification stage, over 99.3% of the DNA was removed, and no infectious baculoviruses remained. After concentration by heparin column chromatography, over 99.9% of the DNA and protein had been removed. The purity achieved by this method exceeds that obtained by DDDDK-tag-based affinity chromatography and sucrose gradient ultracentrifugation, which were used as comparative purification methods. The 3-stage purification of HPV-LPs from silkworm fat bodies described here was a proof of concept and is a scalable method, but the overall yield remains to be improved.

Nanofibers are useful in many areas due to their outstanding characteristics, most importantly their small size and high surface-area-to-volume ratio. Recently, drug delivery systems using polymer nanofibers have gained significant attention. For these systems, a chopped nanofiber is required because the amount of drug released depends on the length of the fiber. Electrospinning is a simple method of fabricating polymer nanofibers. In the process, a high voltage is used to electrify a liquid jet which ultimately produces a solid nanofiber. The jet ejects when a high voltage is applied and vice versa. It is therefore possible to fabricate and chop nanofibers by controlling the value of the voltages applied. In this paper, an IGBT-based pulsed power supply, which can produce square pulses with a width of a few hundred microseconds and amplitudes up to 10 kV, has been designed and built. It was able to fabricate and chop nanofibers with polyethylene oxide (PEO) and a biodegradable polymer, sodium alginate blended with PEO, utilizing the aforementioned pulsed power supply. A jet always ejected during the pulse-on voltage when the duty ratio is more than 40%, with a minimum pulsewidth of approximately 80 ms.

The demand for biologically compatible and stable noble metal nanoparticles (NPs) has increased in recent years due to their inert nature and unique optical properties. In this article, we present 11 different synthetic methods for obtaining gold nanoparticles (Au NPs) through the use of common biological buffers. The results demonstrate that the sizes, shapes, and monodispersity of the NPs could be varied depending on the type of buffer used, as these buffers acted as both a reducing agent and a stabilizer in each synthesis. Theoretical simulations and electrochemical experiments were performed to understand the buffer-dependent variations of size and morphology exhibited by these Au NPs, which revealed that surface interactions and the electrostatic energy on the (111) surface of Au were the determining factors. The long-term stability of the synthesized NPs in buffer solution was also investigated. Most NPs synthesized using buffers showed a uniquely wide range of pH stability and excellent cell viability without the need for further modifications. Electronic supplementary material The online version of this article (doi:10.1186/s11671-016-1290-3) contains supplementary material, which is available to authorized users.