Total Synthesis of (−)-Tuberostemonine

The first total synthesis of the complex pentacyclic Stemona alkaloid tuberostemonine was accomplished in 24 steps and in 1.4% overall yield from a hydroindole intermediate which is readily obtained in three steps from Cbz-l-tyrosine. An innovative synthetic strategy was applied that relays the single stereocenter of the amino acid precursor into nine of the ten stereogenic carbons of the target molecule. Among the highlights of the synthetic methodology are the 3-fold use of ruthenium catalysis, first in an azepine ring-closing metathesis and then in an alkene isomerization followed by a cross-metathesis propenyl−vinyl exchange, as well as the stereoselective attachment of the γ-butyrolactone moiety to the core tetracycle by use of a lithiated ortho ester

Characterization of Polyethers Using Tandem Mass Spectrometry with Hydrogen Abstraction Dissociation and Thermal Activation

The recently developed hydrogen radical-mediated fragmentation technique using an ion trap involving hydrogen attachment/abstraction dissociation-tandem mass spectrometry (HAD-MS/MS) was applied to the analysis of polyethylene glycol (PEG) and its derivatives. HAD was found to be initiated by hydrogen abstraction from carbon atoms in the polyether. Subsequently, the produced carbon-centered radical intermediates underwent radical-induced cleavage of their C–O bonds, with this process being facilitated by heating of the ion trap. The bond cleavage resulted in the formation of b fragments containing double bonds between carbon atoms. A counterpart c• alkoxy radical was discovered to be a fragile radical species. Consequently, c• underwent further radical-induced dissociation to produce small fragments during HAD-MS/MS with thermal activation. As a result, HAD-MS/MS with thermal activation through ion trap heating preferentially provided b fragments, facilitating identification of repeating units and individual end groups of the polyether analytes

Hot Hydrogen Atom Irradiation of Protonated/Deprotonated Peptide in an Ion Trap Facilitates Fragmentation through Heated Radical Formation

Tandem mass spectrometry with fragmentation involving the reaction with hydrogen atoms is expected to be useful for the analysis of peptides and proteins. In general, hydrogen atoms preferentially react with odd-electron radicals. The attachment of hydrogen atoms to even-electron peptide ions is barely observed because of their low reaction rate. To date, only the methodology developed by our group has successfully induced the fragmentation of even-electron peptide ions by reacting with hydrogen atoms. In the present study, we focused on the temperature of the peptide ions and hydrogen atoms in an ion trap mass spectrometer to understand the mechanism of the corresponding reaction. Because the reaction between even-electron peptide ions and hydrogen atoms has a significant transition state barrier, the use of hot hydrogen atoms is required to initiate the reaction. The reaction contributes to increase the internal energy of the resultant peptide radicals because the heat of reaction and kinetic energy of the hydrogen atom are converted to the internal energy of the product. The resultant oxygen- and carbon-centered peptide radicals undergo radical-induced fragmentation with sub-picosecond and sub-millisecond time scales, respectively

The images from the middle layer of the neural network.

<p><b>(</b>A) Representative color fundus photograph of NDR and an image of the middle layer, which has few characteristics. B-F: Representative color fundus photographs of PDR and their images of the middle layer. (B) Laser scars (white arrow head) were enhanced in the middle image. (C) Hard exudates (white arrow head) were enhanced in the middle image. (D) Soft exudates (white arrow head) were enhanced in the middle image. (E) Proliferative membranes (white arrow head) were enhanced in the middle image. (F) Reflections of the retina (white arrow head) were enhanced in the middle image.</p

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase^†^,^‡

Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O2 to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 reduces Kaposi sarcoma tumor growth. Imidazole−dioxolane compounds have recently attracted attention because they have been reported to specifically inhibit HO-1, but not HO-2, unlike Cr-containing protoporphyrin IX, a classical inhibitor of HO, that inhibits not only both HO isoforms but also other hemoproteins. The inhibitory mechanism of imidazole−dioxolane compounds, however, has not yet been characterized. Here, we determine the crystal structure of the ternary complex of rat HO-1, heme, and an imidazole−dioxolane compound, 2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane. This compound bound on the distal side of the heme iron, where the imidazole and 4-chlorophenyl groups were bound to the heme iron and the hydrophobic cavity in HO, respectively. Binding of the bulky inhibitor in the narrow distal pocket shifted the distal helix to open the distal site and moved both the heme and the proximal helix. Furthermore, the biochemical characterization revealed that the catalytic reactions of both HO-1 and HO-2 were completely stopped after the formation of verdoheme in the presence of the imidazole−dioxolane compound. This result should be mainly due to the lower reactivity of the inhibitor-bound verdoheme with O2 compared to the reactivity of the inhibitor-bound heme with O2

X-ray Crystallographic and Biochemical Characterization of the Inhibitory Action of an Imidazole−Dioxolane Compound on Heme Oxygenase^†^,^‡

Heme oxygenase (HO) catalyzes the regiospecific cleavage of the porphyrin ring of heme using reducing equivalents and O2 to produce biliverdin, iron, and CO. Because CO has a cytoprotective effect through the p38-MAPK pathway, HO is a potential therapeutic target in cancer. In fact, inhibition of the HO isoform HO-1 reduces Kaposi sarcoma tumor growth. Imidazole−dioxolane compounds have recently attracted attention because they have been reported to specifically inhibit HO-1, but not HO-2, unlike Cr-containing protoporphyrin IX, a classical inhibitor of HO, that inhibits not only both HO isoforms but also other hemoproteins. The inhibitory mechanism of imidazole−dioxolane compounds, however, has not yet been characterized. Here, we determine the crystal structure of the ternary complex of rat HO-1, heme, and an imidazole−dioxolane compound, 2-[2-(4-chlorophenyl)ethyl]-2-[(1H-imidazol-1-yl)methyl]-1,3-dioxolane. This compound bound on the distal side of the heme iron, where the imidazole and 4-chlorophenyl groups were bound to the heme iron and the hydrophobic cavity in HO, respectively. Binding of the bulky inhibitor in the narrow distal pocket shifted the distal helix to open the distal site and moved both the heme and the proximal helix. Furthermore, the biochemical characterization revealed that the catalytic reactions of both HO-1 and HO-2 were completely stopped after the formation of verdoheme in the presence of the imidazole−dioxolane compound. This result should be mainly due to the lower reactivity of the inhibitor-bound verdoheme with O2 compared to the reactivity of the inhibitor-bound heme with O2

Electrical Generation of Polarized Broadband Radiation from an On-Chip Aligned Carbon Nanotube Film

Microsized light sources with polarized or broadband emission can be used for a variety of applications. However, the system directly generating polarized and broad-spectrum light without using polarizers has not been established. Here, we found that a nano-device of densely packed and highly aligned carbon nanotube (CNT) films on silicon chips can emit polarized light with a broad spectrum. We observed spatial emission patterns that are dependent on the angle between the electrical bias and the CNT alignment direction, which are caused not only by the large thermal conductivity anisotropy of the film but also by finite thermal conductance in the CNT-electrode contact. Utilizing the thermal and electrical anisotropy, strongly localized emission was achieved from a narrow (∼1 μm) strip of aligned CNTs connecting edges of two displaced electrodes. This device’s unique ability to directly generate polarized ultrabroadband radiation may greatly expand the range of applications of microsized light sources

Stable Isotope-Guided Metabolomics Reveals Polar-Functionalized Fatty-Acylated RiPPs from <i>Streptomyces</i>

Ribosomally synthesized and posttranslationally modified peptides (RiPPs) with polar-functionalized fatty acyl groups are a rarely found untapped class of natural products. Although polar-functionalized fatty-acylated RiPPs (PFARs) have potential as antimicrobial agents, the repertoire is still limited. Therefore, expanding the chemical space is expected to contribute to the development of pharmaceutical agents. In this study, we performed genome mining and stable isotope-guided comparative metabolomics to discover new PFAR natural products. We focused on the feature that PFARs incorporate l-arginine or l-lysine as the starter unit of the fatty acyl group and fed 13C6,15N4-l-arginine or 13C6,15N2-l-lysine to bacterial cultures. Metabolites were extracted and compared with those extracted from nonlabeled l-arginine or l-lysine fed cultures. We identified putative PFARs and successfully isolated solabiomycin A and B from Streptomyces lydicus NBRC 13 058 and albopeptin B from Streptomyces nigrescens HEK616, which contained a sulfoxide group in the labionin moiety. The gene disruption experiment indicated that solS, which encodes a putative flavin adenine dinucleotide (FAD)–nicotinamide adenine dinucleotide (phosphate) (NAD(P))-binding protein, is involved in the sulfoxidation of aryl sulfides. The solabiomycins showed antibacterial activity against Gram-positive bacteria, including Mycobacterium tuberculosis H37Rv with a minimum 95% inhibitory concentration (MIC95) of 3.125 μg/mL, suggesting their potential as antituberculosis agents

Evolution of corneal parameters in 2-D tSNE space.

Zigzag, left to right, shows the evolution of tSNE over time starting from initial state which the corneal parameters are simply collapsed onto a 2-D space and then grouping eyes with similar corneal characteristics together over time.</p