Effects of Angiotensin II on Erythropoietin Production in the Kidney and Liver

The kidney is a main site of erythropoietin production in the body. We developed a new method for the detection of Epo protein by deglycosylation-coupled Western blotting. Detection of deglycosylated Epo enables the examination of small changes in Epo production. Using this method, we investigated the effects of angiotensin II (ATII) on Epo production in the kidney. ATII stimulated the plasma Epo concentration; Epo, HIF2α, and PHD2 mRNA expression in nephron segments in the renal cortex and outer medulla; and Epo protein expression in the renal cortex. In situ hybridization and immunohistochemistry revealed that ATII stimulates Epo mRNA and protein expression not only in proximal tubules but also in collecting ducts, especially in intercalated cells. These data support the regulation of Epo production in the kidney by the renin–angiotensin–aldosterone system (RAS).     

Generating 3D molecules conditional on receptor binding sites with deep generative models

The goal of structure-based drug discovery is to find small molecules that bind to a given target protein. Deep learning has been used to generate drug-like molecules with certain cheminformatic properties, but has not yet been applied to generating 3D molecules predicted to bind to proteins by sampling the conditional distribution of protein–ligand binding interactions. In this work, we describe for the first time a deep learning system for generating 3D molecular structures conditioned on a receptor binding site. We approach the problem using a conditional variational autoencoder trained on an atomic density grid representation of cross-docked protein–ligand structures. We apply atom fitting and bond inference procedures to construct valid molecular conformations from generated atomic densities. We evaluate the properties of the generated molecules and demonstrate that they change significantly when conditioned on mutated receptors. We also explore the latent space learned by our generative model using sampling and interpolation techniques. This work opens the door for end-to-end prediction of stable bioactive molecules from protein structures with deep learning.

We generate 3D molecules conditioned on receptor binding sites by training a deep generative model on protein–ligand complexes. Our model uses the conditional receptor information to make chemically relevant changes to the generated molecules.     

Hydrothermal synthesis,crystal structure and magnetic properties of a new one-dimensional polymer [{Cu(4,4′- bipy)(CH<Subscript>3</Subscript>COO)<Subscript>2</Subscript>}·3H<Subscript>2</Subscript>O]<Subscript>n</Subscript>

One new metal – organic coordination framework formulated as [{Cu(4,4′-bipy)(CH₃COO)₂}·3H₂O]_n (1) (where 4,4′-bipy=4,4′-bipyridine) has been hydrothermally synthesised and characterised by elemental analysis, IR and electronic spectroscopy, variable temperature magnetic moment measurement and single crystal X-ray diffraction study. Single crystal X-ray analysis reveals that 1 is one dimensional polymeric compound in which acetate ligand shows both mono- and bidentate bonding mode, and 4,4′-bipy acts as bridging ligand which supports the formation of infinite chains. The global feature of the χ _M T vs. T curve in 1 is characteristic of moderate antiferromagnetic interaction and the best fit parameters from 300 down to 2 K are found as J = −78.7 cm⁻¹.     

Bench-Stable Electrophilic Fluorinating Reagents for Highly Selective Mono- and Difluorination of Silyl Enol Ethers

Efficient methods for the synthesis of fluorinated compounds have been intensively studied, recently. Development of practical fluorinating reagents is indispensable for this purpose. Herein, bench-stable electrophilic fluorinating reagents were synthesized as N-fluorobenzenesulfonimide (NFSI) substitutes. Reagents obtained by replacing one of the NFSI sulfonyl groups with an acyl group led to the highly selective monofluorination of silyl enol ethers with suppression of undesired overreaction, that is, difluorination. On the other hand, reagents bearing electron-withdrawing substituents at NFSI benzenesulfonyl groups efficiently facilitated the difluorination of silyl enol ethers under base-free conditions. Thus, both mono- and difluorinated target materials were prepared from the same substrate.     

Light/Palladium‐Promoted Benzylic C−H Acylation Using a Benzoyl Group as the Photo‐Directing Group

2‐Methylphenyl ketones undergo site‐selective acylation at the benzylic position when treated with acid anhydride under UV irradiation in the presence of a palladium catalyst. The benzoyl carbonyl group serves as the photo‐directing group so that the ortho benzylic C?H bond is activated site‐selectively.     

Temperature-programmed ESDIAD/TOF system as a new technique for characterization of adsorbed molecules and reaction intermediates

A temperature-programmed (TP-) electron stimulated desorption ion angular distribution (ESDIAD)/time-of-flight (TOF) system was developed to monitor changes in adsorbed layers in real time. This system can measure ESDIAD images and TOF spectra of desorbing ions stimulated by pulsed electron beam in temperature programmed surface processes. The coadsorption layers of CO and ammonia, the coadsorption layers of CO and methylamine, and the coadsorption layer of CO and acetylene on Ru(001), which were previously studied by our group using LEED, TPD and HREELS, have been observed by this system. The change in configuration of admolecules, the change in site occupation and the thermal evolution of adspecies can be monitored.     

The synthesis of poly(phenylacetylene)s with bulky chiral silyl groups and the thermal stability of their helical conformation

The polymerization of (−)‐p‐[(tert‐butylmethylphenyl)silyl]phenylacetylene (t‐BuMePhSi*PA) and (+)‐p‐[{methyl(α‐naphthyl)phenyl}silyl]phenylacetylene (MeNpPhSi*PA) with the [(nbd)RhCl]₂ Et₃N catalyst yielded polymers with very high molecular weights over 2 × 10⁶ in high yields. The optical rotations of the formed poly(t‐BuMePhSi*PA) and poly(MeNpPhSi*PA) were as high as −356 and −150° (c = 0.11 g/dL in CHCl₃), respectively. The circular dichroism (CD) spectrum of poly(t‐BuMePhSi*PA) in CHCl₃ exhibited very large molar ellipticities ([θ]) in the UV region: [θ]_max = 9.2 × 10⁴ ° · cm² · dmol⁻¹ at 330 nm and −8.0 × 10⁴ ° · cm² · dmol⁻¹ at 370 nm. The [θ]_max values of poly(MeNpPhSi*PA) were also fairly large: [θ]_max = 7.1 × 10⁴ ° · cm² · dmol⁻¹ at 330 nm and −5.3 × 10⁴ ° · cm² · dmol⁻¹ at 370 nm. The optical rotations of poly(t‐BuMePhSi*PA) and poly(MeNpPhSi*PA), measured in tetrahydrofuran, chloroform, and toluene solutions, were hardly dependent on temperature in the range 22–65 °C. The CD effects of these polymers hardly changed in the temperature range 28–80 °C, either. These results indicate that the helical structures of these polymers are thermally appreciably stable. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 39: 71–77, 2001