Crystal structures of human glyoxalase I and its complex with TLSC702 reveal inhibitor binding mode and substrate preference.

Human glyoxalase I (hGLO I) is an enzyme for detoxification of methylglyoxal (MG) and has been considered an attractive target for the development of new anticancer drugs. In our previous report, the GLO I inhibitor TLSC702 induced apoptosis in tumor cells. Here, we determined the crystal structures of hGLO I and its complex with TLSC702. In the complex, the carboxyl O atom of TLSC702 is coordinated to Zn2+ , and TLSC702 mainly shows van der Waals interaction with hydrophobic residues. In the inhibitor-unbound structure, glycerol, which has similar functional groups to MG, was bound to Zn2+ , indicating that GLO I can easily bind to MG. This study provides a structural basis to develop better anticancer drugs.

Diverse panicle architecture results from various combinations of Prl5/GA20ox4 and Pbl6/APO1 alleles.

Panicle architecture directly affects crop productivity and is a key target of high-yield rice breeding. Panicle length strongly affects panicle architecture, but the underlying regulatory mechanisms are largely unknown. Here, we show that two quantitative trait loci (QTLs), PANICLE RACHIS LENGTH5 (Prl5) and PRIMARY BRANCH LENGTH6 (Pbl6), independently regulate panicle length in rice. Prl5 encodes a gibberellin biosynthesis enzyme, OsGA20ox4. The expression of Prl5 was higher in young panicles resulting in panicle rachis elongation. Pbl6 is identical to ABERRANT PANICLE ORGANIZATION 1 (APO1), encoding an F-box-containing protein. We found a novel function that higher expression of Pbl6 is responsible for primary branch elongation. RNA-seq analysis revealed that these two genes independently regulate panicle length at the level of gene expression. QTL pyramiding of both genes increased panicle length and productivity. By combining these two genes in various combinations, we designed numerous panicle architecture without trade-off relationship.

Lactate Stimulates a Potential for Hypertrophy and Regeneration of Mouse Skeletal Muscle.

The effects of lactate on muscle mass and regeneration were investigated using mouse skeletal muscle tissue and cultured C2C12 cells. Male C57BL/6J mice were randomly divided into (1) control, (2) lactate (1 mol/L in distilled water, 8.9 mL/g body weight)-administered, (3) cardio toxin (CTX)-injected (CX), and (4) lactate-administered after CTX-injection (LX) groups. CTX was injected into right tibialis anterior (TA) muscle before the oral administration of sodium lactate (five days/week for two weeks) to the mice. Oral lactate administration increased the muscle weight and fiber cross-sectional area, and the population of Pax7-positive nuclei in mouse TA skeletal muscle. Oral administration of lactate also facilitated the recovery process of CTX-associated injured mouse TA muscle mass accompanied with a transient increase in the population of Pax7-positive nuclei. Mouse myoblast-derived C2C12 cells were differentiated for five days to form myotubes with or without lactate administration. C2C12 myotube formation with an increase in protein content, fiber diameter, length, and myo-nuclei was stimulated by lactate. These observations suggest that lactate may be a potential molecule to stimulate muscle hypertrophy and regeneration of mouse skeletal muscle via the activation of muscle satellite cells.

Imaging of monochromatic beams by measuring secondary electron bremsstrahlung for carbon-ion therapy using a pinhole x-ray camera.

A feasibility study on the imaging of monochromatic carbon-ion beams for carbon-ion therapy was performed. The evaluation was based on Monte Carlo simulations and beam-irradiation experiments, using a pinhole x-ray camera, which measured secondary electron bremsstrahlung (SEB). The simulation results indicated that the trajectories of the carbon-ion beams with injection energies of 278, 249 and 218 MeV/u in a water phantom, were clearly imaged by measuring the SEB with energies from 30 to 60 keV, using a pinhole camera. The Bragg-peak positions for these three injection energies were located at the positions where the ratios of the counts of SEB acquisitions to the maximum counts were approximately 0.23, 0.26 and 0.29, respectively. Moreover, we experimentally demonstrated that it was possible to identify the Bragg-peak positons, at the positions where the ratios coincided with the simulation results. However, the estimated Bragg-peak positions for the injection energies of 278 and 249 MeV/u were slightly deeper than the expected positions. In conclusion, for both the simulations and experiments, we found that the 25 mm shifts in the Bragg-peak positions can be observed by this method.

Development of a low-energy x-ray camera for the imaging of secondary electron bremsstrahlung x-ray emitted during proton irradiation for range estimation.

Imaging of secondary electron bremsstrahlung x-ray emitted during proton irradiation is a possible method for measurement of the proton beam distribution in phantom. However, it is not clear that the method is used for range estimation of protons. For this purpose, we developed a low-energy x-ray camera and conducted imaging of the bremsstrahlung x-ray produced during irradiation of proton beams. We used a 20 mm × 20 mm × 1 mm finely grooved GAGG scintillator that was optically coupled to a one-inch square high quantum efficiency (HQE)-type position-sensitive photomultiplier tube to form an imaging detector. The imaging detector was encased in a 2 cm-thick tungsten container, and a pinhole collimator was attached to its camera head. After performance of the camera was evaluated, secondary electron bremsstrahlung x-ray imaging was conducted during irradiation of the proton beams for three different proton energies, and the results were compared with Monte Carlo simulation as well as calculated value. The system spatial resolution and sensitivity of the developed x-ray camera with 1.5 mm-diameter pinhole collimator were estimated to be 32 mm FWHM and 5.2 × 10-7 for ~35 keV x-ray photons at 100 cm from the collimator surface, respectively. We could image the proton beam tracks by measuring the secondary electron bremsstrahlung x-ray during irradiation of the proton beams, and the ranges for different proton energies could be estimated from the images. The measured ranges from the images were well matched with the Monte Carlo simulation, and slightly smaller than the calculated values. We confirmed that the imaging of the secondary electron bremsstrahlung x-ray emitted during proton irradiation with the developed x-ray camera has the potential to be a new tool for proton range estimations.