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The effect of hydrogen-enhanced strain-induced lattice defects formed during the incubation period on hydrogen embrittlement fracture of iron was clarified by quantitative evaluation using low-temperature thermal desorption spectroscopy (L-TDS) from −200 ºC. Tensile testing of iron specimens was conducted in solution with various concentrations of ammonium thiocyanate as a catalyst poison. Cathodic electrolysis was employed to establish conditions of low and high hydrogen content to examine the fracture characteristics of the iron specimens. The fracture elongation of the hydrogen-charged iron specimens was lower than that of the hydrogen-free specimens, although the elongation was the same regardless of the hydrogen content. In contrast, the flow stress during the deformation process increased with increasing hydrogen content. Specimens were prepared under the same hydrogen charging conditions and unloaded within a uniform elongation range. L-TDS was used to detect lattice defects with hydrogen re-charged as a probe under equilibrium conditions with dislocation cores and strain fields around the cores and vacancies in the specimens. The formation of vacancy-type defects was promoted in the presence of hydrogen during plastic deformation, and the extent of promotion was similar regardless of the hydrogen content. The concentration of hydrogen-enhanced strain-induced vacancies may thus affect the decrease in ductility due to the presence of hydrogen, and the hydrogen coordination number to its vacancies is responsible for the increase in flow stress.

An experimental investigation was conducted to compare the blast mitigation performances of water layers, whose mass ratios to an explosive were mW/mE=12.2,44.5,and107.2 , with water droplets surrounding the explosive. The blast waveforms were measured using pressure transducers, and the motion of the water layer was recorded using a high-speed camera. When mW/mE was equivalent between the water layer and water droplets, the water layer exhibited less mitigation of the peak overpressure and positive impulse than the water droplets. The results demonstrated high efficiency of the water droplets in blast mitigation and the existence of an optimal apparent density of the water barrier. The velocities of the water layers determined using high-speed photography agreed with the prediction model of the barrier material accelerated by explosion. It suggested that the primary cause of the blast overpressure mitigation by the water layer was the allocation of the explosion energy into the kinetic energy of the water.

The 2.7 µm absorption band, represented by OH groups, in the near-infrared reflectance spectra of primitive Solar System bodies could be an indicator of the cause and degree of space weathering. We compared the absorption bands of particles sampled from the surface (chamber A) and the excavated subsurface (chamber C) on the C-type asteroid Ryugu by the JAXA Hayabusa2 mission. We developed a fitting method using multiple Gaussians to precisely calculate the band’s peak position and depth, providing more reliable information on space weathering effects. We found that the chamber A particles were divided into groups Aα with shorter peak position and deeper band depth (non or poorly space weathered) and Aβ with longer peak position and shallower band depth (rich in space weathering). Chamber C particles are partly show intermediate characteristics between Aα and Aβ, which might imply weak space weathering by solar UV radiation during three months between the excavation by impact experiment and sampling by Hayabusa2. Supplementally, our preliminary experiment of UV irradiation to Ivuna meteorite showed decrease of 2.7 µm band depth and longward shift of the peak position, and further study is needed to investigate the effect of short-term UV space weathering on carbonaceous asteroids.

An efficient adeno-associated virus (AAV) vector was constructed for the treatment of respiratory diseases. AAV serotypes, promoters and routes of administration potentially influencing the efficiency of gene transfer to airway cells were examined in the present study. Among the nine AAV serotypes (AAV1–9) screened in vitro and four serotypes (AAV1, 2, 6, 9) evaluated in vivo , AAV6 showed the strongest transgene expression. As for promoters, the cytomegalovirus (CMV) early enhancer/chicken β-actin (CAG) promoter resulted in more robust transduction than the CMV promoter. Regarding delivery routes, intratracheal administration resulted in strong transgene expression in the lung, whereas the intravenous and intranasal administration routes yielded negligible expression. The combination of the AAV6 capsid and CAG promoter resulted in sustained expression, and the intratracheally administered AAV6-CAG vector transduced bronchial cells and pericytes in the lung. These results suggest that AAV6-CAG vectors are more promising than the previously preferred AAV2 vectors for airway transduction, particularly when administered into the trachea. The present study offers an optimized strategy for AAV-mediated gene therapy for lung diseases, such as cystic fibrosis and pulmonary fibrosis.

Background: Molecular characterisation using gene-expression profiling will undoubtedly improve the prediction of treatment responses, and ultimately, the clinical outcome of cancer patients. Methods: To establish the procedures to identify responders to FOLFOX therapy, 83 colorectal cancer (CRC) patients including 42 responders and 41 non-responders were divided into training (54 patients) and test (29 patients) sets. Using Random Forests (RF) algorithm in the training set, predictor genes for FOLFOX therapy were identified, which were applied to test samples and sensitivity, specificity, and out-of-bag classification accuracy were calculated. Results: In the training set, 22 of 27 responders (81.4% sensitivity) and 23 of 27 non-responders (85.1% specificity) were correctly classified. To improve the prediction model, we removed the outliers determined by RF, and the model could correctly classify 21 of 23 responders (91.3%) and 22 of 23 non-responders (95.6%) in the training set, and 80.0% sensitivity and 92.8% specificity, with an accuracy of 69.2% in 29 independent test samples. Conclusion: Random Forests on gene-expression data for CRC patients was effectively able to stratify responders to FOLFOX therapy with high accuracy, and use of pharmacogenomics in anticancer therapy is the first step in planning personalised therapy.

A two-dimensional numerical simulation of the interaction between a shock wave and a particle cloud curtain (PCC) in a shock tube was conducted to develop the numerical method and to understand how the particle layer mitigates the shock wave. In the present study, computational fluid dynamics/the discrete element method in conjunction with drag force and convective heat transfer models were used to separately solve the continuum fluid and particle dynamics. The applicability of the method to the gas flow and particles was validated through comparison with gas–particle shock-tube experiments, in which the PCC was generated by free fall, and particles initially had a gradient of its volume fraction and falling velocity in height. When the incident shock wave interacted with the PCC, it was reflected from and transmitted through the PCC. The transmitted shock wave had a curved front because the initial gradient in the volume fraction of particles locally changed the interaction between the shock wave and the particles. We calculated the effects of the drag force and heat transfer in mitigating the strength of the transmitted shock wave. The propagation of the transmitted and reflected shock waves and the motion of the PCC induced by the gas flow behind the shock wave agreed well with previous experimental data. After the interaction between the gas flow and the PCC, drag force and heat transfer were activated by the gradients in pressure, velocity, and temperature between them, and the gas flow lost momentum and energy, which weakened the transmitted shock wave. At the same time, the PCC gained momentum and energy and was dispersed. The contact forces between two particles affected the local dispersion of the PCC.

We conducted a series of numerical simulations to understand the effect of the initiation process of cylindrical high explosives on the blast-wave behavior and peak overpressure distribution. The first case involved the explosion of a cylindrical high explosive whose length-to-diameter ratio was equal to 2 and that was vertically placed above the ground surface. The initiation point was at the top of the high explosive. The initiation process induced the detonation momentum directed from top to bottom, and the detonation products forcefully hit the ground surface, resulting in a higher peak overpressure on the ground surface in comparison with the case using an isothermal constant-pressure volume. After the blast wave expanded far from the initiation point, the computed peak overpressures of the two approaches showed good agreement with those from experiments. The second case involved the explosion of a cylindrical high explosive whose length-to-diameter ratio was unity and that was placed in air. The initiation point was the one end side of the high explosive. The blast wave was divided into three regions that originated from the detonation in the high explosive, an oblique shock wave in air, and a bridge wave connected with them, thus causing an azimuthal distribution of peak overpressure. The highest peak overpressure values were computed in the bridge wave region. To understand the propagation behavior of the blast wave, we should thoroughly observe how and when all the waves affecting the blast-wave behavior are generated and how they propagate and interact with each other.

A number of drivers and developments suggest that microdosing and other phase 0 applications will experience increased utilization in the near-to-medium future. Increasing costs of drug development and ethical concerns about the risks of exposing humans and animals to novel chemical entities are important drivers in favor of these approaches, and can be expected only to increase in their relevance. An increasing body of research supports the validity of extrapolation from the limited drug exposure of phase 0 approaches to the full, therapeutic exposure, with modeling and simulations capable of extrapolating even non-linear scenarios. An increasing number of applications and design options demonstrate the versatility and flexibility these approaches offer to drug developers including the study of PK, bioavailability, DDI, and mechanistic PD effects. PET microdosing allows study of target localization, PK and receptor binding and occupancy, while Intra-Target Microdosing (ITM) allows study of local therapeutic-level acute PD coupled with systemic microdose-level exposure. Applications in vulnerable populations and extreme environments are attractive due to the unique risks of pharmacotherapy and increasing unmet healthcare needs. All phase 0 approaches depend on the validity of extrapolation from the limited-exposure scenario to the full exposure of therapeutic intent, but in the final analysis the potential for controlled human data to reduce uncertainty about drug properties is bound to be a valuable addition to the drug development process.

The transient receptor potential cation channel, subfamily V (TRPV), is expressed in the epidermis and considered to be a sensor of extrinsic stimuli such as temperature and other physical or chemical factors. In this study, we examined whether or not the activation of TRPVs by their agonists alters the epidermal tight junction (TJ) function in cultured human epidermal keratinocytes. Reverse transcription-polymerase chain reaction (RT-PCR) analyses showed that mRNA for TRPV1, 3 and 4 were expressed in differentiated keratinocytes in which TJs had formed. Stimulation of the keratinocytes with a TRPV4 agonist (4α-phorbol 12, 13-didecanoate, 4α-PDD) strengthened the TJ-associated barrier, analyzed by means of transepithelial electric resistance measurements and flux measurements of the paracellular tracer. Stimulation with TRPV1 and TRPV3 agonists did not have the same result. Simultaneously, the 4α-PDD-stimulated keratinocytes showed an upregulation of TJ structural proteins, occludin and claudin-4, and TJ regulatory factors, phospho-atypical PKCζ/ι. It was also observed that the amounts of occludin and phospho-atypical PKCζ/ι complex were higher in 4α-PDD stimulated keratinocytes. In conclusion, we demonstrated that the activation of TRPV4 strengthened the TJ-associated barrier of epidermal cells. It was also suggested that the upregulation of TJ structural proteins and/or the posttranslational modification of TJ structural proteins by phospho-atypical PKCζ/ι are responsible for the enhancement of TJ function. Our study supports the hypothesis that TJs change their function in response to a change in the external environment sensed through TRPVs.

Tobacco is a valuable model system for investigating the origin of mitochondrial DNA (mtDNA) in amphidiploid plants and studying the genetic interaction between mitochondria and chloroplasts in the various functions of the plant cell. As a first step, we have determined the complete mtDNA sequence of Nicotiana tabacum. The mtDNA of N. tabacum can be assumed to be a master circle (MC) of 430,597 bp. Sequence comparison of a large number of clones revealed that there are four classes of boundaries derived from homologous recombination, which leads to a multipartite organization with two MCs and six subgenomic circles. The mtDNA of N. tabacum contains 36 protein-coding genes, three ribosomal RNA genes and 21 tRNA genes. Among the first class, we identified the genes rps1 and psirps14, which had previously been thought to be absent in tobacco mtDNA on the basis of Southern analysis. Tobacco mtDNA was compared with those of Arabidopsis thaliana, Beta vulgaris, Oryza sativa and Brassica napus. Since repeated sequences show no homology to each other among the five angiosperms, it can be supposed that these were independently acquired by each species during the evolution of angiosperms. The gene order and the sequences of intergenic spacers in mtDNA also differ widely among the five angiosperms, indicating multiple reorganizations of genome structure during the evolution of higher plants. Among the conserved genes, the same potential conserved nonanucleotide-motif-type promoter could only be postulated for rrn18-rrn5 in four of the dicotyledonous plants, suggesting that a coding sequence does not necessarily move with the promoter upon reorganization of the mitochondrial genome.