Micro-Scale Numerical Simulation of Fatigue Failure for CFRP Subjected to Multiple-Amplitude Cyclic Loadings Based on Entropy Damage Criterion.

Fatigue failure of carbon fiber-reinforced plastics (CFRPs) under cyclic loadings has attracted the attention of researchers recently. In this study, the entropy-based failure criterion is proposed to investigate the fatigue lifetime of unidirectional CFRPs subjected to multiple-amplitude cyclic loadings. Due to the heterogeneity of CFRPs, a micro-finite element model considering matrix resin and fibers independently is developed, and the entropy-based damage criterion is implemented into a user-subroutine of Abaqus to model the progressive damage of matrix resin. The fatigue lifetime of CFRPs under typical loading sequences consisting of two stages, such as varying from low to high (L-H) or from high to low (H-L) loading sequence, is estimated with the proposed failure criterion. Numerical results show that the initial damage occurs near the area between two fibers, and a transverse crack propagates progressively under the cyclic loading. The difference in predicted lifetime to final failure in L-H and H-L stress levels is 6.3%. Thus, the effect of loading sequence on the fatigue lifetime can be revealed via the proposed entropy-based damage criterion. Comparisons with the conventional linear cumulative damage (LCD) and kinetic crack growth (KCG) theories are also conducted to demonstrate the validity of the proposed method. The entropy-based failure criterion is a promising method to predict the residual strength and fatigue lifetime of CFRP components.

Monitoring Carbapenem-Resistant Enterobacterales in the Environment to Assess the Spread in the Community.

The usefulness of wastewater-based epidemiology (WBE) was proven during the COVID-19 pandemic, and the role of environmental monitoring of emerging infectious diseases has been recognized. In this study, the prevalence of carbapenem-resistant Enterobacterales (CRE) in Japanese environmental samples was measured in the context of applying WBE to CRE. A total of 247 carbapenem-resistant isolates were obtained from wastewater, treated wastewater, and river water. Treated wastewater was shown to be an efficient target for monitoring CRE. The results of the isolate analysis showed that WBE may be applicable to Escherichia coli-carrying New Delhi metallo-ß-lactamase (NDM)-type carbapenemase, the Enterobacter cloacae complex and Klebsiella pneumoniae complex-carrying IMP-type carbapenemase. In addition, a certain number of CRE isolated in this study carried Guiana extended spectrum (GES)-type carbapenemase although their clinical importance was unclear. Only a few isolates of Klebsiella aerogenes were obtained from environmental samples in spite of their frequent detection in clinical isolates. Neither the KPC-type, the oxacillinase (OXA)-type nor the VIM-type of carbapenemase was detected in the CRE, which reflected a low regional prevalence. These results indicated the expectation and the limitation of applying WBE to CRE.

Identification of Novel Mutations Contributing to Azole Tolerance of Aspergillus fumigatus through In Vitro Exposure to Tebuconazole.

Azole resistance of Aspergillus fumigatus is a global problem. The major resistance mechanism is through cytochrome P450 14-α sterol demethylase Cyp51A alterations such as a mutation(s) in the gene and the acquisition of a tandem repeat in the promoter. Although other azole tolerance and resistance mechanisms, such as the hmg1 (a 3-hydroxy-3-methylglutaryl coenzyme-A reductase gene) mutation, are known, few reports have described studies elucidating non-Cyp51A resistance mechanisms. This study explored genes contributing to azole tolerance in A. fumigatus by in vitro mutant selection with tebuconazole, an azole fungicide. After three rounds of selection, we obtained four isolates with low susceptibility to tebuconazole. These isolates also showed low susceptibility to itraconazole and voriconazole. Comparison of the genome sequences of the isolates obtained and the parental strain revealed a nonsynonymous mutation in MfsD, a major facilitator superfamily protein (Afu1g11820; R337L mutation [a change of R to L at position 337]), in all isolates. Furthermore, nonsynonymous mutations in AgcA, a mitochondrial inner membrane aspartate/glutamate transporter (Afu7g05220; E535Stop mutation), UbcD, a ubiquitin-conjugating enzyme E2 (Afu3g06030; T98K mutation), AbcJ, an ABC transporter (Afu3g12220; G297E mutation), and RttA, a putative protein responsible for tebuconazole tolerance (Afu7g04740; A83T mutation), were found in at least one isolate. Disruption of the agcA gene led to decreased susceptibility to azoles. Reconstruction of the A83T point mutation in RttA led to decreased susceptibility to azoles. Reversion of the T98K mutation in UbcD to the wild type led to decreased susceptibility to azoles. These results suggest that these mutations contribute to lowered susceptibility to medical azoles and agricultural azole fungicides.

FADS2 and ELOVL6 mutation frequencies in Japanese Crohn's disease patients.

Crohn's disease (CD) development is thought to involve genetic factors related to immune response as well as environmental factors, such as intestinal bacteria and diet, though no clear cause has yet been identified. In our previous study, we found that the concentrations of linoleic acid, stearic acid, and metabolites in erythrocytes differed between CD patients and healthy subjects. These factors related to lipid metabolism are controlled by Δ6 desaturase (fatty acid desaturase 2, FADS2) and elongase 6 (ELOVL6), respectively. In the present study, we analyzed the gene sequences of FADS2 and ELOVL6 in 52 Japanese CD patients, and then compared mutation frequencies with findings in healthy individuals. Nineteen FADS2 mutations and 33 ELOVL6 mutations were found. Furthermore, a new variant in the promoter region was shown in both genes, though no mutation in the coding region was found in either. For the FADS2 intron, the allele frequency of rs227784 (0.3365; 95% CI = 0.0337-0.01460) was higher than that in healthy subjects (0.0190). Furthermore, allele rs227784 had a greater association with CD (odds ratio = 4.4; 95% CI = 2.1-9.3). As compared with healthy Japanese healthy individuals, no mutations were found with a largely deviated allele frequency in the present CD group. However, the number of patients examined was small, thus the reliability of our results is limited. The present findings regarding genetic effects on CD onset and lipid metabolism may be weak.

[Role of the monoamine system in the brain on the development of psychological dependence on toluene].

Abuse of volatile organic solvents among youth remains a major social problem in Japan. Organic solvents are cheap and relatively easy to obtain, so they carry the risk of becoming a so-called "gate-way drug" for users. Psychological dependence assessment systems have been established for drug inhalation using the conditioned place preference (CPP) procedure. We found toluene produced the rewarding effect in this new CPP system. The mesolimbic dopamine pathway, which includes dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAC), is one of the most important substrates for the development of psychological dependence on drugs such as stimulants, cocaine, and heroin. Recently, it has indicated that the VTA-NAC pathway (monoamine system) may play an important role of the expression of psychological dependence on the volatile organic solvent toluene. Clarification of organic solvent's mechanism for the development of psychological dependence focusing on the monoamine system can be exploited for the new medicine and useful treatments for dependence on toluene.

Barium potentiates the conditioned aversion to, but not the somatic signs of, morphine withdrawal in mice.

The effect of barium, a putative blocker of G-protein-activated inwardly rectifying potassium (GIRK) channels, on naltrexone-precipitated withdrawal signs in morphine-dependent mice was investigated. Mice were chronically treated with morphine (8-45 mg/kg) for 6 days. The morphine-dependent mice were then given naltrexone (1 and 3 mg/kg), after which they showed several somatic signs of withdrawal, as well as conditioned aversion, increased cortical noradrenaline turnover, and decreased dopamine turnover in the limbic forebrain. Pretreatment with barium (1.25 and 2.5 nmol) significantly potentiated the naltrexone-precipitated conditioned aversion and augmented the decrease in dopamine turnover in the limbic forebrain. However, barium pretreatment did not affect the naltrexone-precipitated somatic signs of withdrawal and increased cortical noradrenaline turnover. These findings suggest that modification of GIRK channels may be involved in the expression of aversion to morphine withdrawal mediated through the dopaminergic system but it is not involved in the somatic signs of morphine withdrawal mediated through the noradrenergic system.

[Neuroadaptive mechanisms form development of psychological dependence on volatile organic solvents].

Abuse of volatile organic solvents among youth remains a major social problem. Organic solvents are cheap and relatively easy to obtain, so they carry the risk of becoming a so-called "gateway drug" for users. Most research regarding organic solvents has until now focused on their neurotoxicity, specifically examining the mechanism of neuron death in terms of the involvement of substances such as nerve growth factor. However, systems to assess psychological dependence on volatile organic solvents that take into account the mechanism involved in the development of this dependence have not been established due to the difficulty of creating animal models. The conditioned place preference procedure, which can easily assess whether psychological dependence has been formed, has been phased in in recent years, and dependence assessment systems have been established for drug inhalation. There have also been new research developments regarding dependence on volatile organic solvents. The importance of mesolimbic dopamine neurons has been indicated in the expression of CNS stimulant action and the development of psychological dependence on drugs such as stimulants, cocaine, and heroin, which are typical abused drugs. It has recently become apparent that the increase in dopamine release in the nucleus accumbens accompanying activation of mesolimbic dopamine neurons, as has conventionally been proposed, is important to the expression of CNS stimulant action and the formation of psychological dependence in response to inhalation of toluene, a volatile organic solvent. Furthermore, research with regard to organic solvents' site of action is also proceeding based on studies using molecular biological techniques. Research regarding toluene is progressing, and the importance of receptors that gate ion channels such as N-methyl-D-aspartate (NMDA) and y-aminobutyric acid (GABA)A receptors as candidates for toluene's site of action has been indicated. Clarification of organic solvents' mechanism for the development of psychological dependence is expected to progress, thanks to analysis focusing on such new sites of action.

Evaluation of rewarding effect of toluene by the conditioned place preference procedure in mice.

Toluene and many toluene-containing products are abused via inhalation. Previous investigations have used the place preference paradigm to evaluate the rewarding effects of commonly abused drugs such as morphine, cocaine, and amphetamine. A conditioning paradigm of toluene inhalation was developed in order to estimate the rewarding effect in mice. Conditioning sessions (five for toluene, five for air) were conducted twice daily for 5 days using a newly developed airtight inhalation shuttlebox (15x30x15 cm: wxlxh), which was divided into two compartments of equal size. One compartment was white with a textured floor, and the other was black with a smooth floor. All conditioning sessions were 20 min in duration, with a minimum of 7 h between sessions. Test sessions were carried out 1 day after the final training session with mice in a drug-free state. The time spent in each compartment during a 20-min session was measured using a digital video camera. Exposure to toluene vapors (700-3200 ppm) produced a significant conditioned place preference in mice. These results suggest that the conditioned place preference procedure using the newly developed airtight inhalation shuttlebox constitutes an important tool for studying the rewarding effect of abused solvents.