High-intensity interval training using electrical stimulation ameliorates muscle fatigue in chronic kidney disease-related cachexia by restoring mitochondrial respiratory dysfunction.

Background: Exercise, especially high-intensity interval training (HIIT), can increase mitochondrial respiratory capacity and enhance muscular endurance, but its systemic burden makes it difficult to safely and continuously prescribe for patients with chronic kidney disease (CKD)-related cachexia who are in poor general condition. In this study, we examined whether HIIT using electrical stimulation (ES), which does not require whole-body exercise, improves muscle endurance in the skeletal muscle of 5/6 nephrectomized rats, a widely used animal model for CKD-related cachexia. Methods: Male Wistar rats (10 weeks old) were randomly assigned to a group of sham-operated (Sham) rats and a group of 5/6 nephrectomy (Nx) rats. HIIT was performed on plantar flexor muscles in vivo with supramaximal ES every other day for 4 weeks to assess muscle endurance, myosin heavy-chain isoforms, and mitochondrial respiratory function in Nx rats. A single session was also performed to identify upstream signaling pathways altered by HIIT using ES. Results: In the non-trained plantar flexor muscles from Nx rats, the muscle endurance was significantly lower than that in plantar flexor muscles from Sham rats. The proportion of myosin heavy chain IIa/x, mitochondrial content, mitochondrial respiratory capacity, and formation of mitochondrial respiratory supercomplexes in the plantaris muscle were also significantly decreased in the non-trained plantar flexor muscles from Nx rats than compared to those in plantar flexor muscles from Sham rats. Treatment with HIIT using ES for Nx rats significantly improved these molecular and functional changes to the same degrees as those in Sham rats. Furthermore, a single session of HIIT with ES significantly increased the phosphorylation levels of AMP-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase (MAPK), pathways that are essential for mitochondrial activation signaling by exercise, in the plantar muscles of both Nx and Sham rats. Conclusion: The findings suggest that HIIT using ES ameliorates muscle fatigue in Nx rats via restoration of mitochondrial respiratory dysfunction with activation of AMPK and p38 MAPK signaling. Our ES-based HIIT protocol can be performed without placing a burden on the whole body and be a promising intervention that is implemented even in conditions of reduced general performance status such as CKD-related cachexia.

Analysis of Brain, Blood, and Testis Phenotypes Lacking the Vps13a Gene in C57BL/6N Mice.

The Vps13a gene encodes a lipid transfer protein called VPS13A, or chorein, associated with mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondria-endosomes, and lipid droplets. This protein plays a crucial role in inter-organelle communication and lipid transport. Mutations in the VPS13A gene are implicated in the pathogenesis of chorea-acanthocytosis (ChAc), a rare autosomal recessive neurodegenerative disorder characterized by chorea, orofacial dyskinesias, hyperkinetic movements, seizures, cognitive impairment, and acanthocytosis. Previous mouse models of ChAc have shown variable disease phenotypes depending on the genetic background. In this study, we report the generation of a Vps13a flox allele in a pure C57BL/6N mouse background and the subsequent creation of Vps13a knockout (KO) mice via Cre-recombination. Our Vps13a KO mice exhibited increased reticulocytes but not acanthocytes in peripheral blood smears. Additionally, there were no significant differences in the GFAP- and Iba1-positive cells in the striatum, the basal ganglia of the central nervous system. Interestingly, we observed abnormal spermatogenesis leading to male infertility. These findings indicate that Vps13a KO mice are valuable models for studying male infertility and some hematological aspects of ChAc.

Prediction of chronic toxicity of pharmaceuticals in Daphnia magna by combining ortholog prediction, pharmacological effects, and quantitative structure-activity relationship.

To develop a method for predicting chronic toxicity of pharmaceuticals in Daphnia, we investigated the feasibility of combining the presence of drug-target orthologs in Daphnia magna, classification based on pharmacological effects, and ecotoxicity quantitative structure-activity relationship (QSAR) prediction. We established datasets on the chronic toxicity of pharmaceuticals in Daphnia, including information on therapeutic categories, target proteins, and the presence or absence of drug-target orthologs in D. magna, using literature and databases. Chronic toxicity was predicted using ecotoxicity prediction QSAR (Ecological Structure Activity Relationship and Kashinhou Tool for Ecotoxicity), and the differences between the predicted and measured values and the presence or absence of drug-target orthologs were examined. For pharmaceuticals without drug-target orthologs in D. magna or without expected specific actions, the ecotoxicity prediction QSAR analysis yielded acceptable predictions of the chronic toxicity of pharmaceuticals. In addition, a workflow model to assess the chronic toxicity of pharmaceuticals in Daphnia was proposed based on these evaluations and verified using an additional dataset. The addition of biological aspects such as drug-target orthologs and pharmacological effects would support the use of QSARs for predicting the chronic toxicity of pharmaceuticals in Daphnia.

First-night effect reduces the beneficial effects of sleep on visual plasticity and modifies the underlying neurochemical processes.

Individuals experience difficulty falling asleep in a new environment, termed the first night effect (FNE). However, the impact of the FNE on sleep-induced brain plasticity remains unclear. Here, using a within-subject design, we found that the FNE significantly reduces visual plasticity during sleep in young adults. Sleep-onset latency (SOL), an indicator of the FNE, was significantly longer during the first sleep session than the second session, confirming the FNE. We assessed performance gains in visual perceptual learning after sleep and increases in the excitatory-to-inhibitory neurotransmitter (E/I) ratio in early visual areas during sleep using magnetic resonance spectroscopy and polysomnography. These parameters were significantly smaller in sleep with the FNE than in sleep without the FNE; however, these parameters were not correlated with SOL. These results suggest that while the neural mechanisms of the FNE and brain plasticity are independent, sleep disturbances temporarily block the neurochemical process fundamental for brain plasticity.

Creation of Knock-In Alleles of Insulin Receptor Tagged by Fluorescent Proteins mCherry or EYFP in Fruit Fly Drosophila melanogaster.

The insulin/insulin-like growth factor-like signaling (IIS) pathway is highly conserved across metazoans and regulates numerous physiological functions, including development, metabolism, fecundity, and lifespan. The insulin receptor (InR), a crucial membrane receptor in the IIS pathway, is known to be ubiquitously expressed in various tissues, albeit at generally low levels, and its subcellular localization remains incompletely characterized. In this study, we employed CRISPR-mediated mutagenesis in the fruit fly Drosophila to create knock-in alleles of InR tagged with fluorescent proteins (InR::mCherry or InR::EYFP). By inserting the coding sequence of the fluorescent proteins mCherry or EYFP near the end of the coding sequence of the endogenous InR gene, we could trace the natural InR protein through their fluorescence. As an example, we investigated epithelial cells of the male accessory gland (AG), an internal reproductive organ, and identified two distinct patterns of InR::mCherry localization. In young AG, InR::mCherry accumulated on the basal plasma membrane between cells, whereas in mature AG, it exhibited intracellular localization as multiple puncta, indicating endocytic recycling of InR during cell growth. In the AG senescence accelerated by the mutation of Diuretic hormone 31 (Dh31), the presence of InR::mCherry puncta was more pronounced compared to the wild type. These findings raise expectations for the utility of the newly created InR::mCherry/EYFP alleles for studying the precise expression levels and subcellular localization of InR. Furthermore, this fluorescently tagged allele approach can be extended to investigate other membrane receptors with low abundance, facilitating the direct examination of their true expression and localization.

A novel PET probe to selectively image heat shock protein 90α/ß isoforms in the brain.

BACKGROUND: Heat shock proteins (HSPs) are present throughout the brain. They function as molecular chaperones, meaning they help with the folding and unfolding of large protein complexes. These chaperones are vital in the development of neuropathological conditions such as Alzheimer's disease and Lewy body disease, with HSP90, a specific subtype of HSP, playing a key role. Many studies have shown that drugs that inhibit HSP90 activity have beneficial effects in the neurodegenerative diseases. Therefore, HSP90 PET imaging ligand can be used effectively to study HSP90 in neurodegenerative diseases. Among four HSP90 isoforms, two cytosolic isoforms (HSP90α and HSP90ß) thought to be involved in the structural homeostasis of the proteins related to the neurodegenerative diseases. Currently, no useful PET imaging ligands selectively targeting the two cytosolic isoforms of HSP90 have been available yet. RESULTS: In this study, we developed a novel positron emission tomography (PET) imaging ligand, [11C]BIIB021, by 11C-radiolabeling (a positron emitter with a half-life of 20.4 min) 6-Chloro-9-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-9H-purin-2-amine (BIIB021), an inhibitor with a high affinity for and selectivity to HSP90α and HSP90ß. [11C]BIIB021 was synthesized with a high yield, molar activity and radiochemical purity. [11C]BIIB021 showed a high binding affinity for rat brain homogenate as well as human recombinant HSP90α and HSP90ß proteins. Radioactivity was well detected in the rat brain (SUV 1.4). It showed clear specific binding in PET imaging of healthy rats and autoradiography of healthy rat and human brain sections. Radiometabolite was detected in the brain, however, total distribution volume was well quantified using dual-input graphical model. Inhibition of p-glycoprotein increased brain radioactivity concentrations. However, total distribution volume values with and without p-glycoprotein inhibition were nearly the same. CONCLUSIONS: We have developed a new PET imaging agent, [11C]BIIB021, specifically targeting HSP90α/ß. We have been successful in synthesizing [11C]BIIB021 and in vitro and in vivo imaging HSP90α/ß. However, the quantification of HSP90α/ß is complicated by the presence of radiometabolites in the brain and the potential to be a substrate for p-glycoprotein. Further efforts are needed to develop radioligand suitable for imaging of HSP90α/ß.

First-night effect reduces the beneficial effects of sleep on visual plasticity and modifies the underlying neurochemical processes.

Individuals experience difficulty falling asleep in a new environment, termed the first night effect (FNE). However, the impact of the FNE on sleep-induced brain plasticity remains unclear. Here, using a within-subject design, we found that the FNE significantly reduces visual plasticity during sleep in young adults. Sleep-onset latency (SOL), an indicator of the FNE, was significantly longer during the first sleep session than the second session, confirming the FNE. We assessed performance gains in visual perceptual learning after sleep and increases in the excitatory-to-inhibitory neurotransmitter (E/I) ratio in early visual areas during sleep using magnetic resonance spectroscopy and polysomnography. These parameters were significantly smaller in sleep with the FNE than in sleep without the FNE; however, these parameters were not correlated with SOL. These results suggest that while the neural mechanisms of the FNE and brain plasticity are independent, sleep disturbances temporarily block the neurochemical process fundamental for brain plasticity.

Imaging features of mucinous carcinoma arising from mature teratoma showing cytokeratin 7+ and cytokeratin 20+ expression profile: A case report.

Ovarian mature teratomas are benign, but malignant transformation can occur infrequently, especially in women of advanced age. The tissue that undergoes malignant change is mostly squamous cell carcinoma, although adenocarcinoma has been reported in a small number of cases. The immunostaining results of adenocarcinoma usually show a cytokeratin (CK)7-/CK20+ expression profile, corresponding to lower gastrointestinal tract origin. In this report, we describe a case of mucinous carcinoma arising from an ovarian mature teratoma showing a CK7+/CK20+ profile and discuss its imaging features. A 40-year-old woman presented to her primary care physician with abdominal distension and poor oral intake, and she was referred to our hospital. She had been diagnosed with an ovarian mature teratoma at our institution 3 years earlier. At the current presentation, pelvic magnetic resonance imaging showed a large multilocular cystic mass with adipose tissue extending into the upper abdomen. Densely packed cysts were observed inside the mass, which showed weak contrast enhancement on contrast-enhanced imaging and a mildly high signal on diffusion-weighted imaging. A portion of the cysts also showed abnormal 18F-fluorodeoxyglucose uptake (maximum standardized uptake value, 13.2) on positron emission tomography/computed tomography. The patient was subsequently diagnosed with mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma by pathologic examination. This mucinous carcinoma arising from a mature teratoma showed a CK7+/CK20+ profile and took the form of densely packed multilocular cysts. In this respect, it was similar to primary ovarian epithelial mucinous carcinoma on both magnetic resonance imaging and pathologic examination despite showing a much higher maximum standardized uptake value than that of primary ovarian mucinous carcinoma. When a large ovarian teratoma contains a large multilocular cyst, the presence of densely packed multilocular cysts should not be missed even in a mass without solid components. Clinicians should consider the possibility of mucinous carcinoma showing a CK7+/CK20+ profile arising from a mature teratoma in such cases.

Platelet-rich plasma does not accelerate the healing of damaged muscle following muscle strain.

Although platelet-rich plasma (PRP) has been widely used regardless of the severity of muscle strain, there have been very few basic studies in which its effects on muscle injury were examined by using models that accurately mimic the clinical muscle strain injury process. Therefore, the aim of this study was to confirm by physiological and structural analyses whether PRP purified by a general preparation method has a muscle healing effect on muscle damage caused by eccentric contraction (ECC). Male Wistar rats were subjected to muscle injury induced by ECC in bilateral plantar flexor muscles using electrical stimulation and an automatically dorsiflexing footplate. The rats were randomly assigned to three groups by type of injection: phosphate-buffered saline (PBS), leukocyte-poor PRP (LP-PRP), or leukocyte-rich PRP (LR-PRP) injection into gastrocnemius muscles three times at weekly intervals. The platelet concentrations of the LP-PRP and LR-PRP were three to five times higher than that of whole blood. The recovery process of torque strength in the plantar flexor muscle, signal changes in MRI images, and histological evaluation 3 weeks after injury showed no obvious differences among the three groups, and every muscle recovered well from the injury without marked fibrosis. The results that neither LP-PRP nor LR-PRP was found to accelerate healing of muscle injuries suggested that conventional preparation and use of PRP for simple muscle injuries caused by muscle strain should be carefully considered, and further basic research using models that accurately mimic clinical practice should be carried out to determine the optimal use of PRP.

Plasticity-stability dynamics during post-training processing of learning.

Learning continues beyond the end of training. Post-training learning is supported by changes in plasticity and stability in the brain during both wakefulness and sleep. However, the lack of a unified measure for assessing plasticity and stability dynamics during training and post-training periods has limited our understanding of how these dynamics shape learning. Focusing primarily on procedural learning, we integrate work using behavioral paradigms and a recently developed measure, the excitatory-to-inhibitory (E/I) ratio, to explore the delicate balance between plasticity and stability and its relationship to post-training learning. This reveals plasticity-stability cycles during both wakefulness and sleep that enhance learning and protect it from new learning during post-training processing.

Uterine myxoid leiomyosarcoma initially showing low signal intensity on T2 weighted images: A case report.

In the few articles describing MRI findings of myxoid leiomyosarcoma (MLMS), high signal intensity (SI) on T2-weighted images (T2WI) due to myxoid change was believed to be one of the common features. However, we encountered an MLMS with low SI similar to uterine myometrium on T2WI that subsequently grew with extremely edematous change even after 3 cycles of gonadotropin-releasing hormone agonist (GnRHa) treatment. Here we present this atypical MLMS case with radiologic-pathologic correlation. The patient was a 46-year-old woman with a chief complaint of low abdominal pain. The tumor was a pedunculated mass arising from the right anterior wall of the uterus that included a low-SI tumor-like component that partially transitioned into a peripheral high-SI component on T2WI and was diagnosed as hydropic leiomyoma. After 3 cycles of GnRHa therapy, the tumor size increased along with the size of the peripheral high-SI component on T2WI, while the size of the low-SI tumor-like component decreased. A small markedly low-SI area on both T1 and T2WI and a subtle high-SI area on fat-saturated T1WI indicating hemorrhage were present within the tumor. Pathologically, not only the peripheral high-SI component but also the low-SI tumor-like component on T2WI corresponded to MLMS, and the high-SI component was associated mainly with edematous change rather than myxoid change. MLMS may initially show low SI on T2WI and change to high SI mainly due to edematous change with rapid growth. Intratumoral hemorrhage might be the only key feature to differentiates MLMS from hydropic leiomyoma.

Analyses of BER-referred noise-to-signal ratio in online measurements of high-baud-rate coherent receivers.

Digital coherent transmission features a very large transmission bandwidth and has played a main role in core optical transmission networks. With the progress of semiconductor technologies, practical coherent transceivers with rates over 100 Gbaud are becoming feasible. With such advances, the transceiver components must have lower power consumption and lower costs, and it becomes important to know how each component contributes to the overall transmission performance. Here, to decompose the effects of noise factors in high-baud-rate DP-16QAM transmissions, we used the theoretical relationship between the bit error rate (BER) and noise-to-signal ratio (NSR) and performed linear analyses. The NSR could be decomposed into individual noise contributions according to dependences on the inverse signal and local photocurrents. The obtained parameters were shown to be useful for predicting required optical signal-to-noise ratio (ROSNR) characteristics.

Synthesis and evaluation of a novel PET ligand, a GSK'963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain.

BACKGROUND: Receptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer's disease (AD) has been reported; RIPK1 is involved in microglia's phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1. RESULTS: (S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK'963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK'963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK'963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK'963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47-115 GBq/µmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively. CONCLUSIONS: We synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK'963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.

Enhancing developmental and reproductive toxicity knowledge: A new AOP stemming from glutathione depletion.

Integrated approaches to testing and assessments (IATAs) have been proposed as a method to organise new approach methodologies in order to replace traditional animal testing for chemical safety assessments. To capture the mechanistic aspects of toxicity assessments, IATAs can be framed around the adverse outcome pathway (AOP) concept. To utilise AOPs fully in this context, a sufficient number of pathways need to be present to develop fit for purpose IATAs. In silico approaches can support IATA through the provision of predictive models and also through data integration to derive conclusions using a weight-of-evidence approach. To examine the maturity of a developmental and reproductive toxicity (DART) AOP network derived from the literature, an assessment of its coverage was performed against a novel toxicity dataset. A dataset of diverse compounds, with data from studies performed according to OECD test guidelines TG-421 and TG-422, was curated to test the performance of an in silico model based on the AOP network - allowing for the identification of knowledge gaps within the network. One such gap in the knowledge was filled through the development of an AOP stemming from the molecular initiating event 'glutathione reaction with an electrophile' leading to male fertility toxicity. The creation of the AOP provided the mechanistic rationale for the curation of pre-existing structural alerts to relevant key events. Integrating this new knowledge and associated alerts into the DART AOP network will improve its coverage of DART-relevant chemical space. In addition, broadening the coverage of AOPs for a particular regulatory endpoint may facilitate the development of, and confidence in, robust IATAs.

Noradrenaline transporter PET reflects neurotoxin-induced noradrenaline level decrease in the rat hippocampus.

BACKGROUND: The neuropathological changes of early Alzheimer's disease (AD) include neurodegenerative loss of noradrenaline neurons in the locus coeruleus with decreasing noradrenaline availability in their projection areas such as the hippocampus. This diminishing noradrenaline availability is thought to play an important role pathophysiologically in the development of cognitive impairment in AD, because noradrenaline is not only essential for maintaining cognitive functions such as memory, learning and attention, but also its anti-inflammatory action, where its lack is known to accelerate the progression of AD in the mouse model. Therefore, the availability of in vivo biomarkers of the integrity of noradrenaline neurons may be beneficial for furthering our understanding of the role played by the noradrenaline system in the progressive cognitive dysfunction seen in AD patients. In this study, we investigated if PET imaging of noradrenaline transporters can predict the level of noradrenaline in the brain. Our hypothesis was PET measured noradrenaline transporter densities could predict the level of noradrenaline concentrations in the rat hippocampus after lesioning of noradrenaline neurons in this region. RESULTS: We chemically lesioned the hippocampus of rats (n = 15) by administering a neurotoxin, DSP-4, in order to selectively damage axonal terminals of noradrenergic neurons. These rats then underwent PET imaging of noradrenaline transporters using [11C]MRB ((S,S)-[11C]Methylreboxetine). To validate our hypothesis, postmortem studies of brain homogenates of these rats were performed to measure both noradrenaline transporter and noradrenaline concentrations. [11C]MRB PET showed decreased noradrenaline transporter densities in a DSP-4 dose-dependent manner in the hippocampus of these rats. In turn, these PET measured noradrenaline transporter densities correlated very well with in vitro measured noradrenaline concentrations as well as in vitro transporter densities. CONCLUSIONS: [11C]MRB PET may be used as an in vivo biomarker of noradrenaline concentrations in the hippocampus of the neurodegenerating brain. Further studies appear warranted to extend its applicability to AD studies.

Probing Energy-Level Alignment in Molecular Multilayers by Frequency-Modulation Electrostatic Force Microscopy under Tapping-Mode-Combined Fowler-Nordheim Tunneling Spectroscopy.

The alignment of molecular electronic levels in a molecular multilayer is of crucial importance to realize desired functions for molecular devices. Amplitude-modulation-feedback frequency-modulation electrostatic force microscopy combined with Fowler-Nordheim tunneling spectroscopy is utilized as a probe for the energy-level alignment in an organic multilayer. Bias-dependent electrostatic force spectra were examined for bilayers including a Ru complex as a benchmark multilayer system. Electrostatic properties in the low-bias region were captured well by a single-capacitor model, which indicates weak coupling at the bilayer interface between the Ru complex and self-assembled monolayer. In contrast, in the high-bias region, significant disagreement with the expected electrostatic force was recognized for the bilayers and evaluated as the loss of electrostatic energy through the Fowler-Nordheim tunneling process. Alignment of the lowest unoccupied molecular orbital (LUMO) level of the Ru complex was determined by Fowler-Nordheim emission through resonant tunneling. These results indicate an effective method to probe level alignment at interfaces inside multilayers and to provide the partition factor ß that depicts a divided electric field.

Zone 0 TEVAR with femoral artery inflow for an anastomotic pseudoaneurysm.

We describe the case of an 89-year-old female with a distal anastomotic pseudoaneurysm of the ascending aorta after an ascending aorta replacement for an acute type A aortic dissection. Initially, we attempted endovascular repair using a semi-custom-made thoracic fenestrated stent graft. However, this treatment failed due to an endoleak. Two weeks later, we performed a total arch vessel debranching using femoral artery inflow and thoracic endovascular repair. Postoperative computed tomography revealed no signs of the endoleak. This hybrid approach could be an effective treatment option for anastomotic pseudoaneurysms of the ascending aorta.

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms.

Understanding of metabolic processes is a key factor to evaluate biological effects of carcinogen and mutagens. Applicability of fused-grid Template* systems of CYP enzymes (Drug Metab Pharmacokinet 2019, 2020, 2021, and 2022) was tested for three phenomena. (1) Possible causal relationships between CYP-mediated metabolisms of ß-naphthoflavone and 3-methylcholanthrene and the high inducibility of CYP enzymes were examined. Selective involvement of non-constitutive CYP1A1, but not constitutive CYP1A2, was suggested on the oxidative metabolisms of efficient inducers, ß-naphthoflavone and 3-methylcholanthrene. These results supported the view of the causal link of their high inducibility with their inefficient metabolisms due to the lack of CYP1A1 in livers at early periods after the administration of both inducers. (2) Clear differences exist between human and rodent CYP1A1 enzymes on their catalyses with heterocyclic amines, dioxins and polyaromatic hydrocarbons (PAHs). Reciprocal comparison of simulation results with experimental data suggested the rodent specific site and distinct sitting-preferences of ligands on Template for human and rodent CYP1A1 enzymes. (3) Enhancement of metabolic activation and co-mutagenicity have been known as phenomena associated with Salmonella mutagenesis assay. Both the phenomena were examined on CYP-Templates in ways of simultaneous bi-molecule bindings of distinct ligands as trigger and pro-metabolized molecules. α-Naphthoflavone and norharman served consistently as trigger-molecules to support the oxidations of PAHs and arylamines sitting simultaneously as pro-metabolized molecules on Templates of CYP1A1, CYP1A2 and CYP3A4. These CYP-Template simulation systems with deciphering capabilities are promising tools to understand the mechanism basis of metabolic activations and to support confident judgements in safety assessments.