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This study surveyed adult web monitor enrollees about the lives of and stress experienced by Japanese children and adolescents during the prolonged coronavirus disease 2019 (COVID-19) pandemic. The survey was conducted on February 10, 2022 (after the sixth wave) and August 19, 2022 (during the seventh wave of the COVID-19 pandemic in Japan), with 231 and 217 survey participants, respectively. The questionnaire was designed so that adults could assess the frequency of exercise, and difficulties experienced by children and adolescents around them. Regarding exercise opportunities, 22% of parents of middle and high school children reported that children’s exercise opportunities “stayed the same” or “increased considerably” in the first survey. Whereas, in the second survey, all parents of middle and high school children reported that children’s exercise opportunities “decreased.” Regarding stress, 17% of parents of adolescents 18 years and older responded that the stress experienced was the “same as before” or “a little less than before” in the first survey, but all of these parents responded “quite a bit” to the same question in the second survey. The findings suggest that the life changes caused by the COVID-19 pandemic may have a significant impact on children and adolescents and may increase stress. The long-term effects of the COVID-19 pandemic on children and adolescents should be further investigated.

ObjectiveStatus epilepticus (SE) is an emergency condition for which rapid and secured cessation is crucial. Although fosphenytoin (FPHT) is recommended as a second-line treatment, levetiracetam (LEV) reportedly has similar efficacy, but higher safety. Therefore, we herein compared LEV with FPHT in adult SE.MethodsWe initiated a multicentre randomised control trial in emergency departments with adult patients with convulsive SE. Diazepam was initially administered, followed intravenously by FPHT at 22.5 mg/kg or LEV at 1000–3000 mg. The primary outcome was assigned as the seizure cessation rate within 30 min of the administration of the study drug.ResultsA total of 176 adult patients with SE were enrolled (82 FPHT and 94 LEV), and 3 were excluded from the full analysis set. Seizure cessation rates within 30 min were 83.8% (67/80) in the FPHT group and 89.2% (83/93) in the LEV group. The difference in these rates was 5.5% (95% CI −4.7 to 15.7, p=0.29). The non-inferiority of LEV to FPHT was confirmed with pConclusionThe efficacy of LEV was similar to that of FPHT for adult SE following the administration of diazepam. LEV may be recommended as a second-line treatment for SE along with phenytoin/FPHT.Trial registration numberjRCTs031190160.

After a natural disaster, it is important to maintain the health of the victims, but after the Turkey-Syria earthquake, this information has not yet been provided. Tohoku University has compiled information on maintaining health care after the Great East Japan Earthquake of March 2011 into a booklet, which is available to the public. The purpose of this study is to investigate user satisfaction with this booklet. A total of 505 organizations participated in this study by completing questionnaires and evaluating the booklet. Quantitative responses were analyzed and coded by theme. Open-ended responses indicated that it was difficult for the general public to understand the data in the booklet. This study shows the need to keep in mind the ease of understanding for the general public when providing information on post-disaster care. We hope that this study will lead to better health care information for the victims of the Turkey-Syria earthquake.

Supplementary Figure 2 from Cell Survival under Stress Is Enhanced by a Mitochondrial ATP-Binding Cassette Transporter That Regulates Hemoproteins

Supplementary Material and Methods : Plasma pharmacokinetics of topotecan with and without the ABCG2 inhibitor Ko143. Supplementary Figure S1: RNA expression of ABC transporters in human and mouse Group3 medulloblastoma. Supplementary Figure S2: Abcg2 protein expression in mouse bone marrow from Abcg2-null mice and Group3 medulloblastoma tumor cells. Supplementary Figure S3: Dose-response of chemotherapeutic agents alone or with two Abcg2 inhibitors, Ko143 or Tariquidar. Supplementary Figure S4: Weight measurement and Abcg2 protein expression in mouse Group3 medulloblastoma during treatment. Supplementary Table 1: Affymetrix gene array analysis of genes in the porphyrin pathway in granule neuron progenitors (GNPs) and Mouse Group3 medulloblastoma tumor cells. Supplementary Table 2: Chemotherapeutic drugs tested on mouse Group3 medulloblastoma tumor cells. Supplementary Table 3: Plasma PK paramaters of topotecan after administration as single agent or in combination with the Abcg2 inhibitor Ko143.

Supplementary Figure 3 from Cell Survival under Stress Is Enhanced by a Mitochondrial ATP-Binding Cassette Transporter That Regulates Hemoproteins

Supplementary Figure 4 from Cell Survival under Stress Is Enhanced by a Mitochondrial ATP-Binding Cassette Transporter That Regulates Hemoproteins

While a small number of plasma membrane ABC transporters can export chemotherapeutic drugs and confer drug resistance, it is unknown whether these transporters are expressed or functional in less therapeutically tractable cancers such as Group 3 (G3) medulloblastoma. Herein we show that among this class of drug transporters, only ABCG2 was expressed at highly increased levels in human G3 medulloblastoma and a mouse model of this disease. In the mouse model, Abcg2 protein was expressed at the plasma membrane where it functioned as expected on the basis of export of prototypical substrates. By screening ABC substrates against mouse G3 medulloblastoma tumorspheres in vitro, we found that Abcg2 inhibition could potentiate responses to the clinically used drug topotecan, producing a more than 9-fold suppression of cell proliferation. Extended studies in vivo in this model confirmed that Abcg2 inhibition was sufficient to enhance antiproliferative responses to topotecan, producing a significant survival advantage compared with subjects treated with topotecan alone. Our findings offer a preclinical proof of concept for blockade of ABCG2 transporter activity as a strategy to empower chemotherapeutic responses in G3 medulloblastoma. Cancer Res; 75(18); 3879–89. ©2015 AACR.

The ATP-binding cassette (ABC) transporter ABCB6 localizes to the mitochondria, where it imports porphyrins and up-regulates de novo porphyrin synthesis. If ABCB6 also increases the intracellular heme concentration, it may broadly affect the regulation and physiology of cellular hemoproteins. We tested whether the ability of ABCB6 to accelerate de novo porphyrin biosynthesis alters mitochondrial and extramitochondrial heme levels. ABCB6 overexpression increased the quantity of cytosolic heme but did not affect mitochondrial heme levels. We then tested whether the increased extramitochondrial heme would increase the concentration and/or activity of cellular hemoproteins (hemoglobin, catalase, and cytochrome c oxidase). ABCB6 overexpression increased the activity and quantity of hemoproteins found in several subcellular compartments, and reduction of ABCB6 function (by small interfering RNA or knockout) reversed these findings. In complementary studies, suppression of ABCB6 expression sensitized cells to stress induced by peroxide and cyanide, whereas overexpression of ABCB6 protected against both stressors. Our findings show that the ability of ABCB6 to increase cytosolic heme levels produces phenotypic changes in hemoproteins that protect cells from certain stresses. Collectively, these findings have implications for the health and survival of both normal and abnormal cells, which rely on heme for multiple cellular processes. [Cancer Res 2009;69(13):5560–7]

Supplementary Figure 1 from Cell Survival under Stress Is Enhanced by a Mitochondrial ATP-Binding Cassette Transporter That Regulates Hemoproteins

Introduction: Adolescents affected by disasters need mental health support because they tend to be at risk of developing psychiatric disorders and stress as grown-ups. However, it is difficult to develop and validate a support system for adolescents affected by disasters because it is unknown when and where disasters occur, and there is inadequate data related to this in Japan. Methods: To address these issues, we present a mental health support system for high school students affected by the Great East Japan Earthquake. We hypothesized that mental health support could be provided by classroom teachers and school nurses, who are familiar with high school students. We investigated the psychological state of the affected high school students for three years after the earthquake, and the students in psychological crises received interventions from their class teachers and school nurses. Results: The intervention resulted in improvements in depression and post-traumatic stress reaction (PTSR). Conclusion: These results suggest that our high school-based intervention is a feasible solution for mental health support for adolescents affected by the disaster.

All aerobic organisms require the cofactor heme to survive, but its synthesis requires formation of a potentially toxic intermediate protoporphyrin IX (PPIX). Little is known about the extent of PPIX’s cellular interactions. Here, we report the development of PPB, a biotin-conjugated, PPIX-probe that captures proteins capable of interacting with PPIX. Quantitative proteomics with PPB identified common proteins among a diverse panel of mammalian cell lineages. Pathway and quantitative difference analysis revealed PPB-bound proteins related to iron and heme metabolism and suggested that these processes might be altered by heme/porphyrin synthesis. We show that increased heme/porphyrin synthesis in cells promotes ferroptosis that is pharmacologically distinct from canonical ferroptosis driven by erastin, an inhibitor of the cystine/glutamate antiporter. Proteomic data derived from PPB revealed an interactor, PRDX3, a mitochondrial peroxidase, that modulated heme/porphyrin biosynthesis driven ferroptosis. Consistent with a role in porphyrin-induced ferroptotic death targeted gene knockdown of PRDX3, but not peroxidases, PRDX1 or 2, enhanced porphyrin-induced ferroptotic death. The relationship between increased heme/porphyrin synthesis and ferroptosis was also found in a ferrochelatase-deficient T-lymphoblastoid leukemia cell line, suggesting potential strategy for treating certain cancers. We demonstrate that when the PPB probe is coupled with unbiased proteomics a previously unreported relationship between heme/porphyrin synthesis, and ferroptosis was discovered.

Background To date, there is no systematic overview of glutamate in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. Here, we meta-analyzed case-control studies of high-field proton magnetic resonance spectroscopy (1H-MRS) investigating glutamate in DLPFC. Additionally, we estimated variance ratios to investigate homo/heterogeneity. Methods Preregistration of the study was performed on September 20, 2019. The predefined literature search on PubMed comprised articles with search terms (magnetic resonance spectroscopy OR MRS) AND (glutamate OR glut∗ OR GLX) AND (schizophrenia OR psychosis OR schizophren∗). Meta-analyses with a fixed- and random-effects model with inverse variance method, DerSimonian-Laird estimator for τ2, and Cohen's d were calculated. For differences in variability, we calculated a random-effects model for measures of variance ratios. The primary study outcome was the difference in glutamate in the DLPFC in cases versus controls. Secondary outcomes were differences in variability. Results The quantitative analysis comprised 429 cases and 365 controls. Overall, we found no group difference (d = 0.03 [95% confidence interval (CI), −0.20 to 0.26], z = 0.28, p = .78). Sensitivity analysis revealed an effect for medication status (Q = 8.35, p = .039), i.e., increased glutamate in antipsychotic-naive patients (d = 0.46 [95% CI, 0.08 to 0.84], z = 2.37, p = .018). Concerning variance ratios, we found an effect of medication status (Q = 16.95, p Conclusions We carefully interpret the higher levels and lower variability in cortical glutamate in antipsychotic-naive patients as a possible key factor resulting from a putative allostatic mechanism. We conclude that care has to be taken when evaluating metabolite levels in clinical samples in which medication might confound findings.

Introduction: Health professionals and support staff need to be prepared for disasters and know how to respond. This study aimed to examine a one-day “Conductor-type disaster healthcare management personnel” training course and its effect among healthcare professionals. Tohoku University and Fukushima Medical University are experienced in disaster response preparedness and they conducted the one-day course comprising multiple sessions at the World Bosai Forum-2019 (WBF-2019). Method: The course introduced the recent activities of four groups: the Practical Disaster Risk Reduction Research Group; the Natural Science Research Group; the Disaster Humanities Research Group; and the Disaster Medicine Research Group. Unifying four scientific areas based on the theory of the disaster cycle, the research field “disaster science” has been created through interdisciplinary cooperation. The participants completed reports, which were then analyzed using the KJ method. Discussion: The program participants wanted to gain practical knowledge about disasters and have a multifaceted perspective on disaster response. Participants who attended other sessions had an interest in comparing their training with the training provided by other sessions on disaster preparedness. Comparisons included determining the effectiveness of high-level disaster medical preparations from a multilateral viewpoint and involving an interdisciplinary research team in disaster medical preparations to prepare for future disaster events. Conclusion: The participants identified that interdisciplinary activities lead to an improvement in knowledge, skills, or attitudes toward disaster preparedness. There needs to be a greater focus on disaster medicine care teams, including research on both past and future disasters.

ATP-binding cassette sub-family G member 2 (ABCG2) is a homodimeric ATP-binding cassette (ABC) transporter that not only has a key role in helping cancer cells to evade the cytotoxic effects of chemotherapy, but also in protecting organisms from multiple xeno- and endobiotics. Structural studies indicate that substrate and inhibitor (ligands) binding to ABCG2 can be differentiated quantitatively by the number of amino acid contacts, with inhibitors displaying more contacts. Although binding is the obligate initial step in the transport cycle, there is no empirical evidence for one amino acid being primarily responsible for ligand binding. By mutagenesis and biochemical studies, we demonstrated that the phylogenetically conserved amino acid residue, F439, was critical for both transport and the binding of multiple substrates and inhibitors. Structural modeling implied that the π-π interactions from each F439 monomer mediated the binding of a surprisingly diverse array of structurally unrelated substrates and inhibitors and that this symmetrical π-π interaction "clamps" the ligand into the binding pocket. Key molecular features of diverse ABCG2 ligands using the π-π clamp along with structural studies created a pharmacophore model. These novel findings have important therapeutic implications because key properties of ligands interacting with ABCG2 have been disovered. Furthermore, mechanistic insights have been revealed by demonstrating that for ABCG2 a single amino acid is essential for engaging and initiating transport of multiple drugs and xenobiotics.

Various traditional festivals have taken place in most of the community in the coastal areas of the Tohoku region before the 2011 Great East Japan earthquake. Recent studies have revealed that reviving these festivals plays a crucial role for people to reconstruct a community life in the tsunami-affected area. Despite the importance of the intangible cultural properties, not only outfits used but also crafts to make those kits were swept away by the 2011 tsunami. Under this background, this research attempts to record the three-dimensional data of those materials used in festivals and folk performing arts. This project aims to construct the database of those props used for the intangible cultural properties and offer three-dimensional data to the disaster-affected area to rebuild their community life. Another goal of this explorative project is to create a methodology of three-dimensional measurement in the field of the disaster humanity science. By scanning cultural properties in disaster-prone areas not only in Japan but also in other countries, the project attempts to connect international networks to discuss the applicability of this method.

Researchers believe that the impact of repeated trauma on mental health is incrementally more significant than the simple additive effect of one event. This study questioned whether this repetition only further worsens people's mental health. We found that they may report more positive changes than those who haven’t. Thus, we hypothesized that repeatedly experiencing difficult situations and suffering might increase post-traumatic growth (PTG). PTG can be defined as "positive psychological changes experienced due to coping with very difficult life situations," leading to positive outcomes and feelings of well-being. We found that those who experienced a disaster in the past were more depressed, anxious, and stressed than those who had never experienced a disaster and now experienced the COVID-19 pandemic. Additionally, past disaster experience led to a more psychological response to the COVID-19 pandemic, which, in turn, led to an increase PTG. Globally, we found that supportive social interactions, including those with family members, could develop PTG during the COVID-19 pandemic and achieve better well-being during the continuation of the pandemic in the future.

Metabolic studies of human pluripotent stem cells (hPSCs) have focused on how the cells produce energy through the catabolic pathway. The less-studied anabolic pathway, by which hPSCs expend energy in the form of adenosine triphosphate (ATP), is not yet fully understood. Compared to fully differentiated somatic cells, hPSCs undergo significant changes not only in their gene expression but also in their production and/or expenditure of ATP. Here, we investigate how hPSCs tightly control their energy homeostasis by studying the main energy-consuming process, mRNA translation. In addition, change of subcellular organelles regarding energy homeostasis has been investigated. Lysosomes are organelles that play an important role in the elimination of unnecessary cellular materials by digestion and in the recycling system of the cell. We have found that hPSCs control their lysosome numbers in part by regulating lysosomal gene/protein expression. Thus, because the levels of mRNA translation rate are lower in hPSCs than in somatic cells, not only the global translational machinery but also the lysosomal recycling machinery is suppressed in hPSCs. Overall, the results of our study suggest that hPSCs reprogram gene expression and signaling to regulate energy-consuming processes and energy-controlling organelles.

Coronavirus disease 2019 (COVID-19) is causing disruptions in the global social system. Japanese children and adolescents have had their schools closed, government-mandated activity restrictions imposed, and interactions outside the home reduced. These restrictions can have a considerable psychological impact on children and adolescents. This review aims to describe the impacts of COVID-19 pandemic on physical activity and psychological status of this population. The review was conducted by searching PubMed for information on the impact of COVID-19-related activity restrictions on children and adolescents. The search identified 11 articles, three of which contained data on anxiety and psychological problems due to physical inactivity. Next, a PubMed search was conducted about physical activity and psychological status in children and adolescents under psychological stress. The search identified 368 articles, 28 of which were included in the review. For children, data that revealed a correlation between physical activity and psychological health and sedentary time leading to mood disorders were included. For adolescents, there were nine studies that reported a correlation between physical activity and psychological health and four studies that reported no correlation between physical activity and psychological health. Of the studies that reported a correlation, seven reported that physical activity improves psychological health. The impact of psychologically stressful situations such as COVID-19 on children and adolescents has been experienced worldwide. Physical activity has been correlated with psychological health, and it may improve psychological status; physical activity should be recommended to better support the psychological health of children and adolescents under the influence of COVID-19.

Abcg2/Bcrp and Abcb1a/Pgp are xenobiotic efflux transporters limiting substrate permeability in the gastrointestinal system and brain, and increasing renal and hepatic drug clearance. The systemic impact of Bcrp and Pgp ablation on metabolic homeostasis of endogenous substrates is incompletely understood. We performed untargeted metabolomics of cerebrospinal fluid (CSF) and plasma, transcriptomics of brain, liver and kidney from male Sprague Dawley rats (WT) and Bcrp/Pgp double knock-out (dKO) rats, and integrated metabolomic/transcriptomic analysis to identify putative substrates and perturbations in canonical metabolic pathways. A predictive Bayesian machine learning model was used to predict in silico those metabolites with greater substrate-like features for either transporters. The CSF and plasma levels of 169 metabolites, nutrients, signaling molecules, antioxidants and lipids were significantly altered in dKO rats, compared to WT rats. These metabolite changes suggested alterations in histidine, branched chain amino acid, purine and pyrimidine metabolism in the dKO rats. Levels of methylated and sulfated metabolites and some primary bile acids were increased in dKO CSF or plasma. Elevated uric acid levels appeared to be a primary driver of changes in purine and pyrimidine biosynthesis. Alterations in Bcrp/Pgp dKO CSF levels of antioxidants, precursors of neurotransmitters, and uric acid suggests the transporters may contribute to the regulation of a healthy central nervous system in rats. Microbiome-generated metabolites were found to be elevated in dKO rat plasma and CSF. The altered dKO metabolome appeared to cause compensatory transcriptional change in urate biosynthesis and response to lipopolysaccharide in brain, oxidation-reduction processes and response to oxidative stress and porphyrin biosynthesis in kidney, and circadian rhythm genes in liver. These findings present insight into endogenous functions of Bcrp and Pgp, the impact that transporter substrates, inhibitors or polymorphisms may have on metabolism, how transporter inhibition could rewire drug sensitivity indirectly through metabolic changes, and identify functional Bcrp biomarkers.

Background Cognitive deficits such as working memory (WM) impairment are core features of schizophrenia. One candidate marker for the integrity of synaptic neurotransmission necessary for cognitive processes is glutamate. It is frequently postulated that antipsychotic medication possibly alters functional mechanisms in the living brain. We tested in vivo for group differences in activation of the dorsolateral prefrontal cortex (DLPFC) during WM performance and the association with glutamate concentration in DLPFC depending on medication status. Methods A total of 90 subjects (35 control subjects, 36 medicated patients, and 19 unmedicated patients) contributed magnetic resonance spectroscopy data. We estimated glutamate in left DLPFC. Subjects performed an n-back WM task (2-back vs. 0-back) during functional magnetic resonance imaging, and local activation in left DLPFC was measured. For analysis of association with medication status, we calculated linear regression models including an interaction effect with group. Results Medicated and unmedicated patients with schizophrenia showed impaired performance. We found significantly reduced WM activation in left DLPFC in medicated patients and a trendwise reduction in unmedicated patients as compared with control subjects. We found no group difference in local glutamate concentration. However, we found differential effects of medication status on the association between local glutamate concentration and WM activation in left DLPFC, with a positive association in unmedicated patients but not in medicated patients. Conclusions We provide evidence that WM-dependent activation is associated with glutamate concentration in unmedicated patients with schizophrenia. Our finding points to putative allostatic changes that affect the functioning of the brain and might be altered through medication.

Background: Working-memory impairment is a core cognitive dysfunction in people with schizophrenia and people at mental high risk. Recent imaging studies on working memory have suggested that abnormalities in prefrontal activation and in connectivity between the frontal and parietal regions could be neural underpinnings of the different stages of psychosis. However, it remains to be explored whether comparable alterations are present in people with subclinical levels of psychosis, as experienced by a small proportion of the general population who neither seek help nor show constraints in daily functioning.Methods: We compared 24 people with subclinical high delusional ideation and 24 people with low delusional ideation. Both groups performed an n-back working-memory task during functional magnetic resonance imaging. We characterized frontoparietal effective connectivity using dynamic causal modelling.Results: Compared to people who had low delusional ideation, people with high delusional ideation showed a significant increase in dorsolateral prefrontal activation during the working-memory task, as well as reduced working-memory-dependent parietofrontal effective connectivity in the left hemisphere. Group differences were not evident at the behavioural level.Limitations: The current experimental design did not distinguish among the working-memory subprocesses; it remains unexplored whether differences in connectivity exist at that level.Conclusion: These findings suggest that alterations in the working-memory network are also present in a nonclinical population with psychotic experiences who do not display cognitive deficits. They also suggest that alterations in working-memory-dependent connectivity show a putative continuity along the spectrum of psychotic symptoms.

BACKGROUND: Cognitive deficits in schizophrenia are of great importance for clinical outcome. However, the underlying neurobiology is not yet fully understood. One candidate biochemical marker for the integrity of synaptic neurotransmission which is necessary for cognitive processes is Glutamate. Here we tested in vivo for group differences in activation in the dorsolateral prefrontal cortex (DLPFC) during working memory (WM) performance and the association with Glutamate concentration in DLPFC. METHODS: 82 subjects (41 patients and 41 age and gender-matched controls) took part in the study. We estimated Glutamate in left DLPFC using magnetic resonance spectroscopy (1H-MRS) correcting for partial volume effects. Subjects performed the n-back working memory task and local activation in DLPFC was estimated using the general linear model. RESULTS: Here we show, that schizophrenia patients showed lower performance and reduced WM activation in left DLPFC as compared to controls. We found no group difference in local metabolite concentration (p=0.128). To explore the possible effects of local Glutamate levels on WM dependent activation, we correlated local Glutamate with beta parameter estimates from left DLPFC during working memory performance in the left hemisphere. We found a negative association between local Glutamate with beta parameter estimates in patients (R=-0.37; p=0.027) as compared to controls. In order to for unspecific effects of neural integrity, we repeated the same analysis with NAA. We found no association between NAA and working memory dependent activation. DISCUSSION: In conclusion, we could provide in vivo evidence that working memory dependent activation is associated with Glutamate as a marker for synaptic functioning in patients suffering from schizophrenia. This finding points to putative allostatic changes which affect the functioning of the diseased brain.

The overall survival of patients with acute myeloid leukemia (AML) is poor and identification of new disease-related therapeutic targets remains a major goal for this disease. Here we show that expression of MPP1, a PDZ-domain-containing protein, highly correlated with ABCC4 in AML, is associated with worse overall survival in AML. Murine hematopoietic progenitor cells overexpressing MPP1 acquired the ability to serially replate in methylcellulose culture, a property crucially dependent upon ABCC4. The highly conserved PDZ-binding motif of ABCC4 is required for ABCC4 and MPP1 to form a protein complex, which increased ABCC4 membrane localization and retention, to enhance drug resistance. Specific disruption of this protein complex, either genetically or chemically, removed ABCC4 from the plasma membrane, increased drug sensitivity, and abrogated MPP1-dependent hematopoietic progenitor cell replating in methylcellulose. High-throughput screening identified Antimycin A as a small molecule that disrupted the ABCC4–MPP1 protein complex and reversed drug resistance in AML cell lines and in primary patient AML cells. In all, targeting the ABCC4–MPP1 protein complex can lead to new therapies to improve treatment outcome of AML, a disease where the long-term prognosis is poor., ABCC4 is a chemotherapeutic drug exporter highly expressed in acute myeloid leukemia. Here, the authors demonstrate that MPP1 anchors ABCC4 to the outer cell membrane mediating drug resistance in leukemic cells and identify antimycin A as a chemical probe that disrupts such interaction and restores sensitivity.