The Possible Role of TASK Channels in Rank-Ordered Recruitment of Motoneurons in the Dorsolateral Part of the Trigeminal Motor Nucleus.

Because a rank-ordered recruitment of motor units occurs during isometric contraction of jaw-closing muscles, jaw-closing motoneurons (MNs) may be recruited in a manner dependent on their soma sizes or input resistances (IRs). In the dorsolateral part of the trigeminal motor nucleus (dl-TMN) in rats, MNs abundantly express TWIK (two-pore domain weak inwardly rectifying K channel)-related acid-sensitive-K(+) channel (TASK)-1 and TASK3 channels, which determine the IR and resting membrane potential. Here we examined how TASK channels are involved in IR-dependent activation/recruitment of MNs in the rat dl-TMN by using multiple methods. The real-time PCR study revealed that single large MNs (>35 μm) expressed TASK1 and TASK3 mRNAs more abundantly compared with single small MNs (15-20 μm). The immunohistochemistry revealed that TASK1 and TASK3 channels were complementarily distributed in somata and dendrites of MNs, respectively. The density of TASK1 channels seemed to increase with a decrease in soma diameter while there were inverse relationships between the soma size of MNs and IR, resting membrane potential, or spike threshold. Dual whole-cell recordings obtained from smaller and larger MNs revealed that the recruitment of MNs depends on their IRs in response to repetitive stimulation of the presumed Ia afferents. 8-Bromoguanosine-cGMP decreased IRs in small MNs, while it hardly changed those in large MNs, and subsequently decreased the difference in spike-onset latency between the smaller and larger MNs, causing a synchronous activation of MNs. These results suggest that TASK channels play critical roles in rank-ordered recruitment of MNs in the dl-TMN

Activator protein-1 responsive to the group II metabotropic glutamate receptor subtype in association with intracellular calcium in cultured rat cortical neurons

金沢大学大学院自然科学研究科分子作用学Activation of ionotropic glutamate (Glu) receptors, such as N-methyl-d-aspartate receptors, is shown to modulate the gene transcription mediated by the transcription factor activator protein-1 (AP1) composed of Fos and Jun family proteins in the brain, while little attention has been paid to the modulation of AP1 expression by metabotropic Glu receptors (mGluRs). In cultured rat cortical neurons, where constitutive expression was seen with all groups I, II and III mGluR subtypes, a significant and selective increase was seen in the DNA binding activity of AP1 120 min after the brief exposure to the group II mGluR agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV) for 5 min. In cultured rat cortical astrocytes, by contrast, a significant increase was induced by a group I mGluR agonist, but not by either a group II or III mGluR agonist. The increase by DCG-IV was significantly prevented by a group II mGluR antagonist as well as by either an intracellular Ca2+ chelator or a voltage-sensitive Ca2+ channel blocker, but not by an intracellular Ca2+ store inhibitor. Moreover, DCG-IV significantly prevented the increase of cAMP formation by forskolin in cultured neurons. Western blot analysis revealed differential expression profiles of Fos family members in neurons briefly exposed to DCG-IV and NMDA. Prior or simultaneous exposure to DCG-IV led to significant protection against neuronal cell death by NMDA. These results suggest that activation of the group II mGluR subtype would modulate the gene expression mediated by AP1 through increased intracellular Ca2+ levels in cultured rat cortical neurons. © 2007

Antitumor activity of α-pinene in T-cell tumors

T-cell acute leukemia and lymphoma have a poor prognosis. Although new therapeu-tic agents have been developed, their therapeutic effects are suboptimal. α- Pinene, a monoterpene compound, has an antitumor effect on solid tumors; however, few comprehensive investigations have been conducted on its impact on hematologic ma-lignancies. This report provides a comprehensive analysis of the potential benefits of using α- pinene as an antitumor agent for the treatment of T-cell tumors. We found that α- pinene inhibited the proliferation of hematologic malignancies, especially in T- cell tumor cell lines EL-4 and Molt-4, induced mitochondrial dysfunction and re-active oxygen species accumulation, and inhibited NF-κB p65 translocation into the nucleus, leading to robust apoptosis in EL-4 cells. Collectively, these findings suggest that α- pinene has potential as a therapeutic agent for T-cell malignancies, and further investigation is warranted

A survey of problems in the care and support of infants born at very low birth weight

Orientador: Prof. Dr. Clodomiro Unsihuay-VilaCoorientadora: Prof.a Dr. a Thelma Solange P. FernandesDissertação (mestrado) - Universidade Federal do Paraná, Setor de Tecnologia, Programa de Pós-Graduação em Engenharia Elétrica. Defesa : Curitiba, 29/08/2019Inclui referências: p. 127-133Área de concentração: Sistema de energiaResumo: A frota de veículo elétrico (VE) cresce rapidamente no mundo, em 2018 já superou a marca de 5,1 milhões. A inserção de VE nas redes ativas de distribuição significa uma evolução nos sistemas de energia elétrica, mas essa evolução requer avanços no planejamento da operação, de maneira a considerar o aumento da complexidade que esses novos elementos podem causar na rede. Por isso, se faz necessário ferramentas computacionais que permitam analisar os impactos que o VE causa na operação de redes ativas de distribuição, de maneira a auxiliar na definição de estratégias operativas apropriadas e garantir a otimização de todos os recursos energéticos do sistema. Dessa forma, nesta dissertação foi desenvolvido um modelo computacional, formulado como um problema de otimização capaz de determinar a programação diária da operação de redes ativas de distribuição, considerando a inserção do VE na rede. O problema foi abordado através de um Fluxo de Potência Ótimo (FPO) multiperíodo. A intertemporalidade do problema é formulada através da introdução de uma função de acoplamento representada pela energia armazenada pelas baterias do VE. A resolução do FPO foi através do Métodos dos Pontos Interiores versão Primal-Dual. O horizonte de planejamento é de 24 períodos, divididos em horas. Também é considerado a geração distribuída fotovoltaica e um sistema de tarifação horária de energia. O veículo elétrico é incorporado no problema por meio da adição de uma variável de otimização à função objetivo que além de alterar as restrições de balanço de potência também é usada para monitorar a energia armazenada nas baterias. Como resultado, têm-se um FPO multiperíodo que busca, além da minimização dos custos operativos e perdas de transmissão, também a maximização da energia armazenada nas baterias dos veículos elétricos conectados à rede visando a injeção ótima de energia à rede ativa. Nas simulações realizadas, foram utilizados cenários determinísticos de conexão do VE para avaliar seus impactos nas perdas, custos operacionais e perfil de tensão do sistema elétrico. Os resultados de simulações demonstraram que, no cenário de perfil residencial, que possibilitam o carregamento/descarregamento, é perceptível uma melhora no perfil de tensão do sistema. Isso mostra que a apropriada operação dos VEs com possibilidade de injeção de energia à rede podem ser uma boa alternativa para deslocar picos de carga e reduzir custos operacionais da rede ativa de distribuição. Para o perfil comercial, é perceptível uma redução do perfil de tensão para o seu instante de conexão. Entretanto, esse comportamento pode ser complementado através de uma geração fotovoltaica, que apresenta seus picos de geração nos mesmos instantes em que o VE carrega. Para os cenários que consideram uma alta inserção de VE na rede, os impactos no perfil de tensão do sistema são bastante significativos, demonstrando que para que a rede seja capaz de atender uma grande frota de VEs devem ser feitos investimentos na infraestrutura da rede de distribuição. O impacto da inserção do VE à rede pode aumentar em até 40% as perdas do sistema. Os impactos no custo de operação são significativos, podendo aumentar em até 19%, para cenários de alta penetração de VE. Palavras-chave: Planejamento da Operação. Redes Ativas de Distribuição. Veículo Elétrico. Fluxo de Potência Ótimo. Método dos Pontos Interiores versão Primal-Dual. Armazenamento de energia em baterias.Abstract: The electric vehicle (EV) fleet is growing rapidly in the world, by 2018, it has already surpassed the 5.1 million mark. The insertion of EV into active distribution grids means an evolution in power systems, but this evolution requires advances in operation planning in order to consider the increased complexity that these new elements in the grid may cause. Therefore, computational tools are needed to analyze the impacts that EV has on the operation of active distribution networks, in order to help define appropriate operating strategies and ensuring the optimization of all energy resources in the system. Thus, in this dissertation a computational model was developed, formulated as an optimization problem capable of determining the daily programming of the active distribution networks operation, considering the insertion of the EV in the network. The problem was addressed through a Multi-Period Optimal Power Flow (OPF). The intertemporality of the problem is formulated by introducing a coupling function represented by the energy stored by LV batteries. The resolution of the OPF was through the Primal-Dual Interior Point Method. The planning horizon is 24 periods, divided into hours, under the influence of photovoltaic generation and an hourly energy hourly charging system. The electric vehicle is incorporated into the problem by adding an optimization variable to the objective function which in addition to changing the power balance restrictions is also used to monitor the energy stored in the batteries. As a result, there is a MultiPeriod OPF that seeks, in addition to minimizing operating costs and transmission losses, also maximizing the energy stored in the batteries of electric vehicles connected to the grid for optimal injection of power to the grid at peak hours. In the simulations performed, deterministic EV connection scenarios were used to assess their impacts on losses, operating costs and voltage profile. Simulation results showed that, in the residential profile scenario, which enables loading / unloading, an improvement in the system voltage profile is noticeable. Showing that appropriate EV operation can be a good alternative for shifting power generation from light load moments of the system to high load moments, optimizing the use of system energy resources, reducing operating costs of active distribution. For the commercial profile, a reduction of the voltage profile is noticeable for its connection time. However, this behavior can be complemented by a photovoltaic generation, which presents its generation peaks at the same time that the EV charges. For scenarios that consider a high insertion of EV in the grid, the impacts on the system voltage profile are quite significant, demonstrating that for the grid to be able to serve a large fleet of EVs, investments in the distribution network infrastructure must be made. The impacts of EV insertion into the network can increase system losses by up to 40%. The impacts on operating costs are significant and may increase by up to 19% for high EV penetration scenarios. Keywords: Operation Planning. Active Distribution Networks. Electric Vehicle. Optimal Power Flow. Primal-Dual Interior Point Method. Energy storage in batteries

Inhaled steroid therapy and hospitalization for bronchial asthma : trend in Tokushima University Hospital

With the recognition that airway inflammation is present even in patients with mild bronchial asthma, therapy with inhaled corticosteroids is now indicated in various stages of patients. In the present article, we retrospectively examined the prescriptions for inhaled corticosteroids and other drugs for the treatment of outpatients with bronchial asthma at Tokushima University Hospital. We also analyzed asthma control in these patients, in terms of the incidence of emergency consultations and hospitalizations due to asthma exacerbations. To analyze the recent trend, the patients observed from 1998 to 2000 (recent years) were included, and for control purpose, those in 1990 and 1991 (earlier years) were also included. The percentage of patients treated with inhaled corticosteroids remarkably increased in recent years (mean 81.3%) compared to earlier years (mean 23.5%). In contrast, the usage of oral corticosteroids, oral xanthine derivatives, β2-adrenergic receptor agonists and anti-allergic agents tended to decrease in the 10 years period. After the introduction in 1995, considerable patients up to 25% have been treated with anti-leukotrienes. Emergency consultations decreased in recent years (mean 0.18/patient/year) compared to earlier years (mean 0.79/patient/year). Emergency hospitalizations also decreased in recent years (mean 0.043/patient/year) compared to earlier years (mean 0.23/patient/year).In the present study, spread of inhaled corticosteroid therapy and decline in incidence of emergency consultation and hospitalization were simultaneously observed at Tokushima University Hospital, and the former has, at least in part, a contribution to the latter

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection