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Abstract The overexpression of Polo-like kinase 1 (PLK1) is associated with poor clinical outcomes in various malignancies, making it an attractive target for anticancer therapies. Although recent studies suggest PLK1’s involvement in homologous recombination (HR), the impact of its overexpression on HR remains unclear. In this study, we investigated the effect of PLK1 overexpression on HR using bioinformatics and experimental approaches. Analyzing The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) datasets with the Homologous Recombination Deficiency (HRD) score, we found a positive correlation between PLK1 expression and HRD score, indicating that increased PLK1 expression suppresses HR. To validate these findings, we performed cell line-based experiments, demonstrating that PLK1 overexpression attenuates RAD51 focus formation and HR, as measured by ASHRA in T47D cells. Since HR-deficient cells are hypersensitive to PARP inhibitors, we further confirmed that PLK1 overexpression increases sensitivity to PARP inhibitors, both in CCLE dataset analysis and experiments using T47D cells. Additionally, we found that the effects of PLK1 overexpression on HR suppression and increased PARP inhibitor sensitivity were mitigated by either a PLK1 kinase inhibitor or the kinase-dead mutant [T210A]. This suggests that PLK1’s impact on HR and PARP inhibitor sensitivity is mediated through its kinase activity. Moreover, analysis of clinical ovarian cancer samples revealed that higher PLK1 expression correlates with increased sensitivity to PARP inhibitors. Our results suggest that PLK1 overexpression suppresses homologous recombination, leading to enhanced sensitivity to PARP inhibition, presenting a potential therapeutic strategy for targeting cancers with overexpression of PLK1.

Objetivo: Apresentar reflexõesacerca da relação entre os setores de Hemoterapia e Hematologia do Hemorio, a partir do índice de comparecimentos de doadores em 2023. Material e método: O material do estudo é composto de pesquisa documental e levantamento de dados quantitativos coletados no Sistema de Administração ao Ciclo do Sangue (SACS) referentes ao comparecimento de doadores e números de doações em 2023. Resultados: O Hemorio possui a doação personalizada, conhecida em outros hemocentros como fenotipada. Para esse tipo de doação é realizada a fenotipagem sanguínea pelo setor de imunohematologia. Após esta etapa, ocorre a convocação destes doadores. De forma geral, a fenotipagem não influencia na terapia transfusional, mas para pacientes que recebem transfusões ao longo da vida, ela torna-se imprescindível, diminuindo ou evitando reações advindas desse processo. Em 2023, o Hemorio teve 105.001 candidatos à doação de sangue, resultando na coleta de 87.323 (86,16%) bolsas. No mesmo período, ocorreram 479 comparecimentos para doações personalizadas e 462 (96,45%) bolsas coletadas (Hemorio, 2023). Essas bolsas vão diretamente para pacientes internados no hospital e que precisam de transfusões que são realizadas no setor de hematologia e representam o fim do ciclo do sangue, efetivando a relação entre as áreas da hemoterapia e hematologia no instituto. As etapas do ciclo do sangue, anteriormente mencionado, são constituídas pela captação de doadores, cadastro, triagem clínica, hidratação, doação (coleta do sangue), lanche pós doação e transfusão. Discussão: O Hemorio é o Hemocentro Coordenador do Estado do Rio de Janeiro e desempenha papel central nos serviços de hemoterapia. É um hospital especializado no tratamento de doenças hematológicas, servindo a usuários do Sistema Único de Saúde (SUS), além de ser uma instituição de ensino e pesquisa. O setor de Hematologia atende aproximadamente 10.000 pacientes diagnosticados com doenças hematológicas, que frequentemente requerem transfusões de sangue e hemoderivados. Na área de Hemoterapia, o salão de doadores tem capacidade para atender 500 pessoas por dia, embora a média diária em 2023 tenha sido de 288 candidatos, resultando em média 240 bolsas de sangue por dia (Hemorio, 2023). Esses números evidenciam a correlação entre os setores de Hemoterapia e Hematologia, apesar de possuírem estruturas organizacionais, equipes e chefias distintas. Conclusão: Observa-se que as equipes de Hematologia e Hemoterapia, apesar de realizarem intervenções no ciclo do sangue, poderiam ter um melhor diálogo entre si. No Hemorio, o principal elo entre as áreas de hematologia e hemoterapia é o sangue, onde é possível a efetivação de todas as etapas do ciclo, desde a captação de doadores até a transfusão. Destacamos a relevância do Hemorio ser uma instituição onde é possível a realização de todas as etapas do sangue. O Programa de Residência Multiprofissional é um elemento importante que pode efetivar o diálogo entre as duas áreas, visto que os residentes perpassam por ambos os setores, tendo a possibilidade de interlocução entre as equipes, com uma visão crítica das atividades desempenhadas e a possibilidade de propor melhorias na qualidade dos serviços prestados. O diálogo entre as equipes pode possibilitar a integralidade do cuidado, princípio do SUS, superando a fragmentação que se expressa nos serviços e tende a separar as ações de promoção/proteção e recuperação da saúde.

Abstract Histone H2B monoubiquitination (at Lys120 in humans) regulates transcription elongation and DNA repair. In humans, H2B monoubiquitination is catalyzed by the heterodimeric Bre1 complex composed of Bre1A/RNF20 and Bre1B/RNF40. The Bre1 proteins generally function as tumor suppressors, while in certain cancers, they facilitate cancer cell proliferation. To obtain structural insights of H2BK120 ubiquitination and its regulation, we report the cryo-electron microscopy structure of the human Bre1 complex bound to the nucleosome. The two RING domains of Bre1A and Bre1B recognize the acidic patch and the nucleosomal DNA phosphates around SHL 6.0–6.5, which are ideally located to recruit the E2 enzyme and ubiquitin for H2BK120-specific ubiquitination. Mutational experiments suggest that the two RING domains bind in two orientations and that ubiquitination occurs when Bre1A binds to the acidic patch. Our results provide insights into the H2BK120-specific ubiquitination by the Bre1 proteins and suggest that H2B monoubiquitination can be regulated by nuclesomal DNA flexibility.

Abstract Optimal conditions for wound healing require a smooth transition from the early stage of inflammation to proliferation, and during this time alternatively activated (M2) macrophages play a central role. Recently, heat-killed lactic acid bacteria (LAB), such as Lactobacillus plantarum (L. plantarum) have been reported as possible modulators affecting the immune responses in wound healing. However, how signaling molecules regulate this process after the administration of heat-killed LAB remains unclear. In this study, we examined the effect of heat-killed L. plantarum KB131 (KB131) administration on wound healing and the contribution of CARD9, which is an essential signaling adaptor molecule for NF-kB activation upon triggering through C-type lectin receptors, in the effects of this bacterium. We analyzed wound closure, histological findings, and inflammatory responses. We found that administration of KB131 accelerated wound closure, re-epithelialization, granulation area, CD31-positive vessels, and α-SMA-positive myofibroblast accumulated area, as well as the local infiltration of leukocytes. In particular, M2 macrophages were increased, in parallel with CCL5 synthesis. The acceleration of wound healing responses by KB131 was canceled in CARD9-knockout mice. These results indicate that the topical administration of KB131 accelerates wound healing, accompanying increased M2 macrophages, which suggests that CARD9 may be involved in these responses.

Objetivos: - Divulgar e apresentar as atividades executadas pelo Setor de Promoção à Doação de Sangue (STPDS) por meio dos indicadores de produção do setor; - Incentivar a doação voluntária de sangue. Materiais e métodos: Trata-se de um relato de experiência que utiliza como metodologia o levantamento de dados computados no STPDS referentes a 2022. Neste trabalho foi feita uma abordagem quantitativa sobre os indicadores e, posteriormente, os dados foram apresentados através de planilha e embasaram a elaboração do folder informativo. A técnica utilizada para a coleta de dados foi a pesquisa documental que, vale-se de materiais que não receberam ainda um tratamento analítico, ou que ainda podem ser reelaborados de acordo com os objetivos da pesquisa. Trata-se da análise de legislações que regulamentam os serviços de hemoterapia no Brasil. A proposta é a produção de material impresso contendo as informações relativas ao trabalho desenvolvido no STPDS. Resultados: A equipe desenvolve projetos para diferentes públicos, dos quais apresentamos alguns dados da produção do setor em 2022: Palestras: 31 - Público alcançado: 3.612; Hemotur: 26 - Público atendido: 315; Disque Sangue - Ligações atendidas: 12.739; Grupos de Doadores: 82 - Comparecimentos: 1512; Agendamentos de doações por aférese: 289; Doadores Fenotipados: Agendados: 454 - Comparecimentos: 274; Comparecimentos de inaptos temporários resgatados: 42. Além dos citados, a equipe atua no acolhimento no salão de doadores; no Programa Jovem Salva Vidas e em exposições dialogadas em instituições públicas e privadas. Discussão: O Hemorio é o hemocentro coordenador do estado do Rio de Janeiro e abastece com bolsas de sangue as unidades de saúde públicas e privadas conveniadas ao SUS. Além disso, é uma instituição de ensino e pesquisa que presta assistência a pacientes com doenças hematológicas. Conforme o art. 19 da Resolução - RDC nº34 de 2014, todo serviço de hemoterapia que realiza coleta de sangue deve elaborar e implementar um programa de captação de doadores. Dessa forma, o STPDS é responsável pela captação, integrando a primeira etapa do ciclo do sangue. A equipe é composta por assistentes sociais, residentes de Serviço Social e técnicos administrativos capacitados para atuar nesse espaço, em uma perspectiva socioeducativa de promover a doação voluntária de sangue. Visando apresentar o trabalho realizado pelo setor, esclarecer as dúvidas e promover a importância da doação de sangue, as residentes elaboraram um folder, que aponta os indicadores de produção do setor referentes ao ano de 2022. Conclusão: Os resultados apresentam dados expressivos sobre as frentes de trabalho do STPDS e a relevância da promoção à doação de sangue. Diante dos resultados obtidos, analisamos que há lacunas no trabalho, devido ao baixo investimento financeiro e a quantidade reduzida de profissionais. Sendo assim, identificamos a necessidade de publicização dos dados para a população assistida, bem como para a comunidade científica. Espera-se com isso, que haja uma expansão e reconhecimento do trabalho realizado e, consequentemente, um aumento no número de doadores, considerando que a divulgação de informações e serviços sobre a doação de sangue é de extrema relevância para a construção e consolidação dessa prática.

Objetivo: Apresentar e analisar as Ações Estratégicas do Setor de Promoção a Doação de Sangue (SPDS) do Hemorio na direção da fidelização de doadores não recorrentes. Material e método: Textos e legislações sobre a temática e levantamento de dados quantitativos do setor. A metodologia consiste em pesquisa documental com análise quanti-quali a luz materialismo histórico-dialético. Resultados: O hospital de referência em hemoterapia e hematologia do Rio de Janeiro (Hemorio) conta com o Programa Jovem Salva Vidas (PJSV), que visa garantir uma comunicação com a comunidade escolar e a consolidar a cultura da doação de sangue no estado do Rio de Janeiro. No ano de 2022 foram realizadas 13 palestras nas escolas, abrangendo em média 50 pessoas. Contamos ainda com o Resgate de doadores Inaptos Provisórios1 (IP), uma importante estratégia de fidelização do Setor de Promoção à Doação de Sangue (SPDS) que nesse mesmo ano, contactou 180 doadores IP, dos quais 42 retornaram. Discussão: O SPDS faz parte da Hemoterapia, que é a primeira etapa do ciclo de sangue. No Brasil, este setor pode ser formado por profissionais que tenham nível superior na área da saúde e no Hemorio, é majoritariamente formado por assistentes sociais. É fundamental que a atuação desse profissional neste setor, democratize informações e conhecimentos que fomentem a promoção e prevenção no âmbito da saúde, por meio de uma prática que seja educativa crítica e que fortaleça a autonomia do doador (Brasil, 2015). Conclusão: Por ser parte do processo do cotidiano do trabalho profissional, a educação em saúde deve ser compartilhada por profissionais de outras áreas para que as ações sejam aprimoradas e fortaleçam o desejo do doador de praticar um ato solidário. Entendemos que a parceria do PJSV nas escolas, aproxima a importância da relação com outros profissionais de saúde, como professores, estudantes e seus familiares, esclarecendo dúvidas no que cerca à proteção da saúde. Vale destacar que esse Programa nas escolas, por meio da prática educativa, fortalece o conhecimento sobre o hospital o que leva também o acesso a informações sobre e desperta curiosidade sobre as doenças hematológicas. A estratégia de Resgate de doadores IP trabalha na perspectiva de tornar doadores esporádicos em doadores recorrentes. No entanto, notamos que apesar do Hemorio estar localizado no centro do Estado, muitos doadores têm dificuldades de acesso. Assim, pontuamos a necessidade e possibilidade de maior descentralização do Banco de Sangue, visto que, é um desafio para a população chegar até o Hemorio. Seja por questões econômicas, de deslocamento ou de acesso a transporte público, dentre outros fatores. Em síntese, pensando nisso, e na perspectiva do retorno dos doadores, observamos a relevância de aprimorar estratégias efetivas para efetivação e retorno e a fidelização dos mesmos. 1 Doadores Inaptos Provisórios podem ser definidos como “doador inapto temporário: doador que se encontra impedido de doar sangue para outra pessoa por determinado período de tempo, podendo realizar doação autóloga quando possível e necessário” (Brasil, 2016).

Objetivo: Apresentar e analisar as Ações Estratégicas do Setor de Promoção a Doação de Sangue (SPDS) do Hemorio na direção da fidelização de doadores não recorrentes. Material e método: Textos e legislações sobre a temática e levantamento de dados quantitativos do setor. A metodologia consiste em pesquisa documental com análise quanti-quali a luz materialismo histórico-dialético. Resultados: O hospital de referência em hemoterapia e hematologia do Rio de Janeiro (Hemorio) conta com o Programa Jovem Salva Vidas (PJSV), que visa garantir uma comunicação com a comunidade escolar e a consolidar a cultura da doação de sangue no estado do Rio de Janeiro. No ano de 2022 foram realizadas 13 palestras nas escolas, abrangendo em média 50 pessoas. Contamos ainda com o Resgate de doadores Inaptos Provisórios (IP), uma importante estratégia de fidelização do Setor de Promoção à Doação de Sangue (SPDS) que nesse mesmo ano, contactou 180 doadores IP, dos quais 42 retornaram. Discussão: O SPDS faz parte da Hemoterapia, que é a primeira etapa do ciclo de sangue. No Brasil, este setor pode ser formado por profissionais que tenham nível superior na área da saúde e no Hemorio, é majoritariamente formado por assistentes sociais. É fundamental que a atuação desse profissional neste setor, democratize informações e conhecimentos que fomentem a promoção e prevenção no âmbito da saúde, por meio de uma prática que seja educativa crítica e que fortaleça a autonomia do doador. Conclusão: Por ser parte do processo do cotidiano do trabalho profissional, a educação em saúde deve ser compartilhada por profissionais de outras áreas para que as ações sejam aprimoradas e fortaleçam o desejo do doador de praticar um ato solidário. Entendemos quea parceria do PJSV com as escolas, reforça a relação com outros profissionais de saúde, como professores, estudantes e seus familiares, esclarecendo dúvidas no que concerne à proteção da saúde. Vale destacar que esse Programa nas escolas é viabilizado pela prática educativa e fortalece o conhecimento sobre o hospital. Além disso, oportuniza o acesso a informações sobre a temática, despertando a curiosidade sobre as doenças hematológicas. A estratégia de resgate de doadores IP trabalha na perspectiva de tornar doadores esporádicos em doadores recorrentes. No entanto, notamos que apesar do Hemorio ser localizado no centro do Estado, muitos doadores têm dificuldades de acesso. Assim, pontuamos a necessidade e possibilidade de maior descentralização do Banco de Sangue, visto que, é um desafio para a população chegar até o Hemorio. Seja por questões econômicas, de deslocamento ou de acesso a transporte público, dentre outros fatores. Em síntese, pensando nisso, e na perspectiva do retorno dos doadores, observamos a relevância de aprimorar estratégias efetivas para efetivação e retorno e a fidelização dos mesmos.

Objetivo: Apresentar as ações desenvolvidas pelo Setor de Promoção a Doação de Sangue (SPDS) realizadas no período da campanha Junho Vermelho no Hemorio de 2023. Material e método: Trata-se de um estudo descritivo quantitativo com pesquisa documental tendo como base textos e legislações sobre a temática e levantamento de dados quantitativos do setor. Resultados: O hospital de referência em hemoterapia e hematologia do Rio de Janeiro (Hemorio) promoveu ações do Junho Vermelho em vários locais do Rio de Janeiro. Entre as ações realizadas, a campanha Rota Solidária foi lançada em parceria inédita com empresas do setor de mobilidade, gerando um aumento de 52% em relação às bolsas coletadas na campanha de 2022. Ao total, foram 3.117 bolsas de sangue. A coleta externa também é uma importante ação nesse período. Como exemplo, a que foi realizada em parceria com o Hospital Estadual Alberto Torres, em São Gonçalo. No período de 14 de junho de 2023 a 21 de junho de 2023 foram coletadas 1.261 bolsas de sangue. Também foram realizadas atividades pelos residentes multiprofissionais no instituto, através dinâmicas interativas no salão de doadores do hemocentro, visando esclarecer dúvidas a respeito dos critérios para doação de sangue. Esclarecer os critérios para ser um doador. Discussão:: A intenção das campanhas de doação de sangue, que se estenderam no mês de junho, é estimular a doação para abastecer os estoques de sangue no estado. A campanha batizada de Rota Solidária fez parte das ações desenvolvidas, sendo divulgada no Dia Mundial do Doador de Sangue (14 de junho) e durou até o dia 21 de junho. Essa iniciativa contou com o apoio das concessionárias Metrô Rio, VLT Carioca, SuperVia, Semove e empresa de tecnologia 99Táxi, que disponibilizaram 6.350 gratuidades nos transportes. Funcionou da seguinte forma: o doador que se dirigisse ao Hemorio para se candidatar a doação, informando o modal utilizado, recebia duas passagens de acordo com a disponibilidade, para cobrir os gastos de deslocamento de ida e volta ao hemocentro. Já para os que utilizaram o aplicativo da empresa de tecnologia 99Táxi, tiveram cupom de desconto, garantindo o pagamento de 50% do valor de até duas corridas, sendo disponibilizados 5.000 vouchers. A Rodoviária do Rio e o aeroporto RIOgaleão, utilizaram seus espaços para chamar a atenção dos visitantes que chegavam na cidade. Conclusão: Considerando que junho é o período de maior escassez nos estoques de sangue por registrar uma diminuição do número de doadores no Brasil, torna-se indispensável visar o envolvimento do público para não só aumentar o número de doações deste mês, mas incentivar a cultura de doações de sangue em todo o país. Frente a isso, as ações viabilizadas pelo Hemorio durante o Junho Vermelho, garantiram suporte às emergências, maternidades e às unidades de saúde do Estado do Rio. As ações delinearam a divulgação de informações referente a importância da transfusão, conscientizando grupos coletivos, familiares dos pacientes, comunidade acadêmica entre outros, a realizar o ato de solidariedade que pode salvar vidas.

Objetivo: Refletir sobre as questões que atravessam a fidelização dos doadores fenotipados a partir do uso das tecnologias da informação e comunicação (TICs). Materiais e métodos: Levantamento de dados quantitativos do setor, pesquisa e análise bibliográfica acerca do tema, em uma abordagem quanti-quali analisada através do método marxista. Resultados: Em relação ao uso da tecnologia, há dificuldades relativas a contatos repetidos com alguns doadores, pois os candidatos à doação encontram-se em diferentes listagens disponibilizadas ao setor. Ressalta-se também que as mudanças constantes dos contatos dos doadores e a não atualização cadastral, ocasionam prejuízos para organização do trabalho. O uso do aplicativo WhatsApp no Hemorio, para contato com os doadores, é recente. A comunicação sempre ocorreu através de ligações telefônicas e envio de e-mails. Ainda que este recurso tenha facilitado a interlocução com os doadores, apontamos que a utilização de mensagens temporárias por parte destes, impacta no registro das informações, visto que com a confirmação do comparecimento, a equipe organiza o acompanhamento do doador, garantindo sua prioridade no processo. A partir de março de 2023, implementa-se definitivamente o uso do aplicativo, alcançando um total de 429 contatos. Discussão: Há pessoas que fazem tratamento para determinadas patologias que necessitam de transfusão de sangue frequentes, tornando cada vez mais difícil encontrar um doador compatível. A fenotipagem refere-se a uma testagem mais ampla dos vários grupos sanguíneos (A, B, AB e O), considerando as proteínas presentes em cada hemácia. O laboratório de imunogenética é o responsável por mapear os doadores compatíveis, cabendo ao setor de captação convocá-los. Frente à nova realidade imposta pela pandemia, a utilização de meios tecnológicos para o exercício profissional do Serviço Social configurou uma intensificação do processo de trabalho por meio de atividades remotas, considerando que não se deve perder de vista as intencionalidades das ações, mas agregar novas possibilidades ao trabalho e utilizá-la como meio para alcançar as finalidades das demandas no cotidiano profissional. Nesse contexto, os assistentes sociais podem utilizar as TICs para potencializar sua atuação junto às expressões da questão social apropriando-se desse recurso para aperfeiçoar as competências e habilidades no âmbito de sua atuação. Conclusão: O uso das TICs ampliou as possibilidades de contato e convocação com os doadores personalizados para pacientes específicos. Além disso, auxilia na criação de vínculo e na fidelização do doador, aumentando as possibilidades de tratamento para o paciente.

The biological impacts of the nuclear accidents in Chernobyl (1986) and Fukushima (2011) on wildlife have been studied in many organisms over decades, mainly from dosimetric perspectives based on laboratory experiments using indicator species. However, ecological perspectives are required to understand indirect field-specific effects among species, which are difficult to evaluate under dosimetric laboratory conditions. From the viewpoint that microbes play a fundamental role in ecosystem function as decomposers and symbionts for plants, we reviewed studies on microbes inhabiting soil and plants in Chernobyl and Fukushima in an attempt to find supporting evidence for indirect field-specific effects on plants and insect herbivores. Compositional changes in soil microbes associated with decreases in abundance and species diversity were reported, especially in heavily contaminated areas of both Chernobyl and Fukushima, which may accompany explosions of radioresistant species. In Chernobyl, the population size of soil microbes remained low for at least 20 years after the accident, and the abundance of plant-associated microbes, which are related to the growth and defense systems of plants, possibly decreased. These reported changes in microbes likely affect soil conditions and alter plant physiology. These microbe-mediated effects may then indirectly affect insect herbivores through food-mass-mediated, pollen-mediated, and metabolite-mediated interactions. Metabolite-mediated interactions may be a major pathway for ecological impacts at low pollution levels and could explain the decreases in insect herbivores in Fukushima. The present review highlights the importance of the indirect field effects of long-term low-dose radiation exposure under complex field circumstances.

Detector studies for future experiments rely on advanced software tools to estimate performance and optimize their design and technology choices. The Key4hep project provides a flexible turnkey solution for the full experiment life-cycle based on established community tools such as ROOT, Geant4, DD4hep, Gaudi, podio and spack. Members of the CEPC, CLIC, EIC, FCC, and ILC communities have joined to develop this framework and have merged, or are in the progress of merging, their respective software environments into the Key4hep stack. These proceedings will give an overview over the recent progress in the Key4hep project: covering the developments towards adaptation of state-of-theart tools for simulation (DD4hep, Gaussino), track and calorimeter reconstruction (ACTS, CLUE), particle flow (PandoraPFA), analysis via RDataFrame, and visualization with Phoenix, as well as tools for testing and validation.

Abstract The identification of acquired resistance mutations has been essential in non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) active mutations. Rebiopsy plays a pivotal role in selecting the optimal treatment for patients who develop resistance to initial EGFR-tyrosine kinase inhibitors (EGFR-TKIs). This multicenter, observational study was conducted to investigate the details of rebiopsy in Japanese clinical practice. The primary endpoints were the implementation rate of rebiopsy and the concordance rate for T790M mutation detection between histological and cytological specimens using the cobas EGFR Mutation Test, version 2. One hundred ninety-four patients with EGFR-mutant NSCLC were enrolled, and 120 patients developed acquired resistance to EGFR-TKIs. The median age was 68 years (range 20–87), and 52.5% of the patients were women. Rebiopsy was performed in 109 patients, and the implementation rate of rebiopsy was 90.8%. The success rates of rebiopsy in the total, histology, cytology and liquid biopsy populations were 67.9%, 81.3%, 66.7% and 43.8%, respectively. The positive percent agreement and the negative percent agreement in the detection of the T790M mutation between the histological and cytological specimens were both 90.9%. Obtaining histological or cytological tissue samples at rebiopsy may contribute to improving the detection rate of the T790M mutation (trial registration number: UMIN000026019).

Summary: Background: The benefits of artificial nutrition and hydration in patients with head and neck cancer and esophageal cancer in the late stage remain unknown. We performed a secondary analysis of a cohort study to investigate the effects of enteral tube feeding (ETF) and parenteral nutrition and hydration (PNH) on survival in this population. Methods: Patients with head and neck cancer and esophageal cancer admitted to palliative care units were included. Information on primary nutritional administration routes during the first week of admission and data on the averaged calorie sufficiency rate/total calorie intake, e.g., 75%≤/750 kcal/day≤ and

Summary: Background & Aims: The prevalence of artificially administered nutrition and hydration (AANH) in different age groups among patients with advanced cancer remains unknown. The present study investigated the current utilization of AANH according to age groups in palliative care units. Methods: This was a secondary analysis of a prospective cohort study. We obtained information on primary nutritional administration routes during the first week of admission and data on the averaged calorie sufficiency rate or total calorie intake on the 7th day of admission. Patients were divided into five age groups (18–39, 40–59, 60–74, 75–89, and 90- years). Among patients receiving AANH, the proportions of higher-calorie AANH were compared between the five age groups. Results: A total of 1453 patients were included. The proportion of patients categorized as receiving nutrition and hydration via the parenteral route was the highest in the 18–39 and 40–59 groups (52.4 and 41.1%, respectively). Among patients receiving AANH (n = 534), the proportions of patients categorized into the

An upregulation of NSD2, a histone H3 lysine 36 (H3K36) methyltransferase is linked to multiple myeloma and other types of cancer. Here, the authors provide insights into the regulatory mechanism of NSD2 by determining the 2.8 Å cryo-EM structure of the NSD2 bound nucleosome complex, and based on MD simulations they discuss how two oncogenic mutations enhance NSD2 activity.

Segmentation of a natural scene into objects (figures) and background (ground) is one of crucial functions for object recognition and scene understanding. Recent studies have investigated neural mechanisms underlying figure-ground (FG) segregation and reported neural modulation to FG in the intermediate-level visual area, V4, of macaque monkeys (FG neurons). However, whether FG neurons contribute to the perception of FG segregation has not been clarified. To examine the contribution of FG neurons, we examined the correlations between perceptual consistency (PC), which quantified perceptual ambiguity in FG determination, and the reliability of neural signals in response to FG. First, we evaluated PCs for the images that were used in the previous neural recording in V4; specifically, we measured how consistently FG can be determined across trials and participants for each stimulus. The PCs were widely distributed, so that we identified the ambiguity in FG segregation for each stimulus. Next, we analyzed the correlation between the PCs and the reliability of neural modulation to FG. We found that the stimuli with higher PCs evoked more consistent and greater modulation in the responses of single neurons than those with lower PCs. Since perception is expected to show a greater correlation with responses of neural population compared to those of single neurons, we examined the correlation between the PCs and the consistency of the population responses in FG determination. Stimuli with higher PCs evoked higher population consistency than those with lower PCs. Finally, we analyzed the correlation between the PCs and neural latencies in FG modulation. We found that the stimuli with higher PCs showed shorter reaction times in FG perception and evoked shorter modulation latencies in FG neurons. These results indicate that the responses of FG neurons recorded from macaque monkeys show significant correlations with human FG perception, suggesting that V4 neurons with FG-dependent responses contribute to the perception of FG segregation.

Abstract Cryptococcus deneoformans is an opportunistic fungal pathogen that infects the lungs via airborne transmission and frequently causes fatal meningoencephalitis. Claudins (Cldns), a family of proteins with 27 members found in mammals, form the tight junctions within epithelial cell sheets. Cldn-4 and 18 are highly expressed in airway tissues, yet the roles of these claudins in respiratory infections have not been clarified. In the present study, we analyzed the roles of Cldn-4 and lung-specific Cldn-18 (luCldn-18) in host defense against C. deneoformans infection. luCldn-18-deficient mice exhibited increased susceptibility to pulmonary infection, while Cldn-4-deficient mice had normal fungal clearance. In luCldn-18-deficient mice, production of cytokines including IFN-γ was significantly decreased compared to wild-type mice, although infiltration of inflammatory cells including CD4+ T cells into the alveolar space was significantly increased. In addition, luCldn-18 deficiency led to high K+ ion concentrations in bronchoalveolar lavage fluids and also to alveolus acidification. The fungal replication was significantly enhanced both in acidic culture conditions and in the alveolar spaces of luCldn-18-deficient mice, compared with physiological pH conditions and those of wild-type mice, respectively. These results suggest that luCldn-18 may affect the clinical course of cryptococcal infection indirectly through dysregulation of the alveolar space microenvironment.

In chronic myeloid leukaemia (CML), the drivers of blast crisis and resistance to tyrosine kinase inhibitors are not fully characterised. Here, the authors analyse a cohort of CML samples with genomic technologies and find that at least one driver alteration is associated with progression and worse prognosis.

The Fukushima nuclear accident in March 2011 caused biological impacts on the pale grass blue butterfly Zizeeria maha. At least some of the impacts are likely mediated by the host plant, resulting in “field effects”. However, to obtain the whole picture of the impacts, direct exposure effects should also be evaluated. Here, we examined the distribution of experimentally ingested anthropogenic cesium-137 (137Cs) in adult butterfly bodies using imaging plate autoradiography. We showed that 137Cs ingested by larvae was incorporated into adult bodies and was biased to females, although the majority of ingested 137Cs was excreted in the pupal cuticle and excretory material during eclosion. 137Cs accumulation in adult bodies was the highest in the abdomen, followed by the thorax and other organs. These results suggest that 137Cs accumulation in reproductive organs may cause adverse transgenerational or maternal effects mediated by reactive oxygen species (ROS) on germ cells. 137Cs accumulation was detected in field individuals collected in September 2011 and September 2016 but not in May 2011, which is consistent with the abnormality dynamics known from previous studies. Taken together, these results contribute to an integrative understanding of the multifaceted biological effects of the Fukushima nuclear accident in the field.

Abstract Integration of multiple properties of an object is a fundamental function of the visual cortex in object recognition. For instance, surface patterns and contour shapes are thought to be crucial characteristics that jointly contribute to recognition. However, the mechanisms of integration and corresponding cortical representations have not been fully clarified. We investigated the integration of surfaces and shapes by examining the tilt after effects (TAEs) evoked by the symmetry of patterns and contours. As symmetry in both pattern and contour evokes TAEs, we can directly measure the interaction between the two. The measured TAEs exhibited mutual transfer between the symmetry of the pattern (SP) and that of the contour shape (SS), i.e., adaptation by SP (SS) evoked TAEs when tested by SS (SP), suggesting the existence of an integrated representation. Next, we examined the interaction between SP and SS when both were simultaneously presented in adaptation. Congruent adaptors wherein their symmetry axes aligned evoked compressive interaction, whereas incongruent adaptors wherein the axes of SP and SS tilted to the opposite directions evoked subtractive interaction. These results suggest the existence of a cortical representation that integrates the properties of the surface and shape with suppressive interactions, which can provide crucial insights into the formation of object representation as well as the integration of visual information in the cortex.

Abstract A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as “overexpression” and “shorter survival” is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).

Abstract Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A‐priori identification of platinum resistance is therefore crucial to improve on standard first‐line carboplatin–paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum‐induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK‐compliant study of pre‐treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51‐High tumours had shorter progression‐free and overall survival compared to RAD51‐Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR‐proficient cancers (Myriad HRDscore

How lipid metabolism can affect cancer recurrence is still unclear. Here, the authors show that the lysophospholipase D Gdpd3 maintains self-renewal capacity of CML stem cells by regulating the quiescence, and AKT/mTORC1 and Foxo3a/β-catenin signalling in an oncogene-independent manner.

Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational [sevoflurane (Sevo)] and intravenous [propofol (Prop)] anesthetics. Bioinformatics analysis revealed that nuclear factor‐kappa B (NF‐kB) signaling was inhibited by Sevo and promoted by Prop. Moreover, nuclear accumulation of p65 and transcription of NF‐kB‐regulated genes were suppressed in Sevo‐administered mice, suggesting that Sevo inhibits the NF‐kB signaling pathway. Our data demonstrate that NF‐kB signaling is inhibited by Sevo and promoted by Prop. As NF‐kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF‐kB.

A 65-year-old man with nonsevere aplastic anemia received rabbit anti-thymocyte globulin and cyclosporine and partially responded. Six months after the initiation of treatment, he was diagnosed with stage IV angioimmunoblastic T-cell lymphoma and received chemotherapy. PET/CT scan analysis indicated a complete response. However, he showed sustained myelosuppression and was diagnosed with relapse of aplastic anemia. He did not respond to cyclosporine, eltrombopag or methenolone. Fifteen months after eltrombopag administration, he developed MDS with t(3;21)(q26.2;q22). Patients should be monitored carefully for the emergence of not only -7/del(7q) but also 3q26 abnormalities, including t(3;21)(q26.2;q22), during and after eltrombopag treatment.

Neurons in visual area V4 modulate their responses depending on the figure-ground (FG) organization in natural images containing a variety of shapes and textures. To clarify whether the responses depend on the extents of the figure and ground regions in and around the classical receptive fields (CRFs) of the neurons, we estimated the spatial extent of local figure and ground regions that evoked FG-dependent responses (RF-FGs) in natural images and their variants. Specifically, we applied the framework of spike triggered averaging (STA) to the combinations of neural responses and human-marked segmentation images (FG labels) that represent the extents of the figure and ground regions in the corresponding natural image stimuli. FG labels were weighted by the spike counts in response to the corresponding stimuli and averaged over. The bias due to the nonuniformity of FG labels was compensated by subtracting the ensemble average of FG labels from the weighted average. Approximately 50% of the neurons showed effective RF-FGs, and a large number exhibited structures that were similar to those observed in virtual neurons with ideal FG-dependent responses. The structures of the RF-FGs exhibited a subregion responsive to a preferred side (figure or ground) around the CRF center and a subregion responsive to a non-preferred side in the surroundings. The extents of the subregions responsive to figure were smaller than those responsive to ground in agreement with the Gestalt rule. We also estimated RF-FG by an adaptive filtering (AF) method, which does not require spherical symmetry (whiteness) in stimuli. RF-FGs estimated by AF and STA exhibited similar structures, supporting the veridicality of the proposed STA. To estimate the contribution of nonlinear processing in addition to linear processing, we estimated nonlinear RF-FGs based on the framework of spike triggered covariance (STC). The analyses of the models based on STA and STC did not show inconsiderable contribution of nonlinearity, suggesting spatial variance of FG regions. The results lead to an understanding of the neural responses that underlie the segregation of figures and the construction of surfaces in intermediate-level visual areas.

Background: Limited information is available on the relationship between C-reactive protein (CRP) levels and pain in advanced cancer. Objectives: To investigate the relationship between serum levels of CRP and subtypes of pain. Design: A secondary cross-sectional analysis of a prospective cohort study. Setting/Subjects: Patients with advanced cancer admitted to 23 palliative care units in Japan. Measurements: Patients rated the severity of pain on the numerical rating scale (NRS) and physicians evaluated pain on the integrated palliative care outcome scale (IPOS). Physicians assessed neuropathic pain and breakthrough pain based on their presence or absence. Patients were divided into four groups according to CRP levels. Comparisons were performed using the Kruskal?Wallis test or chi-squared test. To evaluate the relationship between CRP and subtypes of pain, adjusted odds ratios (ORs) and 95% confidence intervals (CIs) in logistic models were calculated. Results: We divided 1513 patients into four groups: low CRP (n?=?234), moderate CRP (n?=?513), high CRP (n?=?352), and very high CRP (n?=?414). Spearman's correlation coefficient between CRP and pain NRS and that between CRP and pain IPOS were 0.15 (p?0.001) and 0.16 (p?

The World Health Organization initiated a global surveillance system for respiratory syncytial virus (RSV) in 2015, and the pilot surveillance is ongoing. The real-time RT-PCR RSV assays (Pan-RSV and duplex assays) developed by the United States Centers for Disease Control and Prevention are applied as the standard assays. To introduce these as standard assays in Japan, their practicality was evaluated using 2261 specimens obtained from pediatric inpatients in Japan, which were collected from 2018 to 2021. Although the Pan-RSV and duplex assays had similar analytical sensitivities, they yielded 630 (27.9%) and 786 (34.8%) RSV-positive specimens, respectively (p < 0.001). Although sequencing analysis showed mismatches in the reverse primer used in the Pan-RSV assay, these mismatches did not affect its analytical sensitivity. The analysis of read numbers of RSV isolates from air–liquid interface culture of human bronchial/tracheal epithelial cells showed that the duplex assay had a greater number of reads than did the Pan-RSV assay. Therefore, the duplex assay has superior detection performance compared with the Pan-RSV assay, but the two assays have similar analytical sensitivities.

Biological effects of the Fukushima nuclear accident have been reported in various organisms, including the pale grass blue butterfly Zizeeria maha and its host plant Oxalis corniculata. This plant upregulates various secondary metabolites in response to low-dose radiation exposure, which may contribute to the high mortality and abnormality rates of the butterfly in Fukushima. However, this field effect hypothesis has not been experimentally tested. Here, using an artificial diet for larvae, we examined the ingestional toxicity of three radiation-dependent plant metabolites annotated in a previous metabolomic study: lauric acid (a saturated fatty acid), alfuzosin (an adrenergic receptor antagonist), and ikarugamycin (an antibiotic likely from endophytic bacteria). Ingestion of lauric acid or alfuzosin caused a significant decrease in the pupation, eclosion (survival), and normality rates, indicating toxicity of these compounds. Lauric acid made the egg-larval days significantly longer, indicating larval growth retardation. In contrast, ikarugamycin caused a significant increase in the pupation and eclosion rates, probably due to the protection of the diet from fungi and bacteria. These results suggest that at least some of the radiation-dependent plant metabolites, such as lauric acid, contribute to the deleterious effects of radioactive pollution on the butterfly in Fukushima, providing experimental evidence for the field effect hypothesis.

Virus isolates are not only useful for diagnosing infections, e.g., respiratory syncytial virus (RSV), but can also facilitate many aspects of practical viral studies such as analyses of antigenicity and the action mechanisms of antivirals, among others. We have been isolating RSV from clinical specimens from patients with respiratory symptoms every year since our first isolation of RSV in 1964, and isolation rates have varied considerably over the years. As collected clinical specimens are conventionally stored in a refrigerator from collection to inoculation into cells, we hypothesized that certain storage conditions or associated factors might account for these differences. Hence, we evaluated the thermal stability of a total of 64 viruses isolated from 1998 to 2018 upon storage at 4 °C and 20 °C for a defined duration. Interestingly, and contrary to our current understanding, 22 strains (34%) showed a greater loss of viability upon short-term storage at 4 °C than at 20 °C. Thirty-seven strains (57%) showed an almost equal loss, and only five strains (8%) were more stable at 4 °C than at 20 °C. This finding warrants reconsideration of the temperature for the temporary storage of clinical samples for RSV isolation.

The biological impacts of the Fukushima nuclear accident, in 2011, on wildlife have been studied in many organisms, including the pale grass blue butterfly and its host plant, the creeping wood sorrel Oxalis corniculata. Here, we performed an LC–MS-based metabolomic analysis on leaves of this plant collected in 2018 from radioactively contaminated and control localities in Fukushima, Miyagi, and Niigata prefectures, Japan. Using 7967 peaks detected by LC–MS analysis, clustering analyses showed that nine Fukushima samples and one Miyagi sample were clustered together, irrespective of radiation dose, while two Fukushima (Iitate) and two Niigata samples were not in this cluster. However, 93 peaks were significantly different (FDR < 0.05) among the three dose-dependent groups based on background, low, and high radiation dose rates. Among them, seven upregulated and 15 downregulated peaks had single annotations, and their peak intensity values were positively and negatively correlated with ground radiation dose rates, respectively. Upregulated peaks were annotated as kudinoside D (saponin), andrachcinidine (alkaloid), pyridoxal phosphate (stress-related activated vitamin B6), and four microbe-related bioactive compounds, including antibiotics. Additionally, two peaks were singularly annotated and significantly upregulated (K1R1H1; peptide) or downregulated (DHAP(10:0); decanoyl dihydroxyacetone phosphate) most at the low dose rates. Therefore, this plant likely responded to radioactive pollution in Fukushima by upregulating and downregulating key metabolites. Furthermore, plant-associated endophytic microbes may also have responded to pollution, suggesting their contributions to the stress response of the plant.

Lactic acid bacteria (LAB) are known to have beneficial effects on immune responses when they are orally administered as bacterial products. Although the beneficial effects of LAB have been reported for the genera Lactobacillus and Lactococcus, little has been uncovered on the effects of the genus Enterococcus on skin wound-healing. In this study, we aimed to clarify the effect of heat-killed Enterococcus faecalis KH2 (heat-killed KH2) strain on the wound-healing process and to evaluate the therapeutic potential in chronic skin wounds. We analyzed percent wound closure, re-epithelialization, and granulation area, and cytokine and growth factor production. We found that heat-killed KH2 contributed to the acceleration of re-epithelialization and the formation of granulation tissue by inducing tumor necrosis factor-α, interleukin-6, basic fibroblast growth factor, transforming growth factor (TGF)-β1, and vascular endothelial growth factor production. In addition, heat-killed KH2 also improved wound closure, which was accompanied by the increased production of TGF-β1 in diabetic mice. Topical administration of heat-killed KH2 might have therapeutic potential for the treatment of chronic skin wounds in diabetes mellitus. In the present study, we concluded that heat-killed KH2 promoted skin wound-healing through the formation of granulation tissues and the production of inflammatory cytokines and growth factors.

The biological consequences of the Fukushima nuclear accident have been intensively studied using the pale grass blue butterfly Zizeeria maha and its host plant, the creeping wood sorrel Oxalis corniculata. Here, we performed metabolomic analyses of Oxalis leaves from Okinawa to examine the plant metabolites that were upregulated or downregulated in response to low-dose radiation exposure from Fukushima’s contaminated soil. The cumulative dose of radiation to the plants was 5.7 mGy (34 μGy/h for 7 days). The GC-MS analysis revealed a systematic tendency of downregulation among the metabolites, some of which were annotated as caproic acid, nonanoic acid, azelaic acid, and oleic acid. Others were annotated as fructose, glucose, and citric acid, involved in the carbohydrate metabolic pathways. Notably, the peak annotated as lauric acid was upregulated. In contrast, the LC-MS analysis detected many upregulated metabolites, some of which were annotated as either antioxidants or stress-related chemicals involved in defense pathways. Among them, only three metabolite peaks had a single annotation, one of which was alfuzosin, an antagonist of the α1-adrenergic receptor. We conclude that this Oxalis plant responded metabolically to low-dose radiation exposure from Fukushima’s contaminated soil, which may mediate the ecological “field effects” of the developmental deterioration of butterflies in Fukushima.

This article contains the data showing illustrative examples of plaque classification on coronary computed tomography angiography (CCTA) and measurement of 18F-sodium fluoride (18F-NaF) uptake in coronary atherosclerotic lesions on positron emission tomography (PET). We divided the lesions into one of three plaque types on CCTA (calcified plaque, non-calcified plaque, partially calcified plaque). Focal 18F-NaF uptake of each lesion was quantified using maximum tissue-to-background ratio. This article also provides a representative case with a non-calcified coronary plaque detected on CCTA and identified on 18F-NaF PET/non-contrast computed tomography based on a location of a vessel branch as a landmark. These complement the data reported by Kitagawa et al. (2017) [1].

Segmentation of a natural scene into objects and background is a fundamental but challenging task for recognizing objects. Investigating intermediate-level visual cortical areas with a focus on local information is a crucial step towards understanding the formation of the cortical representations of figure and ground. We examined the activity of a population of macaque V4 neurons during the presentation of natural image patches and their respective variations. The natural image patches were optimized to exclude the influence of global context but included various characteristics of local stimulus. Around one fourth of the patch-responsive V4 neurons exhibited significant modulation of firing activity that was dependent on the positional relation between the figural region of the stimulus and the classical receptive field of the neuron. However, the individual neurons showed low consistency in figure-ground modulation across a variety of image patches (55-62%), indicating that individual neurons were capable of correctly signaling figure and ground only for a limited number of stimuli. We examined whether integration of the activity of multiple neurons enabled higher consistency across a variety of natural patches by training a support vector machine to classify figure and ground of the stimuli from the population firing activity. The integration of the activity of a few tens of neurons yielded discrimination accuracy much greater than that of single neurons (up to 85%), suggesting a crucial role of population coding for figure-ground discrimination in natural images.

Antibodies against influenza virus neuraminidase (NA) protein prevent releasing of the virus from host cells and spreading of infection foci and are considered the 'second line of defence' against influenza. Haemagglutinin inhibition antibody-low responders (HI-LRs) are present among influenza split vaccine recipients. The NA inhibition (NAI) antibody response in vaccinees is worth exploring, especially those in the HI-LRs population. We collected pre- and post-vaccination sera from 61 recipients of an inactivated, monovalent, split vaccine against A/H1N1pdm09 and acute and convalescent sera from 49 unvaccinated patients naturally infected with the A/H1N1pdm09 virus during the 2009 influenza pandemic. All samples were subjected to haemagglutinin inhibition (HI), NAI and neutralisation assays. Most paired sera from naturally infected patients exhibited marked elevation in the NAI activity, and seroconversion rates (SCR) among HI-LRs and HI-responders (HI-Rs) were 60% and 87%, respectively; however, those from vaccinees displayed low increase in the NAI activity, and the SCR among HI-LRs and HI-Rs were 0% and 12%, respectively. In both HI-LRs and HI-Rs, vaccination with the inactivated, monovalent, split vaccine failed to elicit the NAI activity efficiently in the sera of the naive population, compared with the natural infection. Hence, the improvement of influenza vaccines is warranted to elicit not only HI but also NAI antibodies.

The pale grass blue butterfly Zizeeria maha is sensitive to low-dose radioactive pollution from the Fukushima nuclear accident in the field but is also highly tolerant to radioactive cesium (137Cs) in an artificial diet in laboratory experiments. To resolve this field-laboratory paradox, we hypothesize that the butterfly shows vulnerability in the field through biochemical changes in the larval host plant, the creeping wood sorrel Oxalis corniculata, in response to radiation stress. To test this field-effect hypothesis, we examined nutrient contents in the host plant leaves from Tohoku (mostly polluted areas including Fukushima), Niigata, and Kyushu, Japan. Leaves from Tohoku showed significantly lower sodium and lipid contents than those from Niigata. In the Tohoku samples, the sodium content (but not the lipid content) was significantly negatively correlated with the radioactivity concentration of cesium (137Cs) in leaves and with the ground radiation dose. The sodium content was also correlated with other nutrient factors. These results suggest that the sodium imbalance of the plant may be caused by radiation stress and that this nutrient imbalance may be one of the reasons that this monophagous butterfly showed high mortality and morphological abnormalities in the field shortly after the accident in Fukushima.

Detector optimisation and physics performance studies are an integral part of the development of future collider experiments. The Key4hep project aims to design a common set of software tools for future, or even present, High Energy Physics projects. The proceeding describes the main components that are developed as part of Key4hep: the event data model EDM4hep, simulation interfaces to Delphes and Geant4, the k4MarlinWrapper to integrate iLCSoft components, as well as build and validation tools to ensure functionality and compatibility among the components. They also include the different adaptation processes by the CEPC, CLIC, FCC, and ILC communities towards this project, which show that Key4hep is a viable long term solution as baseline software for high energy experiments.

Human metapneumovirus (HMPV) is a major etiological agent of acute respiratory infections in humans. HMPV has been circulating worldwide for more than six decades and is currently divided into five agreed-upon subtypes: A1, A2a, A2b, B1, and B2. Recently, the novel HMPV subtypes A2c, A2b1, and A2b2 have been proposed. However, the phylogenetic and evolutionary relationships between these recently proposed HMPV subtypes are unclear. Here, we report a genome-wide phylogenetic and evolutionary analysis of 161 HMPV strains, including unique HMPV subtype A2b strains with a 180- or 111-nucleotide duplication in the G gene (nt-dup). Our data demonstrate that the HMPV A2b subtype contains two distinct subtypes, A2b1 and A2b2, and that the HMPV subtypes A2c and A2b2 may be different names for the same subtype. HMPV A2b strains with a nt-dup also belong to subtype A2b2. Molecular evolutionary analyses indicate that subtypes A2b1 and A2b2 diverged from subtype A2b around a decade after the subtype A2 was divided into the subtypes A2a and A2b. These data support the A2b1 and A2b2 subtypes proposed in 2012 and are essential for the unified classification of HMPV subtype A2 strains, which is important for future HMPV surveillance and epidemiological studies.

Human metapneumovirus (HMPV) has been a notable etiological agent of acute respiratory infection in humans, but it was not discovered until 2001, because HMPV replicates only in a limited number of cell lines and the cytopathic effect (CPE) is often mild. To promote the study of HMPV, several groups have generated green fluorescent protein (GFP)-expressing recombinant HMPV strains (HMPVGFP). However, the growing evidence has complicated the understanding of cell line specificity of HMPV, because it seems to vary notably among HMPV strains. In addition, unique A2b clade HMPV strains with a 180-nucleotide duplication in the G gene (HMPV A2b180nt-dup strains) have recently been detected. In this study, we re-evaluated and compared the cell line specificity of clinical isolates of HMPV strains, including the novel HMPV A2b180nt-dup strains, and six recombinant HMPVGFP strains, including the newly generated recombinant HMPV A2b180nt-dup strain, MG0256-EGFP. Our data demonstrate that VeroE6 and LLC-MK2 cells generally showed the highest infectivity with any clinical isolates and recombinant HMPVGFP strains. Other human-derived cell lines (BEAS-2B, A549, HEK293, MNT-1, and HeLa cells) showed certain levels of infectivity with HMPV, but these were significantly lower than those of VeroE6 and LLC-MK2 cells. Also, the infectivity in these suboptimal cell lines varied greatly among HMPV strains. The variations were not directly related to HMPV genotypes, cell lines used for isolation and propagation, specific genome mutations, or nucleotide duplications in the G gene. Thus, these variations in suboptimal cell lines are likely intrinsic to particular HMPV strains.

Background Application of 18F‐sodium fluoride (18F‐NaF) positron emission tomography (PET) to coronary artery disease has attracted interest. We investigated the utility of 18F‐NaF uptake for predicting coronary events and evaluated the combined use of coronary computed tomography (CT) angiography (CCTA) and 18F‐NaF PET/CT in coronary artery disease risk assessment. Methods and Results This study included patients with ≥1 coronary atherosclerotic lesion detected on CCTA who underwent 18F‐NaF PET/CT. High‐risk plaque on CCTA was defined as plaque with low density (1.1). Focal 18F‐NaF uptake in each lesion was quantified using the maximum tissue:background ratio (TBRmax), and maximum TBRmax per patient (M‐TBRmax) was determined. Thirty‐two patients having a total of 112 analyzed lesions were followed for 2 years after 18F‐NaF PET/CT scan, and 11 experienced coronary events (acute coronary syndrome and/or late coronary revascularization [after 3 months]). Patients with coronary events had higher M‐TBRmax than those without (1.39±0.18 versus 1.19±0.17, respectively; P=0.0034). The optimal M‐TBRmax cutoff to predict coronary events was 1.28 (area under curve: 0.79). Patients with M‐TBRmax ≥1.28 had a higher risk of earlier coronary events than those with lower M‐TBRmax (P=0.0062 by log‐rank test). In patient‐based (n=41) and lesion‐based (n=143) analyses of CCTA findings that predicted higher coronary 18F‐NaF uptake, the presence of high‐risk plaque was a significant predictor of both M‐TBRmax ≥1.28 and TBRmax ≥1.28. Conclusions 18F‐NaF PET/CT has the potential to detect high‐risk coronary artery disease and individual coronary lesions and to predict future coronary events when combined with CCTA. Clinical Trial Registration URL: www.umin.ac.jp. Unique identifier: UMIN000013735.

Figure-ground (FG) segregation that separates an object from the rest of the image is a fundamental problem in vision science. A majority of neurons in monkey V2 showed the selectivity to border ownership (BO) that indicates which side of a contour owns the border. Although BO could be a precursor of FG segregation, the contribution of BO to FG segregation has not been clarified. Because FG segregation is the perception of the global region that belongs to an object, whereas BO determination provides the local direction of figure (DOF) along a contour, a spatial integration of BO might be expected for the generation of FG. To understand the mechanisms underlying the perception of figural regions, we investigated the interaction between the local BO determination and the global FG segregation through the quantitative analysis of the visual perception and the spatiotemporal characteristics of eye movements. We generated a set of novel stimuli in which translucency induces local DOF along the contour and global FG independently so that DOF and FG could be either consistent or contradictory. The perceptual responses showed better performance in DOF discrimination than FG segregation, supporting distinct mechanisms for the DOF discrimination and the FG segregation. We examined whether the contradiction between DOF and FG modulates the eye movement while participants judged DOF and FG. The duration of the first eye fixation was modulated by the contradiction during FG segregation but not DOF discrimination, suggesting a sequential processing from the BO determination to the FG segregation. These results of human perception and eye fixation provide important clues for understanding the visual processing for FG segregation.

Cleavage and activation of hemagglutinin (HA) by trypsin-like proteases in influenza A virus (IAV) are essential prerequisites for its successful infection and spread. In host cells, some transmembrane serine proteases such as TMPRSS2, TMPRSS4 and HAT, along with plasmin in the bloodstream, have been reported to cleave the HA precursor (HA0) molecule into its active forms, HA1 and HA2. Some trypsinogens can also enhance IAV proliferation in some cell types (e.g., rat cardiomyoblasts). However, the precise activation mechanism for this process is unclear, because the expression level of the physiological activator of the trypsinogens, the TMPRSS15 enterokinase, is expected to be very low in such cells, with the exception of duodenal cells. Here, we show that at least two variant enterokinases are expressed in various human cell lines, including A549 lung-derived cells. The exogenous expression of these enterokinases was able to enhance the proliferation of IAV in 293T human kidney cells, but the proliferation was reduced by knocking down the endogenous enterokinase in A549 cells. The enterokinase was able to enhance HA processing in the cells, which activated trypsinogen in vitro and in the IAV-infected cells also. Therefore, we conclude that enterokinase plays a role in IAV infection and proliferation by activating trypsinogen to process viral HA in human cell lines.

Myotonic dystrophy type 1 (DM1) is caused by transcription of CUG repeat RNA, which causes sequestration of muscleblind-like 1 (MBNL1) and upregulation of CUG triplet repeat RNA-binding protein (CUG-BP1). In DM1, dysregulation of these proteins contributes to many aberrant splicing events, causing various symptoms of the disorder. Here, we demonstrate the occurrence of aberrant splicing of LIM domain binding 3 (LDB3) exon 11 in DM1 skeletal muscle. Exon array surveys, RT-PCR, and western blotting studies demonstrated that exon 11 inclusion was DM1 specific and could be reproduced by transfection of a minigene containing the CTG repeat expansion. Moreover, we found that the LDB3 exon 11-positive isoform had reduced affinity for PKC compared to the exon 11-negative isoform. Since PKC exhibits hyperactivation in DM1 and stabilizes CUG-BP1 by phosphorylation, aberrant splicing of LDB3 may contribute to CUG-BP1 upregulation through changes in its affinity for PKC.

The Fukushima nuclear accident in March 2011 caused the massive release of anthropogenic radioactive materials from the Fukushima Dai-ichi Nuclear Power Plant to its surrounding environment. Its biological effects have been studied using the pale grass blue butterfly, Zizeeria maha (Lepidoptera: Lycaenidae), but the overwintering states of this butterfly remain elusive. Here, we conducted a series of field surveys in March 2018, March 2019, and April 2019 in Fukushima and its vicinity to clarify the overwintering states of this butterfly at the time of the Fukushima nuclear accident. We discovered overwintering individuals in situ associated with the host plant Oxalis corniculata under natural straw mulch as first-instar to fourth-instar larvae in March 2018 and 2019. No other developmental stages were found. The body length and width were reasonably correlated with the accumulated temperature. On the basis of a linear regression equation between body size and accumulated temperature, together with other data, we deduced that the pale grass blue butterfly occurred as fourth-instar larvae in Fukushima and its vicinity at the time of the accident. This study paves the way for subsequent dosimetric analyses that determine the radiation doses absorbed by the butterfly after the accident.

The biological effects of the Fukushima nuclear accident have been examined in the pale grass blue butterfly, Zizeeria maha (Lepidoptera: Lycaenidae). In previous internal exposure experiments, larvae were given field-collected contaminated host plant leaves that contained up to 43.5 kBq/kg (leaf) of radioactive caesium. Larvae ingested up to 480 kBq/kg (larva), resulting in high mortality and abnormality rates. However, these results need to be compared with the toxicological data of caesium. Here, we examined the toxicity of both nonradioactive and radioactive caesium chloride on the pale grass blue butterfly. Larvae were fed a caesium-containing artificial diet, ingesting up to 149 MBq/kg (larva) of radioactive caesium (137Cs) or a much higher amount of nonradioactive caesium. We examined the pupation rate, eclosion rate, survival rate up to the adult stage, and the forewing size. In contrast to previous internal exposure experiments using field-collected contaminated leaves, we could not detect any effect. We conclude that the butterfly is tolerant to ionising radiation from 137Cs in the range tested but is vulnerable to radioactive contamination in the field. These results suggest that the biological effects in the field may be mediated through ecological systems and cannot be estimated solely based on radiation doses.

The adoptive transfer of effector T cells combined with lymphodepletion has demonstrated promising antitumor effects in mice and humans, although the availability of tumor-specific T cells is limited. We and others have also demonstrated that the transfer of polyclonal naïve T cells induces tumor-specific effector T cells and enhances antitumor immunity after lymphodepletion. Because tumors have been demonstrated to induce immunosuppressive networks and regulate the function of T cells, obtaining a sufficient number of fully functional naïve T cells that are able to differentiate into tumor-specific effector T cells remains difficult. To establish culture methods to obtain a large number of polyclonal T cells that are capable of differentiating into tumor-specific effector T cells, naïve T cells were activated with anti-CD3 mAbs in vitro. These cells were stimulated with IL-2 and IL-7 for the CD8 subset or with IL-7 and IL-23 for the CD4 subset. Transfer of these hyperexpanded T cells after lymphodepletion showed significant antitumor efficacy, and tumor-specific effector T cells were primed from these expanded T cells in tumor-bearing hosts. Moreover, these ex vivo-expanded T cells maintained T cell receptor diversity and showed long-term persistence of memory against specific tumors. Further analyses revealed that combination therapy consisting of vaccination with dendritic cells that were co-cultured with irradiated whole tumor cells and the transfer of ex vivo-expanded T cells significantly enhanced antitumor immunity. These results indicate that the transfer of ex vivo-expanded polyclonal T cells can be combined with other immunotherapies and augment antitumor effects.