35 research outputs found

    Spatiotemporal control of mitosis by the conserved spindle matrix protein Megator

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    A putative spindle matrix has been hypothesized to mediate chromosome motion, but its existence and functionality remain controversial. In this report, we show that Megator (Mtor), the Drosophila melanogaster counterpart of the human nuclear pore complex protein translocated promoter region (Tpr), and the spindle assembly checkpoint (SAC) protein Mad2 form a conserved complex that localizes to a nuclear derived spindle matrix in living cells. Fluorescence recovery after photobleaching experiments supports that Mtor is retained around spindle microtubules, where it shows distinct dynamic properties. Mtor/Tpr promotes the recruitment of Mad2 and Mps1 but not Mad1 to unattached kinetochores (KTs), mediating normal mitotic duration and SAC response. At anaphase, Mtor plays a role in spindle elongation, thereby affecting normal chromosome movement. We propose that Mtor/Tpr functions as a spatial regulator of the SAC, which ensures the efficient recruitment of Mad2 to unattached KTs at the onset of mitosis and proper spindle maturation, whereas enrichment of Mad2 in a spindle matrix helps confine the action of a diffusible “wait anaphase” signal to the vicinity of the spindle

    Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

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    Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.We thank all members of the Brain Metastasis Group and A. Chalmers, E. Wagner, O. Fernández-Capetillo, R. Ciérvide and A. Hidalgo for critical discussion of the manuscript; the CNIO Core Facilities for their excellent assistance; and Fox Chase Cancer Center Transgenic Facility for generation of S100A9 mice. We thank EuCOMM repository for providing S100A9 targeted embryonic stem cells. We also thank J. Massagué (MSKCC) for some of the BrM cell lines and M. Bosenberg (Yale) for the YUMM1.1 cell line. Samples from patients included in this study that provided by the Girona Biomedical Research Institute (IDIBGI) (Biobanc IDIBGI, B.0000872) are integrated into the Spanish National Biobanks Network and in the Xarxa de Bancs de Tumors de Catalunya (XBTC) financed by the Pla Director d’Oncologia de Catalunya. All patients consented to the storage of these samples in the biobank and for their use in research projects. This study was funded by MINECO (SAF2017-89643-R) (M.V.), Fundació La Marató de TV3 (201906-30-31-32) (J.B.-B., M.V. and A.C.), Fundación Ramón Areces (CIVP19S8163) (M.V.) and CIVP20S10662 (E.O.P.), Worldwide Cancer Research (19-0177) (M.V. and E.C.-J.M.), Cancer Research Institute (Clinic and Laboratory Integration Program CRI Award 2018 (54545) (M.V.), AECC (Coordinated Translational Groups 2017 (GCTRA16015SEOA) (M.V.), LAB AECC 2019 (LABAE19002VALI) (M.V.), ERC CoG (864759) (M.V.), Portuguese Foundation for Science and Technology (SFRH/bd/100089/2014) (C.M.), Boehringer-Ingelheim Fonds MD Fellowship (L.M.), La Caixa International PhD Program Fellowship-Marie Skłodowska-Curie (LCF/BQ/DI17/11620028) (P.G.-G.), La Caixa INPhINIT Fellowship (LCF/BQ/DI19/11730044) (A.P.-A.), MINECO-Severo Ochoa PhD Fellowship (BES-2017-081995) (L.A.-E.) and an AECC postdoctoral fellowship (POSTD19016PRIE) (N.P.). M.V. is an EMBO YIP member (4053). Additional support was provided by Gertrud and Erich Roggenbuck Stiftung (M.M.), Science Foundation Ireland Frontiers for the Future Award (19/FFP/6443) (L.Y.), Science Foundation Ireland Strategic Partnership Programme, Precision Oncology Ireland (18/SPP/3522) (L.Y.), Breast Cancer Now Fellowship Award with the generous support of Walk the Walk (2019AugSF1310) (D.V.), Science Foundation Ireland (20/FFP-P/8597) (D.V.), Paradifference Foundation (C.F.-T.), “la Caixa” Foundation (ID 100010434) (A.I.), European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 847648 (CF/BQ/PI20/11760029) (A.I.), Champalimaud Centre for the Unknown (N.S.), Lisboa Regional Operational Programme (Lisboa 2020) (LISBOA01-0145-FEDER-022170) (N.S.), NCI (R01 CA227629; R01 CA218133) (S.I.G.), Fundació Roses Contra el Càncer (J.B.-B.), Ministerio de Universidades FPU Fellowship (FPU 18/00069) (P.T.), MICIN-Agencia Estatal de Investigación Fellowships (PRE2020-093032 and BES-2017-080415) (P.M. and E. Cintado, respectively), Ministerio de Ciencia, Innovación y Universidades-E050251 (PID2019-110292RB-I00) (J.L.T.), FCT (PTDC/MED-ONC/32222/2017) (C.C.F.), Fundação Millennium bcp (C.C.F.), private donations (C.C.F.) and the Foundation for Applied Cancer Research in Zurich (E.L.R. and M.W.)

    Capacidade combinatória de híbridos de tomateiro de crescimento determinado, resistentes a Begomovirus e Tospovirus

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    O objetivo deste trabalho foi avaliar a capacidade combinatória de linhagens de tomateiro com hábito de crescimento determinado, com resistência múltipla a espécies dos gêneros Begomovirus e Tospovirus, e identificar combinações híbridas superiores. O experimento foi realizado em casa de vegetação, com 14 híbridos obtidos do cruzamento de sete linhagens femininas (grupo I) com duas linhagens masculinas (grupo II), em um dialelo parcial. As seguintes características agronômicas foram avaliadas: produção total, produção precoce, massa média de frutos, formato, firmeza inicial e firmeza na meia-vida. As linhagens genitoras TOM-680 e TOM-682, do grupo I, se destacaram por exibir as maiores estimativas de capacidade geral de combinação (CGC) quanto às características produção total, produção precoce e massa média de frutos, enquanto a linhagem TOM-585 se destacou quanto aos maiores valores de produção total e massa média de frutos. No grupo II, a linhagem TOM-698 apresentou estimativas superiores de CGC para as características de produção total, produção precoce, massa média dos frutos e firmeza inicial dos frutos. O híbrido TOM-682xTOM-698 apresenta as maiores estimativas de capacidade geral e específica de combinação para produção total, produção precoce e meia-vida da firmeza, e é o genótipo mais promissor entre os materiais testados

    Inquérito sorológico sôbre leptospiroses realizado no Vale do Cariri, Estado do Ceará, pela III Bandeira Científica do Centro Acadêmico Oswaldo Cruz da Faculdade de Medicina da Universidade de São Paulo

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    Agglutination-tests for leptospirosis were performed in 376 sera. The following sero-types of Leptospira were used: L. icterohemorrhagiae, L. canicola, L. grippo-typhosa, L. pomona, L. bataviae, L. australis B, L. sejroe, L. pyrogenes and L. suis. Six sera (1.59%) were positive for L. icterohemorrhagiae. From the whole group two people were born in this region, what makes possible the conclusion that the disease exists in the region.Com o propósito de estudar o problema das leptospiroses no Vale do Cariri, Ceará, foram examinados 376 soros colhidos entre moradores da região. Foram feitas provas de sôro-aglutinação usando-se os seguintes sôro-tipos de Leptospira: L. icterohemorrhagiae, L. canícola, L. grippo-typhosa, L. pomona, L. bataviae, L. australis B, L. sejroe, L. pyrogenes e L. suis. Seis soros reagiram positivamente frente à L. icterohemorrhagiae, o que dá percentual de 1,59%. Dois dos indivíduos haviam nascido e vivido no Vale, donde foi possível concluir que a leptospirose existe, autóctone, na região

    Clustering of ingredients with amino acid composition similar to the nutritional requirement of Nile tilapia

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    The search for balanced diets, which may elicit improved growth of fish, requires appropriate selection of available protein sources. This study aims at clustering feedstuffs according to amino acid profile, determining which ones show essential amino acids (EAA) profiles closer to the ideal dietary amino acids requirements of Nile tilapia (Oreochromis niloticus), and studying the relationship among amino acids feedstuffs groups. Tabled data on EAA more cystine and tyrosine, in relation to lysine contents, of 40 feedstuffs ordinarily used to formulate fish diets were studied. Feedstuffs were grouped according to amino acids profile by cluster analysis of Euclidean distances. The principal components analysis was used to determine the relationship among amino acids in each feedstuff group. Three groups of ingredients were parted and two ingredients, low tannin sorghum and corn gluten meal 60%, did not go with any group. Dietary amino acids requirements of Nile tilapia were similar to the amino acid profile of 22 feedstuffs. The principal component analysis explained with three principal components more than 75% of total variance of amino acids in three feedstuff groups. Therefore, until additional, detailed information on amino acids availability of different ingredients is consolidated, total amino acids profiles will continue to be important information to select and use conventional or surrogate ingredients for formulating and processing feeds for tilapia.A busca de uma ração balanceada, que proporcione maior crescimento aos peixes, passa pela escolha adequada das fontes protéicas disponíveis. Este estudo teve por objetivo agrupar alimentos de acordo com o perfil de aminoácidos essenciais, determinando quais mostram perfis mais próximos do requerimento da tilápia do Nilo (Oreochromis niloticus), e estudar a relação entre os aminoácidos dentro dos agrupamentos obtidos. Foram utilizadas composições de aminoácidos em relação ao conteúdo de lisina, de 40 alimentos comumente utilizados como ingredientes na formulação de dietas para peixes. Os ingredientes foram agrupados de acordo com o perfil de aminoácidos utilizando a análise de agrupamento por meio da distância Euclidiana, enquanto a análise de componentes principais foi utilizada para determinar a relação entre os aminoácidos em cada grupo obtido. Três grupos de ingredientes foram formados e apenas dois ingredientes, sorgo baixo tanino e farelo de glúten de milho 60%, não entraram em nenhum dos três grupos. A exigência de aminoácidos da tilápia do Nilo foi semelhante ao perfil de aminoácidos encontrado em 22 alimentos. A análise de componentes principais conseguiu resumir e explicar 75% da variância total com apenas três componentes principais. Até que maiores informações sobre a disponibilidade de aminoácidos de diferentes ingredientes sejam obtidas, o perfil total de aminoácidos continuará a ser uma informação valiosa na escolha dos ingredientes a serem utilizados na formulação e processamento de alimentos para tilápia do Nilo
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