Repositório RCAAP
Structural variants create new topological-associated domains and ectopic retinal enhancer-gene contact in dominant retinitis pigmentosa
The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.
2025-10-28T12:28:46Z
de Bruijn, Suzanne E. Fiorentino, Alessia Ottaviani, Daniele Fanucchi, Stephanie Melo, Uirá S. Corral-Serrano, Julio C. Mulders, Timo Georgiou, Michalis Rivolta, Carlo Pontikos, Nikolas Arno, Gavin Roberts, Lisa Greenberg, Jacquie Albert, Silvia Gilissen, Christian Aben, Marco Rebello, George Mead, Simon Raymond, F. Lucy Corominas, Jordi Smith, Claire E. L. Kremer, Hannie Downes, Susan Black, Graeme C. Webster, Andrew R. Inglehearn, Chris F. van den Born, L. Ingeborgh Koenekoop, Robert K. Michaelides, Michel Ramesar, Raj S. Hoyng, Carel B. Mundlos, Stefan Mhlanga, Musa Cremers, Frans P. M. Cheetham, Michael E. Roosing, Susanne Hardcastle, Alison J.
Social cognition impairment in genetic frontotemporal dementia within the GENFI cohort
A key symptom of frontotemporal dementia (FTD) is difficulty interacting socially with others. Social cognition problems in FTD include impaired emotion processing and theory of mind difficulties, and whilst these have been studied extensively in sporadic FTD, few studies have investigated them in familial FTD. Facial Emotion Recognition (FER) and Faux Pas (FP) recognition tests were used to study social cognition within the Genetic Frontotemporal Dementia Initiative (GENFI), a large familial FTD cohort of C9orf72, GRN, and MAPT mutation carriers. 627 participants undertook at least one of the tasks, and were separated into mutation-negative healthy controls, presymptomatic mutation carriers (split into early and late groups) and symptomatic mutation carriers. Groups were compared using a linear regression model with bootstrapping, adjusting for age, sex, education, and for the FP recognition test, language. Neural correlates of social cognition deficits were explored using a voxel-based morphometry (VBM) study. All three of the symptomatic genetic groups were impaired on both tasks with no significant difference between them. However, prior to onset, only the late presymptomatic C9orf72 mutation carriers on the FER test were impaired compared to the control group, with a subanalysis showing differences particularly in fear and sadness. The VBM analysis revealed that impaired social cognition was mainly associated with a left hemisphere predominant network of regions involving particularly the striatum, orbitofrontal cortex and insula, and to a lesser extent the inferomedial temporal lobe and other areas of the frontal lobe. In conclusion, theory of mind and emotion processing abilities are impaired in familial FTD, with early changes occurring prior to symptom onset in C9orf72 presymptomatic mutation carriers. Future work should investigate how performance changes over time, in order to gain a clearer insight into social cognitive impairment over the course of the disease.
2025-10-28T12:19:09Z
Russell, Lucy L. Greaves, Caroline V. Bocchetta, Martina Nicholas, Jennifer Convery, Rhian S. Moore, Katrina Cash, David M. van Swieten, John Jiskoot, Lize Moreno, Fermin Sanchez-Valle, Raquel Scarpini, Elio Fumagalli, Giorgio Taipa, Ricardo Cope, Thomas Timberlake, Carolyn Rittman, Timothy Shoesmith, Christen Bartha, Robart Rademakers, Rosa Wilke, Carlo Tiraboschi, Pietro Karnarth, Hans-Otto Bender, Benjamin Bruffaerts, Rose Caroppo, Paola Vandamme, Philip Vandenbulcke, Mathieu Ferreira, Catarina B. Miltenberger-Miltenyi, Gabriel Maruta, Carolina Verdelho, Ana Duro NPsych, Diana Afonso, Sónia Di Fede, Giuseppe Giaccone, Giorgio Muscio, Cristina Prioni, Sara Redaelli, Veronica Rossi, Giacomina Borroni, Barbara Almeida, Maria R. Castelo-Branco, Miguel Leitão, Maria J. Tabuas-Pereira, Miguel Santiago, Beatriz Gauthier, Serge Rosa-Neto, Pedro Finger, Elizabeth Veldsman, Michele Thompson, Paul Langheinrich, Tobias Laforce, Robert Prix, Catharina Hoegen, Tobias Wlasich, Elisabeth Loosli, Sandra Schonecker, Sonja Semler, Elisa Synofzik, Matthis Anderl-Straub, Sarah Masellis, Mario Tartaglia, Maria Carmela Graff, Caroline Rotondo, Emanuela Galimberti, Daniela Rowe, James B. Vandenberghe, Rik De Mendonça, Alexandre Tagliavini, Fabrizio Santana, Isabel Ducharme, Simon Butler, Chris Gerhard, Alex Levin, Johannes van Minkelen, Rick Danek, Adrian Otto, Markus Warren, Jason D. Rohrer, Jonathan D. Rossor, Martin N. Fox, Nick C. Woollacott, Ione O.C. Shafei, Rachelle Heller, Carolin Guerreiro, Rita Pijnenburg, Yolanda Bras, Jose Thomas, David L. Mead, Simon Meeter, Lieke Panman, Jessica Papma, Janne Poos, Jackie Barandiaran, Myriam Indakoetxea, Begoña Gabilondo, Alazne Tainta, Mikel de Arriba, Maria Gorostidi, Ana Zulaica, Miren Villanua, Jorge Keren, Ron Diaz, Zigor Borrego-Ecija, Sergi Olives, Jaume Lladó, Albert Balasa, Mircea Antonell, Anna Bargallo, Nuria Premi, Enrico Cosseddu MPsych, Maura Gazzina, Stefano Tang-Wai, Daid Padovani, Alessandro Gasparotti, Roberto Archetti, Silvana Black, Sandra Mitchell, Sara Rogaeva, Ekaterina Freedman, Morris Öijerstedt, Linn Andersson, Christin Jelic, Vesna Thonberg, Hakan Arighi, Andrea Fenoglio, Chiara
Os batalhões escolares do município de Lisboa: organização e práticas rituais (década de 1880)
Com o presente artigo é nosso propósito refletir sobre o projeto de militarização da infância desenvolvido nas escolas centrais ou graduadas do município de Lisboa, durante a primeira grande experiência de descentralização do ensino em Portugal. A afirmação dos batalhões escolares – ligada à ideia do cidadão-soldado enquanto parte do culto cívico da nação – é explicada no quadro de redes educativas internacionais. Por outro lado, além de darmos atenção às práticas rituais desenvolvidas em determinados momentos solenes e festividades (grandes eventos da história da nação), não deixaremos de estabelecer relação entre a instrução militar e outras áreas curriculares, nomeadamente, a educação física e a educação moral e cívica. Interessa- nos, aliás, perceber de que forma as práticas militares penetraram no quotidiano escolar. Por fim, exploramos as controvérsias que acompanharam a implementação da instrução militar nas escolas municipais de Lisboa e que ditaram, a partir de meados da década de 1880, o seu progressivo ocaso.
As radiações e a formação de uma ecologia institucional da medicina do cancro em Portugal (1912-1948)
Os estudos da radioatividade e o impulso científico e industrial associado à produção de radiações marcaram profundamente a medicina portuguesa no começo do século xx. Neste artigo explora-se o modo como uma noção biomédica do cancro emergiu nessa época, intimamente associada ao desenvolvimento de uma “economia das radiações” que se apoiava nos usos clínicos e científicos da radioatividade. Argumenta-se que essa economia se baseou em ambos os conceitos de “cancro” e de “radiações”, que se constituíram como objetos de fronteira, capazes de sustentar, no caso português, uma nova ecologia institucional da medicina através do seu potencial mediador entre diversos interesses políticos, científicos, médicos e industriais.
A produção de identidades de género e de classe em dois casinos portugueses: o caso das barmaids e das pagadoras de banca
Ser mulher no universo laboral dos casinos analisados implica a performance de diferentes imaginários relacionados com a feminilidade apropriada. O que define a adequação de um determinado tipo de feminilidade é a natureza das funções exercidas e a posição relacional dessas funções na estrutura hierárquica da organização. Este artigo, baseado numa investigação etnográfica, tem como objetivo analisar o contraste entre as performances de género das barmaids e das pagadoras de banca no processo de trabalho de dois casinos portugueses. Segue-se uma linha teórica feminista, assente nos contributos relacionados com os fenómenos da interseccionalidade. Conclui-se que a distinção entre as performances de género das duas funções se relaciona intimamente com a categoria de classe social.
Introduction. Thematic dossier: Migrations. On movement, identity, and belonging. Exploring the seashores of the Atlantic
This thematic dossier1 focuses on the complex and intense field of migration movements across the Atlantic. Its articles explore how migration structurally impacts the social and cultural identities of those who move and those who do not, while addressing key topics such as aspirations and motivations, integration and positioning strategies, transnational links, and family relations at distance. It draws on a problematization of human mobility and migration that equates both movement and stasis (Faist, 2013; Glick Schiller & Salazar, 2013) and analyzes the interconnectivity of these processes in light of identity production and reproduction. The articles discuss not only the purposes and consequences of movement per se, but also, and most significantly, the uprooting activities and identity negotiations of those who migrate and those who stay behind.
2025-10-28T12:08:55Z
Rosales, Marta Vilar Pereira, Cláudia
Cytotoxic activity and mechanism of action of organometallic complexes
No summary/description provided
2025-10-28T12:08:55Z
Bandarra, Daniel Mosebo Fernandes
Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment : routine care data from 13 registries in the EuroSpA collaboration
Objectives: To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries. Methods: Real-life data from 13 European registries participating in the European Spondyloarthritis Research Collaboration Network were pooled. Kaplan-Meier with log-rank test, Cox regression, χ² and logistic regression analyses were performed to assess 6-month and 12-month secukinumab retention, inactive disease/low-disease-activity states (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <2/<4, Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3/<2.1) and response rates (BASDAI50, Assessment of Spondyloarthritis International Society (ASAS) 20/40, ASDAS clinically important improvement (ASDAS-CII) and ASDAS major improvement (ASDAS-MI)). Results: We included 1860 patients initiating secukinumab as part of routine care. Overall 6-month/12-month secukinumab retention rates were 82%/72%, with significant (p<0.001) differences between the registries (6-month: 70-93%, 12-month: 53-86%) and across number of previous b/tsDMARDs (b/tsDMARD-naïve: 90%/73%, 1 prior b/tsDMARD: 83%/73%, ≥2 prior b/tsDMARDs: 78%/66%). Overall 6-month/12-month BASDAI<4 were observed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% of the patients. All rates differed significantly across number of previous b/tsDMARDs, were numerically higher for b/tsDMARD-naïve patients and varied significantly across registries. Overall, time since diagnosis was not associated with secukinumab effectiveness. Conclusions: In this study of 1860 patients from 13 European countries, we present the first comprehensive real-life data on effectiveness of secukinumab in patients with axSpA. Overall, secukinumab retention rates after 6 and 12 months of treatment were high. Secukinumab effectiveness was consistently better for bionaïve patients, independent of time since diagnosis and differed across the European countries.
2025-10-28T12:10:34Z
Michelsen, Brigitte Lindström, Ulf Codreanu, Catalin Ciurea, Adrian Zavada, Jakub Loft, Anne Gitte Pombo-Suarez, Manuel Onen, Fatos Kvien, Tore K. Rotar, Ziga Santos, Maria Iannone, Florenzo Hokkanen, Anna-Mari Gudbjornsson, Bjorn Askling, Johan Ionescu, Ruxandra Nissen, Michael J. Pavelka, Karel Sanchez-Piedra, Carlos Akar, Servet Sexton, Joseph Tomsic, Matija Santos, Helena Sebastiani, Marco Österlund, Jenny Geirsson, Arni Jon Macfarlane, Gary van der Horst-Bruinsma, Irene Georgiadis, Stylianos Brahe, Cecilie Heegaard Ørnbjerg, Lykke Midtbøll Hetland, Merete Lund Østergaard, Mikkel
Ensaio Bibliográfico, “Amália Rodrigues e o século xx português”
No summary/description provided
Recensão “Democratic Practice: Origins of the Iberian Divide in Political Inclusion, Nova Iorque, Oxford University Press, 2019”
No summary/description provided
O CASO CLIMADAPT.LOCAL: CAPACITAÇÃO E AÇÃO CLIMÁTICA EM PORTUGAL
In an era where climate change gained relevance and caused the highest levels of social awareness, the main objective of ClimAdaPT.Local project valued the integration of the climate dimension in municipal planning processes. Based on a questionnaire survey applied in three consecutive rounds throughout the project, this article focuses on the responses of a group of municipal officers who, together with the ClimAdaPT.Local team, developed Municipal Strategies for Adaptation to Climate Change. With the focus on the respondents' evolution concerning acquisition of knowledge, mobilization and awareness, and capacity building throughout the project, the main conclusions will be presented here.
2025-10-28T12:21:14Z
Guerra, João Francisco Luísa Schmidt, Luísa Penha-Lopes, Gil
Quantificação e cartografia da extensão de inundação costeira em Bissau, Guiné-Bissau: perspetiva em cenário de alterações climáticas
Coastal flooding (CF), enhanced by climate change, is one of the most significant impacts of sea level rise (SLR). Bissau city, home to ~25% of Guinea-Bissau population is already affected by CF due to tides and storms. It is anticipated that the situation will deteriorate in coming decades with the expected scenarios of SLR. This article evaluated the vulnerability to coastal flooding of Bissau, using the single-value model, which considers two variables: inundation value and a topographic surface. The inundation value, here referred as total water level (TWL) was estimated by the sum of three vertical components: astronomical tide (AT), storm surge (SS) and the SLR estimation for the considered scenario. Thus, the inundation extension was quantified and mapped using a TWL estimated for the year 2100, and a high-precision global Digital Elevation Model (DEM – TanDEM-X) of the Bissau region. The results indicate that the land potentially to be flooded corresponds to 29.3% of the study area (94.9 km²). The Southwest zone of Bissau presents greater exposure to flooding, due to its low altitude. Also, the disorderly anthropogenic occupation of flooded lands, makes these areas more vulnerable in a climate change scenario.
2025-10-28T12:23:01Z
Fandé, M. B. Ponte Lira, C. Antunes, C. Penha-Lopes, Gil
Differential expansion of circulating human MDSC subsets in patients with cancer, infection and inflammation
Background: Myeloid-derived suppressor cells (MDSC) are a functional myeloid cell subset that includes myeloid cells with immune suppressive properties. The presence of MDSC has been reported in the peripheral blood of patients with several malignant and non-malignant diseases. So far, direct comparison of MDSC across different diseases and Centers is hindered by technical pitfalls and a lack of standardized methodology. To overcome this issue, we formed a network through the COST Action Mye-EUNITER (www.mye-euniter.eu) with the goal to standardize and facilitate the comparative analysis of human circulating MDSC in cancer, inflammation and infection. In this manuscript, we present the results of the multicenter study Mye-EUNITER MDSC Monitoring Initiative, that involved 13 laboratories and compared circulating MDSC subsets across multiple diseases, using a common protocol for the isolation, identification and characterization of these cells. Methods: We developed, tested, executed and optimized a standard operating procedure for the isolation and immunophenotyping of MDSC using blood from healthy donors. We applied this procedure to the blood of almost 400 patients and controls with different solid tumors and non-malignant diseases. The latter included viral infections such as HIV and hepatitis B virus, but also psoriasis and cardiovascular disorders. Results: We observed that the frequency of MDSC in healthy donors varied substantially between centers and was influenced by technical aspects such as the anticoagulant and separation method used. Expansion of polymorphonuclear (PMN)-MDSC exceeded the expansion of monocytic MDSC (M-MDSC) in five out of six solid tumors. PMN-MDSC expansion was more pronounced in cancer compared with infection and inflammation. Programmed death-ligand 1 was primarily expressed in M-MDSC and e-MDSC and was not upregulated as a consequence of disease. LOX-1 expression was confined to PMN-MDSC. Conclusions: This study provides improved technical protocols and workflows for the multi-center analysis of circulating human MDSC subsets. Application of these workflows revealed a predominant expansion of PMN-MDSC in solid tumors that exceeds expansion in chronic infection and inflammation.
2025-10-28T12:23:01Z
Cassetta, Luca Bruderek, Kirsten Skrzeczynska-Moncznik, Joanna Osiecka, Oktawia Hu, Xiaoying Rundgren, Ida Marie Lin, Ang Santegoets, Kim Horzum, Utku Godinho-Santos, Ana Zelinskyy, Gennadiy Garcia-Tellez, Thalia Bjelica, Sunčica Taciak, Bartłomiej Kittang, Astrid Olsnes Höing, Benedikt Lang, Stephan Dixon, Michael Müller, Verena Utikal, Jochen Sven Karakoç, Derya Yilmaz, Kerim Bora Górka, Emilia Bodnar, Lubomir Anastasiou, Olympia Evdoxia Bourgeois, Christine Badura, Robert Kapinska-Mrowiecka, Monika Gotic, Mirjana Ter Laan, Mark Kers-Rebel, Esther Król, Magdalena Santibañez, Juan Francisco Müller-Trutwin, Michaela Dittmer, Ulf Sousa, Ana E. Esendağlı, Güneş Adema, Gosse Loré, Karin Ersvær, Elisabeth Umansky, Viktor Pollard, Jeffrey W. Cichy, Joanna Brandau, Sven
Teatreca : para o estudo do teatro em Portugal no século XX : o arquivo pessoal Osório Mateus
O presente relatório diz respeito a um trabalho de final de mestrado na modalidade de relatório de estágio, de natureza descritiva, técnica e científica, elaborado na sequência de um primeiro estágio realizado no Centro de Estudos de Teatro, da Faculdade de Letras da Universidade de Lisboa. O estágio permitiu o aprofundamento de competências profissionais sobre a temática dos arquivos pessoais, tendo por base o arquivo pessoal de Osório Mateus, relevante para a preservação da memória do teatro em Portugal no século XX. Tem como principais objectivos gerais: compreender o universo, nacional e internacional, dos arquivos pessoais e contribuir para a preservação da memória do teatro em Portugal. Como objectivos específicos: efectuar o estudo biográfico de Osório Mateus; identificar, organizar e representar a informação do arquivo pessoal; promover o acesso democrático e universal à informação, através da web; apreender o lugar de Osório Mateus no teatro em Portugal no século XX. O arquivo pessoal foi doado à Faculdade de Letras da Universidade de Lisboa por Osório Mateus, professor da Faculdade de Letras da Universidade de Lisboa. É um conjunto constituído, na sua maioria, por programas de espectáculos e folhas de sala, cotados manualmente por quem recolheu a colecção em casa do doador, apresentando, uma lógica de organização. Seguiu-se o paradigma positivista, uma vez que se partiu de uma pesquisa bibliográfica, na qual se procurou analisar os estudos já realizados em arquivos de teatro. De seguida, identificaram-se as tipologias documentais, na sua maioria, programas de espectáculos e folhas de sala, tendo-se procedido à sua descrição e representação na base de dados da Biblioteca da Faculdade de Letras da Universidade de Lisboa, segundo a norma ISBD (versão consolidada), havendo a adaptação de alguns campos do template para a descrição dos objectos. Passando a integrar o sistema de informação e pesquisa da referida Biblioteca, a informação encontra-se organizada, representada e disponível para consulta dos utilizadores.
Teatro aveirense
O trabalho desenvolvido no âmbito desta dissertação pretende desvendar como a vontade de um grupo de anónimos, sedentos das artes dramáticas, conseguiu erigir um espaço - o do Teatro Aveirense - que conta com mais de 125 anos de vida. As suas necessidades e motivações, as alegrias e tristezas, as vicissitudes dos tempos e os problemas inerentes a tão grandiosa obra numa cidade de província. Paralelamente, são apresentadas as companhias e peças que se exibiram nos palcos da cidade, tomando em consideração o seu registo cronológico. Dá-se especial destaque às companhias amadoras devido à importância que tiveram na formação de públicos e mentalidades, bem como no seu papel preponderante para a História do Teatro em Portugal.
2025-10-28T12:20:07Z
Lopes, Judite Conceição Afonso
The emergence of genetics in Portugal: J. A. Serra at the crossroads of politics and biological communities (1936-1952)
This thesis aims to contribute to a better understanding of the history of biology in Portugal. Genetics in Portugal emerged in the 1930s. Why not before and how this took place were the two questions I proposed to answer in the fist part of this thesis. My approach focuses on the dynamics between different biological communities and on the influence other “national traditions” in biology had on a periphery such as Portugal. A historical survey of the first decades of the twentieth century regarding the extant sources on Mendelism is provided and the influence of the French tradition in biology is debated. In the second part, following the scientific life of the leading Portuguese geneticist J. A. Serra (from 1936 until 1952), I analyse the emergence of genetics in the Faculty of Sciences of the University of Coimbra, discussing the influence of German genetics during World War II. Here I add a further dimension by looking into the relation between science and politics, as a reciprocal one. Two main conclusions: 1) the emergence of genetics in Portugal during the 1930s played a crucial role on the migration of experimental practices among different biological communities; and 2) the consolidation of genetics in the university context of Coimbra was shaped and occasionally benefited from the political agenda of the New State.
Vulnerability of progeroid smooth muscle cells to biomechanical forces is mediated by MMP13
Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disease in children that leads to early death. Smooth muscle cells (SMCs) are the most affected cells in HGPS individuals, although the reason for such vulnerability remains poorly understood. In this work, we develop a microfluidic chip formed by HGPS-SMCs generated from induced pluripotent stem cells (iPSCs), to study their vulnerability to flow shear stress. HGPS-iPSC SMCs cultured under arterial flow conditions detach from the chip after a few days of culture; this process is mediated by the upregulation of metalloprotease 13 (MMP13). Importantly, double-mutant LmnaG609G/G609GMmp13-/- mice or LmnaG609G/G609GMmp13+/+ mice treated with a MMP inhibitor show lower SMC loss in the aortic arch than controls. MMP13 upregulation appears to be mediated, at least in part, by the upregulation of glycocalyx. Our HGPS-SMCs chip represents a platform for developing treatments for HGPS individuals that may complement previous pre-clinical and clinical treatments.
2025-10-28T12:15:24Z
Pitrez, Patricia R. Estronca, Luís Monteiro, Luís Miguel Colell, Guillem Vazão, Helena Santinha, Deolinda Harhouri, Karim Thornton, Daniel Navarro, Claire Egesipe, Anne-Laure Carvalho, Tânia Dos Santos, Rodrigo L. Lévy, Nicolas Smith, James C. de Magalhães, João Pedro Ori, Alessandro Bernardo, Andreia De Sandre-Giovannoli, Annachiara Nissan, Xavier Rosell, Anna Ferreira, Lino
Pinpointing cell identity in time and space
Mammalian cells display a broad spectrum of phenotypes, morphologies, and functional niches within biological systems. Our understanding of mechanisms at the individual cellular level, and how cells function in concert to form tissues, organs and systems, has been greatly facilitated by centuries of extensive work to classify and characterize cell types. Classic histological approaches are now complemented with advanced single-cell sequencing and spatial transcriptomics for cell identity studies. Emerging data suggests that additional levels of information should be considered, including the subcellular spatial distribution of molecules such as RNA and protein, when classifying cells. In this Perspective piece we describe the importance of integrating cell transcriptional state with tissue and subcellular spatial and temporal information for thorough characterization of cell type and state. We refer to recent studies making use of single cell RNA-seq and/or image-based cell characterization, which highlight a need for such in-depth characterization of cell populations. We also describe the advances required in experimental, imaging and analytical methods to address these questions. This Perspective concludes by framing this argument in the context of projects such as the Human Cell Atlas, and related fields of cancer research and developmental biology.
2025-10-28T12:20:34Z
Savulescu, Anca F. Jacobs, Caron Negishi, Yutaka Davignon, Laurianne Mhlanga, Musa
Host immune genetic variations influence the risk of developing acute myeloid leukaemia : results from the NuCLEAR consortium
The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.
2025-10-28T12:19:09Z
Sánchez-Maldonado, J. M. Campa, D. Springer, J. Badiola, J. Niazi, Y. Moñiz-Díez, A. Hernández-Mohedo, F. González-Sierra, P. Ter Horst, R. Macauda, A. Brezina, S. Cunha, C. Lackner, M. López-Nevot, M. A. Fianchi, L. Pagano, L. López-Fernández, E. Potenza, L. Luppi, M. Moratalla, L. Rodríguez-Sevilla, J. J. Fonseca, João Eurico Tormo, M. Solano, C. Clavero, E. Romero, A. Li, Y. Lass-Flörl, C. Einsele, H. Vazquez, L. Loeffler, J. Hemminki, K. Carvalho, A. Netea, M. G. Gsur, A. Dumontet, C. Canzian, F. Försti, A. Jurado, M. Sainz, J.
The neuroprotective action of amidated-kyotorphin on amyloid β peptide-induced Alzheimer’s disease pathophysiology
Kyotorphin (KTP, l-tyrosyl-l-arginine) is an endogenous dipeptide initially described to have analgesic properties. Recently, KTP was suggested to be an endogenous neuroprotective agent, namely for Alzheimer's disease (AD). In fact, KTP levels were shown to be decreased in the cerebrospinal fluid of patients with AD, and recent data showed that intracerebroventricular (i.c.v.) injection of KTP ameliorates memory impairments in a sporadic rat model of AD. However, this administration route is far from being a suitable therapeutic strategy. Here, we evaluated if the blood-brain permeant KTP-derivative, KTP-NH2, when systemically administered, would be effective in preventing memory deficits in a sporadic AD animal model and if so, which would be the synaptic correlates of that action. The sporadic AD model was induced in male Wistar rats through i.c.v. injection of amyloid β peptide (Aβ). Animals were treated for 20 days with KTP-NH2 (32.3 mg/kg, intraperitoneally (i.p.), starting at day 3 after Aβ administration) before memory testing (Novel object recognition (NOR) and Y-maze (YM) tests). Animals were then sacrificed, and markers for gliosis were assessed by immunohistochemistry and Western blot analysis. Synaptic correlates were assessed by evaluating theta-burst induced long term potentiation (LTP) of field excitatory synaptic potentials (fEPSPs) recorded from hippocampal slices and cortical spine density analysis. In the absence of KTP-NH2 treatment, Aβ-injected rats had clear memory deficits, as assessed through NOR or YM tests. Importantly, these memory deficits were absent in Aβ-injected rats that had been treated with KTP-NH2, which scored in memory tests as control (sham i.c.v. injected) rats. No signs of gliosis could be detected at the end of the treatment in any group of animals. LTP magnitude was significantly impaired in hippocampal slices that had been incubated with Aβ oligomers (200 nM) in the absence of KTP-NH2. Co-incubation with KTP-NH2 (50 nM) rescued LTP toward control values. Similarly, Aβ caused a significant decrease in spine density in cortical neuronal cultures, and this was prevented by co-incubation with KTP-NH2 (50 nM). In conclusion, the present data demonstrate that i.p. KTP-NH2 treatment counteracts Aβ-induced memory impairments in an AD sporadic model, possibly through the rescuing of synaptic plasticity mechanisms.
2025-10-28T12:23:14Z
Belo, Rita F. Martins, Margarida L. F. Shvachiy, Liana Costa-Coelho, Tiago de Almeida-Borlido, Carolina Fonseca-Gomes, João Neves, Vera Vicente Miranda, Hugo Outeiro, Tiago F. Coelho, Joana E Xapelli, Sara Valente, Cláudia A. Heras, Montserrat Bardaji, Eduard Castanho, Miguel A. R. B. Diógenes, Maria José Sebastião, Ana M