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Abstract Glioblastoma is a highly aggressive brain tumour that creates an immunosuppressive microenvironment. Microglia, the brain’s resident immune cells, play a crucial role in this environment. Glioblastoma cells can reprogramme microglia to create a supportive niche that promotes tumour growth. However, the mechanisms controlling the acquisition of a transcriptome associated with a tumour-supportive microglial reactive state are not fully understood. In this study, we investigated changes in the transcriptional profile of BV2 microglia exposed to C6 glioma cells. RNA-sequencing analysis revealed a significant upregulation of microglial inhibitor of DNA binding 1 (Id1) and Id2, helix-loop-helix negative transcription regulatory factors. The concomitant regulation of microglial ETS proto-oncogene 2, transcription factor (ETS2)-target genes, i.e., Dusp6, Fli1, Jun, Hmox1, and Stab1, led us to hypothesize that ETS2 could be regulated by ID proteins. In fact, ID2-ETS2 protein interactions increased in microglia exposed to glioma cells. In addition, perturbation of the ID2-ETS2 transcriptional axis influenced the acquisition of a microglial tumour-supportive phenotype. ID2 and ETS2 genes were found to be expressed by the tumour-associated microglia isolated from human glioblastoma tumour biopsies. Furthermore, ID2 and ETS2 gene expressions exhibited inverse prognostic values in patients with glioma in cohorts from The Cancer Genome Atlas. Collectively, our findings indicate that the regulation of ETS2 by ID2 plays a role in the transcriptional regulation of microglia in response to stimuli originating from glioblastoma cells, information that could lead to developing therapeutic strategies to manipulate microglial tumour-trophic functions.

Abstract The measurement of the flux of muons produced in cosmic ray air showers is essential for the study of primary cosmic rays. Such measurements are important in extensive air shower detectors to assess the energy spectrum and the chemical composition of the cosmic ray flux, complementary to the information provided by fluorescence detectors. Detailed simulations of the cosmic ray air showers are carried out, using codes such as CORSIKA, to estimate the muon flux at sea level. These simulations are based on the choice of hadronic interaction models, for which improvements have been implemented in the post-LHC era. In this work, a deficit in simulations that use state-of-the-art QCD models with respect to the measurement deep underwater with the KM3NeT neutrino detectors is reported. The KM3NeT/ARCA and KM3NeT/ORCA neutrino telescopes are sensitive to TeV muons originating mostly from primary cosmic rays with energies around 10 TeV. The predictions of state-of-the-art QCD models show that the deficit with respect to the data is constant in zenith angle; no dependency on the water overburden is observed. The observed deficit at a depth of several kilometres is compatible with the deficit seen in the comparison of the simulations and measurements at sea level.

The novel in Portugal between 1974 and 2020 is divided into two phases: 1. 1974 and 2000: the Late Modernist or Neomodernist Novel, which socially and politically corresponds to Portugal's integration into Europe; 2. 2000-2020: the Post-Modern Novel, following the literary rhythm of Europe, corresponding to the phase of Late Capitalism. The main objective of Portuguese literature in the first phase is to modernize the country, to participate in European literature, to be as European as France. Being a modern country meant in 1974: 1. Expressing oneself in total freedom, the end to censorship, of any kind; 2. Overcoming the economic poverty in which the population survived; 3. Overcoming the illiteracy and ignorance which plagued the majority of the population; 4. Ending a 13-year colonial war and allowing the colonies to become independent; 5. Democratizing state institutions; 6. Finally, changing the country's course, replacing the historic privilege attributed to the Atlantic with the privilege attributed to Europe. In the second phase, a new generation emerges in Portuguese literature with novels published from 2000 onwards: Gonçalo M. Tavares is its main actor.

Abstract Microbial biodiversity is fundamental to maintain ecosystem functioning in seasonally variable ecosystems. However, it remains unclear how alterations in water availability caused by episodic drying compromise the ability of stream microbes to maintain multiple functions simultaneously (e.g., primary production and carbon cycling). Using data from 32 streams, we investigated how the phenology of annual drying influences stream sediment microbial biodiversity and their capacity to sustain multifunctionality. Our results showed that stream multifunctionality and most bacteria did not respond to changes in drying phenology. Only two bacterial groups, the drying‐resistant Sphingobacteriia and the drying‐sensitive Acidobacteria_Gp7, exhibited positive associations with multifunctionality; whereas, bacterial diversity showed a negative correlation with functions. Among these biodiversity aspects, Sphingobacteriia showed the strongest capacity to maintain multifunctionality at low and moderate performance levels. Our findings will help to better understand the mechanisms through which biodiversity sustains the functioning of seasonally variable streams and their responses to global change.

Abstract Modern humans widely shaped present ecosystems through intentional and unintentional geographical redistribution of wildlife, both in historical and pre‐historical times. However, the patterns of ancient human‐mediated indirect changes in wildlife range are largely unknown, and the mechanisms behind them remain obscure. We used a multidisciplinary approach to (a) reconstruct the process of colonization of the Mediterranean Basin by a long‐lived bird of prey, the Bonelli's eagle (Aquila fasciata), and (b) test the hypothesis that this colonization was unintentionally favoured by anatomically modern humans through a release of competition by dominant species, primarily golden eagles (A. chrysaetos). The fossil record of Bonelli's eagles in the Mediterranean Basin was restricted to the last c. 50 ky. This timing matches the period of modern human presence in Europe. Distribution modelling showed that Bonelli's eagles find more suitable conditions in interglacial periods, while glacial maxima are largely unfavourable unless in coastal refugia. In agreement with this, all Bonelli's eagle's fossils were found in coastal areas, and demographic inference from genetic data revealed a drop in the effective population size by around the last glacial maximum. In today's communities, we found a strongly asymmetric competitive relationship between (subordinate) Bonelli's and (dominant) golden eagles, with the former occupying far more humanized areas than the latter both at the landscape scale and the local (i.e. nesting cliff) scale. Moreover, the nesting habitat overlap analysis indicated that, in the absence of the other species, a notably higher population of Bonelli's eagle, but not of golden eagle, could be expected. Our findings are consistent with the human‐mediated competitor release hypothesis, by which anatomically modern humans could have unintentionally favoured the large‐scale colonization by Bonelli's eagles of a previously competitively hostile Mediterranean Basin. Reconstructing the role of ancient humans in shaping present ecosystems may help to understand the historical, current and future population trajectories of competing species of conservation concern under the ongoing scenario of global environmental change. It also illustrates how human‐mediated apparent competition may promote large‐scale redistribution and colonization of wildlife, including long‐lived species. Read the free Plain Language Summary for this article on the Journal blog.

Julia Sabin,1 Elisa Salas,2 Jesús Martín-Martínez,3 Antonio Candeliere-Merlicco,4 Francisco Javier Barrero Hernández,5 Ana María Alonso Torres,6 José Luis Sánchez-Menoyo,7 Laura Borrega,8 María Rodríguez-Rodríguez,9 Montserrat Gómez-Gutiérrez,10 Sara Eichau,11 Miguel Ángel Hernández-Pérez,12 Carmen Calles,13 Eva Fernandez-Diaz,14 Olga Carmona,15 Aida Orviz,16 Ana López-Real,17 Pablo López-Muñoz,18 Amelia Mendoza Rodríguez,19 Eduardo Aguera-Morales,20 Jorge Maurino2 1Department of Neurology, Hospital Universitario Puerta de Hierro, Madrid, Spain; 2Medical Department, Roche Farma, Madrid, Spain; 3Department of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain; 4Department of Neurology, Hospital Rafael Méndez, Lorca, Spain; 5Department of Neurology, Hospital Clínico Universitario San Cecilio, Granada, Spain; 6Department of Neurology, Hospital Regional Universitario de Málaga, Málaga, Spain; 7Department of Neurology, Hospital de Galdakao-Usansolo, Galdakao, Spain; 8Department of Neurology, Hospital Universitario Fundación Alcorcón, Alcorcón, Spain; 9Department of Neurology, Hospital Universitario Lucus Augusti, Lugo, Spain; 10Department of Neurology, Hospital San Pedro de Alcántara, Cáceres, Spain; 11Department of Neurology, Hospital Universitario Virgen Macarena, Sevilla, Spain; 12Department of Neurology, Hospital Universitario Nuestra Señora de Candelaria, Tenerife, Spain; 13Department of Neurology, Hospital Universitario Son Espases, Palma de Mallorca, Spain; 14Department of Neurology, Hospital Universitario de Albacete, Albacete, Spain; 15Department of Neurology, Fundació Salut Empordà, Figueres, Spain; 16Department of Neurology, Hospital Universitario Fundación Jiménez Díaz, Madrid, Spain; 17Department of Neurology, Complejo Hospitalario Universitario A Coruña, A Coruña, Spain; 18Department of Neurology, Hospital Arnau de Vilanova, Llíria, Spain; 19Department of Neurology, Complejo Asistencial de Segovia, Segovia, Spain; 20Department of Neurology, Hospital Universitario Reina Sofía, Córdoba, SpainCorrespondence: Jorge Maurino, Ribera del Loira 50, Madrid, 28042, Spain, Tel + 34 913 24 81 00, Email jorge.maurino@roche.comPurpose: Shared decision-making is critical in multiple sclerosis (MS) due to the uncertainty of the disease trajectory over time and the large number of treatment options with differing efficacy, safety and administration characteristics. The aim of this study was to assess patients’ decisional conflict regarding the choice of a disease-modifying therapy and its associated factors in patients with mid-stage relapsing-remitting multiple sclerosis (RRMS).Methods: A multicenter, non-interventional study was conducted. Adult patients with a diagnosis of RRMS (2017 revised McDonald criteria) and disease duration of 3 to 8 years were included. The level of uncertainty experienced by a patient when faced with making a treatment choice was assessed using the 4-item Decisional Conflict Scale. A battery of patient-reported and clinician-rated measures was administered to obtain information on symptom severity, illness perception, illness-related uncertainty, regret, MS knowledge, risk taking behavior, preferred role in the decision-making process, cognition, and self-management. Patients were recruited during routine follow-up visits and completed all questionnaires online using electronic tablets at the hospital. A multivariate logistic regression analysis was conducted.Results: A total of 201 patients were studied. Mean age (Standard deviation) was 38.7 (8.4) years and 74.1% were female. Median disease duration (Interquartile range) was 6.0 (4.0– 7.0) years. Median EDSS score was 1.0 (0– 2.0). Sixty-seven (33.3%) patients reported a decisional conflict. These patients had lower MS knowledge and more illness uncertainty, anxiety, depressive symptoms, fatigue, subjective symptom severity, a threatening illness perception, and poorer quality of life than their counterparts. Lack of decisional conflict was associated with MS knowledge (Odds ratio [OR]=1.195, 95% CI 1.045, 1.383, p=0.013), self-management (OR=1.049, 95% CI 1.013, 1.093, p=0.018), and regret after a healthcare decision (OR=0.860, 95% CI 0.756, 0.973, p=0.018) in the multivariate analysis.Conclusion: Decisional conflict regarding the selection of a disease-modifying therapy was a common phenomenon in patients with mid-stage RRMS. Identifying factors associated with decisional conflict may be useful to implement preventive strategies that help patients better understand their condition and strengthen their self-management resources.Keywords: multiple sclerosis, disease-modifying therapies, decision-making, decisional conflict, disease-related knowledge, self-management

The objective of the article is to propose the educational application on DC – DC converters based on the free software Python, which allows the analysis, experimentation, demonstration and design of the functions of DC – DC converters. Among the results is the development of five design modules such as Buck, boost, buck-boost, cuk and flyback converters. Among its practical benefits are that students are able to independently carry out their own experiments and designs in a safe environment and contribute to the national development of free computer applications. This type of software is generally privately licensed, with a high acquisition cost, so its counterparts, in free license, allow a greater reach among students and specialists. For the processing and analysis of the information collected, the calculation of absolute and relative frequencies was used as a statistical method.

Summary: Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we demonstrate interdependent relationships between hallmarks at the junctions of TME and cancer compartments and how they relate to sensitivity to different neoadjuvant treatments in 33 bladder cancer patients from the DUTRENEO trial. In conclusion, our findings may improve our understanding of tumor ecology and help identify new drug biomarkers.