Impact of tumor-specific targeting on the biodistribution and efficacy of siRNA nanoparticles measured by multimodality in vivo imaging

Targeted delivery represents a promising approach for the development of safer and more effective therapeutics for oncology applications. Although macromolecules accumulate nonspecifically in tumors through the enhanced permeability and retention (EPR) effect, previous studies using nanoparticles to deliver chemotherapeutics or siRNA demonstrated that attachment of cell-specific targeting ligands to the surface of nanoparticles leads to enhanced potency relative to nontargeted formulations. Here, we use positron emission tomography (PET) and bioluminescent imaging to quantify the in vivo biodistribution and function of nanoparticles formed with cyclodextrin-containing polycations and siRNA. Conjugation of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid to the 5' end of the siRNA molecules allows labeling with 64Cu for PET imaging. Bioluminescent imaging of mice bearing luciferase-expressing Neuro2A s.c. tumors before and after PET imaging enables correlation of functional efficacy with biodistribution data. Although both nontargeted and transferrin-targeted siRNA nanoparticles exhibit similar biodistribution and tumor localization by PET, transferrin-targeted siRNA nanoparticles reduce tumor luciferase activity by {approx}50% relative to nontargeted siRNA nanoparticles 1 d after injection. Compartmental modeling is used to show that the primary advantage of targeted nanoparticles is associated with processes involved in cellular uptake in tumor cells rather than overall tumor localization. Optimization of internalization may therefore be key for the development of effective nanoparticle-based targeted therapeutics

Coastal morphodynamic emulator for early warning short-term forecasts

- Name of the Software: XBeach version 1.23. Developers: Deltares/XBeach Open-Source Community; First year available: 2009; Cost: Free; Software availability:https://download.deltares.nl/en/download/xbeach-open-source/; Program size: 330.97 MB. - The deep learning-based emulator used for surrogating the XBeach morphodynamic module was implemented in Python language (version 3.9) based on TensorFlow library. The authors used a Windows 11 Home OS environment, CPU Intel(R) Core (TM) i7-8750H 2.20 GHz, RAM 16 GB, GPU Nvidia GeForce GTX 1060. The architecture of the model is available at: http://www.hydroshare.org/resource/b4ae97df748842a1800816b32a3d640 b.Data will be made available on request. Deep learning model for XBeach morphodynamic emulation (Original data) (HydroShare): https://www.hydroshare.org/resource/b4ae97df748842a1800816b32a3d640b/The use of numerical models to anticipate the effects of floods and storms in coastal regions is essential to mitigate the damages of these natural disasters. However, local studies require high spatial and temporal resolution numerical models, limiting their use due to the involved high computational costs. This constraint becomes even more critical when these models are used for real-time monitoring and warning systems. Therefore, the objective of this paper was to reduce the computational time of coastal morphodynamic models simulations by implementing a deep learning emulator. The emulator performance was evaluated using different scenarios run with the XBeach software, which considered different grid resolutions and the effects of a storm event in the morphodynamic patterns around a breakwater and a groin. The morphodynamic simulation time was reduced by 23%, and it was identified that the major restriction to reducing the computational cost was the hydrodynamic numerical model simulation.This research was supported by the Doctoral Grant SFRH/BD/151383/2021 financed by the Portuguese Foundation for Science and Technology (FCT), and with funds from the Ministry of Science, Technology and Higher Education, under the MIT Portugal Program. I. Iglesias also acknowledge the FCT financing through the CEEC program (2022.07420. CEECIND)

Èxits, problemes i grans desafiaments en la transició a una societat lliure de combustibles fòssils

Unidad de excelencia María de Maeztu MdM-2015-0552La resistència contra l'extracció massiva de carbó a Austràlia i el creixent moviment que advoca per una "transició justa" a una societat lliure de combustibles fòssils ha tingut cert èxit però s'enfronta a grans desafiaments, com es mostra en un nou mapa desenvolupat per investigadors del projecte internacional ACKnowl-EJ de l'Institut de Ciència i Tecnologia Ambientals de la Universitat Autònoma de Barcelona (ICTA-UAB) i per l'equip d'investigació australià de Justícia Ambiental (AEJ) per al Centre for Urban Research (RMIT University, Melbourne) en associació amb Friends of the Earth (FoE) Austràlia.La resistencia contra la extracción masiva de carbón en Australia y el creciente movimiento que aboga por una "transición justa" a una sociedad libre de combustibles fósiles ha tenido cierto éxito pero seenfrenta a grandes desafíos, como se muestra en un nuevo mapa desarrollado por investigadores del proyecto internacional ACKnowl-EJ del Instituto de Ciencia y Tecnología Ambientales de la Universidad Autónoma de Barcelona (ICTA-UAB) y por el equipo de investigación australiano de Justicia Ambiental (AEJ) para Centre for Urban Research (RMIT University, Melbourne) en asociación con Friends of the Earth (FoE) Australia.Resistance against massive coal-mining in Australia and a growing movement for a 'just transition' from fossil fuels have enjoyed some success but face massive challenges, as shown in a new map developed by researchers from the international ACKnowl-EJ project of the Institute of Environmental Science and Technology of the Universitat Autònoma de Barcelona (ICTA-UAB) and the Australian Environmental Justice (AEJ) research team at the Centre for Urban Research (RMIT University, Melbourne) in partnership with Friends of the Earth (FoE) Australia

O papel das variantes de significado incerto e variantes em regiões gênicas não codificantes de BRCA1/2 em pacientes com síndrome de predisposição hereditária ao câncer de mama e ovário

Sabe-se que 10% dos casos de câncer de mama e 25% dos casos de câncer de ovário são de origem hereditária e caracterizam a Síndrome do Câncer de Mama e Ovário Hereditários (HBOC), geralmente causada pela presença de variantes patogênicas nos genes BRCA1 e BRCA2, que conferem uma probabilidade aumentada para desenvolvimento destas neoplasias, somando 72%- 69% e 44-17%, respectivamente, até os 70 anos de idade. Pacientes diagnosticadas com HBOC possuem um manejo clínico específico, com ações de profilaxia, rastreamento e tratamento direcionado. Entretanto, um considerável número de pacientes apresenta o fenótipo clínico e se encaixa nos critérios de realização de teste genético para HBOC, apresenta resultado negativo ou inconclusivo, com a detecção de uma Variante de Significado Incerto (VUS). A presença de variantes patogênicas na região não codificante destes genes pode afetar a formação de uma proteína funcional em diferentes níveis, desde a transcrição do DNA em RNA, até sua tradução. Na prática clínica, estas áreas não são comumente analisadas e continuam pouco exploradas. Além disso, não existe um consenso estabelecido para a reavaliação e reclassificação de VUS em um período determinado, assim como a escolha de qual guia de categorização se adequa à nossa população específica. O presente trabalho, portanto, teve como objetivo explorar os mecanismos moleculares possivelmente associados com HBOC em pacientes que possuem resultado de avaliação genética de BRCA1/2 negativo ou inconclusivo, através de análises in silico e in vitro das alterações nas regiões não codificantes destes genes, assim como comparar os guias de classificação de variantes quanto seus critérios e metodologias durante a reclassificação de VUS. Durante este processo, duas variantes foram reclassificadas para provavelmente patogênicas, e uma destas foi avaliada através de bioinformática quanto seu impacto funcional na estrutura proteica para acúmulo de evidência. Foi possível discutir sobre os principais desafios presentes neste processo de reclassificação e os principais erros inerentes possivelmente associados ao mesmo, sugerindo pontos de atenção e monitoramento regular de informações. Foi realizada também uma busca por variantes de regiões não codificantes descritas na população brasileira com o intuito de verificar evidências e informações sobre sua patogenicidade e origem. Observou-se um significativo número de variantes não referenciadas e ausência de correlação com fenótipos clínicos. Além disso, pode-se argumentar sobre as áreas de coberturas dos testes genéticos utilizados e as altas taxas de miscigenação do país, que influenciam de forma negativa em uma possível caracterização e definição da carga genética da população, para identificação de mutações fundadoras e hotspots. Ainda, através de uma busca em bancos de dados, foi estabelecida uma rede de interação entre microRNAs que possuem BRCA1/2 e outras proteínas da via de Recombinação Homóloga como alvo e interagem direta- e indiretamente, resultando em 78 microRNAs citados. A elucidação de suas funções e impacto no processo de reparo está sendo realizado através de uma revisão de literatura.It is known that 10% of breast cancer cases and 25% of ovarian cancer cases are hereditary and characterize the Hereditary Breast and Ovarian Cancer Syndrome (HBOC), derived from the presence of pathogenic variants in BRCA1 and BRCA2 genes, which result in an increased probability of these neoplasms development, adding up to 72%-69% and 44-17%, respectively, to the age of 70. HBOC diagnosed patients receive distinct clinical management, with prophylaxis, screening, and targeted treatment. However, there is a significant number of patients that present the HBOC clinical phenotype and fit the genetic testing criteria, but receive a negative or inconclusive result, with the detection of a variant of uncertain significance (VUS). The presence of pathogenic variants in the non-coding regions of these genes can affect the protein establishment in different levels since the DNA to RNA transcription and its translation. In the current clinical practice, these areas are not commonly evaluated and remain unexplored. Besides, there is no established consensus on the re-evaluation and reclassification of VUS with a defined periodicity, as well as the choice of which classification guideline should we use in our specific population. This work aimed to explore the molecular mechanisms possibly associated with HBOC in patients with a negative or inconclusive result in the BRCA1/2 genetic test through in vitro and in silico evaluations of alterations located in the non-coding regions of these genes, as well as compare the variant classification guidelines and their criteria, and methodologies during a VUS case series reclassification attempt. During this process, two variants were reclassified into likely pathogenic, and one of them was still evaluated through bioinformatics on its functional impact to the protein structure to accumulate evidence. Our group was able to discuss about the main challenges present in the reclassification process and inherent errors possibly associated, making suggestions on lookout points and information regular monitoring, as new evidence arises. A search for variants located in the non-coding regions described in the Brazilian population was carried out in order to verify evidence regarding their pathogenicity and origin. A significant number of non-referenced variants and absence of clinical phenotype correlation were observed. In addition, it was able to argue about the coverage of the genetic tests used and the high miscegenation rates present in the Brazilian population, which can negatively influence in the identification of founder mutations and hotspots regions, in order to characterize and define the genetic loads’ population. Also, through a databases search, an interaction network of microRNAs that target BRCA1/2 and other proteins of homologous recombination pathway directly and indirectly was established, resulting in 78 microRNAs cited. The elucidation of their function and potential impact in the repair process is currently being carried out through a literature review

FUNDAMENTOS HISTÓRICOS DA NECESSIDADE DE NOVOS MODELOS DE GESTÃO DA ESCOLA PÚBLICA NO BRASIL

The central objective of this text is to analyze the historical fundamentals of the necessity of implanting military schools in Brazil. Thus, we historicize the origins of military education, problematize the dispute over the school space in the struggle for capitalist hegemony and finally, we present and analyze the contradiction between military principles and legal documents of education.Specifically we reflect on the context of a conflict which involves two public schools in the state of Paraná, namely: Gildo de Laranjeiras do Sul e Manoel Ribas de Guarapuava. In both schools, the manifestations of repudiation came from students, parents, teachers and employees, subjects directly involved with the school context. To this end, based on the Marxian ontological perspective, we can affirm that new models of public education management from the imposition of military education norms, that is, the transformation of the public school into a military college as if it were the solution to the problems of education, represents a setback for the management of public and democratic education in Brazil.El objetivo central de este texto es analizar los fundamentos históricos de la necesidad de implantar escuelas militares en Brasil.Así, historizamos los orígenes de la educación militar, problematizamos la disputa por el espacio escolar en la lucha por la hegemonía capitalista y finalmente presentamos y analizamos la contradicción entre principios militares y documentos legales de la educación.Específicamente reflexionamos sobre el contexto de un conflicto que involucra a dos escuelas públicas en el estado de Paraná, a saber: Gildo de Laranjeiras do Sul y Manoel Ribas de Guarapuava. En ambas escuelas, las manifestaciones de repudio vinieron de estudiantes, padres, profesores y empleados, sujetos directamente relacionados con el contexto escolar.Para ello, a partir de la perspectiva ontológica marxistapodemos afirmar que nuevos modelos de gestión de la educación pública a partir de la imposición de normas de educación militar, es decir, la transformación de la escuela pública en un colegio militar como si fuera la solución a los problemas de la educación, representa un retroceso para la gestión de la educación pública y democrática en Brasil.O objetivo central deste texto é analisar os fundamentos históricos da necessidade da implantação de escolas militares no Brasil. Assim, historicizamos as origens da educação militar, problematizamos a disputa do espaço escolar na luta pela hegemonia capitalista e por fim, apresentamos e analisamos a contradição entre os princípios militares e os documentos legais da educação. Especificamente refletimos a partir do contexto de conflito que envolve dois colégios públicos no estado do Paraná, a saber: Gildo de Laranjeiras do Sul e Manoel Ribas de Guarapuava. Em ambos os colégios as manifestações de repúdio partiram de estudantes, pais, professores e funcionários, sujeitos envolvidos diretamente com o contexto escolar. Para tanto, tendo como base a perspectiva ontológica marxiana podemos afirmar que novos modelos de gestão da educação pública a partir da imposição de normas da educação militar, ou seja, a transformação da escola pública em colégio militar como se fosse a solução para os problemas da educação, representa um retrocesso para a gestão da educação pública e democrática no Brasil

Childhood overweight and obesity abatement policies in Europe

Over the past two decades, a concerted effort to combat the rising tide of childhood overweight and obesity has taken shape. The World Health Organization (WHO) Commission on Ending Childhood Obesity (ECHO) provides recommendations for six priority areas of action, including the promotion of healthy food consumption, promotion of physical activity, preconception and pregnancy care, early childhood diet and physical activity, healthy nutrition and physical activity for school-aged children, and community-based weight management. This paper provides a snapshot of policies and measures aligned to these areas of action within the WHO European Region in order to encourage other countries to make similar efforts. Examples are drawn from Portugal (sugar-sweetened beverage tax, integrated nutrition strategy), the United Kingdom (soft drink levy, active commuting programs, urban design principles), Lithuania (prohibition of energy drinks), Norway (industry and government partnerships to promote healthier foods, nutrition education curriculum for schools), Hungary (tax subsidies to promote healthy diets), the European Union (cross-border marketing regulations, preconception and pregnancy care), Slovenia (food marketing restrictions), Spain (marketing restrictions within educational settings), Poland (investing in sports infrastructure), Russia (increasing sports participation), Estonia (redevelopment of the physical education curriculum), Netherlands (preconception and pregnancy care), Croatia (conditions to support breastfeeding), Austria (perinatal and early childhood nutrition), Czechia (life-course strategy), San Marino (nutrition and physical activity for school-aged children), Ukraine (potable water for schools), Ireland and Italy (community-based weight management approaches). Our findings suggest that a large disparity exists among the type and breadth of policies adopted by Member States, with a mix of single-issue policy responses and more cohesive strategies. The role of data, implementation research, and ongoing surveillance of country-level progress related to childhood overweight and obesity policies are discussed as an essential part of the iterative process of policy development. Additional work to systematically gather context-specific information on policy development, implementation, and reach according to ECHO's six areas of action by WHO European Region countries will inform future policy paradigms within the region.The authors gratefully acknowledge support through a grant from the Russian government in the context of the WHO European Office for the Prevention and Control of NCDs. Acesso de acordo com página web do editor da revista.info:eu-repo/semantics/publishedVersio

CONOCIMIENTO DE ADOLESCENTES MUJERES SOBRE ANTICONCEPCIÓN

Estudo quantitativo investigou o conhecimento de adolescentes sobre contracepção e foi realizado no segundo semestre de 2006. Os dados foram coletados com um questionário aplicado a 76 meninas com idade entre 13 e 18 anos que manifestaram interesse e obtiveram o consentimento escrito dos pais e/ou responsáveis. As principais fontes de informações sobre contracepção foram os pais, revistas, livros, jornais e profissionais da saúde; a camisinha masculina e a pílula foram os métodos conhecidos pela maioria das participantes. Ilustrando as desigualdades de poder nas relações de gênero, a confiança no parceiro ou a solicitação feita por esse são argumentos aceitos pelas adolescentes para negligenciar o uso do método anticoncepcional. Os resultados confirmaram que conhecer os métodos contraceptivos não é determinante para o seu uso, configurando a necessidade de maiores investimentos na educação sexual das adolescentes.This quantitative study investigated adolescents’ knowledge of contraception and was carried out in the second semester of 2006.The data were collected from a questionnaire given to 76 girls aged between 13 and 18 who had shown interest and who had been given written permission by parents or guardians. The main sources of information about contraception were the parents, magazines, books, newspapers and health professionals; the male condom and the Pill were the methods known to the majority of the participants. Illustrating gender power inequalities, confidence in the male partner or, simply, a request made by him are arguments accepted by female adolescents for neglecting the use of methods of contraception. The results confirm that simply knowing about methods of contraception is not determinant to their use, indicating that it is appropriate to make greater investments in adolescents’ sexual education.Estudio cuantitativo que ha investigado el conocimiento de adolescentes sobre anticoncepción y fue realizado en el segundo semestre de 2006. Los datos fueron recogidos con un cuestionario aplicado a 76 chicas con edad entre 13 y 18 años que manifestaron interés y tuvieron el consentimiento escrito de los padres y/o responsables. Las principales fuentes de información sobre contracepción fueron los padres, revistas, libros, periódicos y profesionales de la salud; el preservativo masculino y a píldora fueron los métodos conocidos por la mayoría de las participantes. Ilustrando las desigualdades de poder en las relaciones de género, la confianza en el compañero o la solicitación hecha por él son argumentos aceptos por las adolescentes para no usar método anticoncepcional. Los resultados confirmaron que conocer los métodos anticonceptivos no es determinante para su uso, configurando la necesidad de más inversiones en la educación sexual de las adolescentes

Toxicity of drilling fluids in aquatic organisms: a review

Offshore oil-well drilling has been a subject of great interest to environmental regulatory agencies worldwide. The drilling fluids used in this process involve a complex mixture of chemicals and are largely discharged into the ocean. Acute and chronic toxicity tests have been done to better understand the effects of different types of drilling fluids on aquatic organisms. The aim of this article was to analyze all the studies related to the toxicity of drilling fluids published during the period of 2000 to 2017 by conducting a thorough review through the Scopus and Science Direct databases. Out of 154 articles, only 25 showed relevant information about the toxicity of drilling fluids. Acute toxicity tests were the predominant tests employed, appearing in 56% of the articles. Invertebrates were the most evaluated taxa, used in 64% of cases and represented mainly by Crustacea (32%), Mollusca (16%), and other invertebrates. Vertebrates were represented only by fish, constituting 32% of the cases. Water-based drilling fluids (WBFs) (32%) were the most frequently tested, followed by synthetic-based fluids or muds (SBFs) (24%) and oil-based fluids (OBFs) (16%). Individual components were tested in 12% of the cases, while 16% of studies included more than one type of drilling fluid. After analyzing the toxicity of drilling fluids and the sensitivity of aquatic organisms presented in 25 articles published in scientific journals, we concluded that WBFs—showing, in general, lower values of median lethal concentrations than do natural oil- and SBFs—are the most toxic drilling fluids to invertebrates in the short term. The gaps of information found in this review indicate that future studies need to address the acute and chronic effects of WBFs in both juvenile and adult fish and in other vertebrates; they also need to address the chronic effects of non-aqueous-based fluids on adult invertebrates. As crustaceans are more sensitive to drilling fluids than are mollusks, it is also recommended that they be used in future studies

Simulation of saltwater intrusion in the Minho river estuary under sea level rise scenarios

Estuaries are areas that are vulnerable to the impacts of climate change. Understanding how these impacts affect these complex environments and their uses is essential. This paper presents a work based on an analytical solution and 2DH and 3D versions of the Delft3D numerical model to simulate the Minho River estuary and its saline wedge length under climate change projections. Temperature observations at several locations in the estuary region were selected to determine which model better simulated the temperature patterns. Specific simulations were performed for the observation periods. Sixteen numerical model scenarios were proposed, considering a varying tide, different river flows, and several SLR projections based on the RCP4.5 and RCP8.5 for 2050 and 2100. The analytical solution was also calibrated using the numerical model solutions. The results show that although there is no relevant stratification, there was a difference in both models in which in the worst climate change scenario, the length of the saline intrusion increased up to 28 km in the 2DH model and 30 km in the 3D model. It was concluded that the 3D model results were more precise, but both configurations can provide insights into how the saline intrusion will be affected. Additionally, the excellent agreement between the analytical solution and the results of the numerical models allowed us to consider the analytical solution a helpful tool for practical applications. It was demonstrated that freshwater discharges and bed slopes are the most critical drivers for the saline intrusion length in the Minho River estuary as they have more impact than the increase in sea level. Therefore, flow regulation can be an excellent way to control saline intrusion in the future.NNI -Nortel Networks Inc(2022.07420

From Stable to Lab—Investigating Key Factors for Sudden Deaths Caused by Streptococcus suis

Swine stocks are endemically infected with the major porcine pathogen Streptococcus (S.) suis. The factors governing the transition from colonizing S. suis residing in the tonsils and the exacerbation of disease have not yet been elucidated. We analyzed the sudden death of fattening pigs kept under extensive husbandry conditions in a zoo. The animals died suddenly of septic shock and showed disseminated intravascular coagulopathy. Genotypic and phenotypic characterizations of the isolated S. suis strains, a tonsillar isolate and an invasive cps type 2 strain, were conducted. Isolated S. suis from dead pigs belonged to cps type 2 strain ST28, whereas one tonsillar S. suis isolate harvested from a healthy animal belonged to ST1173. Neither S. suis growth, induction of neutrophil extracellular traps, nor survival in blood could explain the sudden deaths. Reconstituted blood assays with serum samples from pigs of different age groups from the zoo stock suggested varying protection of individuals against pathogenic cps type 2 strains especially in younger pigs. These findings highlight the benefit of further characterization of the causative strains in each case by sequence typing before autologous vaccine candidate selection