Two-way attack on IAPP proteotoxicity with implications for diabetes

Funding Information: This study was supported by FCT–Fundação para a Ciência e a Tecnologia (grants UIDB/04567/2020 and UIDP/ 04567/2020 to CBIOS, PTDC/BIA-MOL/31104/2017, and PhD grants PD/BD/135504/2018 to AFR and UI/BD/151421/2021 to SF. RM is funded by FCT Scientific Employment Stimulus contract with the reference number CEEC/04567/ CBIOS/2020. Authors also acknowledge COFAC/ILIND – Cooperativa De Formação e Animação Cultural CRL/Instituto Lusófono de Investigação e Desenvolvimento (grant COFAC/ILIND/CBIOS/2/2021). iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344), which is cofunded by Fundação para a Ciência e Tecnologia (FCT) / Ministério da Ciência e do Ensino Superior, through national funds, and by FEDER under the PT2020 Partnership Agreement, is acknowledged (UIDB/04462/2020 and UIDP/04462/2020). CNS acknowledge the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme under Grant Agreement No. 804229. JAB gratefully acknowledges FCT-Fundação para a Ciência e a Tecnologia, I.P. through MOSTMICRO-ITQB R&D Unit-UIDB/04612/2020 and LS4FUTURE Associated Laboratory-LA/P/0087/2020, and by the framework of Article 23 of Decree-Law No.57/2017 of August 29. Publisher Copyright: Copyright © 2022 Raimundo, Ferreira, Pobre, Lopes-da-Silva, Brito, dos Santos, Saraiva, dos Santos and Menezes.Introduction: Diabetes is one of the major metabolic diseases worldwide. Despite being a complex systemic pathology, the aggregation and deposition of Islet Amyloid Polypeptide (IAPP), or amylin, is a recognized histopathological marker of the disease. Although IAPP proteotoxicity represents an important trigger of β-cell dysfunction and ultimately death, its exploitation as a therapeutic tool remains underdeveloped. The bioactivity of (poly)phenols towards inhibition of pathological protein aggregation is well known, however, most of the identified molecules have limited bioavailability. Methods: Using a strategy combining in silico, cell-free and cell studies, we scrutinized a unique in-house collection of (poly)phenol metabolites predicted to appear in the human circulation after (poly)phenols ingestion. Results: We identified urolithin B as a potent inhibitor of IAPP aggregation and a powerful modulator of cell homeostasis pathways. Urolithin B was shown to affect IAPP aggregation pattern, delaying the formation of amyloid fibrils and altering their size and morphology. The molecular mechanisms underlying urolithin B-mediated protection include protein clearance pathways, mitochondrial function, and cell cycle ultimately rescuing IAPP-mediated cell dysfunction and death. Discussion: In brief, our study uncovered urolithin B as a novel small molecule targeting IAPP pathological aggregation with potential to be exploited as a therapeutic tool for mitigating cellular dysfunction in diabetes. Resulting from the colonic metabolism of dietary ellagic acid in the human body, urolithin B bioactivity has the potential to be explored in nutritional, nutraceutical, and pharmacological perspectives.publishersversionpublishe

Guiding organs-on-chips towards applications:a balancing act between integration of advanced technologies and standardization

Organs-on-chips (OoC) are in vitro models that emulate key functionalities of tissues or organs in a miniaturized and highly controlled manner. Due to their high versatility, OoC have evolved as promising alternatives to animal testing for a more effective drug development pipeline. Additionally, OoC are revealing increased predictive power for toxicity screening applications as well as (patho-) physiology research models. It is anticipated that enabling technologies such as biofabrication, multimodality imaging, and artificial intelligence will play a critical role in the development of the next generation of OoC. These domains are expected to increase the mimicry of the human micro-physiology and functionality, enhance screening of cellular events, and generate high-content data for improved prediction. Although exponentially growing, the OoC field will strongly benefit from standardized tools to upgrade its implementational power. The complexity derived from the integration of multiple technologies and the current absence of concrete guidelines for establishing standards may be the reason for the slower adoption of OoC by industry, despite the fast progress of the field. Therefore, we argue that it is essential to consider standardization early on when using new enabling technologies, and we provide examples to illustrate how to maintain a focus on technology standards as these new technologies are used to build innovative OoC applications. Moreover, we stress the importance of informed design, use, and analysis decisions. Finally, we argue that this early focus on standards in innovation for OoC will facilitate their implementation

Multiplex PCR identification of eight clinically relevant Candida species

Invasive fungal infections, specifically candidemia, constitute major public health problems with high mortality rates. Therefore, in the last few years, the development of novel diagnostic methods has been considered a critical issue. Herein we describe a multiplex PCR strategy allowing the identification of 8 clinically relevant yeasts of the Candida genus, namely C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, C. guilliermondii, C. lusitaniae and C. dubliniensis. This method is based on the amplification of two fragments from the ITS1 and ITS2 regions by the combination of 2 yeast-specific and 8 species-specific primers in a single PCR reaction. Results from the identification of 231 clinical isolates are presented pointing to the high specificity of this procedure. Furthermore, several Candida isolates were identified directly from clinical specimens which also attests to the method's direct laboratory application. The results from the multiplex reactions with other microorganisms that usually co-infect patients also confirmed its high specificity in the identification of Candida species. Moreover, this method is simple and presents a sensitivity of approximately 2 cells per ml within 5 hours. Furthermore, it allows discrimination of individual Candida species within polyfungal samples. This novel method may therefore provide a clinical diagnostic procedure with direct applicability.Agostinho Carvalho was financially supported by a fellowship from Fundação para a Ciência e Tecnologia, Portugal (contract SFRH/BD/11837/2003). This study was supported by Fundação para a Ciência e Tecnologia, Portugal (POCI/SAU-ESP/61080/2004)

COVID-19 and lockdown, as lived and felt by university students

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).In the last 2 years, the COVID-19 pandemic has spread all over the world, forcing the closure of universities, among other unusual measures in recent history. (1) Background: This work is based on the study HOUSE-ULisbon, a survey carried out during the second confinement (March-May 2021) in Portugal with the collaboration of all the Faculties of the University of Lisbon (UL). The present work aims to explore gender differences in how first-year college students experienced and felt COVID-19 and the second confinement. (2) Methods: A questionnaire was carried out. In total, 976 university students (19.66 years (SD = 4.033); Min = 17 and Max = 65) from the first year of the UL were included, of which 69.5% (n = 678) were female, and 30.5% were male (n = 298). SPSS v. 26 was used for quantitative data and MAXQDA 2020 for qualitative data. (3) Results: Overall, students reported various symptoms of physical and mental discomfort (especially females). Statistically significant differences were found in the problems that could arise from the pandemic, such as the prevalence of higher anxiety and worries by females, and online gaming by males. In coping strategies, differences were found in leisure and family relationships, with greater difficulty on the female side. Social interaction was perceived as difficult or very difficult by both genders. As strategies for future pandemics, they highlighted a concerted effort between the government and media in the transmission of messages to the population, facilitating information, knowledge and adoption of protective behaviors. (4) Conclusions: These results are important data for activating or maintaining resources and services for first-year university students, who in some university institutions were supported during the pandemic by psychological, material (e.g., computers, internet), and financial support measures, which are now diminished or extinct. The impacts on their lives will certainly not be extinguished post-pandemic, and health, education, and public policy measures should be prioritized for this group. These results are important data for activating resources and services for students, informing health and education professionals, and supporting public policies.Ana Cerqueira—Foundation for Science and Technology (FCT) PhD Grant (SFRH/BD/148403/2019); Fábio Botelho Guedes—Foundation for Science and Technology (FCT) PhD Grant (SFRH/BD/148299/2019).info:eu-repo/semantics/publishedVersio

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

As ações do PET-Letras da UFSC no retorno presencial

This text starts from a politics of care and aims to report on the activities of PET-Letras of the Universidade Federal de Santa Catarina (PET-Letras UFSC) since the face-to-face return, that is, since March 2022 and 2023. Initially, we briefly describe the objectives of the Brazilian Tutorial Education Program and then move on to a brief narrative of the constitution of PET-Letras UFSC. From there, we will go on to list the activities of the six projects that make up PET: Languages, Events, Writing, Groups, Media, Management and Accessibility. We note that the projects are supported by the tripod research, teaching and extension and have a strong dialogue with the community - academic or not. We highlight some fundamental actions, such as language courses (among them, a Portuguese for Refugees), the Slam Estrela D'Alva, the magazine Preguiça, and the series of study groups proposed. Moreover, we show the role of accessibility, especially in Libras, of our PET, and the central role that, in the group, social networks have gained, both as a tool for dissemination and visibility of socially pressing agendas and present themselves as a fundamental space, today, of contact between the University and society. Finally, we conclude the text pointing to the ethical-political commitment that moves us and the importance of building a University that guarantees the permanence and autonomy of its students.Este texto parte de uma política do cuidado e tem por objetivo fazer um relato das atividades do PET-Letras da Universidade Federal de Santa Catarina (PET-Letras UFSC) desde o retorno presencial, ou seja, desde março de 2022 e 2023. Inicialmente, descrevemos sucintamente os objetivos do Programa de Educação Tutorial do Brasil, baseados numa política linguística do cuidado, para, então, passarmos a uma breve narrativa da constituição do PET-Letras UFSC. A partir daí, passamos a elencar as atividades dos seis projetos que compõe o PET: Idiomas, Eventos, Escrita, Grupos, Mídias, Gestão e Acessibilidade. Fazemos notar que os projetos estão apoiados no tripé pesquisa, ensino e extensão e têm forte diálogo com a comunidade – acadêmica ou não. Destacamos algumas ações fundamentais, como os cursos de idiomas (entre eles, um curso de Português para Refugiados), o Slam Estrela D’Alva, a revista Preguiça e a série de grupos de estudos propostos. Ademais, damos a ver o papel da acessibilidade, notadamente em Libras, de nosso PET, e o papel central que, no grupo, as redes sociais ganharam, tanto como ferramenta de divulgação quanto de visibilização de pautas socialmente prementes e se apresentam como espaço fundamental, hoje, de contato da Universidade com a sociedade. Por fim, concluímos o texto apontando para o compromisso ético-político que nos move e para a importância de se construir uma Universidade que garanta a permanência e a autonomia a seus e a suas discentes

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO