Nuevas dianas moleculares de la inflamación en modelos de daño renal. Estrategias de intervención terapéutica

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina. Departamento de Farmacología y Terapéutica. Fecha de lectura: 3-02-2017En este trabajo de tesis caracterizamos mecanismos moleculares de la inflamación renal y de respuestas accesorias inducidas por inmunosupresores de la familia de los anticalcineurínicos (ACNs) los cuales actuarían como inductoras de respuestas patogénicas asociadas a la nefrotoxicidad. En un modelo in vivo de nefrotoxicidad progresiva por CsA, observamos en el riñón incrementos de citoquinas y quimioquinas proinflamatorias, activación endotelial e infiltración de leucocitos desde etapas iniciales del tratamiento y de manera anticipada a la aparición de fibrosis. En este modelo, la inhibición de la quimioquina CCL20, identificada como una de las citoquinas con mayor expresión diferencial en el riñón de animales bajo tratamiento con CsA, resultó en un aparente mayor grado de inflamación y aceleración de la fibrosis. Además, el bloqueo de CCL20 resultó en menor infiltración renal de linfocitos Th17, pero no influyó en la respuesta Treg, ausente en el infiltrado inflamatorio de los ratones tratados con CsA. El bloqueo farmacológico in vivo o el tratamiento de ratones TLR4‐/‐ mejoró la inflamación, el daño tubular y la función renal de los animales tratados con CsA. En estudios in vivo e in vitro, CsA promovió la secreción de HMGB1, principal mediador endógeno de TLR4, y la inhibición del tránsito de HMGB1 impidió la síntesis de citoquinas proinflamatorias en células tubulares. La inactivación de TLR4 también inhibió la activación de la respuesta UPR ligada al estrés del retículo endoplásmico, que demostramos ser un mediador de la respuesta inflamatoria inducida por los ACNs. A nivel vascular, la inhibición farmacológica de TLR4 suprimió la respuesta inflamatoria inducida por ACNs en cultivos de células endoteliales y vasculares, y en cultivos ex vivo de aortas murinas. Una menor respuesta inflamatoria también se confirmó en aortas provenientes de ratones TLR4‐/‐ sometidas al tratamiento con ACNs. Por otra parte, en modelos inflamatorios de sepsis renal in vivo y en cultivo de células intrínsecas del riñón y macrófagos, la nanomedicina QM56 suprimió efectos proinflamatorios inducidos por señalización por TLR4 mediante la inhibición de la actividad de MAPKs. En conclusión, los ACNs desencadenan una respuesta inflamatoria renal y vascular mayoritariamente dependiente de la activación de TLR4 y que en el caso del riñón conduce a la fibrosis. Por lo tanto, TLR4 podría constituir una potencial diana terapéutica para tratamientos adyuvantes que pudieran prevenir la toxicidad renal y vascular dependiente de ACNs. Nanomedicinas de la familia de los polímeros terapéuticos podrían ser de utilidad en la inhibición de la señalización patogénica por TLR4.In this thesis work, we focused on the characterization of the molecular mechanisms of renal and vascular inflammation and associated responses induced by calcineurin inhibitors (CNIs). A murine model of progressive nephrotoxicity induced by CsA showed upregulation of renal proinflammatory cytokines and chemokines and endothelial activation proteins and also leukocyte kidney influx from early stages onwards and also previous to fibrosis onset. In this model, renal expression of the chemokine CCL20 was particularly high in CsA treated mice. Moreover, CCL20 blockade in these mice group resulted in amplification of the inflammatory process and anticipation of renal fibrosis. Moreover, CCL20 blockade led to a lesser renal Th17 lymphocyte infiltration whereas it did not affect the Treg response which otherwise remained absent in CsA‐treated mice. Both in vivo, pharmacological inhibition and the absence of TLR4 expression ameliorated CNI‐induced inflammation, tubular damage and renal function. HMGB1, the main TLR4 endogenous ligand, was secreted in response to CsA both in vivo and in vitro experimental models. Moreover, HMGB1 nuclear‐cytoplasmic transit inhibition, impeded proinflammatory cytokine expression in tubular cells. Furthermore, TLR4 suppression blocked endoplasmic reticulum stress and the unfolding protein response (UPR) activation by CNIs which participate in the CNI‐induced inflammatory response. On the other hand, TLR4 pharmacological inhibition suppressed the CNI‐induced inflammatory response in endothelial and smooth muscle vascular cells, and also in ex vivo model of mouse aorta. Experiments performed in aortas from TLR4‐/‐ mice treated with CNIs, confirmed a lower inflammatory response. Otherwise, the nanomedicine QM56 abolished the TLR4‐dependent CNI‐induced proinflammatory response through MAPK activity inhibition, both in a renal sepsis in vivo model and in relevant cell types involved in kidney injury, namely tubular and endothelial cells and also macrophages. In conclusion, results of this study show that CNIs trigger a TLR4‐dependent renal inflammatory response leading to fibrosis. In addition, TLR4 also mediated CNI inflammatory responses at the vascular level. In such a way, TLR4 could potentially be a relevant pharmacological target for adjuvant therapies aiming to prevent CNI toxic side effects. In addition, polymer‐drug conjugates nanomedicines could result in a novel therapy against pathogenic TLR4 signaling

Implementación de métodos computacionales para estimar las amplitudes angulares de los miembros inferiores durante el squat

In biomechanics, motion capture systems based on video and markers are the most widely used method to estimate kinematic parameters. However, from a technical standpoint, experimental errors in data capture are often related to the masking of markers during motion capture. This phenomenon generates data loss that can affect the analysis of the results. The lack of data is solved by increasing the number of cameras or using additional devices such as inertial sensors. However, those additions increase the experimental cost of this method. Nowadays, new computational methods can be used to solve such problems less expensively. This study implemented two computational methods based on Artificial Neural Networks (ANNs) and Support Vector Regression (SVR) to estimate the amplitude of limb angles during the execution of a movement on a single axis (i.e., the z-axis). The characteristics of the squats were used to train and validate the models. The results obtained include RMSE values lower than 14 (minimum RMSE of 5.35) and CC values close to 0.98. The estimated values are very close to the experimental amplitude angles, and the statistical analyses showed no significant differences between the distributions and means of the estimated amplitude values and their actual counterparts (p-value>0.05). The results show that these methods could help biomechanics researchers perform accurate analyses, decrease the number of cameras needed, reduce uncertainty, and avoid data loss problems.En biomecánica, los sistemas de captura de movimiento basados en video y en marcadores son el método más utilizado para la estimación de parámetros cinemáticos. A nivel técnico, los errores experimentales en la captura de datos suelen estar relacionados con el ocultamiento de los marcadores durante la captura del movimiento. Este fenómeno genera una pérdida de datos que puede afectar el análisis de los resultados. La falta de datos se resuelve aumentando el número de cámaras o utilizando dispositivos adicionales como sensores inerciales. Estas adiciones incrementan el costo experimental de este método. Actualmente, para resolver este tipo de problemas de forma menos costosa, se podrían utilizar nuevos métodos computacionales. Este estudio tiene como objetivo implementar dos métodos computacionales basados en red neuronal artificial (RNA) y regresión de vectores de soporte (RVS) para estimar la amplitud del ángulo de las extremidades durante la ejecución de un movimiento a partir de un solo eje (eje Z). Para entrenar y validar los modelos, se utilizaron características del ejercicio de squat. Los resultados obtenidos incluyeron valores de raíces de error cuadrático medio (RMSE) inferiores a 14 (RMSE mínimo de 5.35) y valores de CC cercanos a 0.98. Los valores estimados son muy cercanos a los ángulos de amplitud experimentales, los análisis estadísticos muestran que no hay diferencias significativas entre las distribuciones y las medias de los valores de amplitud estimados y los valores reales (valor p>0.05). Los resultados demuestran que estos métodos podrían ayudar a los investigadores en biomecánica a realizar análisis precisos, reduciendo el número de cámaras necesarias, reduciendo la incertidumbre y evitando problemas por perdida de datos

Effective nephroprotection against acute kidney injury with a star-shaped polyglutamate-curcuminoid conjugate

The lack of efective pharmacological treatments for acute kidney injury (AKI) remains a signifcant public health problem. Given the involvement of apoptosis and regulated necrosis in the initiation and progression of AKI, the inhibition of cell death may contribute to AKI prevention/recovery. Curcuminoids are a family of plant polyphenols that exhibit attractive biological properties that make them potentially suitable for AKI treatment. Now, in cultured tubular cells, we demonstrated that a crosslinked self-assembled star-shaped polyglutamate (PGA) conjugate of bisdemethoxycurcumin (StPGA-CL-BDMC) inhibits apoptosis and necroptosis induced by Tweak/TNFα/IFNγ alone or concomitant to caspase inhibition. St-PGA-CL-BDMC also reduced NF-κB activation and subsequent gene transcription. In vivo, St-PGA-CL-BDMC prevented renal cell loss and preserved renal function in mice with folic acid-induced AKI. Mechanistically, St-PGA-CL-BDMC inhibited AKI-induced apoptosis and expression of ferroptosis markers and also decreased the kidney expression of genes involved in tubular damage and infammation, while preserving the kidney expression of the protective factor, Klotho. Thus, due to renal accumulation and attractive pharmacological properties, the application of PGAbased therapeutics may improve nephroprotective properties of current AKI treatmentsTis work was supported by grants from the Instituto de Salud Carlos III, FEDER funds: PI16/02057, PI16/01900, PI18/01133, PI19/00815, ISCIII RETIC REDINREN RD16/0009; Sociedad Española de Nefrología; FRIAT; Comunidad de Madrid en Biomedicina B2017/BMD-3686 CIFRA2-CM; ERA-PerMed-JTC2018 (AC18/00071; DTS18/00032); Spanish Ministry of Economy and Competitiveness (Grant numbers SAF2013-44848-R, SAF2016-80427-R). Partly co-funded by FEDER (PO FEDER Valencian Community - 2014–2020

Abordaje de contextos desde los enfoques Narrativos. Departamentos del Valle, Cauca y Risaralda

Este trabajo tiene como objetivo evaluar los eventos psicosociales traumáticos para proponer recursos de afrontamiento psicosocial al sufrimiento por exposición a escenarios de violencia, desde el enfoque narrativo y el análisis del relato. Para ello se utilizan herramientas de análisis, diagnóstico e intervención, como el análisis de casos y relatos de vida para comprender las situaciones que se presentan y su relación con el medio de los protagonistas; la formulación de preguntas como una herramienta clave para conectar con las historias que se exponen; el planteamiento de estrategias de intervención psicosocial para realizar acompañamientos que le permitan a las comunidades fortalecer y potenciar los recursos de afrontamiento frente a los actos de violencia vividos; y la foto-voz como recurso que fortalece la narración mediante imágenes que exponen de manera creativa y artística, las acciones de los individuos y comunidades protagonistas de estos relatos en los escenarios de violencia. Estas herramientas permitieron observar como la narrativa utilizada de diferentes formas se convierte en un instrumento clave para contar historias que representen las vivencias de las personas tanto a nivel individual como a nivel grupal. Por lo tanto, este ejercicio se desarrolla con base en los siguientes textos, el Relato de Modesto Pacayá y el Caso de Peñas Coloradas, los cuales relatan acontecimientos de hechos violentos causados por el conflicto armado y las fuertes repercusiones que este puede traer a la vida de las personas, a su salud mental y desarrollo integral. Estos relatos se abordan bajo la perspectiva de preguntas orientadoras previamente establecidas, con el fin reflexionar en torno a las situaciones que se presentan en cada uno y al abordaje psicosocial. Para el relato de Modesto Pacayá se diseñan nueve preguntas orientadas hacia un acercamiento psicosocial ético y proactivo en la superación de las condiciones de victimización, que funcionen como herramienta de profundización para una oportunidad de entrevistar al protagonista; para el caso de Peñas Coloradas, se exponen tres estrategias psicosociales de fortalecimiento que buscan facilitar la potenciación de recursos de afrontamiento dentro de su comunidad. Finalmente, se recopilan cinco experiencias de foto-voz contando diferentes historias presentadas en algunos lugares del territorio colombiano, por medio de un informe analítico y reflexivo que resalta los actos de violencia en diferentes contextos.The purpose of this document is to evaluate traumatic psychological events from a narrative and story analysis point of view as well as suggest resources for psychological coping with the trauma and suffering causes by exposure to violent scenarios, for this reason, analytical, diagnostic and intervention tools are used, tools such as specific case analysis and life stories analysis in order to help understand the situations presented and their relationship with the environment surrounding the actors or characters. The formulation of questions is also a key tool to connect to the stories that expose. The approach of psychological intervention strategies to accompany different processes that allow communities to strengthen and improve their coping resources which will help them face and endure the acts of violence that are experienced; additionally, the Photovoice approach is a means that enriches the narrative through images that describe the actions of those who are the main characters of these life events in violent scenarios. These tools made it possible to observe how narration used in diverse ways becomes a fundamental aspect in telling stories which represent individual and collective experiences. Therefore, this exercise is developed based on the following texts, the Story of Modesto de Pacayá and the case of Peñas coloradas, which narrate violent events caused by the armed conflict and are about the strong repercussions that this can bring to people's lives, their mental health and integral development. These stories are approached under the perspective of previously established guiding questions to generate reflection upon the situations presented in each story of life and the psychosocial approach. For the story of Modesto Pacayá, nine questions are developed oriented towards an ethical and initiative-taking psychosocial approach in overcoming the conditions of victimization, which function as an-in-depth tool for an opportunity to interview the characters; for the case of Peñas Coloradas, three psychosocial strategies are proposed to facilitate the empowerment of coping resources within their community. Finally, five photo-voice experiences are compiled telling different stories presented in some places of Colombian territory, through an analytical and reflective report that highlights the acts of violence in different contexts

OncoOmics approaches to reveal essential genes in breast cancer: a panoramic view from pathogenesis to precision medicine

[Abstract] Breast cancer (BC) is the leading cause of cancer-related death among women and the most commonly diagnosed cancer worldwide. Although in recent years large-scale efforts have focused on identifying new therapeutic targets, a better understanding of BC molecular processes is required. Here we focused on elucidating the molecular hallmarks of BC heterogeneity and the oncogenic mutations involved in precision medicine that remains poorly defined. To fill this gap, we established an OncoOmics strategy that consists of analyzing genomic alterations, signaling pathways, protein-protein interactome network, protein expression, dependency maps in cell lines and patient-derived xenografts in 230 previously prioritized genes to reveal essential genes in breast cancer. As results, the OncoOmics BC essential genes were rationally filtered to 140. mRNA up-regulation was the most prevalent genomic alteration. The most altered signaling pathways were associated with basal-like and Her2-enriched molecular subtypes. RAC1, AKT1, CCND1, PIK3CA, ERBB2, CDH1, MAPK14, TP53, MAPK1, SRC, RAC3, BCL2, CTNNB1, EGFR, CDK2, GRB2, MED1 and GATA3 were essential genes in at least three OncoOmics approaches. Drugs with the highest amount of clinical trials in phases 3 and 4 were paclitaxel, docetaxel, trastuzumab, tamoxifen and doxorubicin. Lastly, we collected ~3,500 somatic and germline oncogenic variants associated with 50 essential genes, which in turn had therapeutic connectivity with 73 drugs. In conclusion, the OncoOmics strategy reveals essential genes capable of accelerating the development of targeted therapies for precision oncology.Instituto de Salud Carlos III; PI17/0182

Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4−/− mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2 −/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammationThis work was supported by grants from the Instituto de Salud Carlos III (Ministerio de Economía Competitividad, Gobierno de España): FEDER funds ISCIII RETIC REDINREN RD12/0021, PI11/02242, PI13/00047, PI14/0041, PI14/00386, PI15/01460; Comunidad de Madrid (CIFRA S2010/BMD-2378); Sociedad Española de Nefrología. Salary support: RR-D: CIFRA; CO-S: Fundación Conchita Rábago de Jiménez Díaz; CG-G and RRR-D: REDINREN; AO: Programa Intensificación Actividad Investigadora (ISCIII/Agencia Laín-Entralgo/CM); JE and MRO: Universidad Autónoma de Madrid; AMR: Contrato Miguel Serve (ISCIII

Iodotyrosines are biomarkers for preclinical stages of iodine-deficient hypothyroidism in Dehal1 knockout mice

BACKGROUND: Iodine is required for the synthesis of thyroid hormone (TH), but its natural availability is limited. Dehalogenase1 (Dehal1) recycles iodine from mono- and di-iodotyrosines (MIT, DIT) to sustain TH synthesis when iodine supplies are scarce, but its role in the dynamics of storage and conservation of iodine is unknown. METHODS: Dehal1 knockout mice (Dehal1KO) were generated by gene-trapping and the timing of expression and distribution was investigated by X-Gal staining and immunofluorescence using recombinant Dehal1-Betagalactosidase protein produced in fetuses and adult mice. Adult Dehal1KO and wild-type (Wt) animals were fed normal and iodine-deficient diets for 1 month and plasma, urine, and tissues were isolated for analyses. TH status was monitored including T4, T3, MIT, DIT, and urinary iodine concentration using a novel LC-MS-MS method and the Sandell-Kolthoff (S-K) technique throughout the experimental period. RESULTS: Dehal1 is highly expressed in the thyroid, is also present in kidneys, liver, and, unexpectedly, the choroid plexus. In vivo transcription of Dehal1 was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, Dehal1KO mice were euthyroid but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counter-intuitively, the urinary iodine concentration of Dehal1KO mice is two-fold higher than in Wt mice, indicating S-K measures both inorganic and organic iodine. Under iodine restriction, Dehal1KO mice rapidly develop profound hypothyroidism while Wt mice remain euthyroid, suggesting reduced retention of iodine in Dehal1KO mice. Urinary and plasma iodotyrosines were continually elevated throughout their life cycle, including the neonatal period, when pups are still euthyroid. CONCLUSIONS: Plasma and urine iodotyrosine elevation occurs in Dehal1-deficient mice throughout life. Therefore, measurement of iodotyrosines predicts an eventual iodine shortage and development of hypothyroidism in the pre-clinical phase. The prompt establishment of hypothyroidism upon the start of iodine restriction suggests that Dehal1KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage

Iodotyrosines Are Biomarkers for Preclinical Stages of Iodine-Deficient Hypothyroidism in Dehal1-Knockout Mice

[Background]: Iodine is required for the synthesis of thyroid hormone (TH), but its natural availability is limited. Dehalogenase1 (Dehal1) recycles iodine from mono- and diiodotyrosines (MIT, DIT) to sustain TH synthesis when iodine supplies are scarce, but its role in the dynamics of storage and conservation of iodine is unknown.[Methods]: Dehal1-knockout (Dehal1KO) mice were generated by gene trapping. The timing of expression and distribution was investigated by X-Gal staining and immunofluorescence using recombinant Dehal1-beta-galactosidase protein produced in fetuses and adult mice. Adult Dehal1KO and wild-type (Wt) animals were fed normal and iodine-deficient diets for 1 month, and plasma, urine, and tissues were isolated for analyses. TH status was monitored, including thyroxine, triiodothyronine, MIT, DIT, and urinary iodine concentration (UIC) using a novel liquid chromatography with tandem mass spectrometry method and the Sandell–Kolthoff (S-K) technique throughout the experimental period.[Results]: Dehal1 is highly expressed in the thyroid and is also present in the kidneys, liver, and, unexpectedly, the choroid plexus. In vivo transcription of Dehal1 was induced by iodine deficiency only in the thyroid tissue. Under normal iodine intake, Dehal1KO mice were euthyroid, but they showed negative iodine balance due to a continuous loss of iodotyrosines in the urine. Counterintuitively, the UIC of Dehal1KO mice is twofold higher than that of Wt mice, indicating that S-K measures both inorganic and organic iodine. Under iodine restriction, Dehal1KO mice rapidly develop profound hypothyroidism, while Wt mice remain euthyroid, suggesting reduced retention of iodine in the thyroids of Dehal1KO mice. Urinary and plasma iodotyrosines were continually elevated throughout the life cycles of Dehal1KO mice, including the neonatal period, when pups were still euthyroid.[Conclusions]: Plasma and urine iodotyrosine elevation occurs in Dehal1-deficient mice throughout life. Therefore, measurement of iodotyrosines predicts an eventual iodine shortage and development of hypothyroidism in the preclinical phase. The prompt establishment of hypothyroidism upon the start of iodine restriction suggests that Dehal1KO mice have low iodine reserves in their thyroid glands, pointing to defective capacity for iodine storage.The work was supported with public funding (AES PI16/00830) to José Carlos Moreno from the Carlos III Health Institute (ISCIII) of the Spanish Ministry of Health and Research, European FEDER Funds and, in part, from the DK15070 grant to Samuel Refetoff from the National Institutes of Health, USA. The rest of the authors have no funding contributions to declare.Peer reviewe

Case report: Efficacy of immunotherapy as conversion therapy in dMMR/MSI-H colorectal cancer: a case series and review of the literature

Immunotherapy has demonstrated a role in the therapeutic landscape of a small subset of patients with colorectal carcinoma (CRC) that harbor a microsatellite instability (MSI-H) status due to a deficient DNA mismatch repair (dMMR) system. The remarkable responses to immune checkpoint inhibitors (ICIs) are now being tested in the neoadjuvant setting in localized CRC, where the dMMR/MSI-H status can be found in up to 15% of patients, with remarkable results obtained in NICHE2 and 3 trials, among others. This case series aims to report our experience at a tertiary center and provide a comprehensive analysis of the possible questions and challenges to overcome if ICIs were established as standard of care in a neoadjuvant setting, as well as the potential role they may have as conversion therapy not only in locoregional advanced CRC but also in oligometastatic disease

Relatório Diagnóstico sobre o ensino superior e a ciência pós-covid-19 na Ibero-América : perspectivas e desafios 2022

O principal impacto no ensino a partir da declaração da pandemia foi a transição urgente e não planejada para modalidades de ensino remoto de emergência. A pandemia chegou e surpreendeu os países e instituições de ensino superior com capacidades diferentes para o desenvolvimento do ensino remoto de emergência e isso se refletiu nos resultados desiguais e nos desafios que tiveram que superar. Inicialmente apresentada como breve, a suspensão da presencialidade em muitos países da região ultrapassou 40 semanas e é o período sem aulas presenciais mais longo do mundo. A primeira reação das instituições foi criar comitês de crise para lidar com a emergência e garantir a continuidade do ensino de forma remota. A pandemia da covid-19 obrigou asinstituições universitárias a empreenderem esforços institucionais, acadêmicos,tecnológicos, etc., que não estavam em suas agendas e para os quais, em muitos casos,não houve preparação prévia. Esses esforços não foram apresentados de forma equilibrada no panorama regional. Embora as universidades da região já utilizassem plataformas virtuais de apoio ao ensino e à aprendizagem antes da pandemia, a maioria não eram propostas institucionais, mas sim iniciativas individuais. Esta foi a base para a continuidade da aprendizagem durante a emergência, e como a suspensão da presencialidade durou mais tempo, as instituições foram fortalecendo as propostas pedagógicas remotas de emergência no nível institucional, incorporando ferramentas e capacitação de professores. No nível institucional, para favorecer a continuidade da aprendizagem, as universidades não propuseram uma metodologia única, deixando para o pessoal docente a decisão sobre o uso das salas de aulas virtuais. Nelas, foram ministradas a maioria das aulas on-line sincronizadas, pelo menos em um primeiro momento. Embora os esforços das IES para oferecer apoio à comunidade universitária para garantir a continuidade da aprendizagem nas melhores condições possíveis sejam evidentes, havia limitações tecnológicas, tanto em termos de conectividade quanto de equipamentos, que nem sempre puderam ser cobertas. Também foram evidenciadas limitações pedagógicas, apesar do empenho para desenvolver competências básicas nos professores, visando facilitar o uso das possibilidades da educação a distância; e, por último, limitações socioemocionais, com esforços institucionais para reduzir a ansiedade e o stress gerados pelo isolamento e a desconexão social. A função de P&D universitária produziu um duplo movimento: por um lado, parou o planejamento e as ações em desenvolvimento até o surgimento da pandemia e, por outro, teve que disponibilizar e redirecionar recursos para produzir conhecimento sobre o SARS-CoV-2 e a covid-19, bem como para produzir recursos tecnológicos e auxiliar o sistema de saúde na prevenção do contágio, e no atendimento aos doentes e aos efeitos psicossociais da pandemia. As ações dos atores universitários para a contenção epidemiológica quanto à produção tecnológica e de conhecimento, são muito relevantes. Em alguns casos, surgiram de iniciativas institucionais nas IES com um histórico de capacidade de intervenção sociocomunitária e de articulação com o setor produtivo. Nesse sentido, as decisões políticas implementadas e os resultados obtidos foram, em maior ou menor grau, produto da articulação dos setores científicos e governamentais. No campo das IES, foram realizados muitos estudos e pesquisas sobre a SARS-CoV-2, a covid-19, a pandemia e seus efeitos em diferentes campos disciplinares. Em muitos casos, os esforços institucionais foram orientados para a produção e disponibilidade de recursos tecnológicos ou dispositivos de apoio social, especialmente para lidar com os efeitos dos processos do confinamento e luto pessoal. As pesquisas que não estão ligadas à covid-19 ou que não puderam ser mantidas foram adiadas em muitos países e podem enfrentar severas restrições para sua continuidade. Este risco é maior nas universidades dos países mais pobres que dependem de agências doadoras para o financiamento