VIII ENCUENTRO DE JÓVENES INVESTIGADORES EN EL EXTRANJERO

Tomar decisiones sobre el futuro profesional de uno mismo, no es sencillo. Se necesitan ciertos ingredientes para que la carrera profesional y, sobre todo, la progresión entre diferentes puestos no sea un ejercicio difícil y ligado a una incertidumbre excesiva. Las responsabilidades y nuestras metas ligadas, a veces, con una escasa información, nos hace tomar decisiones que podrían estar basadas en mejores datos. En esta ponencia, los investigadores tendrán la posibilidad de conocer los pasos que ayudan a tomar decisiones sobre su futuro profesional y se darán herramientas para facilitar esta toma de decisión y explorar las potenciales carreras que pueden desarrollar.

SIRT7 regulates gene expression via deacetylation of the histone proteins that pack DNA into chromatin. In cancer, SIRT7 maintains genes involved in cancer progression and metastasis, and it is thus regarded as an anticancer target. However, the activity of SIRT7, dependent on binding to DNA-histone complexes (nucleosomes), makes it difficult to develop assays and probe compounds to assess targeted therapies. We elucidated the unique molecular mechanisms that drive SIRT7 binding and activity on nucleosomes, through a combination of mechanism-based stabilization and cryogenic electron microscopy (cryoEM). Moreover, mechanism-based trapping at the different preferred substrate positions of SIRT7 allowed us to dissect its substrate specificity on chromatin and to engineer its activity towards altered selectivity. With this knowledge in hand, we built semi-synthetic nucleosome sensors, with a fluorophore-quencher pair where SIRT7 activity liberates the fluorescence. These fluorogenic tools permit measuring SIRT7 activity in real time and will enable high-throughput screening, probe development, and high-resolution characterization by single-molecule fluorescence microscopy. In summary, we have developed powerful tools for the mechanistic study of SIRT7 and other deacetylases, and to help in the development of cancer therapeutics.

La enfermedad hepática grasa asociada a la disfunción metabólica (en inglés, MAFLD) conlleva la aparición de diversos fenómenos como la inflamación, el depósito de grasa y la fibrosis, que suelen detectarse mediante una biopsia hepática. Sin embargo, esta técnica es muy invasiva y puede dar lugar a complicaciones. El uso de métodos de imagen no invasivos para el diagnóstico de la MAFLD es por lo tanto necesario y puede mejorar el seguimiento de los pacientes. Con la Imagen por Resonancia Magnética podemos obtener diferentes biomarcadores de la MAFDL. Por ejemplo, la elastografía por RM permite cuantificar las propiedades biomecánicas del hígado y con ello evaluar el grado de fibrosis hepática. La investigación en un contexto preclínico es necesaria para desarrollar estos métodos de imagen y así validarlos para su uso clínico.

Las infecciones bacterianas continúan representando una amenaza global significativa, agravada por el aumento de la resistencia a los antibióticos y la falta de nuevos antimicrobianos. Aunque gran parte de la investigación hasta ahora se ha centrado en la resistencia bacteriana, las interacciones entre las bacterias y el huésped, que también son fundamentales en la persistencia de las infecciones, han sido menos exploradas.

Mediante el uso de un modelo de cultivo celular diseñado para replicar las condiciones de las vías respiratorias humanas y caracterizar infecciones, hemos identificado nuevos mecanismos adaptativos y de tolerancia a los antibióticos en infecciones por Pseudomonas aeruginosa que contribuyen a su persistencia y van más allá de la resistencia convencional a los antimicrobianos. Estos hallazgos destacan el papel crítico de las interacciones huésped-patógeno en las infecciones bacterianas y resaltan la importancia de comprender estas dinámicas para desarrollar estrategias terapéuticas más eficaces en el tratamiento de las enfermedades infecciosas.

Evaluating the number of blood leukocytes and their activation status is crucial for infectious diseases diagnosis. Paper-based biosensors using gold nanoparticles (AuNPs) could detect membrane markers in leukocytes, enabling quick immune response testing. However, integrating cells into these sensors presents a challenge. This study aimed to identify the factors influencing leukocyte-substrate interactions and detect immune response biomarkers. Whatman papers with different porous diameter (W42<W40<W43<W41) were used to fabricate 4-layer origamis. First, leukocytes were suspended, labeled with SYTO9, and then applied to the paper. The W42 paper retained all cells, while others, like W43, allowed selective filtration, particularly for lymphocytes and monocytes. The study also tested CD66b detection in neutrophils and HL-60 cells using AuNPs decorated with anti-CD66b antibodies (Ab). The results confirmed that leukocytes can be integrated into paper biosensors and the Ab-AuNPs can be used to analyse them providing precise immune response monitoring. This approach lays the foundation for real-time, decentralized immune monitoring with colorimetric tests based on AuNPs.

This presentation will explore the transformative potential of integrating robots into work teams. As we enter the Fifth Industrial Revolution, robots are becoming proactive teammates, enhancing productivity and innovation. However, they also pose several challenges. Drawing on psychological and team science research, the presentation will discuss the concept of human-robot teams, where humans and robots collaborate on joint tasks and coordinate their actions to achieve shared goals. Real-world examples, such as the Da Vinci Xi Surgical System in healthcare, will illustrate the benefits and challenges of this integration. Emphasis will be placed on the importance of trust, as well as employee experiences and readiness for successful human-robot teaming.

By offering spatial, molecular, and morphological data over time, live-cell imaging provides a deeper comprehension of cellular and signaling events pivotal in cancer-related processes, such as tumor heterogeneity, treatment response, and tumor invasion. This dynamic cellular response holds promise in refining clinical outcomes by pinpointing biomarkers or actionable targets to enhance therapeutic effectiveness. Nevertheless, live imaging of intricate systems, like co-culture assays or intravital microscopy and organotypic brain slices, generates big and complex datasets, necessitating tailored analytical pipelines to interpret the vast amount of dynamic features captured. Dr. Alieva’s group, imAIgene lab, specializes in computational approaches for dynamic imaging analysis. Their focus lies in gaining insights into various aspects of cancer biology, including cellular immunotherapy mode-of-action against tumors, tumor heterogeneity in treatment response, and tumor invasion. In this seminar, Dr. Alieva will highlight several recent research applications that offer biological insights into these topics. These applications encompass a range of techniques, from single-cell dynamic classification and dynamic cellular interactome analysis to the utilization of organoid models for studying intratumor heterogeneity. Additionally, the lab employs multi-omics approaches that integrate imaging with single-cell transcriptomic information, to leverage the results from dynamic imaging assays to improve therapeutic efficacy and facilitate biomarker discovery.

Key references:

Alieva M, et al Bridging live-cell imaging and next-generation cancer treatment. Nat Rev Cancer. 2023

Dekkers JF&Alieva M et al. Uncovering the mode of action of engineered T cells in patient cancer organoids. Nat Biotechnol. 2023

Alieva M, et al. BEHAV3D: a 3D live imaging platform for comprehensive analysis of engineered T cell behavior and tumor response. Nat Protoc. 2024