ITQB: LA - PhD Theses
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- How mitotic transcription inactivation can modulate cell fate and cell identityPublication . Pedro, Catarina Alxandra Dinis de Andrade; Oliveira, Raquel; Duque, Paula"Upon entry into mitosis, transcriptional activity is sharply decreased. For many years, this decrease was viewed mainly as a passive consequence of chromosome condensation, which was thought to block access of the transcription machinery to DNA. However, it is now clear that the highly condensed, X-shaped mitotic chromosomes can still be compatible with transcription. Therefore, the question of why cells shut down transcription during mitosis remains. In order to proliferate, cells need to progress through mitosis fulfilling all the checkpoints required, ensuring mitotic fidelity and proper segregation of chromosomes to the two daughter cells. Similarly, transcriptional programs also need to be transmitted across mitosis. Regulators such as “mitotic bookmarkers” ensure such transcriptional programs and cellular identity propagation.(...)"
- From mechanics to thermodynamics of hexameric molecular motorsPublication . Pessoa, Victor Hugo de Mello; Sartori, Pablo"Molecular motors are protein assemblies that convert chemical energy into motion. This energy conversion can be understood as a transfer between chemical and mechanical processes, mediated by highly orchestrated conformational changes in protein structure. These motors are indispensable for all forms of life, sustaining both their metabolism and spatial organisation. Among them, hexameric ATPases form a broad and diverse group of molecular machines that play central roles in protein and DNA manipulation. Despite major advances in biochemistry, biophysics, and structural biology, the link between conformational changes and energy processing in these proteins remains poorly understood. This thesis aims to address this gap by integrating data from protein structures with novel interdisciplinary analytical tools.(...)"
- Mitotic physiology and chromosome architecture of human pluripotent stem cellsPublication . Pereira, Carolina; Oliveira, Raquel; Milagre, Inês"Human pluripotent stem cells (PSCs) are widely used in both basic and translational research, as well as regenerative medicine. However, 10 to 30% of PSCs present genomic and karyotypic abnormalities. PSCs exhibit unique characteristics that can help explain these abnormalities. For instance, they hyper-transcribe their genomes and experience increased replication stress during the S phase. PSCs are also known to have a more open chromatin and different histone modifications compared to somatic cells. This unique chromatin state may affect PSCs’ capability to establish proper chromosome assembly at the whole chromosome level or at specialised domains such as the centromere.(...)"
- Surround modulation in mouse visual cortex: spatial and feature structure, and the effects of visual experiencePublication . Belbut, Beatriz Ferreira; Petreanu, Leopoldo"Context profoundly shapes visual perception. Surround modulation (SM) in primary visual cortex (V1) - whereby a neuron’s responses are usually suppressed by stimuli beyond its receptive fi eld (RF) - is thought to implement these spatial contextual influences. A potential function of SM is to adapt visual processing to the features of relevant environments, thereby improving code effi ciency. If so, because natural visual statistics are not uniform, its regularities may be reflected in the organization of SM. However, the spatial and feature structure of SM, and its possible dependencies on cortical layer, state and visual experience, remain unresolved.(...)"
- Psychedelics, population dynamics, and the generation of experiencePublication . Arlandis, Jaime; Mainen, Zachary; McNamee, Daniel"At its core, the present work is structured around two different innovative contributions to the field of psychedelic research: first, results from an experimental project studying the effects of a psychedelic drug in rodents, and second, a set of philosophical and theoretical contributions to the field, centered on the extrapharmacological effects of these substances. While these may seem like unrelated contributions, I will argue that they are intimately connected: they can both be seen as additions to a growing body of publications urging for a critical reappraisal of the status of the field.(...)"
- The Role of Biliverdin Reductase A in MalariaPublication . Figueiredo, Ana; Soares, Miguel; Martins, Rui"Malaria, a life-threatening disease caused by Plasmodium spp., remains a major global health burden. While considerable progress has been made in characterizing host resistance mechanisms that reduce parasite burden during Plasmodium infection, our understanding of these pathways remains incomplete. Disease tolerance mechanisms that mitigate tissue damage during infection without directly affecting parasite burden are even less well-understood. This PhD thesis explores the hypothesis that biliverdin reductase A (BVRA) and its end product, unconjugated bilirubin, confer host protection against malaria through both resistance and disease tolerance mechanisms.(...)"
- Mechanisms of cross-modal transfer in cerebellar associative learningPublication . Kruse, Merit; Carey, MeganThe ability to generalize previously learned associations to new stimuli can be an important determinant for survival. Here we investigated neural mechanisms of generalization using delay eyeblink conditioning, a cerebellum-dependent form of learning, in which mice learn to close their eyelid in response to a neutral conditioned stimulus (CS) that predicts an air puff to the eye. Consistent with previous work in other species, we found that learning in response to a CS in one sensory modality subsequently facilitates the rate of acquisition to a different modality, a process termed cross-modal transfer (CMT). We find that in mice, learning to a visual CS is more readily enhanced by previous learning to a whisker somatosensory CS than the other way around. To investigate circuit mechanisms for CMT, we used genetically modified mouse lines in combination with optogenetic delivery of the CS to different cerebellar circuit elements. We found that training to a mossy fiber optogenetic CS induces CMT to both visual and somatosensory modalities
- DeeperInsightsintoSmallMoleculesModeofTargetModulationUsingHydrogenDeuteriumExchange-MassSpectrometryPublication . Malta, Catarina Féliz; Bortoluzzi, Alessio; Bandeiras, Tiago"Hydrogen deuterium exchange mass spectrometry (HDX-MS) has emerged as a powerful tool for probing protein:ligand interactions, providing critical insights into protein dynamics, structural rearrangements, and binding mechanisms. This work explores the application of HDX-MS to study two drug target proteins, Cyclophilin D (CypD) and Autotaxin (ATX). A deeper understanding of the molecular mechanisms underlying protein:ligand interactions emerged by integrating HDX-MS with complementary biophysical techniques, such as Surface Plasmon Resonance (SPR), Isothermal Titration Calorimetry (ITC), Circular Dichroism (CD), and X-ray crystallography,(...)"
- Modeling the directionality of interactions between cortical areasPublication . Carmona, Joana Pernadas; Machens, Christian"Investigating interactions between neural populations and their relationship to coding and behavior lies at the core of neuroscience. Covariance-based approaches are commonly used to study interactions in both local and brain-wide, multi-area circuits. The effective directionality of signal flow, in particular, can be inferred from the temporal structure of cross-covariance functions. Recent studies revealed that the directionality of inter-areal interactions can shift rapidly, depending on stimuli and task demands. These findings suggest that experimentally measured covariance metrics reflect not only the underlying synaptic connectivity but also dynamic influences such as inputs from other regions. Understanding how these metrics relate to circuit-level mechanisms remains a challenging task that warrants theoretical approaches.(...)"
- Olfr56 in Sickness and in HealthPublication . Da Silva Barros, André Boler Cláudio; Moita, Luís; Veldhoen, Marc"Sepsis is a life-threatening condition that originates from an exacerbated host response to infection. Understanding the pathophysiology of sepsis is crucial for the development of new treatments. In this context, a new perspective on the immune response has emerged, focusing on sensing organismal stress as a key factor in modulating the immune system's response to infection. Uncovering the receptors sensing such signals is then a relevant question to address.(...)"