1,061 research outputs found

    Computational techniques to interpret the neural code underlying complex cognitive processes

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    Advances in large-scale neural recording technology have significantly improved the capacity to further elucidate the neural code underlying complex cognitive processes. This thesis aimed to investigate two research questions in rodent models. First, what is the role of the hippocampus in memory and specifically what is the underlying neural code that contributes to spatial memory and navigational decision-making. Second, how is social cognition represented in the medial prefrontal cortex at the level of individual neurons. To start, the thesis begins by investigating memory and social cognition in the context of healthy and diseased states that use non-invasive methods (i.e. fMRI and animal behavioural studies). The main body of the thesis then shifts to developing our fundamental understanding of the neural mechanisms underpinning these cognitive processes by applying computational techniques to ana lyse stable large-scale neural recordings. To achieve this, tailored calcium imaging and behaviour preprocessing computational pipelines were developed and optimised for use in social interaction and spatial navigation experimental analysis. In parallel, a review was conducted on methods for multivariate/neural population analysis. A comparison of multiple neural manifold learning (NML) algorithms identified that non linear algorithms such as UMAP are more adaptable across datasets of varying noise and behavioural complexity. Furthermore, the review visualises how NML can be applied to disease states in the brain and introduces the secondary analyses that can be used to enhance or characterise a neural manifold. Lastly, the preprocessing and analytical pipelines were combined to investigate the neural mechanisms in volved in social cognition and spatial memory. The social cognition study explored how neural firing in the medial Prefrontal cortex changed as a function of the social dominance paradigm, the "Tube Test". The univariate analysis identified an ensemble of behavioural-tuned neurons that fire preferentially during specific behaviours such as "pushing" or "retreating" for the animal’s own behaviour and/or the competitor’s behaviour. Furthermore, in dominant animals, the neural population exhibited greater average firing than that of subordinate animals. Next, to investigate spatial memory, a spatial recency task was used, where rats learnt to navigate towards one of three reward locations and then recall the rewarded location of the session. During the task, over 1000 neurons were recorded from the hippocampal CA1 region for five rats over multiple sessions. Multivariate analysis revealed that the sequence of neurons encoding an animal’s spatial position leading up to a rewarded location was also active in the decision period before the animal navigates to the rewarded location. The result posits that prospective replay of neural sequences in the hippocampal CA1 region could provide a mechanism by which decision-making is supported

    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Converging organoids and extracellular matrix::New insights into liver cancer biology

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    Primary liver cancer, consisting primarily of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a heterogeneous malignancy with a dismal prognosis, resulting in the third leading cause of cancer mortality worldwide [1, 2]. It is characterized by unique histological features, late-stage diagnosis, a highly variable mutational landscape, and high levels of heterogeneity in biology and etiology [3-5]. Treatment options are limited, with surgical intervention the main curative option, although not available for the majority of patients which are diagnosed in an advanced stage. Major contributing factors to the complexity and limited treatment options are the interactions between primary tumor cells, non-neoplastic stromal and immune cells, and the extracellular matrix (ECM). ECM dysregulation plays a prominent role in multiple facets of liver cancer, including initiation and progression [6, 7]. HCC often develops in already damaged environments containing large areas of inflammation and fibrosis, while CCA is commonly characterized by significant desmoplasia, extensive formation of connective tissue surrounding the tumor [8, 9]. Thus, to gain a better understanding of liver cancer biology, sophisticated in vitro tumor models need to incorporate comprehensively the various aspects that together dictate liver cancer progression. Therefore, the aim of this thesis is to create in vitro liver cancer models through organoid technology approaches, allowing for novel insights into liver cancer biology and, in turn, providing potential avenues for therapeutic testing. To model primary epithelial liver cancer cells, organoid technology is employed in part I. To study and characterize the role of ECM in liver cancer, decellularization of tumor tissue, adjacent liver tissue, and distant metastatic organs (i.e. lung and lymph node) is described, characterized, and combined with organoid technology to create improved tissue engineered models for liver cancer in part II of this thesis. Chapter 1 provides a brief introduction into the concepts of liver cancer, cellular heterogeneity, decellularization and organoid technology. It also explains the rationale behind the work presented in this thesis. In-depth analysis of organoid technology and contrasting it to different in vitro cell culture systems employed for liver cancer modeling is done in chapter 2. Reliable establishment of liver cancer organoids is crucial for advancing translational applications of organoids, such as personalized medicine. Therefore, as described in chapter 3, a multi-center analysis was performed on establishment of liver cancer organoids. This revealed a global establishment efficiency rate of 28.2% (19.3% for hepatocellular carcinoma organoids (HCCO) and 36% for cholangiocarcinoma organoids (CCAO)). Additionally, potential solutions and future perspectives for increasing establishment are provided. Liver cancer organoids consist of solely primary epithelial tumor cells. To engineer an in vitro tumor model with the possibility of immunotherapy testing, CCAO were combined with immune cells in chapter 4. Co-culture of CCAO with peripheral blood mononuclear cells and/or allogenic T cells revealed an effective anti-tumor immune response, with distinct interpatient heterogeneity. These cytotoxic effects were mediated by cell-cell contact and release of soluble factors, albeit indirect killing through soluble factors was only observed in one organoid line. Thus, this model provided a first step towards developing immunotherapy for CCA on an individual patient level. Personalized medicine success is dependent on an organoids ability to recapitulate patient tissue faithfully. Therefore, in chapter 5 a novel organoid system was created in which branching morphogenesis was induced in cholangiocyte and CCA organoids. Branching cholangiocyte organoids self-organized into tubular structures, with high similarity to primary cholangiocytes, based on single-cell sequencing and functionality. Similarly, branching CCAO obtain a different morphology in vitro more similar to primary tumors. Moreover, these branching CCAO have a higher correlation to the transcriptomic profile of patient-paired tumor tissue and an increased drug resistance to gemcitabine and cisplatin, the standard chemotherapy regimen for CCA patients in the clinic. As discussed, CCAO represent the epithelial compartment of CCA. Proliferation, invasion, and metastasis of epithelial tumor cells is highly influenced by the interaction with their cellular and extracellular environment. The remodeling of various properties of the extracellular matrix (ECM), including stiffness, composition, alignment, and integrity, influences tumor progression. In chapter 6 the alterations of the ECM in solid tumors and the translational impact of our increased understanding of these alterations is discussed. The success of ECM-related cancer therapy development requires an intimate understanding of the malignancy-induced changes to the ECM. This principle was applied to liver cancer in chapter 7, whereby through a integrative molecular and mechanical approach the dysregulation of liver cancer ECM was characterized. An optimized agitation-based decellularization protocol was established for primary liver cancer (HCC and CCA) and paired adjacent tissue (HCC-ADJ and CCA-ADJ). Novel malignancy-related ECM protein signatures were found, which were previously overlooked in liver cancer transcriptomic data. Additionally, the mechanical characteristics were probed, which revealed divergent macro- and micro-scale mechanical properties and a higher alignment of collagen in CCA. This study provided a better understanding of ECM alterations during liver cancer as well as a potential scaffold for culture of organoids. This was applied to CCA in chapter 8 by combining decellularized CCA tumor ECM and tumor-free liver ECM with CCAO to study cell-matrix interactions. Culture of CCAO in tumor ECM resulted in a transcriptome closely resembling in vivo patient tumor tissue, and was accompanied by an increase in chemo resistance. In tumor-free liver ECM, devoid of desmoplasia, CCAO initiated a desmoplastic reaction through increased collagen production. If desmoplasia was already present, distinct ECM proteins were produced by the organoids. These were tumor-related proteins associated with poor patient survival. To extend this method of studying cell-matrix interactions to a metastatic setting, lung and lymph node tissue was decellularized and recellularized with CCAO in chapter 9, as these are common locations of metastasis in CCA. Decellularization resulted in removal of cells while preserving ECM structure and protein composition, linked to tissue-specific functioning hallmarks. Recellularization revealed that lung and lymph node ECM induced different gene expression profiles in the organoids, related to cancer stem cell phenotype, cell-ECM integrin binding, and epithelial-to-mesenchymal transition. Furthermore, the metabolic activity of CCAO in lung and lymph node was significantly influenced by the metastatic location, the original characteristics of the patient tumor, and the donor of the target organ. The previously described in vitro tumor models utilized decellularized scaffolds with native structure. Decellularized ECM can also be used for creation of tissue-specific hydrogels through digestion and gelation procedures. These hydrogels were created from both porcine and human livers in chapter 10. The liver ECM-based hydrogels were used to initiate and culture healthy cholangiocyte organoids, which maintained cholangiocyte marker expression, thus providing an alternative for initiation of organoids in BME. Building upon this, in chapter 11 human liver ECM-based extracts were used in combination with a one-step microfluidic encapsulation method to produce size standardized CCAO. The established system can facilitate the reduction of size variability conventionally seen in organoid culture by providing uniform scaffolding. Encapsulated CCAO retained their stem cell phenotype and were amendable to drug screening, showing the feasibility of scalable production of CCAO for throughput drug screening approaches. Lastly, Chapter 12 provides a global discussion and future outlook on tumor tissue engineering strategies for liver cancer, using organoid technology and decellularization. Combining multiple aspects of liver cancer, both cellular and extracellular, with tissue engineering strategies provides advanced tumor models that can delineate fundamental mechanistic insights as well as provide a platform for drug screening approaches.<br/

    LIPIcs, Volume 251, ITCS 2023, Complete Volume

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    LIPIcs, Volume 251, ITCS 2023, Complete Volum

    Apraxias in the Diagnosis of Frontotemporal Dementia and Alzheimer’s Disease

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    Alzheimerin tauti alkaa tyypillisesti muistihäiriöllä, mutta työikäisillä alkuoire on usein jokin muu neuropsykologinen häiriö. Yksi näistä on apraksia, joka tarkoittaa aivovaurion aiheuttamaa puutosta tahdonalaisissa liikkeissä ja niiden ymmärtämisessä. Työikäisillä Alzheimerin tauti tunnistetaan epätyypillisyytensä vuoksi hitaammin kuin iäkkäillä potilailla ja sekoitetaan herkästi esimerkiksi otsa-ohimolohkorappeumien aiheuttamiin dementioihin tai psykiatrisiin oireyhtymiin. Apraksioiden yleisyydestä ja muodoista otsa-ohimolohkorappeumissa ei ole kokonaiskuvaa, joten niiden selvittäminen oli väitöstyön ensimmäinen tavoite. Toinen tavoite oli määrittää, millä tarkkuudella apraksioiden arviointiin kehitetty testi tunnistaa varhain alkavan Alzheimerin taudin. Systemaattisessa kirjallisuuskatsauksessa ilmeni, että kuhunkin otsa-ohimolohkorappeumien dementiamuotoon voi kehittyä oma apraksiaprofiilinsa: Käytösjohtoisessa tautimuodossa selkein löydös oli kasvoapraksia, joka auttoi erottelussa Alzheimerin taudista. Yläraaja-apraksia ilmeni hienovaraisempana. Sujumattomassa afasiassa raportoitiin sekä kasvo- että raaja-apraksiaa ja lisäksi puheapraksiaa. Semanttisessa dementiassa ei tyypillisesti havaittu mitään näistä vaan liikkeiden merkityksen ja esineiden käytön ymmärryksen häiriötä. Logopenisessä afasiassa ei ilmennyt kasvo-apraksiaa, ja raaja-apraksia oli samankaltainen kuin Alzheimerin taudissa. Dementia Apraxia Testin erottelutarkkuutta tutkittiin 50–70-vuotiaiden Alzheimer-potilaiden, psykiatristen potilaiden ja terveiden verrokkien välillä. Testin raajapistemäärä erotteli Alzheimer-potilaat terveistä herkkyydellä 92% ja tarkkuudella 100% (Youden-arvo .92). Potilasryhmien välillä erotteluherkkyys oli 83% ja -tarkkuus 100% (Youden-arvo .83). Kasvopistemäärä ja muistitestit olivat epätarkempia: ne erottelivat oikein 70–75% ja 66–78% potilaista. Otsa-ohimolohkorappeumien dementiamuotoihin näyttää siis kehittyvän apraksiaprofiileja, joiden kliininen pätevyys ja erotusdiagnostinen arvo on relevantti jatkotutkimuksen aihe. Varhain alkavan Alzheimerin taudin tunnistukseen Dementia Apraxia Test tuottaa lisähyötyä erityisesti eroteltaessa psykiatrisperäisistä muistihäiriöistä. Jatkossa tarvitaan tietoa testin toimivuudesta muissa etenevissä aivosairauksissa ja psykoosisairauksissa.Early dementia is challenging to diagnose in late middle age if the disease debuts with symptoms other than memory disturbance. Alzheimer’s disease, the most prevalent type of dementia, is commonly confused with psychiatric syndromes and frontotemporal dementia. One of the atypical symptoms of Alzheimer’s disease is apraxia, a deficit in voluntary action. Frontotemporal dementia may also involve apraxia, but there are no integrative data on the topic. This thesis synthesized current evidence on apraxias in frontotemporal dementia and explored whether an apraxia test could support the detection of Alzheimer’s disease in middle age. The systematic literature review suggested specific apraxia profiles for each of the four clinical variants of frontotemporal dementia. The behavioural variant involved early face apraxia, a feature that enabled differentiation from Alzheimer’s disease. Limb apraxia was present but subtler than in Alzheimer’s disease. The nonfluent variant typically showed remarkable face and limb apraxia, often in combination with apraxia of speech. The semantic variant showed preserved production of simple gestures but impaired understanding of tool use and gestures. The apraxia profile of the logopenic variant resembled that of Alzheimer’s disease, with remarkable limb apraxia and spared face praxis. The diagnostic accuracy of the Dementia Apraxia Test was estimated between samples of 50–70-year-old Alzheimer’s disease patients, psychiatric patients and healthy control participants. The limb praxis scale of the test distinguished between the Alzheimer’s disease group and the healthy participants, with 92% sensitivity and 100% specificity (Youden index .92). Between the Alzheimer’s disease and psychiatric groups, the limb scale reached 83% sensitivity and 100% specificity (Youden index 0.83). The face scale and memory tests were diagnostically less accurate, correctly classifying 70–75% and 66–78% of the patients, respectively. Apraxia profiles may thus support differentiation between early dementias, a hypothesis that requires future clinical validation. The Dementia Apraxia Test accurately detects Alzheimer’s disease in middle-aged populations and is especially recommended for clinical use to identify psychiatric aetiology in patients with memory disturbances. The test’s performance in other neurodegenerative diseases and psychotic conditions should be investigated next

    Impact of Yves Meyer's work on Kato's conjecture

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    We discuss how the works of Yves Meyer, together with Raphy Coifman, on Calder{\'o}n's program and singular integrals with minimal smoothness in the seventies, paved the way not only to a solution to Kato's conjecture for square roots of elliptic operators, but also to major developments in elliptic and parabolic boundary value problems with rough coefficients on rough domains.Comment: to be publishe

    Exotic Ground States and Dynamics in Constrained Systems

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    The overarching theme of this thesis is the question of how constraints influence collective behavior. Constraints are crucial in shaping both static and dynamic properties of systems across diverse areas within condensed matter physics and beyond. For example, the simple geometric constraint that hard particles cannot overlap at high density leads to slow dynamics and jamming in glass formers. Constraints also arise effectively at low temperature as a consequence of strong competing interactions in magnetic materials, where they give rise to emergent gauge theories and unconventional magnetic order. Enforcing constraints artificially in turn can be used to protect otherwise fragile quantum information from external noise. This thesis in particular contains progress on the realization of different unconventional phases of matter in constrained systems. The presentation of individual results is organized by the stage of realization of the respective phase. Novel physical phenomena after conceptualization are often exemplified in simple, heuristic models bearing little resemblance of actual matter, but which are interesting enough to motivate efforts with the final goal of realizing them in some way in the lab. One form of progress is then to devise refined models, which retain a degree of simplification while still realizing the same physics and improving the degree of realism in some direction. Finally, direct efforts in realizing either the original models or some refined version in experiment today are mostly two-fold. One route, having grown in importance rapidly during the last two decades, is via the engineering of artificial systems realizing suitable models. The other, more conventional way is to search for realizations of novel phases in materials. The thesis is divided into three parts, where Part I is devoted to the study of two simple models, while artificial systems and real materials are the subject of Part II and Part III respectively. Below, the content of each part is summarized in more detail. After a general introduction to entropic ordering and slow dynamics we present a family of models devised as a lattice analog of hard spheres. These are often studied to explore whether low-dimensional analogues of mean-field glass- and jamming transitions exist, but also serve as the canonical model systems for slow dynamics in granular materials more generally. Arguably the models in this family do not offer a close resemblance of actual granular materials. However, by studying their behavior far from equilibrium, we observe the onset of slow dynamics and a kinetic arrest for which, importantly, we obtain an essentially complete analytical and numerical understanding. Particularly interesting is the fact that this understanding hinges on the (in-)ability to anneal topological defects in the presence of a hardcore constraints, which resonates with some previous proposals for an understanding of the glass transition. As another example of anomalous dynamics arising in a magnetic system, we also present a detailed study of a two-dimensional fracton spin liquid. The model is an Ising system with an energy function designed to give rise to an emergent higher-rank gauge theory at low energy. We show explicitly that the number of zero-energy states in the model scales exponentially with the system size, establishing a finite residual entropy. A purpose-built cluster Monte-Carlo algorithm makes it possible to study the behavior of the model as a function of temperature. We show evidence for a first order transition from a high-temperature paramagnet to a low-temperature phase where correlations match predictions of a higher-rank coulomb phase. Turning away from heuristic models, the second part of the thesis begins with an introduction to quantum error correction, a scheme where constraints are artificially imposed in a quantum system through measurement and feedback. This is done in order to preserve quantum information in the presence of external noise, and is widely believed to be necessary in order to one day harness the full power of quantum computers. Given a certain error-correcting code as well as a noise model, a particularly interesting quantity is the threshold of the code, that is the critical amount of external noise below which quantum error correction becomes possible. For the toric code under independent bit- and phase-flip noise for example, the threshold is well known to map to the paramagnet to ferromagnet transition of the two-dimensional random-bond Ising model along the Nishimori line. Here, we present the first generalization of this mapping to a family of codes with finite rate, that is a family where the number of encoded logical qubits grows linearly with the number of physical qubits. In particular, we show that the threshold of hyperbolic surface codes maps to a paramagnet to ferromagnet transition in what we call the 'dual'' random-bond Ising model on regular tessellations of compact hyperbolic manifolds. This model is related to the usual random-bond Ising model by the Kramers-Wannier duality but distinct from it even on self-dual tessellations. As a corollary, we clarify long-standing issues regarding self-duality of the Ising model in hyperbolic space. The final part of the thesis is devoted to the study of material candidates of quantum spin ice, a three-dimensional quantum spin liquid. The work presented here was done in close collaboration with experiment and focuses on a particular family of materials called dipolar-octupolar pyrochlores. This family of materials is particularly interesting because they might realize novel exotic quantum states such as octupolar spin liquids, while at the same time being described by a relatively simple model Hamiltonian. This thesis contains a detailed study of ground state selection in dipolar-octupolar pyrochlore magnets and its signatures as observable in neutron scattering. First, we present evidence that the two compounds Ce2Zr2O7 and Ce2Sn2O7 despite their similar chemical composition realize an exotic quantum spin liquid state and an ordered state respectively. Then, we also study the ground-state selection in dipolar-octupolar pyrochlores in a magnetic field. Most importantly, we show that the well-known effective one-dimensional physics -- arising when the field is applied along a certain crystallographic axis -- is expected to be stable at experimentally relevant temperatures. Finally, we make predictions for neutron scattering in the large-field phase and compare these to measurements on Ce2Zr2O7
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