@phdthesis{15352, abstract = {Epilepsy affects about 50 to 65 million people globally. It summarizes a spectrum of neurological disorders that have in common a hyperactivity of the neuronal network resulting in seizures. A common assumption is that an imbalance between neuronal excitation and inhibition is a key mechanism in seizure generation and epileptogeneisis. In at least one-third of the patients, current therapies have proven unsuccessful in treating seizure progression. One potential reason could be that the therapies only focus on neurons. Recent studies suggest that neuronal hyperactivity causes a microglial response, which reinstates brain homeostasis. Additionally, interactions between microglia and neurons have been shown to inhibit neuronal firing and dampen seizure activity. However, the exact relationship between microglia and seizure progression in epilepsy is yet to be elucidated. A main bottleneck is that several studies investigate microglia dynamics in ex vivo slice models, which can severely affect the microglia dynamics due to their rapid response to environmental changes. On the other hand, in vivo studies focus mostly on behavior characterization of the epileptic seizure phenotype and their long-term consequences on microglia activity leaving out the direct consequences of acute seizure activity on microglia dynamics. Here, we perform a pilot study to combine electroencephalography (EEG) and in vivo live imaging to directly monitor and correlate the onset of seizure activity with microglia response. To induce seizures, we take advantage of the kainic acid (KA) model, which represents similar neuropathological and electroencephalographic features seen in human patients with temporal lobe epilepsy (TLE). After confirmation of induction of the seizure and microglia activity in the hippocampus as a focal point, we investigated whether these changes also reached the primary visual cortex (V1) as a secondary generalized seizure activity. Indeed, we found that microglia changed their morphology at high doses of KA in the V1. Next, we optimized each of the two methodological components: for the EEG recording, our initial attempts under the microscope suffered from extensive electrical noise, which overlaid the actual signal. Thus, we built a customized Faraday-cage and confirmed that the signal-to-noise ratio was sufficiently reduced to be able to record brain oscillatory activity. For the in vivo live imaging of microglia, we had to optimize the imaging parameters, so that we would be able to detect microglial processes in a sufficient resolution to track their process changes. Finally, we combined both methodologies with the KA model. We confirmed that KA induced seizure activity and found first indication that those correlate with microglia volume changes. Overall, we have developed a first methodological approach, which allows the analysis of the acute effects of seizure onset on microglia. Future studies will have to continue to optimize the drift during imaging recording and the post-image analysis. }, author = {Murmann, Julie Stefanie}, issn = {2791-4585}, pages = {54}, publisher = {Institute of Science and Technology Austria}, title = {{Investigating acute microglia response to seizure activity in vivo: Combining 2-Photon imaging and EEG recording}}, doi = {10.15479/at:ista:15352}, year = {2024}, } @phdthesis{14821, abstract = {The hippocampus is central to memory formation, storage and retrieval over many timescales. Neurons in this brain area are highly selective to spatial position as well as to many other variables of the environment. It is believed that the selectivity patterns of hippocampal neurons reflect the structure of tasks an animal performs. However, especially at timescales longer than a few minutes or hours it is not fully known how these representations evolve, nor how they map to behaviour in the process. In this thesis, I monitored the evolution of hippocampal representations in a novel spatial-associative memory task for rats. Reward locations were associated with global sensory cues (i.e. context); animals had to remember the associations and dig for food in those locations only. I used in vivo electrophysiology to record the activity of the hippocampus dorsal CA1 neurons during the learning period of a few days. I report here a novel and simple method to classify behaviour performance to account for individual variability in learning speed and spurious performance unrelated to true task rule learning. Using this classification I was then able to investigate neural responses on different stages of learning matched across animals. On the first day of learning, I observed a fast formation of single-cell selectivity to task variables which remained stable over days. I also observed that reward tuning was not a single process but dependent on task-related cognitive load. At the population level, a linear decoding approach revealed a hierarchy in the representation of task variables that changed with learning. In the high-dimensional space of population activity, the representation of contexts was specific to each position in the maze, and could thus be better decoded if the position was known. The decoding of position did not improve with knowledge of other variables. As learning progressed, the hippocampal code underwent a reorganisation of high-variance directions in population activity, identified by principal component analysis. I found that dominant dimensions started carrying increasing amounts of information about task context specifically at those positions where it mattered for task performance. When I contrasted this with variables less relevant to task performance (e.g. movement direction), I did not observe differences in decoding quality over positions nor a reduction of dimensionality with learning. Overall, the largest changes in CA1 neural response with task learning happened in a matter of a few trials; over days, changes undetectable in single-cell statistics were responsible for re-structuring the hierarchy of neural representations at the population level; these changes were task-specific and reflected different stages of learning. This indicates that complex task learning may involve different magnitudes of response modulation in CA1, which happen at specific time scales linked to behaviour.}, author = {Chiossi, Heloisa}, issn = {2663-337X}, pages = {89}, publisher = {Institute of Science and Technology Austria}, title = {{Adaptive hierarchical representations in the hippocampus}}, doi = {10.15479/at:ista:14821}, year = {2024}, } @article{15323, abstract = {Supercomplexes of the respiratory chain are established constituents of the oxidative phosphorylation system, but their role in mammalian metabolism has been hotly debated. Although recent studies have shown that different tissues/organs are equipped with specific sets of supercomplexes, depending on their metabolic needs, the notion that supercomplexes have a role in the regulation of metabolism has been challenged. However, irrespective of the mechanistic conclusions, the composition of various high molecular weight supercomplexes remains uncertain. Here, using cryogenic electron microscopy, we demonstrate that mammalian (mouse) tissues contain three defined types of ‘respirasome’, supercomplexes made of CI, CIII2 and CIV. The stoichiometry and position of CIV differs in the three respirasomes, of which only one contains the supercomplex-associated factor SCAF1, whose involvement in respirasome formation has long been contended. Our structures confirm that the ‘canonical’ respirasome (the C-respirasome, CICIII2CIV) does not contain SCAF1, which is instead associated to a different respirasome (the CS-respirasome), containing a second copy of CIV. We also identify an alternative respirasome (A-respirasome), with CIV bound to the ‘back’ of CI, instead of the ‘toe’. This structural characterization of mouse mitochondrial supercomplexes allows us to hypothesize a mechanistic basis for their specific role in different metabolic conditions.}, author = {Vercellino, Irene and Sazanov, Leonid A}, issn = {1545-9985}, journal = {Nature Structural and Molecular Biology}, pages = {1061--1071}, publisher = {Springer Nature}, title = {{SCAF1 drives the compositional diversity of mammalian respirasomes}}, doi = {10.1038/s41594-024-01255-0}, volume = {31}, year = {2024}, } @article{18706, abstract = {We prove discrete-to-continuum convergence for dynamical optimal transport on Zd -periodic graphs with cost functional having linear growth at infinity. This result provides an answer to a problem left open by Gladbach, Kopfer, Maas, and Portinale (Calc Var Partial Differential Equations 62(5), 2023), where the convergence behaviour of discrete boundary-value dynamical transport problems is proved under the stronger assumption of superlinear growth. Our result extends the known literature to some important classes of examples, such as scaling limits of 1 -Wasserstein transport problems. Similarly to what happens in the quadratic case, the geometry of the graph plays a crucial role in the structure of the limit cost function, as we discuss in the final part of this work, which includes some visual representations.}, author = {Portinale, Lorenzo and Quattrocchi, Filippo}, issn = {1469-4425}, journal = {European Journal of Applied Mathematics}, pages = {1--29}, publisher = {Cambridge University Press}, title = {{Discrete-to-continuum limits of optimal transport with linear growth on periodic graphs}}, doi = {10.1017/s0956792524000810}, year = {2024}, } @unpublished{20571, abstract = {We prove the convergence of a modified Jordan--Kinderlehrer--Otto scheme to a solution to the Fokker--Planck equation in $\Omega \Subset \mathbb{R}^d$ with general, positive and temporally constant, Dirichlet boundary conditions. We work under mild assumptions on the domain, the drift, and the initial datum. In the special case where $\Omega$ is an interval in $\mathbb{R}^1$, we prove that such a solution is a gradient flow -- curve of maximal slope -- within a suitable space of measures, endowed with a modified Wasserstein distance. Our discrete scheme and modified distance draw inspiration from contributions by A. Figalli and N. Gigli [J. Math. Pures Appl. 94, (2010), pp. 107--130], and J. Morales [J. Math. Pures Appl. 112, (2018), pp. 41--88] on an optimal-transport approach to evolution equations with Dirichlet boundary conditions. Similarly to these works, we allow the mass to flow from/to the boundary $\partial \Omega$ throughout the evolution. However, our leading idea is to also keep track of the mass at the boundary by working with measures defined on the whole closure $\overline \Omega$. The driving functional is a modification of the classical relative entropy that also makes use of the information at the boundary. As an intermediate result, when $\Omega$ is an interval in $\mathbb{R}^1$, we find a formula for the descending slope of this geodesically nonconvex functional. }, author = {Quattrocchi, Filippo}, booktitle = {arXiv}, keywords = {gradient flows, Jordan–Kinderlehrer–Otto scheme, curves of maximal slope, optimal transport, Dirichlet boundary conditions, Fokker–Planck equation}, title = {{Variational structures for the Fokker-Planck equation with general Dirichlet boundary conditions}}, doi = {10.48550/arXiv.2403.07803}, year = {2024}, } @unpublished{20570, abstract = {We investigate the minimal error in approximating a general probability measure $\mu$ on $\mathbb{R}^d$ by the uniform measure on a finite set with prescribed cardinality $n$. The error is measured in the $p$-Wasserstein distance. In particular, when $1\le p2+ -dependent activator protein for secretion 2 (CAPS2), respectively. SPO modulates augmentation, the short-term plasticity associated with tonic release, and CAPS2 retains the increased RRP for initial responses in phasic response trains. The cytosolic protein CAPS2 showed a SV-associated distribution similar to the vesicular transmembrane protein SPO, and they were colocalized in the same terminals. We developed the “Flash and Freeze-fracture” method, and revealed the release of SPO-associated vesicles in both tonic and phasic modes and activity-dependent recruitment of CAPS2 to the AZ during phasic release, which lasted several minutes. Overall, these results indicate that GBR activation translocates CAPS2 to the AZ along with the fusion of CAPS2-associated SVs, contributing to persistency of the RRP increase. Thus, we identified structural and molecular mechanisms underlying tonic and phasic neurotransmitter release and their transition by GBR activation in MHb terminals.}, author = {Koppensteiner, Peter and Bhandari, Pradeep and Önal, Hüseyin C and Borges Merjane, Carolina and Le Monnier, Elodie and Roy, Utsa and Nakamura, Yukihiro and Sadakata, Tetsushi and Sanbo, Makoto and Hirabayashi, Masumi and Rhee, JeongSeop and Brose, Nils and Jonas, Peter M and Shigemoto, Ryuichi}, issn = {1091-6490}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, number = {8}, publisher = {National Academy of Sciences}, title = {{GABAB receptors induce phasic release from medial habenula terminals through activity-dependent recruitment of release-ready vesicles}}, doi = {10.1073/pnas.2301449121}, volume = {121}, year = {2024}, } @article{14843, abstract = {The coupling between Ca2+ channels and release sensors is a key factor defining the signaling properties of a synapse. However, the coupling nanotopography at many synapses remains unknown, and it is unclear how it changes during development. To address these questions, we examined coupling at the cerebellar inhibitory basket cell (BC)-Purkinje cell (PC) synapse. Biophysical analysis of transmission by paired recording and intracellular pipette perfusion revealed that the effects of exogenous Ca2+ chelators decreased during development, despite constant reliance of release on P/Q-type Ca2+ channels. Structural analysis by freeze-fracture replica labeling (FRL) and transmission electron microscopy (EM) indicated that presynaptic P/Q-type Ca2+ channels formed nanoclusters throughout development, whereas docked vesicles were only clustered at later developmental stages. Modeling suggested a developmental transformation from a more random to a more clustered coupling nanotopography. Thus, presynaptic signaling developmentally approaches a point-to-point configuration, optimizing speed, reliability, and energy efficiency of synaptic transmission.}, author = {Chen, JingJing and Kaufmann, Walter and Chen, Chong and Arai, Itaru and Kim, Olena and Shigemoto, Ryuichi and Jonas, Peter M}, issn = {1097-4199}, journal = {Neuron}, number = {5}, pages = {755--771.e9}, publisher = {Elsevier}, title = {{Developmental transformation of Ca2+ channel-vesicle nanotopography at a central GABAergic synapse}}, doi = {10.1016/j.neuron.2023.12.002}, volume = {112}, year = {2024}, } @phdthesis{15101, abstract = {The coupling between presynaptic Ca2+ channels and release sensors is a key factor that determines speed and efficacy of synapse transmission. At some excitatory synapses, channel–sensor coupling becomes tighter during development, and tightening is often associated with a switch in the reliance on different Ca2+ channel subtypes. However, the coupling topography at many synapses remains unknown, and it is unclear how it changes during development. To address this question, we analyzed the coupling configuration at the cerebellar basket cell (BC) to Purkinje cell (PC) synapse at different developmental stages, combining biophysical analysis, structural analysis, and modeling. Quantal analysis of BC–PC indicated that release probability decreased, while the number of functional sites increased during development. Although transmitter release persistently relied on P/Q-type Ca2+ channels in the time period postnatal day 7–23, effects of the Ca2+ chelator EGTA and BAPTA applied by intracellular pipette perfusion decreased during development, indicative of tightening of source-sensor coupling. Furthermore, presynaptic action potentials became shorter during development, suggesting reduced efficacy of Ca2+ channel activation. Structural analysis by freeze-fracture replica labeling (FRL) and transmission electron microscopy (EM) indicated that presynaptic P/Q-type Ca2+ channels formed nanoclusters throughout development, whereas docked vesicles were only clustered at later developmental stages. The number of functional release sites correlated better with the AZ number early in development, but match better with the Ca2+ channel cluster number at later stages. Modeling suggested a developmental transformation from a more random to a more clustered coupling nanotopography. Thus, presynaptic signaling developmentally approaches a point-to-point configuration, optimizing speed, reliability, and energy efficiency of synaptic transmission.}, author = {Chen, JingJing}, issn = {2663-337X}, pages = {84}, publisher = {Institute of Science and Technology Austria}, title = {{Developmental transformation of nanodomain coupling between Ca2+ channels and release sensors at a central GABAergic synapse}}, doi = {10.15479/at:ista:15101}, year = {2024}, } @phdthesis{18531, abstract = {Sex chromosomes and autosomes exhibit very different evolutionary dynamics. The Y chromosome usually degenerates, leaving many X-linked loci hemizygous in males. Since recessive X-linked mutations are always exposed to selection in males, selection is more efficient on the X chromosome than on autosomes on recessive mutations, leading to faster adaptation on the X chromosome than other genomic regions, if beneficial mutations are on average recessive (known as the Faster-X effect). In the presence of the functional, but non-recombining gametolog on the Y (as is often the case in young non-recombining regions), recessive mutations are sheltered from selection on the X chromosome. We model this scenario and show that the efficiency of selection is reduced on diploid X loci due to sheltering by the Y chromosome. Reduced efficiency of selection leads to slower adaptation and increased accumulation of deleterious mutations (Slower-X effect). We extended this model to explore the effect of sex-specific selection on degeneration of sex chromosomes, showing theoretically that male-limited genes degenerate on the X chromosome and female-biased genes degenerate on the Y chromosome. This prediction depends on the effective population size and the mutation rate, explaining the variety of sex chromosome degeneration patterns observed in nature. To test for direct evidence of a Slower-X (or Slower-Z) effect, we analyzed the ZW sex chromosomes of the flatworm Schistosoma japonicum, which have a very young non-recombining region with non-degenerated W. Diploid Z-linked genes have higher ratios of non-synonymous to synonymous polymorphisms than autosomal genes, supporting reduced efficiency of selection on the diploid Z region. These results provide evidence of sheltering by the W chromosome, a mechanism that could contribute to Z (X) chromosome degeneration, and illustrate contrasting evolutionary patterns in old and young sex chromosome regions. In addition, genes with sexspecific patterns of expression show opposite patterns of selection in the young (diploid) and old (hemizygous) Z, showing the complex manner in which sex-specific selection shapes the evolutionary patterns of sex chromosomes. }, author = {Mrnjavac, Andrea}, issn = {2663-337X}, keywords = {Sex chromosomes, evolution, selection, sheltering}, pages = {181}, publisher = {Institute of Science and Technology Austria}, title = {{Early stages of sex chromosome evolution}}, doi = {10.15479/at:ista:18531}, year = {2024}, } @phdthesis{18661, abstract = {Across the tree of life, distinct designs of cellular membranes have evolved that are both stable and flexible. In bacteria and eukaryotes this trade-off is accomplished by single-headed lipids that self-assemble into flexible bilayer membranes. By contrast, archaea in many cases possess both bilayer and double-headed, monolayer spanning bolalipids. This composition is believed to enable extremophile archaea to survive harsh environments. Here, through the creation of a minimal computational model for bolalipid membranes, we discover trade-offs when forming membranes using lipids of a single type. Similar to living archaea, we can tune the stiffness of bolalipid molecules. We find that membranes made out of flexible bolalipid molecules resemble bilayer membranes as they can adopt U-shaped conformations to enable higher curvatures. Conversely, rigid bolalipid molecules, like those found in archaea at higher temperatures, preferentially take on a straight conformation to self-assemble into liquid membranes that are stable, stiff, prone to pore formation, and which tear during membrane reshaping. Strikingly, however, our analysis reveals that it is possible to achieve the best of both worlds – membranes that are fluid, stable at high temperatures and flexible enough to be reshaped without leaking – through the inclusion of a small fraction of bilayer lipids into a bolalipid membrane. Additionally, the curvature-dependent softening of bolalipid membranes made of lipids with tension-sensitive conformation can also enable high rigidity at low curvatures while softening at high curvatures, making the membrane effectively a plastic material. Taken together, our study compares the different membrane designs across the tree of life and indicates how combining lipids can be used to resolve trade-offs when generating membranes for (bio)technological applications. }, author = {Santana de Freitas Amaral, Miguel}, isbn = {978-3-99078-046-6}, issn = {2663-337X}, pages = {57}, publisher = {Institute of Science and Technology Austria}, title = {{Archaeal membranes : In silico modelling and design}}, doi = {10.15479/at:ista:18661}, year = {2024}, } @unpublished{18670, abstract = {Across the tree of life, distinct designs of cellular membranes have evolved. In bacteria and eukaryotes single-headed lipids self-assemble into flexible bilayer membranes. By contrast, archaea often possess double-headed, monolayer spanning bolalipids, mixed with bilayer lipids, enabling them to survive in harsh environments. Here, using a minimal computational model for bolalipid membranes, we discover trade-offs when forming membranes. We find that membranes made out of flexible bolalipids resemble bilayer membranes as bolalipids exhibit conformational switch into U-shaped conformations to enable higher curvatures. Conversely, stiffer bolalipids, resembling those in extremophile archaea, take on straight conformations and form liquid membranes that are stiff, and prone to pore formation during membrane reshaping. Strikingly, we show how to achieve fluid bolalipid membranes that are both stable and flexible – by including small amounts of bilayer lipids, as archaea do. Our study explains how different organisms resolve trade-offs when generating membranes of desired material properties.}, author = {Santana de Freitas Amaral, Miguel and Frey, Felix F and Jiang, Xiuyun and Baum, Buzz and Šarić, Anđela}, booktitle = {bioRxiv}, title = {{Stability vs flexibility: Reshaping archaeal membranes in silico}}, doi = {10.1101/2024.10.18.619072}, year = {2024}, } @unpublished{18549, abstract = {Sex-linked and autosomal loci experience different selective pressures and evolutionary dynamics. X (or Z) chromosomes are often hemizygous, as Y (or W) chromosomes often degenerate. Such hemizygous regions can be under greater efficacy of selection, as recessive mutations are immediately exposed to selection in the heterogametic sex (the so-called Faster-X or Faster-Z effect). However, in young non-recombining regions, Y/W chromosomes often have many functional genes, and many X/Z-linked loci are therefore diploid. The sheltering of recessive mutations on the X/Z by the Y/W homolog is expected to drive a Slower-X (Slower-Z) effect for diploid X/Z loci, i.e. a reduction in the efficacy of selection. While the Faster-X effect has been studied extensively, much less is known empirically about the evolutionary dynamics of diploid X or Z chromosomes. Here, we took advantage of published population genomic data in the female-heterogametic human parasite Schistosoma japonicum to characterize the gene content and diversity levels of the diploid and hemizygous regions of the Z chromosome. We used different metrics of selective pressures acting on genes to test for differences in the efficacy of selection in hemizygous and diploid Z regions, relative to autosomes. We found consistent patterns suggesting reduced Ne, and reduced efficacy of purifying selection, on both hemizygous and diploid Z regions. Moreover, relaxed selection was particularly pronounced for female-biased genes on the diploid Z, as predicted by Slower-Z theory. }, author = {Mrnjavac, Andrea and Vicoso, Beatriz}, booktitle = {bioRxiv}, title = {{Evidence of a Slower-Z effect in Schistosoma japonicum}}, doi = {10.1101/2024.07.02.601697}, year = {2024}, } @phdthesis{18104, abstract = {We introduce a new all-electric platform, that strong couples light to mechanical motion by ensuring that the external environmental coupling dominates over internal mechanical dissipation. The system only has three everyday components: AC, DC, and a fip-chip, in which a metallized silicon nitride membrane is fipped on top of the device under test. This everyday electromechanical device can be operated at low or room temperature and has 10000× lower insertion loss than a comparable commercial quartz crystal, achieves a position imprecision matching state-of-the-art optical interferometer, and enables remote cooling of mechanical motion. The spatial properties of higher order mechanical modes are a promising feature for reconstructing unknown charge distributions. }, author = {Puglia, Denise}, issn = {2663-337X}, pages = {63}, publisher = {Institute of Science and Technology Austria}, title = {{Everyday electromechanics: Capacitive strong coupling to mechanical motion}}, doi = {10.15479/at:ista:18104}, year = {2024}, } @unpublished{18143, abstract = {Strong optomechanical coupling -- a regime where mechanical motion is damped by environmental radiation -- has traditionally required demanding experimental ingredients such as superconducting resonators, high-quality optical cavities, or large magnetic fields. Here we demonstrate a room temperature, cavity-free, all-electric device reaching this regime at radio frequencies, enabled by a mechanically compliant parallel-plate capacitor with a nanoscale plate separation and an aspect ratio exceeding 1,000. The device has four orders of magnitude lower insertion loss than a comparable commercial quartz crystal, and achieves a position imprecision rivaling an optical interferometer. With the help of a back-action isolation scheme, we observe radiative cooling of mechanical motion by a remote cryogenic load. This work provides a technologically accessible route to high-precision sensing, transduction, and signal processing.}, author = {Puglia, Denise and Odessey, Rachel H and Burns, Peter S. and Luhmann, Niklas and Schmid, Silvan and Higginbotham, Andrew P}, booktitle = {arXiv}, title = {{Room temperature, cavity-free capacitive strong coupling to mechanical motion}}, doi = {10.48550/arXiv.2407.15314}, year = {2024}, } @phdthesis{18642, abstract = {This thesis consists of two pieces of work in the broader feld of computational biology, both of which are methods for the analysis of large scale biological data, implemented in efcient software. Chapter 2 introduces a statistical software for causal discovery and inference from observed genetic marker and phenotypic trait data. We explore in simulation how well the method can fne-map genetic efects, fnd the correct causal structure among tens of traits and millions of genetic markers, and infer the causal efect size for the discovered causal relations. We then apply the method to 8 million markers and 17 traits from the UK Biobank and show that many relationships found with other methods are likely due to the efects of hidden confounders. Chapter 3 describes how this method can be applied to longitudinal data. I show how one can incorporate the background knowledge present in the known order of measurements to improve the accuracy of the causal discovery process, and explore the method’s ability to identify age specifc genetic efects, and how the error rates of this recovery are infuenced by missing data due to diferent censoring mechanisms. Chapter 4 introduces a statistical software for the comparison of chromatin contact maps based on the structural similarity index. We explore the robustness of the method to noise and size diferences of the compared maps, show how it can measure evolutionary conservation of topological features by providing a similarity ranking of syntenic regions, and fnally how it can detect alterations in 3D genome structure due to genetic mutations in samples of medical relevance. }, author = {Machnik, Nick N}, issn = {2663-337X}, pages = {138}, publisher = {Institute of Science and Technology Austria}, title = {{Algorithms for causal learning and comparative analysis for genomic data}}, doi = {10.15479/at:ista:18642}, year = {2024}, } @unpublished{18648, abstract = {Statistical causal learning in genomics relies on the instrumental variable method of Mendelian Randomization (MR). Currently, an overwhelming number of MR studies purport to show causal relationships among a wide range of risk factors and outcomes. Here, we show that selecting instrument variables from genome-wide association study estimates leads to high false discovery rates for many MR approaches, which can be greatly reduced by employing a graphical inference approach which: (i) explicitly tests instrumental variable assumptions; (ii) distinguishes direct from indirect factors in very high-dimensional data; (iii) discriminates pleiotropic from trait-specific markers, controlling for LD genome-wide; (iv) accommodates rare variants and binary outcomes in a principled way; and (v) identifies potential unobserved latent confounding. For 17 traits and 8.4M variants recorded for 458,747 individuals in the UK Biobank, we show that standard MR analysis gives an abundance of findings that disappear under stringent assumption checks, with many relationships reflecting potential unmeasured confounding. This implies that mixtures of temporal precedence and potential for reverse-causality prohibit understanding the underlying nature of phenotypic and genetic correlations in biobank data. We propose that well-curated longitudinal records are likely needed and that our approach provides a first-step toward robust principled screening for potential causal links. }, author = {Machnik, Nick N and Mahmoudi, Seyed Mahdi and Borczyk, Malgorzata and Krätschmer, Ilse and Bauer, Markus J. and Robinson, Matthew Richard}, booktitle = {bioRxiv}, title = {{Causal inference for multiple risk factors and diseases from genomics data}}, doi = {10.1101/2023.12.06.570392}, year = {2024}, } @phdthesis{18574, abstract = {Biological vision is unlike a camera; rather than transmitting light information faithfully, early visual circuits process the visual scene to convey only the relevant information in an efficient manner. Consequentially, the nature of this visual processing then depends on what is the relevant information in a scene and on the notion of efficiency. In this work, I study how visual processing is modulated by two different variations in the visual scene. First, I discovered that in the mouse (Mus musculus) retina, Retinal Ganglion Cells in the upper and lower visual field have differences in the center surround structure of their receptive fields. Comparison with models of efficient coding show that this adaptation likely evolved to cope with the brightness gradient from the sky to the ground that is pervasive in natural scenes. In the second project, I study how the downstream neurons in the Superior Colliculus dynamically change their temporal selectivity depending on the ambient luminance and behavioral state. As the scene gets darker or when the animal is is less aroused, the neuronal responses get laggier, while still maintaining their relative timing with respect to the population. Overall, this work emphasises the need to understand visual processing in the context of specific demands of the animal in its the environment. The adaptive changes in the visual system, from the retinal ganglion cells to the superior colliculus, highlight the intricate ways in which biological vision optimizes the processing of visual information. }, author = {Gupta, Divyansh}, isbn = {978-3-99078-050-3}, issn = {2663-337X}, pages = {86}, publisher = {Institute of Science and Technology Austria}, title = {{Visual adaptations to natural statistics}}, doi = {10.15479/at:ista:18574}, year = {2024}, } @phdthesis{18471, abstract = {Spatial omics technologies are enriching our understanding of complex biological samples, by allowing us to study their molecular composition while preserving the spatial relationships between molecules in their native context. As the field continues to advance, there are technical challenges that need to be addressed in order to take full advantage of the spatial capabilities of these methods. In this work, I present two technical developments that I established for multiplexed error robust FISH (MERFISH) throughout my PhD: (1) pushing the spatial resolution limits to the nanoscale, and (2) adding rich tissue context to the mouse brain transcriptome. To achieve nanoscale resolution with MERFISH in cultured cells, I combined it with stimulated emission depletion (STED) and expansion microscopy (ExM) to achieve a spatial resolution as low as ~20 nm, and explored the compatibility of MERFISH with singlemolecule localization microscopy (SMLM) techniques. To visualize targeted mRNAs in mouse brain tissue, I applied the comprehensive analysis of tissues across scales (CATS) toolbox, which provides an unbiased morphological readout by labeling the extracellular domain. I successfully established this method, which we call CATS-MERFISH-ExM, to work with thick mouse brain slices, being able to extract transcriptomics information with 3D tissue context. CATS-MERFISH-ExM enabled us to identify cell types and further visualize the subcellular distribution of transcripts in mouse brain tissue, shedding light on the neuropil-specific transcriptome. This method provides integrated information on cellular structure and transcriptomes in situ, and could potentially be applied with other modalities, opening new avenues for scientific discovery. }, author = {Agudelo Duenas, Nathalie}, isbn = {978-3-99078-044-2}, issn = {2663-337X}, pages = {97}, publisher = {Institute of Science and Technology Austria}, title = {{Visualizing the neuronal transcriptional landscape with tissue context}}, doi = {10.15479/at:ista:18471}, year = {2024}, }