@unpublished{18648, abstract = {Statistical causal learning in genomics relies on the instrumental variable method of Mendelian Randomization (MR).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{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}, } @article{15084, abstract = {GABAB receptor (GBR) activation inhibits neurotransmitter release in axon terminals in the brain, except in medial habenula (MHb) terminals, which show robust potentiation. However, mechanisms underlying this enigmatic potentiation remain elusive. Here, we report that GBR activation on MHb terminals induces an activity-dependent transition from a facilitating, tonic to a depressing, phasic neurotransmitter release mode. This transition is accompanied by a 4.1-fold increase in readily releasable vesicle pool (RRP) size and a 3.5-fold increase of docked synaptic vesicles (SVs) at the presynaptic active zone (AZ). Strikingly, the depressing phasic release exhibits looser coupling distance than the tonic release. Furthermore, the tonic and phasic release are selectively affected by deletion of synaptoporin (SPO) and Ca 2+ -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{17183, abstract = {The photon blockade breakdown in a continuously driven cavity QED system has been proposed as a prime example for a first-order driven-dissipative quantum phase transition. However, the predicted scaling from a microscopic behavior—dominated by quantum fluctuations—to a macroscopic one—characterized by stable phases—and the associated exponents and phase diagram have not been observed so far. In this work we couple a single transmon qubit with a fixed coupling strength 𝑔 to a superconducting cavity that is in situ bandwidth 𝜅 tunable to controllably approach this thermodynamic limit. Even though the system remains microscopic, we observe its behavior becoming increasingly macroscopic as a function of 𝑔/𝜅. For the highest realized 𝑔/𝜅 of approximately 287, the system switches with a characteristic timescale as long as 6 s between a bright coherent state with approximately 8×103 intracavity photons and the vacuum state. This exceeds the microscopic timescales by 6 orders of magnitude and approaches the perfect hysteresis expected between two macroscopic attractors in the thermodynamic limit. These findings and interpretation are qualitatively supported by neoclassical theory and large-scale quantum-jump Monte Carlo simulations. Besides shedding more light on driven-dissipative physics in the limit of strong light-matter coupling, this system might also find applications in quantum sensing and metrology.}, author = {Sett, Riya and Hassani, Farid and Phan, Duc T and Barzanjeh, Shabir and Vukics, Andras and Fink, Johannes M}, issn = {2691-3399}, journal = {PRX Quantum}, number = {1}, publisher = {American Physical Society}, title = {{Emergent macroscopic bistability induced by a single superconducting qubit}}, doi = {10.1103/prxquantum.5.010327}, volume = {5}, year = {2024}, } @misc{18978, abstract = {Data analysis files for the manuscript "Emergent Macroscopic Bistability Induced by a Single Superconducting Qubit". This contains the raw data and the data analysis files for generating the figures in the manuscript. Figure1 file - The raw data of cavity transmission spectra for 6 different kappas are there. They are fitted with input-output theory in the python file. Figure2 file - The raw data at 8 MHz kappa are included. all hte figures in figure 2 are generated in the python file Figure3 file - The raw data of PBB single shot measurements at all kappas are included. The detailed analysis and the Figure3 generated for the paper are all in the python analysis file. Also, thefiles containing the time-evolution of the intensity from Master Equation solution are included. Figure4 file - The raw data at 2.6 MHz for different drive detunings and the corresponding analyses are included. And the python file includes the analysis of the experimental data as well as approximate neoclassical equations solutions for 2-level and 3-level transmons are included. }, author = {Sett, Riya and Hassani, Farid and Phan, Duc T and Barzanjeh, Shabir and Vukics, Andras and Fink, Johannes M}, publisher = {Zenodo}, title = {{Data Analysis files for "Emergent Macroscopic Bistability Induced by a Single Superconducting Qubit"}}, doi = {10.5281/ZENODO.10518320}, year = {2024}, } @article{17148, abstract = {During neural tube (NT) development, the notochord induces an organizer, the floorplate, which secretes Sonic Hedgehog (SHH) to pattern neural progenitors. Conversely, NT organoids (NTOs) from embryonic stem cells (ESCs) spontaneously form floorplates without the notochord, demonstrating that stem cells can self-organize without embryonic inducers. Here, we investigated floorplate self-organization in clonal mouse NTOs. Expression of the floorplate marker FOXA2 was initially spatially scattered before resolving into multiple clusters, which underwent competition and sorting, resulting in a stable “winning” floorplate. We identified that BMP signaling governed long-range cluster competition. FOXA2+ clusters expressed BMP4, suppressing FOXA2 in receiving cells while simultaneously expressing the BMP-inhibitor NOGGIN, promoting cluster persistence. Noggin mutation perturbed floorplate formation in NTOs and in the NT in vivo at mid/hindbrain regions, demonstrating how the floorplate can form autonomously without the notochord. Identifying the pathways governing organizer self-organization is critical for harnessing the developmental plasticity of stem cells in tissue engineering.}, author = {Krammer, Teresa and Stuart, Hannah T. and Gromberg, Elena and Ishihara, Keisuke and Cislo, Dillon and Melchionda, Manuela and Becerril Perez, Fernando and Wang, Jingkui and Costantini, Elena and Rus, Stefanie and Arbanas, Laura and Hörmann, Alexandra and Neumüller, Ralph A. and Elvassore, Nicola and Siggia, Eric and Briscoe, James and Kicheva, Anna and Tanaka, Elly M.}, issn = {1878-1551}, journal = {Developmental Cell}, number = {15}, pages = {1940--1953.e10}, publisher = {Elsevier}, title = {{Mouse neural tube organoids self-organize floorplate through BMP-mediated cluster competition}}, doi = {10.1016/j.devcel.2024.04.021}, volume = {59}, year = {2024}, } @article{18601, abstract = {Geometrically controlled stem cell differentiation promotes reproducible pattern formation. Here, we present a protocol to fabricate elastomeric stencils for patterned stem cell differentiation. We describe procedures for using photolithography to produce molds, followed by molding polydimethylsiloxane (PDMS) to obtain stencils with through holes. We then provide instructions for culturing cells on stencils and, finally, removing stencils to allow colony growth and cell migration. This approach yields reproducible two-dimensional organoids tailored for quantitative studies of growth and pattern formation. For complete details on the use and execution of this protocol, please refer to Lehr et al.1}, author = {Rus, Stefanie and Merrin, Jack and Kulig, Monika Aleksandra and Minchington, Thomas and Kicheva, Anna}, issn = {2666-1667}, journal = {STAR Protocols}, number = {4}, publisher = {Elsevier}, title = {{Protocol for fabricating elastomeric stencils for patterned stem cell differentiation}}, doi = {10.1016/j.xpro.2024.103187}, volume = {5}, year = {2024}, } @article{14796, abstract = {Key innovations are fundamental to biological diversification, but their genetic basis is poorly understood. A recent transition from egg-laying to live-bearing in marine snails (Littorina spp.) provides the opportunity to study the genetic architecture of an innovation that has evolved repeatedly across animals. Individuals do not cluster by reproductive mode in a genome-wide phylogeny, but local genealogical analysis revealed numerous small genomic regions where all live-bearers carry the same core haplotype. Candidate regions show evidence for live-bearer–specific positive selection and are enriched for genes that are differentially expressed between egg-laying and live-bearing reproductive systems. Ages of selective sweeps suggest that live-bearer–specific alleles accumulated over more than 200,000 generations. Our results suggest that new functions evolve through the recruitment of many alleles rather than in a single evolutionary step.}, author = {Stankowski, Sean and Zagrodzka, Zuzanna B. and Garlovsky, Martin D. and Pal, Arka and Shipilina, Daria and Garcia Castillo, Diego Fernando and Lifchitz, Hila and Le Moan, Alan and Leder, Erica and Reeve, James and Johannesson, Kerstin and Westram, Anja M and Butlin, Roger K.}, issn = {1095-9203}, journal = {Science}, number = {6678}, pages = {114--119}, publisher = {American Association for the Advancement of Science}, title = {{The genetic basis of a recent transition to live-bearing in marine snails}}, doi = {10.1126/science.adi2982}, volume = {383}, 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 p