@phdthesis{20741, abstract = {Life on Earth emerged when biomacromolecules were membrane-enclosed in a confined space where many essential chemical reactions were more likely to happen and thereby accelerate evolution. These kinds of membranes separated internal reactions from the outside chaos while staying flexible so that those primordial cells can move, adopt their shape and, most importantly, propagate. Such membrane plasticity still remains a defining feature of all modern cell types. This remarkable ability to change their shape is most prominently observed during their propagation (i.e., cell division). Throughout division, a cell undergoes drastic change in its shape, usually at the middle of the cell, pulling the two opposite membrane sides inward, closer to each other, and, finally, culminating in pinching off to separate the cell into two daughter cells. To achieve this, a cell needs to employ a protein machinery, usually termed divisome, that can coordinate all necessary intracellular processes with membrane remodelling and synthesis of other extracellular structures that decorate a cell. The focus of this dissertation is a membrane-remodelling FtsZ system that is present across all domains of life. FtsZ forms filaments that further self-organize into ring-like structures at the cell septum and together with other division proteins perform cell envelope synthesis and constriction. However, there are still knowledge gaps in our mechanistic understanding of division in both archaea and bacteria. My work presented in this dissertation centres around a simple yet not well understood question: How is the divisome positioned correctly at the mid-cell? To achieve the proper positioning, the divisome needs to (i) be recruited to the mid-cell and (ii) localized orthogonally to the long cell axis. I tackle these processes in two different systems by applying an in vitro biochemical bottom-up reconstitution approach. I use purified components of Haloferax volcanii and Escherichia coli divisome to explore how divisome is recruited to the mid-cell in archaea and how the Z-ring positions orthogonally to the long cell axis in bacteria, respectively. Firstly, I collaborate with archaeal cell and structural biologists to explore the assembly of early division proteins in two FtsZ-containing archaeon H. volcanii, a standard model system for understudied archaeal organisms. I particularly address the hierarchy of interactions that allow a tripartite complex formation (SepF-CdpB1-CdpB2) and how the hierarchy of interactions ultimately leads to the recruitment of FtsZ filaments to the septum. This part of work has been published in (Nußbaum et al., 2024). In collaboration with evolutionary biologists, I shed light on ancient features that archaeal divisome has retained to this day and also speculate on a property that it might have lost during the course of evolution. Next, I switch my attention to E. coli divisome. Particularly, I address the FtsZ’s intrinsic biophysical property that drives the Z-ring diameter, and thereby the perpendicular orientation of the Z-ring to the long cell axis based on suggested membrane curvature sensing mechanism (Vanhille-Campos et al., 2024). This property allows formation of different Z-ring diameters that match the variety of cell diameters present in prokaryotes. The results showcase that the distribution of charged amino acids in the intrinsically disordered linker at the C-terminus (CTL) of FtsZ is the major determining factor of Z-ring diameter with inter-CTL interactions as an underlying mechanism. Finally, I thoroughly explain the methodology I used to address the abovementioned projects, and I finish with a discussion on how early archaeal divisome assembly and curvature sensing mechanism in bacteria, at first sight unrelated topics, are interconnected and important groundwork for both fundamental and translational research. }, author = {Kojic, Marko}, isbn = {978-3-99078-073-2}, issn = {2663-337X}, publisher = {Institute of Science and Technology Austria}, title = {{Towards understanding the assembly mechanisms of the Z-ring in Archaea and Bacteria}}, doi = {10.15479/AT-ISTA-20741}, year = {2025}, } @phdthesis{19393, abstract = {Rotations constitute one of the fundamental symmetries in physics, characterized by their intricate group structure and infinite dimensional representations. In contrast to classical rotations, quantum mechanics unveils the SO(3) symmetry group structure, manifesting in phenomena without classical counterparts, from angular momentum quantization to non-trivial addition of angular momenta. While most studies of topological physics have focused on two-band systems, the SO(3) symmetry group of quantum rotors offers an inherently more complex platform with unprecedented possibilities for exploring topological phenomena. Despite their ubiquity in nature– from molecules to nanorotors– their potential for hosting topological phases has remained largely unexamined. In this thesis, we mainly focus on periodically driven linear molecules as a prototype for studying topological phenomena in quantum rotors. Recent technological advances in coherent control of molecules, particularly through precisely shaped laser pulses, have made it possible to investigate linear rotors in the context of topology. While planar rotors have received some attention in recent years, threedimensional rotors–particularly linear molecules–harbor substantially richer topological phenomena due to their non-abelian nature and their additional angular degrees of freedom. We demonstrate that these systems can host novel edge states and topological features fundamentally impossible in planar systems. We begin by establishing a theoretical bridge between periodically kicked rotors and "crystalline" lattices in angular momentum space. Using non-interacting linear molecules as our primary example, we show how quantum interference and revival patterns lead to the possibility to simulate band models with arbitrary number of bands N. While our framework applies to various quantum rotors, including nanorotors and kicked Bose-Einstein condensates, linear molecules provide an ideal experimental platform due to their abovementioned precise controllability. The core of this work examines adiabatic dynamics of 3D quantum rotors, establishing a geometric framework based on the Euler class to characterize its non-abelian topology. The non-Hermitian nature of the system enables novel braiding behaviors and topological transitions impossible in static systems, leading to an anomalous Dirac string phase with edge states in each gap, even though the Berry phases are all zero. These features can be directly observed through molecular alignment and rotational level populations. These findings establish quantum rotors as an alternative platform for studying multi-band topological physics, while suggesting practical implementations for quantum computation where topological protection could offer natural resilience against decoherence. The rich structure of three-dimensional rotation groups, combined with the tunability of topological features through driving parameters, makes this platform particularly valuable for exploring fundamental physics and developing quantum technologies.}, author = {Karle, Volker}, issn = {2663-337X}, pages = {192}, publisher = {Institute of Science and Technology Austria}, title = {{Non-equilibrium topological phases with periodically driven molecules and quantum rotors}}, doi = {10.15479/AT-ISTA-19393}, year = {2025}, } @article{18879, abstract = {Our brain has remarkable computational power, generating sophisticated behaviors, storing memories over an individual’s lifetime, and producing higher cognitive functions. However, little of our neuroscience knowledge covers the human brain. Is this organ truly unique, or is it a scaled version of the extensively studied rodent brain? Combining multicellular patch-clamp recording with expansion-based superresolution microscopy and full-scale modeling, we determined the cellular and microcircuit properties of the human hippocampal CA3 region, a fundamental circuit for memory storage. In contrast to neocortical networks, human hippocampal CA3 displayed sparse connectivity, providing a circuit architecture that maximizes associational power. Human synapses showed unique reliability, high precision, and long integration times, exhibiting both species- and circuit-specific properties. Together with expanded neuronal numbers, these circuit characteristics greatly enhanced the memory storage capacity of CA3. Our results reveal distinct microcircuit properties of the human hippocampus and begin to unravel the inner workings of our most complex organ. }, author = {Watson, Jake and Vargas Barroso, Victor M and Morse, Rebecca and Navas Olivé, Andrea C and Tavakoli, Mojtaba and Danzl, Johann G and Tomschik, Matthias and Rössler, Karl and Jonas, Peter M}, issn = {1097-4172}, journal = {Cell}, number = {2}, pages = {501--514.e18}, publisher = {Cell Press}, title = {{Human hippocampal CA3 uses specific functional connectivity rules for efficient associative memory}}, doi = {10.1016/j.cell.2024.11.022}, volume = {188}, year = {2025}, } @article{19404, abstract = {Cell migration is a fundamental process during embryonic development. Most studies in vivo have focused on the migration of cells using the extracellular matrix (ECM) as their substrate for migration. In contrast, much less is known about how cells migrate on other cells, as found in early embryos when the ECM has not yet formed. Here, we show that lateral mesendoderm (LME) cells in the early zebrafish gastrula use the ectoderm as their substrate for migration. We show that the lateral ectoderm is permissive for the animal-pole-directed migration of LME cells, while the ectoderm at the animal pole halts it. These differences in permissiveness depend on the lateral ectoderm being more cohesive than the animal ectoderm, a property controlled by bone morphogenetic protein (BMP) signaling within the ectoderm. Collectively, these findings identify ectoderm tissue cohesion as one critical factor in regulating LME migration during zebrafish gastrulation.}, author = {Tavano, Ste and Brückner, David and Tasciyan, Saren and Tong, Xin and Kardos, Roland and Schauer, Alexandra and Hauschild, Robert and Heisenberg, Carl-Philipp J}, issn = {2211-1247}, journal = {Cell Reports}, number = {3}, publisher = {Cell Press}, title = {{BMP-dependent patterning of ectoderm tissue material properties modulates lateral mesendoderm cell migration during early zebrafish gastrulation}}, doi = {10.1016/j.celrep.2025.115387}, volume = {44}, year = {2025}, } @article{19602, abstract = {N4-methylcytosine (4mC) is an important DNA modification in prokaryotes, but its relevance and even its presence in eukaryotes have been mysterious. Here we show that spermatogenesis in the liverwort Marchantia polymorpha involves two waves of extensive DNA methylation reprogramming. First, 5-methylcytosine (5mC) expands from transposons to the entire genome. Notably, the second wave installs 4mC throughout genic regions, covering over 50% of CG sites in sperm. 4mC requires a methyltransferase (MpDN4MT1a) that is specifically expressed during late spermiogenesis. Deletion of MpDN4MT1a alters the sperm transcriptome, causes sperm swimming and fertility defects, and impairs post-fertilization development. Our results reveal extensive 4mC in a eukaryote, identify a family of eukaryotic methyltransferases, and elucidate the biological functions of 4mC in reproductive development, thereby expanding the repertoire of functional eukaryotic DNA modifications.}, author = {Walker, James and Zhang, Jingyi and Liu, Yalin and Xu, Shujuan and Yu, Yiming and Vickers, Martin and Ouyang, Weizhi and Tálas, Judit and Dolan, Liam and Nakajima, Keiji and Feng, Xiaoqi}, issn = {1097-4172}, journal = {Cell}, number = {11}, pages = {2890--2906.e14}, publisher = {Cell Press}, title = {{Extensive N4 cytosine methylation is essential for Marchantia sperm function}}, doi = {10.1016/j.cell.2025.03.014}, volume = {188}, year = {2025}, } @article{19703, abstract = {An enlarged brain underlies the complex central nervous system of vertebrates. The dramatic expansion of the brain that diverges its shape from the spinal cord follows neural tube closure during embryonic development. Here, we show that this differential deformation is encoded by a pre-pattern of tissue material properties in chicken embryos. Using magnetic droplets and atomic force microscopy, we demonstrate that the dorsal hindbrain is more fluid than the dorsal spinal cord, resulting in a thinning versus a resisting response to increasing lumen pressure, respectively. The dorsal hindbrain exhibits reduced apical actin and a disorganized laminin matrix consistent with tissue fluidization. Blocking the activity of neural-crest-associated matrix metalloproteinases inhibits hindbrain expansion. Transplanting dorsal hindbrain cells to the spinal cord can locally create an expanded brain-like morphology in some cases. Our findings raise questions in vertebrate head evolution and suggest a general role of mechanical pre-patterning in sculpting epithelial tubes.}, author = {Mclaren, Susannah B.P. and Xue, Shi-lei and Ding, Siyuan and Winkel, Alexander K. and Baldwin, Oscar and Dwarakacherla, Shreya and Franze, Kristian and Hannezo, Edouard B and Xiong, Fengzhu}, issn = {1878-1551}, journal = {Developmental Cell}, number = {17}, pages = {2237--2247.e4}, publisher = {Cell Press}, title = {{Differential tissue deformability underlies fluid pressure-driven shape divergence of the avian embryonic brain and spinal cord}}, doi = {10.1016/j.devcel.2025.04.010}, volume = {60}, year = {2025}, } @article{20143, abstract = {Bacteria and archaea deploy diverse antiviral defense systems, many of which remain mechanistically uncharacterized. Here, we characterize Kiwa, a widespread two-component system composed of the transmembrane sensor KwaA and the DNA-binding effector KwaB. Cryogenic electron microscopy (cryo-EM) analysis reveals that KwaA and KwaB assemble into a large, membrane-associated supercomplex. Upon phage binding, KwaA senses infection at the membrane, leading to KwaB binding of ejected phage DNA and inhibition of replication and late transcription, without inducing host cell death. Although KwaB can bind DNA independently, its antiviral activity requires association with KwaA, suggesting spatial or conformational regulation. We show that the phage-encoded DNA-mimic protein Gam directly binds and inhibits KwaB but that co-expression with the Gam-targeted RecBCD system restores protection by Kiwa. Our findings support a model in which Kiwa coordinates membrane-associated detection of phage infection with downstream DNA binding by its effector, forming a spatially coordinated antiviral mechanism.}, author = {Zhang, Zhiying and Todeschini, Thomas C. and Wu, Yi and Kogay, Roman and Naji, Ameena and Cardenas Rodriguez, Joaquin and Mondi, Rupavidhya and Kaganovich, Daniel and Taylor, David W. and Bravo, Jack Peter Kelly and Teplova, Marianna and Amen, Triana and Koonin, Eugene and Patel, Dinshaw J. and Nobrega, Franklin L.}, issn = {1097-4172}, journal = {Cell}, number = {21}, pages = {5862--5877.e23}, publisher = {Cell Press}, title = {{Kiwa is a membrane-embedded defense supercomplex activated at phage attachment sites}}, doi = {10.1016/j.cell.2025.07.002}, volume = {188}, year = {2025}, } @article{19846, abstract = {The Ca2+-release-activated Ca2+ (CRAC) channel Orai1 is activated by interaction with the Ca2+ sensor Stromal Interaction Molecule 1 (STIM1). Owing to the lack of structurally resolved Orai1/STIM1 complexes, the impact of their coupling on individual Orai1 transmembrane domain (TM) movements is unclear. This study investigates STIM1-independent and STIM1-dependent Orai1-TM dynamics using photocrosslinking unnatural amino acids (UAAs) at each individual TM position. We primarily identify CRAC-channel-like currents directly after UAA incorporation or additional UV-light irradiation at TM3 sites that interface with non-pore-lining TMs. Using UAAs combined with conventional site-directed mutagenesis and molecular dynamics simulations, we discover that pore opening involves a widening of interfaces formed by TM3 with non-pore-lining TMs. Orai1 mutants with a UAA in TM3 exhibit weaker STIM1-induced activation after UV exposure, possibly caused by a restricted widening of non-pore-lining TM interfaces. We demonstrate that photocrosslinking UAAs are excellent tools for improving our understanding of key determinants and ion channel dynamics modulating pore opening.}, author = {Najjar, Hadil and Weiß, Sarah and Horvath, Ferdinand and Hopl, Valentina and Tiffner, Adéla and Höbarth, Lorenz and Söllner, Julia and Fröhlich, Maximilian and Prantl, Magdalena and Müller, Nora and Nazarenko, Yuliia and Harant, Selina and Weissenböck, Lukas and Grabmayr, Herwig and Sallinger, Matthias and Maltan, Lena and Echefu, Linda V. and Radiskovic, Tamara and Leopold, Melanie and Lindinger, Sonja and Humer, Christina and Höglinger, Carmen and Krobath, Heinrich and Renger, Thomas and Derler, Isabella}, issn = {2666-3864}, journal = {Cell Reports Physical Science}, number = {6}, publisher = {Cell Press}, title = {{STIM1-induced widening of non-pore-lining TM interfaces is crucial for Orai1 pore opening}}, doi = {10.1016/j.xcrp.2025.102623}, volume = {6}, year = {2025}, } @article{20029, abstract = {Vacuolar acidification is crucial for the homeostasis of intracellular pH and the recycling of proteins and nutrients in cells, thereby playing important roles in various physiological processes related to vacuolar function. The key factors regulating vacuolar acidification and underlying mechanisms remain unclear. Here, we report that Arabidopsis phospholipase Dζ2 (PLDζ2) promotes the acidification of the vacuolar lumen to stimulate autophagic degradation under phosphorus deficiency. The pldζ2 mutant massively accumulates autophagic structures while exhibiting premature leaf senescence under nutrient starvation. Impaired autophagic flux, lytic vacuole morphology, and lytic degradation in pldζ2 indicate that PLDζ2 regulates autophagy by affecting the vacuolar function. PLDζ2 locates in both tonoplast and cytoplasm. Genetic, structural, and biochemical studies demonstrate that PLDζ2 directly interacts with vacuolar-type ATPase (V-ATPase) subunit D (VATD) to promote vacuolar acidification and autophagy under phosphorus starvation. These findings reveal the importance of V-ATPase and vacuolar pH in autophagic activity and provide clues in elucidating the regulatory mechanism of vacuolar acidification.}, author = {Guan, Bin and Xie, Ke Xuan and Du, Xin Qiao and Bai, Yu Xuan and Hao, Peng Chao and Lin, Wen Hui and Friml, Jiří and Xue, Hong Wei}, issn = {2211-1247}, journal = {Cell Reports}, number = {7}, publisher = {Cell Press}, title = {{Arabidopsis phospholipase Dζ2 facilitates vacuolar acidification and autophagy under phosphorus starvation by interacting with VATD}}, doi = {10.1016/j.celrep.2025.116024}, volume = {44}, year = {2025}, } @article{20116, abstract = {Auxin regulates various aspects of plant growth and development by modulating the transcription of target genes through the degradation of auxin/indole-3-acetic acid (Aux/IAA) repressors via the 26S proteasome. Proteasome regulator 1 (PTRE1), a positive regulator of proteasome activity, has been implicated in auxin-mediated proteasome suppression; however, the mechanism by which auxin modulates PTRE1 function remains unclear. Here, we demonstrate that auxin promotes the interaction between germin-like protein 1 (GLP1) and PTRE1, facilitating PTRE1 retention at the plasma membrane. The relocation of PTRE1 results in reduced nuclear 26S proteasome activity, and thus the attenuated Aux/IAA degradation and altered Aux/IAA homeostasis, ultimately resulting in suppressed auxin-mediated transcriptional regulation. Our findings uncover a previously uncharacterized regulatory axis in auxin signaling that controls Aux/IAA protein stability, functioning alongside the TIR1- and TRANSMEMBRANE KINASE 1 (TMK1)-mediated pathways, and highlight the coordination of auxin signaling from the cell surface to the nucleus via auxin-induced PTRE1 relocation, which fine-tunes Aux/IAA protein homeostasis and auxin responses.}, author = {Xu, Faqing and Yu, Yongqiang and Guan, Bin and Xu, Tongda and Xu, Zhihong and Xue, Hongwei}, issn = {2211-1247}, journal = {Cell Reports}, number = {8}, publisher = {Cell Press}, title = {{Germin-like protein 1 interacts with proteasome regulator 1 to regulate auxin signaling by controlling Aux/IAA homeostasis}}, doi = {10.1016/j.celrep.2025.116056}, volume = {44}, year = {2025}, } @article{20374, abstract = {Pioneer transcription factors (TFs) engage chromatinized DNA motifs. However, it is unclear how the resultant TF-nucleosome complexes are decoded by co-factors. In humans, the TF p53 regulates cell-cycle progression, apoptosis, and the DNA damage response, with a large fraction of p53-bound sites residing in nucleosome-harboring inaccessible chromatin. We examined the interaction of chromatin-bound p53 with co-factors belonging to the ubiquitin proteasome system (UPS). At two distinct motif locations on the nucleosome (super-helical location [SHL]−5.7 and SHL+5.9), the E3 ubiquitin ligase E6-E6AP was unable to bind nucleosome-engaged p53. The deubiquitinase USP7, on the other hand, readily engages nucleosome-bound p53 in vitro and in cells. A corresponding cryo-electron microscopy (cryo-EM) structure shows USP7 engaged with p53 and nucleosomes. Our work illustrates how chromatin imposes a co-factor-selective barrier for p53 interactors, whereby flexibly tethered interaction domains of co-factors and TFs govern compatibility between co-factors, TFs, and chromatin.}, author = {Chakraborty, Deyasini and Sandate, Colby R. and Isbel, Luke and Kempf, Georg and Weiss, Joscha and Cavadini, Simone and Kater, Lukas and Seebacher, Jan and Kozicka, Zuzanna and Stoos, Lisa and Grand, Ralph S. and Schübeler, Dirk and Michael, Alicia and Thomä, Nicolas H.}, issn = {1097-2765}, journal = {Molecular Cell}, number = {15}, pages = {2919--2936.e12}, publisher = {Cell Press}, title = {{Nucleosomes specify co-factor access to p53}}, doi = {10.1016/j.molcel.2025.06.027}, volume = {85}, year = {2025}, } @article{19594, abstract = {In this issue of Developmental Cell, Lee et al. identify a pivotal role for glutathione (GSH) in plant regeneration, a vital biological process enabling plants to regrow tissues and organs after injury. Applying single-cell RNA sequencing (scRNA-seq) and live imaging, the authors demonstrate that GSH, released upon tissue damage, accelerates cell-cycle transitions, particularly shortening the G1 phase, thereby facilitating efficient organ regeneration.}, author = {Benková, Eva}, issn = {1878-1551}, journal = {Developmental Cell}, number = {8}, pages = {1137--1139}, publisher = {Cell Press}, title = {{Unlocking plant regeneration: The role for glutathione}}, doi = {10.1016/j.devcel.2025.03.012}, volume = {60}, year = {2025}, } @article{19795, abstract = {Super-resolution microscopy often entails long acquisition times of minutes to hours. Since drifts during the acquisition adversely affect data quality, active sample stabilization is commonly used for some of these techniques to reach their full potential. Although drifts in the lateral plane can often be corrected after acquisition, this is not always possible or may come with drawbacks. Therefore, it is appealing to stabilize sample position in three dimensions (3D) during acquisition. Various schemes for active sample stabilization have been demonstrated previously, with some reaching sub-nanometer stability in 3D. Here, we present a scheme for active drift correction that delivers the nanometer-scale 3D stability demanded by state-of-the-art super-resolution techniques and is straightforward to implement compared to previous schemes capable of reaching this level of stabilization precision. Using a refined algorithm that can handle various types of reference structure, without sparse signal peaks being mandatory, we stabilized sample position to ∼1 nm in 3D using objective lenses both with high and low numerical aperture. Our implementation requires only the addition of a simple widefield imaging path and we provide an open-source control software with graphical user interface to facilitate easy adoption of the module. Finally, we demonstrate how this has the potential to enhance data collection for diffraction-limited and super-resolution imaging techniques using single-molecule localization microscopy and cryo-confocal imaging as showcases.}, author = {Vorlaufer, Jakob and Semenov, Nikolai and Kreuzinger, Caroline and Javoor, Manjunath and Zens, Bettina and Agudelo Duenas, Nathalie and Tavakoli, Mojtaba and Suplata, Marek and Jahr, Wiebke and Lyudchik, Julia and Wartak, Andreas and Schur, Florian Km and Danzl, Johann G}, issn = {2667-0747}, journal = {Biophysical Reports}, number = {2}, publisher = {Cell Press}, title = {{Image-based 3D active sample stabilization on the nanometer scale for optical microscopy}}, doi = {10.1016/j.bpr.2025.100211}, volume = {5}, year = {2025}, } @article{18754, abstract = {Exploring the molecular correlates of metabolic health measures may identify their shared and unique biological processes and pathways. Molecular proxies of these traits may also provide a more objective approach to their measurement. Here, DNA methylation (DNAm) data were used in epigenome-wide association studies (EWASs) and for training epigenetic scores (EpiScores) of six metabolic traits: body mass index (BMI), body fat percentage, waist-hip ratio, and blood-based measures of glucose, high-density lipoprotein cholesterol, and total cholesterol in >17,000 volunteers from the Generation Scotland (GS) cohort. We observed a maximum of 12,033 significant findings (p < 3.6 × 10−8) for BMI in a marginal linear regression EWAS. By contrast, a joint and conditional Bayesian penalized regression approach yielded 27 high-confidence associations with BMI. EpiScores trained in GS performed well in both Scottish and Singaporean test cohorts (Lothian Birth Cohort 1936 [LBC1936] and Health for Life in Singapore [HELIOS]). The EpiScores for BMI and total cholesterol performed best in HELIOS, explaining 20.8% and 7.1% of the variance in the measured traits, respectively. The corresponding results in LBC1936 were 14.4% and 3.2%, respectively. Differences were observed in HELIOS for body fat, where the EpiScore explained ∼9% of the variance in Chinese and Malay -subgroups but ∼3% in the Indian subgroup. The EpiScores also correlated with cognitive function in LBC1936 (standardized βrange: 0.08–0.12, false discovery rate p [pFDR] < 0.05). Accounting for the correlation structure across the methylome can vastly affect the number of lead findings in EWASs. The EpiScores of metabolic traits are broadly applicable across populations and can reflect differences in cognition.}, author = {Smith, Hannah M. and Ng, Hong Kiat and Moodie, Joanna E. and Gadd, Danni A. and Mccartney, Daniel L. and Bernabeu, Elena and Campbell, Archie and Redmond, Paul and Taylor, Adele and Page, Danielle and Corley, Janie and Harris, Sarah E. and Tay, Darwin and Deary, Ian J. and Evans, Kathryn L. and Robinson, Matthew Richard and Chambers, John C. and Loh, Marie and Cox, Simon R. and Marioni, Riccardo E. and Hillary, Robert F.}, issn = {1537-6605}, journal = {American Journal of Human Genetics}, number = {1}, pages = {106--115}, publisher = {Cell Press}, title = {{DNA methylation-based predictors of metabolic traits in Scottish and Singaporean cohorts}}, doi = {10.1016/j.ajhg.2024.11.012}, volume = {112}, year = {2025}, } @article{20099, abstract = {The hippocampus, critical for learning and memory, is dogmatically described as a trisynaptic circuit where dentate gyrus granule cells (GCs), CA3 pyramidal neurons (PNs), and CA1 PNs are serially connected. However, CA3 also forms an autoassociative network, and its PNs have diverse morphologies, intrinsic properties, and GC input levels. How PN subtypes compose this recurrent network is unknown. To determine the synaptic arrangement of identified CA3 PNs, we combine multicellular patch-clamp recording and post hoc morphological analysis in mouse hippocampal slices. PNs can be divided into distinct “superficial” and “deep” subclasses, the latter including previously reported “athorny” cells. Subclasses have distinct input-output transformations and asymmetric connectivity, which is more abundant from superficial to deep PNs, splitting CA3 locally into two parallel recurrent networks. Coincident spontaneous inhibition occurs frequently within but not between subclasses, implying subclass-specific inhibitory innervation. Our results suggest two separately controlled sublayers for parallel information processing in hippocampal CA3.}, author = {Watson, Jake and Vargas Barroso, Victor M and Jonas, Peter M}, issn = {2211-1247}, journal = {Cell Reports}, number = {8}, publisher = {Cell Press}, title = {{Cell-specific wiring routes information flow through hippocampal CA3}}, doi = {10.1016/j.celrep.2025.116080}, volume = {44}, year = {2025}, } @phdthesis{20206, abstract = {The internal structure of biomolecules and their organization in higher-order arrangements are key factors governing the working principles of biological systems. Bioimaging has successfully revealed arrangements across relevant spatial scales. For example, cryo-electron tomography has become widely used for analyzing biomolecular structures in situ due to its comprehensive structural visualization of near-natively preserved samples, and its capability of sub-nm resolution via averaging. However, the identification of molecules within crowded cellular environments is often hindered by low contrast. Fluorescence microscopy, on the other hand, routinely visualizes specifically labeled targets at single-molecule contrast against essentially zero background. Moreover, it provides comparatively high throughput and is amenable to multiplexing. Due to this complementarity, combining datasets from both modalities acquired on the same region via correlative light and electron microscopy can reveal novel types of information. The spatial scale at which information can be extracted depends on imaging resolution and correlation accuracy. Since diffraction of light limits the resolution of conventional fluorescence microscopy to few hundreds of nanometers, reaching the full potential of correlative imaging requires super-resolution approaches. Performing imaging at cryogenic temperature preserves structures in a near-native state and minimizes distortions between the fluorescence and the electron microscopy datasets. Implementations of this concept have achieved correlation on the scale of cellular organelles or bacterial domains. We have worked towards pushing correlative imaging to the single-molecule scale by improving cryo-super-resolution microscopy, and devising a refined image correlation workflow. As part of this project, I constructed a microscopy setup and adopted it for super-resolution fluorescence microscopy at room temperature and cryogenic conditions. I explored different cryo-stages and acquisition strategies. Specifically, I developed a new scheme for correcting sample drift, thus increasing mechanical stability during microscopy acquisitions. }, author = {Vorlaufer, Jakob}, issn = {2663-337X}, pages = {107}, publisher = {Institute of Science and Technology Austria}, title = {{Construction of a cryo-super-resolution microscope to guide in situ structure analysis}}, doi = {10.15479/AT-ISTA-20206}, year = {2025}, } @article{19506, abstract = {Hippocampal reactivation of waking neuronal assemblies in sleep is a key initial step of systems consolidation. Nevertheless, it is unclear whether reactivated assemblies are static or whether they reorganize gradually over prolonged sleep. We tracked reactivated CA1 assembly patterns over ∼20 h of sleep/rest periods and related them to assemblies seen before or after in a spatial learning paradigm using rats. We found that reactivated assembly patterns were gradually transformed and started to resemble those seen in the subsequent recall session. Periods of rapid eye movement (REM) sleep and non-REM (NREM) had antagonistic roles: whereas NREM accelerated the assembly drift, REM countered it. Moreover, only a subset of rate-changing pyramidal cells contributed to the drift, whereas stable-firing-rate cells maintained unaltered reactivation patterns. Our data suggest that prolonged sleep promotes the spontaneous reorganization of spatial assemblies, which can contribute to daily cognitive map changes or encoding new learning situations.}, author = {Bollmann, Lars and Baracskay, Peter and Stella, Federico and Csicsvari, Jozsef L}, issn = {1097-4199}, journal = {Neuron}, number = {9}, pages = {1446--1459.e6}, publisher = {Cell Press}, title = {{Sleep stages antagonistically modulate reactivation drift}}, doi = {10.1016/j.neuron.2025.02.025}, volume = {113}, year = {2025}, } @article{19443, abstract = {In cryo-electron microscopy, accurate particle localization and classification are imperative. Recent deep learning solutions, though successful, require extensive training datasets. The protracted generation time of physics-based models, often employed to produce these datasets, limits their broad applicability. We introduce FakET, a method based on neural style transfer, capable of simulating the forward operator of any cryo transmission electron microscope. It can be used to adapt a synthetic training dataset according to reference data producing high-quality simulated micrographs or tilt-series. To assess the quality of our generated data, we used it to train a state-of-the-art localization and classification architecture and compared its performance with a counterpart trained on benchmark data. Remarkably, our technique matches the performance, boosts data generation speed 750x, uses 33x less memory, and scales well to typical transmission electron microscope detector sizes. It leverages GPU acceleration and parallel processing. The source code is available at https://github.com/paloha/faket/.}, author = {Harar, Pavol and Herrmann, Lukas and Grohs, Philipp and Haselbach, David}, issn = {1878-4186}, journal = {Structure}, number = {4}, pages = {820--827.e4}, publisher = {Cell Press}, title = {{FakET: Simulating cryo-electron tomograms with neural style transfer}}, doi = {10.1016/j.str.2025.01.020}, volume = {33}, year = {2025}, } @article{20154, abstract = {In long-lived mammals, including humans, brain cell homeostasis is critical for maintaining brain function throughout life. Most neurons are generated during development and must maintain their cellular identity and plasticity to preserve brain function. Although extensive studies indicate the importance of recycling and regenerating cellular molecules to maintain cellular homeostasis, recent evidence has shown that some proteins and RNAs do not turn over for months and even years. We propose that these long-lived cellular molecules may be the basis for maintaining brain function in the long term, but also a potential convergent target of brain aging. We highlight key discoveries and challenges, and propose potential directions to unravel the mystery of brain cell longevity.}, author = {Hetzer, Martin W and Toda, Tomohisa}, issn = {1878-108X}, journal = {Trends in Neurosciences}, number = {9}, pages = {645--654}, publisher = {Cell Press}, title = {{Long-lived cellular molecules in the brain}}, doi = {10.1016/j.tins.2025.07.004}, volume = {48}, year = {2025}, } @article{20427, abstract = {Animal cells migrating up chemotactic gradients often show speed oscillations. A new study describes a molecular circuit that switches zebrafish germ cells between phases of straight runs, tumbling and directional reorientation.}, author = {Li, Ziqiang and Sixt, Michael K}, issn = {1879-0445}, journal = {Current Biology}, number = {18}, pages = {R890--R892}, publisher = {Cell Press}, title = {{Cell migration: How animal cells run and tumble}}, doi = {10.1016/j.cub.2025.08.016}, volume = {35}, year = {2025}, }