Biology subjects

Zimmer, M.

Publications and source records attributed to Zimmer, M..

At least 19 recordsLinked to original sources

bioRxiv2026

One-carbon metabolism sustains effector T cell function through cell-surface glycosylation

Folate is a driver of one-carbon metabolism that is essential in T cells. The cellular consequences of its deprivation in CD8+ T cells and impact on anti-tumor function are unknown. Single cell RNA-seq analysis of primary central nervous system lymphoma (PCNSL) patients' tumor samples revealed exhaustion in T cells with high folate metabolism gene expression signature. Functional genomics, metabolite profiling, and glycomics identified disrupted cell surface glycosylation as a major consequence of folate deprivation in CD8+ T cells. Mechanistically, folate deprivation reduced nucleotide sugar levels, perturbed glycosylation, and triggered the apoptotic unfolded protein response. Overexpressing folate transporters in adoptively transferred CD8+ T cells increased intratumoral T cell numbers and reduced exhaustion. Therefore, our data draw a mechanistic line between one-carbon metabolism, cell-surface glycosylation, and anti-tumor T cell function, and support a hypothesis that increased folate uptake can enhance CD8+ T cell function including ex vivo and in vivo CAR-T cells.

cell biology↗

bioRxiv2026

Flexible modulation of neuronal population dynamics drives variable decision-making in C. elegans

Behavior arises from the interplay between spontaneous brain dynamics and sensory-driven responses, yet how spontaneous neural activity shapes variability in decision-making remains unclear. We leverage the tractable C. elegans nervous system to address this question. During oxygen avoidance, we observe binary trial-to-trial variability in behavioral responses. Whole-brain calcium imaging reveals a brain-wide sensory-to-motor transformation in which sensory neurons faithfully encode the stimulus but do not predict choice. Instead, decision-related information is distributed across interneurons and motor neurons, encoded through a neuronal subspace. This decision-biasing state evolves slowly during the pre-stimulus period, resembling preparatory dynamics for spontaneous behavioral transitions but receives neuromodulatory contributions. Optogenetic manipulations reveal that only a subset of neurons within this distributed representation are causally connected to choice. This reveals a dissociation between broad information sharing and control via dedicated localized nodes. Thus, response variability arises from slowly evolving modulation of brain states rather than stochastic circuit noise.

neuroscience↗

bioRxiv2026

Discovery of a buried charge-network GFP-fold family spanning prokaryotes and eukaryotes (Draft manuscript)

The GFP fold has long been viewed as a specialized fluorescent scaffold found principally in marine animals. A structure-first search reveals a rare buried charge-network GFP-fold family spanning bacteria, fungi, and corals. Its members retain the eleven-stranded barrel and conserved chromophore-forming machinery but replace the canonical central tyrosine with methionine or other hydrophobic residues. Ancestral reconstruction supports a non-tyrosine state early in the lineage. Instead of a conventional chromophore, the barrel encloses an invariant five-residue network of two arginines, two glutamates, and Tyr168, whereas the chromophore-equivalent residue varies. The network is more conserved than the protein surface, occupies the most strongly constrained evolutionary sites, and remains formed across independent structure predictions and explicit-solvent molecular-dynamics trajectories. Fold-independent searches identify the same two-cation/two-anion/tyrosine network in 238 members of DUF2490, an unrelated outer-membrane beta-barrel family, consistent with convergent evolution of the buried network. These findings expand the known sequence and chemical space of the GFP barrel, although the biochemical function of the network remains unknown.

bioinformatics↗

bioRxiv2026

Factors Affecting Germination of a Dominant Salt Marsh Species are Context-Dependent: Implications for Coastal Seed-Based Restoration

Restoration of coastal salt marshes is often limited by their capability to revegetate, either through natural recruitment or active planting methods. Despite the critical need for efficient revegetation methods, direct seeding remains an underrepresented approach in coastal wetland restoration. Additionally, tidal inundation poses special challenges for coastal Seed-Based Restoration (SBR) relative to terrestrial habitats, with tides displacing seeds from the marsh platform. To determine factors potentially influencing successful establishment in coastal wetlands, we conducted a series of greenhouse and lab experiments with Salicornia pacifica (pickleweed), the dominant plant in California marshes. We determined pickleweed seed viability using standardized germination tests. Additionally, we tested factors that influence pickleweed seed viability and germination rates, such as soil moisture, soil type, and sowing depth. We found that pickleweed seeds had an average viability of 22.5%, which increased with larger-sized seeds. We also determined that the most effective dormancy-breaking pretreatments varied by soil type: a one-day cold stratification in freshwater maximized germination in benign soils, whereas a seven-day cold stratification in saltwater maximized germination in stressful soils. Finally, we determined that the optimal conditions for sowing seeds are surface sowing under moderate moisture. Creating conditions to maximize viability and germination is crucial to ensure the greatest chance of successful revegetation post restoration. Our study, which sequentially tested factors affecting different phases of the early life history of a dominant foundation species, can inform SBR for other coastal plants. This approach can help coastal land managers successfully implement SBR for habitat restoration.

plant biology↗

bioRxiv2026

Lempel-Ziv complexity of simultaneous surface electromyography and magnetomyography during muscle fatigue

ObjectiveComplexity-based metrics have been applied to surface electromyography (sEMG) to characterize fatigue-related changes in the temporal structure of myoelectric signals beyond amplitude and spectral features. Optically pumped magnetometers (OPM) are sensors that enable non-invasive recordings of magnetomyographic (MMG) signals from skeletal muscle and are increasingly used to complement surface electromyography; however, it remains unclear whether complexity measures derived from magnetic recordings are comparable to those obtained from sEMG. Here, we directly compared fatigue-related dynamics of conventional and complexity-based signal features of sEMG and OPM-MMG measured from the biceps brachii during sustained elbow flexion. ApproachHealthy participants performed isometric contractions at 20% maximal voluntary contraction (MVC; 20 min) or 60% MVC (3 min). sEMG and OPM-based MMG were recorded simultaneously, and signal median frequency, root mean square (RMS), and Lempel-Ziv (LZ) complexity were calculated over time. Main resultsAcross contraction intensities, sEMG and MMG showed consistent fatigue-related changes, characterized by increasing RMS, decreasing median frequency, and a progressive decline in LZ over time. In addition, multiple regression analyses indicated that the decrease in LZ was not fully accounted for by concurrent amplitude or spectral changes, suggesting that complexity captures aspects of signal organization that are not fully explained by established features. Finally, while sEMG showed higher LZ complexity and median frequency at 60% compared to 20% MVC, corresponding intensity-dependent effects were not observed in OPM-based MMG. SignificanceThese findings suggest that complexity-based metrics capture fatigue-related changes in neuromuscular signal organization beyond conventional measures, and that sEMG and OPM-based MMG provide similar, though modality-specific, information. Together, the results support the use of complexity metrics in multimodal electrophysiological and biomagnetic assessments of neuromuscular fatigue.

neuroscience↗

bioRxiv2025

BarlowTrack: A Self-Supervised Framework for Zero-Shot Multi-Object Cell Tracking

Recent advances in neuroscience have made it possible to image large brain regions at single-cell resolution. However, classic methods for processing these videos into neuronal time series fail in the presence of large and nonrigid deformations, in particular for freely moving animals. Several successful algorithms have been proposed to solve this problem in moving C. elegans, but they are highly specific to the conditions of a single research setting. We propose a tracking pipeline based on self-supervised learning that achieves a high level of zero-shot accuracy across conditions, and, for the first time, independent laboratories. We contribute a novel term in the Barlow Twins loss function to encourage decorrelation of features across detected instances at the same time point. To encourage broad adoption, we use the standardized Neurodata Without Borders (NWB) format and we provide a GUI for visualization of the final results and neuronal time series. Finally, we provide a benchmark of datasets with ground truth annotations in the NWB format for further algorithmic development.

bioinformatics↗

bioRxiv2025

Cerebral Organoids Uncover Mechanisms of Neural Activity Changes in Epileptogenesis

Neurological disorders often originate from progressive brain network dysfunctions that start years before symptoms appear. How these changes emerge in the developing human brain remains elusive due to a lack of tractable model systems. Here, we show a cerebral organoid model of Tuberous Sclerosis Complex (TSC) that recapitulates hallmarks of epileptogenesis in vitro. We compare extracellular recordings of TSC organoids with intraoperative electrocorticography from TSC patients to reveal striking functional similarities, including high-frequency oscillations - an electrical biomarker for epileptogenic tissue. In TSC, a human-specific interneuron sub-type derived from the caudal ganglionic eminence drives network hyper-synchronization through increased spontaneous firing and altered excitability. Inhibiting overproliferation of its progenitors via long-term epidermal growth factor receptor inhibition prevented the onset of this pathological phenotype at functional and morphological levels. Our work shows that organoids allow mechanistic analysis of emerging neural network phenotypes, enabling anti-epileptogenic drug testing in a human brain development model.

neuroscience↗

bioRxiv2025

An intrinsic neuronal manifold underlies brain-wide hierarchical organization of behavior in C. elegans

Large-scale neuronal recordings in various species have revealed behavior-related activity patterns. Surprisingly, these activities are distributed across brain regions, including sensory areas. However, their origins and functions are incompletely understood. Using whole-brain imaging in freely behaving C. elegans, we discover that such distributed brain activity is dominated by a low dimensional manifold, corresponding to the major action sequence of C. elegans. The manifold originates largely from intrinsic dynamics, with minor contributions from movement-induced sensations. We discover a new function of the manifold: to gate the activity of a large number of neuron classes. This gating constrains them to selectively encode faster time-scale motor patterns during specific brain states. We therefore propose that one principle function of brain-wide dynamics is to enable hierarchical organization of behavior: information about major actions is broadcast via a distributed manifold, to enable nesting of granular motor patterns within those major actions.

neuroscience↗

bioRxiv2023

Neuro-Cognitive Multilevel Causal Modeling: A Framework that Bridges the Explanatory Gap between Neuronal Activity and Cognition

Explaining how neuronal activity gives rise to cognition arguably remains the most significant challenge in cognitive neuroscience. We introduce neuro-cognitive multilevel causal modeling (NC-MCM), a framework that bridges the explanatory gap between neuronal activity and cognition by construing cognitive states as (behaviorally and dynamically) causally consistent abstractions of neuronal states. Multilevel causal modeling allows us to interchangeably reason about the neuronal- and cognitive causes of behavior while maintaining a physicalist (in contrast to a strong dualist) position. We introduce an algorithm for learning cognitive-level causal models from neuronal activation patterns and demonstrate its ability to learn cognitive states of the nematode C. elegans from calcium imaging data. We show that the cognitive-level model of the NC-MCM framework provides a concise representation of the neuronal manifold of C. elegans and its relation to behavior as a graph, which, in contrast to other neuronal manifold learning algorithms, supports causal reasoning. We conclude the article by arguing that the ability of the NC-MCM framework to learn causally interpretable abstractions of neuronal dynamics and their relation to behavior in a purely data-driven fashion is essential for understanding more biological systems whose complexity prohibits the development of hand-crafted computational models.

neuroscience↗

bioRxiv2023

Key determinants of the dual clamp/activator function of Complexin

Complexin determines magnitude and kinetics of synchronized secretion, but the underlying molecular mechanisms remained unclear. Here, we show that the hydrophobic face of the amphipathic helix at the C-terminus of Complexin II (CpxII, amino acids 115- 134) binds to fusion-promoting SNARE proteins, prevents premature secretion and allows vesicles to accumulate in a release-ready state. Specifically, we demonstrate that an unrelated amphipathic helix functionally substitutes for the CTD of CpxII and that amino acid substitutions on the hydrophobic side compromise the arrest of the prefusion intermediate. To facilitate synchronous vesicle fusion, the N-terminal domain (NTD) of CpxII (amino acids 1-27) specifically cooperates with synaptotagmin I (SytI), but not with synaptotagmin VII. Expression of CpxII rescues the slow release kinetics of the Ca2+- binding mutant Syt I R233Q, whereas the N-terminally truncated variant of CpxII further delays it. These results indicate that the CpxII NTD regulates mechanisms which are governed by the forward rate of Ca2+ binding to Syt I. Overall, our results shed new light on key molecular properties of CpxII that hinder premature exocytosis and accelerate synchronous exocytosis.

neuroscience↗

bioRxiv2022

AlphaFold2 and RoseTTAFold Predict Posttranslational modifications. Chromophore Formation in GFP-like Proteins.

AlphaFold2 and RoseTTAfold are able to predict, based solely on their sequence whether GFP-like proteins will post-translationally form a chromophore or not. Their training has not only taught them protein structure and folding, but also chemistry. The structures of 21 sequences of GFP-like fluorescent proteins that will post-translationally form a chromophore and of 23 GFP-like non-fluorescent proteins that do not have the residues required to form a chromophore were determined by AlphaFold2 and RoseTTAfold. The resultant structures were mined for a series of geometric measurements that are crucial to chromophore formation. Statistical analysis of these measurements showed that both programs conclusively distinguished between chromophore forming and non-chromophore forming proteins. A clear distinction between sequences capable of forming a chromophore and those that do not have the residues required for chromophore formation can be obtained by examining a single measurement - the RMSD of the overlap of the central alpha helices of the crystal structure of S65T GFP and the AlphaFold2 determined structure.

biochemistry↗

bioRxiv2020

Modular deep learning enables automated identification of monoclonal cell lines

Monoclonalization refers to the isolation and expansion of a single cell derived from a cultured population. This is a valuable step in cell culture so as to minimize a cell lines technical variability downstream of cell-altering events, such as reprogramming or gene editing, as well as for processes such as monoclonal antibody development. However, traditional methods for verifying clonality do not scale well, posing a critical obstacle to studies involving large cohorts. Without automated, standardized methods for assessing clonality post-hoc, methods involving monoclonalization cannot be reliably upscaled without exacerbating the technical variability of cell lines. We report the design of a deep learning workflow that automatically detects colony presence and identifies clonality from cellular imaging. The workflow, termed Monoqlo, integrates multiple convolutional neural networks and, critically, leverages the chronological directionality of the cell culturing process. Our algorithm design provides a fully scalable, highly interpretable framework, capable of analyzing industrial data volumes in under an hour using commodity hardware. In the present study, we focus on monoclonalization of human induced pluripotent stem cells (HiPSCs) as a case example. Monoqlo standardizes the monoclonalization process, enabling colony selection protocols to be infinitely upscaled while minimizing technical variability.

cell biology↗

bioRxiv2020

Jasmonate biosynthesis arising from altered cell walls is prompted by turgor-driven mechanical compression and guides root hydrotropism

Despite the vital roles of jasmonoyl-isoleucine (JA-Ile) in governing plant growth and environmental acclimation, it remains unclear what intracellular processes lead to its induction. Here, we provide compelling genetic evidence that mechanical and osmotic regulation of turgor pressure represents a key factor in eliciting JA-Ile biosynthesis. After identifying cell wall mutant alleles in KORRIGAN1 (KOR1) with elevated JA-Ile in seedling roots, we found that ectopic JA-Ile resulted from cell non-autonomous signals deriving from enlarged cortex cells compressing inner tissues and stimulating JA-Ile production. Restoring cortex cell size by cell-type-specific KOR1 complementation, by isolating a genetic kor1 suppressor, and by lowering turgor pressure with hyperosmotic treatments, abolished JA-Ile signalling. Strikingly, heightened JA-Ile levels guided kor1 roots towards greater water availability, uncovering a previously unrecognized JA-Ile function in root hydrotropism. Collectively, these findings enhance our understanding of JA-Ile biosynthesis initiation, and reveal a novel role of JA-Ile in orchestrating environmental resilience.

plant biology↗

bioRxiv2020

Residue-by-residue analysis of cotranslational membrane protein integration in vivo

We follow the cotranslational biosynthesis of three multi-spanning E. coli inner membrane proteins in vivo using high-resolution Force Profile Analysis. The force profiles show that the nascent chain is subjected to rapidly varying pulling forces during translation, and reveal unexpected complexities in the membrane integration process. We find that an N-terminal cytoplasmic domains can fold in the ribosome exit tunnel before membrane integration starts, that charged residues and membrane-interacting segments such as re-entrant loops and surface helices flanking a transmembrane helix (TMH) can advance or delay membrane integration, and that point mutations in an upstream TMH can affect the pulling forces generated by downstream TMHs in a highly position-dependent manner, suggestive of residue-specific interactions between TMHs during the integration process.

molecular biology↗

bioRxiv2020

A direct RNA-protein interaction atlas of the SARS-CoV-2 RNA in infected human cells

SARS-CoV-2 infections pose a global threat to human health and an unprecedented research challenge. Among the most urgent tasks is obtaining a detailed understanding of the molecular interactions that facilitate viral replication or contribute to host defense mechanisms in infected cells. While SARS-CoV-2 co-opts cellular factors for viral translation and genome replication, a comprehensive map of the host cell proteome in direct contact with viral RNA has not been elucidated. Here, we use RNA antisense purification and mass spectrometry (RAP-MS) to obtain an unbiased and quantitative picture of the human proteome that directly binds the SARS-CoV-2 RNA in infected human cells. We discover known host factors required for coronavirus replication, regulators of RNA metabolism and host defense pathways, along with dozens of potential drug targets among direct SARS-CoV-2 binders. We further integrate the SARS-CoV-2 RNA interactome with proteome dynamics induced by viral infection, linking interactome proteins to the emerging biology of SARS-CoV-2 infections. Validating RAP-MS, we show that CNBP, a regulator of proinflammatory cytokines, directly engages the SARS-CoV-2 RNA. Supporting the functional relevance of identified interactors, we show that the interferon-induced protein RYDEN suppresses SARS-CoV-2 ribosomal frameshifting and demonstrate that inhibition of SARS-CoV-2-bound proteins is sufficient to manipulate viral replication. The SARS-CoV-2 RNA interactome provides an unprecedented molecular perspective on SARS-CoV-2 infections and enables the systematic dissection of host dependency factors and host defense strategies, a crucial prerequisite for designing novel therapeutic strategies.

microbiology↗

bioRxiv2020

WHIMP links the actin nucleation machinery to Src-family kinase signaling during protrusion and motility

Cell motility is governed by cooperation between the Arp2/3 complex and nucleation factors from the Wiskott-Aldrich Syndrome Protein (WASP) family, which together assemble actin filament networks to drive membrane protrusion. Here we identify WHIMP (WAVE Homology In Membrane Protrusions) as a new member of the WASP family. The Whimp gene is encoded on the X-chromosome of multiple animals, including mice. Murine WHIMP promotes Arp2/3-dependent actin assembly, but is less potent than other nucleation factors. Nevertheless, WHIMP-mediated Arp2/3 activation enhances both plasma membrane ruffling and wound healing migration, whereas WHIMP depletion impairs protrusion and slows motility. WHIMP expression also increases Src-family kinase activity, and WHIMP-induced ruffles contain the additional nucleation factors WAVE1, WAVE2, and N-WASP, but not JMY or WASH. Perturbing the function of Src-family kinases, WAVE proteins, or Arp2/3 complex inhibits WHIMP-driven ruffling. These results suggest that WHIMP-mediated actin assembly plays a direct role in membrane protrusion, but also results in feedback control of tyrosine kinase signaling to modulate the activation of multiple WASP-family proteins. AUTHOR SUMMARYThe actin cytoskeleton is a collection of protein polymers that assemble and disassemble within cells at specific times and locations. Sophisticated cytoskeletal regulators called nucleation factors ensure that actin polymerizes when and where it is needed, and most nucleation factors are members of the Wiskott-Aldrich Syndrome Protein (WASP) family. Several of the 8 known WASP-family proteins function in cell motility, but how the different factors collaborate with one another is not well understood. In this study, we identified WHIMP, a new WASP-family member which is encoded on the X chromosome of a variety of animals. In mouse cells, WHIMP enhances cell motility by assembling actin filaments that push the cell membrane forward. Unexpectedly, WHIMP also activates tyrosine kinase enzymes, proteins that stimulate multiple WASP-family members during motility. Our results open new avenues of research into how nucleation factors cooperate during movement and how the molecular activities that underlie motility differ in distinct cell types and organisms.

cell biology↗

bioRxiv2019

CD49f is a novel marker to purify functional human iPSC-derived astrocytes

Astrocytes play a central role in the central nervous system (CNS), maintaining brain homeostasis, providing metabolic support to neurons, regulating connectivity of neural circuits, and controlling blood flow as an integral part of the blood-brain barrier. They have been increasingly implicated in the mechanisms of neurodegenerative diseases, prompting a greater need for methods that enable their study. The advent of human induced pluripotent stem cell (iPSC) technology has made it possible to generate patient-specific astrocytes and CNS cells using protocols developed by our team and others as valuable disease models. Yet isolating astrocytes from primary specimens or from in vitro mixed cultures for downstream analyses has remained challenging. To address this need, we performed a screen for surface markers that allow FACS sorting of astrocytes. Here we demonstrate that CD49f is an effective marker for sorting functional human astrocytes. We sorted CD49f+ cells from a protocol we previously developed that generates a complex culture of oligodendrocytes, neurons and astrocytes from iPSCs. CD49f+-purified cells express all canonical astrocyte markers and perform characteristic functions, such as neuronal support and glutamate uptake. Of particular relevance to neurodegenerative diseases, CD49f+ astrocytes can be stimulated to take on an A1 neurotoxic phenotype, in which they secrete pro-inflammatory cytokines and show an impaired ability to support neuronal maturation. This study establishes a novel marker for isolating functional astrocytes from complex CNS cell populations, strengthening the use of iPSC-astrocytes for the study of their regulation and dysregulation in neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Inhibition of jasmonate-mediated plant defences by the fungal metabolite higginsianin B

Infection of Arabidopsis thaliana by the ascomycete fungus Colletotrichum higginsianum is characterised by an early symptomless biotrophic phase followed by a destructive necrotrophic phase. The fungal genome contains 77 secondary metabolism-related biosynthetic gene clusters (BGCs), and their expression during the infection process is tightly regulated. Deleting CclA, a chromatin regulator involved in repression of some BGCs through H3K4 trimethylation, allowed overproduction of 3 families of terpenoids and isolation of 12 different molecules. These natural products were tested in combination with methyl jasmonate (MeJA), an elicitor of jasmonate responses, for their capacity to alter defence gene induction in Arabidopsis. Higginsianin B inhibited MeJA-triggered expression of the defence reporter VSP1p:GUS, suggesting it may block bioactive JA-Ile synthesis or signalling in planta. Using the JA-Ile sensor Jas9-VENUS, we found that higginsianin B, but not three other structurally-related molecules, suppressed JA-Ile signalling by preventing degradation of JAZ proteins, the repressors of JA responses. Higginsianin B likely blocks the 26S proteasome-dependent degradation of JAZ proteins because it inhibited chymotrypsin- and caspase-like protease activities. The inhibition of target degradation by higginsianin B also extended to auxin signalling, as higginsianin B treatment reduced IAA-dependent expression of DR5p:GUS. Overall, our data indicate that specific fungal secondary metabolites can act similarly to protein effectors to subvert plant immune and developmental responses.\n\nHighlightA diterpene secondary metabolite produced by a fungal pathogen suppresses plant jasmonate defense signalling by preventing the proteasomal degradation of JAZ repressor proteins.

plant biology↗