Biology subjects

Kuhn, A.

Publications and source records attributed to Kuhn, A..

12 recordsLinked to original sources

bioRxiv2026

Probabilistic mouse-human brain correspondence by multimodal optimal transport

The mouse is the principal model for brain mechanism and disease, allowing experiments that cannot be performed in humans. However, findings often translate poorly because homologous regions differ in relative size and some human territories have no clear mouse counterpart. Here we present OTTER, which learns mouse-human brain correspondence as a probabilistic, parcel-resolution coupling using multimodal fused Gromov-Wasserstein optimal transport, integrating functional and structural connectivity with spatial position and curated homologies. OTTER recovers established homologues on a transcriptomic benchmark and preserves broad cross-species organisation along the cortical areal hierarchy. Applying the coupling to human functional connectivity reveals a graded decline in mouse-based reconstruction across evolutionarily expanded association cortex, with the lowest values in lateral prefrontal territory. Finally, the bidirectional map generates testable human predictions from mouse experiments and ranks mouse circuits corresponding to human clinical targets.

neuroscience↗

bioRxiv2025

An agent-based model of Trypanosoma brucei social motility to explore determinants of colony pattern formation

In vitro colonies of the unicellular parasite Trypanosoma brucei expand radially and establish fingering instabilities, a collective behavior known as social motility. The underlying mechanisms are thought to involve single-cell motility, chemical communication among cells, and mechanical interactions with the liquid boundary, but their relative contributions remain unclear. We aimed to determine which of the mechanisms are necessary to quantitatively reproduce the morphological characteristics of social motility. We developed a two-dimensional agent-based model that simulates colonies of 105 - 106 cells at single-cell resolution--two to four orders of magnitude larger than previous models. Cells are represented as point particles executing directional random walks with auto-chemotactic alignment, combined with reflective and mutable boundaries and exponential colony growth. The model was quantitatively evaluated by applying our previously established morphology metrics. We show quantitative agreement of the simulation results and experimental data in terms of colony morphology. Parameter exploration revealed that finger formation arises within a narrow range of trypanosome motility parameters that balance stochasticity and alignment, while boundary conditions modulate the speed of colony expansion. The diffusion coefficient of the chemotactic signal is the key determinant of pattern formation. Realistic behavior occurs at 2x 10-11 - 10-10 m2/s which corresponds to molecules of 12.1-1690 kDa. These results demonstrate that complex colony morphologies can emerge from minimal cell-level rules, suggesting testable hypotheses for the molecular drivers of trypanosome social motility. Furthermore, our approach provides a framework for dissecting the interplay between motility, signaling, and mechanical confinement in other microbial systems exhibiting collective behavior. Author summaryIn vitro colonies of the unicellular parasite Trypanosoma brucei expand radially and form finger-like patterns, a behavior known as social motility. The ability of trypanosomes to exhibit social motility has been linked to their successful journey through their insect vector, the tsetse fly, which facilitates their survival and spreading between hosts. However, the mechanisms driving this behavior are not yet clear. Experimental data suggest that the movement and growth of individual cells, their interactions with each other, and their effects on colony boundaries may all play a role. These different factors are difficult to separate in experiments. We employed mathematical modeling to investigate the relative importance of these factors and developed a model that represents individual cells. The simulations reproduced finger formation patterns similar to those observed in experiments. The results show that complex colony shapes can emerge from simple cell behaviors. We also found that the speed at which a signaling chemical spreads between cells is crucial, and that the predicted values do not match the properties of the chemicals that have been proposed so far. Identifying and testing candidate signaling molecules in experiments could be the next step. Additionally, our approach may also aid in understanding collective behaviors in other microorganisms.

biophysics↗

bioRxiv2025

Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine

Microglia have been implicated in the pathogenesis for several psychiatric disorders, yet comparatively little is known about their role in treatments for these conditions. Prior work showed that the rapid-acting antidepressant ketamine increases synaptic density in the prefrontal cortex (PFC), and that brain-derived neurotrophic factor (BDNF) signaling is required for its synaptic and behavioral effects. These studies assumed that neurons were the primary source of BDNF, but other studies have since demonstrated that microglia can produce BDNF in the brain. Still, it remains unclear if microglial BDNF is important for the antidepressant-like effects of ketamine. Our initial studies show that the behavioral and synaptic effects of ketamine are associated with increased Bdnf expression in sorted PFC microglia 24 hours after injection. We then demonstrate that conditional BDNF depletion in microglia (Cx3cr1Cre/+:Bdnffl/fl) reduces GluN2B levels in PFC synaptoneurosomes and attenuates antidepressant-like responses following ketamine treatment compared to genotype controls (Cx3cr1Cre/+:Bdnf+/+). Consistent with this, we found that Cx3cr1Cre/+:Bdnffl/fl mice show no change in dendritic spine density in the PFC following ketamine. These results indicate that microglial BDNF is important for the effects of ketamine on brain and behavior, expanding upon the role of microglia in pharmacological interventions for psychiatric disorders.

neuroscience↗

bioRxiv2024

The role of IAA and its transport in the complex streptophyte algae Chara braunii

The role of auxin indole-3-acetic acid (IAA), a phytohormone with numerous morphogenic functions, is now well-established in land plants. Although the role of IAA and its transport in algae remains unclear, PIN-driven auxin export is probably an ancient and conserved trait within Streptophytes. Among streptophyte algae, Chara represents a genus with a considerable degree of complexity in body arrangement. This study investigates the auxin response and characterizes homologs of land plant PIN auxin efflux carriers in Chara braunii. Through regeneration experiments, we observed that IAA significantly promotes elongation of thallus and side branch development upon thallus tip decapitation, indicating an effect on morphogenesis. We show that IAA is actively uptaken and metabolized by thallus cells and that this process is influenced by N-1-naphthylphthalamic acid (NPA). To elucidate the underlying mechanisms, we cloned and sequenced the most expressed Chara braunii PINs, CbPINa and CbPINc. Using epitope-specific antibodies, we showed their presence in the plasma membrane (PM) of vegetative internodal cells and generative antheridial cells. Functional tests in tobacco BY-2 cells, supported by in silico docking of IAA and NPA to CbPINa and CbPINc, showed that PM-localized CbPINa interferes with auxin transport in contrast to ER-localized CbPINc. Finally, our phosphoproteome analysis indicated that IAA rapidly induces specific phosphorylation events, including RAF-like kinase phosphorylation, highlighting a potential role for IAA in fast signaling processes in Chara braunii. Altogether, we provide new insights into IAA role in Chara braunii morphogenesis and suggest that while the canonical auxin transport mechanism may not be conserved, auxin still may likely play a role in rapid signaling pathways in this close relative of land plants.

plant biology↗

bioRxiv2024

Analysis of auxin responses in the fern Ceratopteris richardii identifies tissue ontogeny as a major determinant for response properties

The auxin signalling molecule regulates a range of plant growth and developmental processes. The core transcriptional machinery responsible for auxin-mediated responses is conserved across all land plants. Genetic, physiological and molecular exploration in bryophyte and angiosperm model species have shown both qualitative and quantitative differences in auxin responses. Given the highly divergent ontogeny of the dominant gametophyte (bryophytes) and sporophyte (angiosperms) generations, however, it is unclear whether such differences derive from distinct phylogeny or ontogeny. Here, we address this question by comparing a range of physiological, developmental and molecular responses to auxin in both generations of the model fern Ceratopteris richardii. We find that auxin response in Ceratopteris gametophytes closely resembles that of a thalloid bryophyte, whereas the sporophyte mimics auxin response in flowering plants. This resemblance manifests both at phenotypic and transcriptional level. Furthermore, we show that disrupting auxin transport can lead to ectopic sporophyte induction on the gametophyte, suggesting a role for auxin in the alternation of generations. Our study thus identifies ontogeny, rather than phylogeny, as a major determinant of auxin response properties in land plants. Summary statementStudies in angiosperms and bryophytes have left unresolved the roles of tissue ontogeny and species phylogeny in auxin response. We address that problem by characterizing auxin response in a fern.

plant biology↗

bioRxiv2024

Quantification of Trypanosoma Brucei social motilityindicates different colony growth phases

In vitro colonies of the flagellated parasite Trypanosoma brucei grow in characteristic fingering instability patterns. The underlying cause of this this type of collective migration and the associated behavior called social motility remains a topic of intense debate in the scientific community. In order to study these mechanisms in detail, it is crucial to develop quantitative methods to assess and measure social motility patterns at the level of the whole colony beyond qualitative image comparisons. Here, we show a quantification of the growth process based on two scale free metrics designed to quantify the shape of two-dimensional colonies. While initially developed for yeast colonies, we adapted, modified and extended the analysis pipeline for the Trypanosoma system. Combining the quantitative measurements with colony growth simulations based on the Eden model, we discovered two distinct growth phases in social motility showing colonies: In the first phase, the colonies shown mainly circular expansion and later switch to an almost exclusive finger growing phase. These phases are robust when increasing the number of cells as well as upon partial inhibition of the finger formation. A newly developed anisotropy index shows that upon partial inhibition the anisotropy in the colony increases over time. Our results provide objective measurements that help advance the understanding of social motility of trypanosomes. Furthermore, our approach is suitable as a blueprint for investigations of other colony forming cells such as yeast or bacteria.

biophysics↗

bioRxiv2024

Machine Learning-based Classification of transcriptome Signatures of non-ulcerative Bladder Pain Syndrome

Lower urinary tract dysfunction (LUTD) presents a global health challenge with symptoms impacting a substantial percentage of the population. The absence of reliable biomarkers complicates the accurate classification of LUTD subtypes with shared symptoms such as non- ulcerative Bladder Pain Syndrome (BPS) and overactive bladder caused by bladder outlet obstruction with Detrusor Overactivity (DO). This study introduces a machine learning (ML)- based approach for the identification of mRNA signatures specific to non-ulcerative BPS. Using next-generation sequencing (NGS) transcriptome data from bladder biopsies of patients with BPS, benign prostatic obstruction with DO and controls, our statistical approach successfully identified 13 candidate genes capable of discerning BPS from control and DO patients. This set was subsequently validated using Quantitative Polymerase Chain Reaction (QPCR) in a larger patient cohort. To confirm our findings, we applied both supervised and unsupervised ML approaches to the QPCR dataset. Notably, a three-mRNA signature TPPP3, FAT1, and NCALD, emerged as a robust classifier, effectively distinguishing patients with non- ulcerative BPS from controls and patients with DO. This signature was universally selected by both supervised and unsupervised approaches. The ML-based framework used to define BPS classifiers not only establishes a solid foundation for comprehending the specific gene expression changes in the bladder of the patients with BPS but also serves as a valuable resource and methodology for advancing signature identification in other fields. The proposed ML pipeline demonstrates its efficacy in handling challenges associated with limited sample sizes, offering a promising avenue for applications in similar domains.

bioinformatics↗

bioRxiv2022

An ultra-fast, proteome-wide response to the plant hormone auxin

The plant signaling molecule auxin controls growth and development through a simple nuclear pathway that regulates gene expresion. There are however several cellular and physiological responses to auxin that occur within seconds, far too rapid to be mediated by transcriptional changes, for which no molecular mechanism has yet been identified. Using a phosphoproteomic strategy in Arabidopsis thaliana roots, we identify an ultra-rapid auxin response system that targets over 1700 proteins, many within 30 seconds. Auxin response is chemically specific, requires known auxin-binding proteins, and targets various pathways. Through exploring its temporal dynamics, we infer auxin-triggered kinase-substrate networks and identify apoplastic pH changes as a target of signaling and as part of a relay mechanism. By generating a variety of phosphoproteomic datasets, integrated with structural information in a web-app, and by demonstrating analysis and inference strategies, we offer a resource to explore rapid and dynamic signaling in plants.

plant biology↗

bioRxiv2022

A RAF-like kinase mediates a deeply conserved, ultra-rapid auxin response

The plant signaling molecule auxin triggers both fast and slow cellular responses across the plant kingdom, including both land plants and algae. A nuclear response pathway mediates auxin-dependent gene expression, and controls a range of growth and developmental processes in land plants. It is unknown what mechanisms underlie both the physiological responses occurring within seconds, and the responses in algae, that lack the nuclear auxin response pathway. We discovered an ultra-fast proteome-wide phosphorylation response to auxin across 5 land plant and algal species, converging on a core group of shared target proteins. We find conserved rapid physiological responses to auxin in the same species and identified a RAF-like protein kinase as a central mediator of auxin-triggered phosphorylation across species. Genetic analysis allowed to connect this kinase to both auxin-triggered protein phosphorylation and a rapid cellular response, thus identifying an ancient mechanism for fast auxin responses in the green lineage.

plant biology↗

bioRxiv2022

Spatially Multiplexed Single-molecule Translocations through a Nanopore at Controlled Speeds

Nanopores are one of the most successful label-free single-molecule techniques with several sensing applications such as biological screening, diagnostics, DNA and protein sequencing1-4. In current nanopore technologies, stochastic processes influence both the selection of the translocating molecule, translocation rate and translocation velocity5,6. As a result, single-molecule translocations are difficult to control spatially and temporally. Here we present a novel method where we engineer precise spatial and temporal control into the single-molecule experiment. We use a glass nanopore mounted on a 3D nanopositioner to spatially select molecules, deterministically tethered on a glass surface, for controlled translocations. By controlling the distance between the nanopore and the glass surface, we can actively select the region of interest on the molecule and scan it a controlled number of times and at controlled velocity. Decreasing the velocity and averaging thousands of consecutive readings of the same molecule increases the signal-to-noise ratio (SNR) by two orders of magnitude compared to free translocations. We applied our method to various DNA constructs, achieving down to single nucleotide gap resolution. The spatial multiplexing combined with the sub-nanometer resolution could be used in conjunction with micro-array technologies to enable screening of DNA, improving point of care devices, or enabling high-density, addressable DNA data storage.

biophysics↗

bioRxiv2022

Pallidal neuromodulation of the explore/exploit trade-off in decision-making

Every decision that we make involves a conflict between exploiting our current knowledge of an actions value or exploring alternative courses of action that might lead to a better, or worse outcome. The sub-cortical nuclei that make up the basal ganglia have been proposed as a neural circuit that may contribute to resolving this explore-exploit dilemma. To test this hypothesis, we examined the effects of neuromodulating the basal ganglias output nucleus, the globus pallidus interna, in patients who had undergone deep brain stimulation (DBS) for isolated dystonia. Neuromodulation enhanced the number of exploratory choices to the lower value option in a 2-armed bandit probabilistic reversal-learning task. Enhanced exploration was explained by a reduction in the rate of evidence accumulation (drift rate) in a reinforcement learning drift diffusion model. We estimated the functional connectivity profile between the stimulating DBS electrode and the rest of the brain using a normative functional connectome derived from heathy controls. Variation in the extent of neuromodulation induced exploration between patients was associated with functional connectivity from the stimulation electrode site to a distributed brain functional network. We conclude that the basal ganglias output nucleus, the globus pallidus interna, can adaptively modify decision choice when faced with the dilemma to explore or exploit.

neuroscience↗

bioRxiv2019

Direct ETTIN-auxin interaction controls chromatin state in gynoecium development

Hormonal signalling in animals often involves direct transcription factor-hormone interactions that modulate gene expression1, 2. In contrast, plant hormone signalling is most commonly based on de-repression via the degradation of transcriptional repressors3. Recently, we uncovered a non-canonical signalling mechanism for the plant hormone auxin in organ development with strong similarity to animal hormonal pathways. In this mechanism, auxin directly affects the activity of the auxin response factor ETTIN (ETT) towards regulation of target genes without the requirement for protein degradation4, 5. Here we show that auxin binds ETT to modulate gene expression and that this ETT-auxin interaction leads to the dissociation of ETT from co-repressor proteins of the TOPLESS/TOPLESS-RELATED family followed by histone acetylation and the induction of target gene expression. Whilst canonical ARFs are classified as activators or repressors6, ETT is able to switch chromatin locally between repressive and de-repressive states in an instantly-reversible auxin-dependent manner.

plant biology↗