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Biology subjects

Koch, D.

Publications and source records attributed to Koch, D..

9 recordsLinked to original sources

Near-critical slow dynamics enable flexible temporal computations and generalization

Although neural activity often evolves along low-dimensional manifolds, such descriptions do not explain the dynamical mechanisms that generate, constrain, and stabilize computation. Identifying these mechanisms is essential for predicting responses to perturbations, understanding generalization to untrained signals, and explaining how similar computations arise from distinct circuit implementations. Here we use recurrent neural networks trained on an interval timing task as a model system to uncover the dynamical mechanisms of neural computation. We show that, despite converging to highly diverse attractor architectures, trained networks share a conserved transient dynamics. During learning, networks self-organize near dynamical bifurcations, forming structured ghost sets of slow points characterized by graded spectra of near-zero eigenvalues. These slow sets form a dynamical scaffold that constrains trajectory evolution. Inputs transiently reconfigure the vector field and reposition activity within this scaffold, while the underlying slow set governs subsequent dynamics. As a result, temporal computation is implemented through structured transient evolution rather than convergence to fixed points or persistent activity states. The extent of the slow sets predicts generalization to unseen temporal intervals, and networks lacking such organization fail to extrapolate reliably. To test sufficiency, we construct a minimal dynamical system endowed with analogous slow set geometry that reproduces interval timing without learning, providing a benchmark for identifying the essential dynamical ingredients of temporal computation. Together, these results identify structured slow transients as a candidate dynamical mechanism for temporal computation, provide a mechanistic interpretation of slow low-dimensional manifolds as emergent consequences of underlying state-space structure, and suggest that computational capacity in near-critical systems arises from the organization of transient flow rather than attractor states alone.

neuroscience↗

Homeorhetic regulation of cellular phenotype

How cells translate growth factor (GF) signals into context-specific phenotypes remains a fundamental question in cell biology. The classical view holds that cells translate a constant concentration of a GF with specific chemical identity to a steady state activation of the underlying signaling pathway, resulting in a defined phenotypic response. However, recent findings suggest that even a single GF, when presented in a pulsatile manner, drives differential phenotypic responses depending on the frequency of stimulation. To reconcile these views, we introduce a novel conceptual framework of "signaling homeorhesis". Unlike homeostasis, homeorhesis describes the stable evolution of signaling trajectories over time. Defining this concept quantitatively using a dynamical systems framework, we use mathematical models of the Epidermal Factor Growth Receptor (EGFR) and the Tropomyosin receptor kinase A (TrkA) networks, as well as available experimental temporal protein activity recordings in PC-12 cells to demonstrate that cells classify GF signals to unique signaling trajectories that encode for distinct cell phenotypes, irrespective of the GF identity. We thereby propose that the cellular phenotype is determined in real-time, as the cell actively interprets the growth factor signals from its environment.

cell biology↗

Spatial control of myosin regulatory light chain phosphorylation modulates cardiac thick filament mechano-sensing

The heart can adapt its performance in response to changing metabolic demands of the rest of the body. A central mechanism intrinsic to the heart is to modulate the function of the cardiac contractile proteins via post-translational modifications. Although phosphorylation of the cardiac myosin motor-associated regulatory light chain (RLC) by cardiac myosin light chain kinase (cMLCK) has been recognized as a key signalling pathway to increase myocardial contractile function, little is known about its molecular mechanism of action. Here, we show that phosphorylation of RLC is not a stochastic process but a spatially tightly controlled mechanism. Myosin motors in the region of the thick filament associated with cardiac myosin binding protein-C (cMyBP-C) are the primary target for phosphorylation by cMLCK. Moreover, phosphorylation of RLC likely only leads to activation of one of the two myosin motors of the cardiac myosin molecule and increases their force-dependent recruitment. We propose that RLC phosphorylation exerts its functional effects via increasing the gain of the mechano-signalling between different zones of the thick filament. A better mechanistic understanding of the role of RLC phosphorylation likely underpins the development of therapeutic interventions for both heart disease and heart failure.

biochemistry↗

Processes essential for Physcomitrium patens protonemal development require distinct levels of total activity provided by functionally redundant PpROP GTPases

RHO GTPases are key regulators of cellular and developmental processes in most eukaryotic organisms. ROPs (RHO of plants) constitute a plant-specific RHO subfamily. ROP families expanded and functionally diversified during the evolution of structurally complex vascular plants, but generally contain few members in non-vascular plants with ancient features. In vascular and non-vascular plants, ROP proteins are required for cell polarization, directional cell expansion, and mitotic cell plate positioning. All these processes are impaired by the disruption of PpROP activity in the non-vascular moss Physcomitrium patens. The aim of the study presented here was to further characterize PpROP functions during P. patens protonemal development by a) knocking out individually or in all possible combinations each of the four RpROP genes, which encode nearly identical proteins, b) complementing knock-out mutants with WT or mutant PpROP isoforms, or with heterologous homologs, and c) performing overexpression experiments. PpROPs were found to have additional previously unknown functions in the regulation of cell proliferation, caulonema differentiation, and gametophore formation. Furthermore, different cellular and developmental processes were shown to require distinct levels of total PpROP activity, rather than individual PpROP isoforms. Implications of the remarkable sequence conservation and functional integration within the PpROP protein family are discussed. One-sentence summaryKnock-out, complementation, and overexpression experiments further defined PpROP functions in P. patens development, and demonstrated their dependence on distinct levels of total PpROP activity.

cell biology↗

The cardiac myosin binding protein-C phosphorylation state as a function of multiple protein kinase and phosphatase activities

Phosphorylation of cardiac myosin binding protein-C (cMyBP-C) is a crucial determinant of cardiac myofilament function. Although cMyBP-C phosphorylation by various protein kinases has been extensively studied, the influence of protein phosphatases on cMyBP-Cs multiple phosphorylation sites has remained largely obscure. Here we provide a detailed biochemical characterization of cMyBP-C dephosphorylation by protein phosphatases 1 and 2A (PP1 and PP2A) and develop an integrated kinetic model for cMyBP-C phosphorylation using data for both PP1, PP2A and protein kinases A (PKA), C and RSK2. We find strong site-specificity and a hierarchical mechanism for both phosphatases, proceeding in the opposite direction of sequential phosphorylation by PKA. The model is consistent with published data from human patients and predicts complex non-linear cMyBP-C phosphorylation patterns that are validated experimentally. Our results emphasize the importance of phosphatases for cMyBP-C regulation and prompt us to propose reciprocal relationships between cMyBP-C m-motif conformation, phosphorylation state and myofilament function.

biochemistry↗

Obscurin Rho GEF domains are phosphorylated by MST-family kinases but do not exhibit nucleotide exchange factor activity towards Rho GTPases in vitro

Obscurin is a giant muscle protein (>800 kDa) featuring multiple signalling domains, including an SH3-DH-PH domain triplet from the Trio-subfamily of guanosine nucleotide exchange factors (GEFs). While previous research suggests that these domains can activate the small GTPases RhoA and RhoQ in cells, in vitro characterization of these interactions using biophysical techniques has been hampered by the intrinsic instability of obscurin GEF domains. To study substrate specificity, mechanism and regulation of obscurin GEF function by individual domains, we successfully optimized recombinant production of obscurin GEF domains and found that MST-family kinases phosphorylate the obscurin DH domain at Thr5798. Despite extensive testing of multiple GEF domain fragments, we did not detect any nucleotide exchange activity in vitro against 9 representative small GTPases. Bioinformatic analyses show that obscurin differs from other Trio-subfamily GEFs in several important aspects. While further research is necessary to evaluate obscurin GEF activity in vivo, our results indicate that obscurin has atypical GEF domains that, if catalytically active at all, are subject to complex regulation.

biochemistry↗

Post-stroke dendritic arbor regrowth - a cortical repair process requiring the actin nucleator Cobl

Ischemic stroke is a major cause of death and long-term disability. We demonstrate that middle cerebral artery occlusion in mice leads to a strong decline in dendritic arborization of penumbral neurons. These defects were subsequently repaired by an ipsilateral recovery process requiring the actin nucleator Cobl. Ischemic stroke and excitotoxicity, caused by calpain-mediated proteolysis, significantly reduced Cobl levels. In an apparently unique manner among excitotoxicity-affected proteins, this Cobl decline was rapidly restored by increased mRNA expression and Cobl then played a pivotal role in post-stroke dendritic arbor repair in peri-infarct areas. In Cobl KO mice, the dendritic repair window determined to span day 2-4 post-stroke in WT strikingly passed without any dendritic regrowth. Instead, Cobl KO penumbral neurons of the primary motor cortex continued to show the dendritic impairments caused by stroke. Our results thereby highlight a powerful post-stroke recovery process and identified causal molecular mechanisms critical during post-stroke repair.

neuroscience↗

Molecular Noise-Filtering in the β-adrenergic Signaling Network by Phospholamban Pentamers

Phospholamban (PLN) is an important regulator of calcium handling in cardiomyocytes due to its ability to inhibit the sarco(endo)plasmic reticulum calcium-ATPase (SERCA) {beta}-adrenergic stimulation reverses SERCA inhibition via PLN phosphorylation and facilitates fast calcium reuptake PLN also forms pentamers whose physiological significance has remained elusive Using biochemical experiments and mathematical modeling, we show that pentamers regulate both the dynamics and steady-state levels of monomer phosphorylation Substrate competition by pentamers and a feed-forward loop involving inhibitor-can delay monomer phosphorylation by protein kinase A (PKA) Steady-state phosphorylation of PLN is predicted to be bistable due to cooperative dephosphorylation of pentamers Both effects act as complementary noise-filters which can reduce the effect of random fluctuations in PKA activity Pentamers thereby ensure consistent monomer phosphorylation and SERCA activity in spite of noisy upstream signals Preliminary analyses suggest that the PLN mutation R del could impair noise-filtering, offering a new perspective on how this mutation causes cardiac arrhythmias.

systems biology↗

Homo-Oligomers in Signal Transduction: ModellingApproaches, Homeostasis, Ultrasensitivity, Bistability

Homo-oligomerisation of proteins is a ubiquitous phenomenon whose exact role remains unclear in many cases. To identify novel functions, this paper provides an exploration of general dynamical mathematical models of homo-oligomerisation. Simulation and analysis of these models show that homo-oligomerisation on its own allows for a remarkable variety of complex dynamic and steady-state regulatory behaviour such as transient overshoots or homeostatic control of monomer concentration. If post-translational modifications are considered, however, conventional mass-action kinetics leads to thermodynamic inconsistencies due to asymmetric combinatorial expansion of reaction routes. Introducing a conservation principle to balance rate equations re-establishes thermodynamic consistency. Using such balanced models it is shown that oligomerisation can lead to bistability by enabling pseudo-multisite modification and kinetic pseudo-cooperativity via multi-enzyme regulation, thereby constituting a novel motif for bistable modification reactions. Due to these potential signal processing capabilities, homo-oligomerisation could play far more versatile roles in signal transduction than previously appreciated.

systems biology↗