Biology subjects

Huber, G.

Publications and source records attributed to Huber, G..

17 recordsLinked to original sources

bioRxiv2026

PySTARC: GPU-accelerated Brownian dynamics for bimolecular association rate constants

Drug-target association and dissociation rates often determine in vivo efficacy more than affinity alone. The association rate constant, however, is computationally challenging to predict since the productive encounter is a rare event in a large translational and orientational search space, which lies beyond the reach of conventional atomistic simulations. We present PySTARC (Python Simulation Toolkit for Association Rate Constants), a GPU-accelerated Brownian dynamics engine for estimating bimolecular association rate constants. PySTARC is a Python reimplementation of the BrownDye engine that converges even small reaction probabilities on a single GPU, at a throughput that would otherwise require a large CPU cluster. The current framework resolves reactions between integration steps with a closed-form Brownian bridge, models the internal flexibility of the solute through a coarse-grained bead chain, distributes trajectories across multiple GPUs, checkpoints long runs, monitors convergence, and automates the entire workflow from input structures to rate estimates. PySTARC is validated against protein-ligand and protein-protein complexes spanning five orders of magnitude in the association rate constant, with most estimates within one order of magnitude of experiment.

biophysics↗

bioRxiv2026

Environment-driven active transport of influenza A virus

Biological media such as airway mucus and extracellular matrix are usually viewed as transport barriers that particles cross by passive diffusion or with internal engines. We show instead that a particle can move actively by modifying the landscape it traverses, creating environmental memory and directional cues in two and three dimensions. Influenza A virus (IAV) realizes this principle through its envelope proteins hemagglutinin (HA) and neuraminidase (NA), which bind and cleave sialylated glycan receptors, respectively. Combining theory, simulations and single-virus tracking, we connect bind--cleave kinetics and HA--NA organization to macroscopic transport. Cleavage dissipates chemical free energy, biases rebinding to the edited landscape and leaves a trail that shapes future encounters. In heterogeneous receptor landscapes, multivalent binding biases motion toward higher receptor density, while receptor destruction by NA can amplify this bias by sharpening the contrast sampled by HA. Experiments on reconstituted glycan membranes show that IAV steps are biased up local receptor gradients, as predicted. The theory suggests that virion-to-virion variability can distribute transport functions across a population, providing a physical hedge against complex receptor environments. Together, these results establish environment-driven active matter as a mechanism for motorless transport powered and guided by chemical modification of the environment.

biophysics↗

bioRxiv2026

GSNOR-dependent nitric oxide homeostasis promotes recovery from repeated climate stress across generations in Arabidopsis thaliana

Climate change exposes plants to recurrent and interacting stresses, yet the extent to which these effects persist across generations, and the mechanisms involved, remain unclear. We propagated Arabidopsis thaliana wild type (WT, Col-0) and nitric oxide homeostasis mutant gsnor1-3 (hereafter, gsnor-ko) for five successive generations. Plants were grown under control, drought, elevated CO2, O3, warm temperature, and combined treatment scenarios for the first three generations (G1-G3), followed by two recovery generations under control conditions (G4-G5). We quantified rosette growth, photosynthetic traits, seed production, and transcriptome dynamics by RNA-seq. Across environments, gsnor-ko showed reduced vegetative growth and reproductive output relative to WT. Transcriptomic responses were strongly scenario- and generation-dependent, with the largest differential expression shifts observed under warm-climate and combined-treatment conditions. Compared with WT, gsnor-ko displayed broader gene overlap across generations and stronger retention or reconfiguration of stress-responsive states after stress withdrawal. Functional enrichment and candidate-gene analyses identified pathways/components linked to DNA methylation, heterochromatin maintenance, histone ubiquitination, m6A RNA regulation, and methyl-donor metabolism. Together, these results support a model in which GSNOR activity promotes transcriptomic recovery after repeated climate stress, whereas impaired GSNOR function shifts responses toward multi-generational persistence and epigenetically associated regulatory reconfiguration. HighlightGSNOR-dependent nitric oxide homeostasis promotes transcriptomic resetting after repeated climate stress, whereas impaired NO homeostasis favours multigenerational persistence and chromatin- and RNA-linked regulatory reconfiguration. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/742973v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@6031c6org.highwire.dtl.DTLVardef@163be5borg.highwire.dtl.DTLVardef@1665e9eorg.highwire.dtl.DTLVardef@1cde833_HPS_FORMAT_FIGEXP M_FIG C_FIG

plant biology↗

bioRxiv2025

A non-rectifying potassium channel increases cassava drought tolerance and storage root yield

Cassava (Manihot esculenta) is an important crop for food security in the tropics, particularly for smallholder farmers in sub-Saharan Africa, where yields are often severely limited by pathogen pressure, nutrient deficiency, and water scarcity. We expressed a non-rectifying Arabidopsis thaliana potassium (K+) channel gene version, AKT2var, in the vascular tissue of cassava plants. The transgenic cassava plants had higher electron transport and CO2 assimilation rates, a higher bulk flow velocity, and increased source-sink carbohydrate transport, as demonstrated by comparative 11C-positron emission tomography and tissue-specific metabolite profiling. Cassava storage root yield was significantly increased in greenhouse experiments and in a multi-year field trial conducted under subtropical conditions. AKT2var plants were also more tolerant to drought stress and had higher storage root yield. Targeted alteration of K+ transport is therefore a promising strategy to improve cassava productivity without additional fertilizer input and in climate-adverse growing conditions.

plant biology↗

bioRxiv2024

Multiomics plasticity in seed traits of pan-genome wheat cultivars

The molecular basis of cultivar-level variations in polyploid wheat that enables environmental adaptation while maintaining yield and quality in polyploid wheat remains poorly understood. We conducted a detailed phenotypic assessment and multiomics analysis of nine pan-genome polyploid wheat cultivars grown under control and drought conditions. We aimed to investigate the subgenome-level variations, cultivar differences and biochemical mechanisms affecting plant fitness under moderate drought stress. Intrinsic water use efficiency, grain yield, and grain protein content and quality differed among cultivars, supporting the plasticity of drought stress responses. Biased proteome and metabolome abundance changes in response to moderate drought stress during the vegetative stage indicate different strategies for the utilization of homeologous protein isoforms assigned to the A, B, and D subgenomes. Drought effects were detected at the protein level, but significant changes were observed in central carbon pathway metabolites and micronutrient profiles. The subgenomic localization of seed storage proteins highlight differences in nutrient reservoir accumulation and emphasizes the enhanced role of S-rich prolamins in the stress response. Subgenomic variations define cultivar phenotypes by producing molecules that accumulate and enable the underlying trade-offs between environmental adaptation and yield- or quality-related traits. These variations can be used to select crops with increased stress resistance without compromising yield.

plant biology↗

bioRxiv2024

The Endoplasmic Reticulum as an Active Liquid Network

The peripheral endoplasmic reticulum (ER) forms a dense, interconnected, and constantly evolving network of membrane-bound tubules in eukaryotic cells. While individual structural elements and the morphogens that stabilize them have been described, a quantitative understanding of the dynamic large-scale network topology remains elusive. We develop a physical model of the ER as an active liquid network, governed by a balance of tension-driven shrinking and new tubule growth. This minimalist model gives rise to steady-state network structures with density and rearrangement timescales predicted from the junction mobility and tubule spawning rate. Several parameter-independent geometric features of the liquid network model are shown to be representative of ER architecture in live mammalian cells. The liquid network model connects the time-scales of distinct dynamic features such as ring closure and new tubule growth in the ER. Furthermore, it demonstrates how the steady-state network morphology on a cellular scale arises from the balance of microscopic dynamic rearrangements. SIGNIFICANCEThe peripheral endoplasmic reticulum (ER) forms a continuous, dynamic network of tubules that plays an important role in protein sorting, export, and quality control, as well as cellular signaling and stress response. Elucidating how the unique morphology of the ER arises and supports its function is critical to developing a mechanistic understanding of the many neurological diseases associated with ER structural perturbations. We develop a physical model of the ER as an active liquid network to understand how its cellular-scale structure emerges from small-scale dynamic rearrangements. The model demon-strates how key features of ER architecture can arise from a balance of tubule growth and tension-driven sliding. This work provides insight into the fundamental physical mechanisms underlying the emergent morphology of the ER.

biophysics↗

bioRxiv2024

The kinetics and optimality of influenza A virus locomotion

Influenza A viruses (IAVs) must navigate through a dense extracellular mucus to infect airway epithelial cells. The mucous layer, composed of glycosylated biopolymers (mucins), presents sialic acid that binds to ligands on the viral envelope and can be irreversibly cleaved by viral enzymes. It was recently discovered that filamentous IAVs exhibit directed persistent motion along their long axis on sialic acid-coated surfaces. This study demonstrates through stochastic simulations and mean-field theory, how IAVs harness a burnt-bridge Brownian ratchet mechanism for directed persistent translational motion. Importantly, our analysis reveals that equilibrium features of the system primarily control the dynamics, even out-of-equilibrium, and that ligand asymmetry allows for more robust directed transport. We show viruses occupy the optimal parameter range ( Goldilocks zone) for efficient mucous transport, possibly due to the evolutionary adaptation of enzyme kinetics. Our findings suggest novel therapeutic targets and provide insight into possible mechanisms of zoonotic transmission.

biophysics↗

bioRxiv2023

Configurational entropy is an intrinsic driver of tissue structural heterogeneity

Tissues comprise ordered arrangements of cells that can be surprisingly disordered in their details. How the properties of single cells and their microenvironment contribute to the balance between order and disorder at the tissue-scale remains poorly understood. Here, we address this question using the self-organization of human mammary organoids as a model. We find that organoids behave like a dynamic structural ensemble at the steady state. We apply a maximum entropy formalism to derive the ensemble distribution from three measurable parameters - the degeneracy of structural states, interfacial energy, and tissue activity (the energy associated with positional fluctuations). We link these parameters with the molecular and microenvironmental factors that control them to precisely engineer the ensemble across multiple conditions. Our analysis reveals that the entropy associated with structural degeneracy sets a theoretical limit to tissue order and provides new insight for tissue engineering, development, and our understanding of disease progression.

bioengineering↗

bioRxiv2023

Zebrahub - Multimodal Zebrafish Developmental Atlas Reveals the State Transition Dynamics of Late Vertebrate Pluripotent Axial Progenitors

Elucidating the developmental processes of organisms requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by trajectory reconstructions. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling in silico fate mapping experiments. To demonstrate the versatility of our multi-modal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of Neuro-Mesodermal Progenitors (NMPs). Our publicly accessible web-based platform, Zebrahub, is a foundational resource for studying developmental processes at both transcriptional and spatiotemporal levels, providing researchers with an integrated approach to exploring and analyzing the complexities of cellular lineages during zebrafish embryogenesis.

developmental biology↗

bioRxiv2021

Collagen VI regulates motor circuit plasticity and motor performance by cannabinoid modulation

Collagen VI is a key component of muscle basement membranes, and genetic variants can cause monogenic muscular dystrophies. Conversely, human genetic studies recently implicated collagen VI in central nervous system function, with variants causing the movement disorder dystonia. To elucidate the neurophysiological role of collagen VI, we generated mice with a truncation of the dystonia-related collagen 3 (VI) (COL6A3) C-terminal domain (CTD). These Col6a3CTT mice showed a recessive dystonia-like phenotype. We found that COL6A3 interacts with the cannabinoid receptor 1 (CB1R) complex in a CTD-dependent manner. Col6a3CTT mice have impaired homeostasis of excitatory input to the basal pontine nuclei (BPN), a motor control hub with dense COL6A3 expression, consistent with deficient endocannabinoid signaling. Aberrant synaptic input in the BPN was normalized by a CB1R agonist, and motor performance in Col6a3CTT mice was improved by CB1R agonist treatment. Our findings identify a readily therapeutically addressable synaptic mechanism for motor control. SIGNIFICANCE STATEMENTDystonia is a movement disorder characterized by involuntary movements. We previously identified genetic variants affecting a specific domain of the COL6A3 protein as a cause of dystonia. Here, we we created mice lacking the affected domain and observed an analogous movement disorder. Using a protein interaction screen, we found that the affected COL6A3 domain mediates an interaction with the cannabinoid receptor CB1R. Concordantly, our COL6A3-deficient mice showed a deficit in synaptic plasticity linked to a deficit in cannabinoid signaling. Pharmacological cannabinoid augmentation rescued the motor impairment of the mice. Thus, cannabinoid augmentation could be a promising avenue for treating dystonia, and we have identified a possible molecular mechanism mediating this.

neuroscience↗

bioRxiv2021

In vivo imaging and quantification of carbon tracer dynamics in nodulated root systems of pea plants

Legumes associate with root colonizing rhizobia that provide fixed nitrogen to its plant host in exchange for recently fixed carbon. There is a lack in understanding how individual plants modulate carbon allocation to a nodulated root system as a dynamic response to abiotic stimuli. One reason is that most approaches are based on destructive sampling, making quantification of localized carbon allocation dynamics in the root system difficult. We established an experimental workflow for routinely using non-invasive Positron Emission Tomography (PET) to follow the allocation of leaf-supplied 11C tracer towards individual nodules in a three-dimensional (3D) root system of pea (Pisum sativum). Nitrate was used for triggering the shutdown of biological nitrogen fixation (BNF) expected to rapidly affect carbon allocation dynamics in the root-nodule system. This nitrate treatment lead to a reduction of 11C tracer allocation to nodules by 40% - 47% in 5 treated plants while the variation in control plants was less than 11%. The established experimental pipeline enabled for the first time that several plants could consistently be labelled and measured using 11C tracer in a PET approach to quantify C-allocation to individual nodules following a BNF shutdown. This demonstrates the strength of using 11C tracers in a PET approach for non-invasive quantification of dynamic carbon allocation in several growing plants over several days. A major advantage of the approach is the possibility to investigate carbon dynamics in small regions of interest in a 3D system such as nodules in comparison to whole plant development. One sentence summaryPositron Emission Tomography for quantification of carbon allocation dynamics in individual nodules within a 3D root system revealed strong effect of nitrate on carbon allocation.

plant biology↗

bioRxiv2021

Polymorphism of Genetic Ambigrams

Double synonyms in the genetic code can be used as a tool to test competing hypotheses regarding ambigrammatic narnavirus genomes. Applying the analysis to recent observations of Culex narnavirus 1 and Zhejiang mosquito virus 3 ambigrammatic viruses indicates that the open reading frame on the complementary strand of the segment coding for RNA-dependent RNA polymerase does not code for a functional protein. Culex narnavirus 1 has been shown to possess a second segment, also ambigrammatic, termed Robin. We find a comparable segment for Zhejiang mosquito virus 3, a moderately diverged relative of Culex narnavirus 1. Our analysis of Robin polymorphisms suggests that its reverse open reading frame also does not code for a functional protein. We make a hypothesis about its role.

genomics↗

bioRxiv2020

Performing Parentage Analysis for Polysomic Inheritances Based on Allelic Phenotypes

Polyploidy poses several problems for parentage analysis. We present a new polysomic inheritance model for parentage analysis based on genotypes or allelic phenotypes to solve these problems. The effects of five factors are simultaneously accommodated in this model: (i) double-reduction, (ii) null alleles, (iii) negative amplification, (iv) genotyping errors and (v) self-fertilization. To solve genotyping ambiguity (unknown allele dosage), we developed a new method to establish the likelihood formulas for allelic phenotype data and to simultaneously include the effects of our five chosen factors. We then evaluated and compared the performance of our new method with three established methods by using both simulated data and empirical data from the cultivated blueberry (Vaccinium corymbosum). We also developed and compared the performance of two additional estimators to estimate the geno-typing error rate and the sample rate. We make our new methods freely available in the software package O_SCPLOWPOLYGENEC_SCPLOW, at http://github.com/huangkang1987/polygene.

genetics↗

bioRxiv2020

Multiscale simulations examining glycan shield effects on drug binding to influenza neuraminidase

Influenza neuraminidase is an important drug target. Glycans are present on neuraminidase, and are generally considered to inhibit antibody binding via their glycan shield. In this work we studied the effect of glycans on the binding kinetics of antiviral drugs to the influenza neuraminidase. We created all-atom in silico systems of influenza neuraminidase with experimentally-derived glycoprofiles consisting of four systems with different glycan conformations and one system without glycans. Using Brownian dynamics simulations, we observe a two- to eight-fold decrease in the rate of ligand binding to the primary binding site of neuraminidase due to the presence of glycans. These glycans are capable of covering much of the surface area of neuraminidase, and the ligand binding inhibition is derived from glycans sterically occluding the primary binding site on a neighboring monomer. Our work also indicates that drugs preferentially bind to the primary binding site (i.e. the active site) over the secondary binding site, and we propose a binding mechanism illustrating this. These results help illuminate the complex interplay between glycans and ligand binding on the influenza membrane protein neuraminidase. Statement of SignificanceThe influenza glycoprotein neuraminidase is the target for three FDA-approved influenza drugs in the US. However, drug resistance and low drug effectiveness merits further drug development towards neuraminidase, which is hindered by our limited understanding of glycan effects on ligand binding. Generally, drug developers do not include glycans in their development pipelines. Here, we show that even though glycans can reduce drug binding towards neuraminidase, we recommend future drug development work to focus on strong binders with a long lifetime. Furthermore, we examine the binding competition between the primary and secondary binding sites on neuraminidase, leading us to propose a new, to the best of our knowledge, multivalent binding mechanism.

biophysics↗

bioRxiv2019

An exploration of ambigrammatic sequences in narnaviruses

Narnaviruses have been described as positive-sense RNA viruses with a remarkably simple genome of [~] 3 kb, encoding only a highly conserved RNA-dependent RNA polymerase (RdRp). Many narnaviruses, however, are ambigrammatic and harbour an additional uninterrupted open reading frame (ORF) covering almost the entire length of the reverse complement strand. No function has been described for this ORF, yet the absence of stops is conserved across diverse narnaviruses, and in every case the codons in the reverse ORF and the RdRp are aligned. The > 3 kb ORF overlap on opposite strands, unprecedented among RNA viruses, motivates an exploration of the constraints imposed or alleviated by the codon alignment. Here, we show that only when the codon frames are aligned can all stop codons be eliminated from the reverse strand by synonymous single-nucleotide substitutions in the RdRp gene, suggesting a mechanism for de novo gene creation within a strongly conserved amino-acid sequence. It will be fascinating to explore what implications this coding strategy has for other aspects of narnavirus biology. Beyond narnaviruses, our rapidly expanding catalogue of viral diversity may yet reveal additional examples of this broadly-extensible principle for ambigrammatic-sequence development.

genomics↗

bioRxiv2019

Terasaki Spiral Ramps and Intracellular Diffusion

The sheet-like endoplasmic reticulum (ER) of eukaryotic cells has been found to be riddled with spiral dislocations, known as Terasaki ramps, in the vicinity of which the doubled bilayer membranes which make up ER sheets can be approximately modeled by helicoids. Here we analyze diffusion on a surface with locally helicoidal topological dislocations, and use the results to argue that the Terasaki ramps facilitate a highly efficient transport of water-soluble molecules within the lumen of the endoplasmic reticulum.

biophysics↗

bioRxiv2019

Persistent Features of Intermittent Transcription

Here we report statistical studies of single-cell mRNA counts from cells derived from different tissues of adult mice. By examining correlations between mRNA gene counts we find strong evidence that when genes are only observed in a small fraction of cells, this is as a consequence of intermittent transcription rather than of expression only in specialized cell types. Count statistics are used to estimate a peak transcription level for each gene, and a probability for the gene to be active in any given cell. We find that the peak transcription levels are approximately constant across different tissue types, but the gene expression probabilities may be markedly different. Both these quantities have very wide ranges of values, with a probability density function well approximated by a power law.\n\nAuthor summaryUsing evidence from single-cell mRNA counts, we argue that the expression of many genes in individual mouse cells is highly intermittent. Comparing cells from different tissues, we find that the peak activity of a given gene is approximately the same in all tissue types, whereas the probability of a gene being active can differ markedly.

genomics↗