Biology subjects

Lang, L.

Publications and source records attributed to Lang, L..

10 recordsLinked to original sources

bioRxiv2026

AI-driven discovery and engineering of human endogenous nanocage proteins for mRNA delivery

Safe and effective gene delivery remains a central challenge for therapeutic applications. While non-viral and viral vectors have enabled substantial progress, their reliance on non-human components often triggers immune responses, limiting their use in chronic treatments. Here, we developed DeepDelivery, an artificial intelligence-driven platform to repurpose human proteins for mRNA delivery. An unbiased screening of the human proteome nominated 512 candidates, with experimental validation confirming that 80% of top-ranked hits form mRNA-encapsulating particles and mediate efficient functional delivery in human cells without provoking detectable inflammation. Notably, multiple tripartite motif (TRIM) family proteins, typically linked to antiviral responses, exhibited strong assembly and delivery activity. Quantitative analysis and interpretation of the model revealed structural domains that govern nanocage formation, enabling domain-guided engineering of TRIM25 variants with enhanced function. Our work establishes a generalizable framework for discovering human-derived delivery vehicles and provides a path toward programmable, non-immunogenic mRNA therapeutics.

synthetic biology↗

bioRxiv2025

Transcriptional control of meiotic recombination by the DREAM complex

Meiotic chromosome segregation and recombination, essential for sexual reproduction and evolution, require a specialized gene set. However, how meiotic gene expression is controlled remains largely unclear in multicellular eukaryotes. Here, we identify the DREAM complex as a transcriptional regulator of meiotic recombination in Arabidopsis. We show that the DREAM complex localizes to meiotic chromosomes, and that reduced DREAM function disrupts recombination and causes sterility. Meiocyte-specific transcriptomics combined with genome-wide binding analyses revealed that recombination genes, including the crossover-promoting helicase MER3, are direct DREAM targets. Notably, bypassing DREAM regulation of MER3 partially restores recombination in DREAM-deficient plants. Our findings establish the DREAM complex as a major meiotic regulator. Given that reduced DREAM function causes reproductive defects in species such as Drosophila and mice, this role may be conserved across multicellular eukaryotes.

cell biology↗

bioRxiv2025

Linear and categorical coding units in the mouse gustatory cortex drive population dynamics and behavior in taste decision-making

Cortical circuits produce time-varying patterns of population and single neuron activity that play a fundamental role in perceptual and behavioral processes. However, the functional contributions of individual neuron activity to population dynamics and behavior remain unclear. Here we addressed this issue focusing on the mouse gustatory cortex (GC) and using a taste mixture-based decision-making task, high-density electrophysiology, and computational modeling. GC population dynamics represented stimuli linearly during taste sampling and choices categorically before decisions. Single neurons were classified by their linear and categorical activity patterns, revealing subpopulations encoding sensory, perceptual, and decisional variables. To test their functional role, we built a recurrent neural network model of GC. Model perturbations showed linear and categorical neurons were essential for driving normal population dynamics and behavioral performance, whereas many units with other activity patterns could be silenced without consequence. These results have implications that extend beyond GC, and demonstrate the role of linear and categorical coding neurons in cortical dynamics and behavior during perceptual decision-making.

neuroscience↗

bioRxiv2025

Heterooligomerization drives structural plasticity of eukaryotic peroxiredoxins

Peroxiredoxins are highly conserved thiol peroxidases essential for peroxide detoxification, redox signaling, and chaperone activity. Prx1/AhpC-type peroxiredoxins are found throughout the eukaryotic kingdom, where multiple isoforms frequently coexist within the same cell and even in the same subcellular compartment. Long thought to form exclusively homooligomeric structures, we reveal that heterooligomerization is a conserved and important feature of eukaryotic Prx1/AhpC-type peroxiredoxins. We demonstrate that heterooligomer formation modulates peroxoredoxin oligomeric state and enhances structural stability. In yeast, Tsa1-Tsa2 peroxiredoxin heterodecamers form in response to oxidative stress and incorporated Tsa2 stabilizes the decameric state. Beyond yeast, we show that human PRDX1 and PRDX2, as well as plant and parasitic peroxiredoxins, engage in functional heterooligomerization. These findings challenge the long-held paradigm of peroxiredoxin homooligomerization and reveal a novel mechanism for regulating redox homeostasis. Our study provides new insights into peroxiredoxin structural plasticity with broad implications for redox biology, stress responses, and cellular adaptation.

biochemistry↗

bioRxiv2025

H2S is a potential universal reducing agent for Prx6-type peroxiredoxins

The absence of a universal reducing agent distinguishes the Prx6-type subfamily of peroxiredoxins from the structurally similar Prx1-type subfamily. A likely explanation for the lack of reactivity of Prx6-type enzymes with common reducing agents is that a Prx6-specific histidyl residue at the bottom of the active-site pocket traps the oxidized enzyme with a potentially hypervalent cysteinyl sulfur atom in an inaccessible fully-folded protein conformation. Here, we analyzed the reduction of oxidized PfPrx6 from the human malaria parasite Plasmodium falciparum and human PrxVI by the hydrosulfide ion, HS-, as the smallest possible sulfur-containing universal electron donor using stopped-flow kinetic measurements. We show that HS- rapidly reacts with oxidized wild-type PfPrx6 or human PrxVI (but not the histidyl mutant PfPrx6H39Y) with a second-order rate constant of >108 M-1s-1 at pH 7.4. The potential protein-persulfide species of PfPrx6 is neither reduced by thioredoxin nor glutaredoxin and glutathione, but further reacts with an excess of HS- with a second-order rate constant of 6.3x103 M-1s-1, yielding the reduced enzyme. In summary, we identified HS- as a highly reactive, potential universal electron donor for Prx6-type enzymes in eukaryotes, bacteria, and archaea. Our study marks the starting point for the characterization of the complex reduction pathway of Prx6-type enzymes with potential implications for H2S detoxification, redox signaling, and iron-sulfur metabolism.

biochemistry↗

bioRxiv2024

Dynamic Wt1 expression in the gastrulation-stage mouse embryo specifies vascular and visceral smooth muscle cell fate independently from mesothelial fate.

1.The Wilms Tumour protein (WT1) was previously linked to the mesothelial and vascular smooth muscle cell (vSMC) lineage in the mouse intestine, with evidence suggesting that intestinal vSMCs arise from the mesothelium. Here, we report that WT1 is already expressed, unexpectedly, during gastrulation, in cells that specify a population of SMC precursor cells in the lateral plate mesoderm (LPM). Tamoxifen-induced genetic lineage tracing of Wt1-expressing cells revealed that vSMC and visceral smooth muscle cells (visSMCs) of the foetal mid-gut, but not mesothelial cells, were labelled after Tamoxifen administration at E7.5 or E8.5. Analysis of single cell RNA sequencing (scRNAseq) datasets of gastrulation-stage mouse embryos and confocal microscopy demonstrated Wt1 expression in epiblast, primitive streak, emerging mesoderm and, from E7.5 onwards, in the LPM. Co-expression of signature smooth muscle markers in Wt1-expressing cells in gastrulation-stage embryos revealed that vSMC and visSMC fate is specified independently from visceral mesothelium formation. Furthermore, Tamoxifen-induced Wt1 knock-out at E7.5 affected vascularisation in the E12.5 intestine. Taken together, our study provides novel insight into the developmental lineage of smooth muscle specified by WT1 expression during gastrulation. Summary StatementThis study provides novel insight into the developmental lineage of smooth muscle cells in the intestine and mesentery, specified by WT1 expression during gastrulation.

developmental biology↗

bioRxiv2024

Tsa1 is the dominant peroxide scavenger and a source of H2O2-dependent GSSG production in yeast

Hydrogen peroxide (H2O2) is an important biological molecule, functioning both as a second messenger in cell signaling and, especially at higher concentrations, as a cause of cell damage. Cells harbor multiple enzymes that have peroxide reducing activity in vitro. However, the contribution of each of these enzymes towards peroxide scavenging in vivo is less clear. Therefore, to directly investigate in vivo peroxide scavenging, we used the genetically encoded peroxide sensors, roGFP2-Tsa2{Delta}CR and HyPer7, to systematically screen the peroxide scavenging capacity of yeast thiol and heme peroxidase mutants. We show that the 2-Cys peroxiredoxin Tsa1 alone is responsible for almost all exogenous H2O2 and tert-butyl hydroperoxide scavenging. The two catalases and cytochrome c peroxidase only produce observable scavenging defects at higher H2O2 concentrations when these three heme peroxidases are deleted in combination. We also analyzed the reduction of Tsa1 in vitro, revealing that the enzyme is efficiently reduced by thioredoxin 1 with a rate constant of 2.8x106 M-1s-1. When thioredoxins are oxidized, Tsa1 can become an important source of H2 O2 -dependent cytosolic glutathione disulfide production in yeast. Our findings clarify the importance of the various thiol and heme peroxidases for peroxide removal and suggest that most thiol peroxidases have alternative or specialized functions in specific subcellular compartments.

biochemistry↗

bioRxiv2023

The two plant-specific DREAM components FLIC and FLAC repress floral transition in Arabidopsis

The DREAM complex is a key transcriptional regulator especially involved in the control of the cell cycle and development. Here, we characterise two novel plant- specific DREAM components, FLIC and FLAC, which we identified through tandem affinity purification experiments as interactors of conserved core DREAM constituents. We demonstrate that plants lacking both FLIC and FLAC exhibit pleiotropic phenotypes, including stunted growth and reduced fertility. Notably, flic flac double mutants show an early-flowering phenotype, an aspect that we found to be shared with mutants of the core DREAM component LIN37, with which FLIC and FLAC interact in binary protein-protein interaction assays. Performing reverse affinity purification experiments, we detected the JMJ14/NAC050/NAC052 module, known for its involvement in flowering repression, in the interactome of both FLIC and FLAC. Subsequent binary interaction studies then link the JMJ14/NAC050/NAC052 module via LIN37 to the DREAM complex providing a mechanistic framework on how flowering time could be transcriptionally controlled by the DREAM complex. Summary blurbThis study identifies two plant-specific members of the DREAM complex, explores their roles by mutant analysis and protein interaction investigation, and links them and additional DREAM complex components to the regulation of floral transition.

developmental biology↗

bioRxiv2022

Temporal progression along discrete coding states during decision-making in the mouse gustatory cortex

The mouse gustatory cortex (GC) is involved in taste-guided decision-making in addition to sensory processing. Rodent GC exhibits metastable neural dynamics during ongoing and stimulus-evoked activity, but how these dynamics evolve in the context of a taste-based decision-making task remains unclear. Here we employ analytical and modeling approaches to i) extract metastable dynamics in ensemble spiking activity recorded from the GC of mice performing a perceptual decision-making task; ii) investigate the computational mechanisms underlying GC metastability in this task; and iii) establish a relationship between GC dynamics and behavioral performance. Our results show that activity in GC during perceptual decision-making is metastable and that this metastability may serve as a substrate for sequentially encoding sensory, abstract cue, and decision information over time. Perturbations of the models metastable dynamics indicate that boosting inhibition in different coding epochs differentially impacts network performance, explaining a counterintuitive effect of GC optogenetic silencing on mouse behavior.

neuroscience↗

bioRxiv2018

Subtilase-mediated activation of CLEL peptides involves several processing events in consecutive compartments of the secretory pathway

Post-translationally modified peptides are involved in many aspects of plant growth and development. The maturation of these peptides from their larger precursors is still poorly understood. We show here that the biogenesis of CLEL6 and CLEL9 peptides in Arabidopsis thaliana requires a series of processing events in consecutive compartments of the secretory pathway. Following cleavage of the signal peptide upon entry into the endoplasmic reticulum (ER), the peptide precursors are processed in the cis-Golgi by the subtilase SBT6.1. SBT6.1-mediated cleavage within the variable domain allows for continued passage of the partially processed precursors through the secretory pathway, and is a prerequisite for subsequent post-translational modifications including tyrosine sulfation and proline hydroxylation within, and proteolytic maturation after exit from the Golgi. Activation by subtilase SBT3.8 in post-Golgi compartments depends on the N-terminal aspartate of the mature peptides. Our work highlights the complexity of post-translational precursor maturation allowing for stringent control of peptide biogenesis.

plant biology↗