Biology subjects

Rasmussen, K.

Publications and source records attributed to Rasmussen, K..

7 recordsLinked to original sources

bioRxiv2026

A pyoverdine-type metallophore is required for lanthanide-dependent growth in Pseudomonas putida

Lanthanides (Ln) are recently discovered cofactors for alcohol metabolism in a growing number of bacteria, including the soil-dwelling bacterium Pseudomonas putida, yet the mechanisms for Ln uptake are poorly defined. Here, we discovered that the non-ribosomal peptide synthase biosynthetic gene cluster, pvdLIJD, was essential to Ln-dependent growth in P. putida. Pyoverdine G4R and its precursor ferribactin were identified as pvdLIJD gene products with La-responsive abundances, and both chelated La as well as iron. Deletion of the putative pyoverdine outer membrane transport system encoded by fpvA and exbBD:tonB were strongly linked to Ln-dependent growth in a concentration-dependent manner. Global transcriptomes were remodeled in response to La, but weak evidence of transcriptional pvdLIJD regulation and no evidence of discernment between La provided as chloride versus oxide were observed. Overall, this work establishes pyoverdines as metallophores involved in La uptake, re-framing them from strictly iron-scavenging siderophores to dual-purpose metallophores with Ln-binding activity.

microbiology↗

bioRxiv2024

Efficient High-Throughput DNA Breathing Features Generation Using Jax-EPBD

DNA breathing dynamics--transient base-pair opening and closing due to thermal fluctuations--are vital for processes like transcription, replication, and repair. Traditional models, such as the Extended Peyrard-Bishop-Dauxois (EPBD), provide insights into these dynamics but are computationally limited for long sequences. We present JAX-EPBD, a high-throughput Langevin molecular dynamics framework leveraging JAX for GPU-accelerated simulations, achieving up to 30x speedup and superior scalability compared to the original C-based EPBD implementation. JAX-EPBD efficiently captures time-dependent behaviors, including bubble lifetimes and base flipping kinetics, enabling genome-scale analyses. Applying it to transcription factor (TF) binding affinity prediction using SELEX datasets, we observed consistent improvements in R2 values when incorporating breathing features with sequence data. Validating on the 77-bp AAV P5 promoter, JAX-EPBD revealed sequence-specific differences in bubble dynamics correlating with transcriptional activity. These findings establish JAX-EPBD as a powerful and scalable tool for understanding DNA breathing dynamics and their role in gene regulation and transcription factor binding.

bioinformatics↗

bioRxiv2024

Scalable DNA Feature Generation and Transcription Factor Binding Prediction via Deep Surrogate Models

Simulating DNA breathing dynamics, for instance Extended Peyrard-Bishop-Dauxois (EPBD) model, across the entire human genome using traditional biophysical methods like pyDNA-EPBD is computationally prohibitive due to intensive techniques such as Markov Chain Monte Carlo (MCMC) and Langevin dynamics. To overcome this limitation, we propose a deep surrogate generative model utilizing a conditional Denoising Diffusion Probabilistic Model (DDPM) trained on DNA sequence-EPBD feature pairs. This surrogate model efficiently generates high-fidelity DNA breathing features conditioned on DNA sequences, reducing computational time from months to hours-a speedup of over 1000 times. By integrating these features into the EPBDxDNABERT-2 model, we enhance the accuracy of transcription factor (TF) binding site predictions. Experiments demonstrate that the surrogate-generated features perform comparably to those obtained from the original EPBD framework, validating the models efficacy and fidelity. This advancement enables real-time, genome-wide analyses, significantly accelerating genomic research and offering powerful tools for disease understanding and therapeutic development.

genomics↗

bioRxiv2024

Temporal and anteriorly positioned mitotic zones drive asymmetric microtubule patterns needed for Left-Right Organizer development.

Cellular proliferation is vital for tissue development, including the Left-Right Organizer (LRO), a transient organ critical for establishing the vertebrate LR body plan. This study investigates cell redistribution and the role of specific progenitor cells in LRO formation, focusing on cell lineage and behavior. Using zebrafish as a model, we mapped all mitotic events in Kupffers Vesicle (KV), revealing an FGF-dependent, anteriorly enriched mitotic pattern. With a KV-specific fluorescent microtubule (MT) line, we observed that mitotic spindles align along the KVs longest axis until the rosette stage, spindles that form after spin, and are excluded from KV. Early aligned spindles assemble cytokinetic bridges that point MT bundles toward a tight junction where a rosette will initially form. Post-abscission, repurposed MT bundles remain targeted at the rosette center, facilitating actin recruitment. Additional cells, both cytokinetic and non-cytokinetic, are incorporated into the rosette, repurposing or assembling MT bundles before actin recruitment. These findings show that initial divisions are crucial for rosette assembly, MT patterning, and actin remodeling during KV development.

developmental biology↗

bioRxiv2022

Age-dependent dysregulation of locus coeruleus firing in a transgenic rat model of Alzheimers disease

Accumulation of hyperphosphorylated tau in the locus coeruleus (LC) is a ubiquitous feature of prodromal Alzheimers disease (AD), and LC neurons degenerate as AD progresses. Tau-mediated LC dysfunction may contribute to early neuropsychiatric symptoms, while loss of LC integrity is associated with conversion to cognitive impairment. Hyperphosphorylated tau alters firing rates in other brain regions, but its effects on LC neurons have not been described. The purpose of this study was to characterize changes in firing properties of LC neurons when they are the only cells containing hyperphosphorylated tau, as well as later in disease when {beta}-amyloid (A{beta}) and tau pathology is abundant in the forebrain. Single unit LC activity was recorded from anesthetized wild-type (WT) and TgF344-AD rats, which carry the APP/PS1 transgene. Similar to human AD, these rats develop hyperphosphorylated tau in the LC (at 6 months) prior to A{beta} or tau pathology in forebrain regions (at 12-15 months). At baseline, LC neurons from TgF344-AD rats were hypoactive at both ages compared to WT littermates, but showed elevated spontaneous bursting properties, particularly in younger animals. Differences in footshock-evoked LC firing depended on age, with 6-month TgF344-AD rats demonstrating aspects of hyperactivity, and aged transgenic rats showing hypoactivity relative to WT. Tau-induced alterations in LC firing rates may contribute to the pathophysiology of AD, with early hyperactivity associated with prodromal symptoms, followed by hypoactivity contributing to cognitive impairment. These results support further investigation into disease stage-dependent noradrenergic interventions for AD. HighlightsO_LIRecorded locus coeruleus (LC) neurons in a rat model of Alzheimers disease (AD) C_LIO_LITgF344-AD rats develop early endogenous LC tau pathology akin to human AD C_LIO_LI6- and 15-month TgF344-AD rats had reduced tonic LC firing C_LIO_LILC neurons from 6-month TgF344-AD rats were hyperactive in response to footshock C_LIO_LILC neuron dysfunction may contribute to AD symptoms C_LI

neuroscience↗

bioRxiv2022

Enhanced photosynthetic efficiency for increased carbon assimilation and woody biomass production in hybrid poplar INRA 717-1B4

Increasing CO2 levels in the atmosphere and the resulting negative impacts on climate change have compelled global efforts to achieve carbon neutrality or negativity. Most such efforts focus on carbon sequestration through chemical or physical approaches. We aim to harness the power of synthetic biology to enhance plants natural ability to draw down and sequester carbon, thereby positively affecting climate change. Past decades of scientific progress have shed light on strategies to overcome the intrinsic limitations of carbon drawdown and fixation through photosynthesis, particularly in row crops in hopes of improving agricultural productivity for food security. Incorporating a photorespiration bypass in C3 plants has shown promising results of increased biomass and grain yield. Despite their globally dominant role in atmospheric carbon flux, the drawdown rates of most trees are currently limited by their C3 photosynthetic metabolism, and efforts to improve the photosynthetic capacity of trees, such as by reducing energy loss in photorespiration, are currently lacking. Here, we selected a photorespiration bypass pathway and tested its effectiveness on photosynthetic enhancement in hybrid poplar INRA717-IB4. The design includes a RNAi strategy to reduce the transportation of the photorespiration byproduct, glycolate, out of chloroplast and a shunt pathway to metabolize the retained glycolate back to CO2 for fixation through the Calvin-Benson cycle. Molecular and physiological data collected from two repeated growth experiments indicates that transgenic plants expressing genes in the photorespiration bypass pathway have increased photosynthetic efficiency, leading to faster plant growth and elevated biomass production. One lead transgenic event accumulated 53% more above-ground dry biomass over a five month growth period in a controlled environment. Pilot projects with photosynthesis-enhanced trees in the field are in progress. Our results provide a proof-of-concept for engineering trees to help combat climate change.

plant biology↗

bioRxiv2018

TET2 binding to enhancers facilitates transcription factor recruitment in hematopoietic cells

The epigenetic regulator TET2 is frequently mutated in hematological diseases. Mutations have been shown to arise in hematopoietic stem cells early in disease development, lead to altered DNA methylation landscapes and to an increased risk of hematopoietic malignancy. Here, we show by genome-wide mapping of TET2 binding sites in different cell types that TET2 localizes to regions of open chromatin and cell-type specific enhancers. We find that deletion of Tet2 in native hematopoiesis as well as fully transformed Acute Myeloid Leukemia (AML) results in changes in transcription factor (TF) activity within these regions, and we demonstrate that loss of TET2 leads to enzymatic activity-dependent attenuation of chromatin binding of the hematopoietic TF CDX4. Together, these findings demonstrate that TET2 activity shapes the local chromatin environment at enhancers to facilitate TF binding and provide a compelling example of how epigenetic dysregulation can affect gene expression patterns and drive disease development.

cancer biology↗