Biology subjects

Jacobsen, A.

Publications and source records attributed to Jacobsen, A..

9 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte-specific loss of Smyd5 leads to a robust activation of inflammatory signaling and heart failure in mice.

Background: Cardiomyocytes respond to stress by undergoing hypertrophic growth driven by dynamic changes in gene expression. Epigenetic mechanisms, including histone methylation, play critical roles in regulating these transcriptional programs, yet the enzymes controlling these modifications during cardiac disease remain largely unknown. The SMYD family of histone methyltransferases regulates gene expression in multiple biological contexts, but the function of SMYD5 in the mammalian heart has never been investigated. Methods: SMYD5 expression was assessed in human heart failure samples and in a mouse model of cardiac hypertrophy. To define its functional role in vivo, we generated inducible cardiomyocyte-specific Smyd5 knockout mice and characterized their cardiac phenotype using molecular, histological, and functional analyses. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) was performed to examine histone H4 lysine 20 trimethylation (H4K20me3) at the Il-6 promoter. Results: SMYD5 expression was altered in diseased human and mouse hearts. Under basal conditions, cardiomyocyte-specific deletion of Smyd5 resulted in baseline structural cardiac remodeling and transcriptional signatures characteristic of pathological stress. Smyd5-deficient hearts exhibited marked inflammatory activation resembling a cytokine storm with immune cell infiltration and heart failure. Notably, Smyd5 knockout mice displayed a 100-fold increase in Il-6 expression, accompanied by a global reduction in H4K20me3. ChIP-qPCR analysis of the Il-6 promoter, together with loss- and gain-of-function analysis of SMYD5, supports a direct epigenetic role of SMYD5 in regulating Il-6 expression through H4K20me3 in cardiomyocytes. Conclusions: SMYD5 is a previously unrecognized epigenetic regulator of cardiac homeostasis that restrains inflammatory signaling in cardiomyocytes under normal conditions. Loss of Smyd5 disrupts H4K20me3, leading to derepression of Il-6 in cardiomyocytes and a robust inflammatory response characterized by immune cell recruitment and fibrosis, accompanied by rapid progression of cardiac remodeling and heart failure. These findings identify SMYD5 as a critical regulator of intrinsic cardiomyocyte inflammatory signaling and reveal a novel chromatin-based mechanism contributing to inflammatory cardiomyopathies.

molecular biology↗

bioRxiv2026

A neuroimmune IL-13 axis is associated with human enteric nervous system development

The mechanisms governing maturation of the human enteric nervous system (ENS) during early postnatal life remain poorly defined. Here, we characterize the transcriptomic, cellular, and functional landscape of the neonatal human ileum and identify a neuro-immune axis associated with ENS expansion. Using human tissue transcriptomics, flow cytometry, iPSC-derived enteric neural lineages, and single-cell interactome analyses, we show that the neonatal ileum is enriched for pro-neurogenic transcriptional programs and harbors a greater abundance of enteric neurons and glia than the adult tissue. T cells emerge as a predominant source of interleukin-13 (IL-13) in the neonatal gut, and enteric neurons express its receptor IL13RA1, enabling direct immune-to-neuron signaling. Functional experiments demonstrate that IL-13 enhances expression of key enteric neuronal markers in a concentration-dependent manner. In parallel, single-cell analyses identify enteric neurons as a major predicted source of macrophage migration inhibitory factor (MIF), with signaling directed toward T and NK cell populations, suggesting that the ENS actively shapes the immune environment it depends upon. Together, these findings support a model in which bidirectional neuro-immune communication establishes a pro-neurogenic niche during a critical window of ENS development. This work positions the neonatal immune system as an active contributor to ENS maturation and offers a new perspective on how neuro-immune crosstalk shapes intestinal development in early life.

neuroscience↗

bioRxiv2025

Effect of plastic and seaweed shelters on the skin microbiome of lumpfish Cyclopterus lumpus used as cleaner fish in aquaculture pens

Atlantic salmon (Salmo salar) aquaculture is a major industry in several countries worldwide and a growing enterprise in others. One of the main challenges the industry faces is infestations with the parasitic copepod Lepeoptheirus salmonis, or salmon lice. Several different chemical and mechanical methods are available for alleviating the problem, but often at cost to salmon welfare and/or the environment. In some regions cleaner fish have been introduced to farming facilities as an environmentally and salmon welfare friendly option for reducing the sea lice infestations. In some North Atlantic countries, lumpfish (Cyclopterus lumpus) are being used as cleaner fish. However, the welfare and high mortality rates of lumpfish in salmon farming is frequently a problem, and the need to improve lumpfish welfare is great. One adaptation for salmon farms is to provide the lumpfish with shelters to meet their need to rest and hide. Plastic shelters are the most widely used form, but seaweed shelters have more recently also been applied as a more natural solution. This project investigated the potential effect of seaweed and plastic shelters on the skin and gill microbiome of lumpfish and any potential correlation to their welfare. In an experimental setup in a commercial salmon farming facility, lumpfish from pens with either plastic or seaweed shelters were sampled over a period of approximatly three months. The results showed that the bacterial communities on the two shelter types were significantly different and fewer potentially pathogenic bacteria dominated the skin microbiota of lumpfish living with seaweed shelters than of those living with plastic shelters. No differences were detected in the welfare of the lumpfish and further investigations are needed to clarify any potential implications of the differences detected in the skin microbiota of lumpfish including responses to stressful conditions.

molecular biology↗

bioRxiv2024

Open-source cell culture automation system with integrated cell counting for passaging microplate cultures

Tissue culture in 96-well microplates is conventionally a tedious, highly manual process sensitive to individual technique and experimenter error. Here, we describe the Automated Cell Culture Splitter (ACCS), a system for passaging plates of adherent or suspension cells, for routine culture maintenance or specialized applications such as seeding plates for microscopy. The system is built around the Opentrons OT-2 liquid handling robot and incorporates a novel on-deck imaging-based cell counter which allows it to compensate for density disparities across a source plate and control the number of cells seeded on a per-well basis. We find this solution can cut hands-on time by 61% and the results compare favorably to our existing manual cell culture processes in terms of both seeding density precision and bio-logical outcomes, achieving a control of seeding density with a well-to-well coefficient of variation (CV) under 11%. The system is designed to be adaptable and an accessible entry point into automation for high-throughput cell culture; to that end, all of the source code and hardware designs are released under open source licenses.

bioengineering↗

bioRxiv2024

The digestion time for salmon louse (Lepeoptheirus salmonis) in lumpfish (Cyclopterus lumpus) in relation to freshness, developmental stage, and temperature

Sea lice infestations cause significant economic losses in the Atlantic salmon aquaculture industry. To biologically control sea lice at farming sites, cleaner fish such as lumpfish are employed. However, the efficacy of lumpfish is under constant debate, primarily due to limited knowledge of digestion times, which makes it difficult to interpret the number of salmon lice found in the stomach contents of dissected lumpfish. The aim of this study was to provide quantitative estimates of the degradation of salmon lice over a period of 12 days. After an acclimation period of approximately one week, batches of eight lumpfish (average weight 94.3 g, SD {+/-} 33.2) were fed salmon lice and arranged in tanks. Each batch received six large mobile lice and two adult female lice. Samplings were conducted at 24-hour intervals during the first four days and at 48-hour intervals over the remaining eight days. The experiment was conducted twice, each at a different temperature regime (6{degrees}C and 9{degrees}C), using live lice in both trials. To investigate if the freshness of the louse influenced degradation and digestion, the setup was replicated in the 9{degrees}C experiment with lice that had been stored frozen at -80{degrees}C, with an additional 12-hour sampling point for comprehensive observation. The analysis of salmon lice revealed expected digestion times of 6.8 days and 12 days for large mobile and adult female salmon lice, respectively. Temperature and lice freshness did not seem to influence digestion times, but the developmental stage of the lice did. The findings of this study can be used to estimate the cleaning efficacy of lumpfish based on the stomach contents.

ecology↗

bioRxiv2023

An immunohistochemical atlas of necroptotic pathway expression

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo. HighlightsO_LI13 automated immunohistochemistry protocols for detecting the necroptotic pathway C_LIO_LINecroptotic pathway expression is confined to fast-cycling immune barriers C_LIO_LINecroptotic pathway expression changes at sites of immunoinflammatory challenge C_LIO_LIImmunodetection of necrosomes in IBD patients is a putative new diagnostic tool C_LI

cell biology↗

bioRxiv2023

Collaborative network analysis for the interpretation of transcriptomics data in rare diseases, an application to Huntington's disease

BackgroundRare diseases may affect the quality of life of patients and in some cases be life-threatening. Therapeutic opportunities are often limited, in part because of the lack of understanding of the molecular mechanisms that can cause disease. This can be ascribed to the low prevalence of rare diseases and therefore the lower sample sizes available for research. A way to overcome this is to integrate experimental rare disease data with prior knowledge using network-based methods. Taking this one step further, we hypothesized that combining and analyzing the results from multiple network-based methods could provide data-driven hypotheses of pathogenicity mechanisms from multiple perspectives. ResultsWe analyzed a Huntingtons disease (HD) transcriptomics dataset using six network-based methods in a collaborative way. These methods either inherently reported enriched annotation terms or their results were fed into enrichment analyses. The resulting significantly enriched Reactome pathways were then summarized using the ontological hierarchy which allowed the integration and interpretation of outputs from multiple methods. Among the resulting enriched pathways, there are pathways that have been shown previously to be involved in HD and pathways whose direct contribution to disease pathogenesis remains unclear and requires further investigation. ConclusionsIn summary, our study shows that collaborative network analysis approaches are well-suited to study rare diseases, as they provide hypotheses for pathogenic mechanisms from multiple perspectives. Applying different methods to the same case study can uncover different disease mechanisms that would not be apparent with the application of a single method.

bioinformatics↗

bioRxiv2020

Interleukin-3 is a predictive marker for severity and outcome during SARS-CoV-2 infections

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a worldwide health threat. Here, we report that low plasma interleukin-3 (IL-3) levels were associated with increased severity and mortality during SARS-CoV-2 infections. IL-3 promoted the recruitment of antiviral circulating plasmacytoid dendritic cells (pDCs) into the airways by stimulating CXCL12 secretion from pulmonary CD123+ epithelial cells. This study identifies IL-3 as a predictive disease marker and potential therapeutic target for SARS-CoV-2 infections.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2018

The ability of transcription factors to differentially regulate gene expression is a crucial component of the mechanism underlying inversion, a frequently observed genetic interaction pattern

Genetic interactions, a phenomenon whereby combinations of mutations lead to unexpected effects, reflect how cellular processes are wired and play an important role in complex genetic diseases. Understanding the molecular basis of genetic interactions is crucial for deciphering pathway organization as well as understanding the relationship between genetic variation and disease. Several putative molecular mechanisms have been linked to different genetic interaction types. However, differences in genetic interaction patterns and their underlying mechanisms have not yet been compared systematically between different functional gene classes. Here, differences in the occurrence and types of genetic interactions are compared for two classes, gene-specific transcription factors (GSTFs) and signaling genes (kinases and phosphatases). Genome-wide gene expression data for 63 single and double deletion mutants in bakers yeast reveals that the two most common genetic interaction patterns are buffering and inversion. Buffering is typically associated with redundancy and is well understood. In inversion, genes show opposite behavior in the double mutant compared to the corresponding single mutants. The underlying mechanism is poorly understood. Although both classes show buffering and inversion patterns, the prevalence of inversion is much stronger in GSTFs. To decipher potential mechanisms, a Petri Net modeling approach was employed, where genes are represented as nodes and relationships between genes as edges. This allowed over 9 million possible three and four node models to be exhaustively enumerated. The models show that a quantitative difference in interaction strength is a strict requirement for obtaining inversion. In addition, this difference is frequently accompanied with a second gene that shows buffering. Taken together, these results provide a mechanistic explanation for inversion. Furthermore, the ability of transcription factors to differentially regulate expression of their targets provides a likely explanation why inversion is more prevalent for GSTFs compared to kinases and phosphatases.\n\nAuthor SummaryThe relationship between genotype and phenotype is one of the major challenges in biology. While many previous studies have identified genes involved in complex genetic diseases, there is still a gap between genotype and phenotype. One of the difficulties in filling this gap has been attributed to genetic interactions. Large-scale studies have revealed that genetic interactions are widespread in model organisms such as bakers yeast. Several molecular mechanisms have been proposed for different genetic interaction types. However, differences in occurrence and underlying molecular mechanism of genetic interactions have not yet been compared between gene classes of different function. Here, we compared genetic interaction patterns identified using gene expression profiling for two classes of genes: gene specific transcription factors and signaling related genes. We modelled all possible molecular networks to unravel putative molecular differences underlying different genetic interaction patterns. Our study proposes a new mechanistic explanation for a certain genetic interaction pattern that is more strongly associated with transcription factors compared to signaling related genes. Overall, our findings and the computational methodologies implemented here can be valuable for understanding the molecular mechanisms underlying genetic interactions.

genetics↗