Biology subjects

Verhoeven, A.

Publications and source records attributed to Verhoeven, A..

9 recordsLinked to original sources

bioRxiv2026

User-driven development and evaluation of an agentic framework for analysis of large pathway diagrams

As biomedical knowledge keeps growing, resources storing available information multiply and grow in size and complexity. Such resources can be in the format of molecular interaction maps, which represent cellular and molecular processes under normal or pathological conditions. However, these maps can be complex and hard to navigate, especially to novice users. Large Language Models (LLMs), particularly in the form of agentic frameworks, have emerged as a promising technology to support this exploration. In this article, we describe a user-driven process of prototyping, development, and user testing of Llemy, an LLM-based system for exploring these molecular interaction maps. By involving domain experts from the very first prototyping in the form of a hackathon and collecting both fine-grained and general feedback on more refined versions, we were able to evaluate the perceived utility and quality of the developed system, in particular for summarising maps and pathways, as well as prioritise the development of future features. We recommend continued user-driven development and benchmarking to keep the community engaged. This will also facilitate the transition towards open-weight LLMs to support the needs of the open research environment in an ever-changing technology landscape.

bioinformatics↗

bioRxiv2024

Exercise training at different intensities induces heat stress, disrupts barrier function and alters microbiota in the gut of mice

Exercise is generally beneficial for health but strenuous exercise can have detrimental effects on the gastrointestinal tract. The combination of ischemia and heat shock during exercise is a crucial contributor to intestinal epithelial damage. Growing evidence points towards an important regulatory role of gut microbes in intestinal homeostasis. Here, we characterize and compare the effects of moderate and vigorous exercise training on intestinal epithelial damage, stress response, inflammatory response, and gut microbiota alterations in mice and investigate the mechanisms underlying exercise-induced intestinal injury. Exercise training for six weeks caused heat stress in the intestine, resulting in the disruption of the intestinal epithelial barrier and local inflammation. This was characterized by increased colonic HSP-70 and HSF-1 protein expression, increased epithelial permeability, decreased colonic expression of tight junction proteins ZO-1 and occludin and intestinal morphological changes. Daily moderate exercise training caused hereby more severe injury than vigorous training on alternating days. Furthermore, exercise training altered the gut microbiota profile. The abundance of Lactobacillaceae was reduced, potentially contributing to the deteriorated intestinal status, while the abundance of short-chain fatty acid-producing Lachnospiraceae was increased, especially following vigorous training. This increase in short-chain fatty acid-producing bacteria following vigorous training possibly counteracted the impairment of the intestinal barrier function. In summary, exercise disrupts the intestinal barrier function, with vigorous exercise training with intermittent rest days being less damaging than daily moderate exercise training.

physiology↗

bioRxiv2024

Deciphering Arabidopsis thaliana Acclimation to Sublethal Combined Abiotic Stresses

Plants are frequently exposed to environmental challenges. Responses to sub-lethal abiotic stress combinations are complex and often distinct from responses to individual stresses and remain poorly understood. Investigating traits and molecular factors mediating acclimation to stress combinations is essential for the development of climate change-resilient field crops. Here, we studied the morphological, physiological, and molecular responses of Arabidopsis thaliana to i) co-occurring high temperature and drought and ii) flooding sequentially followed by drought, both of which have increased in frequency due to climate change. A set of 15 physiological and morphological traits were assessed during single and combined stresses. By combining these comprehensive trait analyses with transcriptome characterization, we established the generally additive effects of simultaneous or sequential stresses on plant morphology and physiology compared to the corresponding individual stresses. Although drought had a mild effect in both stress combinations, a unique transcriptome signature emerged upon combination with high temperature simultaneously or flooding sequentially. Molecular processes identified as important for multi-stress resilience included plastid-nucleus communication, ABA signaling and photo-acclimation. Based on the RNA-seq data, a set of 39 genes was identified as potential multi-stress response regulators. Mutants were tested to validate their contribution to plant survival and phenotypic acclimation under combined stress. We confirmed the involvement of several genes in regulating phenotypic acclimation traits. Among the novel identified factors are EARLY FLOWERING 6 (ELF6) and ARABIDOPSIS TOXICOS EN LEVADURA (ATL80), with significant effects on plant growth, leaf development and plant survival (wilting) during high-temperature drought and post-submergence drought respectively.

plant biology↗

bioRxiv2022

Arabidopsis latent virus 1, a comovirus widely spread in Arabidopsis thaliana collections

O_LITranscriptome studies of Illumina RNA-seq datasets of different Arabidopsis thaliana natural accessions and T-DNA mutants revealed the presence of two virus-like RNA sequences which showed the typical two segmented genome characteristics of a comovirus. C_LIO_LIThis comovirus did not induce any visible symptoms in infected Arabidopsis plants cultivated under standard laboratory conditions. Hence it was named Arabidopsis latent virus 1 (ArLV1). Virus infectivity in Arabidopsis plants was confirmed by RT-qPCR, transmission electron microscopy and mechanical inoculation. ArLV1 can also mechanically infect Nicotiana benthamiana, causing distinct mosaic symptoms. C_LIO_LIA bioinformatics investigation of Arabidopsis RNA-Seq repositories, including nearly 6500 Sequence Read Archives (SRAs) in the NCBI SRA database, revealed the presence of ArLV1 in 25% of all archived natural Arabidopsis accessions and in 8.5% of all analyzed SRAs. ArLV1 could also be detected in Arabidopsis plants collected from the wild. C_LIO_LIArLV1 is highly seed-transmissible with up to 40% incidence on the progeny derived from infected Arabidopsis plants. This has likely led to a worldwide distribution in the model plant Arabidopsis with yet unknown effects on plant performance in a substantial number of studies. C_LI Plain language summaryWe identified Arabidopsis latent virus 1 (ArLV1), a comovirus that infects the model plant Arabidopsis thaliana without causing any visible symptoms. It is efficiently spread by transmission via seeds to the plant progeny. ArLV1 is infectious to Arabidopsis plants and another model plant, Nicotiana benthamiana. By analyzing public sequencing data, we found that ArLV1 is widely spread in Arabidopsis laboratory collections worldwide. Moreover, it was also detected in wild Arabidopsis plants collected from different locations in the Netherlands and Spain, suggesting that it is a virus that naturally occurs in Arabidopsis.

plant biology↗

bioRxiv2021

Asymptomatic gut colonization by extended-spectrum beta-lactamase-producing Escherichia coli is not associated with an altered gut microbiome or metabolome in Dutch adults

BackgroundGut colonization by antibiotic resistant E. coli strains, including extended-spectrum beta-lactamase (ESBL)-producing E. coli is a risk factor for developing overt infection. The gut microbiome can provide colonization resistance against enteropathogens, but it remains unclear whether it confers resistance against potentially pathogenic ESBL-producing E. coli. MaterialsFrom a Dutch cross-sectional population study (PIENTER-3), feces from 2751 individuals were used to culture ESBL-producing bacteria. Of these, we selected 49 samples which were positive for an ESBL-producing Escherichia coli (ESBL+), and negative for a variety of variables known to affect microbiome composition. These were matched in a 1:1 ratio to ESBL- samples based on age, sex, having been abroad in the past six months and ethnicity. Shotgun metagenomic sequencing was performed and taxonomic species composition and functional annotations (microbial metabolism and carbohydrate-active enzymes) were determined. Targeted quantitative metabolic profiling (1H NMR-spectroscopy) was performed to investigate metabolomic profiles. ResultsNo differences in alpha or beta diversity were observed, nor in relative abundance, between ESBL+ and ESBL- individuals based on bacterial species level composition. Machine learning approaches based on microbiota composition did not accurately predict ESBL status (area under the receiver operating characteristic curve (AUROC)=0.53), neither when based on functional profiles. The metabolome did also not convincingly differ between ESBL groups as assessed by a variety of approaches, including machine learning through random forest (AUROC=0.61). ConclusionUsing a combination of multi-omics and machine learning approaches, we conclude that asymptomatic gut carriage of ESBL-producing E. coli is not associated with an altered microbiome composition or function. This may suggest that microbiome-mediated colonization resistance against ESBL-producing E. coli is not as relevant as it is against other enteropathogens.

microbiology↗

bioRxiv2020

Microbiota-derived short chain fatty acids promote Aβ plaque deposition

Previous studies have identified a crucial role of the gut microbiome in modifying Alzheimers disease (AD) progression. However, the mechanisms of microbiome-brain interaction in AD, including the microbial mediators and their cellular targets in the brain, were so far unknown. Here, we identify microbiota-derived short chain fatty acids (SCFA) as key metabolites along the gut-brain axis in AD. Germ-free (GF) AD mice exhibit a substantially reduced A{beta} plaque load and markedly reduced SCFA plasma concentrations; conversely, SCFA supplementation to GF AD mice was sufficient to increase the A{beta} plaque load to levels of conventionally colonized animals. While A{beta} generation was only mildly affected, we observed strong microglial activation and upregulation of ApoE upon the SCFA supplementation. Taken together, our results demonstrate that microbiota-derived SCFA are the key mediators along the gut-brain axis resulting in increased microglial activation, ApoE upregulation and A{beta} deposition.

neuroscience↗

bioRxiv2019

The genomic architecture of blood metabolites based on a decade of genome-wide analyses

Metabolomics examines the small molecules involved in cellular metabolism. Approximately 50% of total phenotypic differences in metabolite levels is due to genetic variance, but heritability estimates differ across metabolite classes and lipid species. We performed a review of all genetic association studies, and identified > 800 class-specific metabolite loci that influence metabolite levels. In a twin-family cohort (N = 5,117), these metabolite loci were leveraged to simultaneously estimate total heritability (h2total), and the proportion of heritability captured by known metabolite loci (h2Metabolite-hits) for 309 lipids and 52 organic acids. Our study revealed significant differences in h2Metabolite-hits among different classes of lipids and organic acids. Furthermore, phosphatidylcholines with a high degree of unsaturation had higher h2Metabolite-hits estimates than phosphatidylcholines with a low degree of unsaturation. This study highlights the importance of common genetic variants for metabolite levels, and elucidates the genetic architecture of metabolite classes and lipid species.

genetics↗

bioRxiv2019

Genome-wide association study of plasma lipids

There is continuous interest in the genetic determinants of plasma triglycerides (TGs) and phospholipids and their role in the etiology of cardiovascular disease (CVD). Here, we report the results of a Dutch genome wide association study (GWAS) of an in-house developed lipidomics platform, focusing on 90 plasma lipids. Lipids were assessed by liquid chromatography mass spectrometry in participants from the Leiden Longevity Study, the Netherlands Twin Register and the Erasmus Rucphen Family (ERF) study and meta-analysed, resulting in a sample size of 5537 participants. In addition, we performed genetic correlation analyses between the 90 plasma lipids and markers of metabolic health, as well as vascular pathology and CVD combining our GWAS results with publicly available GWAS outputs. We replicated previously known associations between 34 lipids and 10 lipid quantitative trait loci (lipQTL) (GCKR, APOA1, FADS1, SGPP1,TMEM229B, LIPC, PDXDC1, CETP, CERS4 and SPTLC3) with metabolome-wide (P < 1.61 x 10-9) significance. Moreover, we report 6 novel phospholipid-related and 5 triglyceride (TG)-related loci: SGGP1 (SM21:0), SPTLC3 (SM21:0 and SM25:1), FADS1 (LPCO16:1, PC38:2, PEO36:5, PEO38:5, TG56:5, TG56:6, and TG56:7), TMEM229 (LPCO16:1), GCKR (TG50:2), and APOA1 (TG54:4). In addition, we report suggestively significant (P < 5 x 10-8) associations mapping to eleven novel lipid quantitative trait loci (lipQTLs), three of which are supported by mining previous GWAS data: MAU (PC34:4), LDLR (SM16:0), and MLXIPL (TG48:1 and TG50:1)). Genetic correlation analysis indicates that one specific specific sphingomyelin, SM22:0, shares common genetic background with CVD. Levels of SM22:0 also positively associate with carotid artery intima-media thickness in the ERF study, and this observation is independent of LDL-C level. Our findings yield higher resolution of plasma lipid species and new insights in the biology of circulating phosholipids and their relation to CVD risk.

epidemiology↗

bioRxiv2017

Proteomic identification of Axc, a novel beta-lactamase with carbapenemase activity in a meropenem-resistant clinical isolate of Achromobacterxylosoxidans

The development of antibiotic resistance during treatment is a threat to patients and their environment. Insight in the mechanisms of resistance development is important for appropriate therapy and infection control. Here, we describe how through the application of mass spectrometry-based proteomics, a novel beta-lactamase Axc was identified as an indicator of acquired carbapenem resistance in a clinical isolate of Achromobacter xylosoxidans.\n\nComparative proteomic analysis of consecutively collected susceptible and a resistant isolates from the same patient revealed that high Axc protein levels were only observed in the resistant isolate. Heterologous expression of Axc in Escherichia coli significantly increased the resistance towards carbapenems. Importantly, direct Axc mediated hydrolysis of imipenem was demonstrated using pH shift assays and 1H-NMR, confirming Axc as a legitimate carbapenemase. Whole genome sequencing revealed that the susceptible and resistant isolates were remarkably similar.\n\nTogether these findings provide a molecular context for the fast development of meropenem resistance in A. xylosoxidans during treatment and demonstrate the use of mass spectrometric techniques in identifying novel resistance determinants.

microbiology↗