Biology subjects

Mertens, A.

Publications and source records attributed to Mertens, A..

8 recordsLinked to original sources

bioRxiv2026

Tuning inhibitor susceptibility of human 4-hydroxyphenylpyruvate dioxygenase to rescue tyrosine catabolism in the presence of β-triketones

Human 4-hydroxyphenylpyruvate dioxygenase (HPD) catalyses a key step in tyrosine degradation via homogentisate in liver and kidney cells. Pharmacological inhibition of HPD with nitisinone (NTBC) is standard treatment for tyrosinemia type 1 (HT1) and alkaptonuria (AKU). Although life-changing, continuous NTBC treatment limits metabolic flexibility and complicates emerging gene- and cell-based therapeutic approaches. Engineering HPD variants that retain catalytic activity during NTBC exposure could facilitate restoration of tyrosine metabolism, yet the molecular determinants of inhibitor tolerance remain poorly understood. Here, we applied Knowledge Gaining Directed Evolution (KnowVolution) to enhance NTBC tolerance while considering enzyme activity, predicted stability, and MHC-II peptide binding. Random mutagenesis, site-saturation mutagenesis, and computational analyses identified beneficial substitutions that improved enzyme activity in the presence of NTBC. These substitutions are predominantly located outside the catalytic cavity, suggesting that NTBC tolerance may involve distal structural effects rather than direct modification of inhibitor-binding residues. Recombination of selected substitutions, guided by activity and computational predictions of stability and MHC-II binding, yielded multi-substitution HPD variants with markedly increased NTBC tolerance. The leading variant, HPD-M8, exhibited up to 40-fold greater NTBC tolerance than wild-type HPD and increased tolerance to structurally related {beta}-triketone inhibitors, without an overall increase in predicted MHC-II binder burden. Computational analyses suggested altered catalytic access-pathway energetics without major perturbation of the conserved catalytic machinery, consistent with a possible contribution of distal substitutions to inhibitor tolerance. Together, these findings provide insight into HPD inhibitor tolerance and establish a foundation for future HT1 and AKU therapeutic strategies.

biochemistry↗

bioRxiv2026

Shroom3-dependent pillar cell constriction establishes a mechanical threshold for respiratory lamellar stability

How developing organs acquire complex architectures while maintaining tissue integrity under mechanical stress is a fundamental question in mechanobiology. In the gill, pillar cells support the thin respiratory lamellae, but how they withstand hemodynamic forces is unknown. Here, we show that actomyosin-rich contractile apparatuses (CA) in zebrafish pillar cells act as load-bearing units that generate contractile forces and stabilize the lamellae through adhesion to and enclosure of extracellular collagen columns. CA number correlates with pillar cell constriction, linking subcellular architecture to tissue geometry. We further identify Shroom3 and Vinculin b as key regulators of CA assembly and force transmission: shroom3 deficiency or loss of vclb impairs CA formation and reduces pillar cell constriction, while loss of shroom3 causes lamellar collapse. Together, these findings support a mechanical threshold model in which lamellar integrity depends on a minimum number of CAs per pillar cell and establish the gill lamellae as a model for linking subcellular contractility to tissue-scale mechanical stability.

developmental biology↗

bioRxiv2025

Lifelong development of zebrafish gills: Asymmetries in early vascular patterning predict adult gill architecture

Gills are essential for fish respiration and have a highly specialized cellular architecture enabling efficient gas exchange. Surprisingly, the developmental processes underlying gill formation in zebrafish remain poorly understood. Here, we present for the first time a comprehensive analysis of the morphogenesis of gill arteries, filaments and lamellae during lifelong development. Our results provide important insights into the temporal and spatial pattern of gill angiogenesis, revealing fundamental differences in the formation of lateral versus medial filaments along the dorso-ventral axis. These early asymmetries correlate with, and likely underlie, the structural asymmetries observed in adult gills, which we quantitatively characterize. This indicates that a region-specific developmental programme establishes a blueprint for gill architecture maintained throughout life. We further show that lamellae develop through a complex interplay between endothelial and cranial neural crest-derived pillar cells. Notably, lamellar size, which strongly influences respiratory efficiency, depends on the position of the filament in the arch. Together, our work identifies key cellular and temporal mechanisms driving gill development and provides a framework to investigate broader principles of branching morphogenesis and angiogenesis in vertebrates.

developmental biology↗

bioRxiv2025

Associations between floor material and E. coli contamination in rural Bangladeshi households

Soil floors are common in low-income countries and can harbor contamination from unsafely managed human and animal fecal waste. Soil/dust ingestion directly from floors or indirectly via hands, drinking water and food can significantly contribute to childrens ingestion of fecal organisms. We assessed if finished (e.g., concrete) floors are associated with lower E. coli contamination in the domestic environment in rural Bangladesh. We collected samples from 1864 households over 3.5 years, including stored drinking water, child and caregiver hand rinses, courtyard soil, food, and flies (n=24,118 samples), and enumerated E. coli using IDEXX Quanti-Tray/2000. Controlling for potential confounders (socio-demographics, water/sanitation status, animal ownership), households with finished floors had slightly lower log10-transformed E. coli counts ({Delta}log10= -0.10 (-0.20, 0.00)) and prevalence (prevalence ratio=0.90 (0.83, 0.98)) on child hands than households with soil floors; floor material was not associated with contamination levels in other sample types. Finished floors were associated with lower E. coli contamination of child hands, food and stored drinking water following periods of higher rainfall and temperature, and lower E. coli contamination of child hands in households with more domestic animals. Measures to control enteric infections in low-income countries should test flooring improvements to reduce exposure to fecal contamination.

microbiology↗

bioRxiv2022

Phylotranscriptomics Reveals the Reticulate Evolutionary History of a Widespread Diatom Species Complex

In contrast to surveys based on a few genes that often provide limited taxonomic resolution, transcriptomes provide a wealth of genomic loci that can resolve relationships among taxonomically challenging lineages. Diatoms are a diverse group of aquatic microalgae that includes important bioindicator species and many such lineages. One example is Nitzschia palea, a widespread species complex with several morphologically based taxonomic varieties, some of which are critical pollution indicators. Morphological differences among the varieties are subtle and phylogenetic studies on a few genes fail to resolve their evolutionary relationships. We conducted morphometric and transcriptome analyses of 10 Nitzschia palea strains to resolve the relationships among strains and taxonomic varieties. Nitzschia palea was resolved into three clades, one of which corresponds to a group of strains with narrow linear-lanceolate valves. The other morphological group recovered in the shape outline analysis was not monophyletic and consisted of two clades. Subsequent gene-tree concordance analyses and phylogenetic network estimations revealed patterns of incomplete lineage sorting and gene flow between intraspecific lineages. We detected reticulated evolutionary patterns among lineages with different morphologies and a resulting putative recent hybrid. Our study shows that phylogenomic analyses of many unlinked nuclear loci, complemented with morphometrics, can resolve complex evolutionary histories of recently diverged species complexes.

genomics↗

bioRxiv2021

Genetic diversity of the pathogenic banana Fusarium wilt in northern Viet Nam

Fusarium is one of the most important fungal genera of plant pathogens that affect the cultivation of a wide range of crops. Agricultural losses caused by Fusarium oxysporum f. sp. cubense (Foc) have a direct effect on the income, subsistence and nourishment of thousands of smallholder farmers worldwide. In addition, also commercial growers are strongly affected. For Viet Nam, predictions on the impact of Foc for the future are dramatic with an estimated loss in banana production area of 8% within the next 5 years and up to 71% within the next 25 years. In the current study we applied a combined morphological - molecular approach to assess the taxonomic identity and phylogenetic position of the different Foc isolates that were collected in northern Viet Nam. In addition, we aim to estimate the proportion of the different Fusarium races that are infecting bananas in northern Viet Nam. The morphology of the isolates was investigated by growing the collected Fusarium isolates on four distinct nutritious media (PDA, SNA, CLA, and OMA). Molecular phylogenetic relationships were inferred by sequencing partial rpb1, rpb2 and tef1a genes and adding the obtained sequences into a large phylogenetic framework. The present study showed that Foc Race 1 is the most common strain in northern Viet Nam, causing 74% of all the infections. A more in-depth molecular characterization shows that of the Foc Race 1 infections, 92% are caused by Fusarium tardichlamydosporum and 8% by F. duoseptatum. Compared to Foc Race 1, Foc TR4 (represented by F. odoratissimum) account for only 10.5% of the Fusarium wilting in northern Viet Nam demonstrating that Foc TR4 is not yet a dominant strain in the region. Foc Race 2 infections of Vietnamese bananas also account for 10.5% of the Fusarium wilting in northern Viet Nam. One of the isolates cultured from diseased bananas collected in northern Viet Nam was phylogenetically not positioned within the F. oxysporum species complex (FOSC), but in contrast fell within the Fusarium fujikuroi species complex (FFSC). As a result, it is possible that a new pathogen for bananas has been found. Besides being present on several ABB Tay banana, Foc Race 1 was also found as pathogen on wild Musa lutea, showing the importance of wild bananas as possible sink for Foc.

evolutionary biology↗

bioRxiv2021

Maximizing genetic representation in seed collections from populations of self and cross-pollinated banana wild relatives

BackgroundConservation of plant genetic resources, including the wild relatives of crops, plays an important and well recognised role in addressing some of the key challenges faced by humanity and the planet including ending hunger and biodiversity loss. However, the genetic diversity and representativeness of ex situ collections, especially that contained in seed collections, is often unknown. This limits meaningful assessments against conservation targets, impairs targeting of future collecting and limits their use. We assessed genetic representation of seed collections compared to source populations for three wild relatives of bananas and plantains. Focal species and sampling regions were Musa acuminata subsp. banksii (Papua New Guinea), M. balbisiana (Viet Nam) and M. maclayi s.l. (Bougainville, Papua New Guinea). We sequenced 445 samples using suites of 16-20 existing and newly developed taxon-specific polymorphic microsatellite markers. Samples of each species were from five populations in a region; 15 leaf samples and 16 seed samples from one infructescence ( bunch) for each population. ResultsAllelic richness of seeds compared to populations was 51%, 81% and 93% (M. acuminata, M. balbisiana and M. maclayi respectively). Seed samples represented all common alleles in populations but omitted some rarer alleles. The number of collections required to achieve the 70% target of the Global Strategy for Plant Conservation was species dependent, relating to mating systems. Musa acuminata populations had low heterozygosity and diversity, indicating self-fertilization; many bunches were needed (>15) to represent regional alleles to 70%; over 90% of the alleles from a bunch are included in only two seeds. Musa maclayi was characteristically cross-fertilizing; only three bunches were needed to represent regional alleles; within a bunch, 16 seeds represent alleles. Musa balbisiana, considered cross-fertilized, had low genetic diversity; seeds of four bunches are needed to represent regional alleles; only two seeds represent alleles in a bunch. ConclusionsWe demonstrate empirical measurement of representation of genetic material in seeds collections in ex situ conservation towards conservation targets. Species mating systems profoundly affected genetic representation in seed collections and therefore should be a primary consideration to maximize genetic representation. Results are applicable to sampling strategies for other wild species.

genetics↗

bioRxiv2019

A large-scale species level dated angiosperm phylogeny for evolutionary and ecological analyses

Phylogenies are a central and indispensable tool for evolutionary and ecological research. Even though most angiosperm families are well investigated from a phylogenetic point of view, there are far less possibilities to carry out large-scale meta-analyses at order level or higher. Here, we reconstructed a large-scale dated phylogeny including nearly 1/8th of all angiosperm species based on two plastid barcoding genes, matK and rbcL. Novel sequences were generated for several species, while the rest of the data were mined from GenBank. The resulting tree was dated using 56 angiosperm fossils as calibration points. The resulting megaphylogeny is one of the largest dated phylogenetic tree of angiosperms yet, consisting of 36,101 sampled species, representing 8,399 genera, 426 families and all orders. This novel framework will be useful to investigate different broad scale research questions in ecological and evolutionary biology.

evolutionary biology↗