Biology subjects

Lind, A.

Publications and source records attributed to Lind, A..

9 recordsLinked to original sources

bioRxiv2026

Among-population variation in the threespine stickleback ( Gasterosteus aculeatus ) liver metabolome: effects of ancestry and environment

Untargeted metabolomics offers a powerful lens for quantifying high-dimensional phenotypic variation within and among species in nature, but has yet to be widely adopted in evolutionary ecology. Some important initial questions are whether metabolome composition differs among populations, and to what extent such variation is genetic or plastic. Here, we use untargeted liquid chromatography tandem mass spectrometry to characterize the relative abundance of 5,939 molecular features of the threespine stickleback (Gasterosteus aculeatus) liver metabolome. Native lake populations differ in metabolome composition, reflecting effects of sex, size, geography, and population ecotype (benthic versus limnetic). Stickleback from these lakes were translocated to found new populations in nine recently fishless lakes, permuting fish ecotypes across benthic and limnetic lake habitats. Several generations later, metabolomes in these experimental populations reflect effects both of their genetic ancestry (e.g., taurocholic acid, a cholane steroid bile acid, was elevated in limnetic-ancestries), as well as their present habitat (e.g., acylcarnitines). Additionally, ecotypes transplanted into a habitat to which they were maladapted exhibited a distinctive metabolomic profile. We conclude that stickleback exhibit both heritable and plastic among-population differences in liver metabolome, which could represent an important phenotypic basis of rapid evolution, population divergence, and perhaps local adaptation.

Molecular Biology↗

bioRxiv2024

Destabilized host-parasite dynamics in newly founded populations

When species disperse into previously unoccupied habitats, new populations encounter unfamiliar species interactions such as altered parasite loads. Theory predicts that newly founded populations should exhibit destabilized eco-evolutionary fluctuations in infection rates and immune traits. However, to understand founder effects biologists typically rely on retrospective studies of range expansions, missing early-generation infection dynamics. To remedy this, we experimentally founded whole-lake populations of threespine stickleback. Infection rates were temporally stable in native source lakes. In contrast, newly founded populations exhibit destabilized host-parasite dynamics: high starting infection rates led to increases in a heritable immune trait (peritoneal fibrosis), suppressing infection rates. The resulting temporal auto-correlation between infection and immunity suggest that newly founded populations can exhibit rapid host-parasite eco-evolutionary dynamics.

evolutionary biology↗

bioRxiv2023

Hybrid assemblies of microbiome Blastocystis protists reveal evolutionary diversification reflecting host ecology

Blastocystis, an obligate host-associated protist, is the most common microbial eukaryote in the human gut and is widely distributed across vertebrate hosts. The evolutionary transition of Blastocystis from its free-living stramenopile ancestors to a radiation of host-associated organisms is poorly understood. To explore this, we cultured and sequenced eight strains representing the significant phylogenetic diversity of the genus using long-read, short-read, and Hi-C DNA sequencing, alongside gene annotation and RNA sequencing. Comparative genomic analyses revealed significant variation in gene content and genome structure across Blastocystis. Notably, three strains from herbivorous tortoises, phylogenetically distant from human subtypes, have markedly larger genomes with longer introns and intergenic regions, and retain canonical stop codons absent in the human-associated strains. Despite these genetic differences, all eight isolates exhibit gene losses linked to the reduced cellular complexity of Blastocystis, including losses of cilia and flagella genes, microtubule motor genes, and signal transduction genes. Isolates from herbivorous tortoises contained higher numbers of plant carbohydrate-metabolizing enzymes, suggesting that like gut bacteria, these protists ferment plant material in the host gut. We find evidence that some of these carbohydrate-metabolizing enzymes were horizontally acquired from bacteria, indicating that horizontal gene transfer is an ongoing process in Blastocystis that has contributed to host-related adaptation. Together, these results highlight substantial genetic and metabolic diversity within the Blastocystis genus, indicating different lineages of Blastocystis have varied ecological roles in the host gut.

microbiology↗

bioRxiv2022

Multiplexed measurement of binding- and neutralizing antibodies to SARS-CoV-2 variants in 12.000 post-vaccine sera

Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.

immunology↗

bioRxiv2020

Beyond the biosynthetic gene cluster paradigm: Genome-wide co-expression networks connect clustered and unclustered transcription factors to secondary metabolic pathways

Fungal secondary metabolites are widely used as therapeutics and are vital components of drug discovery programs. A major challenge hindering discovery of novel secondary metabolites is that the underlying pathways involved in their biosynthesis are transcriptionally silent in typical laboratory growth conditions, making it difficult to identify the transcriptional networks that they are embedded in. Furthermore, while the genes participating in secondary metabolic pathways are typically found in contiguous clusters on the genome, known as biosynthetic gene clusters (BGCs), this is not always the case, especially for global and pathway-specific regulators of pathways activities. To address these challenges, we used 283 genome-wide gene expression datasets of the ascomycete cell factory Aspergillus niger generated during growth under 155 different conditions to construct two gene co-expression networks based on Spearmans correlation coefficients (SCC) and on mutual rank-transformed Pearsons correlation coefficients (MR-PCC). By mining these networks, we predicted six transcription factors named MjkA - MjkF to concomitantly regulate secondary metabolism in A. niger. Over-expression of each transcription factor using the Tet-on cassette modulated production of multiple secondary metabolites. We found that the SCC and MR-PCC approaches complemented each other, enabling the delineation of global (SCC) and pathway-specific (MR-PCC) transcription factors, respectively. These results highlight the great potential of co-expression network approaches to identify and activate fungal secondary metabolic pathways and their products. More broadly, we argue that novel drug discovery programs in fungi should move beyond the BGC paradigm and focus on understanding the global regulatory networks in which secondary metabolic pathways are embedded. ImportanceThere is an urgent need for novel bioactive molecules in both agriculture and medicine. The genomes of fungi are thought to contain vast numbers of metabolic pathways involved in the biosynthesis of secondary metabolites with diverse bioactivities. Because these metabolites are biosynthesized only under specific conditions, the vast majority of fungal pharmacopeia awaits discovery. To discover the genetic networks that regulate the activity of secondary metabolites, we examined the genome-wide profiles of gene activity of the cell factory Aspergillus niger across hundreds of conditions. By constructing global networks that link genes with similar activities across conditions, we identified six global and pathway-specific regulators of secondary metabolite biosynthesis. Our study shows that elucidating the behavior of the genetic networks of fungi under diverse conditions harbors enormous promise for understanding fungal secondary metabolism, which ultimately may lead to novel drug candidates.

microbiology↗

bioRxiv2020

Functional characterization of clinical isolates of the opportunistic fungal pathogen Aspergillus nidulans

Aspergillus nidulans is an opportunistic fungal pathogen in patients with immunodeficiency and virulence of A. nidulans isolates has mainly been studied in the context of the chronic granulomatous disease (CGD), with characterization of clinical isolates obtained from non-CGD patients remaining elusive. This study therefore carried out a detailed biological characterization of two A. nidulans clinical isolates (CIs), obtained from a patient with breast carcinoma and pneumonia and from a patient with cystic fibrosis that underwent lung transplantation, and compared them to the reference, non-clinical A4 strain. Both CIs presented increased growth in comparison to the reference strain in the presence of physiologically-relevant carbon sources. Metabolomic analyses showed that the three strains are metabolically very different from each other in these carbon sources. Furthermore, the CIs were highly susceptible to cell wall perturbing agents but not to other physiologically-relevant stresses. Genome analyses identified several frame-shift variants in genes encoding cell wall integrity (CWI) signalling components. Significant differences in CWI signalling were confirmed by western blotting among the three strains. In vivo virulence studies using several different models revealed that strain MO80069 had significantly higher virulence in hosts with impaired neutrophil function when compared to the other strains. In summary, this study presents detailed biological characterization of two A. nidulans sensu stricto clinical isolates. Just like in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits. Further studies are required to fully characterize A. nidulans strain-specific virulence traits and pathogenicity. ImportanceImmunocompromised patients are susceptible to infections with opportunistic filamentous fungi from the genus Aspergillus. Although A. fumigatus is the main etiological agent of Aspergillus spp.-related infections, other species, such as A. nidulans are prevalent in a condition-specific manner. A. nidulans is a predominant infective agent in patients suffering from chronic granulomatous disease (CGD). A. nidulans isolates have mainly been studied in the context of CGD, although infection with A. nidulans also occurs in non-CGD patients. This study carried out a detailed biological characterization of two non-CGD A. nidulans clinical isolates and compared it to a reference strain. Phenotypic, metabolomic and genomic analyses highlight fundamental differences in carbon source utilization, stress responses and maintenance of cell wall integrity among the strains. One clinical strain had increased virulence in models with impaired neutrophil function. Just as in A. fumigatus, strain heterogeneity exists in A. nidulans clinical strains that can define virulence traits.

microbiology↗

bioRxiv2019

Regional glia-related metabolite levels are higher at older age and scale negatively with visuo-spatial working memory: A cross-sectional proton MR spectroscopy study at 7 tesla on normal cognitive ageing

Proton MR spectroscopy (1H-MRS) has been used to assess regional neurochemical brain changes during normal ageing, but results have varied. Exploiting the increased sensitivity at ultra-high field strength, we performed 1H-MRS in 60 healthy volunteers to asses age-related differences in neuron- and glia-related metabolite levels and their relation to cognitive ageing. Gender was balanced and participants were assigned to a younger, middle and older group according to their age, ranging from 18 to 79 years. They underwent 1H-MRS of anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC), hippocampus and thalamus and performed a visuo-spatial working memory task outside the scanner. Multivariate ANCOVA revealed a significant overall effect of age group on metabolite levels in all brain regions of interest. Considering specific metabolites, elevated levels of glia-related metabolites in older age groups were observed in all brain regions. For the neuron-related metabolites, differences among age groups were only observed in two regions. We found higher levels of total N-acetyl aspartate in hippocampus for the older than the middle group, and lower levels of glutamate in DLPFC in the older than the younger group. Working memory performance correlated negatively with levels of glia-related metabolites for total creatine and total choline in ACC and myo-inositol in hippocampus and thalamus, but not with neuron-related metabolites. Together, the results show that age effects on glia-related metabolites scale with cognitive ageing in multiple brain regions. We conclude that 1H-MRS-derived glia-related markers may be of value in longitudinal studies of brain ageing. Significance statementNeurochemical ageing is an integral component of age-related cognitive decline. Proton MR spectroscopy (1H-MRS) studies of in vivo neurochemical changes across the lifespan have, however, yielded inconclusive results. Due to the higher spectral resolution and sensitivity, 7 tesla 1H-MRS has potential to improve consistency of the results. Here we apply this technique to demonstrate that glia-related metabolites are elevated in older age in anterior cingulate cortex, hippocampus and thalamus with a novel link to cognitive ageing of visuo-spatial working memory. This study is the first to investigate normal ageing in these brain regions using 7 tesla 1H-MRS and the results indicate that glia-related metabolites could be of value in longitudinal studies of cognitive ageing.

neuroscience↗

bioRxiv2019

A high-resolution, chromosome-assigned Komodo dragon genome reveals adaptations in the cardiovascular, muscular, and chemosensory systems of monitor lizards

Monitor lizards are unique among ectothermic reptiles in that they have a high aerobic capacity and distinctive cardiovascular physiology which resembles that of endothermic mammals. We have sequenced the genome of the Komodo dragon (Varanus komodoensis), the largest extant monitor lizard, and present a high resolution de novo chromosome-assigned genome assembly for V. komodoensis, generated with a hybrid approach of long-range sequencing and single molecule physical mapping. Comparing the genome of V. komodoensis with those of related species showed evidence of positive selection in pathways related to muscle energy metabolism, cardiovascular homeostasis, and thrombosis. We also found species-specific expansions of a chemoreceptor gene family related to pheromone and kairomone sensing in V. komodoensis and several other lizard lineages. Together, these evolutionary signatures of adaptation reveal genetic underpinnings of the unique Komodo sensory, cardiovascular, and muscular systems, and suggest that selective pressure altered thrombosis genes to help Komodo dragons evade the anticoagulant effects of their own saliva. As the only sequenced monitor lizard genome, the Komodo dragon genome is an important resource for understanding the biology of this lineage and of reptiles worldwide.

genomics↗

bioRxiv2017

A LaeA- and BrlA-dependent cellular network governs tissue-specific secondary metabolism in the human pathogen Aspergillus fumigatus

Biosynthesis of many ecologically important secondary metabolites (SMs) in filamentous fungi is controlled by several global transcriptional regulators, like the chromatin modifier LaeA, and tied to both development and vegetative growth. In Aspergillus molds, asexual development is regulated by the BrlA>AbaA>WetA transcriptional cascade. To elucidate BrlA pathway involvement in SM regulation, we examined the transcriptional and metabolic profiles of {Delta}brlA, {Delta}abaA, {Delta}wetA and wild-type strains of the human pathogen Aspergillus fumigatus. We find that BrlA, in addition to regulating production of developmental SMs, regulates vegetative SMs and the SrbA-regulated hypoxia stress response in a concordant fashion to LaeA. We further show that the transcriptional and metabolic equivalence of {Delta}brlA and {Delta}laeA is mediated by a LaeA requirement preventing heterochromatic marks in the brlA promoter. These results provide a framework for the cellular network regulating not only fungal SMs but diverse cellular processes linked to virulence of this pathogen.

microbiology↗