Biology subjects

Otto, T.

Publications and source records attributed to Otto, T..

9 recordsLinked to original sources

bioRxiv2026

A partition-based spatial entropy for co-occurrence analysis with broad application.

Despite the advent of spatial data science, including spatial biology, there exist few methods that study the distribution of points e.g. cells or individuals, accounting for both their own characteristics and environmental factors. We propose a new spatial entropy measure, termed the Regional Co-occurrence Entropy (RCE), that detects when categorical co-occurrences happen preferentially in specific environments. We demonstrate its use over a broad range of application fields. As examples, we study brain cell dynamics in Alzheimers Disease, identifying both known and likely novel interactions between immune cells around beta-amyloid plaques. We also investigate the diversity of buildings across a town neighborhoods, to detect potential drivers of social mixing at local scale. Finally, we dissect bird species distribution across a natural reserve, identifying potential vegetation-driven changes in community composition. Altogether, the proposed RCE enables rapid insights into interactions with an environmental component, making it a useful addition to the spatial data science toolbox. Significance StatementSpatial data is rapidly accumulating across fields as diverse as spatial biology, geography, ecology or astrophysics and promises to allow major scientific advances. For example, spatial biology is transforming our ability to study complex tissue organization and disease mechanisms. A key challenge remains the quantification of spatial relationships between individual points, such as cell types, in a statistically rigorous way. We propose a spatial entropy-based measure to quantify context-dependent interactions between categories, such as cell types across tissue subregions. Our novel method deriving from Information Science provides an efficient and versatile way to extract information from spatial datasets, with broad applicability across research fields.

bioinformatics↗

bioRxiv2025

Human Fibroblast-Myeloid cell tissue atlas across lung, synovium, skin and heart

Single-cell RNA sequencing (scRNAseq) of human tissues has expanded our understanding of the complexity of cellular subsets and their changes in disease. The availability of scRNAseq data in different tissues and disease states provides an opportunity to compare cellular subsets and identify common and unique cellular activation. In this study, we aimed to characterize shared and tissue-specific myeloid and stromal phenotypes and uncover key cellular subtypes involved in pathogenic tissue activation. We analyzed scRNAseq data from 14 public datasets, comprising heart, lung, skin, and synovium in both healthy and diseased states. Our analysis identified distinct and overlapping myeloid and stromal cell populations in these tissues. Despite significant inter-individual variability, we were able to identify both shared and disease-specific changes in these cell populations. These findings provide insights into the conserved and tissue-specific roles of myeloid and stromal cells in health and disease and contribute to a better understanding of tissue pathology and potential therapeutic targets.

cell biology↗

bioRxiv2024

Identification of novel PfEMP1 variants containing domain cassettes 11, 15 and 8 that mediate the Plasmodium falciparum virulence-associated rosetting phenotype

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) is a diverse family of variant surface antigens, encoded by var genes, that mediates binding of infected erythrocytes to human cells and plays a key role in parasite immune evasion and malaria pathology. The increased availability of parasite genome sequence data has revolutionised the ability to study PfEMP1 diversity across multiple P. falciparum isolates. However, making functional sense of genomic data relies on the ability to infer binding phenotype from var gene sequence. For P. falciparum rosetting, the binding of infected erythrocytes to uninfected erythrocytes, the analysis of var gene/PfEMP1 sequences encoding the phenotype is limited, with only eight rosette-mediating PfEMP1 variants described to date. These known rosetting PfEMP1 variants fall into two types, characterised by N- terminal domains known as "domain cassette" 11 (DC11) and DC16. Here we test the hypothesis that DC11 and DC16 are the only PfEMP1 types in the P. falciparum genome that mediate rosetting, by examining a set of thirteen recent culture-adapted Kenyan parasite lines. We first analysed the var gene/PfEMP1 repertoires of the Kenyan lines and identified an average of three DC11 or DC16 PfEMP1 variants per genotype. In vitro rosette selection of the parasite lines yielded four with a high rosette frequency, and analyses of their var gene transcription, infected erythrocyte PfEMP1 surface expression, rosette disruption and erythrocyte binding function identified four novel rosette- mediating PfEMP1 variants. Two of these were of the predicted DC11 type (one showing the dual rosetting/IgM-Fc-binding phenotype), whereas two contained DC15 (DBL1.2-CIDR1.5b) a PfEMP1 type not previously associated with rosetting. We also showed that a Thai parasite line expressing a DC8-like PfEMP1 binds to erythrocytes to form rosettes. Hence, these data expand current knowledge of rosetting mechanisms and emphasize that the PfEMP1 types mediating rosetting are more diverse than previously recognised. Author summary Malaria is an infectious tropical disease caused by the parasite Plasmodium falciparum that kills more than half a million people every year, mostly young children in sub-Saharan Africa. Life- threatening episodes of malaria are characterised by huge numbers of parasitised red blood cells in the infected host, many of which bind to blood vessel walls and block blood flow, causing tissue damage and organ failure. Sometimes parasitised red cells also bind to uninfected red cells to form clusters of cells called rosettes, which make the blockage of blood flow in vital organs even worse. Previous research has begun to decipher how parasitised red cells bind to uninfected red cells to form rosettes, but little is yet known about the process. Here we identify some new versions of the "sticky proteins" (adhesion molecules) that are made by malaria parasites and displayed on the surface of infected red cells to bring about rosette formation. The rosette-mediating adhesion molecules are members of a large family, and we identify here a few characteristic types within this family that mediate rosetting. This work is an important step towards the goal of understanding how malaria parasite rosettes form rosettes in order to develop preventions or treatments to reverse rosetting and reduce the number of people dying from severe malaria.

microbiology↗

bioRxiv2024

Salinisation and warming disrupt predator-induced drift behaviour in aquatic predator-prey interactions

Predators act as a major selective force impacting biological communities in riverine ecosystems. Often predation risk is mediated by chemical cues upon which prey species display distinct morphological or behavioural defences. For stream invertebrates, predator-induced behaviours can be drifting and hiding. However, anthropogenic stressors increasingly impact freshwater ecosystems, with predicted consequences on the chemical information transfer, potentially affecting anti-predator behaviour. Despite this, knowledge and research on the extent to which these stressors may affect evolved predator-induced behaviour and subsequent ecosystems is scarce. Therefore, we conducted an outdoor mesocosm experiment (ExStream system) at a lowland stream in Germany, in which we investigated the effects of direct and indirect fish predation on invertebrate communities under different stressor conditions. As stressors, we tested elevated salinity (ambient vs + 136 mg/L NaCl), elevated temperature (ambient vs. + 3.4{degrees}C), and the combination of both. Our findings reveal distinct predator-induced drift behaviour, characterised by a greater number of drifting invertebrates and a concurrent reduction in overall invertebrate numbers in the communities. Increased salinity and temperature hampered the predator-induced drift behaviour. Our results support the possibility that stressors negatively impact the preys ability to perceive predators presence and respond appropriately. This disruption may alter predator-prey relationships, thereby affecting communities and potentially ecosystem functions. Highlights[vrecto] We hypothesised that anthropogenic stressors disrupt predator-induced behaviours in invertebrate prey species. [vrecto]Predator-induced drift behaviour was experimentally studied under ambient and elevated salinity and temperature conditions. [vrecto]Fish exposure elicited predator-induced drift behaviour, which decreased the number of invertebrate individuals of the communities. [vrecto]Elevated salt and elevated temperatures alone and in combination did not induce drift behaviour. [vrecto]We found that both stressors disrupted predator-induced drift behaviour, altering the anti-predator response of invertebrate prey. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=78 SRC="FIGDIR/small/601583v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@1eef03borg.highwire.dtl.DTLVardef@1ddda7corg.highwire.dtl.DTLVardef@332bdaorg.highwire.dtl.DTLVardef@1842dbb_HPS_FORMAT_FIGEXP M_FIG C_FIG

ecology↗

bioRxiv2023

Repeated Plasmodium vivax blood stage infection provides sterile protection against homologous challenge in non-human primates

The malaria parasite Plasmodium vivax remains a major global public health challenge, causing major morbidity across tropical and subtropical regions. Several candidate vaccines are in preclinical and clinical trials, however no vaccine against P. vivax malaria is approved for use in humans. Here we assessed whether P. vivax strain-transcendent immunity can be achieved by repeated infection in Aotus monkeys. For this purpose, we repeatedly infected six animals with blood stages of the P. vivax Salvador 1 (SAL-1) strain until sterile immune, and then challenged with the AMRU-1 strain. Sterile immunity was achieved in 4/4 Aotus monkeys after two homologous infections with the SAL-1 strain, while partial protection against a heterologous AMRU-1 challenge (i.e., delay to infection and reduction in peak parasitemia compared to control) was achieved in 3/3 monkeys. IgG levels based on P. vivax lysate ELISA and protein microarray increased with repeated infections and correlated with the level of homologous protection. Analysis of parasite transcriptional profiles across inoculation levels provided no evidence of major antigenic switching upon homologous or heterologous challenge. In contrast, we observed significant transcriptional differences in the P. vivax core gene repertoire between SAL-1 and AMRU-1. Together with the strain-specific genetic diversity between SAL-1 and AMRU-1 these data suggest that the partial protection upon heterologous challenge is due to molecular differences between strains (at genome and transcriptome level) rather than immune evasion by antigenic switching. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated homologous blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines. Author summaryPlasmodium vivax is the most widespread human malaria parasite. Elimination efforts are complicated due to the peculiar biology of P. vivax including dormant liver forms, cryptic reservoirs in bone marrow and spleen and a large asymptomatic infectious reservoir in affected populations. Currently there is no vaccine against malaria caused by P. vivax. Here we induce sterile immunity by repeated P. vivax infection with the SAL-1 strain in non-human primates. In contrast, heterologous challenge with the AMRU-1 strain only provided partial protection. Antibody levels against a crude antigen and a protein microarray correlated with the level of homologous protection. Parasite transcriptional profiles across inoculation levels failed to show major antigenic switching across SAL-1 infections or upon heterologous challenge, instead suggesting other mechanisms of immune evasion. Our study demonstrates that sterile immunity against P. vivax can be achieved by repeated blood stage infection in Aotus monkeys, thus providing a benchmark to test the efficacy of candidate blood stage P. vivax malaria vaccines.

microbiology↗

bioRxiv2021

Using topic modeling to detect cellular crosstalk in scRNA-seq

Cell-cell interactions are vital for numerous biological processes including development, differentiation, and response to inflammation. Currently most methods for studying interactions on scRNA-seq level are based on curated databases of ligands and receptors. While those methods are useful, they are limited to our current biological knowledge. Recent advances in single cell protocols have allowed for physically interacting cells to be captured and as such we have the potential to study interactions in a complimentary way without relying on prior knowledge. We introduce a new method for detecting genes that change as a result of interaction based on Latent Dirichlet Allocation (LDA). We apply our method to synthetic datasets to demonstrate its ability to detect genes that change in an interacting population compared to a reference population. Next, we apply our approach to two datasets of physically interacting cells and identify genes that change as a result of interaction, examples include adhesion and co-stimulatory molecules which confirm physical interaction between cells. For each dataset we produce a ranking of genes that are changing in subpopulations of the interacting cells. In addition to genes, discussed in the original publications we highlight further candidates for interaction in the top 100 and 300 ranked genes. Lastly, we apply our method to a dataset generated by a standard droplet based protocol, not designed to capture interacting cells and discuss its suitability for analysing interactions. We present a method that streamlines the detection of interactions and does not require prior clustering and generation of synthetic reference profiles to detect changes in expression. Author summaryWhile scRNA-seq research is a dynamic area, progress is lacking when it comes to developing methods that allow analysis of interaction that is independent of curated resources of known interacting pairs. Recent advances of sequencing protocols have allowed for interacting cells to be captured. We propose a novel method based on LDA that captures changes in gene expression as a result of interaction. Our method does not require prior information in the form of clustering or generation of synthetic reference profiles. We demonstrate the suitability of our approach by applying it to synthetic and real datasets and manage to capture biologically interesting candidates of interaction.

bioinformatics↗

bioRxiv2020

Varia: Prediction, analysis and visualisation of variable genes

Assessing the diversity or expression of variable gene families in pathogens can inform about immune escape mechanisms or host interaction phenotypes of clinical relevance. However, obtaining the sequences and quantifying their expression is a challenge. Here, we present a tool, which based on unique sequence tag similarity between members of a gene family, predicts the domains encoded by the queried gene. As an example, we are using the var gene family, encoding the major virulence proteins (PfEMP1) of the human malaria parasite, Plasmodium falciparum. We developed Varia, which predicts the likely var gene sequence and encoded protein domain composition of a gene from short sequence tags. We provide a new extended annotated var genome database, in which Varia identifies genes with identical tag sequences and compares these to return the most probable domain composition of the query gene. Varias ability to predict correct PfEMP1 domain compositions from short var sequence tags was tested in two complementary pipelines to (a) return the putative gene sequences and domain compositions of the query gene from any partial sequence provided, thereby enabling detailed assessment of specific genes putative function and experimental validation of these (b) to accommodate rapid profiling of var gene expression in complex patient samples, by compiling the overall domain prevalence among var transcripts predicted identified and quantified by next generation sequencing of so-called var DBL-sequence tags. Availability and implementationVaria is available on GitHub (https://github.com/GCJMacken-zie/Varia) under the MIT license. Contactthomasl@sund.ku.dk, thomasdan.otto@glasgow.ac.uk

bioinformatics↗

bioRxiv2018

WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates in pathogenic mycobacteria.

The mycobacterial type VII secretion system ESX-1 is responsible for the secretion of a number of proteins that play important roles during host infection. The regulation of the expression of secreted proteins is often essential to establish successful infection. Using transcriptome sequencing, we found that the abrogation of ESX-1 function in Mycobacterium marinum leads to a pronounced increase in gene expression levels of the espA operon during the infection of macrophages, suggesting an important role in ESX-1-mediated virulence during the early phase of infection. In addition, the disruption of ESX-1-mediated protein secretion also leads to a specific down-regulation of the ESX-1 substrates, but not of the structural components of this system, during growth in culture medium. This effect is observed in both M. marinum and M. tuberculosis. We established that down-regulation of ESX-1 substrates is the result of a regulatory process that is influenced by the putative transcriptional regulator whib6, which is located adjacent to the esx-1 locus. In addition, the overexpression of the ESX-1-associated PE35/PPE68 protein pair resulted in a significantly increased secretion of the ESX-1 substrate EsxA, demonstrating a functional link between these proteins. Taken together, these data show that WhiB6 is required for the secretion-dependent regulation of ESX-1 substrates and that ESX-1 substrates are regulated independently from the structural components, both during infection and as a result of active secretion.

microbiology↗

bioRxiv2017

Plasmodium vivax-like genome sequences shed new insights into Plasmodium vivax biology and evolution

Plasmodium vivax is responsible of the majority of malaria infections outside Africa. Its closer genetic relative, Plasmodium vivax-like, was discovered in African great apes and suggested to have given rise to P. vivax in humans. We generated two newly P. vivax-like reference genomes and 9 additional P. vivax-like genotypes, to unravel the evolutionary history of P. vivax. We showed a clear separation between the two clades, a higher genetic diversity of P. vivax-like parasites in comparison to the P. vivax ones, and the potential existence of two sub-clades of P. vivax-like. We dated the relative split between P. vivax and P. vivax-like as three times shorter than the split between P. ovale wallikeri and P. ovale curtesi and 1.5 times longer than the split between Plasmodium malariae. The sequencing of the P. vivax-like genomes is an undeniable advance in the understanding of P. vivax biology, evolution and emergence in human populations.

evolutionary biology↗