Biology subjects

Lange, M.

Publications and source records attributed to Lange, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Modelling the transmission and spread of yellow fever in forest landscapes with different spatial configurations

Yellow fever (YF) is a major public health issue in tropical and subtropical areas of Africa and South America. The disease is caused by the yellow fever virus (YFV), an RNA virus transmitted to humans and other animals through the bite of infected mosquitoes (Diptera: Culicidae). In Brazil and other South American countries, YFV is restricted to the sylvatic cycle, with periodic epizootic outbreaks affecting non-human primate (NHP) populations and preceding the emergence of human infections in areas close to forests. In recent epizootic-epidemic waves, the virus has expanded its range and spread across highly fragmented landscapes of the Brazilian Atlantic coast. Empirical evidence has suggested a possible relationship between highly fragmented areas, increased risk of disease in NHP and humans, and easier permeability of YFV through the landscape. Here, we present a hybrid compartmental and network-based model to simulate the transmission and spread of YFV in forest landscapes with different spatial configurations (forest cover and edge densities) and apply the model to test the hypothesis of faster virus percolation in highly fragmented landscapes. The model was parameterized and tested using the pattern- oriented modelling approach. Two different scenarios were simulated to test variations in model outputs, a first where the landscape has no influence on model parameters (default) and a second based on the hypothesis that edge density influences mosquito and dead-end host abundance and dispersal (landscape-dependent). The model was able to reproduce empirical patterns such as the percolation speed of the virus, which presented averages close to 1 km/day, and provided insights into the short persistence time of the virus in the landscape, which was approximately three months on average. When assessing the speed of virus percolation across landscapes, it was found that in the default scenario virus percolation tended to be faster in landscapes with greater forest cover and lower edge density, which contradicts empirical observations. Conversely, in the landscape- dependent scenario, virus percolation was faster in landscapes with high edge density and intermediate forest cover, supporting empirical observations that highly fragmented landscapes favour YFV spread. The proposed model can contribute to the understanding of the dynamics of YFV spread in forested areas, with the potential to be used as an additional tool to support prevention and control measures. The potential applications of the model for YFV and other mosquito-borne diseases are discussed.

ecology↗

bioRxiv2023

Novel YAP1/TAZ pathway inhibitors identified through phenotypic screening with potent anti-tumor activity via blockade of GGTase-I / Rho-GTPase signaling

This study describes the identification and target deconvolution of novel small molecule inhibitors of oncogenic YAP1/TAZ activity with potent anti-tumor activity in vivo. A high-throughput screen (HTS) of 3.8 million compounds was conducted using a cellular YAP1/TAZ reporter assay. Target deconvolution studies identified the geranylgeranyltransferase-I (GGTase-I) complex, as the direct target of YAP1/TAZ pathway inhibitors. The novel small molecule inhibitors block the activation of Rho-GTPases, leading to subsequent inactivation of YAP1/TAZ and inhibition of cancer cell proliferation in vitro. Multi-parameter optimization resulted in BAY-593, an in vivo probe with favorable PK properties, which demonstrated anti-tumor activity and blockade of YAP1/TAZ signaling in vivo. SIGNIFICANCEYAP1/TAZ have been shown to be aberrantly activated oncogenes in several human solid tumors, resulting in enhanced cell proliferation, metastasis and provision of a pro-tumorigenic microenvironment, making YAP1/TAZ targets for novel cancer therapies. Yet, the development of effective inhibitors of these potent oncogenes has been challenging. In this work, we break new ground in this direction through the identification of novel inhibitors of YAP1/TAZ activity. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=192 HEIGHT=200 SRC="FIGDIR/small/555331v2_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@4aac3forg.highwire.dtl.DTLVardef@728b6forg.highwire.dtl.DTLVardef@203a2eorg.highwire.dtl.DTLVardef@1cbc5f9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LINovel YAP1/TAZ pathway inhibitors identified by phenotypic high-throughput screen C_LIO_LITarget deconvolution identifies GGTase-I as the direct target of the novel YAP1/TAZ pathway inhibitors C_LIO_LIGGTase-I inhibitors block Rho-GTPase signaling and downstream YAP1/TAZ C_LIO_LIGGTase-I inhibitor BAY-593 demonstrates potent anti-tumor activity in vivo C_LI

cancer biology↗

bioRxiv2023

Unified fate mapping in multiview single-cell data

Single-cell RNA sequencing allows us to model cellular state dynamics and fate decisions using expression similarity or RNA velocity to reconstruct state-change trajectories. However, trajectory inference does not incorporate valuable time point information or utilize additional modalities, while methods that address these different data views cannot be combined and do not scale. Here, we present CellRank 2, a versatile and scalable framework to study cellular fate using multiview single-cell data of up to millions of cells in a unified fashion. CellRank 2 consistently recovers terminal states and fate probabilities across data modalities in human hematopoiesis and mouse endodermal development. Our framework also allows combining transitions within and across experimental time points, a feature we use to recover genes promoting medullary thymic epithelial cell formation during pharyngeal endoderm development. Moreover, we enable estimating cell-specific transcription and degradation rates from metabolic labeling data, which we apply to an intestinal organoid system to delineate differentiation trajectories and pinpoint regulatory strategies.

bioinformatics↗

bioRxiv2023

A Cell Cycle-Dependent Ferroptosis Sensitivity Switch Governed by EMP2

Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation. Ferroptosis can be induced by system xc- cystine/glutamate antiporter inhibition or by direct inhibition of the phospholipid hydroperoxidase glutathione peroxidase 4 (GPX4). The regulation of ferroptosis in response to system xc- inhibition versus direct GPX4 inhibition may be distinct. Here, we show that cell cycle arrest enhances sensitivity to ferroptosis triggered by GPX4 inhibition but not system xc- inhibition. Arrested cells have increased levels of oxidizable polyunsaturated fatty acid-containing phospholipids, which drives sensitivity to GPX4 inhibition. Epithelial membrane protein 2 (EMP2) expression is reduced upon cell cycle arrest and is sufficient to enhance ferroptosis in response to direct GPX4 inhibition. An orally bioavailable GPX4 inhibitor increased markers of ferroptotic lipid peroxidation in vivo in combination with a cell cycle arresting agent. Thus, responses to different ferroptosis-inducing stimuli can be regulated by cell cycle state.

cancer biology↗

bioRxiv2023

Mapping cells through time and space with moscot

Single-cell genomics technologies enable multimodal profiling of millions of cells across temporal and spatial dimensions. Experimental limitations prevent the measurement of all-encompassing cellular states in their native temporal dynamics or spatial tissue niche. Optimal transport theory has emerged as a powerful tool to overcome such constraints, enabling the recovery of the original cellular context. However, most algorithmic implementations currently available have not kept up the pace with increasing dataset complexity, so that current methods are unable to incorporate multimodal information or scale to single-cell atlases. Here, we introduce multi-omics single-cell optimal transport (moscot), a general and scalable framework for optimal transport applications in single-cell genomics, supporting multimodality across all applications. We demonstrate moscots ability to efficiently reconstruct developmental trajectories of 1.7 million cells of mouse embryos across 20 time points and identify driver genes for first heart field formation. The moscot formulation can be used to transport cells across spatial dimensions as well: To demonstrate this, we enrich spatial transcriptomics datasets by mapping multimodal information from single-cell profiles in a mouse liver sample, and align multiple coronal sections of the mouse brain. We then present moscot.spatiotemporal, a new approach that leverages gene expression across spatial and temporal dimensions to uncover the spatiotemporal dynamics of mouse embryogenesis. Finally, we disentangle lineage relationships in a novel murine, time-resolved pancreas development dataset using paired measurements of gene expression and chromatin accessibility, finding evidence for a shared ancestry between delta and epsilon cells. Moscot is available as an easy-to-use, open-source python package with extensive documentation at https://moscot-tools.org.

bioinformatics↗

bioRxiv2023

Mapping lineage-traced cells across time points with moslin

Simultaneous profiling of single-cell gene expression and lineage history holds enormous potential for studying cellular decision-making beyond simpler pseudotime-based approaches. However, it is currently unclear how lineage and gene expression information across experimental time points can be combined in destructive experiments, which is particularly challenging for in-vivo systems. Here we present moslin, a Fused Gromov-Wasserstein-based model to couple matching cellular profiles across time points. In contrast to existing methods, moslin leverages both intra-individual lineage relations and inter-individual gene expression similarity. We demonstrate on simulated and real data that moslin outperforms state-of-the-art approaches that use either one or both data modalities, even when the lineage information is noisy. On C. elegans embryonic development, we show how moslin, combined with trajectory inference methods, predicts fate probabilities and putative decision driver genes. Finally, we use moslin to delineate lineage relationships among transiently activated fibroblast states during zebrafish heart regeneration. We anticipate moslin to play a crucial role in deciphering complex state change trajectories from lineage-traced single-cell data.

bioinformatics↗

bioRxiv2023

Selenium reduction of ubiquinone via SQOR suppresses ferroptosis

The canonical biological function of selenium is in the production of selenocysteine residues of selenoproteins, and this forms the basis for its role as an essential antioxidant and cytoprotective micronutrient. Here, we demonstrate that selenium, via its metabolic intermediate hydrogen selenide, efficiently donates its electrons to ubiquinone to form ubiquinol in the mitochondria through catalysis by sulfide quinone oxidoreductase (SQOR). Hydrogen selenide is superior to hydrogen sulfide as an electron donor owing to its larger valence shell. We show that this mechanism, independently of selenoprotein production, protects against ferroptosis via ubiquinol production in a manner that depends on xCT mediated selenide formation and SQOR activity. Our findings identify a regulatory mechanism against ferroptosis that implicates SQOR and expands our understanding of selenium in biology.

biochemistry↗

bioRxiv2023

Plant diversity stabilizes soil temperature

Extreme weather events are occurring more frequently, and research has shown that plant diversity can help mitigate impacts of climate change by increasing plant productivity and ecosystem stability1,2. Although soil temperature and its stability are key determinants of essential ecosystem processes related to water and nutrient uptake3 as well as soil respiration and microbial activity4, no study has yet investigated whether plant diversity can buffer soil temperature fluctuations. Using 18 years of a continuous dataset with a resolution of 1 minute ([~]795,312,000 individual measurements) from a large-scale grassland biodiversity experiment, we show that plant diversity buffers soil temperature throughout the year. Plant diversity helped to prevent soil heating in hot weather, and cooling in cold weather. Moreover, this effect of plant diversity increased over the 18-year observation period with the aging of experimental communities and was even stronger under extreme conditions, i.e., on hot days or in dry years. Using structural equation modelling, we found that plant diversity stabilized soil temperature by increasing soil organic carbon concentrations and, to a lesser extent, by increasing the plant leaf area index. We suggest that the diversity-induced stabilization of soil temperature may help to mitigate the negative effects of extreme climatic events such as soil carbon release, thus slow global warming.

ecology↗

bioRxiv2023

Uptake of plant-derived carbon and proximity to the root determine differences in temporal and spatial stability among microbial groups

The interactions between plants and soil microorganisms are fundamental for ecosystem functioning. However, it remains unclear if seasonality of plant growth impacts plant-microbial interactions, such as by inducing shifts in the microbial community composition, their biomass, or changes in the microbial uptake of plant-derived carbon. Here, we investigate the stability of microbial biomass of different functional groups and their net assimilation of plant-derived carbon over an entire growing season. Using a C3-C4 vegetation change experiment, and taking advantage of natural abundances of 13C, we measured the plant-derived carbon in lipid biomarkers of soil microorganisms in rhizosphere and non-rhizosphere soil. We found that temporal and spatial stability was higher in bacterial than in fungal biomass, while the high temporal stability of all bacterial groups even increased in close proximity to roots. Moreover, differences in the association to plants, i.e., symbionts vs. free-living microorganisms, tend to determine the stability in the uptake of plant-derived carbon. Our results indicate, the inputs of plant-derived carbon over the growing season did not result in a shift in the microbial community composition, but instead, functional groups that are not in obligate symbiosis with plants showed a varying use of soil- and plant-derived carbon.

ecology↗

bioRxiv2023

Zebrahub - Multimodal Zebrafish Developmental Atlas Reveals the State Transition Dynamics of Late Vertebrate Pluripotent Axial Progenitors

Elucidating the developmental processes of organisms requires a comprehensive understanding of cellular lineages in the spatial, temporal, and molecular domains. In this study, we introduce Zebrahub, a dynamic atlas of zebrafish embryonic development that integrates single-cell sequencing time course data with lineage reconstructions facilitated by light-sheet microscopy. This atlas offers high-resolution and in-depth molecular insights into zebrafish development, achieved through the sequencing of individual embryos across ten developmental stages, complemented by trajectory reconstructions. Zebrahub also incorporates an interactive tool to navigate the complex cellular flows and lineages derived from light-sheet microscopy data, enabling in silico fate mapping experiments. To demonstrate the versatility of our multi-modal resource, we utilize Zebrahub to provide fresh insights into the pluripotency of Neuro-Mesodermal Progenitors (NMPs). Our publicly accessible web-based platform, Zebrahub, is a foundational resource for studying developmental processes at both transcriptional and spatiotemporal levels, providing researchers with an integrated approach to exploring and analyzing the complexities of cellular lineages during zebrafish embryogenesis.

developmental biology↗

bioRxiv2022

Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis

Ferroptosis is a regulated form of cell death associated with the iron-dependent accumulation of lipid peroxides. Inducing ferroptosis is a promising approach to treat therapy resistant cancer. Ferroptosis suppressor protein 1 (FSP1) promotes ferroptosis resistance in cancer by generating the antioxidant form of coenzyme Q10 (CoQ). Despite the important role of FSP1, few molecular tools exist that target the CoQ-FSP1 pathway. Exploiting a series of chemical screens, we identify several structurally diverse FSP1 inhibitors. The most potent of these compounds, ferroptosis sensitizer 1 (FSEN1), is an uncompetitive inhibitor that acts selectively through on target inhibition of FSP1 to sensitize cancer cells to ferroptosis. Furthermore, a synthetic lethality screen reveals that FSEN1 synergizes with endoperoxide-containing ferroptosis inducers, including dihydroartemisinin, to trigger ferroptosis. These results provide new tools that catalyze the exploration of FSP1 as a therapeutic target and highlight the value of combinatorial therapeutic regimes targeting FSP1 and additional ferroptosis inducers.

cancer biology↗

bioRxiv2022

A genome-wide CRISPR screen implicates plasma membrane asymmetry in exogenous C6-ceramide toxicity

The bioactive sphingolipid ceramide impacts diverse cellular processes (e.g., apoptosis and cell proliferation) through its effects on membrane dynamics and intracellular signalling pathways. The dysregulation of ceramide metabolism has been implicated in cancer evasion of apoptosis and targeting ceramide metabolism has potential therapeutic benefits as a strategy to kill cancer cells and slow tumor growth. However, the mechanisms of cancer cell resistance to ceramide-mediated cell death are vastly intertwined and incompletely understood. To shed light on this mystery, we performed a genome wide CRISPR-Cas9 screen to systematically identify regulators of cancer resistance to the soluble short chain ceramide, C6 ceramide (C6-Cer). Our results reveal a complex landscape of genetic modifiers of C6-Cer toxicity, including genes associated with ceramide and sphingolipid metabolism, vesicular trafficking, and membrane biology. Furthermore, we find that loss of the phospholipid flippase subunit TMEM30A impairs the plasma membrane trafficking of its binding partner the P4-type ATPase ATP11B, and depletion of TMEM30A or ATP11B disrupts plasma membrane asymmetry and promotes resistance to C6-Cer toxicity independent of alterations in C6-Cer uptake. Together, our findings provide a resource of genetic modifiers of C6-Cer toxicity and reveal an unexpected role of plasma membrane asymmetry in C6-Cer induced cell death.

cell biology↗

bioRxiv2022

DivBrowse - interactive visualization and exploratory data analysis of variant call matrices

BackgroundThe sequencing of whole genomes is becoming increasingly affordable. In this context large-scale sequencing projects are generating ever larger datasets of species-specific genomic diversity. As a consequence, more and more genomic data needs to be made easily accessible and analyzable to the scientific community. FindingsWe present DivBrowse, a web application for interactive visualization and exploratory analysis of genomic diversity data stored in Variant Call Format (VCF) files of any size. By seamlessly combining BLAST as an entry point together with interactive data analysis features such as principal component analysis in one graphical user interface, DivBrowse provides a novel and unique set of exploratory data analysis capabilities for genomic biodiversity datasets. The capability to integrate DivBrowse into existing web applications supports interoperability between different web applications. Built-in interactive computation of principal component analysis allows users to perform ad-hoc analysis of the population structure based on specific genetic elements such as genes and exons. Data interoperability is supported by the ability to export genomic diversity data in VCF and General Feature Format (GFF3) files. ConclusionDivBrowse offers a novel approach for interactive visualization and analysis of genomic diversity data and optionally also gene annotation data by including features like interactive calculation of variant frequencies and principal component analysis. The use of established standard file formats for data input supports interoperability and seamless deployment of application instances based on the data output of established bioinformatics pipelines.

bioinformatics↗

bioRxiv2022

African swine fever virus - variants on the rise

African swine fever virus (ASFV), a large and complex DNA-virus circulating between soft ticks and indigenous suids in sub-Saharan Africa, has made its way into swine populations from Europe to Asia. This virus, causing a severe haemorrhagic disease (African swine fever) with very high lethality rates in wild boar and domestic pigs, has demonstrated a remarkably high genetic stability for over 10 years. Consequently, analyses into virus evolution and molecular epidemiology often struggled to provide the genetic basis to trace outbreaks while few resources have been dedicated to genomic surveillance on whole-genome level. During its recent incursion into Germany in 2020, ASFV has unexpectedly diverged into five clearly distinguishable linages with at least ten different variants characterized by high-impact mutations never identified before. Noticeably, all new variants share a frameshift mutation in the 3 end of the DNA polymerase PolX gene O174L, suggesting a causative role as possible mutator gene. Although epidemiological modelling supported the influence of increased mutation rates, it remains unknown how fast virus evolution might progress under these circumstances. Moreover, a tailored Sanger sequencing approach allowed us, for the first time, to trace variants with genomic epidemiology to regional clusters. In conclusion, our findings suggest that this new factor has the potential to dramatically influence the course of the ASFV pandemic with unknown outcome. Therefore, our work highlights the importance of genomic surveillance of ASFV on whole-genome level, the need for high-quality sequences and calls for a closer monitoring of future phenotypic changes of ASFV.

genomics↗

bioRxiv2022

Parallel CRISPR-Cas9 screens reveal mechanisms of PLIN2 and lipid droplet regulation

Lipid droplets (LDs) are lipid storage organelles that consist of a central core of neutral lipids surrounded by a phospholipid monolayer decorated with a unique set of integral and peripheral proteins. Invariably, at least one member of the perilipin family of proteins (PLIN1-5) associates with LDs in all cell types. Despite key roles of PLIN2 in governing hepatic lipid metabolism, the mechanisms that regulate PLIN2 levels remain incompletely understood. Here, we develop a set of genome-edited PLIN2 reporter cell lines that facilitate the analysis of genes that regulate PLIN2 and LD abundance. Leveraging these reporter cells in a series of CRISPR-Cas9 loss-of-function screens, we generate a comprehensive inventory of genes that influence PLIN2 levels under different metabolic conditions. Moreover, we uncouple their effects on PLIN2 expression and post-translational stability. Identified genetic modifiers include canonical genes that control LD metabolism (e.g., ACSL3, DGAT2, PNPLA2, ABHD5) as well as genes with less characterized roles in PLIN2 and LD regulation such as ubiquitination machinery (e.g., MARCH6, UBE2J2), transcription regulators (e.g., HNF4A, HDAC3), mitochondrial pathways (e.g., electron transport chain and mitochondrial fatty acid synthesis), and others. These CRISPR screens, and several published screens that focus on different aspects of lipid metabolism, provide the foundation for CRISPRlipid (http://crisprlipid.org), a versatile, online data commons for lipid-related functional genomics data. Together, our study uncovers new mechanisms of PLIN2 regulation and provides an extensive, phenotype-rich resource for the exploration of LD biology and lipid metabolism.

cell biology↗

bioRxiv2021

Epilipidomics platform for holistic profiling of oxidized complex lipids in blood plasma of obese individuals

Lipids are a structurally diverse class of biomolecules which can undergo a variety of chemical modifications. Among them, lipid (per)oxidation attracts most of the attention due to its significance in regulation of inflammation, cell proliferation and death programs. Despite their apparent regulatory significance, the molecular repertoire of oxidized lipids remains largely elusive as accurate annotation of lipid modifications is challenged by their low abundance and largely unknown, biological context-dependent structural diversity. Here we provide a holistic workflow based on the combination of bioinformatics and LC-MS/MS technologies to support identification and relative quantification of oxidized complex lipids in a modification type- and position-specific manner. The developed methodology was used to identify epilipidomics signatures of lean and obese individuals with and without type II diabetes. Characteristic signature of lipid modifications in lean individuals, dominated by the presence of modified octadecanoid acyl chains in phospho- and neutral lipids, was drastically shifted towards lipid peroxidation-driven accumulation of oxidized eicosanoids, suggesting significant alteration of endocrine signalling by oxidized lipids in metabolic disorders.

biochemistry↗

bioRxiv2021

GiPS: Genomics-informed parent selection uncovers the breeding value of wheat genetic resources

The great efforts spent in the maintenance of past diversity in genebanks are rationalized by the potential role of plant genetic resources in future crop improvement - a concept whose practical implementation has fallen short of expectations. Here, we implement genomics-informed parent selection to expedite pre-breeding without discriminating against non-adapted germplasm. We collect dense genetic profiles for a large winter wheat collection and evaluate grain yield and resistance to yellow rust in representative coresets. Genomic prediction within and across genebanks identified the best parents for PGR x elite derived crosses that outyielded current elite cultivars in multiple field trials.

genomics↗

bioRxiv2021

Myth-busting the provider-user relationship for digital sequence information

The United Nations Convention on Biological Diversity (CBD) formally recognized the sovereign rights of nations over their biological diversity. Implicit within the treaty is the idea that mega-biodiverse countries will provide genetic resources and grant access to them and scientists in high-income countries will use these resources and share back benefits. However, little research has been conducted on how this framework is reflected in real-life scientific practice. Currently, parties to the CBD) are debating whether or not digital sequence information (DSI) should be regulated under a new benefit-sharing framework. At this critical time point in the upcoming international negotiations, we test the fundamental hypothesis of provision and use by looking at the global patterns of access and use in scientific publications. Our data reject the provider-user relationship and suggest far more complex information flow for digital sequence information. Therefore, any new policy decisions on digital sequence information should be aware of the high level of use of DSI across low- and middle-income countries and seek to preserve open access to this crucial common good.

scientific communication and education↗