Biology subjects

Lange, M.

Publications and source records attributed to Lange, M..

54 records · Page 3Linked to original sources

bioRxiv2021

Quantitative monitoring of nucleotide sequence data from genetic resources in context of their citation in the scientific literature

BackgroundLinking nucleotide sequence data (NSD) to scientific publication citations can enhance understanding of NSDs provenance, scientific use, and re-use in the community. By connecting publications with NSD records, NSD geographical provenance information, and author geographical information, it becomes possible to assess the contribution of NSD to infer trends in scientific knowledge gain at the global level. FindingsFor this data note, we extracted and linked records from the European Nucleotide Archive to citations in open-access publications aggregated at Europe PubMed Central. A total of 8,464,292 ENA accessions with geographical provenance information were associated with publications. We conducted a data quality review to uncover potential issues in publication citation information extraction and author affiliation tagging and developed and implemented best-practice recommendations for citation extraction. Flat data tables and an data warehouse with an interactive web application were constructed to enable ad hoc exploration of NSD use and summary statistics. ConclusionsThe extraction and linking of NSD with associated publication citations enables transparency. The quality review contributes to enhanced text mining methods for identifier extraction and use. Furthermore, the global provision and use of NSD enables scientists around the world to join literature and sequence databases in a multidimensional fashion. As a concrete use case, statistics of country clusters were visualized with respect to NSD access in the context of discussions around digital sequence information under the United Nations Convention on Biological Diversity.

bioinformatics↗

bioRxiv2021

ZAF -- An Open Source Fully Automated Feeder for Aquatic Facilities

In the past few decades, aquatic animals have become popular model organisms in biology, spurring a growing need for establishing aquatic facilities. Zebrafish are widely studied and relatively easy to culture using commercial systems. However, a challenging aspect of maintaining aquatic facilities is animal feeding, which is both time- and resource-consuming. We have developed an open-source fully automatic daily feeding system, Zebrafish Automatic Feeder (ZAF). ZAF is reliable, provides a standardized amount of food to every tank, is cost-efficient and easy to build. The advanced version, ZAF+, allows for the precise control of food distribution as a function of fish density per tank, and has a user-friendly interface. Both ZAF and ZAF+ are adaptable to any laboratory environment and facilitate the implementation of aquatic colonies. Here we provide all blueprints and instructions for building the mechanics, electronics, fluidics, as well as to setup the control software and its user-friendly graphical interface. Importantly, the design is modular and can be scaled to meet different user needs. Furthermore, our results show that ZAF and ZAF+ do not adversely affect zebrafish culture, enabling fully automatic feeding for any aquatic facility.

developmental biology↗

bioRxiv2021

The prostate cancer therapy enzalutamide compared with abirateroneacetate/prednisone impacts motivation for exploration, spatial learning andalters dopaminergic transmission in aged castrated mice

Cognitive side effects after cancer treatment, threatening quality of life (QoL) and adherence to treatments, now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next generation therapy (NGT) administered with androgen deprivation therapy to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment have been recently reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ during 5 days per week for six consecutive weeks. After behavioral tests, brain and plasma were collected for immunohistochemical studies. The objective was to elucidate the impact of NGT on spontaneous activity, cognitive functions and emotional reactivity, as well as neurobiological functions. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus, highlighted ENZ-induced dopaminergic regulation whithin the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory or behavioral flexibility performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. These results establish the consequences of the mCRPC treatment ENZ in aged castrated mouse motivation to exploration and cognition, of particular importance for future management of patients elderly postrate cancer patients and their QoL.

animal behavior and cognition↗

bioRxiv2021

Identification of a Nervous System Gene Expression Signature in Colon Cancer Stem Cells Reveals a Role for Neural Crest Regulators EGR2 and SOX2 in Tumorigenesis

Recent data support a hierarchical model of colon cancer driven by a population of cancer stem cells (CSCs). Greater understanding of the mechanisms that regulate CSCs may therefore lead to more effective treatments. Serial limiting dilution xenotransplantation assays of colon cancer patient-derived tumors demonstrated ALDHPositive cells to be enriched for tumorigenic self-renewing CSCs. In order to identify CSC modulators, we performed RNA-sequencing analysis of ALDHPositive CSCs from a panel of colon cancer patient-derived organoids (PDOs) and xenografts (PDXs). These studies demonstrated CSCs to be enriched for embryonic and neural development gene sets. Functional analyses of genes differentially expressed in both ALDHPositive PDO and PDX CSCs demonstrated the neural crest stem cell (NCSC) regulator and wound response gene EGR2 to be required for CSC tumorigenicity and to control expression of homeobox superfamily embryonic master transcriptional regulator HOX genes and the embryonic and neural stem cell regulator SOX2. In addition, we identify EGR2, HOXA2, HOXA4, HOXA5, HOXA7, HOXB2, HOXB3 and the tumor suppressor ATOH1 as new prognostic biomarkers in colorectal cancer.

cell biology↗

bioRxiv2021

RNA-Sequencing of Long-Term Label-Retaining Colon Cancer Stem Cells Identifies Novel Regulators of Quiescence

Recent data suggests that colon tumors contain a subpopulation of therapy resistant quiescent cancer stem cells (qCSCs) that are the source of relapse following treatment. Here, using colon cancer patient-derived organoids (PDOs) and xenograft (PDX) models, we identify a rare population of long-term label-retaining (PKH26Positive) qCSCs that can re-enter the cell cycle to generate new tumors. RNA-sequencing analyses demonstrated that these cells are enriched for stem cell associated gene sets such as Wnt and hedgehog signaling, epithelial-to-mesenchymal transition (EMT), embryonic development, tissue development and p53 pathway but have downregulated expression of genes associated with cell cycle, transcription, biosynthesis and metabolism. Furthermore, qCSCs are enriched for p53 interacting negative regulators of cell cycle, including AKAP12, CD82, CDKN1A, FHL2, GPX3, KIAA0247, LCN2, TFF2, UNC5B and ZMAT3, that we show are indicators of poor prognosis and may be targeted for qCSC abolition. Interestingly, CD82, KIAA0247 and UNC5B proteins localize to the cell surface and may therefore be potential markers for the prospective isolation of qCSCs. These data support the temporal inhibition of p53 signaling for the elimination of qCSCs and prevention of relapse in colorectal cancer.

cell biology↗

bioRxiv2021

AdipoAtlas: A Reference Lipidome for Human White Adipose Tissue

Obesity, characterized by expansion and metabolic dysregulation of white adipose tissue (WAT), has reached pandemic proportions and acts as a primer for a wide range of metabolic disorders. Remodelling of WAT lipidome in obesity and associated comorbidities can explain disease etiology and provide valuable diagnostic and prognostic markers. To support understanding of WAT lipidome remodelling at the molecular level, we performed in-depth lipidomics profiling of human subcutaneous and visceral WAT of lean and obese individuals. Tissue-tailored preanalytical and analytical workflows allowed accurate identification and semi-absolute quantification of 1636 and 737 lipid molecular species, respectively, and summarized here in a form of human WAT reference lipidome. Deep lipidomic profiling allowed to identify main lipid (sub)classes undergoing depot/phenotype specific remodelling. Furthermore, previously unanticipated diversity of WAT ceramides was uncovered. AdipoAtlas reference lipidome will serve as a data-rich resource for the development of WAT-specific high-throughput methods and as a scaffold for systems medicine data integration.

biochemistry↗

bioRxiv2020

CellRank for directed single-cell fate mapping

Computational trajectory inference enables the reconstruction of cell-state dynamics from single-cell RNA sequencing experiments. However, trajectory inference requires that the direction of a biological process is known, largely limiting its application to differentiating systems in normal development. Here, we present CellRank (https://cellrank.org) for mapping the fate of single cells in diverse scenarios, including perturbations such as regeneration or disease, for which direction is unknown. Our approach combines the robustness of trajectory inference with directional information from RNA velocity, derived from ratios of spliced to unspliced reads. CellRank takes into account both the gradual and stochastic nature of cellular fate decisions, as well as uncertainty in RNA velocity vectors. On data from pancreas development, we show that it automatically detects initial, intermediate and terminal populations, predicts fate potentials and visualizes continuous gene expression trends along individual lineages. CellRank also predicts a novel dedifferentiation trajectory during regeneration after lung injury, which we follow up experimentally by confirming the existence of previously unknown intermediate cell states.

bioinformatics↗

bioRxiv2020

High-Resolution, Large Field-of-View, and Multi-View Single Objective Light-Sheet Microscopy

Recent developments in Oblique Plane Microscopy (OPM) have shown that it can achieve high spatio-temporal resolution. Here we describe a single objective light-sheet microscope based on oblique plane illumination that achieves: (i) large field of view and high-resolution imaging via a custom remote focusing objective; (ii) fast volumetric imaging by means of light-sheet stabilised stage scanning - a novel scanning modality that extends the imaging volume without compromising imaging speed nor quality; (iii) multi-view imaging by alternating the orientation of light-sheet illumination and detection to improve the image quality on large samples; (iv) simpler design and ergonomics by remote placement of coverslips to allow inverted imaging, enabling imaging across scales in a high-throughput format. Overall, we achieved a resolution of 450 nm laterally and 2 m axially and a field of view of 3000 m x 800 m x 300 m. We demonstrate the speed, field of view, resolution and versatility of our novel instrument by imaging various systems, including zebrafish whole brain activity, Drosophila egg chamber development, and zebrafish development - up to nine embryos simultaneously.

developmental biology↗

bioRxiv2020

The effect of plant-derived carbon on rhizospheric microbial communities decomposing different litter types and nutrient return

Interactions between plants and microorganisms strongly affect ecosystem functioning as processes of plant productivity, litter decomposition and nutrient cycling are controlled by both organisms. Though two-sided interactions between plants and microorganisms and between microorganisms and litter decomposition are areas of major scientific research, our understanding of the three-sided interactions of plant-derived carbon flow into the soil microbial community and their follow-on effects on ecosystem processes like litter decomposition and plant nutrient uptake remains limited. Therefore, we performed a greenhouse experiment with two plant communities differing in their ability to associate with arbuscular mycorrhizal fungi (AMF). By applying a 13CO2 pulse label to the plant communities and adding various 15N labelled substrate types to ingrowth cores, we simultaneously traced the flow of plant-derived carbon into soil microbial communities and the return of mineralized nitrogen back to the plant communities. We observed that net 13C assimilation by the rhizosphere microbial communities and their community composition not only depended on plant-AMF association but also type of substrate being decomposed. AMF-association resulted in lower net 13C investment into the decomposer community than absence of the association for similar 15N uptake. This effect was driven by a reduced carbon flow to fungal and bacterial saprotrophs and a simultaneous increase of carbon flow to AMF. Additionally, in presence of AMF association CN flux also depended on the type of substrate being decomposed. Lower net 13C assimilation was observed for decomposition of plant-derived and microorganism-derived substrates whereas opposite was true for inorganic nitrogen. Interestingly, the decomposer communities assembled in the rhizosphere were structured by both the plant community and substrate amendments which suggests existence of functional overlap between the two soil contexts. Moreover, we present preliminary evidence that AMF association helps plants access nutrients that are locked in bacterial and plant necromass at a lower carbon cost. Therefore, we conclude that a better understanding of ecosystem processes like decomposition can only be achieved when the whole plant-microorganism-litter context is investigated.

microbiology↗

bioRxiv2020

Optical Aberration Correction via Phase Diversity and Deep Learning

In modern microscopy imaging systems, optical components are carefully designed to obtain diffraction-limited resolution. However, live imaging of large biological samples rarely attains this limit because of sample induced refractive index inhomogeneities that create unknown temporally variant optical aberrations. Importantly, these aberrations are also spatially variant, thus making it challenging to correct over wide fields of view. Here, we present a framework for deep-learning based wide-field optical aberration sensing and correction. Our model consists of two modules which take in a set of three phase-diverse images and (i) estimate the wavefront phase in terms of its constituent Zernike polynomial coefficients and (ii) perform blind-deconvolution to yield an aberration-free image. First, we demonstrate our framework on simulations that incorporate optical aberrations, spatial variance, and realistic modelling of sensor noise. We find that our blind deconvolution achieves a 2-fold improvement in frequency support compared to input images, and our phase-estimation achieves a coefficient of determination (r2) of at least 80% when estimating astigmatism, spherical aberration and coma. Second, we show that our results mostly hold for strongly varying spatially-variant aberrations with a 30% resolution improvement. Third, we demonstrate practical usability for light-sheet microscopy: we show a 46% increase in frequency support even in imaging regions affected by detection and illumination scattering.

developmental biology↗

bioRxiv2020

Distinct Vegfa isoforms control endothelial cell proliferation through PI3 kinase signalling mediated regulation of cdkn1a/p21

The formation of appropriately patterned blood vessel networks requires endothelial cell migration and proliferation. Signaling through the Vascular Endothelial Growth Factor A (VEGFA) pathway is instrumental in coordinating these processes. mRNA splicing generates short (diffusible) and long (extracellular matrix bound) Vegfa isoforms. The differences between these isoforms in controlling cellular functions are not understood. In zebrafish, vegfaa generates short and long isoforms, while vegfab only generates long isoforms. We found that mutations in vegfaa affected endothelial cell migration and proliferation. Surprisingly, mutations in vegfab specifically reduced endothelial cell proliferation. Analysis of downstream signaling revealed no change in MAPK (ERK) activation, while inhibiting PI3 kinase signaling phenocopied vegfab mutants. The cell cycle inhibitor cdkn1a/p21 was upregulated in vegfab deficient embryos. Accordingly, reducing cdkn1a/p21 restored endothelial cell proliferation. Together, these results suggest that extracellular matrix bound Vegfa acts through PI3K signaling to specifically control endothelial cell proliferation during angiogenesis independently of MAPK (ERK) regulation.

developmental biology↗

bioRxiv2019

Generalizing RNA velocity to transient cell states through dynamical modeling

The introduction of RNA velocity in single cells has opened up new ways of studying cellular differentiation. The originally proposed framework obtains velocities as the deviation of the observed ratio of spliced and unspliced mRNA from an inferred steady state. Errors in velocity estimates arise if the central assumptions of a common splicing rate and the observation of the full splicing dynamics with steady-state mRNA levels are violated. With scVelo (https://scvelo.org), we address these restrictions by solving the full transcriptional dynamics of splicing kinetics using a likelihood-based dynamical model. This generalizes RNA velocity to a wide variety of systems comprising transient cell states, which are common in development and in response to perturbations. We infer gene-specific rates of transcription, splicing and degradation, and recover the latent time of the underlying cellular processes. This latent time represents the cells internal clock and is based only on its transcriptional dynamics. Moreover, scVelo allows us to identify regimes of regulatory changes such as stages of cell fate commitment and, therein, systematically detects putative driver genes. We demonstrate that scVelo enables disentangling heterogeneous subpopulation kinetics with unprecedented resolution in hippocampal dentate gyrus neurogenesis and pancreatic endocrinogenesis. We anticipate that scVelo will greatly facilitate the study of lineage decisions, gene regulation, and pathway activity identification.

bioinformatics↗

bioRxiv2019

The results of biodiversity-ecosystem functioning experiments are realistic

A large body of research shows that biodiversity loss can reduce ecosystem functioning, thus providing support for the conservation of biological diversity1-4. Much of the evidence for this relationship is drawn from biodiversity-ecosystem functioning experiments (hereafter: biodiversity experiments), in which biodiversity loss is simulated by randomly assembling communities of varying species diversity, and ecosystem functions are measured5-9. This random assembly has led some ecologists to question the relevance of biodiversity experiments to real-world ecosystems, where community assembly may often be non-random and influenced by external drivers, such as climate or land-use intensification10-18. Despite these repeated criticisms, there has been no comprehensive, quantitative assessment of how experimental and real-world plant communities really differ, and whether these differences invalidate the experimental results. Here, we compare data from two of the largest and longest-running grassland biodiversity experiments globally (Jena Experiment, Germany; BioDIV, USA) to related real-world grassland plant communities in terms of their taxonomic, functional, and phylogenetic diversity and functional-trait composition. We found that plant communities of biodiversity experiments have greater variance in these compositional features than their real-world counterparts, covering almost all of the variation of the real-world communities (82-96%) while also containing community types that are not currently observed in the real world. We then re-analysed a subset of experimental data that included only ecologically-realistic communities, i.e. those comparable to real-world communities. For ten out of twelve biodiversity-ecosystem functioning relationships, biodiversity effects did not differ significantly between the full dataset of biodiversity experiments and the ecologically-realistic subset of experimental communities. This demonstrates that the results of biodiversity experiments are largely insensitive to the inclusion/exclusion of unrealistic communities. By bridging the gap between experimental and real-world studies, these results demonstrate the validity of inferences from biodiversity experiments, a key step in translating their results into specific recommendations for real-world biodiversity management.

ecology↗

bioRxiv2019

Rere-dependent Retinoic Acid signaling controls brain asymmetry and handedness

While the vertebrate brain appears largely bilaterally symmetrical in humans, it presents local morphological Left-Right (LR) asymmetries as, for instance, in the petalia. Moreover, higher functions such as speech or handedness are asymmetrically localized in the cortex. How these brain asymmetries are generated remains unknown. Here, we reveal a striking parallel between the control of bilateral symmetry in the brain and in the precursors of vertebrae called somites, where a \"default\" asymmetry is buffered by Retinoic Acid (RA) signaling. This mechanism is evident in zebrafish and mouse and, when perturbed in both species, it translates in the brain into lateralized alterations of patterning, neuronal differentiation and behavior. We demonstrate that altering levels of the mouse RA coactivator Rere results in subtle cortex asymmetry and profoundly altered handedness, linking patterning and function in the motor cortex. Together our data uncover a novel mechanism that could underlie the establishment of brain asymmetries and handedness in vertebrates.

neuroscience↗

bioRxiv2019

scSLAM-seq reveals core features of transcription dynamics in single cells

Current single-cell RNA sequencing approaches gives a snapshot of a cellular phenotype but convey no information on the temporal dynamics of transcription. Moreover, the stochastic nature of transcription at molecular level is not recovered. Here, we present single-cell SLAM-seq (scSLAM-seq), which integrates metabolic RNA labeling, biochemical nucleoside conversion and single-cell RNA-seq to directly measure total transcript levels and transcriptional activity by differentiating newly synthesized from pre-existing RNA for thousands of genes per single cell. scSLAM-seq recovers the earliest virus-induced changes in cytomegalovirus infection and reveals a so far hidden phase of viral gene expression comprising promiscuous transcription of all kinetic classes. It depicts the stochastic nature of transcription and demonstrates extensive gene-specific differences. These range from stable transcription rates to on-off dynamics which coincide with gene-/promoter-intrinsic features (Tbp-TATA-box interactions and DNA methylation). Gene but not cell-specific features thus explain the heterogeneity in transcriptomes between individual cells and the transcriptional response to perturbations.

genomics↗

bioRxiv2018

Phytoplankton thermal responses adapt in the absence of hard thermodynamic constraints

To better predict how populations and communities respond to climatic temperature variation, it is necessary to understand how the shape of the response of fitness-related traits to temperature evolves (the thermal performance curve). Currently, there is disagreement about the extent to which the evolution of thermal performance curves is constrained. One school of thought has argued for the prevalence of thermodynamic constraints through enzyme kinetics, whereas another argues that adaptation can--at least partly--overcome such constraints. To shed further light on this debate, we perform a phylogenetic meta-analysis of the thermal performance curves of growth rate of phytoplankton--a globally important functional group--, controlling for environmental effects (habitat type and thermal regime). We find that thermodynamic constraints have a minor influence on the shape of the curve. In particular, we detect a very weak increase of maximum performance with the temperature at which the curve peaks, suggesting a weak "hotter-is-better" constraint. Also, instead of a constant thermal sensitivity of growth across species, as might be expected from strong constraints, we find that all aspects of the thermal performance curve evolve along the phylogeny. Our results suggest that phytoplankton thermal performance curves adapt to thermal environments largely in the absence of hard thermodynamic constraints.

evolutionary biology↗

bioRxiv2018

Functional composition rather than species richness drive carbon gain and allocation in experimental grasslands

Numerous experiments have shown positive diversity effects on plant productivity, but little is known about related processes of carbon gain and allocation. We investigated these processes in a controlled environment (Montpellier European Ecotron) applying a continuous 13CO2 label for three weeks to 12 soil-vegetation monoliths originating from a grassland biodiversity experiment (Jena Experiment) and representing two diversity levels (4 and 16 sown species). Plant species richness did not affect community- and species-level 13C abundances neither in total biomass nor in non-structural carbohydrates (NSC). Community-level 13C excess tended to be higher in the 16-species than in the 4-species mixtures. Community-level 13C excess was positively related to canopy leaf nitrogen (N), i.e. leaf N per unit soil surface. At the species level shoot 13C abundances varied among plant functional groups and were larger in legumes and tall herbs than in grasses and small herbs and correlated positively with traits as leaf N concentrations, stomatal conductance and shoot height. The 13C abundances in NSC were larger in transport sugars (sucrose, raffinose-family oligosaccharides) than in free glucose, fructose and compounds of the storage pool (starch) suggesting that newly assimilated carbon is to a small portion allocated to storage. Our results emphasize that the functional composition of communities is key in explaining carbon assimilation in grasslands.

ecology↗

bioRxiv2018

Asymmetric adaptation reveals functional lateralization for graded versus discrete stimuli

Abstract 150 wordsAnimal navigation strategies depend on the nature of the environmental cues used. In the nematode Caenorhabditis elegans, navigation has been studied in the context of gradients of attractive or repellent stimuli as well is in response to acute aversive stimuli. We wanted to better understand how sensory responses to the same stimulus vary between graded and acute stimuli, and how this variation relates to behavioral responses. C. elegans has two salt-sensing neurons, ASEL and ASER, that show opposite responses to stepped changes in stimulus levels, however only ASER has been shown to play a prominent role in salt chemotaxis. We used pre-exposure to natural stimuli to manipulate the responsiveness of these neurons and tested their separate contributions to behavior. Our results suggest ASEL is specialized for responses to acute stimulus changes. We also found that ASER remains responsive to graded stimuli under conditions where it is unresponsive to large steps.

neuroscience↗