Biology subjects

Busch, K.

Publications and source records attributed to Busch, K..

5 recordsLinked to original sources

bioRxiv2020

Hematopoietic stem cells self-renew symmetrically or gradually proceed to differentiation

It is not known whether hematopoietic stem cells (HSCs) undergo symmetric or asymmetric cell divisions in the unperturbed bone marrow. Here, we integrate data from HSC fate mapping and cell-cycle-dependent labeling through mathematical inference and thus gain insight into how HSCs coordinate self-renewal with differentiation. We find that most HSC divisions in adult mice are symmetric self-renewing, replacing HSCs lost by direct differentiation and death, and slowly expanding the HSC population. This expansion maintains constant HSC output to multipotent progenitors (MPPs), despite declining HSC differentiation rate with age. We identify a linear hierarchy of differentiation states between tip HSCs and MPPs, where Tie2-driven HSC fate mapping fully covers the progression of the differentiating cells. A turning point from self-renewal to accelerated cell differentiation occurs between early-stage and late-stage MPPs, just before lineage differentiation becomes manifest in single-cell transcriptomes. This stem cell hierarchy precedes lineage differentiation and may limit mutation accumulation in the hematopoietic system.

systems biology↗

bioRxiv2020

Microbial strategies for survival in the glass sponge Vazella pourtalesii

Few studies have thus far explored the microbiomes of glass sponges (Hexactinellida). The present study seeks to elucidate the composition of the microbiota associated with the glass sponge Vazella pourtalesii and the functional strategies of the main symbionts. We combined microscopic approaches with metagenome-guided microbial genome reconstruction and amplicon community profiling towards this goal. Microscopic imaging revealed that the host and microbial cells appeared within dense biomass patches that are presumably syncytial tissue aggregates. Based on abundances in amplicon libraries and metagenomic data, SAR324 bacteria, Crenarchaeota, Patescibacteria and Nanoarchaeota were identified as abundant members of the V. pourtalesii microbiome and their genomic potentials were thus analyzed in detail. A general pattern emerged in that the V. pourtalesii symbionts had very small genome sizes in the range of 0.5-2.2 Mb and low GC contents, even below those of seawater relatives. Based on functional analyses of metagenome-assembled genomes (MAGs), we propose two major microbial strategies: the "givers", namely Crenarchaeota and SAR324, heterotrophs and facultative anaerobes, produce and partly secrete all required amino acids and vitamins. The "takers", Nanoarchaeota and Patescibacteria, are anaerobes with reduced genomes that tap into the microbial community for resources, e.g., lipids and DNA, likely using pili-like structures. We posit that the existence of microbial cells in sponge syncytia together with the low-oxygen conditions in the seawater environment are factors that shape the unique compositional and functional properties of the microbial community associated with V. pourtalesii. ImportanceWe investigated the microbial community of V. pourtalesii that forms globally unique, monospecific sponge grounds under low-oxygen conditions on the Scotian Shelf, where it plays a key role for its vulnerable ecosystem. The microbial community was found to be concentrated within biomass patches and is dominated by small cells (<1 m). MAG analyses showed consistently small genome sizes and low GC contents, which is unusual in comparison to known sponge symbionts. These properties as well as the (facultatively) anaerobic metabolism and a high degree of interdependence between the dominant symbionts regarding amino acid and vitamin synthesis are likely adaptations to the unique conditions within the syncytial tissue of their hexactinellid host and the low-oxygen environment.

microbiology↗

bioRxiv2020

GraphGR: A graph neural network to predict the effect of pharmacotherapy on the cancer cell growth

Genomic profiles of cancer cells provide valuable information on genetic alterations in cancer. Several recent studies employed these data to predict the response of cancer cell lines to treatment with drugs. Nonetheless, due to the multifactorial phenotypes and intricate mechanisms of cancer, the accurate prediction of the effect of pharmacotherapy on a specific cell line based on the genetic information alone is problematic. High prediction accuracies reported in the literature likely result from significant overlaps among training, validation, and testing sets, making many predictors inapplicable to new data. To address these issues, we developed GraphGR, a graph neural network with sophisticated attention propagation mechanisms to predict the therapeutic effects of kinase inhibitors across various tumors. Emphasizing on the system-level complexity of cancer, GraphGR integrates multiple heterogeneous data, such as biological networks, genomics, inhibitor profiling, and genedisease associations, into a unified graph structure. In order to construct diverse and information-rich cancer-specific networks, we devised a novel graph reduction protocol based on not only the topological information, but also the biological knowledge. The performance of GraphGR, properly cross-validated at the tissue level, is 0.83 in terms of the area under the receiver operating characteristics, which is notably higher than those measured for other approaches on the same data. Finally, several new predictions are validated against the biomedical literature demonstrating that GraphGR generalizes well to unseen data, i.e. it can predict therapeutic effects across a variety of cancer cell lines and inhibitors. GraphGR is freely available to the academic community at https://github.com/pulimeng/GraphGR.

bioinformatics↗

bioRxiv2020

Microbial diversity of the glass sponge Vazella pourtalesii in response to anthropogenic activities

Establishment of adequate conservation areas represents a challenging but crucial task in the conservation of genetic diversity and biological variability. Anthropogenic pressures on marine ecosystems and organisms are steadily increasing. Whether and to what extent these pressures influence marine genetic biodiversity is only starting to be revealed. Using 16S rRNA gene amplicon sequencing, we analysed the microbial community structure of 33 individuals of the habitat-forming glass sponge Vazella pourtalesii, as well as reference seawater, sediment, and biofilm samples. We assessed how two anthropogenic impacts, i.e. habitat destruction by trawling and artificial substrate provision (moorings made of composite plastic), correspond with in situ V. pourtalesii microbiome variability. In addition, we evaluated the role of two bottom fishery closures in preserving sponge-associated microbial diversity on the Scotian Shelf, Canada. Our results illustrate that V. pourtalesii sponges collected from pristine sites within fishery closures contained distinct and taxonomically largely novel microbial communities. At the trawled site we recorded significant quantitative differences in distinct microbial phyla, such as a reduction in Nitrospinae in sponges and environmental references. Individuals of V. pourtalesii growing on the mooring were significantly enriched in Bacteroidetes, Verrucomicrobia and Cyanobacteria in comparison to sponge individuals growing on the natural seabed. Due to a concomitant enrichment of these taxa in the mooring biofilm, we propose that biofilms on artificial substrates may prime sponge-associated microbial communities when small sponges settle on such substrates. These observations likely have relevant management implications when considering the increase of artificial substrates in the marine environment, e.g., marine litter, off-shore wind parks, and petroleum platforms.

ecology↗

bioRxiv2020

Resolving fate and transcriptome of hematopoietic stem cell clones

Adult bone marrow harbors a mosaic of hematopoietic stem cell (HSC) clones of embryonic origin, and recent work suggests that such clones may have coherent lineage fates. To probe under physiological conditions whether HSC clones with different fates are transcriptionally distinct, we developed PolyloxExpress - a Cre recombinase-dependent DNA substrate for in situ barcoding that allows parallel readout of barcodes and transcriptomes in single cells. We describe differentiation-inactive, multilineage and lineage-restricted HSC clones, find that they reside in distinct regions of the transcriptional landscape of hematopoiesis, and identify corresponding gene signatures. All clone types contain proliferating HSCs, indicating that differentiation-inactive HSCs can undergo symmetric self-renewal. Our work establishes an approach for studying determinants of stem cell fate in vivo and provides molecular evidence for fate coherence of HSC clones.

immunology↗