Eulerian simulation of complex suspensions and biolocomotion in three dimensions

We present a numerical method specifically designed for simulating three-dimensional fluid–structure interaction (FSI) problems based on the reference map technique (RMT). The RMT is a fully Eulerian FSI numerical method that allows fluids and large-deformation elastic solids to be represented on a single fixed computational grid. This eliminates the need for meshing complex geometries typical in other FSI approaches and greatly simplifies the coupling between fluid and solids. We develop a three-dimensional implementation of the RMT, parallelized using the distributed memory paradigm, to simulate incompressible FSI with neo-Hookean solids. As part of our method, we develop a field extrapolation scheme that works efficiently in parallel. Through representative examples, we demonstrate the method’s suitability in investigating many-body and active systems, as well as its accuracy and convergence. The examples include settling of a mixture of heavy and buoyant soft ellipsoids, lid-driven cavity flow containing a soft sphere, and swimmers actuated via active stress.

High Resolution Single Cell Maps Reveals Distinct Cell Organization and Function Across Different Regions of the Human Intestine

The colon is a complex organ that promotes digestion, extracts nutrients, participates in immune surveillance, maintains critical symbiotic relationships with microbiota, and affects overall health. To better understand its organization, functions, and its regulation at a single cell level, we performed CODEX multiplexed imaging, as well as single nuclear RNA and open chromatin assays across eight different intestinal sites of four donors. Through systematic analyses we find cell compositions differ dramatically across regions of the intestine, demonstrate the complexity of epithelial subtypes, and find that the same cell types are organized into distinct neighborhoods and communities highlighting distinct immunological niches present in the intestine. We also map gene regulatory differences in these cells suggestive of a regulatory differentiation cascade, and associate intestinal disease heritability with specific cell types. These results describe the complexity of the cell composition, regulation, and organization for this organ, and serve as an important reference map for understanding human biology and disease.

A Reference Map of Microbiome Composition in Crop Production Across 8 Chinese Provinces

Background: Although microbiome profiling of crop leaves is a relatively new research area, we know that leaf microorganism communities affect the leaf chemical composition, promote growth, and confer protection against deleterious microbes.Results: Here, we used 16S rDNA sequencing to profile the microbiomes of 78 primary dried tobacco leaf samples from plants grown at 26 locations in 8 Chinese provinces. After analyzing leaf microbial communities and identifying 4,473 operational taxonomic units (OTU) representing 1,234 species, we obtained a national core microbiome with 14 OTU representing 9 species, with functions for processes including nitrogen fixation, detoxification of diverse pollutants, and heavy-metal reduction. Although there are no obvious impacts from single environmental factors (e.g., temperature, precipitation), there are significant differences in microbial community structures among provinces and clear clustering by region. Finally, LEfSe analysis screened the significantly different species between different sampling locations.Conclusions: Our study demonstrates that both climactic and industrial factors drive microbial diversity on crop plant leaves, and many potentially useful functional bacterial resources present on tobacco leaves are still waiting for harnessing for a variety of bioprocess, agricultural, and environmental detoxification applications.

The landscape of metabolic brain alterations in Alzheimer's disease

We present a comprehensive reference map of metabolic brain changes in Alzheimer's disease (AD). In a multi-center study within the Accelerating Medicines Partnership in AD, we metabolically profiled 500 samples from the dorsolateral prefrontal cortex (DLPFC) and 83 samples from the temporal cortex (TCX). In the DLPFC, 298 metabolites were correlated with AD-related traits, including late-life cognitive performance and neuropathological β-amyloid and tau tangle burden. Out of these 298 metabolites, 35 replicated in TCX and a previous study. A conditional analysis suggests that metabolic associations with tangle burden were largely independent of β-amyloid load in the brain. Our results provide evidence of brain alterations in bioenergetic pathways, cholesterol metabolism, neuroinflammation, osmoregulation, and other pathways. In a detailed investigation of the glutamate/GABA neurotransmitter pathway, we demonstrate how integration of complementary omics data can provide a comprehensive view of dysregulated biochemical processes. All associations are available as an interactive network at https://omicscience.org/apps/brainmwas/.

Reference Mapping Pediatric Leukemia Using Single Cell Multiomic Atlas of Pediatric Hematopoiesis

Acute lymphoblastic leukemia is the most common pediatric cancer and leading cause of cancer related mortality in pediatric populations. A key challenge to bridge better therapies to patients that fail conventional therapy are to understand their tumor landscape and aberrations in cell signaling, particularly in relation to normal hematopoietic development. To address this gap, we produced a unified reference map of pediatric T, B, and myeloid cell development from the HSPC using single cell RNA-seq and single-cell ATAC-seq on healthy pediatric bone marrow and thymus. We employed 6 different FACS sorting strategies in order to capture rare, but informative, progenitor cell states, including those of the CCR9+ CD34+ CD1A- CD4- CD8- early-T-cell precursor, CD34+ CD1A- CD4- CD8- pro-T cell, and CD34+ CD1A+ CD4- CD8- pre-T cell and Lin-CD34+CD38- multipotent, lymphoid, and myeloid progenitors from the bone marrow. We mapped leukemic cells from patients from 4 different subtypes of pediatric leukemia (T-ALL, ETP-ALL, MPAL, AML) to our healthy reference and found that our reference map can distinguish between subtle differences in transcriptome and epigenome that were undetectable using surface marker or canonical gene expression. Notably, using trajectories inferred from our healthy reference map, we discovered a large amount of inter-tumoral and intra-tumoral heterogeneity, with leukemic blasts from different patients and different populations within any one patient projecting to different cell states along normal development. Finally, we mapped engrafted leukemic cells from patient derived xenografts (PDX) back to our healthy reference. While we observed patient-specific transcriptomic shifts in engrafted versus primary leukemic blasts, we found that the overall transcriptomic hierarchy is maintained in the most PDX, with engrafted cells projecting to near-identical stages of arrest along our healthy hematopoietic trajectory. Interestingly, for PDX that projected to different areas in development compared to primary sample, we discovered alterations in expression of key transcription factors that regulate hematopoietic development. Our single cell multi-omic reference map of pediatric hematopoiesis serves as a valuable reference for mapping RNA-seq and ATAC-seq data back to nearest healthy precursors in normal hematopoietic development. On-going analysis is utilizing single cell transcriptomic, chromatin accessibility data from additional leukemic patients, including patients with B-ALL, to determined key genes and regulators that are altered in comparison to nearest healthy cell-types. In addition, population level signatures learned from healthy reference are being tested in bulk-transcriptomic ALL datasets. We are eager to present the results of these analyses at ASH. *CC and JX, as well as, DTT and KT contributed equally to this work Figure 1 Figure 1. Disclosures Teachey: Janssen: Consultancy; NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding.

Electronic Mapping of a Bacterial Genome with Dual Solid-State Nanopores and Active Single-Molecule Control

We present the first electronic mapping of a bacterial genome using solid-state nanopore technology. A dual-nanopore architecture and active control logic are used to produce single-molecule data that enables estimation of distances between physical tags installed at sequence motifs within double-stranded DNA (dsDNA). Previously developed dual-pore "DNA flossing" control generates multiple scans of tagged regions of each captured DNA. The control logic was extended here in two ways: first, to automate "zooming out" on each molecule to progressively increase the number of tags scanned during DNA flossing; and second, to automate recapture of a molecule that exited flossing to enable interrogation of the same and/or different regions of the molecule. New analysis methods were developed to produce consensus alignments from each multi-scan event. The combined multi-scanning and multi-capture method was applied to the challenge of mapping from a heterogeneous mixture of single-molecule fragments that make up the Escherichia coli (E. coli) chromosome. Coverage of 3.1X across 2,355 resolvable sites (68% of reference sites) of the E. coli genome was achieved after 5.6 hours of recording time. The recapture method showed a 38% increase in the merged-event alignment length compared to single-scan alignments. The observed inter-tag resolution was 150 bp in engineered DNA molecules and 166 bp natively within fragments of E. coli DNA, with detection of 133 inter-site intervals shorter than 200 bp in the E. coli reference map. Proof of concept results on estimating distances in repetitive regions of the E. coli genome are also provided. With an appropriately designed array and future refinements to the control logic, higher throughput implementations can enable human-sized genome and epigenome mapping applications.