Biology subjects

Grimes, H. L.

Publications and source records attributed to Grimes, H. L..

7 recordsLinked to original sources

bioRxiv2024

Variations in human trigeminal and facial nerve branches and foramina identified by dissection and microcomputed tomography

The aim of this study was to identify branches of the trigeminal and facial nerves relevant to surgical incisions and injections and the scalp block techniques in the frontotemporal region, and to determine their relationships with superficial vascular structures and bony landmarks. Half-heads from consenting embalmed donors (6 male, 2 female, mean age at death 78.4 years) were used in this study. Detailed dissection was carried out to identify the position of the auriculotemporal nerve (ATN) relative to the superior temporal artery (STA) and the facial nerve (FN) in six subjects (5 male, 1 female). The results provide a minimum safe distance of 5 mm between the STA and the frontotemporal branches of the FN at the level of the low edge of zygoma and 8mm between the low edge of zygoma and the FN trunk, providing a pre-auricular triangle of safety for incisions and injections. Variability between subjects was up to 60%. Microcomputed tomography (microCT) scans were taken from all eight subjects and the three-dimensional reconstructions were used to identify the supraorbital notch (SON), the zygomaticotemporal foramen (ZTF) and the zygomaticofacial foramen (ZFF). The volume and relative locations of these foramina were calculated for 5-8 subjects. The closest distance between ZTF and the FZS ranged from 9 to 21mm (26% variation); 3 subjects had a single ZTF while 5 subjects had two ZTF. The angle at the centre of the orbit between ZFF and the FZS ranged from 156 to 166 degrees (2.5% variation). These findings demonstrate that both traditional cadaveric dissection methods as well as contemporary microCT methods can be used to investigate the relative locations of nerves or their foramina in the human head. The findings provide anatomical considerations for fronto-temporal incisions and local anaesthesia.

neuroscience↗

bioRxiv2024

Broad de-regulated U2AF1 splicing is prognostic and augments leukemic transformation via protein arginine methyltransferase activation

The role of splicing dysregulation in cancer is underscored by splicing factor mutations; however, its impact in the absence of such rare mutations is poorly understood. To reveal complex patient subtypes and putative regulators of pathogenic splicing in Acute Myeloid Leukemia (AML), we developed a new approach called OncoSplice. Among diverse new subtypes, OncoSplice identified a biphasic poor prognosis signature that partially phenocopies U2AF1-mutant splicing, impacting thousands of genes in over 40% of adult and pediatric AML cases. U2AF1-like splicing co-opted a healthy circadian splicing program, was stable over time and induced a leukemia stem cell (LSC) program. Pharmacological inhibition of the implicated U2AF1-like splicing regulator, PRMT5, rescued leukemia mis-splicing and inhibited leukemic cell growth. Genetic deletion of IRAK4, a common target of U2AF1-like and PRMT5 treated cells, blocked leukemia development in xenograft models and induced differentiation. These analyses reveal a new prognostic alternative-splicing mechanism in malignancy, independent of splicing-factor mutations. Statement of significanceUsing a new in silico strategy we reveal counteracting determinants of patient survival in Acute Myeloid Leukemia that co-opt well-defined mutation-dependent splicing programs. Broad poor-prognosis splicing and leukemia stem cell survival could be rescued through pharmacological inhibition (PRMT5) or target deletion (IRAK4), opening the door for new precision therapies. Competing InterestsConflict-of-interest disclosure: DTS. serves on the scientific advisory board at Kurome Therapeutics; is a consultant for and/or received funding from Kurome Therapeutics, Captor Therapeutics, Treeline Biosciences, and Tolero Therapeutics; and has equity in Kurome Therapeutics. AV has received research funding from GlaxoSmithKline, BMS, Jannsen, Incyte, MedPacto, Celgene, Novartis, Curis, Prelude and Eli Lilly and Company, has received compensation as a scientific advisor to Novartis, Stelexis Therapeutics, Acceleron Pharma, and Celgene, and has equity ownership in Throws Exception and Stelexis Therapeutics.

cancer biology↗

bioRxiv2022

Resilient anatomy and local microplasticity of na&iumlve and stress hematopoiesis

The bone marrow has an extraordinary capacity to adjust blood cell production to meet physiological demands in response to insults. The spatial organization of normal and stress responses is largely unknown due to the lack of methods to visualize most steps of blood production. Here we develop strategies to image multipotent hematopoiesis, megakaryopoiesis, erythropoiesis, and lymphopoiesis in mice. We combine these with imaging of myelopoiesis1 to define the anatomy of hematopoiesis in homeostasis, after acute insults, and during geriatric age. Blood production takes place via long-range migration of multipotent progenitors away from stem cells. Lineage-committed progenitors are then serially recruited to blood vessels where they contribute to lineage-specific microanatomical structures, composed of progenitors and immature cells, which function as production lines for mature blood cells. This anatomy is durable and resilient to insults as it was maintained after hemorrhage, acute bacterial infection, and with aging. Production lines enable hematopoietic plasticity as they differentially -and selectively-modulate their numbers and output in response to acute insults and then return to homeostasis. In geriatric mice the number of production lines is maintained, but their microanatomy becomes permanently remodeled in a cell- and lineage-specific manner indicating chronic anatomical adaptations to hematopoietic aging. Our studies uncover the sophisticated and durable anatomy of blood production -defined by distinct migratory behaviors depending on the maturation stage- and identify discrete microanatomical production lines that confer plasticity to hematopoiesis.

physiology↗

bioRxiv2021

scTriangulate: Decision-level integration of multimodal single-cell data

Decisively delineating cell identities from uni- and multimodal single-cell datasets is complicated by diverse modalities, clustering methods, and reference atlases. We describe scTriangulate, a cooperative game-theory framework that mixes-and-matches multiple clustering results, modalities, associated algorithms, and resolutions to achieve an optimal solution. Rather than ensemble approaches which select the "consensus", scTriangulate picks the most stable solution. When evaluated on diverse multimodal technologies, scTriangulate outperforms alternative approaches to identify consistent high-confidence novel cell populations and modality-specific subtypes. Unlike existing integration strategies that rely on modality-specific joint embedding or geometric graphs, scTriangulate makes no assumption about the distributions of raw underlying values. As a result, this approach can solve unprecedented integration challenges, including the ability to automate reference cell-atlas construction, resolve clonal architecture within molecularly defined cell-populations and subdivide clusters to discover novel splicing-defined disease subtypes. scTriangulate is a flexible strategy for unified integration of single-cell or multimodal clustering solutions, from nearly unlimited sources.

bioinformatics↗

bioRxiv2020

Three-dimensional mapping identifies distinct vascular niches for myelopoiesis

In contrast to virtually all other tissues in the body the anatomy of differentiation in the bone marrow remains unknown. This is due to the lack of strategies to examine blood cell production in situ, which are required to better understand differentiation, lineage commitment decisions, and to define how spatial organizing cues inform tissue function. Here we developed imaging approaches to map all myeloid cells in whole bones and generated 3D atlases of granulocyte and monocyte/dendritic cell differentiation during homeostasis. We found that myeloid progenitors leave the hematopoietic stem cell niche during differentiation. Granulocyte and monocyte dendritic cell progenitors (MDP) do not interact, instead they localize to different sinusoids where they give rise to clusters of immature cells. MDP cluster with Ly6Clo monocytes and conventional dendritic cells; these localize to a unique subset of colony stimulating factor 1 (CSF1, the major regulator of monopoiesis1) -expressing sinusoids. Csf1 deletion in the vasculature disrupted the MDP clusters and their interaction with sinusoids, leading to reduced MDP numbers and differentiation ability, with subsequent loss of peripheral Ly6Clo monocytes and dendritic cells. These data indicate that there is a specific spatial organization of definitive hematopoiesis and that local cues produced by distinct blood vessels are responsible for this organization. These maps provide a blueprint for in situ analyses of hematopoiesis in blood disorders.

immunology↗

bioRxiv2018

CellHarmony: Cell-level matching and comparison of single-cell transcriptomes

To understand the molecular pathogenesis of human disease, precision analyses to define molecular alterations within (and between) disease-associated cell populations are desperately needed. Single-cell genomics represents an ideal platform to enable the identification and comparison of normal and diseased transcriptional cell states. We note that disease-associated perturbations usually retain cellular-identity programs (core genes), providing an appropriate reference for secondary comparison analyses. Thus, we created cellHarmony, an integrated solution for the unsupervised analysis and classification of cell types from diverse scRNA-Seq datasets. cellHarmony is an automated and easy-to-use tool that efficiently matches single-cell transcriptomes using a community clustering and alignment strategy. Utilizing core genes and community clustering to reveal disease and cell-state systems-level insights overcomes bias toward donor and disease effects that can be imposed by joint-alignment approaches. Moreover, cellHarmony directly compares cell frequencies and gene expression in a cell-type-specific manner, then produces a holistic representation of these differences across potentially dozens of cell populations and impacted regulatory networks. Using this approach, we identify gene regulatory programs that are selectively impacted in distinct hematopoietic and heart cell populations that suggest novel disease mechanisms and drug targets. Thus, this approach holds tremendous promise in revealing the molecular and cellular origins of complex diseases.

bioinformatics↗

bioRxiv2018

DoubletDecon: Cell-State Aware Removal of Single-Cell RNA-Seq Doublets

Methods for single-cell RNA sequencing (scRNA-Seq) have greatly advanced in recent years. While droplet- and well-based methods have increased the capture frequency of cells for scRNA-Seq, these technologies readily produce technical artifacts, such as doublet-cell and multiplet-cell captures. Doublets occurring between distinct cell-types can appear as hybrid scRNA-Seq profiles, but do not have distinct transcriptomes from individual cell states. We introduce DoubletDecon, an approach that detects doublets with a combination of deconvolution analyses and the identification of unique cell-state gene expression. We demonstrate the ability of DoubletDecon to identify synthetic and cell-hashing cell singlets and doublets from scRNA-Seq datasets of varying cellular complexity. DoubletDecon is able to account for cell-cycle effects and is compatible with diverse species and unsupervised population detection algorithms (e.g., ICGS, Seurat). We believe this approach has the potential to become a standard quality control step for the accurate delineation of cell states.

bioinformatics↗