Biology subjects

Whitley, O.

Publications and source records attributed to Whitley, O..

4 recordsLinked to original sources

bioRxiv2024

Glioblastoma stem cells show transcriptionally correlated spatial organization

Glioblastoma (GBM) is an aggressive brain cancer with a poor survival rate. Despite hundreds of clinical trials, there is no effective targeted therapy. Glioblastoma stem cells (GSCs) are an important GBM model system. In culture, these cells form spatial structures that share morphological aspects with their source tumors. We collected 17,000 phase contrast images of 15 patient-derived GSC lines growing to confluence. We find that GSCs grow in characteristic multicellular patterns depending on their transcriptional state. Interpretable computer vision algorithms identified specific image features that predict transcriptional state across multiple cell confluency levels. This relationship will be useful in developing GSC screens where image features can be used to identify how GSC biology changes in response to perturbations simply by imaging cultured cells on plates.

cancer biology↗

bioRxiv2023

Diagnostic Potential of Shallow Depth Gut Metagenomics Sequencing for Atherosclerotic Cardiovascular Disease Risk Stratification

BackgroundCardiovascular disease, specifically atherosclerotic cardiovascular disease (ACVD), presents a burden on society in terms of financial resources and quality of life that is only expected to grow in the coming years. Current diagnostic methods lack the sensitivity or specificity to confidently screen for atherosclerotic cardiovascular disease and are either costly, invasive, or both. Building on previous research linking ACVD to changes in the microbiome, we hypothesized that one could build a machine learning classifier for ACVD that makes use of shallow depth microbiome data. Methods and FindingsRaw metagenomics Illumina paired end sequencing data was downloaded from the European Bioinformatics Institute (EBI) public database under accession ERP023788. The dataset includes 383 Han Chinese subjects of which 170 are control subjects and 214 are ACVD subjects. The raw sequencing data was subsampled using seqtk to generate in silico shallow depth datasets at various depths. Each subsampled experiment was processed through KneadData for quality control, and finally relative abundances were acquired through Kraken2. Based on in-silico down sampling experiments, we demonstrate that species level information is still captured at read depths as low as 50K reads per sample, consistent with current literature. In addition, the shallow depth data (50K) contains relevant taxa information for stratification of ACVD patients. Differential expression analysis identified a variety of Streptococcus species and Escherichia coli enriched in ACVD patients and a few low abundance Bacteroides species in ACVD patients, which have been previously reported. ConclusionHere, using publicly available data, we show with in silico experiments that species-level microbiome information is preserved at low sequencing depths that would allow a screening or diagnostic tool to be cost-competitive with currently used methods such as stress ECGs and stress ECHO tests. Additionally, we show that we can indeed make a microbiome-based model with performance metrics comparable to or better than front-line or mid-tier tests.

bioinformatics↗

bioRxiv2019

Genetics and Pathway Analysis of Normative Cognitive Variation in the Philadelphia Neurodevelopmental Cohort

An open challenge in human genetics is to better understand the link between genotype variation and the various molecular, cellular, anatomical and physiological systems that it can affect. To address this challenge, we performed genotype-phenotype-systems analysis for accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (3,319 individuals aged 8-21 years). We report a region of genome-wide significance within the 3 end of the FBLN1 gene (p=4.6x10-8), associated with nonverbal reasoning, a heritable form of complex reasoning ability. Integration of published brain-specific omic maps reveals that FBLN1 shows greatest expression in the fetal brain, is a marker of neural progenitor cells, is differentially expressed in schizophrenia and increases genetic risk for bipolar disorder. These findings suggest that nonverbal reasoning and FBLN1 variation warrant further investigation in studies of neurodevelopmental disorders and psychosis. Using genotype-pathway analysis, we identify pathways related to development and to autonomic nervous system dysfunction associated with working memory accuracy. Top-ranking pathway genes include those genetically associated with multiple diseases with working memory deficits, such as schizophrenia and Parkinsons disease, and that are also markers for specific brain cell types. Our findings identify novel molecular players involved in specific cognitive tasks and link variants to genes, pathways, cell types, diseases and drugs. This work advances the "molecules-to-behaviour" view of cognition, and provides a framework for using systems-level organization of data for other biomedical domains.

genomics↗

bioRxiv2018

Oscillatory cortical forces promote three dimensional cell intercalations that shape the mandibular arch

Multiple vertebrate embryonic structures such as organ primordia are composed of a volume of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show 3D mesenchymal cell intercalations, rather than cell divisions and biophysical tissue properties, are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor, we show that cortical force oscillations promote these intercalations. Genetic loss and gain of function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity with cytoskeletal oscillation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin bias and cytosolic calcium transients, respectively, to ensure appropriate tissue form during growth. Our data support oriented 3D cell neighbour exchange as a conserved mechanism driving volumetric morphogenesis.

developmental biology↗