Biology subjects

Craig, S.

Publications and source records attributed to Craig, S..

9 recordsLinked to original sources

bioRxiv2025

macpie: scalable workflow for high-throughput transcriptomic profiling

High-throughput transcriptomic profiling (HTTr) enables scalable characterisation of transcriptional responses to chemical and genetic perturbations. While plate-based technologies such as MAC-Seq, TempO-seq and PLATE-seq have made HTTr more accessible, they pose unique computational challenges in modelling data and integration across modalities. We present macpie, an R package designed to streamline the analysis of HTTr data from plate-based screens. Built on the tidySeurat framework, macpie streamlines the entire analytical pipeline from preprocessing and quality control to pathway enrichment, chemical feature extraction, and multimodal data integration. The package incorporates multiple statistical frameworks and leverages parallelisation for scalability. By leveraging Docker and Nextflow, macpie ensures reproducibility and ease of use for transcriptome-wide screening. AvailabilityThe R package macpie is freely available at https://github.com/PMCC-BioinformaticsCore/macpie, with images of the working environment hosted at Docker Hub: xliu81/macpie. A companion Nextflow pipeline for preprocessing from FASTQ files is available at https://github.com/PMCC-BioinformaticsCore/dinoflow. Contactnenad.bartonicek@petermac.org Supplementary informationPackage vignettes with the full analytical workflow available at https://pmcc-bioinformaticscore.github.io/macpie/articles/macpie.html

bioinformatics↗

bioRxiv2024

Rapid parallel adaptation in distinct invasions of Ambrosia artemisiifolia is driven by large-effect structural variants

When introduced to multiple distinct ranges, invasive species provide a compelling natural experiment for understanding the repeatability of adaptation. Ambrosia artemisiifolia is an invasive, noxious weed and chief cause of hay fever. Leveraging over 400 whole-genome sequences spanning the native range in North America and two invasions in Europe and Australia, we inferred demographically distinct invasion histories on each continent. Despite substantial differences in genetic source and effective population size changes during introduction, scans of both local climate adaptation and divergence from the native range revealed genomic signatures of parallel adaptation between invasions. Disproportionately represented among these parallel signatures are 37 large haploblocks - indicators of structural variation - that cover almost 20% of the genome and exist as standing genetic variation in the native range. Many of these haploblocks are associated with traits important for adaptation to local climate, like size and the timing of flowering, and have rapidly reformed native range clines in invasive ranges. Others show extreme frequency divergence between ranges, consistent with a response to divergent selection on different continents. Our results demonstrate the key role of large-effect standing variants in rapid adaptation during range expansion, a pattern that is robust to diverse invasion histories.

genomics↗

bioRxiv2022

A Clinically Useful and Biologically Informative Genomic Classifier for Papillary Thyroid Cancer

Clinical management of papillary thyroid cancer depends on estimations of prognosis. Standard care, which relies on prognostication based on clinicopathologic features, is inaccurate. We applied a machine learning algorithm (HighLifeR) to 502 cases annotated by The Cancer Genome Atlas Project to derive an accurate molecular prognostic classifier. Unsupervised analysis of the 82 genes that were most closely associated with recurrence after surgery enabled identification of three unique molecular subtypes. One subtype had a high recurrence rate, an immunosuppressed microenvironment, and enrichment of the EZH2-HOTAIR pathway. Two other unique molecular subtypes with a lower rate of recurrence were identified, including one subtype with a paucity of BRAFV600E mutations and a high rate of RAS mutations. The genomic risk classifier, in addition to tumor size and lymph node status, enabled effective prognostication that outperformed the American Thyroid Association clinical risk stratification. The genomic classifier we derived can potentially be applied preoperatively to direct clinical decision-making. Distinct biological features of molecular subtypes also have implications regarding sensitivity to radioactive iodine, EZH2 inhibitors, and immune checkpoint inhibitors.

cancer biology↗

bioRxiv2022

Unravelling specific diet and gut microbial contributions to inflammatory bowel disease

Inflammatory bowel diseases (IBDs) are chronic conditions characterized by periods of spontaneous intestinal inflammation and are increasing in industrialized populations. Combined with host genetics, diet and gut bacteria are thought to contribute prominently to IBDs, but mechanisms are still emerging. In mice lacking the IBD-associated cytokine, Interleukin-10, we show that low dietary fiber promotes bacterial erosion of colonic mucus, leading to lethal colitis. A fiber-free exclusive enteral nutrition diet also induces mucus erosion but inhibits inflammation by simultaneously increasing an anti-inflammatory bacterial metabolite, isobutyrate. Diet-induced inflammation is driven by Th1 immune responses, which increase in the presence of mucin-degrading bacteria and are preceded by expansion of natural killer cells and altered immunoglobulin-A coating of some bacteria. Inflammation occurs first in intestinal regions with thinner mucus. Our work underscores the importance of focusing on microbial functions--not taxa--contributing to IBDs and some diet-mediated functions block those that promote disease.

microbiology↗

bioRxiv2022

Large haploblocks underlie rapid adaptation in an invasive weed

Adaptation is the central feature and leading explanation for the evolutionary diversification of life. Adaptation is also notoriously difficult to study in nature, owing to its complexity and logistically prohibitive timescale. We leverage extensive contemporary and historical collections of Ambrosia artemisiifolia--an aggressively invasive weed and primary cause of pollen-induced hayfever--to track the phenotypic and genetic causes of recent local adaptation across its native and invasive ranges in North America and Europe, respectively. Large haploblocks-- indicative of chromosomal inversions--contain a disproportionate share (26%) of genomic regions conferring parallel adaptation to local climates between ranges, are associated with rapidly adapting traits, and exhibit dramatic frequency shifts over space and time. These results highlight the importance of large-effect standing variants in rapid adaptation, which have been critical to A. artemisiifolias global spread across vast climatic gradients.

evolutionary biology↗

bioRxiv2022

Integrating Math Modeling, Coding, and Biology in aCURE Lab

The development of mathematical and quantitative skills is increasingly critical for biology students. Literacy in coding, statistics, and mathematical modeling enables students to engage in systems-thinking and the analysis of large data sets. Here we present a flexible tool illustrating concepts in mathematical modeling, coding, and biology for integration into both traditional cookbook and inquiry-driven labs for freshmen biology students. We developed simple and complex mathematical models of potato catechol oxidase, a popular system to teach enzyme kinetics in undergraduate biology labs. We integrated both models into a freely-available web app for simulation and parameter estimation. The models are usable even if experimental details are unknown or poorly controlled, so that even novice students can work through the problem. We illustrate this by estimating the kinetic parameters of catechol oxidase in the complex model using data obtained from two sections of a course-based undergraduate research experience (CURE) freshman biology lab. Worksheets with questions motivating model building and simulation comprehension are provided. The effect of these exercises on students opinions of math, biology, and coding are evaluated using pre- and post-test surveys and student feedback. Our results show that these tools illustrate enzyme kinetics mathematically, students are not intimidated by the degree of math or coding involved, and in some cases are interested to do more, despite being unaware of the focus of the lab when signing up.

scientific communication and education↗

bioRxiv2021

Ultraviolet light-induced collagen degradation inhibits melanoma invasion

Ultraviolet radiation (UVR) increases the incidence of cutaneous melanoma1-4. The ageing, sun-exposed dermis accumulates UVR damage5, and older patients develop more melanomas at UVR-exposed sites4,6,7. As fibroblasts are functionally heterogeneous and play key roles in the stromal contribution to cancer8,9, we asked whether UVR modifies dermal fibroblast function. Here we confirmed the expression of collagen-cleaving matrix metalloprotein-1 (MMP1) by UVR-damaged fibroblasts was persistently upregulated to reduce local levels of collagen 1 (COL1A1), and found dermal COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, we show inhibiting extracellular matrix degradation and MMP1 expression restored melanoma invasion to UVR damaged dermis. We confirmed in vitro findings in a cohort of primary cutaneous melanomas of aged humans, showing more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen. We found collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. These data indicate melanomas arising over UVR-damaged, collagen-poor skin of the elderly are less invasive, and this reduced invasion improves survival. Consequently, although UVR increases tumour incidence, it delays primary melanoma invasion by degrading collagen. However, we show melanoma-associated fibroblasts can restore invasion in low-collagen primary tumours by increasing collagen synthesis. Finally, we demonstrate high COL1A1 gene expression is a biomarker of poor outcome across a broad range of primary cancers.

cancer biology↗

bioRxiv2021

Female immunity protects from cutaneous squamous cell carcinoma

PurposeCancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women are more protected from aggressive cutaneous squamous cell carcinoma (cSCC) due to strong immune activation. MethodsWe explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients (N= 738, N=160) with carcinoma cSCC, in FVB/N mice exposed to equal doses of DMBA, and in human keratinocytes by whole exome sequencing, bulk and single cell RNA sequencing. ResultsWe show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test if sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T cell infiltration independently of mutations. In contrast, males increase the rate of mitoses and proliferation in response to carcinogen. Human female skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at ultraviolet radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women. ConclusionsThis work shows the immune response is sex biased in cSCC, and highlights female immunity offers greater protection than male immunity.

cancer biology↗

bioRxiv2017

Infant Weight Gain Trajectories Linked To Oral Microbiome Composition

Gut and oral microbiome perturbations have been observed in obese adults and adolescents. Less is known about how weight gain in early childhood is influenced by gut, and particularly oral, microbiomes. Here we analyze the relationships among weight gain and gut and oral microbiomes in 226 two-year-olds who were followed during the first two years of life, as part of a larger study, with weight and length measured at seven time points. We used these data to identify children with rapid weight gain (a strong risk factor for childhood obesity), and to derive growth curves with novel Functional Data Analysis (FDA) techniques. The childrens oral and gut microbiomes were sampled at the end of the two-year period, and surveyed with 16S sequencing. First, we show that growth curves are associated negatively with diversity and positively with Firmicutes-to-Bacteroidetes ratio of the oral microbiome - a relationship that is also observed in children with rapid (vs. non-rapid) weight gain. We also demonstrate an association between the gut microbiome and child growth, but only when considering the effect of diet on the microbiome. Lastly, we identify several bacterial genera that are associated with child growth patterns. These results suggest that by the age of two, the oral microbiome may have already begun to establish patterns often seen in older obese individuals. They also suggest that the gut microbiome, while strongly influenced by diet, at age two does not harbor obesity signatures many researchers identified in later life stages.

genomics↗