Biology subjects

Shelton, J.

Publications and source records attributed to Shelton, J..

9 recordsLinked to original sources

bioRxiv2026

Personalised prediction of anomalous bone regeneration in multiple myeloma patients

Recent advances in immunotherapies have dramatically extended the lives of patients with multiple myeloma, resulting in a growing population of elderly patients suffering from damage to their vertebrae caused by this blood cancer. Clinicians typically intervene to fill in these lytic lesions in an attempt to reduce the risk of vertebral collapse and spinal cord injury, however observations of rapid bone regeneration post-cancer treatment suggest that surgery may not always be required. Here we develop a series of mechanistic computational models, optimised using cohorts of healthy volunteer and patient data, to show that vertebrae of recovering multiple myeloma patients rapidly strengthen in a manner not entirely explained by known bone remodelling mechanisms. Furthermore, using pathways informed by genomics data and patient-specific bone biomarkers, we demonstrate the potential for these models to provide personalised predictions of bone disease trajectory.

bioengineering↗

bioRxiv2025

Signatures of Motion: Decomposition of Adaptive Morphing Flight in Harris' Hawks

Birds outperform engineered aircraft with exceptional maneuverability, achieved by continuously morphing their wings and tails in flight. Yet the coordination and control of these shape changes remain poorly understood. Using high-speed motion capture of Harris hawks, we analyzed 289,000 wing-tail configurations in over 2000 flights and identified four fundamental shape change patterns, or "morphing shape modes", that capture over 96% of wing and tail variation. Further modes reflect subtle but critical fine-tuning, in line with known morphing control mechanics. The hawks morphing flight is highly structured yet flexible, and we find adaptive strategies in response to obstacles, added weight, with maturity, while each individual shows unique morphing signatures. Our approach defines a shared kinematic morphospace for hawk flight, and more broadly a framework that enables future comparative biomechanics, bio-inspired design, and for interpreting high-dimensional natural motion.

animal behavior and cognition↗

bioRxiv2025

Lancet2: Improved and accelerated somatic variant calling with joint multi-sample local assembly graph

Here, we present Lancet2, an open-source somatic variant caller designed to improve detection of small variants in short-read sequencing data. Lancet2 introduces significant enhancements, including: 1) Improved variant discovery and genotyping through partial order multiple sequence alignment of assembled haplotype contigs and re-alignment of sample reads to the best supporting allele. 2) Optimized somatic variant scoring with Explainable Machine Learning models leading to better somatic filtering throughout the sensitivity scale. 3) Integration with Sequence Tube Map for enhanced visualization of variants with aligned sample reads in graph space. When benchmarked against enhanced two-tech truth sets generated using high-coverage short-read (Illumina) and long-read (Oxford Nanopore) data from four well characterized matched tumor/normal cell lines, Lancet2 outperformed other industry-leading tools in variant calling performance, especially for InDels. In addition, significant runtime performance improvements compared to Lancet1 ([~]10x speedup and 50% less peak memory usage) and most other state of the art somatic variant callers (at least 2x speedup with 8 cores or more) make Lancet2 an ideal tool for accurate and efficient somatic variant calling.

bioinformatics↗

bioRxiv2024

Development and extensive sequencing of a broadly-consented Genome in a Bottle matched tumor-normal pair for somatic benchmarks

The Genome in a Bottle Consortium (GIAB), hosted by the National Institute of Standards and Technology (NIST), is developing new matched tumor-normal samples, the first to be explicitly consented for public dissemination of genomic data and cell lines. Here, we describe a comprehensive genomic dataset from the first individual, HG008, including DNA from an adherent, epithelial-like pancreatic ductal adenocarcinoma (PDAC) tumor cell line and matched normal cells from duodenal and pancreatic tissues. Data for the tumor-normal matched samples comes from seventeen distinct state-of-the-art whole genome measurement technologies, including high depth short and long-read bulk whole genome sequencing (WGS), single cell WGS, and Hi-C, and karyotyping. In future publications, these data will be used by the GIAB Consortium to develop matched tumor-normal benchmarks for somatic variant detection. We expect these data to facilitate innovation for whole genome measurement technologies, de novo assembly of tumor and normal genomes, and bioinformatic tools to identify small and structural somatic mutations. This first-of-its-kind broadly consented open-access resource will facilitate further understanding of sequencing methods used for cancer biology.

genomics↗

bioRxiv2024

Cancer Cachexia in STK11/LKB1-mutated NSCLC is Dependent on Tumor-secreted GDF15

Cachexia is a wasting syndrome comprised of adipose, muscle, and weight loss observed in cancer patients. Tumor loss-of-function mutations in STK11/LKB1, a regulator of the energy sensor AMP-activated protein kinase, induce cancer cachexia (CC) in preclinical models and are associated with cancer-related weight loss in NSCLC patients. Here we characterized the relevance of the NSCLC-associated cachexia factor growth differentiation factor 15 (GDF15) in several patient-derived and genetically engineered STK11/LKB1-mutant NSCLC cachexia lines. Both tumor mRNA expression and serum concentrations of tumor-derived GDF15 were significantly elevated in multiple mice transplanted with patient-derived STK11/LKB1-mutated NSCLC lines. GDF15 neutralizing antibody administered to mice transplanted with patient- or mouse-derived STK11/LKB1-mutated NSCLC lines suppressed cachexia-associated adipose loss, muscle atrophy, and changes in body weight. The silencing of GDF15 in multiple human NSCLC lines was also sufficient to eliminate in vivo circulating GDF15 levels and abrogate cachexia induction, suggesting that tumor and not host tissues represent a key source of GDF15 production in these cancer models. Finally, reconstitution of wild-type STK11/LKB1 in a human STK11/LKB1 loss-of-function NSCLC line that normally induces cachexia in vivo correlated with the absence of tumor-secreted GDF15 and rescue from the cachexia phenotype. The current data provide evidence for tumor-secreted GDF15 as a conduit and a therapeutic target through which NSCLCs with STK11/LKB1 loss-of-function mutations promote cachexia-associated wasting.

cancer biology↗

bioRxiv2022

Visual versus visual-inertial guidance in hawks pursuing terrestrial targets

The flight behaviour of predatory birds is well modelled by a guidance law called proportional navigation, which commands steering in proportion to the angular rate of the line-of-sight from predator to prey. The line-of-sight rate is defined with respect to an inertial frame of reference, so proportional navigation is necessarily implemented using visual-inertial sensor fusion. In Harris hawks, pursuit of terrestrial targets may be even better modelled by assuming that visual-inertial information on the line-of-sight rate is combined with visual information on the deviation angle between the attackers velocity and the line-of-sight. Here we ask whether a new variant of this mixed guidance law can model Harris hawk pursuit behaviour successfully using visual information alone. We use high-speed motion capture to record n=228 attack fights from N=4 Harris hawks, and confirm that proportional navigation and mixed guidance using visual-inertial information both model the trajectory data well. Moreover, the mixed guidance law still models the data closely if visual-inertial information on the line-of-sight rate is replaced with purely visual information on the apparent motion of the target relative to the background. Although the original form of the mixed guidance law provides the closest fit, all three models provide an adequate phenomenological model of the behavioural data, whilst each making different predictions on the physiological pathways involved.

animal behavior and cognition↗

bioRxiv2021

Angiocrine IGFBP3 Spatially Coordinates IGF Signaling During Neonatal Cardiac Regeneration

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins - which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

cell biology↗

bioRxiv2020

Somatic variant analysis of linked-reads sequencing data with Lancet

Summary We present a new version of the popular somatic variant caller, Lancet, that supports the analysis of linked-reads sequencing data. By seamlessly integrating barcodes and haplotype read assignments within the colored De Bruijn graph local-assembly framework, Lancet computes a barcode-aware coverage and identifies variants that disagree with the local haplotype structure.Availability and Implementation Lancet is implemented in C++ and is available for academic and non-commercial research purposes as an open-source package at https://github.com/nygenome/lancet.Contact gnarzisi{at}nygenome.orgCompeting Interest StatementThe authors have declared no competing interest.View Full Text

bioinformatics↗

bioRxiv2019

Deep sequencing of 3 cancer cell lines on 2 sequencing platforms

To test the performance of a new sequencing platform, develop an updated somatic calling pipeline and establish a reference for future benchmarking experiments, we sequenced 3 common cancer cell lines along with their matched normal cell lines to great sequencing depths (up to 278X coverage) on both Illumina HiSeqX and NovaSeq sequencing instruments. Somatic calling was generally consistent between the two platforms despite minor differences at the read level. We designed and implemented a novel pipeline for the analysis of tumor-normal samples, using multiple variant callers. We show that coupled with a high-confidence filtering strategy, it improves the accuracy of somatic calls. We also demonstrate the utility of the dataset by creating an artificial purity ladder to evaluate the somatic pipeline and benchmark methods for estimating purity and ploidy from tumor-normal pairs. The data and results of the pipeline are made accessible to the cancer genomics community.

genomics↗