Biology subjects

Davies, D.

Publications and source records attributed to Davies, D..

4 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Proteome Remodeling Directs Human Hematopoietic Stem Cells via a Metabolic-Cytoskeletal Axis

Hematopoietic stem cells (HSCs) sustain the lifelong production of all blood and immune cells and are central to transplantation and gene therapies. However, the clinical use of these approaches remains limited due to the functional attrition of HSCs during ex vivo adaptation and expansion in culture. As these transitions are executed at the protein and structural level, the primary drivers of cellular adaptation have remained elusive in transcriptional studies. Here, we overcome the technical resolution limits of rare primary cells by integrating a scalable, ultra-low input proteomics pipeline with 3D super-resolution imaging to map the proteomic and spatial organization of primary human HSCs during ex vivo expansion. Our analysis reveals a previously unrecognized, metabolic-cytoskeletal axis that coordinates organelle reorganization and structural polarity. Perturbation of this axis preserves structural polarity while uncoupling it from biomass expansion, demonstrating that growth and functional deterioration are separable processes in ex vivo HSC culture. These findings establish a framework for understanding ex vivo HSC adaptation and expansion and inform the rational development of next-generation cellular therapies.

cell biology↗

bioRxiv2023

Impaired migration and premature differentiation underlie the neurological phenotype associated with PCDH12 loss of function

Protocadherins (PCDHs) are cell adhesion molecules that regulate many essential neurodevelopmental processes related to neuronal maturation, dendritic arbor formation, axon pathfinding, and synaptic plasticity. Bi-allelic loss-of-function variants in PCDH12 are associated with several neurodevelopmental disorders (NDDs) such as diencephalic-mesencephalic dysplasia syndrome, cerebral palsy, cerebellar ataxia, and microcephaly. Despite the highly deleterious outcome resulting from loss of PCDH12, little is known about its role during brain development and disease. Here, we show that PCDH12 loss severely impairs cerebral organoid development with reduced proliferative areas and disrupted laminar organization. 2D models further show that neural progenitor cells lacking PCDH12 prematurely exit cell cycle and differentiate earlier when compared to wildtype. Furthermore, we show that PCDH12 regulates neuronal migration through a mechanism requiring ADAM10-mediated ectodomain shedding and membrane recruitment of cytoskeleton regulators. Our data demonstrate a critical and broad involvement of PCDH12 in cortical development, revealing the pathogenic mechanisms underlying PCDH12-related NDDs.

neuroscience↗

bioRxiv2020

Hypoxia-Sensing CAR T-Cells Provide Safety and Efficacy in Treating Solid Tumors

There has been significant interest in the prospects of chimeric antigen receptor (CAR) T-cell therapy in the treatment of solid malignancies, and multiple clinical trials are in progress 1. However, the scope of these trials has been restricted by the lack of availability of tumor-specific targets to direct CAR binding. Tumor specificity is crucial as on-target off-tumor activation of CAR T-cells in healthy tissues can result in potentially lethal toxicities due to uncontrolled cytokine release syndrome 2. Here we engineer a stringent hypoxia-sensing CAR T-cell system which achieves selective expression of a pan-ErbB-targeted CAR within a solid tumor, a microenvironment characterized by an inadequate oxygen supply. Using murine xenograft models, we demonstrate that despite widespread expression of ErbB receptors in healthy organs, the approach provides anti-tumor efficacy without off-tumor toxicity. This dynamic on/off oxygen-sensing safety switch has the potential to facilitate the unlimited expansion of the CAR T-cell target repertoire for treating solid malignancies.Competing Interest StatementYes there is potential Competing Interest. J.M. is co-founder and chief scientific officer, T.M. is an employee, and D.M.D., D.L.Y. are consultants to Leucid Bio, which is a spinout company focused on development of cellular therapeutic agents. J.N.A., J.M. and P.K. are named inventors on a patent submitted in relation to this work. All other authors have declared that there are no competing financial interests or conflicts of interest in relation to this study.View Full Text

synthetic biology↗

bioRxiv2019

Rhinovirus 2A is the predominant protease responsible for instigating the early block to gene expression encountered in infected cells

Human rhinoviruses express 2 cysteine proteases, 2A and 3C, that are responsible for viral polyprotein processing. Both proteases also suppress host gene expression by inhibiting mRNA transcription, nuclear export and cap-dependent translation. However, the relative contribution that each makes in achieving this goal remains unclear. In this study we have compared both the combined and individual ability of the 2 proteases to shut down in cellulo gene expression using a novel dynamic reporter system. Our findings show that 2A inhibits host gene expression much more rapidly than 3C. By comparing the activities of a representative set of proteases from the three different Human Rhinovirus (HRV) species, we also find variation in the speed at which host gene expression is suppressed. Our work highlights the key role that 2A plays in early suppression of the infected host cell response and shows that this can be influenced by natural variation in the activity of this enzyme.

microbiology↗