Biology subjects

Taylor, W. R.

Publications and source records attributed to Taylor, W. R..

9 recordsLinked to original sources

bioRxiv2026

Extending Musculoskeletal Modelling Validation Beyond Gait: Knee Loading and Kinematics During Daily Activities

Musculoskeletal (MSK) modelling enables non-invasive estimation of internal body loads, which could inform the design of novel orthopedic implants and guide personalized treatment strategies. Extensive validation is a pre-requisite for the translation of MSK-modelling frameworks into clinical applications. This study validates predicted knee loads and local kinematics across multiple activities of daily living (ADLs) using motion-capture data from 184 activity cycles collected in six subjects performing five ADLs from the CAMS-Knee datasets. Personalized models incorporated subject-specific anthropometric, radiographic, and implantation data, along with a 6-DOF elastic-foundation contact model between implant components and a surgically balanced ligament model derived from cadaveric testing. Across activities, predicted knee contact force magnitudes showed good agreement with instrumented implant measurements (RMSE 0.46 BW; R2 = 0.81). The highest accuracy was found during level walking, whereas stair descent exhibited the largest discrepancies. Predicted implant kinematics showed qualitatively similar trends to fluoroscopic measurements across all ADLs, although with varying levels of accuracy across different degrees of freedom. EMG comparisons revealed broadly consistent activation timing between model predictions and experimental data, although gastrocnemius activation was poorly estimated during stair descent and downhill walking. By validating MSK model predictions across the complete range of activities available in the CAMS-Knee datasets, this study extends validation beyond previously analysed gait or bending tasks and reveals activity-specific discrepancies that reflect current limitations in modelling assumptions and would remain undetected in single-activity analyses. These findings provide a robust basis for future refinement of MSK models and support their development toward clinically meaningful applications.

bioengineering↗

bioRxiv2026

Rod pathway blockade improves visual function in a mouse model of photoreceptor degeneration

Retinitis pigmentosa (RP) refers to a group of inherited photoreceptor degenerations characterized by the initial death of rods and secondary loss of cones. In animal models of RP, the ganglion cells (GCs) exhibit increased spontaneous activity that can mask residual photoreceptor signals and reduce the efficacy of treatments for vision restoration. The A2 amacrine cells (ACs) are inhibitory interneurons that propagate aberrant activity to GCs, but it remains unclear whether rod or cone pathways drive altered A2-AC signaling or whether the relative contributions of these pathways change with disease progression. We examined the circuit mechanisms underlying aberrant activity in the rd10 mouse model and found that blocking rod pathway input to A2-ACs suppressed aberrant activity and improved the signal-to-noise ratio of residual cone-driven responses in On- GCs. The results also indicate that the On- but not the Off-pathway exhibits circuit-level compensation during the loss of photoreceptor input. The results suggest that pharmacological blockade of the rod pathway may improve residual cone-mediated function and improve the efficacy of vision restoration in rod-cone photoreceptor degenerations.

systems biology↗

bioRxiv2026

Force sharing between plantarflexor muscles in sheep during treadmill gait

Muscle force sharing during locomotion is influenced by the mechanical demands of movement and the contractile properties of synergistic muscles. In cats, plantarflexor muscles exhibit distinct functional specialization, with the slow-fibred soleus maintaining relatively constant force across conditions while faster muscles such as the plantaris and gastrocnemius increase force production with increasing locomotor demand. However, it remains unclear whether similar force-sharing patterns occur in larger animals with different musculoskeletal designs. Therefore, the purpose of this study was to examine force sharing between the superficial digital flexor (SDF) and medial gastrocnemius (MG) muscles during treadmill locomotion in sheep. Tendon buckle force transducers were surgically implanted on the SDF and MG tendons of seven sheep, and in vivo muscle forces were recorded during walking and trotting across different speeds and inclines. Both muscles increased force with increasing speed and incline; however, speed had a substantially greater effect than incline. The SDF consistently produced greater absolute force than the MG across all conditions, whereas the MG exhibited slightly larger relative increases in force with increasing speed. Time to peak force decreased with increasing speed in both muscles, although the SDF reached peak force later in stance than the MG across conditions. In contrast to the distinct specialization observed in cats, neither muscle displayed a relatively condition-independent, soleus-like force contribution. These findings suggest that force sharing in sheep is more distributed across synergistic muscles and may reflect the influence of musculoskeletal design, tendon compliance, and mixed fibre-type composition on muscle function in larger species.

bioengineering↗

bioRxiv2021

Satellite Cell Expression of RAGE is Important for Collateral Vessel Formation

ObjectiveThe growth and remodeling of vascular networks is an important component of the prognosis for patients with peripheral artery disease. One protein that has been previously implicated to play a role in this process is the receptor for advanced glycation end products or RAGE. This study sought to determine the cellular source of RAGE in the ischemic hindlimb and the role of RAGE signaling in this cell type. Approach and ResultsUsing a hind limb ischemia model of vascular growth, this study found skeletal muscle satellite cells to be a novel major cellular source of RAGE in ischemic tissue by both staining and cellular sorting. While wild type satellite cells increased TNF and MCP-1 production in response to ischemia in vivo and a RAGE ligand in vitro, satellite cells from RAGE knockout mice lacked the increase in cytokine production both in vivo in response to ischemia and in vitro after stimuli with the RAGE ligand HMGB-1. Furthermore, encapsulated wild type satellite cells improved perfusion after hind limb ischemia surgery by both perfusion staining and vessel quantification but RAGE knockout satellite cells provided no improvement over empty capsules. ConclusionsThus, RAGE expression and signaling in satellite cells is crucial for their response to stimuli and angiogenic and arteriogenic functions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/433612v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@73dc28org.highwire.dtl.DTLVardef@7acb74org.highwire.dtl.DTLVardef@1c34bb1org.highwire.dtl.DTLVardef@9e62c8_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2021

Characterization of Poldip2 knockout mice: avoiding incorrect gene targeting

POLDIP2 is a multifunctional protein whose roles are only partially understood. Our laboratory previously reported physiological studies performed using a mouse gene trap model, which suffered from two limitations: perinatal lethality in homozygotes and constitutive Poldip2 inactivation. To overcome these limitations, we developed a new conditional floxed Poldip2 model. The first part of the present study shows that our initial floxed mice were affected by an unexpected mutation, which was not readily detected by Southern blotting and traditional PCR. It consisted of a 305 kb duplication around Poldip2 with retention of the wild type allele and could be traced back to the original targeted ES cell clone. We offer simple suggestions to rapidly detect similar accidents, which may affect genome editing using both traditional and CRISPR-based methods. In the second part of the present study, correctly targeted floxed Poldip2 mice were generated and used to produce a new constitutive knockout line by crossing with a Cre deleter. In contrast to the gene trap model, many homozygous knockout mice were viable, in spite of having no POLDIP2 expression. To further characterize the effects of Poldip2 ablation in the vasculature, an RNA-seq experiment was performed in constitutive knockout carotid arteries. Results support the involvement of POLDIP2 in multiple cellular processes and provide new opportunities for future in-depth study of its functions.

genetics↗

bioRxiv2021

hC9ORF78 localizes to kinetochores and is required for proper chromosome segregation.

C9ORF78 is a poorly characterized protein found in diverse eukaryotes. Previous work indicated overexpression of hC9ORF78 (aka HCA59) in malignant tissues indicating a possible involvement in growth regulatory pathways. Additional studies in fission yeast and humans uncover a potential function in regulating the spliceosome. In studies of GFP-tagged hC9ORF78 we observed a dramatic reduction in protein abundance in cells grown to confluence and/or deprived of serum growth factors. Serum stimulation induced synchronous re-expression of the protein in HeLa cells. This effect was also observed with the endogenous protein. Overexpressing either E2F1 or N-Myc resulted in elevated hC9ORF78 expression potentially explaining the serum-dependent upregulation of the protein. Immunofluorescence analysis indicates that hC9ORF78 localizes to nuclei in interphase but does not appear to concentrate in speckles as would be expected for a splicing protein. Surprisingly, a subpopulation of hC9ORF78 co-localizes with ACA, Mad1 and Hec1 in mitotic cells suggesting that this protein may associate with kinetochores or centromeres. Furthermore, knocking-down hC9ORF78 caused mis-alignment of chromosomes in mitosis. These studies uncover novel mitotic function and subcellular localization of cancer antigen hC9ORF78. SUMMARY STATEMENThC9ORF78 regulates chromosome segregation.

cell biology↗

bioRxiv2020

Gbx2 identifies two amacrine cell subtypes with distinct molecular, morphological, and physiological properties

Our understanding of how the nervous sytem works is limited by our ability to identify the neuronal subtypes that comprise functional circuits. Using a genetic approach, we show that the transcription factor Gbx2 labels two amacrine cell (AC) subtypes in the mouse retina that have distinct morphological, physiological, and molecular properties. One subtype of Gbx2+ ACs are likely the previously characterized On-type GABAergic CRH-1 AC. The other Gbx2+ AC population is a previously uncharacterized non-GABAergic, non-Glycinergic (nGnG) AC subtype. Gbx2+ nGnG ACs are On-Off type cells with asymmetric dendritic arbors. Gbx2+ nGnG ACs also exhibit tracer coupling to bipolar cells (BCs) through gap junctions that are modulated by dopamine signaling. This study genetically identifies a previously uncharacterized AC subtype and reveals an unusual AC-BC connectivity through gap junctions that may provide a novel model of synaptic communication and visual circuit function.

neuroscience↗

bioRxiv2018

Critical Limb Ischemia Induces Remodeling of Skeletal Muscle Motor Unit and Myonuclear- and Mitochondrial-Domains

Critical limb ischemia, the most severe form of peripheral artery disease, leads to extensive damage and alterations in skeletal muscle homeostasis. Although recent developments towards revascularization therapies have been introduced, there has been limited research into treatments for ischemic myopathy. To elucidate the regenerative mechanism of the muscle stem cell and its niche components in response to ischemic insults, we explored interactions between the vasculature, motor neuron, muscle fiber, and the muscle stem cell. We first investigated changes in the neuromuscular junction and motor neuron innervation following a surgical hindlimb ischemia model of critical limb ischemia in mice. Along with previous findings that support remodeling of the neuromuscular junction, we report that ischemic injury also causes significant alterations to the myofiber through a muscle stem cell-mediated increase of myonuclei number per fiber, a concomitant decrease in myonuclear domain size, and an increase in relative mitochondrial content per myonucleus. These results indicate that as a regenerative response to critical limb ischemia, myofibers exhibit myonuclear expansion to allow enhanced transcriptional support and an increase in mitochondrial content for bioenergetic need of the energy-demanding tissue regeneration.

physiology↗

bioRxiv2016

Genome sequence of a diabetes-prone desert rodent reveals a mutation hotspot around the ParaHox gene cluster

The sand rat Psammomys obesus is a gerbil native to deserts of North Africa and the Middle East1. Sand rats survive with low caloric intake and when given high carbohydrate diets can become obese and develop type II diabetes2 which, in extreme cases, leads to pancreatic failure and death3,4. Previous studies have reported inability to detect the Pdx1 gene or protein in gerbils5-7, suggesting that absence of this key insulin-regulating homeobox gene might underlie diabetes susceptibility. Here we report sequencing of the sand rat genome and discovery of an extensive, mutationally-biased GC-rich genomic domain encompassing many essential genes, including the elusive Pdx1. The sequence of Pdx1 has been grossly affected by GC-biased mutation leading to the highest divergence observed in the animal kingdom. In addition to molecular insights into restricted caloric intake in a desert species, the discovery that specific chromosomal regions can be subject to elevated mutation rate has widespread significance to evolution.

evolutionary biology↗