Biology subjects

Gill, N. K.

Publications and source records attributed to Gill, N. K..

4 recordsLinked to original sources

bioRxiv2026

Deformability screening identifies NUDT5 as a mediator of cellular mechanobiology

How cells deform, sense, and respond to mechanical cues drives physiological and disease processes ranging from development to cancer metastasis; however, unbiased approaches to identify mechanical mediators are lacking. We screened 1280 compounds to identify modulators of cancer cell deformability using a cellular filtration assay and identified 92 compounds that significantly reduced deformability of ovarian cancer cells; top hits also reduced migration and invasion. Connectivity mapping of the top 21 compounds identified NUDT5 (Nudix hydrolase 5) as a predicted mechanical mediator; transcriptomic analyses implicated NUDT5 in mechanobiology and metabolic processes. We confirmed that NUDT5 mediates intracellular ATP and cellular mechanical behaviors, including morphology and deformability. In ovarian cancer, increased NUDT5 levels were associated with higher tumor stage and worse patient survival; NUDT5 inhibition reduced migration and colony formation in vitro and peritoneal tumor burden in mice. These findings establish deformability-based screening as a platform for discovering mechanical mediators and identify NUDT5 as a therapeutic target in ovarian cancer. TeaserScreening cells based on deformability provides an unbiased approach to identify NUDT5 as a mediator of cell mechanics

cell biology↗

bioRxiv2025

Cortical Representation of Pitch Perception in Mice

Pitch perception arises from temporal and spectral cues in sound. We hypothesized that mice rely on temporal cues because they have wide auditory filters, resembling humans with hearing loss or cochlear implants. Using computational modeling, behavioral assays, and widefield calcium imaging, we found that the structure of periodotopy in auditory cortex predicts how well mice recognize temporal pitch cues, establishing mice as a robust model for temporal pitch perception.

neuroscience↗

bioRxiv2023

Repetition plasticity in primary auditory cortex occurs across long timescales for spectrotemporally randomized pure-tones

Repetition plasticity is a ubiquitous property of sensory systems in which repetitive sensation causes either a decrease ("repetition suppression", i.e. "adaptation") or increase ("repetition enhancement", i.e. "facilitation") in the amplitude of neural responses. Timescales of repetition plasticity for sensory neurons typically span milliseconds to tens of seconds, with longer durations for cortical vs subcortical regions. Here, we used 2-photon (2P) imaging to study repetition plasticity in mouse primary auditory cortex (A1) layer 2/3 (L2/3) during the presentation of spectrotemporally randomized pure-tone frequencies. Our study revealed subpopulations of neurons with repetition plasticity for equiprobable frequencies spaced minutes apart over a 20-minute period. We found both repetition suppression and enhancement in individual neurons and on average across populations. Each neuron tended to show repetition plasticity for 1-2 pure-tone frequencies near the neurons best frequency. Moreover, we found correlated changes in neural response amplitude and latency across stimulus repetitions. Together, our results highlight cortical specialization for pattern recognition over long timescales in complex acoustic sequences.

neuroscience↗

bioRxiv2018

DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces.

DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1/TOR1A gene, which encodes torsinA, the luminal ATPase-associated (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown. Here, we define the mechanotype of mouse fibroblasts lacking functional torsinA as well as human fibroblasts isolated from DYT1 dystonia patients. We find that the deletion of torsinA or the expression of torsinA containing the DYT1 dystonia-causing {Delta}E302/303 ({Delta}E) mutation results in a more deformable cellular mechanotype. We observe a similar increased deformability of mouse fibroblasts that lack lamina-associated polypeptide 1 (LAP1), which interacts with and stimulates the ATPase activity of torsinA in vitro; as well as with depletion of the LINC complex proteins, Sad1/UNC-84 (SUN)1 and SUN2, lamin A/C, or lamin B1. Moreover, we report that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results support a model where the physical connectivity between the cytoskeleton and nucleus contributes to cellular mechanotype. These findings establish the foundation for future mechanistic studies to understand how altered cellular mechanotype may contribute to DYT1 dystonia pathogenesis; this may be particularly relevant in the context of how neurons sense and respond to mechanical forces during traumatic brain injury, which is known to be a major cause of acquired dystonia.

biophysics↗