Biology subjects

Ross, A. J.

Publications and source records attributed to Ross, A. J..

4 recordsLinked to original sources

bioRxiv2026

Stopping and Changing Expected and Unexpected Movements

The capacity to cancel or adapt planned actions in response to changing environmental demands is essential for navigating our complex world. While past research has shown that an individuals expectations of upcoming movement demands influence the speed of action initiation, the effect this has on subsequent cancellation or adaption of that movement remains unknown. 25 healthy adults completed stop signal tasks and stop change tasks in which biasing cues (e.g., "70% left") accurately indicated the probability that a left, or right button press would be required. As expected, responses that were congruent with the cue were faster than incongruent responses; however, biasing cues had no effect on behavioural or physiological (electromyographical) indices of stopping speed. Stopping latencies were found to be faster in the stop change task than the stop signal task, corroborating other recent work. However, a second experiment (25 healthy adults) which used the same stimuli for both tasks (varying only the instructions), revealed no difference - highlighting the sensitivity of the stop process to stimulus effects, and a common confound in the literature. We also observed that physiological indices of action reprogramming (following a stop) were faster in congruent than incongruent trials. Collectively, these results suggests that preparatory changes that accompany expected movements influence the enaction of movement both prior to, and after stopping, but the stop mechanism itself, remains independent of these preparations. These results inform how action cancellation and adaption are applied in real world environments, where expectations continually interface with our motor plans. HighlightsO_LI* Anticipating a movement increases the speed of its enaction but not subsequent cancellation C_LIO_LI* Expected movements can be reprogrammed more quickly than unexpected movements C_LIO_LI* The latency of action cancellation is highly sensitive to stimulus effects C_LI

neuroscience↗

bioRxiv2025

PMAT enhances sexual dimorphism of fear behaviors and facilitates female mice's generalized contextual fear extinction

Enhanced signaling of dopamine and/or serotonin during highly arousing situations can be reduced or terminated by monoamine transporters. One such transporter, plasma membrane monoamine transporter (PMAT, Slc29a4), attenuates both dopamine and serotonin signaling. An absence of selective pharmacological inhibitors means genetically modified mice constitutively deficient in PMAT remain the best tool with which to study PMATs organism-level functional effects. Fear conditioning is a high arousal process. Generalization of fear is an evolutionarily advantageous process, whereby information learned from one experience is applied to other new but similar encounters. Pathological fear generalization, in contrast, is a core feature of most anxiety disorders. Given our previous findings indicating PMAT function reduces male mices context fear and enhances extinction of female mices cued fear, we hypothesized that PMAT would similarly reduce generalization (i.e., enhance discrimination) of context and cued fear in male and female mice, respectively. Our context and cued fear conditioning experiments in adult PMAT wildtype (+/+) and heterozygous (+/-) male and female mice partially supported our hypotheses. We discovered PMAT functions to facilitate extinction of contextually generalized fear, plus subsequent extinction of context-specific fear, selectively in females. Moreover, when specific fear cues or contexts were temporally presented before cues or contexts that were similar enough to make generalization possible, PMAT enhanced biological sex differences. Growing evidence reports common PMAT polymorphisms elicit measurable effects when PMAT function is reduced. Thus, we suspect future experiments may reveal positive associations between PMAT polymorphisms and risk for anxiety disorder symptoms, particularly in people assigned female at birth. Inclusion of these genetic variations in pharmacogenomic analyses may prove therapeutically beneficial.

neuroscience↗

bioRxiv2025

Selective targeting of oncogenic KRAS G12D using peptide nucleic acid oligomers attached to cell-penetrating peptides

KRAS is a proto-oncogene that contains activating mutations in up to 30% of tumors. Many conventional therapies inhibit both cancerous and normal cells, which may cause toxicity. Thus, programmable mutant-selective targeted inhibitors are needed. Peptide nucleic acids (PNAs) incorporate base sequences analogous to DNA, with modified peptide backbones instead of ribose-phosphate backbones, allowing PNAs to hybridize with DNA with high avidity to suppress transcription. Here, we developed KRAS G12D-selective PNA oligomers with novel cell-penetrating flanking regions. Fluorescein-labeled PNA oligomers displayed high uptake rates in cells and nuclei. Exposure to PNA-delivery peptide conjugates resulted in repression of KRAS G12D mRNA and protein expression within 2 hours and lasting up to 48 hours. Varying cell-penetrating peptide (CPP) compositions and lengths of complementary KRAS sequences were tested using dose-response cell viability assays. These experiments identified configurations that were effective at selectively preventing growth of on-target KRAS G12D cells, while relatively sparing off-target KRAS G12C cells. Electrophoretic mobility shift assays demonstrated in vitro binding and selectivity for KRAS G12D DNA sequences. CPP-PNA-G12D-1 was effective against a panel of pancreatic ductal adenocarcinoma cell lines and patient-derived xenografts in vivo. These results show promise for an enhanced PNA-delivery peptide conjugate strategy as both a tool for studying tumors driven by oncogenic point mutations and as a potential therapeutic strategy to selectively target mutant cancer cells.

cancer biology↗

bioRxiv2024

The T-cell niche tunes immune function through modulation of the cytoskeleton and TCR-antigen forces

Obesity is a major public health crisis given its rampant growth and association with an increased risk for cancer. Interestingly, patients with obesity tend to have an increased tumor burden and decreased T-cell function. It remains unclear how obesity compromises T-cell mediated immunity. To address this question, we modeled the adipocyte niche using the secretome released from adipocytes as well as the niche of stromal cells and investigated how these factors modulated T-cell function. We found that the secretomes altered antigen-specific T-cell receptor (TCR) triggering and activation. RNA-sequencing analysis identified thousands of gene targets modulated by the secretome including those associated with cytoskeletal regulation and actin polymerization. We next used molecular force probes to show that T-cells exposed to the adipocyte niche display dampened force transmission to the TCR-antigen complex and conversely, stromal cell secreted factors lead to significantly enhanced TCR forces. These results were then validated in diet-induced obese mice. Importantly, secretome-mediated TCR force modulation mirrored the changes in T-cell functional responses in human T-cells using the FDA-approved immunotherapy, blinatumomab. Thus, this work shows that the adipocyte niche contributes to T-cell dysfunction through cytoskeletal modulation and reduces TCR triggering by dampening TCR forces consistent with the mechanosensor model of T-cell activation.

bioengineering↗