Biology subjects

Sullivan, E. C.

Publications and source records attributed to Sullivan, E. C..

3 recordsLinked to original sources

bioRxiv2026

Tired and wired: sleep deprivation prevents emotional adaptation to prolonged and ambiguous threat

Sleep problems are strongly linked to anxiety, but the psychological mechanisms underpinning this relationship are poorly understood. In this pre-registered study, we combined virtual reality, psychophysiology and multidimensional experience sampling to test the hypothesis that sleep deprivation disrupts emotional adaptation to sustained or resolving threat, giving rise to a heightened state of anxiety. Following a night of restful sleep or total sleep deprivation, healthy young adults navigated an immersive virtual world that alternated between ambiguously threatening and non-threatening contexts. Despite initial increases in emotional arousal, sleep-rested individuals quickly downregulated affective responses to ambiguous threat, reflecting efficient adaptation to the aversive virtual environment. Sleep-deprived individuals, by contrast, were unable to overturn elevated arousal responses, and exhibited a breakdown of goal-orientated, emotional control. Interestingly, resting heart rate variability, an index of affective regulatory capacity, mitigated arousal responses to ambiguous threat after sleep deprivation. These findings suggest that impaired adaptation to prolonged threat may represent a key mechanistic pathway linking insufficient sleep to anxiety.

neuroscience↗

bioRxiv2025

Chimeric Antigen Receptors Transmit Piconewton Forces that are Coupled with T Cell Function

Chimeric antigen receptor (CAR) T cells are engineered to display a receptor that binds antigens expressed on the surface of cancerous cells, which leads to cancer cytotoxicity. Recently, the T cell field has come to recognize the role of small, piconewton level forces in establishing specificity and cytotoxicity in naive T cells with the {beta} TCR, raising the possibility that these forces could be present in CAR T cells. Using DNA-based tension probes, we reveal 8-19 pN mechanical forces with [~]1 sec timescales transmitted by CAR T cells to their target antigens. CAR-antigen force magnitude is independent of CAR expression level and shows heterogeneity across different T cell donors, suggesting utility as a biomarker of T cell fitness. Using an established exhaustion model, we show strong correlation between CAR exhaustion, cytotoxic capacity, and CAR-antigen force, suggesting that CAR mechanics provide a biomarker of CAR potency complementary to functional assays. Pharmacological inhibition studies demonstrate that CAR forces are driven by actin, Zap70 and Src family proximal kinases. Titration of dasatinib, a clinically used tyrosine kinase inhibitor also dampens both CAR-antigen tension and CAR function in a dose-dependent manner. Structural engineering of the CAR confirms that force levels are modulated by the scFv receptor and co-stimulatory domains, but force transmission requires CD3{zeta} ITAMs. Taken together, this work shows that CAR T cells transmit pN force to their cognate antigens which holds potential significance in the design and screening of CAR therapeutic candidates and for predicting treatment outcomes in a personalized fashion.

biophysics↗

bioRxiv2022

Multicolor Light-Induced Immune Activation via Polymer Photocaged Cytokines

Cytokines act as potent, extracellular signals of the human immune system and can elicit striking treatment responses in patients with autoimmune disease, tissue damage, and cancer. Yet despite their therapeutic potential, recombinant cytokine-mediated immune responses remain difficult to control as their administration is often systemic whereas their intended sites of action are localized. To address the challenge of spatially and temporally constraining cytokine signals, we recently devised a strategy whereby recombinant cytokines are reversibly inactivated via chemical modification with photo-labile polymers that respond to visible LED light. Extending this approach to enable both in vivo and multicolor immune activation, here we describe a strategy whereby cytokines appended with heptamethine cyanine-polyethylene glycol are selectively re-activated ex vivo using tissue-penetrating near-infrared (NIR) light. We show that NIR LED light illumination of caged, pro-inflammatory cytokines restores cognate receptor signaling and potentiates the activity of T cell-engager cancer immunotherapies ex vivo. Using combinations of visible- and NIR-responsive cytokines, we further demonstrate multi-wavelength optical control of T cell cytolysis ex vivo, as well as the ability to perform Boolean logic using multicolored light and orthogonally photocaged cytokine pairs as inputs, and T cell activity as outputs. Together, this work demonstrates a novel approach to control extracellular immune cell signals using light, a strategy that in the future may improve our understanding of and ability to treat cancer and other diseases.

bioengineering↗