Biology subjects

Chong, T.

Publications and source records attributed to Chong, T..

6 recordsLinked to original sources

bioRxiv2026

Effect of dopamine D2 blockade on behavioural and electrophysiological measures of inhibitory control

Inhibitory control is an essential executive function that encompasses both the stopping of an action in response to an unexpected stop signal (reactive response inhibition) and slowing of responses in anticipation of stopping (proactive response inhibition). Fronto-basal-ganglia circuits are thought to differentially contribute to response inhibition, with the indirect pathway implicated in proactive inhibition. Given the high expression of dopamine D2 receptors in the indirect pathway, pharmacological blockade of D2 receptors is expected to impact proactive inhibition, as indicated by response times on Go trials. The current study aimed to investigate this experimentally and study the effect of 600 mg of sulpiride, a D2 receptor antagonist, on behavioural and electrophysiological measures of proactive and reactive inhibition in humans. Human participants (N=24) completed an anticipated response version of the stop-signal task on either sulpiride or placebo in a double-blind within-subjects design. Sulpiride led to increased variability of Go response times and attenuation of the frontocentral negativity/readiness potential, considered to be a signature of proactive inhibition. In contrast, sulpiride had no effect on stop-signal reaction time or event-related potential components associated with reactive inhibition. These findings suggest that D2 receptor blockade selectively alters processes involved in proactive inhibition while leaving reactive inhibition unaffected, consistent with a key role for the indirect basal ganglia pathway in proactive response inhibition.

neuroscience↗

bioRxiv2026

Investigating cross-memory interactions of timing structures

Motor and episodic memories are classically conceptualised as distinct memory domains. However, both memory sequences are characterised by order and timing of their elements. Generalisation has been previously documented between these different memories, with a shared ordinal structure facilitating learning. However, it is unclear whether this generalisation also applies to the timing structure of a sequence. In a between-subject design, healthy adults (N = 143) learned and reproduced motor and episodic memory sequences with either the same or different timing structures. Contrary to expectations, recall of an episodic timeline was poorer when preceded by learning a motor sequence with the same timing structure. Motor sequence reproduction was not affected by prior episodic encoding. The findings do not support the hypothesis of cross-domain generalisation of timing structure between episodic and motor memories. However, the observed interference may suggest some overlap in the mechanism encoding timing information between memory systems.

neuroscience↗

bioRxiv2025

Armoring STEAP1 CAR T cells with IL-18 potentiates antitumor activity in Ewing sarcoma

BackgroundEwing sarcoma (EwS) is a highly aggressive cancer driven by the EWS::FLI1 fusion oncoprotein affecting children, adolescents, and young adults. Six transmembrane epithelial antigen 1 (STEAP1) is a cell surface antigen transcriptionally controlled by EWS::FLI1 that is broadly expressed in EwS, positioning it as a rational immunotherapy target. However, translating CAR T therapy to solid tumors requires overcoming barriers to potency while maintaining safety. MethodsAnalyses of transcriptome and proteome data were performed to evaluate the effects of EWS::FLI1 perturbation on STEAP1 expression at the transcript and protein levels in EwS models. STEAP1 expression was validated in EwS patient tissues by immunohistochemistry. Second-generation STEAP1-BB{zeta} CAR T cells were tested in orthotopic and disseminated EwS xenograft models. To enhance antitumor activity, an IL-18-armored STEAP1 CAR was engineered. Dose-dependent therapeutic efficacy and safety were evaluated through measurement of tumor burden, survival, and observation for gross toxicities. ResultsSTEAP1 was expressed in [~]97% of primary EwS tumors and directly associated with EWS::FLI1 fusion protein expression in EwS cell lines. In orthotopic EwS models, STEAP1 CAR T cells induced complete tumor regression at 5 x 106 cells. In disseminated disease models, responses were dose-dependent with no evidence of antigen loss. Notably, IL-18 armored STEAP1 CAR T cells achieved complete responses in [~]80% of mice at a reduced dose of 106 cells without overt toxicity. ConclusionsThese data establish STEAP1 as a clinically relevant and highly expressed target in EwS and demonstrate that IL-18 armoring significantly improves CAR T cell efficacy by enhancing potency evident through antitumor activity at reduced cell dose. STEAP1 CAR T cells are currently under evaluation in a first-in-human phase 1/2 dose-escalation clinical trial for metastatic castration-resistant prostate cancer (NCT06236139) and these studies support future clinical translation of STEAP1 CAR T cell therapy for relapsed/refractory EwS.

cancer biology↗

bioRxiv2025

Collagen-binding IL-12 expressing STEAP1 CAR-T cells reduce toxicity and eradicate mouse prostate cancer in combination with checkpoint inhibitors

Immunosuppressive microenvironments, the lack of immune infiltration, and antigen heterogeneity pose significant challenges for chimeric antigen receptor (CAR)-T cell therapies to tackle solid tumors. CAR-T cells were armed with immunostimulatory payloads, such as interleukin-12 (IL-12), to overcome this issue, but faced intolerable toxicity during clinical development. Here, we show that collagen-binding domain-fused IL-12 (CBD-IL-12) was retained within syngeneic murine prostate tumors, after secretion from CAR-T cells targeting human six transmembrane epithelial antigen of the prostate 1 (STEAP1). This led to equivalently high intratumoral interferon-{gamma} levels without hepatotoxicity and infiltration of T cells into non-target organs, compared with unmodified IL-12. Both innate and adaptive immune compartments were dramatically activated and recognized diverse tumor antigens after CBD-IL-12 CAR-T cell treatment. Combination immunotherapy of CBD-IL-12 CAR-T cells and immune checkpoint inhibitors eradicated large tumors in an established prostate cancer model, without pre-conditioning chemotherapy. The therapy generated anti-tumor immunological memory. CBD-fusion to potent yet toxic payloads of CAR-T therapy may remove obstacles to their clinical translation towards elimination of solid tumors.

bioengineering↗

bioRxiv2024

Relationships between measures of neurovascular integrity and fluid transport in aging: a multi-modal neuroimaging study

Fluid transport in the neurovascular unit (NVU) is essential for maintaining brain health through nutrient delivery and waste clearance. NVU integrity and fluid regulation can be assessed through MRI measures, including water exchange rate through the NVU (BBB kw), enlarged perivascular spaces (ePVS), cerebral blood flow (CBF), free water (FW), and white matter hyperintensities (WMH). This study investigated relationships between these MRI measures using Bayesian mixed models, and their variation with chronological age or biological brain age (brainageR) using linear regression in 132 non-clinical older adults (mean age=67 years; 68% female). BBB kw positively associated with CBF ({beta}^=0.08, 95% credible interval (CI)=[0.02,0.15]). FW positively associated with both ePVS ({beta}^=0.44, CI=[0.30,0.63]) and WMH ({beta}^=0.13, CI=[0.04,0.21]). BBB kw, CBF and ePVS decreased with age, while FW and WMH increased (all p<.05). There were no associations with brain age (all p>.05). Relationships between FW, ePVS and WMH likely reflect interconnectivity of fluid regulation within different compartments, while the relationship between BBB kw and CBF indicates a link between NVU fluid flow and vessel function. While individual metrics of NVU integrity are associated with age, their inter-relationships appear stable, providing a baseline for future research in fluid transport and vascular health in neurodegenerative disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=190 SRC="FIGDIR/small/622194v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@df1273org.highwire.dtl.DTLVardef@1343e84org.highwire.dtl.DTLVardef@f475c2org.highwire.dtl.DTLVardef@15f32d1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO Neurovascular function and the fluid transport system. The brains fluid transport system comprises the neurovascular unit, interstitial fluid exchange in the parenchyma and venous outflow. a. The flow of water molecules from the vessel to the perivascular space through the blood-brain barrier, and subsequently into the brain (facilitated by aquaporin-4 (AQP4) channels) in quantified by BBB kw. b. Greater cerebral blood flow rate (CBF) is associated with greater BBB kw, possibly due to vessel pulsations increasing osmotic pressure. c. Enlarged perivascular spaces (ePVS) may indicate reduced fluid flow within the NVU and are associated with (d.) increased extracellular free water (FW) in the parenchyma, suggesting a link between fluid regulation within the vasculature and the surrounding brain tissue. Greater white matter hyperintensity (WMH) volume also occurs alongside increase FW, in line with WMH reflecting more severe fluid flow stagnation occurring in concert with neuroinflammation and/or neuronal demyelination. C_FIG

neuroscience↗

bioRxiv2019

Single-cell atlas of the first intra-mammalian developmental stage of the human parasite Schistosoma mansoni

Over 250 million people suffer from schistosomiasis, a tropical disease caused by parasitic flatworms known as schistosomes. Humans become infected by free-swimming, water-borne larvae, which penetrate the skin. The earliest intra-mammalian stage, called the schistosomulum, undergoes a series of developmental transitions. These changes are critical for the parasite to adapt to its new environment as it navigates through host tissues to reach its niche, where it will grow to reproductive maturity. Unravelling the mechanisms that drive intra-mammalian development requires knowledge of the spatial organisation and transcriptional dynamics of different cell types that comprise the schistomulum body. To fill these important knowledge gaps, we performed single-cell RNA sequencing on two-day old schistosomula of Schistosoma mansoni. We identified likely gene expression profiles for muscle, nervous system, tegument, parenchymal/primordial gut cells, and stem cells. In addition, we validated cell markers for all these clusters by in situ hybridisation in schistosomula and adult parasites. Taken together, this study provides a comprehensive cell-type atlas for the early intra-mammalian stage of this devastating metazoan parasite.

genomics↗