Biology subjects

Tse, D.

Publications and source records attributed to Tse, D..

11 recordsLinked to original sources

bioRxiv2026

Causal Evidence for Left DLPFC Contributions to Working Memory, Attention, and Cognitive Control in Ageing: A cTBS/ERP Study

Ageing is characterised by progressive neurodegeneration and marked declines in working memory (WM), a domain critically dependent on the integrity of the dorsolateral prefrontal cortex (DLPFC). Although non-invasive brain stimulation is widely used to target this region, the causal contribution of the DLPFC to WM performance in older adults remains insufficiently understood. Here, we applied continuous theta burst stimulation (cTBS) to transiently inhibit the left DLPFC in twenty healthy older adults and assessed the behavioural and neurophysiological consequences during verbal and visuospatial N-back tasks. Behaviourally, moderate learning effects emerged exclusively in the verbal task following vertex stimulation, whereas learning after DLPFC stimulation remained inconclusive. Performance in the visuospatial task showed no reliable evidence of learning across conditions, consistent with greater interindividual variability and age-related decline in spatial WM. Neurophysiologically, ERP amplitudes were stable across conditions; however, marked latency perturbations were observed. In the verbal task, P200 and N200 latencies robustly predicted performance, with P200 latency significantly prolonged after DLPFC inhibition, indicating disrupted early attentional gating. N200 and P300 latency modulations further suggested load-dependent compensatory strategies, reflecting adaptive slowing of cognitive control processes. In contrast, visuospatial performance was not reliably predicted by P200 latency, although N200 and P300 latencies remained informative, indicating domain-specific differences in DLPFC involvement. Taken together, these findings provide causal evidence that left DLPFC disruption selectively interferes with the temporal coordination of verbal WM, emphasising the central role of processing speed and compensatory dynamics in cognitive ageing. ERP latency markers emerge as sensitive indices of subtle stimulation-induced perturbations in older adults.

neuroscience↗

bioRxiv2025

Balancing Efficiency and Compensation: Age-related Theta and Alpha Dynamics in High-load Working Memory

Working memory (WM) declines with age, yet older adults often preserve performance through compensatory mechanisms. Oscillatory dynamics in the theta and alpha bands are central to these adaptations, but their distinct roles across maintenance, manipulation, and recall remain unclear. We examined behavioural and neural differences in WM using electroencephalography (EEG) during verbal (Letter Span) and visuospatial (Corsi Block) tasks under retention and manipulation conditions. Behaviourally, older adults preserved performance in the Letter Span but showed deficits in the Corsi Test, suggesting domain-specific declines, while higher task demands reduced accuracy across both groups. At the neural level, younger adults exhibited stronger mid-frontal and temporal theta activity, supporting more efficient recruitment of WM processes and stronger performance associations. Older adults showed attenuated theta power, indicative of neural saturation, and appeared to compensate through alpha-mediated mechanisms during the delay period (maintenance / manipulation): reduced alpha suppression in the Letter Span facilitated rehearsal and updating, whereas increased upper alpha in the Corsi Test protected stored visuospatial information. These findings suggest theta oscillations underpin core WM functions, whereas alpha oscillations flexibly support compensatory strategies in ageing.

neuroscience↗

bioRxiv2025

Hippocampal reactivation of planned trajectories is required for effective goal choice in an allocentric memory task

Hippocampal activity provides a representation of the world around us, as well as our position within that world. However, it is not known if and to what extent the chosen navigational reference frame can influence hippocampal representations during memory-based tasks, including those focused on future activity. Here, we develop and employ two naturalistic, carefully controlled variants of the everyday memory task to model the use of egocentric and allocentric coordinates in the same arena. By recording hippocampal neural activity through miniature microscopes in male rats performing each of the two tasks, we uncover differences in the representation of space, and in the features of memory-based action planning. By also deploying optogenetic inactivation during navigational decision making, we find that hippocampal representations observed during the planning phase are necessary for solving the allocentric, but not the egocentric version of the task. Overall, our findings reveal a functional link between non-local hippocampal representations and allocentric navigation.

neuroscience↗

bioRxiv2025

Boosting Brainpower in Ageing: Task-Specific and Transfer Effects of tDCS-Enhanced Working Memory Training

Ageing is associated with neural alterations that impair cognitive abilities, particularly working memory (WM)--the capacity to temporarily store and manipulate information essential for daily functioning. Transcranial Direct Current Stimulation (tDCS) has shown promise in enhancing WM in older adults by modulating cortical excitability and promoting neuroplasticity. However, findings on the combined effects of tDCS and WM training remain inconsistent, particularly regarding transfer effects to non-trained WM tasks (near transfer) or other cognitive domains (far transfer). This study examined the behavioural and neural effects of tDCS on distinct WM phases (encoding, retention/manipulation, recall) in older adults. Over three weeks, participants underwent six sessions of adaptive WM training paired with tDCS targeting the left dorsolateral prefrontal cortex (DLPFC). Neural activity was assessed via EEG, focusing on theta and alpha bands. Participants were divided into tDCS and placebo groups and completed two WM tests, the Letter Span and Corsi Test, with retention and manipulation conditions. Results showed no additional behavioural or neural benefits of tDCS. However, both groups exhibited near-transfer effects that persisted one-month post-training. Neural changes varied by task: the Letter Span showed increased alpha power during manipulation, indicating enhanced maintenance of information during that phase, while the Corsi Test showed reduced left-hemisphere theta power during recall, reflecting reduced hemispheric asymmetry. Inter-individual variability likely contributed to inconsistencies and a lack of correlations between outcomes. These findings highlight the importance of personalised tDCS protocols and suggest adaptive WM training can yield enduring cognitive and neural benefits in older adults.

neuroscience↗

bioRxiv2024

Exploring working memory updating processes of the human subcortex using 7T MRI

A growing body of research suggests that dopamine is involved in working memory updating and that the striatum takes up a critical role in the subprocess of working memory gating (Braver & Cohen, 2000; Cools & DEsposito, 2011; DArdenne et al., 2012; Jongkees, 2020). In this study, we investigated subcortical-in particular, possible dopaminergic-involvement in working memory updating subprocesses using the reference-back task and ultra-high field 7 Tesla fMRI. Using a scanning protocol optimized for BOLD-sensitivity in the subcortex, we found no evidence of subcortical activation during working memory gate opening, predominantly activations in frontoparietal network regions, which challenges the idea of a striatal gating mechanism. However, during gate closing, subcortical activation was observed. Furthermore, a ready-to-update mode demonstrated large-spread subcortical activation, including basal ganglia nuclei, suggesting that the basal ganglia are engaged in general updating processes rather than specifically controlling the working memory gate. Moreover, substituting new information into working memory elicited activation in dopamine-producing midbrain regions along with the striatum, thalamus, and prefrontal cortex, indicating engagement of the basal ganglia-thalamo-cortical loop possibly driven by (potential) dopaminergic activity. These findings expand our understanding of subcortical regions involved in working memory updating, shifting the focus from gate opening to substitution as a midbrain-driven updating process.

neuroscience↗

bioRxiv2023

Activation of Multiple Eph Receptors on Neuronal Membranes Correlates with The Onset of Traumatic Optic Neuropathy

BackgroundOptic neuropathy (ON) is a major cause of irreversible blindness, yet the molecular determinants that contribute to neuronal demise have not been fully elucidated. Several studies have identified ephrin signaling as one of the most dysregulated pathways in the early pathophysiology of ON with varied etiologies. Developmentally, gradients in ephrin signaling coordinate retinotopic mapping via repulsive modulation of cytoskeletal dynamics in neuronal membranes. Little is known about the role ephrin signaling played in the post-natal visual system and its correlation with the onset of optic neuropathy. MethodsPostnatal mouse retinas were collected for mass spectrometry analysis for Eph receptors. Optic nerve crush (ONC) model was employed to induce optic neuropathy, and proteomic changes during the acute phase of neuropathic onset were analyzed. Confocal and super-resolution microscopy determined the cellular localization of activated Eph receptors after ONC injury. Eph receptor inhibitors assessed the neuroprotective effect of ephrin signaling modulation. ResultsMass spectrometry revealed expression of seven Eph receptors (EphA2, A4, A5, B1, B2, B3, and B6) in postnatal mouse retinal tissue. Immunoblotting analysis indicated a significant increase in phosphorylation of these Eph receptors 48 hours after ONC. Confocal microscopy demonstrated the presence of both subclasses of Eph receptors in the inner retinal layers. STORM super-resolution imaging combined with optimal transport colocalization analysis revealed a significant co-localization of activated Eph receptors with injured neuronal processes, compared to uninjured neuronal and/or injured glial cells, 48 hours post-ONC. Eph receptor inhibitors displayed notable neuroprotective effects after 6 days of ONC injury. ConclusionsOur findings demonstrate the functional presence of diverse Eph receptors in the postnatal mammalian retina, capable of modulating multiple biological processes. Pan-Eph receptor activation contributes to the onset of neuropathy in ONs, with preferential activation of Eph receptors on neuronal processes in the inner retina following optic nerve injury. Notably, Eph receptor activation precedes neuronal loss. We observed neuroprotective effects upon inhibiting Eph receptors. Our study highlights the importance of investigating this repulsive pathway in early optic neuropathies and provides a comprehensive characterization of the receptors present in the developed retina of mice, relevant to both homeostasis and disease processes.

neuroscience↗

bioRxiv2023

An interpretable, finite sample valid alternative to Pearson's X2 for scientific discovery

Contingency tables, data represented as counts matrices, are ubiquitous across quantitative research and data-science applications. Existing statistical tests are insufficient however, as none are simultaneously computationally efficient and statistically valid for a finite number of observations. In this work, motivated by a recent application in reference-free genomic inference (1), we develop OASIS (Optimized Adaptive Statistic for Inferring Structure), a family of statistical tests for contingency tables. OASIS constructs a test-statistic which is linear in the normalized data matrix, providing closed form p-value bounds through classical concentration inequalities. In the process, OASIS provides a decomposition of the table, lending interpretability to its rejection of the null. We derive the asymptotic distribution of the OASIS test statistic, showing that these finitesample bounds correctly characterize the test statistics p-value up to a variance term. Experiments on genomic sequencing data highlight the power and interpretability of OASIS. The same method based on OASIS significance calls detects SARS-CoV-2 and Mycobacterium Tuberculosis strains de novo, which cannot be achieved with current approaches. We demonstrate in simulations that OASIS is robust to overdispersion, a common feature in genomic data like single cell RNA-sequencing, where under accepted noise models OASIS still provides good control of the false discovery rate, while Pearsons X2 test consistently rejects the null. Additionally, we show on synthetic data that OASIS is more powerful than Pearsons X2 test in certain regimes, including for some important two group alternatives, which we corroborate with approximate power calculations. Significance StatementContingency tables are pervasive across quantitative research and data-science applications. Existing statistical tests fall short, however; none provide robust, computationally efficient inference and control Type I error. In this work, motivated by a recent advance in reference-free inference for genomics, we propose a family of tests on contingency tables called OASIS. OASIS utilizes a linear test-statistic, enabling the computation of closed form p-value bounds, as well as a standard asymptotic normality result. OASIS provides a partitioning of the table for rejected hypotheses, lending interpretability to its rejection of the null. In genomic applications, OASIS performs reference-free and metadata-free variant detection in SARS-CoV-2 and M. Tuberculosis, and demonstrates robust performance for single cell RNA-sequencing, all tasks without existing solutions.

bioinformatics↗

bioRxiv2020

I-CONVEX: Fast and Accurate de Novo Transcriptome Recovery from Long Reads

Long-read sequencing technologies demonstrate high potential for de novo discovery of complex transcript isoforms, but high error rates pose a significant challenge. Existing error correction methods rely on clustering reads based on isoform-level alignment and cannot be efficiently scaled. We propose a new method, I-CONVEX, that performs fast, alignment-free isoform clustering with almost linear computational complexity, and leads to better consensus accuracy on simulated, synthetic, and real datasets.

bioinformatics↗

bioRxiv2018

Systematic characterization of genome editing in primary T cells reveals proximal genomic insertions and enables machine learning prediction of CRISPR-Cas9 DNA repair outcomes

The Streptococcus pyogenes Cas9 (SpCas9) nuclease has become a ubiquitous genome editing tool due to its ability to target almost any location in DNA and create a double-stranded break1,2. After DNA cleavage, the break is fixed with endogenous DNA repair machinery, either by non-templated mechanisms (e.g. non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ)), or homology directed repair (HDR) using a complementary template sequence3,4. Previous work has shown that the distribution of repair outcomes within a cell population is non-random and dependent on the targeted sequence, and only recent efforts have begun to investigate this further5-11. However, no systematic work to date has been validated in primary human cells5,7. Here, we report DNA repair outcomes from 1,521 unique genomic locations edited with SpCas9 ribonucleoprotein complexes (RNPs) in primary human CD4+ T cells isolated from multiple healthy blood donors. We used targeted deep sequencing to measure the frequency distribution of repair outcomes for each guide RNA and discovered distinct features that drive individual repair outcomes after SpCas9 cleavage. Predictive features were combined into a new machine learning model, CRISPR Repair OUTcome (SPROUT), that predicts the length and probability of nucleotide insertions and deletions with R2 greater than 0.5. Surprisingly, we also observed large insertions at more than 90% of targeted loci, albeit at a low frequency. The inserted sequences aligned to diverse regions in the genome, and are enriched for sequences that are physically proximal to the break site due to chromatin interactions. This suggests a new mechanism where sequences from three-dimensionally neighboring regions of the genome can be inserted during DNA repair after Cas9-induced DNA breaks. Together, these findings provide powerful new predictive tools for Cas9-dependent genome editing and reveal new outcomes that can result from genome editing in primary T cells.

cell biology↗

bioRxiv2018

One read per cell per gene is optimal for single-cell RNA-Seq

An underlying question for virtually all single-cell RNA sequencing experiments is how to allocate the limited sequencing budget: deep sequencing of a few cells or shallow sequencing of many cells? A mathematical framework reveals that, for estimating many important gene properties, the optimal allocation is to sequence at the depth of one read per cell per gene. Interestingly, the corresponding optimal estimator is not the widely-used plugin estimator but one developed via empirical Bayes.

bioinformatics↗

bioRxiv2018

Somatic Mutations Render Human Exome and Pathogen DNA more Similar

Immunotherapy has recently shown important clinical successes in a substantial number of oncology indications. Additionally, the tumor somatic mutation load has been shown to associate with response to these therapeutic agents, and specific mutational signatures are hypothesized to improve this association, including signatures related to pathogen insults. We sought to study in silico the validity of these observations and addressed three questions. First, we investigated whether somatic mutations typically involved in cancer may increase, in a statistically meaningful manner, the similarity between common pathogens and the human exome. Our study shows that specific common mutagenic processes like those resulting from exposure to ultraviolet light (in melanoma) or smoking (in lung cancer) induce, in the upper range of biologically plausible frequencies, peptides in the cancer exome that are statistically more similar to pathogen peptides than the normal exome. Second, we investigated whether this increased similarity is due to the specificities of the mutagenic process or uniformly random mutations at equal rate would trigger the same effect. For certain pathogens the increased similarity is more pronounced for specific mutagenic processes than for uniformly random mutations and for other pathogens the effects cannot be distinguished. Finally, we investigated whether specific mutational processes result in amino-acid changes with functional relevance that are more likely to be immunogenic. We showed that functional tolerance to mutagenic processes across species generally suggests more resilience to natural processes than to denovo mutagenesis. These results support the idea that recognition of pathogen sequences as well as differential functional tolerance to mutagenic processes may play an important role in the immune recognition process involved in tumor infiltration by lymphocytes.

cancer biology↗