Biology subjects

Keung, W.

Publications and source records attributed to Keung, W..

5 recordsLinked to original sources

bioRxiv2025

The dynamics of explore-exploit decisions suggest a threshold mechanism for reduced random exploration in older adults

When faced with a choice between exploring an unknown option vs exploiting an option they know well, older adults explore less and exploit more than younger adults. Recent work has suggested that one cause of this age difference in exploration is a reduction in the extent to which older adults use "random exploration" - exploration driven by behavioral variability. Here we investigate potential mechanisms for this age-related difference in random exploration through the lens of a drift diffusion model (DDM) of the explore-exploit choice. In this model, random exploration can be modulated by two mechanisms - the fidelity with which information about the choice is represented in the brain, the "signal-to-noise ratio" (SNR), and the amount of information required to make a decision, the "decision threshold." Reduced random exploration in aging could be caused either by an increase in signal-to-noise ratio or an increase in decision threshold in older adults. By fitting the DDM to choices and response times in a sample of healthy younger and older adults, we found that older adults had a lower SNR and a higher threshold than younger adults. This suggests that reduced random exploration in aging is driven by higher response thresholds in older adults, which may compensate for the reduced signal-to-noise ratio with which decision information is represented in the brain. Author SummaryThe balance of deciding to explore the unknown, versus exploiting the well-known, changes with age. Compared to younger counterparts, healthy older adults have reduced random exploration, in which choices appear uninfluenced by the value of options. To investigate the mechanism of reduced random exploration, reaction time and choices between two slot machines in the Horizon Task were modelled using the drift diffusion model (DDM). In the DDM there is an accumulation of evidence over time, until a boundary threshold for either the explore or exploit option is crossed. The DDM used here can distinguish between two different drivers of random exploration, changes in the signal-to-noise ratio (SNR), with which reward information is represented, and changes in the threshold required to make a decision. We showed that reduced random exploration in older adults results from a higher decision threshold. Whilst older adults had a lower SNR than younger adults, which could lead to more mistakes, older adults actually performed slightly better in the Horizon task than younger adults. Together this suggests that the higher decision threshold could be a healthy aging adaptation, which is overcompensating for the less accurate choices that could result from a lower SNR alone.

neuroscience↗

bioRxiv2024

Reversal of contractile defects by mediating calcium homeostasis in human mini-heart models of heart failure with preserved ejection fraction (HFpEF) leads to first-in-human gene therapy clinical trial

AimsHeart failure with preserved ejection fraction (HFpEF), is a global health problem lacking disease-modifying therapeutic options, reflecting a lack of predictive models for preclinical drug testing. Aligned with FDA Modernization Act 2.0, we aimed to create the first in vitro human-specific mini-heart models of HFpEF, and to test the efficacy of a candidate gene therapy to improve cardiac kinetics and correct the disease phenotype. Methods and ResultsHealthy human pluripotent stem cell-derived ventricular cardiomyocytes were used to bioengineer beating cardiac tissue strips and pumping cardiac chambers. When conditioned with transforming growth factor-{beta}1 and endothelin-1, these mini-heart models exhibited signature disease phenotypes of significantly elevated diastolic force and tissue stiffness, and slowed contraction and relaxation kinetics, with no significant deficit in systolic force or ejection fraction versus unconditioned controls. Bioinformatic analysis of bulk RNA sequencing data from HFpEF mini-heart models and patient ventricular samples identified downregulation of SERCA2a of the calcium signalling pathway as a key differentially expressed gene. After dosage optimization, AAV-mediated expression of SERCA2a abrogated the disease phenotype and improved the cardiac kinetics in HFpEF mini-Hearts. ConclusionsThese findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF, with Fast Track designation. We conclude that such human-based disease-specific mini-heart platforms are relevant for target discovery and validation that can facilitate clinical translation of novel cardiac therapies. Translational PerspectiveHeart failure with preserved ejection fraction (HFpEF) is a significant and growing global health concern lacking disease-modifying therapeutic options, reflecting inadequate preclinical models of the disease. Aligned with FDA Modernization Act 2.0, we created the first in vitro human-specific mini-heart models of HFpEF, demonstrated phenotypic disease characteristics of elevated stiffness and slowed kinetics, showed transcriptomic consistency with HFpEF patient data, identified SERCA2a as a key downregulated gene, performed dosing titration of SERCA2a gene therapy, and showed improvement of cardiac kinetics post-treatment. The findings contributed to FDA approval of an ongoing first-in-human gene therapy clinical trial for HFpEF.

bioengineering↗

bioRxiv2023

APLNR marks a cardiac progenitor derived with human induced pluripotent stem cells

Cardiomyocytes can be readily derived from human induced pluripotent stem cell (hiPSC) lines, yet its efficacy varies across different batches of the same and different hiPSC lines. To unravel the inconsistencies of in vitro cardiac differentiation, we utilized single cell transcriptomics on hiPSCs undergoing cardiac differentiation and identified cardiac and extra-cardiac lineages throughout differentiation. We further identified APLNR as a surface marker for in vitro cardiac progenitors and immunomagnetically isolated them. Differentiation of isolated in vitro APLNR+ cardiac progenitors derived from multiple hiPSC lines resulted in predominantly cardiomyocytes accompanied with cardiac mesenchyme. Transcriptomic analysis of differentiating in vitro APLNR+ cardiac progenitors revealed transient expression of cardiac progenitor markers before further commitment into cardiomyocyte and cardiac mesenchyme. Analysis of in vivo human and mouse embryo single cell transcriptomic datasets have identified APLNR expression in early cardiac progenitors of multiple lineages. This platform enables generation of in vitro cardiac progenitors from multiple hiPSC lines without genetic manipulation, which has potential applications in studying cardiac development, disease modelling and cardiac regeneration.

cell biology↗

bioRxiv2019

A divisive model of evidence accumulation explains uneven weighting of evidence over time

Divisive normalization has long been used to account for computations in various neural processes and behaviours. The model proposes that inputs into a neural system are divisively normalized by the total activity of the system. More recently, dynamical versions of divisive normalization have been shown to account for how neural activity evolves over time in value-based decision making. Despite its ubiquity, divisive normalization has not been studied in decisions that require evidence to be integrated over time. Such decisions are important when we do not have all the information available at once. A key feature of such decisions is how evidence is weighted over time, known as the integration kernel. Here we provide a formal expression for the integration kernel in divisive normalization, and show that divisive normalization can quantitatively account for the perceptual decision making behaviour of 133 human participants, performing as well as the state-of-the-art Drift Diffusion Model, the predominant model for perceptual evidence accumulation.

neuroscience↗

bioRxiv2018

Regulation of evidence accumulation by pupil-linked arousal processes

Integrating evidence over time is crucial for effective decision making. For simple perceptual decisions, a large body of work suggests that humans and animals are capable of integrating evidence over time fairly well, but that their performance is far from optimal. This suboptimality is thought to arise from a number of different sources including: (1) noise in sensory and motor systems, (2) unequal weighting of evidence over time, (3) order effects from previous trials and (4) irrational side biases for one choice over another. In this work we investigated these di.erent sources of suboptimality and how they are related to pupil dilation, a putative correlate of norepinephrine tone. In particular, we measured pupil response in humans making a series of decisions based on rapidly-presented auditory information in an evidence accumulation task. We found that people exhibited all four types of suboptimality, and that some of these suboptimalities covaried with each other across participants. Pupillometry showed that only noise and the uneven weighting of evidence over time, the integration kernel, were related to the change in pupil response during the stimulus. Moreover, these two different suboptimalities were related to different aspects of the pupil signal, with the individual differences in pupil response associated with individual differences in integration kernel, while trial-by-trial fluctuations in pupil response were associated with trial-by-trial fluctuations in noise. These results suggest that di.erent sources of suboptimality in human perceptual decision making are related to distinct pupil-linked processes possibly related to tonic and phasic norepinephrine activity.

neuroscience↗