Biology subjects

Holmes, W.

Publications and source records attributed to Holmes, W..

5 recordsLinked to original sources

bioRxiv2026

A harmonized phantom MRI quality control framework identifies sources of longitudinal and multi-site variability

The shift towards open science in preclinical research requires high-quality, comparable data adhering to FAIR principles, yet rigorous quality assurance (QA) and quality control (QC) frameworks remain less established in preclinical magnetic resonance imaging (MRI) than in clinical imaging. To address this limitation, a multicenter study was conducted across 21 international laboratories using standardized commercial liquid phantoms for mouse and rat MRI setups and a harmonized acquisition protocol. Data processing was centralized using AIDAqc, an automated pipeline extracting quantitative metrics including signal-to-noise ratio (SNR), temporal SNR (tSNR), ghost-to-signal ratio (GSR), and motion-equivalent temporal instability, combined with five complementary outlier-detection algorithms. The evaluated datasets encompassed magnetic field strengths from 3.0 to 16.4 T and heterogeneous coil and acquisition configurations. In mouse phantom data, SNR and tSNR were significantly lower at 3 T than at 7 and 9.4 T, whereas artifact-related metrics did not differ significantly between field-strength groups. In rat phantom data, differences between field strengths were less pronounced. At 7 T, substantial dataset-specific differences were observed in anatomical and functional quality metrics, also among datasets using the similar coil configuration. Multicenter reference values for frequently represented 7 T configurations were established, including SNR/tSNR of 48 {+/-} 3/48 {+/-} 1 dB for mouse surface-coil datasets and 49 {+/-} 3/44 {+/-} 4 dB for rat array-coil datasets. Longitudinal anatomical SNR showed generally low variability, whereas ghosting was more variable across time. Automated outlier detection additionally identified transient acquisition instabilities that were not always apparent by visual inspection. Together, these findings show that field strength and nominal coil configuration alone do not adequately characterize MRI performance and support standardized, longitudinal phantom-based QC combined with automated analysis as a practical approach for improving the reliability, transparency, and interoperability of multicenter preclinical MRI data.

bioengineering↗

bioRxiv2023

Predicting Molecular Docking Affinity of Per- and Polyfluoroalkyl Substances (PFAs) Towards Human Blood Proteins Using Generative AI Algorithm DiffDock

This study computationally evaluates the molecular docking affinity of various perfluoroalkyl and polyfluoroalkyl substances (PFAs) using a generative machine learning algorithm, DiffDock, specialized in protein-ligand blind-docking learning and prediction. Concerns about the chemical pathways and accumulation of PFAs in the environment and eventually in human body has been rising due to empirical findings that levels of PFAs in human blood has been rising. Though there is currently a heightened need to understand the pathways of PFAs, empirical studies on PFAs have been relatively slow due to the time-scale and cost of standard chemical analysis such as those in blood samples. The current study demonstrates the implementation of DiffDock and assesses the prediction results in relation to empirical findings. The capability of an advanced generative artificial intelligence (AI) algorithm designed for protein-ligand docking such as DiffDock offers a fast approach in determining the potential molecular pathways of PFAs in human body.

bioinformatics↗

bioRxiv2019

Urgency, Leakage, and the Relative Nature of Information Processing in Decision Making

Over the last decade, there has been a robust debate in decision neuroscience and psychology about what mechanism governs the time course of decision making. Historically, the most prominent hypothesis is that neural architectures accumulate information over time until some threshold is met, the so-called Evidence Accumulation hypothesis. However, most applications of this theory rely on simplifying assumptions, belying a number of potential complexities. Is changing stimulus information perceived and processed in an independent manner or is there a relative component? Does urgency play a role? What about evidence leakage? Although the latter questions have been the subject of recent investigations, most studies to date have been piecemeal in nature, addressing one aspect of the decision process or another. Here we develop a modeling framework, an extension of the Urgency Gating Model, in conjunction with a changing information experimental paradigm to simultaneously probe these aspects of the decision process. Using state-of-the-art Bayesian methods to perform parameter-based inference, we find that 1) information processing is relative with early information influencing the perception of late information, 2) time varying urgency and evidence accumulation are of roughly equal importance in the decision process, and 3) leakage is present with a time scale of ~200-250ms. To our knowledge, this is the first comprehensive study to utilize a changing information paradigm to jointly and quantitatively estimate the temporal dynamics of human decision-making.

neuroscience↗

bioRxiv2019

Microtubules Regulate Spatial Localization and Availability of Insulin Granules in Pancreatic Beta Cells.

Two key prerequisites for glucose stimulated insulin secretion (GSIS) in Beta cells are the proximity of insulin granules to the plasma membrane and their anchoring or docking to the plasma membrane (PM). While recent evidence has indicated that both of these factors are altered in the context of diabetes, it is unclear what regulates localization of insulin and its interactions with the PM within single cells. Here we demonstrate that microtubule (MT) motor mediated transport dynamics have a critical role in regulating both factors. Super-resolution imaging shows that while the MT cytoskeleton resembles a random meshwork in the cells interior, MTs near the cells surface are preferentially aligned with the PM. Computational modeling demonstrates two consequences of this alignment. First, this structured MT network preferentially withdraws granules from the PM. Second, the binding and transport of insulin granules by MT motors prevents their stable anchoring to the PM. The MT cytoskeleton thus negatively regulates GSIS by both limiting the amount of insulin proximal to the PM and preventing/breaking interactions between the PM and the remaining nearby insulin. These results predict that altering MT structure in beta cells can be used to tune GSIS. Thus, our study points to a potential of an alternative therapeutic strategy for diabetes by targeting specific MT regulators.

cell biology↗

bioRxiv2018

Sub-diffusive dynamics lead to depleted particle densities near cellular borders

It has long been known that the complex cellular environment leads to anomalous motion of intracellular particles. At a gross level, this is characterized by mean squared displacements that deviate from the standard linear profile. Statistical analysis of particle trajectories has helped further elucidate how different characteristics of the cellular environment can introduce different types of anomalousness. A significant majority of this literature has however focused on characterizing the properties of trajectories that do not interact with cell borders (e.g. cell membrane or nucleus). Numerous biological processes ranging from protein activation to exocytosis however require particles to be near a membrane. This study investigates the consequences of a canonical type of sub-diffusive motion, Fractional Brownian Motion (FBM), and its physical analogue Generalized Langevin Equation (GLE) Dynamics, on the spatial localization of particles near reflecting boundaries. Results show that this type of sub-diffusive motion leads to the formation of significant zones of depleted particle density near boundaries, and that this effect is independent of the specific model details encoding those dynamics. Rather these depletion layers are a natural and robust consequence of the anti-correlated nature of motion increments that is at the core of FBM / GLE dynamics. If such depletion zones are present, it would be of profound importance given the wide array of signaling and transport processes that occur near membranes. If not, that would suggest our understanding of this type of anomalous motion may be flawed. Either way, this result points to the need to further investigate the consequences of anomalous particle motions near cell borders from both theoretical and experimental perspectives.

biophysics↗