Biology subjects

Griffith, E.

Publications and source records attributed to Griffith, E..

4 recordsLinked to original sources

bioRxiv2025

Developmental Toxicity and Lethality of Structurally Diverse PFAS in Zebrafish

Per-and polyfluoroalkyl substances (PFAS) are ubiquitous environmental contaminants that have been associated with adverse health effects in highly exposed populations. Manufacturers have taken steps to replace toxic long-chain perfluoroalkyl acids (PFAAs) with short-chain PFAAs and perfluoroether acids (PFEAs). There is little to no toxicity data for many of these chemicals. Most of the data that are available are taken from studies that do not account for the pH of highly concentrated PFAS solutions, resulting in highly acidic conditions that do not accurately reflect real-world exposures. The goal of this study was to evaluate the lethality and developmental toxicity of 17 structurally diverse PFAS in zebrafish in a pH-neutral environment. We then compared results to determine the impacts of chain length, head group, and ether linkages on toxicity. The potency of PFAS to induce mortality and developmental toxicity endpoints increased with chain length, and sulfonic acids were more potent than carboxylic acids. The inclusion of ether oxygens was associated with reduced potency relative to PFAAs with equal chain length and head group. Perfluorooctane sulfonic acid (PFOS) was the most potent compound, followed by perfluoroundecanoic acid (PFUnDA) and perfluorododecanoic acid (PFDoDA). Short-chain compounds perfluoro-2-methoxyacetic acid (PFMOAA) and perfluorobutanoic acid (PFBA) were the least potent. These data were used to construct a multiple linear regression model for PFAS potency. Failed swim bladder inflation was the most sensitive developmental toxicity endpoint for all assessed chemicals. Other common phenotypes included spinal curvature, edema, craniofacial malformations, and ocular malformations. Ocular malformations were more common in response to sulfonic acids. No other phenotypes exhibited significant structural specificity. Our study provides new toxicity data for a diverse set of PFAS under environmentally relevant conditions. Future studies should be expanded to include more branched structures and head groups not present in our testing set to allow for improved understanding of how other structural features impact toxicity.

pharmacology and toxicology↗

bioRxiv2024

Mechanism of an Intrinsic Oscillation in Rat Geniculate Interneurons

Depolarizing current injections produced a rhythmic bursting of action potentials - a bursting oscillation - in a set of local interneurons in the lateral geniculate nucleus (LGN) of rats. The current dynamics underlying this firing pattern have not been determined, though this cell type constitutes an important cellular component of thalamocortical circuitry, and contributes to both pathologic and non-pathologic brain states. We thus investigated the source of the bursting oscillation using pharmacological manipulations in LGN slices in vitro and in silico. 1. Selective blockade of calcium channel subtypes revealed that high-threshold calcium currents IL and IP contributed strongly to the oscillation. 2. Increased extracellular K+ concentration (decreased K+ currents) eliminated the oscillation. 3. Selective blockade of K+ channel subtypes demonstrated that the calcium-sensitive potassium current (IAHP ) was of primary importance. A morphologically simplified, multicompartment model of the thalamic interneuron characterized the oscillation as follows: 1. The low-threshold calcium current (IT ) provided the strong initial burst characteristic of the oscillation. 2. Alternating fluxes through high-threshold calcium channels and IAHP then provided the continuing oscillations burst and interburst periods respectively. This interplay between IL and IAHP contrasts with the current dynamics underlying oscillations in thalamocortical and reticularis neurons, which primarily involve IT and IH, or IT and IAHP respectively. These findings thus point to a novel electrophysiological mechanism for generating intrinsic oscillations in a major thalamic cell type. Because local interneurons can sculpt the behavior of thalamocortical circuits, these results suggest new targets for the manipulation of ascending thalamocortical network activity.

neuroscience↗

bioRxiv2024

A Randomized, Controlled Clinical Trial Demonstrates Improved Cognitive Function in Senior Dogs Supplemented with a Senolytic and NAD+ Precursor Combination.

Age-related decline in mobility and cognition are associated with cellular senescence and NAD+ depletion in dogs and people. A combination of a novel NAD+ precursor and senolytic, LY-D6/2 was examined in this randomized controlled trial. Seventy dogs were enrolled and allocated into placebo, low or full dose groups. Primary outcomes were change in cognitive impairment measured with the owner-reported Canine Cognitive Dysfunction Rating (CCDR) scale and change in activity measured with physical activity monitors. Fifty-nine dogs completed evaluations at the three-month primary endpoint, and 51 reached the six-month secondary endpoint. There was a significant difference in CCDR score across treatment groups from baseline to the primary endpoint (p=0.02) with the largest decrease in the full dose group. There were no significant differences between groups in changes in measured activity. However, the proportion of dogs that improved in frailty and owner-reported activity levels and happiness was higher in the full dose group than other groups. Adverse events occurred equally across groups. All groups showed improvement in cognition, frailty, and activity suggesting placebo effect and benefits of trial participation. We conclude that LY-D6/2 significantly improves owner-assessed cognitive function and may have broader effects on frailty, activity and happiness as reported by owners.

animal behavior and cognition↗

bioRxiv2020

Taxonomy of neural oscillation events in primate auditory cortex

Electrophysiological oscillations in the brain have been shown to occur as multi-cycle events, with onset and offset dependent on behavioral and cognitive state. To provide a baseline for state-related and task-related events, we quantified oscillation features in resting-state recordings. We used two invasively-recorded electrophysiology datasets: one from human, and one from non-human primate auditory system. After removing incidentally occuring event related potentials, we used a wavelet transform based method to quantify oscillation features. We identified about 2 million oscillation events, classified within traditional frequency bands: delta, theta, alpha, beta, low gamma, gamma, high gamma. Oscillation events of 1-44 cycles were present in at least one frequency band in 90% of the time in human and non-human primate recordings. Individual oscillation events were characterized by non-constant frequency and amplitude. This result naturally contrasts with prior studies which assumed such constancy, but is consistent with evidence from event-associated oscillations. We measured oscillation event duration, frequency span, and waveform shape. Oscillations tended to exhibit multiple cycles per event, verifiable by comparing filtered to unfiltered waveforms. In addition to the clear intra-event rhythmicity, there was also evidence of inter-event rhythmicity within bands, demonstrated by finding that coefficient of variation of interval distributions and Fano Factor measures differed significantly from a Poisson distribution assumption. Overall, our study demonstrates that rhythmic, multi-cycle oscillation events dominate auditory cortical dynamics.

neuroscience↗