Biology subjects

McComas, S.

Publications and source records attributed to McComas, S..

3 recordsLinked to original sources

bioRxiv2026

Cognitive reserve depends on cortical neurochemistry to predict memory after partner-inflicted brain injury

Memory problems are commonplace following brain injury (BI). However, it remains unclear why some report memory problems while others do not, especially following repeated neurotrauma. Cognitive reserve has been widely hypothesized to account for this variation, but testing this account has yielded inconsistent results and proven difficult, likely as it requires a sample spanning a wide range of BI burden with concurrent neuroimaging and cognitive measurement. Here, we combined a wide range of cognitive assessments with measures of neuronal health using magnetic resonance spectroscopy across three brain regions in 62 women who had experienced physical intimate partner violence. Partner-inflicted BI counts ranged from 0 to 420, yet we found that the number of BIs alone did not explain the variance in memory outcomes. Among a small subset with high BI exposure ([≥]10 BIs; n = 11), BI count explained 5% of the variance in delayed recall, the primary memory outcome, whereas cognitive reserve, inferred from a measure of premorbid functioning, explained almost half (unadjusted in-sample associations). In the full cohort, cognitive reserve predicted memory only among the most heavily injured participants. In a separate model, cognitive reserve predicted memory only when creatine-referenced total N-acetylaspartate, a marker of neuronal health, was lower in the posterior cingulate gyrus and dorsolateral prefrontal cortex. Ultimately, our findings provide behavioral and neurochemical evidence consistent with the cognitive reserve hypothesis and shed new light on why, despite a high burden of neurotrauma, memory may remain resilient.

neuroscience↗

bioRxiv2022

Determinants of sugar-induced influx in the mammalian fructose transporter GLUT5

In mammals, glucose transporters (GLUT) control organism-wide blood glucose homeostasis. In human, this is accomplished by fourteen different GLUT isoforms, that transport glucose and other monosaccharides with varying substrate preferences and kinetics. Nevertheless, there is little difference between the sugar-coordinating residues in the GLUT proteins and even the malarial plasmodium falciparum transporter PfHT1, which is uniquely able to transport a wide range of different sugars. PfHT1 was captured in an intermediate "occluded" state, revealing how the extracellular gating helix TM7b has moved to break and occlude the sugar-binding site. Sequence difference and kinetics indicated that the TM7b gating helix dynamics and interactions likely evolved to enable substrate promiscuity in PfHT1, rather than the sugar-binding site itself. It was unclear, however, if the TM7b structural transitions observed in PfHT1 would be similar in the other GLUT proteins. Here, using enhanced sampling molecular dynamics simulations, we show that the fructose transporter GLUT5 spontaneously transitions through an occluded state that closely resembles PfHT1. The coordination of fructose lowers the energetic barriers between the outward and inward-facing states, and the observed binding mode for fructose is consistent with biochemical analysis. Rather than a substrate binding site that achieves strict specificity by having a high-affinity for the substrate, we conclude GLUT proteins have allosterically coupled sugar binding with an extracellular gate that forms the high-affinity transition-state instead. This substrate-coupling pathway presumably enables the catalysis of fast sugar flux at physiological relevant blood-glucose concentrations.

biophysics↗

bioRxiv2021

An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing Asparagine

Voltage-gated sodium (Nav) channels play critical roles in propagating action potentials and otherwise manipulating ionic gradients in excitable cells. These channels open in response to membrane depolarization, selectively permeating sodium ions until rapidly inactivating. Structural characterization of the gating cycle in this channel family has proved challenging, particularly due to the transient nature of the open state. A structure from the bacterium Magnetococcus marinus Nav (NavMs) was initially proposed to be open, based on its pore diameter and voltage-sensor conformation. However, the functional annotation of this model, and the structural details of the open state, remain disputed. In this work, we used molecular modeling and simulations to test possible open-state models of NavMs. The full-length experimental structure, termed here the -model, was consistently dehydrated at the activation gate, indicating an inability to conduct ions. Based on a spontaneous transition observed in extended simulations, and sequence/structure comparison to other Nav channels, we built an alternative {pi}-model featuring a helix transition and the rotation of a conserved asparagine residue into the activation gate. Pore hydration, ion permeation and state-dependent drug binding in this model were consistent with an open functional state. This work thus offers both a functional annotation of the full-length NavMS structure, and a detailed model for a stable Nav open state, with potential conservation in diverse ion-channel families.

biophysics↗