Bock, A. S. | bioRxiv Science

bioRxiv2026

Exploring the GM-CSF Histidine Triad as a Modulator of Structure, Molecular Motion, and Ligand Binding

Granulocyte macrophage-colony stimulating factor (GM-CSF) is a cytokine that plays a role in immune modulation. Its expression is associated with a multitude of different effects ranging from harmful, as in diseases such as rheumatoid arthritis and multiple sclerosis, to beneficial, as in the case of mitigation of diabetes type I and neutropenia. However, there is a large gap in knowledge explaining how GM-CSF toggles its structure for such physiological and pathological interactions. Our work describes an ongoing attempt to address this gap by focusing on a clustered histidine triad within -helices near the N-terminus, which prior studies have suggested play a role in binding ligands at an acidic pH. While GM-CSF is known to be highly flexible at a more acidic pH, several properties of its histidine triad remain unclear at the physiological pH at which GM-CSF would encounter its binding partners. We describe an effort to characterize the role of the GM-CSF histidines under physiological pH, specifically to determine if these histidines are key to GM-CSF structural integrity, and whether individual histidine residues modulate binding as they do at a lower pH. Our findings reveal that, while the histidine residues have an impact on GM-CSF structure, flexibility, and stability, they alone do not modulate the affinity for ligands at neutral pH. These data provide an initial explanation for the pleiotropic functions and interactions of GM-CSF within a biophysical context. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/700583v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@a6fffcorg.highwire.dtl.DTLVardef@1f00c30org.highwire.dtl.DTLVardef@b04c50org.highwire.dtl.DTLVardef@6224d9_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2023

Temporal sensitivity for achromatic and chromatic flicker across the visual cortex

The retinal ganglion cells (RGCs) receive different combinations of L, M, and S cone inputs and give rise to one achromatic and two chromatic post-receptoral channels. Beyond the retina, RGC outputs are subject to filtering and normalization along the geniculo-striate pathway, ultimately producing the properties of human vision. The goal of the current study was to determine temporal sensitivity across the three post-receptoral channels in subcortical and cortical regions involved in vision. We measured functional magnetic resonance imaging (MRI) responses at 7 Tesla from three participants (two males, one female) viewing a high-contrast, flickering, spatially-uniform wide field (~140{degrees}). Stimulus flicker frequency varied logarithmically between 2 and 64 Hz and targeted the L+M+S, L-M, and S-[L+M] cone combinations. These measurements were used to create temporal sensitivity functions of primary visual cortex (V1) across eccentricity, and spatially averaged responses from lateral geniculate nucleus (LGN), V2/V3, hV4, and V3A/B. Functional MRI responses reflected known properties of the visual system, including higher peak temporal sensitivity to achromatic vs. chromatic stimuli, and low-pass filtering between the LGN and V1. Peak temporal sensitivity increased across levels of the cortical visual hierarchy. Unexpectedly, peak temporal sensitivity varied little across eccentricity within area V1. Measures of adaptation and distributed pattern activity revealed a subtle influence of 64 Hz achromatic flicker in area V1, despite this stimulus evoking only a minimal overall response. Comparison of measured cortical responses to a model of integrated retinal output to our stimuli demonstrates that extensive filtering and amplification is applied to post-retinal signals. Significance StatementWe report the temporal sensitivity of human visual cortex across the three canonical post-receptoral channels from central vision to the far periphery. Functional MRI measurements of responses from the LGN, V1, and higher visual cortical areas demonstrate modification of temporal sensitivity across the visual hierarchy. This includes amplification of chromatic signals between the LGN and V1, and an increase in peak temporal sensitivity in visual areas beyond V1. Within V1, we find a surprising stability of peak temporal sensitivity in the periphery for all three post-receptoral directions. Comparison of our results to a model of retinal output demonstrates the presence of substantial post-retinal filtering, yielding greater uniformity of responses across area V1 than would be predicted from unmodified retinal signals.

neuroscience↗