Biology subjects

Soto, G.

Publications and source records attributed to Soto, G..

5 recordsLinked to original sources

bioRxiv2026

Antibodies with Engineered Fc Domains Having Absolute Binding Selectivity to either FcγRIIa or FcγRI Delineate the Respective Effector Phenotypes by Human Monocytes and Macrophages

IgG1 immune complexes bind to all the Fc{gamma} receptors (Fc{gamma}R) expressed on myeloid cells, making it challenging to determine the precise role of each Fc{gamma}R on Fc effector phenotypes. Here we report the engineering of Fc2KG, an aglycosylated human IgG1 Fc domain that binds with near physiological affinity to Fc{gamma}RIIa/b with no detectable binding to any other Fc{gamma}Rs. Crystallographic analysis elucidated the structural basis of how mutations in the Fc domain compensate for the absence of the N297 glycan and enable selective binding. Using single-cell phagocytosis assays, we show that particles opsonized with Fc-engineered antibodies formatted with Fc2KG or with an Fc domain that binds only Fc{gamma}RI (Fc5), are ingested by THP-1 cells with near identical kinetics. We find that with CD16+ primary human monocytes, selective Fc{gamma}RII engagement is a major contributor to the ADCP mediated by wild-type IgG1. Additionally, we showed that Fc2KG formatted antibodies induce high levels of GM-CSF. With M1-like monocyte-derived human macrophages, trastuzumab formatted with wild-type IgG1 Fc, with Fc2KG or Fc5 were all equally proficient in the trogocytotic killing of opsonized SK-BR-3 HER2+ cells but only Fc{gamma}RI engagement led to secretion of proinflammatory cytokines. Collectively, our results highlight how precisely tuned, Fc-engineered antibodies can be deployed to answer long-standing questions regarding the precise effector functions mediated by human Fc{gamma}Rs, information which is key for the optimization of therapeutic antibodies.

immunology↗

bioRxiv2025

Species-specific oculomotor control tolerances predict saccadic suppression strength in macaques and zebrafish

Active sensing necessarily requires integrating information about both self-generated movements as well as past, present, and future afferent inputs. However, such information is inherently variable and relies, at least in part, on uncertain extrapolations. Here, using saccadic suppression of visual sensitivity as a classic example of sensory-motor integration, we show that suppression strength in two drastically different species, macaque monkeys and zebrafish larvae, may be a direct outcome of efficient state estimation in the presence of uncontrollable sensory and motor variability. Bayesian estimator models suggest that optimal saccadic suppression should rely not just on the sensory-motor information being processed, but also on the time-dependent magnitude of unexplained variability in the nervous system encoding it. In both macaques and zebrafish larvae, and using matching visual stimulation regimes optimized for each species receptive field properties, we experimentally measured saccadic suppression strength in the superior colliculus (SC) of the monkeys and the homologous optic tectum (OT) of the fish. We also experimentally quantified additive and multiplicative motor noise components in the oculomotor behavior of both species, and we furthermore estimated noise in the sensory systems. We found that inter-species differences in sensory and motor noise levels and their theoretically predicted impacts on visual sensitivity are consistent with our experimentally observed differences in saccadic suppression strength between the fish and the monkeys. Because sensory and motor noise levels can reflect the amounts of available neural resources committed to a given task, our results strongly underscore the value of incorporating computational resource limits into investigating performance differences that have evolved in homologous brain areas.

neuroscience↗

bioRxiv2025

Saccadic Suppression Enhances Saliency of Prey-Like Stimuli in the Optic Tectum

Saccadic suppression, a reduction in visual sensitivity around the time of rapid eye movements, is well-documented in primate psychophysics but its mechanisms and functions remain debated. Here, we use zebrafish to trace the origins of saccadic suppression and we demonstrate how saccadic suppression selectively enhances the visual salience of ecologically relevant stimuli. Saccadic suppression thus contributes to more than just compensation for rapid saccade-induced image shifts. We first established a behavioral correlate of saccadic suppression in larval zebrafish escape behavior. Then, using electrophysiology, we show that retinal ganglion cells jumpstart saccadic suppression in a spatial frequency dependent manner. Calcium imaging, combined with 360{degrees} visual stimulation and behavioral tracking, revealed that motor signals enhance peri-saccadic suppression strength in the optic tectum, where suppression lasts for more than 3000 ms. Notably, saccadic suppression is much weaker and more short-lived for stimuli related to hunting or escape behavior than for behaviorally less relevant global flashes. This unequal attenuation effectively increases the salience of the ecologically relevant stimuli in the optic tectum after saccades. Our results demonstrate that saccadic suppression integrates visual and motor signals to optimize sensory processing within neural constraints, and they provide insights into evolutionarily conserved visual strategies.

neuroscience↗

bioRxiv2021

Cell type and subcellular compartment specific APEX2 proximity labeling proteomics in the mouse brain

The vertebrate brain consists of diverse neuronal types, classified by distinct anatomy and function, along with divergent transcriptomes and proteomes. Defining the cell type-specific neuroproteome is important for understanding the development and functional organization of neural circuits. This task remains challenging in complex tissue, due to suboptimal protein isolation techniques that often result in loss of cell-type specific information and incomplete capture of subcellular compartments. Here, we develop a genetically targeted proximity labeling approach to identify cell-type specific subcellular proteome in the mouse brain. Using adeno- associated viral transduction, we express subcellular-localized APEX2 to map the proteome of the nucleus, cytosol, and cell membrane of Drd1 receptor-positive striatal neurons. We show that each APEX2 construct can differentially and rapidly biotinylate proteins in situ across various subcellular compartments, confirmed by imaging, electron microscopy, and mass spectrometry. This method enables flexible, cell-type specific quantitative profiling of subcellular proteome in the mouse brain.

neuroscience↗

bioRxiv2020

Pathway-specific deregulation of striatal excitatory synapses in LRRK2 mutations

LRRK2 is a kinase expressed in striatal spiny projection neurons (SPNs), cells which lose dopaminergic input in Parkinsons disease (PD). R1441C and G2019S are the most common pathogenic mutations of LRRK2. How these mutations alter the structure and function of individual synapses on direct and indirect pathway SPNs is unknown and may reveal pre-clinical changes in dopamine-recipient neurons that predispose towards disease. Here, R1441C and G2019S knock-in mice enabled thorough evaluation of dendritic spines and synapses on pathway-identified SPNs. Biochemical synaptic preparations and super-resolution imaging revealed increased levels and altered organization of glutamatergic AMPA receptors in LRRK2 mutants. Relatedly, decreased frequency of excitatory post-synaptic currents accompanied changes in dendritic spine nano-architecture, and single-synapse currents, evaluated using 2-photon glutamate uncaging. Overall, LRRK2 mutations reshaped synaptic structure and function, an effect exaggerated in R1441C dSPNs. These data open the possibility of new neuroprotective therapies aimed at SPN synapse function, prior to disease onset.

neuroscience↗