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Salinas, C.

Publications and source records attributed to Salinas, C..

5 recordsLinked to original sources

Nutrient-sensitive histone propionylation regulates T cell fate and function

Tissue microenvironments differ widely in nutrient composition; yet how local nutrient conditions shape epigenetic programs that direct immune cell fate is poorly understood. We identify histone lysine propionylation (Kpr) as a chromatin mechanism linking nutrient availability to T cell fate decisions. Proteomic analysis reveals that Kpr is broadly reduced in exhausted T cells. H3K18pr is enriched at stemness-associated loci in effector T cells and depleted upon exhaustion. Isoleucine and propionate supply propionyl-CoA in T cells, and restricted nutrient availability within the tumor microenvironment limits histone Kpr, promoting T cell exhaustion. Disrupting isoleucine catabolism in T cells further suppresses Kpr, without altering histone acetylation, and impairs T cell function and antitumor immunity in a manner rescued by propionate. Dietary supplementation of isoleucine and propionate increases Kpr in tumor infiltrating lymphocytes, limits exhaustion, and improves tumor control. These findings establish a microenvironment-chromatin axis crucial for antitumor immunity and amenable to nutritional intervention.

immunology↗

Alpha oscillations in the temporoparietal junction causally shift feedback-based social learning computations in strategic negotiation

Human interactions span a range of contexts, from cooperation to competition. Negotiation, in particular, is a complex and extended social process in which individuals must reach mutually acceptable decisions despite conflicting incentives. The neural computations that support strategic behavior in such social dilemmas remain insufficiently understood. Here, we combine cognitive computational modeling, electroencephalography (EEG), functional Magnetic Resonance Imaging (fMRI), and fMRI-guided Transcranial Magnetic Stimulation (TMS) to demonstrate that oscillatory activity anchored in the temporoparietal junction (TPJ) causally shifts social learning during strategic bargaining. We found that TPJ metabolic activity and alpha-band oscillations are associated with the use of a feedback-based learning strategy during bargaining. Causal perturbation with rhythmic alpha-frequency TMS selectively modulates this strategy, increasing endogenous alpha oscillations and shifting behavioral learning parameters. Together, these findings reveal a frequency-specific mechanism within the neural substrates of social cognition that implements adaptive social learning, offering insights into potential neuromodulatory targets for ameliorating social dysfunction in neuropsychiatric conditions. Significance StatementStrategic negotiation requires predicting how others will respond to our actions, yet the neural computations supporting this form of social learning have remained elusive. By integrating computational modeling with EEG, fMRI, and frequency-specific TMS, we identify a mechanistic link between alpha-band activity in the temporoparietal junction (TPJ) and feedback-based learning during social exchange. Trial-by-trial estimates of this learning strategy were tracked by TPJ metabolic and oscillatory signals, and rhythmic alpha TMS causally enhanced both the neural signature and the behavioral expression of this strategy. These findings provide causal evidence for a frequency-specific mechanism within the neural systems that supports adaptive social learning. They also highlight the TPJ-alpha system as a promising target for neuromodulatory interventions to improve social functioning in neuropsychiatric conditions. Key FindingsO_LIModel-based behavioral analyses revealed two distinct strategies during social negotiation: a feedback-based learning mechanism (U-strategy) and a reputation-based updating mechanism (A-strategy). C_LIO_LIBoth strategies robustly predicted participants adaptive behavior across samples and conditions, and their modulation accounted for differences in negotiation outcomes. C_LIO_LIEEG analyses revealed frequency-specific alpha and beta power modulation linked to U-strategy computations during partner anticipation, localized to right temporoparietal regions. C_LIO_LIfMRI analyses revealed that trial-by-trial U-strategy estimates selectively modulated BOLD activity within the temporoparietal network associated with mentalizing. C_LIO_LIRhythmic alpha-frequency TMS over individually localized Theory-of-Mind TPJ sites causally altered negotiation behavior, shifting U-learning parameters toward a more conservative strategy. C_LIO_LITMS-EEG analyses demonstrated that alpha-frequency TMS induced time-locked alpha activity in functionally connected frontal sites, consistent with enhanced anticipatory computations. C_LIO_LITogether, these multimodal findings establish a causal, frequency-specific mechanism in the TPJ that implements social value learning during strategic bargaining. C_LI

neuroscience↗

Protocol to isolate oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons from a single mouse brain using magnetic-activated cell sorting

The isolation of specific cell types of the brain is essential to study cell-type-specific differences in complex neurological diseases such as Alzheimers disease. This protocol isolates oligodendrocytes, microglia, endothelial cells, astrocytes, and neurons from a single mouse brain. The process involves gentle tissue homogenization, debris removal, and sequential sorting of five distinct cell types. We validate cell purity and viability using flow cytometry and RT-qPCR. This protocol is well-suited for a range of downstream applications, including genomics, transcriptomics, and proteomics. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/666877v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1426b97org.highwire.dtl.DTLVardef@1a5bb77org.highwire.dtl.DTLVardef@1b69f32org.highwire.dtl.DTLVardef@8da416_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

Lateral Prefrontal Theta Oscillations Causally Drive a Computational Mechanism Underlying Conflict Expectation and Adaptation

Adapting our behavior to environmental demands relies on our capacity to perceive and manage potential conflicts within our surroundings. While evidence implicates the involvement of the lateral prefrontal cortex and theta oscillations in detecting conflict stimuli, their roles in conflict expectation remain elusive. Consequently, the exact computations and neural mechanisms underlying these cognitive processes still need to be determined. To address this gap, we employed an integrative approach involving cognitive computational modeling, fMRI, TMS, and EEG. Our results revealed a computational process underlying conflict expectation, which correlated with activity in the superior frontal gyrus (SFG). Furthermore, rhythmic TMS in the theta range applied over the SFG, but not over the inferior frontal junction, induced endogenous theta activity, enhancing computations associated with conflict expectation. These findings provide compelling evidence for the causal involvement of SFG theta activity in learning and allocating cognitive resources to address forthcoming conflict stimuli. Significant StatementAlterations in the processing of expectations of conflict events have been associated with several neuropsychiatric disorders that significantly affect the quality of life for many individuals. This article describes a cognitive computation underlying the conflict expectation and its causal neural mechanism involving theta brain activity in the superior frontal gyrus (SFG). Thus, unraveling this mechanism holds promise for developing interventions to address cognitive alterations related to anticipation of conflict events in neuropsychiatric disorders, improving overall cognitive function and quality of life.

neuroscience↗

Fast isolation of sub-nanomolar affinity alpaca nanobody against the Spike RBD of SARS-CoV-2 by combining bacterial display and a simple single-step density gradient selection

Despite unprecedented global efforts to rapidly develop SARS-CoV-2 treatments, in order to reduce the burden placed on health systems, the situation remains critical. Effective diagnosis, treatment, and prophylactic measures are urgently required to meet global demand: recombinant antibodies fulfill these requirements and have marked clinical potential. Here, we describe the fast-tracked development of an alpaca Nanobody specific for the receptor-binding-domain (RBD) of the SARS-CoV-2 Spike protein with therapeutic potential applicability. We present a rapid method for nanobody isolation that includes an optimized immunization regimen coupled with VHH library E. coli surface display, which allows single-step selection of high-affinity nanobodies using a simple density gradient centrifugation of the bacterial library. The selected single and monomeric Nanobody, W25, binds to the SARS-CoV-2 S RBD with sub-nanomolar affinity and efficiently competes with ACE-2 receptor binding. Furthermore, W25 potently neutralizes SARS-CoV-2 wild type and the D614G variant with IC50 values in the nanomolar range, demonstrating its potential as antiviral agent.

molecular biology↗