Biology subjects

Verheij, M.

Publications and source records attributed to Verheij, M..

3 recordsLinked to original sources

bioRxiv2025

Increased cocaine self-administration and prefrontal cortical dysregulation of glutamatergic and GABAergic signaling in a rat model for sensory processing sensitivity

While all organisms are tuned to the environment, some are more sensitive than others. In humans, this is reflected by the trait sensory processing sensitivity (SPS), comprising 20-30% of the population, which is characterized by heightened emotional reactivity, deeper information processing, greater awareness of their environment, and susceptibility to overstimulation. It is expected but unproven that high SPS increases the risk for psychostimulant use. To clarify this, we selected Wistar rats on behavioral extremes related to SPS and subjected them to isolation, neutral, and enriched housing conditions, followed by cocaine self-administration (S/A). Subsequently, we investigated neurobiological differences in excitatory/inhibitory neurotransmission of the low- and high SPS-like rats by evaluating key glutamatergic and GABAergic proteins in the infralimbic (ILc) and prelimbic (PLc) subregions of the prefrontal cortex. High SPS-like rats displayed higher cocaine intake during 1h S/A training sessions in isolated versus social conditions, whereas low SPS-like rats showed similar intake across housing conditions. During 6h S/A sessions, high SPS-like rats displayed a higher cocaine intake regardless of housing and greater motivation for cocaine under a progressive ratio scheme. High SPS-like cocaine-naive rats exhibited lower expression of glutamatergic and GABAergic markers in ILc and PLc compared to low SPS-like cocaine-naive rats. The opposite occurred after cocaine exposure: low and high SPS-like rats showed lower and higher expression levels, respectively, compared to naive counterparts. In conclusion, these findings suggest that a high SPS-like trait with associated glutamatergic and GABAergic alterations might be a risk factor for the development of cocaine use disorder.

neuroscience↗

bioRxiv2024

TRIP12 governs DNA Polymerase β involvement in DNA damage response and repair

The multitude of DNA lesion types, and the nuclear dynamic context in which they occur, present a challenge for genome integrity maintenance as this requires the engagement of different DNA repair pathways. Specific repair controllers that facilitate DNA repair pathway crosstalk between double strand break (DSB) repair and base excision repair (BER), and regulate BER protein trafficking at lesion sites, have yet to be identified. We find that DNA polymerase {beta} (Pol{beta}), crucial for BER, is ubiquitylated in a BER complex-dependent manner by TRIP12, an E3 ligase that partners with UBR5 and restrains DSB repair signaling. Here we find that, TRIP12, but not UBR5, controls cellular levels and chromatin loading of Pol{beta}. Required for Pol{beta} foci formation, TRIP12 regulates Pol{beta} involvement after DNA damage. Notably, excessive TRIP12-mediated shuttling of Pol{beta} affects DSB formation and radiation sensitivity, underscoring its precedence for BER. We conclude that the herein discovered trafficking function at the nexus of DNA repair signaling pathways, towards Pol{beta}-directed BER, optimizes DNA repair pathway choice at complex lesion sites. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=165 SRC="FIGDIR/small/588474v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@70c5bdorg.highwire.dtl.DTLVardef@1c60dfborg.highwire.dtl.DTLVardef@1c00ef6org.highwire.dtl.DTLVardef@1677f2_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2018

Radiotherapy and cisplatin increase immunotherapy efficacy by enabling local and systemic intratumoral T-cell activity

To increase cancer immunotherapy success, PD-1 blockade must be combined with rationally selected treatments. Here, we examined in a poorly immunogenic mouse breast cancer model the potential of antibody-based immunomodulation and conventional anti-cancer treatments to collaborate with anti-PD-1 treatment. One important requirement to improve anti-PD-1-mediated tumor control was to promote tumor-specific cytotoxic T cell (CTL) priming, which was achieved by stimulating the CD137 costimulatory receptor. A second requirement was to overrule PD-1-unrelated mechanisms of CTL suppression in the tumor micro-environment (TME). This was achieved by radiotherapy and cisplatin treatment. In the context of CD137/PD-1-targeting immunotherapy, radiotherapy allowed for tumor elimination by altering the TME, rather than intrinsic CTL functionality. Combining this radioimmunotherapy regimen with low-dose cisplatin improved CTL-dependent regression of a contralateral tumor outside the radiation field. Thus, systemic tumor control may be achieved by combining immunotherapy protocols that promote T cell priming with (chemo)radiation protocols that permit CTL activity in both the irradiated tumor and (occult) metastases.\n\nSummary statementThis study reveals that radiotherapy and cisplatin can be re-purposed to improve antibody-based immunotherapy success in poorly immunogenic breast cancer by overruling PD-1 unrelated mechanisms of T cell suppression in the tumor micro-environment.

cancer biology↗