Biology subjects

Sipos, E.

Publications and source records attributed to Sipos, E..

4 recordsLinked to original sources

bioRxiv2025

Spatial dissection of ADC/RPT targets defines therapeutic opportunities inrhabdoid tumors

Rhabdoid tumors (RT) are among the most aggressive pediatric malignancies, characterized by early onset, loss of SWI/SNF complex members (SMARCB1 or SMARCA4), and dismal outcomes despite multimodal therapy. Refractory and relapsing RT remain almost uniformly fatal, and targeted or immune-based approaches have yet to demonstrate clinical benefit. To explore novel therapeutic vulnerabilities, we systematically investigated the expression of clinically actionable surface proteins that could serve as targets for antibody-drug conjugates (ADCs), radiopharmaceutical therapy (RPT), or cellular immunotherapies. Based on large-scale transcriptomic analyses, we prioritized FAP, CXCR4, and IL13RA2 and performed comprehensive protein-level validation by immunohistochemistry in an unprecedented cohort of 60 rhabdoid tumors spanning all molecular subgroups (ATRT-TYR, ATRT-SHH, ATRT-MYC, and eMRT). Integrating these data with spatial and single-nucleus transcriptomic profiling, we identified subgroup- and cell-type-specific expression patterns, including heterogeneous FAP distribution between stromal and tumor compartments and a distinct IL13RA2-positive rhabdoid cell population with melanosomal and stem-like features. These findings define a set of biologically and clinically relevant surface targets in RT and provide a translational blueprint for rational ADC and RPT target discovery in pediatric cancer.

cancer biology↗

bioRxiv2025

Epigenetic mechanisms governing cell type specific somatic expansion and toxicity in Huntington's disease

Huntingtons disease (HD) is characterized by neuronal dysfunction and degeneration that varies markedly by brain region and cell type. Using high-resolution epigenetic profiling of postmortem human cell types we identify a pathogenic cascade linking cell type specific enhancer activity to somatic CAG expansion, and toxicity to epigenetic dysregulation. Enhancers regulating mismatch-repair (MMR) gene expression explain the specificity of expansion. In the second, toxic phase of HD we identify two distinct epigenetic mechanisms that disrupt regulation of hundreds of genes in the majority of HD MSNs, including several that cause haploinsufficient neurological disorders. Together, these data unify enhancer function, impaired DNA demethylation, and transcriptional dysregulation into a single model highlighting therapeutic opportunities that combine inhibition of somatic CAG expansion with restoration of neuronal DNA demethylation.

neuroscience↗

bioRxiv2025

Optical recordings of unitary synaptic connections reveal high and random local connectivity between CA3 pyramidal cells

The hippocampal CA3 region is thought to play crucial roles in episodic memory functions because of the extensive recurrent connections between CA3 pyramidal cells (CA3PCs). However, different methods provided contradicting observations about the synaptic connectivity between CA3PCs. Therefore, we estimated the connectivity rate between individual CA3PCs using a new approach that is not affected by the confounds of conventional methods. Specifically, we used voltage imaging with the Voltron sensor in acute slices from rats of both sexes to test CA3PC connections by detecting spontaneous spiking and subthreshold responses in anatomically identified neurons. We detected 164 monosynaptic excitatory connections in 3078 tested CA3PC-CA3PC pairs. This 5.3% connectivity rate was much higher than that we observed with the theoretically more sensitive patch clamp method in similar experimental conditions, but it remained below the anatomically observed number of CA3PC-CA3PC contacts. We verified that the imaged excitatory connections were mediated by AMPA receptors. Our results also showed that the recurrent connections did not enrich into preferred connectivity motifs and followed a distribution that was consistent with random connectivity in general. Moreover, voltage imaging revealed CA3PCs with distinct firing properties and somatic locations corresponding to previously established heterogeneity and showed that specific connectivity rules create preferred information routes among these subpopulations. Finally, we showed that there is at least one condition, influencing patch clamp recordings but not voltage imaging, that affects the observable functional connections between CA3PCs. Altogether, our results obtained with a new voltage imaging approach argue for high local connectivity rates between CA3PCs. Significance StatementVoltage imaging offers new opportunities to measure synaptic connectivity between individual identified neurons. We employed the Voltron sensor to measure the monosynaptic connectivity between local CA3 pyramidal cells (CA3PCs) in acute slices from rats. Recurrent CA3PC connections are thought to play crucial roles in storing memory. However, the estimated connectivity rates between CA3PCs differ depending on the methods used. We showed that in spite of having a lower signal-to-noise ratio, voltage imaging results showed a much higher connectivity between CA3PCs than patch clamp recordings. Our results also suggest that the recurrent excitatory connections between CA3PCs are random, with preferred connectivity between and within subpopulations of CA3PCs.

neuroscience↗

bioRxiv2020

Somatostatin neurons of the bed nucleus of stria terminalis enhance associative fear memory consolidation in mice

Excessive fear learning and extinction-resistant fear memories are core symptoms of anxiety and trauma-related disorders. Despite significant evidence from clinical studies reporting hyperactivity of the bed nucleus of stria terminalis (BNST) under these conditions, the role of BNST in fear learning and expression is still not clarified. Here, we tested how BNST modulates fear learning in mice using a chemogenetic approach. Activation of GABAergic neurons of BNST during fear acquisition, more specifically the consolidation phase, resulted in enhanced cued fear recall. Importantly, BNST activation had no acute impact on fear expression during conditioning or recalls, but it enhanced cued fear recall subsequently, potentially via altered activity of downstream regions as indicated by c-Fos. Enhanced fear memory consolidation could be replicated by selectively activating somatostatin neurons (but not corticotropin releasing factor neurons), suggesting significant modulation of fear memory strength by specific circuits of BNST.

neuroscience↗