Biology subjects

Kalinousky, A.

Publications and source records attributed to Kalinousky, A..

4 recordsLinked to original sources

bioRxiv2026

Auditory Evoked Potentials Differ from Controls and Correlate with Aspects of Cognition in Kabuki Syndrome and Rubinstein-Taybi Syndrome

Objective Kabuki syndrome (KS) and Rubinstein-Taybi syndrome (RSTS) are two disorders caused by dysfunctional components of the epigenetic machinery and both result in intellectual disability. Mouse models of both KS and RSTS have seen reversal of cognitive impairment with epigenetic treatments. However, a great need exists for biomarkers in these disorders to improve the likelihood of successful clinical trials. This study aimed to investigate cortical auditory evoked potentials (AEPs) in KS and RSTS so that it could potentially be developed into a response biomarker in the future. Methods The amplitude of the N1-P2-N2 complex was measured for passive listening to monotonal auditory stimuli in individuals with KS, with RSTS, and typically developing controls. A standardized cognitive assessment battery was performed and specific subtests were correlated with AEP values. Results Groups differed significantly in P2, N2, and P2-N2 amplitude although RSTS was consistently more different from typically developing controls than was KS. The mid- to late-phase AEP components (P2 and N2) also correlate with cognition within and across these groups particularly with language whereas earlier components N1 and P2 correlate more with measures of executive functioning. Conclusion Late-phase components of AEPs differ in KS and RSTS from each other and from controls. KS and RSTS differ from controls in P2 and N2 amplitude in the same direction and both show a positive correlation between language and P2 amplitude and a negative correlation between language and N2 amplitude. Together they also show an association with N1 and P2 amplitude and executive functioning. Significance AEPs may turn out to be a valuable response biomarker in KS and RSTS individually and together.

neuroscience↗

bioRxiv2022

Dynamic changes in the niche and transcription trigger early murine and human pluripotent stem cell-derived liver organogenesis

The shift from collective migration to differentiation is a crucial process in epithelial biology but recreating this intricate transition has thus far proved elusive. We provide experimental, mechanistic, in vivo, and bioinformatic data supporting an undoubtable link between human pluripotent stem cell (hPSC)- derived collectively migrating hepatoblasts (MHB), and transcriptionally mature, functional hPSC- hepatocytes (HEPs), which incorporates two unrecognized steps. The protocol induces FOXA-dependent induction of HBs, leading to TBX3-positive, YAP-TEAD active MHBs which provide a transcriptional match with murine liver E9.5 MHBs. Simple cultivation changes trigger MHBs to rapidly form functional day 18 HEPs, predicted by a deep-learning designed gene circuit, resulting in a [~]236% fold- increase in maturation (PACNet), on par with the highest score, but with enhanced global transcriptional shaping. Overall, incorporating the MHB to HEP transition establishes a new, unrecognized, and highly efficient mechanism for differentiation that can be cumulatively integrated with existing methods to overcome barriers to maturation.

bioengineering↗

bioRxiv2020

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

The Mendelian Disorders of the Epigenetic Machinery (MDEMs) have emerged as a class of Mendelian disorders caused by loss-of-function variants in epigenetic regulators. Although each MDEM has a different causative gene, they exhibit several overlapping disease manifestations. Here, we hypothesize that this phenotypic convergence is a consequence of common abnormalities at the epigenomic level, which directly or indirectly lead to downstream convergence at the transcriptomic level. Therefore, we seek to identify abnormalities shared across multiple MDEMs, in order to pinpoint locations where epigenetic variation is causally related to disease phenotypes. To this end, we perform a comprehensive interrogation of chromatin (ATAC-Seq) and expression (RNA-Seq) states in B cells from mouse models of three MDEMs (Kabuki types 1&2 and Rubinstein-Taybi syndromes). We build on recent work in covariate-powered multiple testing to develop a new approach for the overlap analysis, which enables us to find extensive overlap primarily localized in gene promoters. We show that disruption of chromatin accessibility at promoters often leads to disruption of downstream gene expression, and identify 463 loci and 249 genes with shared disruption across all three MDEMs. As an example of how widespread dysregulation leads to specific phenotypes, we show that subtle expression alterations of multiple, IgA-relevant genes, collectively contribute to IgA deficiency in KS1 and RT1. In contrast, we predict that KS2 does not have IgA deficiency, and confirm this observation in vivo. We propose that the joint study of MDEMs offers a principled approach for systematically mapping functional epigenetic variation in mammals.

genetics↗

bioRxiv2020

Mesenchyme modulates three-dimensional, collective cell migration of liver cells in vitro - a role for TGFβ pathway

Three dimensional (3D) collective cell migration (CCM) is critical for improving liver cell therapies, eliciting mechanisms of liver disease, and modeling human liver development/ organogenesis. Here, we modeled liver organogenesis to induce 3D CCM and improve existing models. The liver diverticulum, normally surrounded by septum transversum mesenchyme (STM) at E8.5, was modeled with a miniature liver spheroid surrounded by mesenchymal cells and matrix. In mixed spheroid models with both liver and uniquely MRC5 (fetal lung) fibroblasts, we observed co-migration of cells, and a significant increase in length and number of liver spheroid protrusions, and this was highly sensitive to TGFB1 stimulation. To understand paracrine effects between MRC-5 cells and liver, we performed conditioned medium (M-CM) experiments. Interestingly, the addition of M-CM increased liver 3D CCM, with thin, 3D, dose-dependent branching morphogenesis, an upregulation of Twist1, and a sensitivity to a broad TGFB inhibitor. To test the effects of cell-cell interactions of 3D CCM, the STM was modeled with a spheroid of MRC-5 cells, and we performed co-spheroid culture of liver with MRC-5. We observed a complex morphogenesis, whereby thin, linear, 3D liver cell strands attach to the MRC-5 spheroid, anchor, and thicken to form permanent and thick anchoring contacts between the two spheroids. We also observed spheroid fusion, a form of interstitial migration. In conclusion, we present several novel cultivation systems that induce distinct features of 3D CCM, as judged by the presence of branching, linearity, thickness, and interstitial migration. These methodologies will greatly improve our molecular, cellular, and tissue-scale understanding of liver organogenesis, liver diseases, and liver cell therapy, and will serve as a tool to bridge conventional 2D studies and preclinical in vivo studies.

cell biology↗