Biology subjects

Dzyubachyk, O.

Publications and source records attributed to Dzyubachyk, O..

6 recordsLinked to original sources

bioRxiv2022

Transcriptional and cell type profiles of cortical brain regions showing ultradian cortisol rhythm dependent responses to emotional face stimulation

The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling - the ANXA1 gene and retrograde endocannabinoid signaling - show top differential expression and the most significant enrichment. Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies.

neuroscience↗

bioRxiv2021

Iron-loading is a prominent feature of activated microglia in Alzheimer's disease patients

Brain iron accumulation has been found to accelerate disease progression in Amyloid {beta}-positive Alzheimer patients, though the mechanism is still unknown. Microglia have been identified as key-players in the disease pathogenesis, and are highly reactive cells responding to aberrations such as increased iron levels. Therefore, using histological methods, multispectral immunofluorescence and an automated in-house developed microglia segmentation and analysis pipeline, we studied the occurrence of iron-accumulating microglia and the effect on its activation state in human Alzheimer brains. We identified a subset of microglia with increased expression of the iron storage protein ferritin light chain (FTL), together with increased Iba1 expression, decreased TMEM119 and P2RY12 expression. This activated microglia subset represented iron-accumulating microglia and appeared morphologically dystrophic. Multispectral immunofluorescence allowed for spatial analysis of FTL+Iba1+-microglia, which were found to be the predominant A{beta}-plaque infiltrating microglia. Finally, an increase of FTL+Iba1+-microglia was seen in patients with high Amyloid-{beta} load and Tau load. These findings suggest iron to be taken up by microglia and to influence the functional phenotype of these cells, especially in conjunction with A{beta}.

neuroscience↗

bioRxiv2020

Transcriptomic signatures associated with regional cortical thickness changes in Parkinson's disease

Cortical atrophy is a common manifestation in Parkinsons disease, particularly in later disease stages. Here, we investigated patterns of cortical thickness using T1-weighted anatomical MRI data of 149 Parkinsons disease patients and 369 controls. To elucidate the molecular underpinnings of cortical thickness changes in Parkinsons disease, we performed an integrated analysis of brain-wide healthy transcriptomic data from the Allen Human Brain Atlas and neuroimaging features. For this purpose, we used partial least squares regression to identify gene expression patterns correlated with cortical thickness changes. In addition, we identified gene expression patterns underlying the relationship between cortical thickness and clinical domains of Parkinsons disease. Our results show that genes whose expression in the healthy brain is associated with cortical thickness changes in Parkinsons disease are enriched in biological pathways related to sumoylation, regulation of mitotic cell cycle, mitochondrial translation, DNA damage responses, and ER-Golgi traffic. The associated pathways were highly related to each other and all belong to cellular maintenance mechanisms. The expression of genes within most pathways was negatively correlated with cortical thickness changes, showing higher expression in regions associated with decreased cortical thickness (atrophy). On the other hand, sumoylation pathways were positively correlated with cortical thickness changes, showing higher expression in regions with increased cortical thickness (hypertrophy). Our findings suggest that alterations in the balanced interplay of these mechanisms play a role in changes of cortical thickness in Parkinsons disease and possibly influence motor and cognitive functions.

bioinformatics↗

bioRxiv2020

The biomedical sensor Cell-Fit-HD4D, reveals individual tumor cell fate in response to microscopic ion deposition.

Here we present the biomedical sensor cell-fluorescent ion track hybrid detector4D (Cell-Fit-HD4D) to reveal individual tumor cell fate in response to microscopic ion deposition in ion beam therapy. The sensor enables long-term monitoring of single tumor cells after clinical ion beam irradiation in combination with single-cell dosimetry. Cell-Fit-HD4D is read out in-situ by conventional optical microscopy. Direct visualization of a clinical ion beam is hereby possible for the first time. The possibility to reveal fate of individual cells from a cell cohort demonstrates that our biomedical sensor clearly differs from conventional experiments that characterize cellular response after radiation on a population level. Cell-Fit-HD4D is therefore used to mimics the clinical situation of a defined tumor depth during tumor treatment by ion beam therapy. Our biomedical sensor is able to provide crucial input for current mechanistic approaches to biophysical modelling of the effect of ionizing radiation on biological matter. In the clinical context, obtaining multi-dimensional physical and biological information on individual tumor cells is an important step to further transform ion beam therapy into a highly precise discipline within oncology.

cancer biology↗

bioRxiv2019

Cholinergic circuit genes in the healthy brain are differentially expressed in regions that exhibit gray matter loss in Parkinson's disease

Structural covariance networks are able to identify functionally organized brain regions by gray matter volume covariance. In Parkinsons disease, the posterior cingulate network and anterior cingulate network showed decreased gray matter and therefore we examined the underlying molecular processes of these anatomical networks in the healthy brain. Whole brain transcriptomics from post-mortem samples from healthy adults, revealed upregulation of genes associated with serotonin, GPCR, GABA, glutamate, and RAS signaling pathways in these PD-related regions. Our results also suggest involvement of the cholinergic circuit, in which genes NPPA, SOSTDC1, and TYRP1 may play a protective role. Furthermore, both networks were associated with memory and neuropsychiatric disorders that overlap with Parkinsons disease symptoms. The identified genes and pathways contribute to healthy functions of the posterior and anterior cingulate networks and disruptions to these functions may in turn contribute to the pathological and clinical events observed in Parkinsons disease.

bioinformatics↗

bioRxiv2019

Molecular characterization of the stress network in the human brain

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of neural stress sensitivity. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low or high stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for psychiatric disorders and play a role in mounting an adaptive stress response, making them potentially druggable targets for stress-related diseases.

neuroscience↗