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Detection of subpopulation-specific neuronal membrane molecules using single-cell expression data
Zátko, Matěj ; Modrák, Martin (advisor) ; Kubovčiak, Jan (referee)
Single-cell RNA sequencing is a powerful technology that allows the investigation of gene expression at an unprecedented level. Insights into gene expression in individual cells can help biologists uncover cellular heterogeneity and identify previously unknown cell types. Here, we use single-cell RNA sequencing datasets that reveal subtypes of mouse neurons to find population-specific membrane proteins. These proteins could potentially serve as entry points for targeted drug distribution, allowing for drugs to act only on se- lected neuronal populations. We start by identifying five suitable single-cell mouse neuron datasets. Next, we present an overview and a comparison of currently available methods for differential gene expression analysis, an approach that involves quantifying variations in gene expression between groups and/or conditions, based on previous benchmarks. Lastly, we apply the Wilcoxon rank-sum test to selected datasets in order to identify population-specific membrane proteins. 1
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Transcriptional changes associated with melanoma resistance to small inhibitor treatment
Dorčáková, Terézia ; Kolář, Michal (advisor) ; Modrák, Martin (referee)
Malignant melanoma is an aggressive skin tumour with increasing incidence and, in advanced stages, limited therapeutic results. The major oncogenic alteration in melanoma is mutational activation of the B-Raf protein, with the predominant mutation V600E, which occurs in 60% of cases and hyperactivates the ERK signaling pathway. This cascade of Raf, MEK and ERK protein kinases is an integral part of an evolu- tionarily conserved signaling network that allows eukaryotic cells to sense a variety of extracellular signals. These protein kinases sequentially activate each other and translate extracellular signals into cellular responses such as proliferation, di↵erentiation, cell cycle changes, apoptosis or cell migration. The central role of the ERK pathway in oncogen- esis has made it one of the targets for therapeutic intervention, and inhibitors targeting mutant Raf, such as vemurafenib or dabrafenib, have been approved for the treatment of melanoma. These molecules specifically target B-Raf(V600E) and have led to a revo- lution in melanoma treatment. Unfortunately, such targeted therapy is complicated by the ability of cancer cells to acquire resistance. The aim of this work is to study at the transcriptional level the emergence of this resistance in patients who respond well to treatment and in...
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Representation of chemical compounds and its utilization in similarity search
Škoda, Petr ; Hoksza, David (advisor) ; Brezovský, Jan (referee) ; Modrák, Martin (referee)
Virtual screening is a well-established part of computer-aided drug design, which heavily employs similarity search and similarity modeling methods. Most of the popular methods are target agnostic, leaving space for design of new methods that would take into account the specifics of the particular molecular target. Additionally, newly developed methods suffer from two related issues: benchmarking and availability. Benchmarking in the domain often suffers from the use of inappropriate reference methods, lack of reproducibility, and the use of nonstandard benchmark datasets. Although there have been several benchmarking studies in the domain that aim at addressing these issues, mainly by offering a standardized comparison, they often suffer from similar drawbacks. For these reasons, new methods fail to gain trust and therefore fail to become a part of the standard toolbox, which thus consists mostly of older methods. In this work, we address the above-described issues. First, we introduce new adaptive methods for virtual screening. Then, to make our and other newly developed methods readily available, we have designed and implemented a virtual screening tool. To address the benchmarking issue, we have compiled a publicly available collection of benchmarking datasets and proposed a platform offering a...
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