Ensemble and constrained clustering with applications

Diese Arbeit stellt neue Entwicklungen in Ensemble und Constrained Clustering vor und enthält die folgenden wesentlichen Beiträge: 1) Eine Vereinigung von Constrained und Ensemble Clustering in einem einheitlichen Framework. 2) Eine neue Methode zur Messung und Visualisierung der Variabilität von Ensembles. 3) Ein neues, Random Walker basiertes Verfahren für Ensemble Clustering. 4) Anwendung von Ensemble Clustering für Bildsegmentierung. 5) Eine neue Consensus-Funktion für das Ensemble Clustering Problem. Schließlich 6) Anwendung von Constrained Clustering zur Segmentierung von Nervenfasern in der Diffusions-Tensor-Bildgebung. In umfangreichen Experimenten wurden diese Verfahren getestet und ihre Überlegenheit gegenüber existierenden Methoden aus der Literatur demonstriert

Modelling cell cycle entrainment during cortical brain development

Radial glial cells play an important role during embryonic development in mammals. They are not only important for neural production but help to organise the architecture of the neocortex. Glial cells proliferate during the development of the brain in the embryo, before differentiating to produce neurons at a rate which increases towards the end of embryonic brain development. Glial cells communicate via Adenosine tri-phosphate (ATP) mediated calcium waves, which may have the effect of locally synchronising cell cycles, so that clusters of cells proliferate together, shedding cells in uniform sheets. Hence radial glial cells are not only responsible for the production of most neocortical neurons but also contribute to the architecture of the brain. It has been argued that human developmental disorders which are associated with cortical malfunctions such as infantile epilepsies and mental retardation may involve defects in neuronal production and/or architecture and mathematical modelling may shed some light upon these disorders. This thesis investigates, among other things, the conditions under which radial glial cells' cell cycles become `phase locked', radial glia proliferation and stochastic effects. There are various models for the cell cycle and for intracellular calcium dynamics. As part of our work, we marry two such models to form a model which incorporates the effect of calcium on the cell cycle of a single radial glial cell. Furthermore, with this achieved we consider populations of cells which communicate with each other via the secretion of ATP. Through bifurcation analysis, direct numerical simulation and the application of the theory of weakly coupled oscillators, we investigate and compare the behaviour of two models which differ from each other in the time during the cell cycle at which ATP is released. Our results from this suggest that cell cycle synchronisation is highly dependent upon the timing of ATP release. This in turn suggests that a malfunction in the timing of ATP release may be responsible for some cortical development disorders. We also show how the increase in radial glia proliferation may mostly be down to radial glial cells' ability to recruit quiescent cells onto the cell cycle. Furthermore, we consider models with an additive noise term and through the application of numerical techniques show that noise acts to advance the onset of oscillatory type solutions in both models. We build upon these results and show as a proof of concept how noise may act to enhance radial glia proliferation

Modelling cell cycle entrainment during cortical brain development

Radial glial cells play an important role during embryonic development in mammals. They are not only important for neural production but help to organise the architecture of the neocortex. Glial cells proliferate during the development of the brain in the embryo, before differentiating to produce neurons at a rate which increases towards the end of embryonic brain development. Glial cells communicate via Adenosine tri-phosphate (ATP) mediated calcium waves, which may have the effect of locally synchronising cell cycles, so that clusters of cells proliferate together, shedding cells in uniform sheets. Hence radial glial cells are not only responsible for the production of most neocortical neurons but also contribute to the architecture of the brain. It has been argued that human developmental disorders which are associated with cortical malfunctions such as infantile epilepsies and mental retardation may involve defects in neuronal production and/or architecture and mathematical modelling may shed some light upon these disorders. This thesis investigates, among other things, the conditions under which radial glial cells' cell cycles become `phase locked', radial glia proliferation and stochastic effects. There are various models for the cell cycle and for intracellular calcium dynamics. As part of our work, we marry two such models to form a model which incorporates the effect of calcium on the cell cycle of a single radial glial cell. Furthermore, with this achieved we consider populations of cells which communicate with each other via the secretion of ATP. Through bifurcation analysis, direct numerical simulation and the application of the theory of weakly coupled oscillators, we investigate and compare the behaviour of two models which differ from each other in the time during the cell cycle at which ATP is released. Our results from this suggest that cell cycle synchronisation is highly dependent upon the timing of ATP release. This in turn suggests that a malfunction in the timing of ATP release may be responsible for some cortical development disorders. We also show how the increase in radial glia proliferation may mostly be down to radial glial cells' ability to recruit quiescent cells onto the cell cycle. Furthermore, we consider models with an additive noise term and through the application of numerical techniques show that noise acts to advance the onset of oscillatory type solutions in both models. We build upon these results and show as a proof of concept how noise may act to enhance radial glia proliferation

NMR STUDIES OF BACTERIAL TYPE III SECRETION APPARATUS NEEDLE AND TIP PROTEINS AND THE NMR STRUCTURE OF THE HANTAVIRUS NUCLEOCAPSID COILED-COIL DOMAIN

Many Gram-negative bacterial pathogens utilize type III secretion systems (TTSSs) for subverting the normal cellular functions of their target eukaryotic cells. The type III secretion apparatus (TTSA) functions like a syringe to inject proteins through an external needle and into a target cell's membrane and cytosol. The TTSA basal body spans the bacterial inner and outer membranes, and the external needle is topped with a tip complex that controls the secretion and delivery of translocator and effector proteins. The needle is formed by the polymerization of ~120 copies of a small acidic protein that is conserved among diverse pathogens. At the tip of the needle, a tip complex is assembled by tip proteins into a ring-like structure which serves as a platform for the assembly of the translocon by translocator proteins. We use NMR spectroscopy to understand how the needle is assembled and how the tip complex is assembled on top of the needle. We determined the solution structures of the BsaL needle monomer from Burkholderia pseudomallei and the PrgI needle monomer from Salmonella typhimurium. We characterized PrgI monomer-monomer interaction using NMR chemical shift mapping; and multiple contacts were found to be involved in Salmonella needle assembly. The tip complex is assembled by SipD, the tip protein in Salmonella, and BipD, the tip protein in Burkholderia. We also characterized PrgI-SipD and BipD-BsaL interactions by NMR. Despite weak binding affinities we learned that distinct binding sites of PrgI were involved in the PrgI-PrgI and PrgI-SipD interactions. Tip proteins were also reported to interact with deoxycholate (DOC), a small molecule component of bile acids. We also characterized the SipD-DOC interactions by NMR. Based on data described in this dissertation, we conclude that electrostatic contacts are important in needle assembly and needle-packing interactions may be different among these bacteria. With respect to PrgI the binding sites involved in the PrgI-PrgI and PrgI-SipD interactions are also distinct. In addition, SipD-PrgI and SipD-DOC interactions provide valuable structural information to understand the activation mechanism of type III secretion. The hantaviruses are emerging infectious viruses that in humans can cause a cardiopulmonary syndrome or a hemorrhagic fever with renal syndrome. The nucleocapsid (N) is the most abundant viral protein, and during viral assembly, the N protein forms trimers and packages the viral RNA genome. We determined the NMR structure of the N-terminal domain (residues 1-74, called N1-74) of the Andes hantavirus N protein. N1-74 forms two long helices (alpha 1 and alpha 2) that intertwine into a coiled coil domain. The conserved hydrophobic residues at the helix alpha 1-alpha 2 interface stabilize the coiled coil; however, there are many conserved surface residues whose function is not known. Site-directed mutagenesis, CD spectroscopy, and immunocytochemistry reveal that a point mutation in the conserved basic surface formed by Arg22 or Lys26 lead to antibody recognition based on the subcellular localization of the N protein. Thus, Arg22 and Lys26 are likely involved in a conformational change or molecular recognition when the N protein is trafficked from the cytoplasm to the Golgi, the site of viral assembly and maturation

ICTERI 2020: ІКТ в освіті, дослідженнях та промислових застосуваннях. Інтеграція, гармонізація та передача знань 2020: Матеріали 16-ї Міжнародної конференції. Том II: Семінари. Харків, Україна, 06-10 жовтня 2020 р.

This volume represents the proceedings of the Workshops co-located with the 16th International Conference on ICT in Education, Research, and Industrial Applications, held in Kharkiv, Ukraine, in October 2020. It comprises 101 contributed papers that were carefully peer-reviewed and selected from 233 submissions for the five workshops: RMSEBT, TheRMIT, ITER, 3L-Person, CoSinE, MROL. The volume is structured in six parts, each presenting the contributions for a particular workshop. The topical scope of the volume is aligned with the thematic tracks of ICTERI 2020: (I) Advances in ICT Research; (II) Information Systems: Technology and Applications; (III) Academia/Industry ICT Cooperation; and (IV) ICT in Education.Цей збірник представляє матеріали семінарів, які були проведені в рамках 16-ї Міжнародної конференції з ІКТ в освіті, наукових дослідженнях та промислових застосуваннях, що відбулася в Харкові, Україна, у жовтні 2020 року. Він містить 101 доповідь, які були ретельно рецензовані та відібрані з 233 заявок на участь у п'яти воркшопах: RMSEBT, TheRMIT, ITER, 3L-Person, CoSinE, MROL. Збірник складається з шести частин, кожна з яких представляє матеріали для певного семінару. Тематична спрямованість збірника узгоджена з тематичними напрямками ICTERI 2020: (I) Досягнення в галузі досліджень ІКТ; (II) Інформаційні системи: Технології і застосування; (ІІІ) Співпраця в галузі ІКТ між академічними і промисловими колами; і (IV) ІКТ в освіті

How digital data are used in the domain of health: A short review of current knowledge

In the era of digitalization, digital data is available about every aspect of our daily lives, including our physical and mental health. Digital data has been applied in the domain of healthcare for the detection of an outbreak of infectious diseases, clinical decision support, personalized care, and genomics. This paper will serve as a review of the rapidly evolving field of digital health. More specifically, we will discuss (1) big data and physical health, (2) big data and mental health, (3) digital contact tracing during the COVID-19 pandemic, and finally, (4) ethical issues with using digital data for health-related purposes. With this review, we aim to stimulate a public debate on the appropriate usage of digital data in the health sector

[¹⁸F]fluorination of biorelevant arylboronic acid pinacol ester scaffolds synthesized by convergence techniques

Aim: The development of small molecules through convergent multicomponent reactions (MCR) has been boosted during the last decade due to the ability to synthesize, virtually without any side-products, numerous small drug-like molecules with several degrees of structural diversity.(1) The association of positron emission tomography (PET) labeling techniques in line with the “one-pot” development of biologically active compounds has the potential to become relevant not only for the evaluation and characterization of those MCR products through molecular imaging, but also to increase the library of radiotracers available. Therefore, since the [18F]fluorination of arylboronic acid pinacol ester derivatives tolerates electron-poor and electro-rich arenes and various functional groups,(2) the main goal of this research work was to achieve the 18F-radiolabeling of several different molecules synthesized through MCR. Materials and Methods: [18F]Fluorination of boronic acid pinacol esters was first extensively optimized using a benzaldehyde derivative in relation to the ideal amount of Cu(II) catalyst and precursor to be used, as well as the reaction solvent. Radiochemical conversion (RCC) yields were assessed by TLC-SG. The optimized radiolabeling conditions were subsequently applied to several structurally different MCR scaffolds comprising biologically relevant pharmacophores (e.g. β-lactam, morpholine, tetrazole, oxazole) that were synthesized to specifically contain a boronic acid pinacol ester group. Results: Radiolabeling with fluorine-18 was achieved with volumes (800 μl) and activities (≤ 2 GBq) compatible with most radiochemistry techniques and modules. In summary, an increase in the quantities of precursor or Cu(II) catalyst lead to higher conversion yields. An optimal amount of precursor (0.06 mmol) and Cu(OTf)2(py)4 (0.04 mmol) was defined for further reactions, with DMA being a preferential solvent over DMF. RCC yields from 15% to 76%, depending on the scaffold, were reproducibly achieved. Interestingly, it was noticed that the structure of the scaffolds, beyond the arylboronic acid, exerts some influence in the final RCC, with electron-withdrawing groups in the para position apparently enhancing the radiolabeling yield. Conclusion: The developed method with high RCC and reproducibility has the potential to be applied in line with MCR and also has a possibility to be incorporated in a later stage of this convergent “one-pot” synthesis strategy. Further studies are currently ongoing to apply this radiolabeling concept to fluorine-containing approved drugs whose boronic acid pinacol ester precursors can be synthesized through MCR (e.g. atorvastatin)