Exploring Inter-Species Regulatory Differences Through Single Cell Analysis of Drosophila Embryogenesis

Variationen in der Genexpression spielen eine zentrale Rolle bei der evolutionären Divergenz, die zur Speziation führt. Dies wird durch Veränderungen sowohl in nicht-kodierenden cis-wirkenden regulatorischen Elementen (CREs) wie Promotoren und Enhancern als auch in trans-wirkenden regulatorischen Elementen bestimmt. Veränderungen in den regulatorischen Sequenzen können Entwicklungsmuster verändern und wirken als eine der treibenden Kräfte der Evolution der Genexpression. Hier untersuche ich die Anwendung der Einzelzell-Multiomik in der evolutionären vergleichenden Genomik, wobei der Schwerpunkt auf den funktionellen Auswirkungen der Divergenz bei cis-regulatorischen Elementen liegt. Unter Verwendung von Hybrid-Embryonen von Drosophila melanogaster und sechellia generiere ich ein diploides Referenzgenom und führe allelspezifische Einzelzellanalysen von scRNA-seq und scATAC-seq durch. Zusammen können diese beiden komplimentären Ansätze einen integrativen Überblick über die Transkription und die Zugänglichkeit des Chromatins liefern, wodurch CREs identifiziert und mit allelspezifischen Veränderungen in den Genen, die sie regulieren, in Verbindung gebracht werden können. Die computergestützte Rekonstruktion verschiedener Zellidentitäten durch Clustering einzelner Zellen ermöglicht es uns auch zu untersuchen, wie sich das Allel-Ungleichgewicht während der Zelltyp-Spezifikation räumlich verändern kann. Im Gegensatz zu früheren Forschungsarbeiten stelle ich fest, dass Gene, die an der Entwicklung und Musterbildung beteiligt sind, ein unterschiedliches allelisches Ungleichgewicht in der Expression und Zugänglichkeit über die Zelltypen hinweg aufweisen. Diese Arbeit zeigt das Potenzial der Kombination von Einzelzell-Multiomik und artübergreifenden Vergleichen in der vergleichenden Genomik und wirft ein neues Licht auf die Rolle von cis-regulatorischen Elementen in der adaptiven Evolution.Variation in gene expression plays a pivotal role in the evolutionary divergence that leads to speciation. This is determined by changes in both non-coding cis-acting regulatory elements (CREs) like promoters and enhancers, as well as trans-acting regulatory elements. Changes in regulatory sequences can alter developmental patterns, acting as one of the driving forces behind gene expression evolution. However, poor sequence conservation of CREs makes it challenging to identify them and link changes in regulatory sequences to new phenotypes. Here, I explore the application of single cell multiomics in evolutionary comparative genomics, with a focus on functional effects of divergence in cis-regulatory elements. Using hybrid embryos of Drosophila melanogaster and Drosophila sechellia, I generate a diploid reference genome and conduct single cell allele-specific analysis of scRNA-seq and scATAC-seq data. Together, these two assays can provide an integrative read-out of transcription and chromatin accessibility, allowing CREs to be identified and linked to allele-specific changes (allelic imbalance) in the genes they regulate. The computational reconstruction of different cell identities via single cell clustering also allows us to investigate how allelic imbalance may vary spatially during cell-type specification. In contrast to previous research, I find that genes involved in development and patterning display differential allelic imbalance in expression and accessibility across cell types. In addition, I investigate the role of neurodevelopmental allelic imbalance in the sechellia lineage and identify candidate genes for sechellia-specific adaptations. While highlighting current computational limitations, this thesis demonstrates the potential of combining single cell multiomics and cross-species comparisons in comparative genomics and shedding new light on the role of cis-regulatory elements and mechanisms of adaptive evolution

Holographic duals of 6d RG flows

A notable class of superconformal theories (SCFTs) in six dimensions is parameterized by an integer $N$, an ADE group $G$, and two nilpotent elements $\mu_\mathrm{L,R}$ in $G$. Nilpotent elements have a natural partial ordering, which has been conjectured to coincide with the hierarchy of renormalization-group flows among the SCFTs. In this paper we test this conjecture for $G=\mathrm{SU}(k)$, where AdS$_7$ duals exist in IIA. We work with a seven-dimensional gauged supergravity, consisting of the gravity multiplet and two $\mathrm{SU}(k)$ non-Abelian vector multiplets. We show that this theory has many supersymmetric AdS$_7$ vacua, determined by two nilpotent elements, which are naturally interpreted as IIA AdS$_7$ solutions. The BPS equations for domain walls connecting two such vacua can be solved analytically, up to a Nahm equation with certain boundary conditions. The latter admit a solution connecting two vacua if and only if the corresponding nilpotent elements are related by the natural partial ordering, in agreement with the field theory conjecture.Comment: 33 pages, 2 figure

Synthesis and Applications of Smart Glycopolymers and Their Interactions with Lectins

The last two decades have seen an urgent need to find more efficient methods with minimal health impact to diagnose and treat common diseases. Recent research on drug and gene delivery by polymeric vectors has shown promising results because polymers provide excellent drug protection whilst showing low toxicity both in vitro and in vivo. Nevertheless, targeted delivery is a major characteristic that polymeric vectors often lack. Glycopolymers, however, can form specific interactions with lectins by mimicking biological interactions. These interactions are responsible for numerous biological mechanisms and can be exploited to achieve targeted delivery of medicines. Herein, different polymerisation techniques for the synthesis of glycopolymers with different architectures and properties are explored. First, the preparation of star shaped glycopolymers as a way to increase drug encapsulation and lectin binding is discussed. Thereafter, reducible glycopolymers prepared via step growth polymerisation are investigated as potential gene transporters. Furthermore, the interactions between glycopolymers and a lectin are measured under physiological conditions and the results are discussed. Finally, recent progress on glycopolymers and the gaps that still need to be addressed are discussed

Relevance of lactate level detection in migrane and fibromyalgia

The aim of this study was to determine the blood lactate levels in healthy and pathological subjects, particularly with migraine and fibromyalgia. Moreover we investigated the possible correlation between lactate concentration, postural stability and balance disorders; the composition of the groups were: migraine (n = 25; age 49.7 +/- 12.5), fibromyalgia (n = 10; age 43.7 +/- 21.2), control group (n = 16 age 28.52 +/- 2.4). The results showed that patients with fibromyalgia (FG) had higher lactate levels compared to migraine (MG) and control group (CG) (mean +/- sd: FG = 1.78 +/- 0.9 mmol/L; MG = 1.45 +/- 1 mmol/L; CG = 0,85 +/- 0,07 mmol/L). The same situation was highlighted about the sway path length with eyes closed (FG = 518 +/- 195 mm; MG = 465 +/- 165 mm; CG = 405 +/- 94,72 mm) and with eyes open (FG = 430 +/- 220 mm; MG = 411 +/- 143 mm; CG = 389 +/- 107 mm). This can be explained by the fact that energy-intensive postural strategies must be used to optimize both static and dynamic coordination, in particular with repeated contractions of tonic oxidative muscle cells responsible for postural control

Evolutionary Modeling to Evaluate the Shear Behavior of Circular Reinforced Concrete Columns

Despite their frequent occurrence in practice, only limited studies on the shear behavior of reinforced concrete (RC) circular members are available in the literature. Such studies are based on poor assumptions about the physical model, often resulting in being too conservative, as well as technical codes that essentially propose empirical conversion rules. On this topic in this paper, an evolutionary approach named EPR is used to create a structured polynomial model for predicting the shear strength of circular sections. The adopted technique is an evolutionary data mining methodology that generates a transparent and structured representation of the behavior of a system directly from experimental data. In this study experimental data of 61 RC circular columns, as reported in the technical literature, are used to develop the EPR models. As final result, physically consistent shear strength models for circular columns are obtained, to be used in different design situations. The proposed formulations are compared with models available from building codes and literature expressions, showing that EPR technique is capable of capturing and predicting the shear behavior of RC circular elements with very high accuracy. A parametric study is also carried out to evaluate the physical consistency of the proposed models

On the electronic structure of small carbon grains of astrophysical interest

In a previous paper Mennella et al. (1995a) studied the evolution of the UV spectrum of small carbon grains due to thermal annealing in the range 250-800°C. The spectral variations were interpreted in terms of internal structural rearrangement of the grains caused by hydrogen loss. The electronic transitions (Ï-Ï* and Ï-Ï*) of the sp2 clusters forming the grains were indicated as the major factors responsible for determining their extinction properties. In this paper we present the results of new measurements aimed at probing the heat-induced structural changes. The thermal evolution of the optical gap and of the Raman spectrum, both sensitive to the sp2 clustering degree, confirms that the observed spectral changes do depend on structural variations. In fact, the Ï electron delocalization of the sp2 clusters determines a link between structural and electronic properties in carbons. We find a basic correlation between the UV peak position and the optical gap. It is interpreted in terms of a dependence of the dipole matrix momentum of Ï transitions on the sp2 cluster size. The attribution of the spectral changes to the grain internal structure is corroborated by morphological analyses. Scanning and transmission electron microscope images show that the fluffy structure of the samples as well as the dimension and the shape of the single grains do not change after the annealing process. In the astrophysical context, the present results can be relevant for the attribution of the 217.5 nm feature, as they show that the internal structure of carbon grains, having sizes similar to those expected for the "bump" carriers, controls the interaction with UV photons

Integrated care for the management of ageing-related non-communicable diseases: current gaps and future directions

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Laboratory experiments on cosmic dust analogues: the structure of small carbon grains

In this paper we present new results of our experiments aimed to study the internal structure of cosmic analogue carbon grains. The samples, produced by arc discharge between two carbon electrodes in an argon atmosphere, were annealed in the temperature range 250-780°C in order to produce modification of the internal grain structure. These changes were monitored by analysing the variations of the extinction profile between 190 and 2600 nm and of the optical gap as a function of the annealing temperature. The shift of the UV peak position towards longer wavelengths. the overall increase of the extinction coefficient and the closing of the gap as the temperature increases are all consistent with the evolution of carbon grains outlined by Mennella et al. (Astrophys. J., 444, 288, 1995 ; Astrophys. J. Suppl. Ser., 100, 149, 1995). It provides a growth in number and size of the sp2 clusters forming the grains during the annealing. The relevance of the electronic structure of the aromatic clusters in the extinction processes and the dependence of the energy Ï transitions on their size are confirmed by the present results. These results may be relevant in the context of interstellar bump attribution, as they show that the internal structure of small carbon grains is dominant in extinction processes. © 1995