Free-form image registration of human cochlear μCT data using skeleton similarity as anatomical prior

AbstractBetter understanding of the anatomical variability of the human cochlear is important for the design and function of Cochlear Implants. Proper non-rigid alignment of high-resolution cochlear μCT data is a challenge for the typical cubic B-spline registration model. In this paper we study one way of incorporating skeleton-based similarity as an anatomical registration prior. We extract a centerline skeleton of the cochlear spiral, and generate corresponding parametric pseudo-landmarks between samples. These correspondences are included in the cost function of a typical cubic B-spline registration model to provide a more global guidance of the alignment. The resulting registrations are evaluated using different metrics for accuracy and model behavior, and compared to the results of a registration without the prior

The study of renal function and toxicity using zebrafish (Danio rerio) larvae as a vertebrate model

Zebrafish (Danio rerio) is a powerful model in biomedical and pharmaceutical sciences. The zebrafish model was introduced to toxicological sciences in 1960, followed by its use in biomedical sciences to investigate vertebrate gene functions. As a consequence of many research projects in this field, the study of human genetic diseases became instantly feasible. Consequently, zebrafish have been intensively used in developmental biology and associated disciplines. Due to the simple administration of medicines and the high number of offspring, zebrafish larvae became widely more popular in pharmacological studies in the following years. In the past decade, zebrafish larvae were further established as a vertebrate model in the field of pharmacokinetics and nanomedicines. In this PhD thesis, zebrafish larvae were investigated as an earlystage in vivo vertebrate model to study renal function, toxicity, and were applied in drug-targeting projects using nanomedicines. The first part focused on the characterization of the renal function of three-to four-dayold zebrafish larvae. Non-renal elimination processes were additionally described. Moreover, injection techniques, imaging parameters, and post-image processing scripts were established to serve as a toolbox for follow-up projects. The second part analyzed the impact of gentamicin (a nephrotoxin) on the morphology of the pronephros of zebrafish larvae. Imaging methodologies such as fluorescent-based laser scanning microscopy and X-ray-based microtomography were applied. A profound comparison study of specimens acquired with different laboratory X-ray-based microtomography devices and a radiation facility was done to promote the use of X-ray-based microtomography for broader biomedical applications. In the third part, the toxicity of nephrotoxins on mitochondria in renal epithelial cells of proximal tubules was assessed using the zebrafish larva model. Findings were compared with other teleost models such as isolated renal tubules of killifish (Fundulus heteroclitus). In view of the usefulness and high predictability of the zebrafish model, it was applied to study the pharmacokinetics of novel nanoparticles in the fourth part. Various in vivo pharmacokinetic parameters such as drug release, transfection of mRNA/pDNA plasmids, macrophage clearance, and the characterization of novel drug carriers that were manipulated with ultrasound were assessed in multiple collaborative projects. Altogether, the presented zebrafish model showed to be a reliable in vivo vertebrate model to assess renal function, toxicity, and pharmacokinetics of nanoparticles. The application of the presented model will hopefully encourage others to reduce animal experiments in preliminary studies by fostering the use of zebrafish larvae

Virtuální rekonstrukce, její význam a přínos k paleobiologickému studiu fosilního člověka

Zachovalost kosterního materiálu je hlavní překážkou paleoantropologických studií. Virtuální metody se od 90. let 20. století staly důležitou součástí antropologického výzkumu, přičemž značně pomáhají překonat problémy zachovalosti, a to dvěma hlavními způsoby: zlepšují extrakci informací z fragmentárního materiálu a umožňují objektivnější rekonstrukci fragmentárních a nekompletních nálezů. Tato práce se zaměřila na virtuální rekonstrukci dvou fosilních nálezů: lebky moderního člověka Zlatý kůň (ZK; Česká republika) ze svrchního paleolitu a neandertálské pánve Regourdou 1 (R1) z Francie. Rekonstrukce lebky ZK nám umožnila revidovat pohlavní diagnózu a analyzovat její morfologickou afinitu. Na základě sekundární pohlavní diagnózy byl jedinec ZK s vysokou pravděpodobností žena a lebka vykazuje afinitu k rané svrchně paleolitické populaci. Pánev R1 vykazuje značnou asymetrii, která byla nejprve analyzována na křížové kosti v porovnání se zdravými moderními lidmi a neandertálci. Asymetrie výrazně překračuje variabilitu pozorovanou v současné populaci a mohla souviset s asymetrickým přenosem zátěže. Výrazná asymetrie byla proto zohledněna při následné rekonstrukci pánve, která nám umožnila posoudit pohlaví jedince a analyzovat transverzální rozměry pánevního kanálu a orientaci křížové kosti. Na základě...Preservation is a major obstacle in paleoanthropological studies. Since 1990s virtual methods have become an important part of anthropological research helping to overcome preservation problems in two principle ways: they improve extraction of information from a fragmentary material, and they permit a more objective reconstruction of fragmentary and incomplete remains. This thesis has focused on the virtual reconstruction of two fossil specimens: the modern human cranium from the Upper Paleolithic site of Zlatý kůň (ZK; Czech Republic) and the Neandertal Regourdou 1 (R1) pelvis (France). The reconstruction of the ZK cranium allowed us to revise sex attribution and analyze morphological affinity. Based on the secondary sex diagnosis, the ZK individual was most probably a female and exhibits a great affinity to Early Upper Paleolithic population. The R1 pelvis shows considerable asymmetry that was first analyzed on the sacrum in comparison with healthy modern humans and Neandertals. The asymmetry exceeds normal variation observed in the extant population and could have related to asymmetrical load dissipation. Therefore, the asymmetry was considered in the subsequent preliminary pelvic reconstruction which allowed us to assess sex of the individual and to analyze transverse dimensions of the pelvic...Katedra antropologie a genetiky člověkaDepartment of Anthropology and Human GeneticsPřírodovědecká fakultaFaculty of Scienc

Frameshift mutations at the C-terminus of HIST1H1E result in a specific DNA hypomethylation signature

BACKGROUND: We previously associated HIST1H1E mutations causing Rahman syndrome with a specific genome-wide methylation pattern. RESULTS: Methylome analysis from peripheral blood samples of six affected subjects led us to identify a specific hypomethylated profile. This "episignature" was enriched for genes involved in neuronal system development and function. A computational classifier yielded full sensitivity and specificity in detecting subjects with Rahman syndrome. Applying this model to a cohort of undiagnosed probands allowed us to reach diagnosis in one subject. CONCLUSIONS: We demonstrate an epigenetic signature in subjects with Rahman syndrome that can be used to reach molecular diagnosis