Musterung und Differenzierung des periotischen Mesenchyms der Maus

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Structure-guided selection of specificity determining positions in the human kinome

Background: The human kinome contains many important drug targets. It is well-known that inhibitors of protein kinases bind with very different selectivity profiles. This is also the case for inhibitors of many other protein families. The increased availability of protein 3D structures has provided much information on the structural variation within a given protein family. However, the relationship between structural variations and binding specificity is complex and incompletely understood. We have developed a structural bioinformatics approach which provides an analysis of key determinants of binding selectivity as a tool to enhance the rational design of drugs with a specific selectivity profile. Results: We propose a greedy algorithm that computes a subset of residue positions in a multiple sequence alignment such that structural and chemical variation in those positions helps explain known binding affinities. By providing this information, the main purpose of the algorithm is to provide experimentalists with possible insights into how the selectivity profile of certain inhibitors is achieved, which is useful for lead optimization. In addition, the algorithm can also be used to predict binding affinities for structures whose affinity for a given inhibitor is unknown. The algorithm’s performance is demonstrated using an extensive dataset for the human kinome. Conclusion: We show that the binding affinity of 38 different kinase inhibitors can be explained with consistently high precision and accuracy using the variation of at most six residue positions in the kinome binding site. We show for several inhibitors that we are able to identify residues that are known to be functionally important

Fibro-Vascular Coupling in the Control of Cochlear Blood Flow

Transduction of sound in the cochlea is metabolically demanding. The lateral wall and hair cells are critically vulnerable to hypoxia, especially at high sound levels, and tight control over cochlear blood flow (CBF) is a physiological necessity. Yet despite the importance of CBF for hearing, consensus on what mechanisms are involved has not been obtained.We report on a local control mechanism for regulating inner ear blood flow involving fibrocyte signaling. Fibrocytes in the super-strial region are spatially distributed near pre-capillaries of the spiral ligament of the albino guinea pig cochlear lateral wall, as demonstrably shown in transmission electron microscope and confocal images. Immunohistochemical techniques reveal the inter-connected fibrocytes to be positive for Na+/K+ ATPase β1 and S100. The connected fibrocytes display more Ca(2+) signaling than other cells in the cochlear lateral wall as indicated by fluorescence of a Ca(2+) sensor, fluo-4. Elevation of Ca(2+) in fibrocytes, induced by photolytic uncaging of the divalent ion chelator o-nitrophenyl EGTA, results in propagation of a Ca(2+) signal to neighboring vascular cells and vasodilation in capillaries. Of more physiological significance, fibrocyte to vascular cell coupled signaling was found to mediate the sound stimulated increase in cochlear blood flow (CBF). Cyclooxygenase-1 (COX-1) was required for capillary dilation.The findings provide the first evidence that signaling between fibrocytes and vascular cells modulates CBF and is a key mechanism for meeting the cellular metabolic demand of increased sound activity

Essential genes for astroglial development and axon pathfinding during zebrafish embryogenesis

The formation of the central nervous system depends on the coordinated development of neural and glial cell types that arise from a common precursor. Using an existing group of zebrafish mutants generated by viral insertion, we performed a “shelf-screen” to identify genes necessary for astroglial development and axon scaffold formation. We screened 274 of 315 viral insertion lines using antibodies that label axons (anti-Acetylated Tubulin) and astroglia (anti-Gfap) and identified 25 mutants with defects in gliogenesis, glial patterning, neurogenesis, and axon guidance. We also identified a novel class of mutants affecting radial glial cell numbers. Defects in astroglial patterning were always associated with axon defects, supporting an important role for axon-glial interactions during axon scaffold development. The genes disrupted in these viral lines have all been identified, providing a powerful new resource for the study of axon guidance, glio- and neurogenesis, and neuron-glial interactions during development of the vertebrate CNS.National Institutes of Health (U.S.) (Grant T32MH020051)National Institutes of Health (U.S.) (Grant F32NS043872

Stem Cells, Self-Renewal, and Lineage Commitment in the Endocrine System

The endocrine system coordinates a wide array of body functions mainly through secretion of hormones and their actions on target tissues. Over the last decades, a collective effort between developmental biologists, geneticists, and stem cell biologists has generated a wealth of knowledge related to the contribution of stem/progenitor cells to both organogenesis and self-renewal of endocrine organs. This review provides an up-to-date and comprehensive overview of the role of tissue stem cells in the development and self-renewal of endocrine organs. Pathways governing crucial steps in both development and stemness maintenance, and that are known to be frequently altered in a wide array of endocrine disorders, including cancer, are also described. Crucially, this plethora of information is being channeled into the development of potential new cell-based treatment modalities for endocrine-related illnesses, some of which have made it through clinical trials

Differential requirements for Gli2 and Gli3 in the regional specification of the mouse hypothalamus.

Secreted protein Sonic hedgehog (Shh) ventralizes the neural tube by modulating the crucial balance between activating and repressing functions (GliA, GliR) of transcription factors Gli2 and Gli3. This balance—the Shh-Gli code—is species- and context-dependent and has been elucidated for the mouse spinal cord. The hypothalamus, a forebrain region regulating vital functions like homeostasis and hormone secretion, shows dynamic and intricate Shh expression as well as complex regional differentiation. Here we asked if particular combinations of Gli2 and Gli3 and of GliA and GliR functions contribute to the variety of hypothalamic regions, i.e. we wanted to clarify the hypothalamic version of the Shh-Gli code. Based on mouse mutant analysis, we show that: 1) hypothalamic regional heterogeneity is based in part on differentially stringent requirements for Gli2 or Gli3; 2) another source of diversity are differential requirements for Shh of neural vs non-neural origin; 3) Gli2 is indispensable for the specification of a medial progenitor domain generating several essential hypothalamic nuclei plus the pituitary and median eminence; 4) the suppression of Gli3R by neural and non-neural Shh is essential for hypothalamic specification. Finally, we have mapped our results on a recent model which considers the hypothalamus as a transverse region with alar and basal portions. Our data confirm the model and are explained by it

Morphometrical differentiation of Anoplocephalidae cysticercoids with a contribution to reproduction of oribatid mites experimentally infected

Die komplette Dissertation im pdf-Format : diss.pdfOribatid mites of the genus Scheloribates (Oribatei) were experimentally infected with eggs of Anoplocephala perfoliata, Paranoplocephala mamillana, Moniezia benedeni and Moniezia expansa (Cestoda: Anoplocephalidae). The series of tests were maintained in an incubator at 28°C for 28 days to accelerate the development of cysticercoids in the oribatid mites. After this period the surviving mites were dissected. The length and the width of isolated cysticercoids and oribatid mites were microscopally measured and the prevalence of mite eggs were revealed. The infection rates of mites with cysticercoids of A. perfoliata, P. mamillana, M. benedeni and M. expansa amounted to 27,2%, to 11,8%, to 37,3% and to 36,5% respectively; the number of cysticercoids per mite ranged from 1 to 9, from 1 to 3, from 1 to 5 and from 1 to 4 respectively. 9,5% of the infected oribatid mites and 22,6% of the non-infected mites harboured mite eggs. Non-infected mites had more eggs than infected mites. The volumes of each cysticercoid and each oribatid mite body cavity were computed from their length and width. This was the basis for the examinations of the dependence of the cysticercoid volume on the mite body cavity volume, the influence of infection intensity on cysticercoid volume and for the comparison of the cysticercoid volumes of the 4 examined Anoplocephalidae species. A correlation between cysticercoid volume and mite body cavity volume was not found. Both large and small cysticercoids were isolated from large oribatid mites. The infection intensity distinctly influenced the cysticercoid volume. At increasing infection intensity the cysticercoid volumes of A. perfoliata, P. mamillana and M. expansa were smaller, the variation of them decreased. On the other hand, cysticercoids of M. benedeni were smaller at lower infection intensity and conversely. The variation of the volumes got bigger, as the number of cysticercoids in the mite rose. For the first time the cysticercoid volume of different Anoplocephalidae species was compared. P. mamillana and A. perfoliata (cestodes of Equidae) occasionally developed larger cysticercoids in oribatid mites than M. expansa and M. benedeni (cestoda of ruminants). The cysticercoid volumes of P. mamillana, A. perfoliata, M. expansa and M. benedeni ranged from 0,980 * 106 to 3,730 * 106 µm3, from 0,825 * 106 to 3,360 * 106 µm3, from 0,567 * 106 to 3,222 * 106 µm3 and from 0,445 * 106 to 1,590 * 106 µm3 respectively. Cysticercoids of these Anoplocephalidae species can not be differentiated alone by their volumes. Other characteristics of Anoplocephalidae cysticercoids like diameter of scolex and suckers or the structure of cyst wall should be examined and tested for the differentiation

Re-defining ’woman’ in Canada : gender and social planning in support services for immigrant women

In Canada’s increasingly poly-ethnic society, questions of how to define and build an inclusive society are becoming particularly important. Within social planning one of the key areas of debate is how to construct and provide appropriate and responsive social/economic support services for the immigrant community, especially for visible minority immigrant women. In this context, what is inclusion? How and where does inclusion matter? The differing roles that gender considerations play in the personal experience of immigration are too seldom recognized within immigrant services policy and program planning. It is simply not the same to move to Canada as a woman as it is for a man. Particularized instances of gender difference can influence a whole range of experiences for female immigrants, including the accessibility of support services. Chapter 1 of this study discusses how Canadian immigrant women are currently accessing existing social services and outlines some of the contemporary discourse surrounding Canadian multiculturalism. Chapter 2 details the narrative-oriented methodological framework, and emergent method(s) of analysis that were utilized in conducting this research. This chapter also presents pertinent details regarding the research participants as well as the immigrant serving agency along with its ethno-specific service partner that was examined as a case study. Chapter 3 narrates some of the current experiences of ’place’ for immigrant women in Canada, and discusses contemporary practices of how existing immigrant service organizations plan social programs for immigrant women. Chapter 4 presents the implications and considerations for social planning practice, particularly with non-Canadian born women, that emerged out of the field-work conducted for this study. The research then concludes with a narrative overview of my perspectives on this project, as well as personal and practice-oriented lessons learned.Applied Science, Faculty ofCommunity and Regional Planning (SCARP), School ofGraduat