The macaque monkey superior parietal lobule (SPL) is part of a neuronal network involved in the integration of information from visual and somatosensory cortical areas for execution of reaching and grasping movements. We applied quantitative in vitro receptor autoradiography to analyse the distribution patterns of 15 different receptors for glutamate, GABA, acetylcholine, serotonin, dopamine, and adenosine in the SPL of three adult male Macaca fascicularis monkeys. For each area, mean (averaged over all cortical layers) receptor densities were visualized as a receptor fingerprint of that area. Multivariate analyses were conducted to detect clusters of areas according to the degree of (dis)similarity of their receptor organization. Differences in regional and laminar receptor distributions confirm the location and extent of areas V6, V6Av, V6Ad, PEc, PEci, and PGm as found in cytoarchitectonic and functional studies, but also enable the definition of three subdivisions within area PE. Receptor densities are higher in supra- than in infragranular layers, with the exception of kainate, M2, and adenosine receptors. Glutamate and GABAergic receptors are the most expressed in all areas analysed. Hierarchical cluster analyses demonstrate that SPL areas are organized in two groups, an organization that corresponds to the visual or sensory-motor characteristics of those areas. Finally, based on present results and in the framework of our current understanding of the structural and functional organization of the primate SPL, we propose a novel pattern of homologies between human and macaque SPL areas.
3D-Polarized Light Imaging (3D-PLI) enables high-resolution three-dimensional mapping of the nerve fiber architecture in unstained histological brain sections based on the intrinsic birefringence of myelinated nerve fibers. The interpretation of the measured birefringent signals comes with conjointly measured information about the local fiber birefringence strength and the fiber orientation. In this study, we present a novel approach to disentangle both parameters from each other based on a weighted least squares routine (ROFL) applied to oblique polarimetric 3D-PLI measurements. This approach was compared to a previously described analytical method on simulated and experimental data obtained from a post mortem human brain. Analysis of the simulations revealed in case of ROFL a distinctly increased level of confidence to determine steep and flat fiber orientations with respect to the brain sectioning plane. Based on analysis of histological sections of a human brain dataset, it was demonstrated that ROFL provides a coherent characterization of cortical, subcortical, and white matter regions in terms of fiber orientation and birefringence strength, within and across sections. Oblique measurements combined with ROFL analysis opens up new ways to determine physical brain tissue properties by means of 3D-PLI microscopy.
High-resolution multiscale and multimodal 3D models of the brain are essential tools to understand its complex structural and functional organization. Neuroimaging techniques addressing different aspects of brain organization should be integrated in a reference space to enable topographically correct alignment and subsequent analysis of the various datasets and their modalities. The Waxholm Space (http://software.incf.org/software/waxholm-space) is a publicly available 3D coordinate-based standard reference space for the mapping and registration of neuroanatomical data in rodent brains. This paper provides a newly developed pipeline combining imaging and reconstruction steps with a novel registration strategy to integrate new neuroimaging modalities into the Waxholm Space atlas. As a proof of principle, we incorporated large scale high-resolution cyto-, muscarinic M2 receptor, and fiber architectonic images of rat brains into the 3D digital MRI based atlas of the Sprague Dawley rat in Waxholm Space. We describe the whole workflow, from image acquisition to reconstruction and registration of these three modalities into the Waxholm Space rat atlas. The registration of the brain sections into the atlas is performed by using both linear and non-linear transformations. The validity of the procedure is qualitatively demonstrated by visual inspection, and a quantitative evaluation is performed by measurement of the concordance between representative atlas-delineated regions and the same regions based on receptor or fiber architectonic data. This novel approach enables for the first time the generation of 3D reconstructed volumes of nerve fibers and fiber tracts, or of muscarinic M2 receptor density distributions, in an entire rat brain. Additionally, our pipeline facilitates the inclusion of further neuroimaging datasets, e.g., 3D reconstructed volumes of histochemical stainings or of the regional distributions of multiple other receptor types, into the Waxholm Space. Thereby, a multiscale and multimodal rat brain model was created in the Waxholm Space atlas of the rat brain. Since the registration of these multimodal high-resolution datasets into the same coordinate system is an indispensable requisite for multi-parameter analyses, this approach enables combined studies on receptor and cell distributions as well as fiber densities in the same anatomical structures at microscopic scales for the first time.
Due to rising resistance, new antibacterial strategies are needed, including methods for targeted antibiotic release. As targeting vectors, chelating molecules called siderophores that are released by bacteria to acquire iron have been investigated for conjugation to antibacterials, leading to the clinically approved drug cefiderocol. The use of smallmolecule catalysts for prodrug activation within cells has shown promise in recent years, and here we investigate siderophore-linked ruthenium catalysts for the activation of antibacterial prodrugs within cells. Moxifloxacin-based prodrugs were synthesised, and their catalyst-mediated activation was demonstrated under anaerobic, biologically relevant conditions. In the absence of catalyst, decreased antibacterial activities were observed compared to moxifloxacin versus Escherichia coli K12 (BW25113). A series of siderophore-linked ruthenium catalysts were investigated for prodrug activation, all of which displayed a combinative antibacterial effect with the prodrug, whereas a representative example displayed little toxicity against mammalian cell lines. By employing complementary bacterial growth assays, conjugates containing siderophore units based on catechol and azotochelin were found to be most promising for intracellular prodrug activation.
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