Linking complement C3 and B cells in nasal polyposis

Nasal polyposis often is characterized by a persistent inflammation of the sinonasal mucosa, disease recurrence after medical or surgical intervention, and asthma comorbidity. Dysregulated complement activation may contribute to immunologic alterations and disease. To date, there is only scattered knowledge on the source and regulation of the central complement factors in the pathogenesis of nasal polyps. Here, we aim to study complement signatures, especially the C3-C3aR axis, and focus on cellular sources and targets in nasal polyps. Expression of complement factors, including C3, C5, and the anaphylatoxin receptors, was analyzed in nasal polyp tissue samples, the corresponding inferior turbinates, and healthy controls using transcriptomic methods and protein measurements. Distinct patterns of complement expression were found in nasal polyps compared to controls, characterized by an increased C3 activation and an increase in C3aR-bearing cells. In contrast, no difference was shown for epithelial-dependent C3 production. Besides low intracellular C3-expression levels for lymphocytes in general, we could identify an enlarged B lymphocyte population in nasal polyps displaying high amounts of intracellular C3. Our data suggest a prominent role for the C3-C3aR-axis in nasal polyps and, for the first time, describe a B cell population containing high levels of intracellular C3, suggesting a new role of B cells in the maintenance of the inflammation by complement

A role for talin in presynaptic function

Talin, an adaptor between integrin and the actin cytoskeleton at sites of cell adhesion, was recently found to be present at neuronal synapses, where its function remains unknown. Talin interacts with phosphatidylinositol-(4)-phosphate 5-kinase type Iγ, the major phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2]–synthesizing enzyme in brain. To gain insight into the synaptic role of talin, we microinjected into the large lamprey axons reagents that compete the talin–PIP kinase interaction and then examined their effects on synaptic structure. A dramatic decrease of synaptic actin and an impairment of clathrin-mediated synaptic vesicle endocytosis were observed. The endocytic defect included an accumulation of clathrin-coated pits with wide necks, as previously observed after perturbing actin at these synapses. Thus, the interaction of PIP kinase with talin in presynaptic compartments provides a mechanism to coordinate PI(4,5)P2 synthesis, actin dynamics, and endocytosis, and further supports a functional link between actin and clathrin-mediated endocytosis

Proteome Profile of Myelin in the Zebrafish Brain

The velocity of nerve conduction along vertebrate axons depends on their ensheathment with myelin. Myelin membranes comprise specialized proteins well characterized in mice. Much less is known about the protein composition of myelin in non-mammalian species. Here, we assess the proteome of myelin biochemically purified from the brains of adult zebrafish (Danio rerio), considering its increasing popularity as model organism for myelin biology. Combining gel-based and gel-free proteomic approaches, we identified > 1,000 proteins in purified zebrafish myelin, including all known constituents. By mass spectrometric quantification, the predominant Ig-CAM myelin protein zero (MPZ/P0), myelin basic protein (MBP), and the short-chain dehydrogenase 36K constitute 12%, 8%, and 6% of the total myelin protein, respectively. Comparison with previously established mRNA-abundance profiles shows that expression of many myelin-related transcripts coincides with the maturation of zebrafish oligodendrocytes. Zebrafish myelin comprises several proteins that are not present in mice, including 36K, CLDNK, and ZWI. However, a surprisingly large number of ortholog proteins is present in myelin of both species, indicating partial evolutionary preservation of its constituents. Yet, the relative abundance of CNS myelin proteins can differ markedly as exemplified by the complement inhibitor CD59 that constitutes 5% of the total zebrafish myelin protein but is a low-abundant myelin component in mice. Using novel transgenic reporter constructs and cryo-immuno electron microscopy, we confirm the incorporation of CD59 into myelin sheaths. These data provide the first proteome resource of zebrafish CNS myelin and demonstrate both similarities and heterogeneity of myelin composition between teleost fish and rodents

Early volumetric changes of hippocampus and medial prefrontal cortex following medial temporal lobe resection

Previous studies have shown that cognitive demands and physical exercise stimulate adult neurogenesis in the dentate gyrus and hippocampus. Recent observations in healthy humans and patients with mild cognitive impairment moreover suggest that training-induced increases in hippocampal volume may be associated with improved memory performance. The corresponding plasticity processes in hippocampal volume may occur on timescales of months to years. For patients with focal lesions in this region, previous functional imaging studies suggest that increased recruitment of the contralateral hippocampus and extratemporal regions may be an important part of the reorganization of episodic memory. However, it is currently unclear whether focal damage to the medial temporal lobe (MTL) induces gray matter (GM) volume changes in the intact contralateral hippocampus and in connected network regions on a shorter timescale. We therefore investigated whether unilateral resection of the MTL, including the hippocampus, induces measurable volumetric changes in the contralateral hippocampus and in the default mode network (DMN). We recruited 31 patients with unilateral left (N = 19) or right (N = 12) hippocampal sclerosis undergoing MTL resection for treatment of drug-resistant epilepsy. Structural MRI was acquired immediately before and 3 months after surgery. Longitudinal voxel-based morphometry (VBM) analysis revealed a significant increase of right hippocampal volume following resection of the left anterior MTL. Furthermore, this patient group showed GM volume increases in the DMN. These results demonstrate significant structural plasticity of the contralateral hippocampus, even in patients with a long-standing unilateral hippocampal dysfunction and structural reorganization processes extending to distant, but functionally connected brain regions

Constitutional absence of epithelial integrin α3 impacts the composition of the cellular microenvironment of ILNEB keratinocytes

Integrin α3β1, a major epidermal adhesion receptor is critical for organization of the basement membrane during development and wound healing. Integrin α3 deficiency leads to interstitial lung disease, nephrotic syndrome and epidermolysis bullosa (ILNEB), an autosomal recessive multiorgan disease characterized by basement membrane abnormalities in skin, lung and kidney. The pathogenetic chains from ITGA3 mutation to tissue abnormalities are still unclear. Although integrin α3 was reported to regulate multiple extracellular proteins, the composition of the extracellular compartment of integrin α3-negative keratinocytes has not been resolved so far. In a comprehensive approach, quantitative proteomics of deposited extracellular matrix, conditioned cultured media as well as of the intracellular compartment of keratinocytes isolated from an ILNEB patient and from normal skin were performed. By mass spectrometry-based proteomics, 167 proteins corresponding to the GO terms “extracellular” and “cell adhesion”, or included in the “human matrisome” were identified in the deposited extracellular matrix, and 217 in the conditioned media of normal human keratinocytes. In the absence of integrin α3, 33% and 26% respectively were dysregulated. Dysregulated proteins were functionally related to integrin α3 or were known interaction partners. The results show that in the absence of integrin α3 ILNEB keratinocytes produce a fibronectin-rich microenvironment and make use of fibronectin-binding integrin subunits αv and α5. The most important results were validated in monolayer and organotypic coculture models. Finally, the in vivo relevance of the most dysregulated components was demonstrated by immunostainings of skin, kidney and lung samples of three ILNEB patients

The Tandem-L Mission Proposal: Monitoring Earth’s Dynamics with High Resolution SAR Interferometry

Tandem-L is a proposal for an innovative interferometric and polarimetric radar mission that enables the systematic monitoring of dynamic processes on the Earth surface. Important mission objectives are global forest height and biomass inventories, large scale measurements of millimetric displacements due to tectonic shifts, and systematic observations of glacier movements. The innovative mission concept and the high data acquisition capacity of Tandem-L provide a unique data source to observe, analyze and quantify the dynamics of a wide range of mutually interacting processes in the bio-, litho-, hydro- and cryosphere. By this, Tandem-L will be an essential step to advance our understanding of the Earth system and its intricate dynamics. This paper provides an overview of the Tandem-L mission concept and its main application areas. Performance predictions show the great potential of Tandem-L to acquire a wide range of bio- and geophysical parameters with high accuracy on a global scale. Innovative aspects like the employment of advanced digital beamforming techniques to improve performance and coverage are discussed in detail