Genome-Wide Association Study of Serum Creatinine Levels during Vancomycin Therapy

Vancomycin, a commonly used antibiotic, can be nephrotoxic. Known risk factors such as age, creatinine clearance, vancomycin dose / dosing interval, and concurrent nephrotoxic medications fail to accurately predict nephrotoxicity. To identify potential genomic risk factors, we performed a genome-wide association study (GWAS) of serum creatinine levels while on vancomycin in 489 European American individuals and validated findings in three independent cohorts totaling 439 European American individuals. In primary analyses, the chromosome 6q22.31 locus was associated with increased serum creatinine levels while on vancomycin therapy (most significant variant rs2789047, risk allele A, β = -0.06, p = 1.1 x 10^-7). SNPs in this region had consistent directions of effect in the validation cohorts, with a meta-p of 1.1 x 10^-7. Variation in this region on chromosome 6, which includes the genes TBC1D32/C6orf170 and GJA1 (encoding connexin43), may modulate risk of vancomycin-induced kidney injury.     

Studies on bucephalid digeneans parasitising molluscs and fishes in Finland. II. The description of Rhipidocotyle fennica n. sp. and its discrimination by principal components analysis

Rhipidocotyle fennica n. sp. (= Rhipidocotyle Type A of Taskinen et al., 1991) from the intestine of Esox lucius in central Finland is described and compared by means of a principal components analysis (PCA) with R. campanula (= Rhipidocotyle Type B of Taskinen et al., 1991). Its cercaria develops in the bivalve Anodonta anatina and the metacercaria occurs in the skin and fins of Rutilus rutilus. The metacercaria is discriminated from that of R. campanula by PCA and is described along with aspects of the chaetotaxy of the cercaria. The new species is distinguished from R. campanula, R. kovalae, R. papillosa and R. septpapillata.     

Targeted Disruption of the Pemphigus Vulgaris Antigen (Desmoglein 3) Gene in Mice Causes Loss of Keratinocyte Cell Adhesion with a Phenotype Similar to Pemphigus Vulgaris

In patients with pemphigus vulgaris (PV), autoantibodies against desmoglein 3 (Dsg3) cause loss of cell–cell adhesion of keratinocytes in the basal and immediate suprabasal layers of stratified squamous epithelia. The pathology, at least partially, may depend on protease release from keratinocytes, but might also result from antibodies interfering with an adhesion function of Dsg3. However, a direct role of desmogleins in cell adhesion has not been shown. To test whether Dsg3 mediates adhesion, we genetically engineered mice with a targeted disruption of the DSG3 gene. DSG3 −/− mice had no DSG3 mRNA by RNase protection assay and no Dsg3 protein by immunofluorescence (IF) and immunoblots. These mice were normal at birth, but by 8–10 d weighed less than DSG3 +/− or +/+ littermates, and at around day 18 were grossly runted. We speculated that oral lesions (typical in PV patients) might be inhibiting food intake, causing this runting. Indeed, oropharyngeal biopsies showed erosions with histology typical of PV, including suprabasilar acantholysis and “tombstoning” of basal cells. EM showed separation of desmosomes. Traumatized skin also had crusting and suprabasilar acantholysis. Runted mice showed hair loss at weaning. The runting and hair loss phenotype of DSG3 −/− mice is identical to that of a previously reported mouse mutant, balding (bal). Breeding indicated that bal is coallelic with the targeted mutation. We also showed that bal mice lack Dsg3 by IF, have typical PV oral lesions, and have a DSG3 gene mutation. These results demonstrate the critical importance of Dsg3 for adhesion in deep stratified squamous epithelia and suggest that pemphigus autoantibodies might interfere directly with such a function.     

Body size and population dynamics of enchytraeids with different disturbance histories and nutrient dynamics

The population dynamics of the enchytraeid Cognettia sphagnetorum originating from an unmanaged forest (FP), a clear-cut area (CCP) or a plot treated with birch ash (APP) and the effects of population origin on labile C and N dynamics were investigated. Twenty individuals of C. sphagnetorum were introduced in microcosms containing humus from the unmanaged forest devoid of enchytraeids and amended with sucrose, and incubated for 14 weeks. Triplicate microcosms from FP, CCP and APP treatments were destructively sampled every second week and enchytraeid population density, individual length, nematode abundance and trophic structure, humus properties and dissolved organic C (DOC) and N (DON), and NH₄–N in soil were determined. The enchytraeid body size was initially smaller in CCP and APP than in FP. The enchytraeid propagation rate was lower and individual size less variable in APP than in FP or CCP, and although enchytraeid size increased in all treatments, exponential population models indicated that APP was less stable. Nematode community was dominated by bacterial-feeders especially in the microcosms with APP. N mineralization rate was lower and DOC decomposition rate greater in APP systems. The results show that C. sphagnetorum is more sensitive to wood ash than clear-cutting, and its altered body size distribution has the potential to affect the dynamics of soluble nutrients.     

Applying water scarcity footprint methodologies to milk production in Finland

The International Journal of Life Cycle Assessment - Food production without consuming scarce local freshwater resources in an unsustainable way needs to be ensured. A robust method to assess water...     

IDR knowledge base for primary immunodeficiencies

Background

Structural information about epitopes, particularly the three-dimensional (3D) structures of antigens in complex with immune receptors, presents a valuable source of data for immunology. This information is available in the Protein Data Bank (PDB) and provided in curated form by the Immune Epitope Database and Analysis Resource (IEDB). With continued growth in these data and the importance in understanding molecular level interactions of immunological interest there is a need for new specialized molecular visualization and analysis tools.

Results

The EpitopeViewer is a platform-independent Java application for the visualization of the three-dimensional structure and sequence of epitopes and analyses of their interactions with antigen-specific receptors of the immune system (antibodies, T cell receptors and MHC molecules). The viewer renders both 3D views and two-dimensional plots of intermolecular interactions between the antigen and receptor(s) by reading curated data from the IEDB and/or calculated on-the-fly from atom coordinates from the PDB. The 3D views and associated interactions can be saved for future use and publication. The EpitopeViewer can be accessed from the IEDB Web site http://www.immuneepitope.org through the quick link 'Browse Records by 3D Structure.'

Conclusion

The EpitopeViewer is designed and been tested for use by immunologists with little or no training in molecular graphics. The EpitopeViewer can be launched from most popular Web browsers without user intervention. A Java Runtime Environment (RJE) 1.4.2 or higher is required.     

Advocacy groups as research organizations: the PXE International example

Advocacy organizations for genetic diseases are increasingly becoming involved in biomedical research, particularly translational research, in order to meet the needs of the individuals that they serve. PXE International, an advocacy organization for the disease pseudoxanthoma elasticum, provides an example of how research can be accelerated by these groups. It has adopted methods that were pioneered by other advocacy organizations, and has integrated these along with new approaches into franchizable elements. The model has been followed for other conditions and has led to the establishment of a common infrastructure to enable advocacy groups to initiate, conduct and accelerate research.     

High-affinity binding of the NC1 domain of collagen VII to laminin 5 and collagen IV

Anchoring functions of collagen VII depend on its ability to form homotypic fibrils and to bind to other macromolecules to form heterotypic complexes. Biosensor-based binding assays were employed to analyze the kinetics of the NC1 domain-mediated binding of collagen VII to laminin 5, collagen IV, and collagen I. We showed that collagen VII interacts with laminin 5 and collagen IV with a Kd value of 10(-9) M. In contrast, the NC1-mediated binding to collagen I was weak with a Kd value of 10(-6) M. Binding assays also showed that the NC1 domain utilizes the same region to bind to both laminin 5 and collagen IV. We postulate that the ability of the NC1 domains to bind with high affinities to laminin 5 and collagen IV facilitates stabilization of the structure of the basement membrane itself and that the NC1-collagen I interaction may be less important for stabilization of the dermal-epidermal junction.