A goodness-of-fit test for multinomial logistic regression

This article presents a score test to check the fit of a logistic regression model with two or more outcome categories. The null hypothesis that the model fits well is tested against the alternative that residuals of samples close to each other in covariate space tend to deviate from the model in the same direction. We propose a test statistic that is a sum of squared smoothed residuals, and show that it can be interpreted as a score test in a random effects model. By specifying the distance metric in covariate space, users can choose the alternative against which the test is directed, making it either an omnibus goodness-of-fit test or a test for lack of fit of specific model variables or outcome categories.     

Translocation boost protein-folding efficiency of double-barreled chaperonins

Incorrect folding of proteins in living cells may lead to malfunctioning of the cell machinery. To prevent such cellular disasters from happening, all cells contain molecular chaperones that assist nonnative proteins in folding into the correct native structure. One of the most studied chaperone complexes is the GroEL-GroES complex. The GroEL part has a "double-barrel" structure, which consists of two cylindrical chambers joined at the bottom in a symmetrical fashion. The hydrophobic rim of one of the GroEL chambers captures nonnative proteins. The GroES part acts as a lid that temporarily closes the filled chamber during the folding process. Several capture-folding-release cycles are required before the nonnative protein reaches its native state. Here we report molecular simulations that suggest that translocation of the nonnative protein through the equatorial plane of the complex boosts the efficiency of the chaperonin action. If the target protein is correctly folded after translocation, it is released. However, if it is still nonnative, it is likely to remain trapped in the second chamber, which then closes to start a reverse translocation process. This shuttling back and forth continues until the protein is correctly folded. Our model provides a natural explanation for the prevalence of double-barreled chaperonins. Moreover, we argue that internal folding is both more efficient and safer than a scenario where partially refolded proteins escape from the complex before being recaptured.     

Evolution of Afrotropical freshwater crab lineages obscured by morphological convergence

We use sequence data derived from six DNA gene loci to examine evolutionary and biogeographic affinities among all freshwater crab families. With an emphasis on the Afrotropical fauna that includes Africa, Madagascar, and the Seychelles, we test the proposed Gondwanan cladogenesis of the group. Phylogenetic results demonstrate that contemporary distribution patterns of freshwater crab lineages are incongruent with the expected area cladogram of continental fragmentation. Instead, our phylogenetic estimate and divergence time estimation indicate a post-Gondwanan, early Cretaceous cladogenesis for freshwater crabs implying that the acquisition of a freshwater lifestyle was achieved more recently. A dispersal hypothesis as opposed to vicariance appears to best explain the contemporary distribution pattern of this group. However, our results do not explicitly disprove a Gondwanan origin for the Afrotropical freshwater crabs. Alarmingly, these results suggest that most of the currently recognized freshwater crab families are unreliable taxonomic groupings since virtually no Afrotropical freshwater crab families formed monophyletic units thus obscuring inferred biogeographic relationships. Convergence in characters associated with the terminal segment of the mandibular palp is clearly a pervasive obstacle in the taxonomy of this group.     

Renal IL-17 expression in human ANCA-associated glomerulonephritis

Interleukin-17A (IL-17) promotes inflammatory renal tissue damage in mouse models of crescentic glomerulonephritis, including murine experimental autoimmune anti-myeloperoxidase glomerulonephritis, which most likely depends on IL-17-producing Th17 cells. In human anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, however, the cellular sources of IL-17 remain to be elucidated. Therefore, we analyzed human kidney biopsies of active necrotizing and crescentic ANCA-associated glomerulonephritis by immunohistochemistry using an IL-17-specific antibody and by immunofluorescent colocalization with cell type markers. We detected numerous IL-17-expressing (IL-17(+)) cells in the glomeruli and in the tubulointerstitium. Unexpectedly, most of these IL-17(+) cells were polymorphonuclear neutrophilic granulocytes, while IL-17(+) T cells and IL-17(+) mast cells were present at significantly lower frequencies. IL-17 was not detected in other infiltrating or resident kidney cells. In those patients who had not received immunosuppressive treatment before biopsy, serum creatinine levels were positively correlated with tubulointerstitial IL-17(+) neutrophils as well as IL-17(+) T cells. Furthermore, we could demonstrate that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro. In conclusion, these results support a pathogenic role for IL-17 in human ANCA-associated glomerulonephritis. Our data suggest that in the acute stage of the disease neutrophils may act as an important immediate-early innate source of IL-17 and may thereby initiate and promote ongoing renal inflammation. IL-17 may thus be a target for treating acute ANCA-associated glomerulonephritis.     

Influence of drying on the secondary structure of intrinsically disordered and globular proteins

Circular dichroism (CD) spectroscopy of five Arabidopsis late embryogenesis abundant (LEA) proteins constituting the plant specific families LEA_5 and LEA_6 showed that they are intrinsically disordered in solution and partially fold during drying. Structural predictions were comparable to these results for hydrated LEA_6, but not for LEA_5 proteins. FTIR spectroscopy showed that verbascose, but not sucrose, strongly affected the structure of the dry proteins. The four investigated globular proteins were only mildly affected by drying in the absence, but strongly in the presence of sugars. These data highlight the larger structural flexibility of disordered compared to globular proteins and the impact of sugars on the structure of both disordered and globular proteins during drying.