Aberrant polycystin-1 expression results in modification of activator protein-1 activity, whereas Wnt signaling remains unaffected

Polycystin-1, the polycystic kidney disease 1 gene product, has been implicated in several signaling complexes that are known to regulate essential cellular functions. We investigated the role of polycystin-1 in Wnt signaling and activator protein-1 (AP-1) activation. To this aim, a membrane-targeted construct encoding the conserved C-terminal region of mouse polycystin-1 reported to mediate signal transduction activity was expressed in human embryonic and renal epithelial cells. To ensure specificity and minimal cotransfection effects, we focused our study on the endogenous proteins that actually transduce the signals, beta-catenin and T-cell factor/lymphoid-enhancing factor for Wnt signaling and (phosphorylated) c-Jun, ATF2, and c-Fos for AP-1. Our data indicate that the C-terminal region of polycystin-1 activates AP-1 by inducing phosphorylation and expression of at least c-Jun and ATF2, whereas c-Fos was not affected. Under our experimental conditions, polycystin-1 did not modulate Wnt signaling. AP-1 activity was aberrant in human autosomal dominant polycystic kidney disease (ADPKD) renal cystic epithelial cells and in renal epithelial cells expressing transgenic full-length polycystin-1, resulting in decreased Jun-ATF and increased Jun-Fos activity, whereas Wnt signaling remained unaffected. Since our data indicate that aberrant polycystin-1 expression results in altered AP-1 activity, polycystin-1 may be required for adequate AP-1 activity.     

A structured overview of simultaneous component based data integration

Background  

Data integration is currently one of the main challenges in the biomedical sciences. Often different pieces of information are gathered on the same set of entities (e.g., tissues, culture samples, biomolecules) with the different pieces stemming, for example, from different measurement techniques. This implies that more and more data appear that consist of two or more data arrays that have a shared mode. An integrative analysis of such coupled data should be based on a simultaneous analysis of all data arrays. In this respect, the family of simultaneous component methods (e.g., SUM-PCA, unrestricted PCovR, MFA, STATIS, and SCA-P) is a natural choice. Yet, different simultaneous component methods may lead to quite different results.     

Spatial structure and interspecific cooperation: theory and an empirical test using the mycorrhizal mutualism

Explaining mutualistic cooperation between species remains a major challenge for evolutionary biology. Why cooperate if defection potentially reaps greater benefits? It is commonly assumed that spatial structure (limited dispersal) aligns the interests of mutualistic partners. But does spatial structure consistently promote cooperation? Here, we formally model the role of spatial structure in maintaining mutualism. We show theoretically that spatial structure can actually disfavor cooperation by limiting the suite of potential partners. The effect of spatial structuring depends on the scale (fine or coarse level) at which hosts reward their partners. We then test our predictions by using molecular methods to track the abundance of competing, closely related, cooperative, and less cooperative arbuscular mycorrhizal (AM) fungal symbionts on host roots over multiple generations. We find that when spatial structure is reduced by mixing soil, the relative success of the more cooperative AM fungal species increases. This challenges previous suggestions that high spatial structuring is critical for stabilizing cooperation in the mycorrhizal mutualism. More generally, our results show, both theoretically and empirically, that contrary to expectations, spatial structuring can select against cooperation.     

In silico discovery and experimental validation of new protein-protein interactions

We introduce a framework for predicting novel protein-protein interactions (PPIs), based on Fisher's method for combining probabilities of predictions that are based on different data sources, such as the biomedical literature, protein domain and mRNA expression information. Our method compares favorably to our previous method based on text-mining alone and other methods such as STRING. We evaluated our algorithms through the prediction of experimentally found protein interactions underlying Muscular Dystrophy, Huntington's Disease and Polycystic Kidney Disease, which had not yet been recorded in protein-protein interaction databases. We found a 1.74-fold increase in the mean average prediction precision for dysferlin and a 3.09-fold for huntingtin when compared to STRING. The top 10 of predicted interaction partners of huntingtin were analysed in depth. Five were identified previously, and the other five were new potential interaction partners. The full matrix of human protein pairs and their prediction scores are available for download. Our framework can be extended to predict other types of relationships such as proteins in a complex, pathway or related disease mechanisms.     

Ecological interactions drive evolutionary loss of traits

Loss of traits can dramatically alter the fate of species. Evidence is rapidly accumulating that the prevalence of trait loss is grossly underestimated. New findings demonstrate that traits can be lost without affecting the external phenotype, provided the lost function is compensated for by species interactions. This is important because trait loss can tighten the ecological relationship between partners, affecting the maintenance of species interactions. Here, we develop a new perspective on so-called `compensated trait loss' and how this type of trait loss may affect the evolutionary dynamics between interacting organisms. We argue that: (1) the frequency of compensated trait loss is currently underestimated because it can go unnoticed as long as ecological interactions are maintained; (2) by analysing known cases of trait loss, specific factors promoting compensated trait loss can be identified and (3) genomic sequencing is a key way forwards in detecting compensated trait loss. We present a comprehensive literature survey showing that compensated trait loss is taxonomically widespread, can involve essential traits, and often occurs as replicated evolutionary events. Despite its hidden nature, compensated trait loss is important in directing evolutionary dynamics of ecological relationships and has the potential to change facultative ecological interactions into obligatory ones.     

A placebo-controlled randomized HPV16 synthetic long-peptide vaccination study in women with high-grade cervical squamous intraepithelial lesions

The aim of this study was to investigate the capacity of an HPV16 E6/E7 synthetic overlapping long-peptide vaccine to stimulate the HPV16-specific T-cell response, to enhance the infiltration of HPV16-specific type 1 T cells into the lesions of patients with HPV16+ high-grade cervical squamous intraepithelial lesion (HSIL) and HPV clearance. This was a placebo-controlled randomized phase II study in patients with HPV16-positive HSIL. HPV16-specific T-cell responses were determined pre- and post-vaccination by ELISPOT, proliferation assay and cytokine assays in PBMC and HSIL-infiltrating lymphocytes, and delayed-type hypersensitivity skin tests. Motivational problems of this patient group to postpone treatment of their premalignant lesions affected the inclusion rates and caused the study to stop prematurely. Of the accrued patients, 4 received a placebo and 5 received 1-2 vaccinations. Side effects mainly were flu-like symptoms and injection site reactions. A strong HPV-specific IFNγ-associated T-cell response was detected by ELISPOT in all vaccinated patients. The outcome of the skin tests correlated well with the ELISPOT analysis. The cytokine profile associated with HPV16-specific proliferation varied from robust type 1 to dominant type 2 responses. No conclusions could be drawn on vaccine-enhanced T-cell infiltration of the lesion, and there was no HPV clearance at the time of LEEP excision. Thus, vaccination of HSIL patients results in increased HPV16-specific T-cell immunity. Further development of this type of treatment relies on the ability to motivate patients and in the reduction in the side effects.