G Protein-Coupled Receptors in and on the Cell Nucleus: A New Signaling Paradigm?

Signaling from internalizing and endosomal receptors has almost become a classic GPCR paradigm in the last several years. However, it has become clear in recent years that GPCRs also elicit signals when resident at other subcellular sites including the endoplasmic reticulum, Golgi apparatus, and the nucleus. In this review we discuss the nature, function, and trafficking of nuclear GPCR signaling complexes, as well as potential sources of endogenous and exogenous ligands. Finally, we pose a series of questions that will need to be answered in the coming years to confirm and extend this as a new paradigm for GPCR signaling.     

New directions in biogeography?

The deduction of biogeographic process from the study of its history is complicated by the fact that history is a singular thing. This singularity allows no estimation of the degree of determinism surrounding the realization of biogeographic processes, and consequently we know almost nothing about the generality of such deductions. Here we discuss a new approach, called 'experimental biogeography', that exploits computers to model faunal build-up repeatedly against a fixed vicariant background over ecological and evolutionary time scales. This new approach enables a biogeographer to be omniscient - to know both vicariant history and actual phylogeny. Moreover, history can be replayed repeatedly to accumulate a sample of multiple phylogenies and to estimate probability density functions for biogeographic variables. Roles of stochastic, historical and ecological processes in adaptive radiations can also be assessed. Experimental biogeography allows examination of the reliability of various methods of recovering historical patterns.     

Species-Specific Bacterial Communities in the Phycosphere of Microalgae?

Specific associations of bacteria with phytoplankton have recently been reported in the literature. In our study, we analyzed bacterial communities of microalgal cultures related to algal growth phases. Seven freshly isolated key diatom and dinoflagellate species from Helgoland Roads, North Sea, were investigated. The community composition of associated bacteria as well as the cell numbers, the photosynthetic efficiency of the algae, and the depletion of inorganic nutrients in the medium were recorded over a period of 8 weeks in batch cultures. Diversity and succession of bacterial communities was analyzed by ribosomal intergenic spacer analysis. Phylogenetic analysis of bacterial populations was performed by denaturing gradient gel electrophoresis of 16S rRNA genes followed by DNA sequence analysis. Members of Alphaproteobacteria and Gammaproteobacteria and the Flavobacteria–Sphingobacteria group within the Bacteroidetes phylum predominated in the cultures. Differences in free-living and attached bacterial populations were observed between the phylogenetic groups. Shifts in the bacterial communities could not be correlated to changes of nutrient levels or algal growth phases. Regarding our results, it should not be generalized that the compositions of the bacterial communities are strictly species specific for microalgae. The importance of factors like the composition of exudates is apparent.     

Ligation of α-Dystroglycan on Podocytes Induces Intracellular Signaling: A New Mechanism for Podocyte Effacement?

Background

α-Dystroglycan is a negatively charged glycoprotein that covers the apical and basolateral membrane of the podocyte. Its transmembrane binding to the cytoskeleton is regulated via tyrosine phosphorylation (pY892) of β-dystroglycan. At the basolateral side α-dystroglycan binds the glomerular basement membrane. At the apical membrane, it plays a role in the maintenance of the filtration slit. In this study, we evaluated whether ligation of α-dystroglycan with specific antibodies or natural ligands induces intracellular signaling, and whether there is an effect on podocyte architecture.

Methodology/Principal Findings

Conditionally immortalized podocytes were exposed in vitro to antibodies to α-dystroglycan, and to fibronectin, biglycan, laminin and agrin. Intracellular calcium fluxes, phosphorylation of β-dystroglycan and podocyte architecture were studied. Antibodies to α-dystroglycan could specifically induce calcium signaling. Fibronectin also induced calcium signaling, and led to dephosphorylation of pY892 in β-dystroglycan. Ligation of α-dystroglycan resulted in an altered actin architecture, a decreased number of podocyte pedicles and a more flattened appearance of the podocyte.

Conclusions/Significance

We conclude that ligation of α-dystroglycan on podocytes induces intracellular calcium signaling, which leads to an altered cytoskeleton architecture akin to the situation of foot process effacement. In particular the ability of fibronectin to induce intracellular signaling events is of interest, since the expression and excretion of this protein is upregulated in several proteinuric diseases. Therefore, fibronectin-induced signaling via dystroglycan may be a novel mechanism for foot process effacement in proteinuric diseases.     

Rhabdomyolysis in Community Acquired Bacterial Sepsis – A Retrospective Cohort Study

Background and Objectives

Rhabdomyolysis is often associated with sepsis and gram positive bacterial pathogens are reported to be the most frequent cause of sepsis induced rhabdomyolysis. We report the pattern of infecting bacterial pathogens and associated causal factors in a South-Indian cohort.

Design, Setting, Participants & Measurements

Retrospective cohort study of adult patients with community acquired bacterial sepsis complicated by rhabdomyolysis from March 2003 - August 2008. Rhabdomyolysis was defined as serum creatine kinase >2000 IU/L. The study population was divided into group-I (sepsis with gram positive pathogens), group–II (sepsis with gram negative pathogens) and group-III (culture negative sepsis).

Results

103 patients (group I -15, group II- 34 and group III- 54) formed the study cohort. Mean age was 55 years and two-third had diabetes. Mean creatine kinase was 7114 IU/L and mean serum creatinine on admission was 2.4 mg/dl. Causative pathogen of sepsis was identified in 47.5%. Gram negative pathogens were more frequently (33%) associated with rhabdomyolysis than gram positive pathogens (14.5%). Lung was the commonest foci of sepsis (38.8%). 78.6% of the study population had one or more additional causal factor for rhabdomyolysis like statin intake, chronic alcoholism, hypokalemia, hypernatremia and hypophosphatemia. Mortality was 59%.

Conclusions

Gram negative bacterial pathogens were more frequently associated with rhabdomyolysis than gram positive pathogens. Rhabdomyolysis in patients with sepsis is multifactorial and is associated with high mortality.     

Tuberin – A New Molecular Target in Alzheimer’s Disease?

Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected individuals develop mental retardation, developmental brain defects and seizures. The TSC gene products, hamartin and tuberin, form a complex, of which tuberin is assumed to be the functional component being involved in a wide variety of different cellular processes. Here we report that tuberin protein levels are decreased in the frontal cortex of patients with Alzheimer’s disease. In addition, tuberin levels are also decreased in Down syndrome brain samples positive for β-amyloid plaques and neurofibrillary tangles. Analysis of NeuN revealed that this regulation is not a consequence of differences in the amount of postmitotic neurons. This first connection of tuberin to another common disease beside TSC stimulates new approaches to investigate the molecular development and to establish new therapeutic strategies.     

Poor Diet in Shift Workers: A New Occupational Health Hazard?

The PLoS Medicine Editors discuss the link between shift work, diet, and type 2 diabetes, and argue that unhealthy eating should be considered a new form of occupational hazard.     

PHOR1: A U-Box GA Signaling Component With a Role in Proteasome Degradation?

Recent identification of U-box proteins as E3 ubiquitin ligases suggests that the U-box arm-repeat protein PHOR1, for which we have demonstrated a role in GA signal transduction, may play a role in GA signaling by ubiquitinating one or more components of the GA response pathway to target them for proteasome degradation. Here we show that PHOR1 function in GA signaling is not exclusive of potato plants, but it is also conserved in Arabidopsis. Three PHOR1-homologs have been identified in this plant species, which would correspond to PHOR1-orthologs. Experimental evidence has recently been obtained for the involvement of proteasome-dependent protein degradation in GA-mediated destabilization of the SLN1 DELLA protein, thus pointing to this repressor as a likely substrate for ubiquitination by the PHOR1 ubiquitin ligase activity.