Hook Proteins: Association with Alzheimer Pathology and Regulatory Role of Hook3 in Amyloid Beta Generation

Defects in intracellular transport are implicated in the pathogenesis of Alzheimer’s disease (AD). Hook proteins are a family of cytoplasmic linker proteins that participate in endosomal transport. In this study we show that Hook1 and Hook3 are expressed in neurons while Hook2 is predominantly expressed in astrocytes. Furthermore, Hook proteins are associated with pathological hallmarks in AD; Hook1 and Hook3 are localized to tau aggregates and Hook2 to glial components within amyloid plaques. Additionally, the expression of Hook3 is reduced in AD. Modelling of Hook3 deficiency in cultured cells leads to slowing of endosomal transport and increases β-amyloid production. We propose that Hook3 plays a role in pathogenic events exacerbating AD.     

Decline in Coronary Mortality in Sweden between 1986 and 2002: Comparing Contributions from Primary and Secondary Prevention

BackgroundThe relative importance of risk factor reduction in healthy people (primary prevention) versus that in patients with coronary heart disease (secondary prevention) has been debated. We aimed to quantify the contribution of the two.MethodologyWe used the previously validated IMPACT model to estimate contributions from primary prevention (reducing risk factors in the population, particularly smoking, cholesterol and systolic blood pressure) and from secondary prevention (reducing risk factors in coronary heart disease patients) in the Swedish population.ConclusionsThe largest effects on mortality came from primary prevention, giving markedly larger mortality reductions than secondary prevention.     

Genus-Wide Comparative Genomics of Malassezia Delineates Its Phylogeny,Physiology, and Niche Adaptation on Human Skin

Malassezia is a unique lipophilic genus in class Malasseziomycetes in Ustilaginomycotina, (Basidiomycota, fungi) that otherwise consists almost exclusively of plant pathogens. Malassezia are typically isolated from warm-blooded animals, are dominant members of the human skin mycobiome and are associated with common skin disorders. To characterize the genetic basis of the unique phenotypes of Malassezia spp., we sequenced the genomes of all 14 accepted species and used comparative genomics against a broad panel of fungal genomes to comprehensively identify distinct features that define the Malassezia gene repertoire: gene gain and loss; selection signatures; and lineage-specific gene family expansions. Our analysis revealed key gene gain events (64) with a single gene conserved across all Malassezia but absent in all other sequenced Basidiomycota. These likely horizontally transferred genes provide intriguing gain-of-function events and prime candidates to explain the emergence of Malassezia. A larger set of genes (741) were lost, with enrichment for glycosyl hydrolases and carbohydrate metabolism, concordant with adaptation to skin’s carbohydrate-deficient environment. Gene family analysis revealed extensive turnover and underlined the importance of secretory lipases, phospholipases, aspartyl proteases, and other peptidases. Combining genomic analysis with a re-evaluation of culture characteristics, we establish the likely lipid-dependence of all Malassezia. Our phylogenetic analysis sheds new light on the relationship between Malassezia and other members of Ustilaginomycotina, as well as phylogenetic lineages within the genus. Overall, our study provides a unique genomic resource for understanding Malassezia niche-specificity and potential virulence, as well as their abundance and distribution in the environment and on human skin.     

EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα⁺) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.     

Sources of phenotypic variance in egg and larval traits in a marine invertebrate

Contrary to many separate sex systems, the evolutionary ecology of polyandry in simultaneous hermaphrodites, and in particular in those with internal fertilization, has received little attention. Recent studies on the promiscuous gastropod Chelidonura sandrana showed that offspring size, an important determinant of offspring performance in many marine invertebrates, varies with the number of different mating partners. However, the source of this differential allocation by mothers remained unclear. Using a quantitative genetic model, we here tested for parental effects on offspring size and the importance of ‘good gene’ effects on early life history traits. Our analysis revealed no significant sire but strong dam effects for all investigated traits. Moreover, embryo viability tended to increase with egg capsule volume, thus linking offspring size with offspring performance. Our findings suggest that in C. sandrana (1) differential allocation is a maternal effect in response to the number of different partners, and that (2) additive genetic variance is of negligible importance in early life history traits.     

3-(3-Aryloxyaryl)imidazo[1,2-a]pyridine sulfones as liver X receptor agonists

Replacement of a quinoline with an imidazo[1,2-a]pyridine in a series of liver X receptor (LXR) agonists incorporating a [3-(sulfonyl)aryloxyphenyl] side chain provided high affinity LXR ligands 7. In functional assays of LXR activity, good agonist potency and efficacy were found for several analogs.     

Macronutrient balancing in free‐ranging populations of moose

At northern latitudes, large spatial and temporal variation in the nutritional composition of available foods poses challenges to wild herbivores trying to satisfy their nutrient requirements. Studies conducted in mostly captive settings have shown that animals from a variety of taxonomic groups deal with this challenge by adjusting the amounts and proportions of available food combinations to achieve a target nutrient balance. In this study, we used proportions‐based nutritional geometry to analyze the nutritional composition of rumen samples collected in winter from 481 moose (Alces alces) in southern Sweden and examine whether free‐ranging moose show comparable patterns of nutrient balancing. Our main hypothesis was that wild moose actively regulate their rumen nutrient composition to offset ecologically imposed variation in the nutritional composition of available foods. To test this, we assessed the macronutritional composition (protein, carbohydrates, and lipids) of rumen contents and commonly eaten foods, including supplementary feed, across populations with contrasting winter diets, spanning an area of approximately 10,000 km². Our results suggest that moose balanced the macronutrient composition of their rumen, with the rumen contents having consistently similar proportional relationship between protein and nonstructural carbohydrates, despite differences in available (and eaten) foods. Furthermore, we found that rumen macronutrient balance was tightly related to ingested levels of dietary fiber (cellulose and hemicellulose), such that the greater the fiber content, the less protein was present in the rumen compared with nonstructural carbohydrates. Our results also suggest that moose benefit from access to a greater variety of trees, shrubs, herbs, and grasses, which provides them with a larger nutritional space to maneuver within. Our findings provide novel theoretical insights into a model species for ungulate nutritional ecology, while also generating data of direct relevance to wildlife and forest management, such as silvicultural or supplementary feeding practices.     

Growth in Children with Cerebral Palsy during five years after Selective Dorsal Rhizotomy: a practice-based study

Background  

Overweight is reported as a side effect of SDR. The aims were to study the development of weight, height and body mass index (BMI) during five years after SDR.     

Mechanical integrin stress and magnetic forces induce biological responses in mesenchymal stem cells which depend on environmental factors

The control of mesenchymal stem cells (MSC) by physical cues is of great interest in regenerative medicine. Because integrin receptors function as mechanotransducers, we applied drag forces to β1 integrins on the apical surface of adherent human MSC. In addition to mechanical forces, the technique we used involved also the exposure of the cells to an inhomogeneous magnetic field. In order to assess the influence of the substrate on cell adhesion, cells were cultured on plain tissue culture polystyrene (TCP) or on coated well plates, which allowed only adhesion to embedded fibronectin or RGD peptides. We found that the expression of collagen I, which is involved in osteogenesis, and VEGF, a factor which stimulates angiogenesis, increased as a result of short-term mechanical integrin stress. Whereas, collagen I expression was stimulated by mechanical forces when the cells were cultured on fibronectin and RGD peptides but not on TCP, VEGF expression was enhanced by physical stimulation on TCP. The study further revealed that magnetic forces enhanced Sox 9 expression, a marker of chondrogenesis, and reduced the expression of ALP. Concerning the intracellular mechanisms involved, we found that the expression of VEGF induced by physical forces depended on Akt activation. Together, the results implicate that biological functions of MSC can be stimulated by integrin-mediated mechanical forces and a magnetic field. However, the responses of cells depend strongly on the substrate to which they adhere and on the cross-talk between integrin-mediated signals and soluble factors.