Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease

Microglia are the principal immune cells of the brain. In Alzheimer disease, these brain mononuclear phagocytes are recruited from the blood and accumulate in senile plaques. However, the role of microglia in Alzheimer disease has not been resolved. Microglia may be neuroprotective by phagocytosing amyloid-beta (Abeta), but their activation and the secretion of neurotoxins may also cause neurodegeneration. Ccr2 is a chemokine receptor expressed on microglia, which mediates the accumulation of mononuclear phagocytes at sites of inflammation. Here we show that Ccr2 deficiency accelerates early disease progression and markedly impairs microglial accumulation in a transgenic mouse model of Alzheimer disease (Tg2576). Alzheimer disease mice deficient in Ccr2 accumulated Abeta earlier and died prematurely, in a manner that correlated with Ccr2 gene dosage, indicating that absence of early microglial accumulation leads to decreased Abeta clearance and increased mortality. Thus, Ccr2-dependent microglial accumulation plays a protective role in the early stages of Alzheimer disease by promoting Abeta clearance.     

An Integrated Framework for Risk Management and Population Health

The traditional medical model of health and health policy development has focused on individuals and the role of medical care in preventing and treating disease and injury. Recent attention to health inequities and social determinants of health has raised the profile of population heath and evidence-based strategies for improving the health of whole populations. At the same time, risk science has emerged as an important new discipline for the assessment and management of risks to health. This article reviews historical developments in the fields of risk management and population health and proposes a joint population health risk management framework that integrates the key elements of both fields. Applying this integrated approach to managing population health risks will facilitate the development of evidence-based health policy. It will encourage a more systematic and comprehensive evaluation of population health issues and promote the use of a broader suite of interventions to reduce health risks and enhance population health status.     

Conserved actin cysteine residues are oxidative stress sensors that can regulate cell death in yeast

Actin's functional complexity makes it a likely target of oxidative stress but also places it in a prime position to coordinate the response to oxidative stress. We have previously shown that the NADPH oxidoreductase Oye2p protects the actin cytoskeleton from oxidative stress. Here we demonstrate that the physiological consequence of actin oxidation is to accelerate cell death in yeast. Loss of Oye2p leads to reactive oxygen species accumulation, activation of the oxidative stress response, nuclear fragmentation and DNA degradation, and premature chronological aging of yeast cells. The oye2Delta phenotype can be completely suppressed by removing the potential for formation of the actin C285-C374 disulfide bond, the likely substrate of the Oye2p enzyme or by treating the cells with the clinically important reductant N-acetylcysteine. Because these two cysteines are coconserved in all actin isoforms, we theorize that we have uncovered a universal mechanism whereby actin helps to coordinate the cellular response to oxidative stress by both sensing and responding to oxidative load.     

Human adipose-derived adult stem cells upregulate palladin during osteogenesis and in response to cyclic tensile strain

Cell morphology may be an important stimulus during differentiation of human adipose-derived adult stem (hADAS) cells, but there are limited studies that have investigated the role of the cytoskeleton or associated proteins in hADAS cells undergoing differentiation. Palladin is an actin-associated protein that plays an integral role in focal adhesion and cytoskeleton organization. In this study we show that palladin was expressed by hADAS cells and was modulated during osteogenic differentiation and in response to cyclic tensile strain. Human ADAS cells expressed the 90- and 140-kDa palladin isoforms and upregulated expression of both isoforms after culture in conditions that promoted osteogenesis. Palladin mRNA expression levels were also increased in hADAS cells subjected to cyclic tensile strain. Knockdown of the palladin gene during osteogenesis resulted in decreased actin stress fibers and decreased protein levels of Eps8, an epidermal growth factor receptor tyrosine kinase that colocalizes with actin. Silencing the palladin gene, however, did not affect hADAS cells' commitment down the osteogenic lineage.     

Engineered antifouling microtopographies - effect of feature size, geometry, and roughness on settlement of zoospores of the green alga Ulva

The effect of feature size, geometry, and roughness on the settlement of zoospores of the ship fouling alga Ulva was evaluated using engineered microtopographies in polydimethylsiloxane elastomer. The topographies studied were designed at a feature spacing of 2 microm and all significantly reduced spore settlement compared to a smooth surface. An indirect correlation between spore settlement and a newly described engineered roughness index (ERI) was identified. ERI is a dimensionless ratio based on Wenzel's roughness factor, depressed surface fraction, and the degree of freedom of spore movement. Uniform surfaces of either 2 mum diameter circular pillars (ERI=5.0) or 2 microm wide ridges (ERI=6.1) reduced settlement by 36% and 31%, respectively. A novel multi-feature topography consisting of 2 mum diameter circular pillars and 10 microm equilateral triangles (ERI=8.7) reduced spore settlement by 58%. The largest reduction in spore settlement, 77%, was obtained with the Sharklet AF topography (ERI=9.5).     

The Mcf1 toxin induces apoptosis via the mitochondrial pathway and apoptosis is attenuated by mutation of the BH3-like domain

Photorhabdus are Gram-negative, nematode-vectored bacteria that produce toxins to kill their insect hosts. The expression of one of these, Makes caterpillars floppy 1 (Mcf1), is sufficient to allow Escherichia coli to survive within, and kill, caterpillars which are otherwise able to clear E. coli infection. Mcf1 treated caterpillars show rapid loss of body turgor (the 'floppy' phenotype) and death is associated with massive apoptosis of both the midgut epithelium and insect phagocytes. Mammalian tissue culture cells treated with Mcf1 also display key features of apoptosis including zeiosis, apoptotic nuclear morphology, DNA laddering, activation of the effector caspase-3 and PARP cleavage. As Mcf1 carries a single BH3-like domain, here we investigate the hypothesis that this toxin promotes apoptosis via the mitochondrial pathway by mimicking a BH3 domain-only protein. Consistent with this hypothesis, a double mutant within the BH3-like domain causes a dramatic decline in apoptosis. Mcf1 also alters mitochondrial membrane potential and triggers the release of cytochrome c. Cells overexpressing Bcl-x(L), an anti-apoptotic Bcl-2 family member, are resistant to Mcf1-mediated apoptosis, as are cells deficient in Bax. In addition, translocation of Bax to the mitochondrion is observed in response to Mcf1 treatment. Together, these results show that Mcf1 mediates apoptosis via the mitochondrial pathway, and are consistent with the hypothesis that the BH3-like domain in Mcf1 is a functional requirement for the pro-apoptotic activity of Mcf1.     

Effect of selected non-ionic surfactants on the flow behavior of aqueous veegum suspensions

The aim of this work was to investigate the influence of some non-ionic surfactants, Tween 80 and Brij 98, on the viscosity and flow behavior of a commercial montmorillonite clay, Veegum Granules. The effect of different concentrations of the surfactants on the shear stress-shear rate rheograms of hydrated concentrated clay suspensions was determined by shear viscometry. The addition of either surfactant increased the plastic viscosity and the yield stress of the suspensions. Furthermore both surfactants altered the thixotropy of the suspensions to an extent that depended on both the surfactant concentration and the time of equilibration of the surfactant and Veegum. Brij 98 had a greater and more rapid effect. It is proposed that the surfactant polar head-groups anchor at the tetrahedral sheet surface, leaving the alkyl chains extending away from the edges and faces. Consequently, the alkyl chains undergo hydrophobic interactions that facilitate the association between the platelets and increase the physical structure within the suspension. Stereochemical differences between the polar groups may lead to differences in the way the surfactants associate with the tetrahedral sheet and hence their ultimate effect on the rheological behavior. There is a significant interaction between these surfactants and montmorillonite clays, and the rheological changes that occur could have a major impact on any pharmaceutical formulation that uses these ingredients. Published: March 30, 2007     

Ranking the direct threats to biodiversity in sub-Saharan Africa

Biodiversity and Conservation - Sub-Saharan Africa receives large investments in biodiversity conservation, and if these investments can be concentrated on the highest threats to biodiversity, the...     

Ecological Succession and Viability of Human-Associated Microbiota on Restroom Surfaces

Human-associated bacteria dominate the built environment (BE). Following decontamination of floors, toilet seats, and soap dispensers in four public restrooms, in situ bacterial communities were characterized hourly, daily, and weekly to determine their successional ecology. The viability of cultivable bacteria, following the removal of dispersal agents (humans), was also assessed hourly. A late-successional community developed within 5 to 8 h on restroom floors and showed remarkable stability over weeks to months. Despite late-successional dominance by skin- and outdoor-associated bacteria, the most ubiquitous organisms were predominantly gut-associated taxa, which persisted following exclusion of humans. Staphylococcus represented the majority of the cultivable community, even after several hours of human exclusion. Methicillin-resistant Staphylococcus aureus (MRSA)-associated virulence genes were found on floors but were not present in assembled Staphylococcus pan-genomes. Viral abundances, which were predominantly enterophages, human papilloma virus, and herpesviruses, were significantly correlated with bacterial abundances and showed an unexpectedly low virus-to-bacterium ratio in surface-associated samples, suggesting that bacterial hosts are mostly dormant on BE surfaces.