Apolipoprotein E genotype and alpha-tocopherol modulate amyloid precursor protein metabolism and cell cycle regulation

Apolipoprotein E4 (apoE4) genotype is associated with an increased risk for Alzheimer's disease (AD). This is thought to be in part attributable to an impact of apoE genotype on the processing of the transmembrane amyloid precursor protein (APP) thereby contributing to amyloid beta peptide formation in apoE4 carriers, which is a primary patho-physiological feature of AD. As apoE and alphato-copherol (alpha-toc) have been shown to modulate membrane bilayer properties and hippocampal gene expression, we studied the effect of apoE genotype on APP metabolism and cell cycle regulation in response to dietary a-toc. ApoE3 and apoE4 transgenic mice were fed a diet low (VE) or high (+VE) in vitamin E (3 and 235 mg alpha-toe/kg diet, respectively) for 12 weeks. Cholesterol levels and membrane fluidity were not different in synaptosomal plasma membranes isolated from brains of apoE3 and apoE4 mice (-VE and +VE). Non-amyloidogenic alpha-secretase mRNA concentration and activity were significantly higher in brains of apoE3 relative to apoE4 mice irrespective of the dietary a-toe supply, while amyloidogenic beta-secretase and gamma-secretase remained unchanged. Relative mRNA concentration of cell cycle related proteins were modulated differentially by dietary a-toc supplementation in apoE3 and apoE4 mice, suggesting genotype-dependent signalling effects on cell cycle regulation.

Can drug-bearing liposomes penetrate intact skin?

Using liposomes to deliver drugs to and through human skin is controversial, as their function varies with type and composition. Thus they may act as drug carriers controlling release of the medicinal agent. Alternatively, they may provide a localized depot in the skin so minimizing systemic effects or can be used for targeting delivery to skin appendages (hair follicles and sweat glands). Liposomes may also enhance transdermal drug delivery, increasing systemic drug concentrations. With such a multiplicity of functions, it is not surprising that mechanisms of liposomal delivery of therapeutic agents to and through the skin are unclear. Accordingly, this article provides an overview of the modes and mechanisms of action of different vesicles as drug delivery vectors in human skin. Our conclusion is that vesicles, depending on the composition and method of preparation, can vary with respect to size, lamellarity, charge, membrane fluidity or elasticity and drug entrapment. This variability allows for multiple functions ranging from local to transdermal effects. Application to dissimilar skins (animal or human) via diverse protocols may reveal different mechanisms of action with possible vesicle skin penetration reaching different depths, from surface assimilation to (rarely) the viable tissue and subsequent systemic absorption.

Effect of dietary fatty acid composition on inositol-, choline- and ethanolamine-phospholipids of mammary tissue and erythrocytes in the rat

The present study investigated the effect of feeding maize-oil, olive-oil and fish-oil diets, from weaning to adulthood, on rat mammary tissue and erythrocyte phospholipid fatty acid compositions. Effects of diet on the relative proportions of membrane phospholipids in the two tissues were also investigated. Mammary tissue phosphatidylinositol (PI) fatty acids were unaltered by diet, but differences in phosphatidylethanolamine (PE) and, to a lesser extent, phosphatidylcholine (PC) fractions were found between animals fed on different diets from weaning. Differences observed were those expected from the dietary fatty acids fed; n-6 fatty acids were found in greatest amounts in maize-oil-fed rats, n-9 in olive-oil-fed rats, and n-3 in fish-oil-fed rats. In erythrocytes the relative susceptibilities of the individual phospholipids to dietary modification were: PE > PC > PI, but enrichment with n-9 and n-3 fatty acids was not observed in olive-oil- and fish-oil-fed animals and in PC and PE significantly greater amounts of saturated fatty acids were found when animals fed on olive oil or fish oil were compared with maize-oil-fed animals. The polyunsaturated:saturated fatty acid ratios of PE and PC fractions were significantly lower in olive-oil- and fish-oil-fed animals. No differences in the relative proportions of phospholipid classes were found between the three dietary groups. It is suggested that differences in erythrocyte fatty acid composition may reflect dietary-induced changes in membrane cholesterol content and may form part of a homoeostatic response the aim of which is to maintain normal erythrocyte membrane fluidity. The resistance of mammary tissue PI fatty acids to dietary modification suggests that alteration of PI fatty acids is unlikely to underlie effects of dietary fat on mammary tumour incidence rates.

Social networks, migration, and care in Tanzania

This paper explores the impacts of the HIV/AIDS epidemic on children and families in northern Tanzania using the concept of social resilience.1 The study is based on the findings of childfocused research with street children and children and families from HIV/AIDS-affected households. The paper illustrates the coping strategies that children and young people, and parents and caregivers adopt at the household level. In particular, it examines how the burden of care affects different generations of women and highlights their resilience, together with the importance of social networks and the fluidity of movement between rural and urban areas. The research suggests that migrating to urban areas to seek a living in the informal sector represents a survival strategy adopted by some children and young people orphaned by AIDS when their families and communities are unable or unwilling to support them. The paper concludes by exploring parents’, caregivers’, children’s, and young people’s views on the forms of social support that would promote their resilience and thereby help to mitigate the impacts of the epidemic at the household level.

Characterization of a Listeria monocytogenes Scott A isolate with high tolerance towards high hydrostatic pressure

An isolate of L. monocytogenes Scott A that is tolerant to high hydrostatic pressure (HHP), named AK01, was isolated upon a single pressurization treatment of 400 MPa for 20 min and was further characterized. The survival of exponential- and stationary-phase cells of AK01 in ACES [N-(2-acetamido)-2-aminoethanesulfonic acid] buffer was at least 2 log units higher than that of the wild type over a broad range of pressures (150 to 500 MPa), while both strains showed higher HHP tolerance (piezotolerance) in the stationary than in the exponential phase of growth. In semiskim milk, exponential-phase cells of both strains showed lower reductions upon pressurization than in buffer, but again, AK01 was more piezotolerant than the wild type. The piezotolerance of AK01 was retained for at least 40 generations in rich medium, suggesting a stable phenotype. Interestingly, cells of AK01 lacked flagella, were elongated, and showed slightly lower maximum specific growth rates than the wild type at 8, 22, and 30°C. Moreover, the piezotolerant strain AK01 showed increased resistance to heat, acid, and H2O2 compared with the wild type. The difference in HHP tolerance between the piezotolerant strain and the wild-type strain could not be attributed to differences in membrane fluidity, since strain AK01 and the wild type had identical in situ lipid melting curves as determined by Fourier transform infrared spectroscopy. The demonstrated occurrence of a piezotolerant isolate of L. monocytogenes underscores the need to further investigate the mechanisms underlying HHP resistance of food-borne microorganisms, which in turn will contribute to the appropriate design of safe, accurate, and feasible HHP treatments.

Western Britain in late antiquity

The relevance of the concept of ‘Late Antiquity’ to fifth- and sixth-century Western Britain is demonstrated with reference to the archaeology of the British kingdom of Dumnonia, and then used to reinterpret portable material culture. Themes discussed include the dating of Palestinian amphorae in Britain, the extent of the settlement at Tintagel, tin as a motivation for Byzantine trade, the re-use of Roman-period artefacts, and ‘Anglo-Saxon’ artefacts on Western British sites. The central paradoxes of Late Antiquity: simultaneous conservatism and fluidity, continuity and innovation, are seen to illuminate ‘Dark Age’ Britain and offer new avenues for future research.

Conversion in late antiquity: Christianity, Islam, and beyond

The papers in this volume were presented at a Mellon-Sawyer Seminar held at the University of Oxford in 2009-2010, which sought to investigate side by side the two important movements of conversion that frame late antiquity: to Christianity at its start, and to Islam at the other end. Challenging the opposition between the two stereotypes of Islamic conversion as an intrinsically violent process, and Christian conversion as a fundamentally spiritual one, the papers seek to isolate the behaviours and circumstances that made conversion both such a common and such a contested phenomenon. The spread of Buddhism in Asia in broadly the same period serves as an external comparator that was not caught in the net of the Abrahamic religions. The volume is organised around several themes, reflecting the concerns of the initial project with the articulation between norm and practice, the role of authorities and institutions, and the social and individual fluidity on the ground. Debates, discussions, and the expression of norms and principles about conversion conversion are not rare in societies experiencing religious change, and the first section of the book examines some of the main issues brought up by surviving sources. This is followed by three sections examining different aspects of how those principles were - or were not - put into practice: how conversion was handled by the state, how it was continuously redefined by individual ambivalence and cultural fluidity, and how it was enshrined through different forms of institutionalization. Finally, a topographical coda examines the effects of religious change on the iconic holy city of Jerusalem.

The Phantom Carriage (1921)

The reputation of The Phantom Carriage (Körkarlen) as one of the major films of Swedish silent cinema is in some respects securely established. Yet the film has attracted surprisingly little detailed discussion. It may be that its most striking stylistic features have deflected or discouraged closer scrutiny. Tom Gunning, for instance, in making the case for Sjöström’s Masterman, argues that ‘Körkarlen wears its technique on its sleeve, overtly displays its unquestionable mastery of superimposition and complex narrative structure. Mästerman tucks its mastery of editing and composition up its sleeve, so to speak’. This article makes an argument for a different evaluation of The Phantom Carriage, bringing a critical and interpretative understanding of the film’s style into conversation with the historical accounts of film form which predominate in the scholarship around silent cinema. It suggests that the film achieves ‘mastery of editing and composition’ with a flexibility and fluidity in the construction of dramatic space that is in itself remarkable for its period, but that Sjöström’s achievements extend well beyond his handling of film space. Specifically, it discusses a segment which is in several respects at the heart of the film: the first meeting between the two central characters, David Holm (Victor Sjöström) and Sister Edit (Astrid Holm); it spans the film’s exact mid-point; and at almost twelve and a half minutes it is the longest uninterrupted passage to take place in a single setting. The chapter argues that the dramatic and structural centrality of the hostel segment is paralleled by its remarkably rich articulation of the relationships between action, character and space. We show how Sjöström’s creation of a three-dimensional filmic space - with no hint of frontality - becomes the basis for a reciprocal relationship between spatial naturalism and performance style, and for a mise-en-scene that can take on discrete interpretive force. The argument also places the hostel sequences within the film as a whole in order to show how relationships articulated through the detailed decisions in this section take on their full resonance within patterns and motifs that develop across the film.

The role of lipid composition on the interaction between a tryptophan-rich protein and model bacterial membranes

The interaction between tryptophan-rich puroindoline proteins and model bacterial membranes at the air-liquid interface has been investigated by FTIR spectroscopy, surface pressure measurements and Brewster angle microscopy. The role of different lipid constituents on the interactions between lipid membrane and protein was studied using wild type (Pin-b) and mutant (Trp44 to Arg44 mutant, Pin-bs) puroindoline proteins. The results show differences in the lipid selectivity of the two proteins in terms of preferential binding to specific lipid head groups in mixed lipid systems. Pin-b wild type was able to penetrate mixed layers of phosphatidylethanolamine (PE) and phosphatidylglycerol (PG) head groups more deeply compared to the mutant Pin-bs. Increasing saturation of the lipid tails increased penetration and adsorption of Pin-b wild type, but again the response of the mutant form differed. The results provide insight as to the role of membrane architecture, lipid composition and fluidity, on antimicrobial activity of proteins. Data show distinct differences in the lipid binding behavior of Pin-b as a result of a single residue mutation, highlighting the importance of hydrophobic and charged amino acids in antimicrobial protein and peptide activity.

Self-assembly of telechelic tyrosine end-capped PEO and poly(alanine) polymers in aqueous solution

The self-assembly in aqueous solution of three novel telechelic conjugates comprising a central hydrophilic polymer and short (trimeric or pentameric) tyrosine end-caps has been investigated. Two of the conjugates have a central poly(oxyethylene) (polyethylene oxide, PEO) central block with different molar masses. The other conjugate has a central poly(l-alanine) (PAla) sequence in a purely amino-acid based conjugate. All three conjugates self-assemble into β-sheet based fibrillar structures, although the fibrillar morphology revealed by cryogenic-TEM is distinct for the three polymers—in particular the Tyr5-PEO6k-Tyr5 forms a population of short straight fibrils in contrast to the more diffuse fibril aggregates observed for Tyr5-PEO2k-Tyr5 and Tyr3-PAla-Tyr3. Hydrogel formation was not observed for these samples (in contrast to prior work on related systems) up to quite high concentrations, showing that it is possible to prepare solutions of peptide–polymer-peptide conjugates with hydrophobic end-caps without conformational constraints associated with hydrogelation. The Tyr5-PEO6k-Tyr5 shows significant PEO crystallization upon drying in contrast to the Tyr5-PEO2k-Tyr5 conjugate. Our findings point to the remarkable ability of short hydrophobic peptide end groups to modulate the self-assembly properties of polymers in solution in model peptide-capped “associative polymers”. Retention of fluidity at high conjugate concentration may be valuable in potential future applications of these conjugates as bioresponsive or biocompatible materials, for example exploiting the enzyme-responsiveness of the tyrosine end-groups