A direct comparison of one- and two-component dendritic self-assembled materials: elucidating molecular recognition pathways

This paper compares and contrasts, for the first time, one- and two-component gelation systems that are direct structural analogues and draws conclusions about the molecular recognition pathways that underpin fibrillar self-assembly. The new one-component systems comprise L-lysine-based dendritic headgroups covalently connected to an aliphatic diamine spacer chain via an amide bond, One-component gelators with different generations of headgroup (from first to third generation) and different length spacer chains are reported. The self-assembly of these dendrimers in toluene was elucidated using thermal measurements, circular dichroism (CD) and NMR spectroscopies, scanning electron microscopy (SEM), and small-angle X-ray scattering (SAXS). The observations are compared with previous results for the analogous two-component gelation system in which the dendritic headgroups are bound to the aliphatic spacer chain noncovalently via acid-amine interactions. The one-component system is inherently a more effective gelator, partly as a consequence of the additional covalent amide groups that provide a new hydrogen bonding molecular recognition pathway, whereas the two-component analogue relies solely on intermolecular hydrogen bond interactions between the chiral dendritic headgroups. Furthermore, because these amide groups are important in the assembly process for the one-component system, the chiral information preset in the dendritic headgroups is not always transcribed into the nanoscale assembly, whereas for the two-component system, fiber formation is always accompanied by chiral ordering because the molecular recognition pathway is completely dependent on hydrogen bond interactions between well-organized chiral dendritic headgroups.

A new tetrameric Cu-II cluster with square topology exhibiting ferro- and antiferromagnetic magnetic pathways: which is which?

[Cu4L2(bpy)(4)(H2O)(3)](ClO4)(4).2.5H(2)O, 1, a new tetranuclear Cu-II cluster showing square planar geometry, formed with aspartate bridging ligand (L) has been synthesized. The global magnetic coupling is ferromagnetic but theoretical DFT/B3LYP calculations are necessary to assign which Cu-L-Cu side is ferro or antiferromagnetically coupled.

Innovation care pathways and the healthcare built environment: An explanatory framework and research agenda

The built environment in which health and social care is delivered can have an impact on the efficiency and outcomes of care processes. The health-care estate is large and growing and is expensive to build, adapt and maintain. The design of these buildings is a complex, difficult and political process. Better use of care pathways as an input to the design and use of the built environment has the potential to deliver significant benefits. A number of variations on the idea of care pathways are already used in designing health-care buildings but this is under-researched. This paper provides a framework for thinking about care pathways and the health-care built environment. The framework distinguishes between five different pathway ‘types’ defined for the purpose of understanding the relationship between pathways and infrastructure. The five types are: ‘care pathways’, ‘integrated care pathways’, ‘patient pathways’, ‘patient journeys’ and ‘patient flows’. The built environment implications of each type are discussed and recommendations made for those involved in either building development or care pathway projects.

Care pathways and designing the healthcare built environment: an explanatory framework

The built environment in which health and social care is delivered can have an impact on the efficiency and outcomes of care processes. The health-care estate is large and growing and is expensive to build, adapt and maintain. The design of these buildings is a complex, difficult and political process. Better use of care pathways as an input to the design and use of the built environment has the potential to deliver significant benefits. A number of variations on the idea of care pathways are already used in designing health-care buildings but this is under-researched. This paper provides a framework for thinking about care pathways and the health-care built environment. The framework distinguishes between five different pathway ‘types’ defined for the purpose of understanding the relationship between pathways and infrastructure. The five types are: ‘care pathways’, ‘integrated care pathways’, ‘patient pathways’, ‘patient journeys’ and ‘patient flows’. The built environment implications of each type are discussed and recommendations made for those involved in either building development or care pathway projects.

The pro-inflammatory oxidant hypochlorous acid induces Bax-dependent mitochondrial permeabilisation and cell death through AIF-/EndoG-dependent pathways

At sites of chronic inflammation, such as in the inflamed rheumatoid joint, activated neutrophils release hydrogen peroxide (H2O2) and the enzyme myeloperoxidase to catalyse the formation of hypochlorous acid (HOCl). 3-chlorotyrosine, a marker of HOCl in vivo, has been observed in synovial fluid proteins from rheumatoid arthritis patients. However the mechanisms of HOCl-induced cytotxicity are unknown. We determined the molecular mechanisms by which HOCl induced cell death in human mesenchymal progenitor cells (MPCs) differentiated into a chondrocytic phenotype as a model of human cartilage cells and show that HOCl induced rapid Bax conformational change, mitochondrial permeability and release of intra-mitochondrial pro-apoptotic proteins which resulted in nuclear translocation of AIF and EndoG. siRNA-mediated knockdown of Bax substantially prevented mitochondrial permeability, release of intra-mitochondrial pro-apoptotic proteins. Cell death was inhibited by siRNA-mediated knockdown of Bax, AIF or EndoG. Although we observed several biochemical markers of apoptosis, caspase activation was not detected either by western blotting, fluorescence activity assays or by using caspase inhibitors to inhibit cell death. This was further supported by findings that (1) in vitro exposure of recombinant human caspases to HOCl caused significant inhibition of caspase activity and (2) the addition of HOCl to staurosporine-treated MPCs inhibited the activity of cellular caspases. Our results show for the first time that HOCl induced Bax-dependent mitochondrial permeability which led to cell death without caspase activity by processes involving AIF/EndoG-dependent pathways. Our study provides a novel insight into the potential mechanisms of cell death in the inflamed human joint. (c) 2006 Elsevier Inc. All rights reserved.

Activation of pro-survival Akt and ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons

There is growing interest in the potential beneficial effects of flavonoids in the aging and diseased brain. We have investigated the potential of the flavanone hesperetin and two of its metabolites, hesperetin-7-O-beta-D-glucuronide and 5-nitro-hesperetin, to inhibit oxidative stress-induced neuronal apoptosis. Exposure of cortical neurons to hydrogen peroxide led to the activation of apoptosis signal-regulating kinase 1 via its de-phosphorylation at Ser963, the phosphorylation of c-jun N-terminal kinase and c-Jun (Ser73) and the activation of caspase 3 and caspase 9. Whilst hesperetin glucuronide failed to exert protection, both hesperetin and 5-nitro-hesperetin were effective at preventing neuronal apoptosis via a mechanism involving the activation/phosphorylation of both Akt/protein kinase B and extracellular signal-regulated kinase 1 and 2 (ERK1/2). Protection against oxidative injury and the activation of Akt and ERK1/2 followed a bell-shaped response and was most apparent at 100 nmol/L concentrations. The activation of ERK1/2 and Akt by flavanones led to the inhibition of the pro-apoptotic proteins, apoptosis signal-regulating kinase 1, by phosphorylation at Ser83 and Bad, by phosphorylation at both Ser136 and Ser112 and to the inhibition of peroxide-induced caspase 9 and caspase 3 activation. Thus, flavanones may protect neurons against oxidative insults via the modulation of neuronal apoptotic machinery.

The interactions of flavonoids within neuronal signalling pathways

Emerging evidence suggests that dietary phytochemicals, in particular flavonoids, may exert beneficial effects in the central nervous system by protecting neurons against stress-induced injury, by suppressing neuroinflammation and by promoting neurocognitive performance, through changes in synaptic plasticity. It is likely that flavonoids exert such effects in neurons, through selective actions on different components within a number of protein kinase and lipid kinase signalling cascades, such as phosphatidylinositol-3 kinase (PI3K)/Akt, protein kinase C and mitogen-activated protein kinase. This review details the potential inhibitory or stimulatory actions of flavonoids within these pathways, and describes how such interactions are likely to affect cellular function through changes in the activation state of target molecules and/or by modulating gene expression. Although, precise sites of action are presently unknown, their abilities to: (1) bind to ATP binding sites on enzymes and receptors; (2) modulate the activity of kinases directly; (3) affect the function of important phosphatases; (4) preserve neuronal Ca2+ homeostasis; and (5) modulate signalling cascades lying downstream of kinases, are explored. Future research directions are outlined in relation to their precise site(s) of action within the signalling pathways and the sequence of events that allow them to regulate neuronal function in the central nervous system.

Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study

Background: The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well established and likely to contribute to cardioprotective benefits. Objectives: We aimed to determine the effect of moderate EPA and DHA intakes (< 2 g EPA + DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed responses. Design: Three hundred twelve adults aged 20-70 y, who were prospectively recruited according to age, sex, and APOE genotype, completed a double-blind placebo-controlled crossover study. Participants consumed control oil, 0.7 g EPA + DHA/d (0.7FO), and 1.8 g EPA + DHA/d (1.8FO) capsules in random order, each for an 8-wk intervention period, separated by 12-wk washout periods. Results: In the group as a whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after 0.7FO and 1.8FO, respectively (P < 0.001): significant sex x treatment (P = 0.038) and sex x genotype x treatment (P = 0.032) interactions were observed, and the greatest triacylglycerol-lowering responses (reductions of 15% and 23% after 0.7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol (P = 0.026) and higher LDL-cholesterol (P = 0.010), HDL-cholesterol (P < 0.001), and HDL2 (P < 0.001) concentrations were evident after fish-oil intervention. Conclusions: Supplements providing EPA + DHA at doses as low as 0.7 g/d have a significant effect on the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in females.

Analysis of second messenger pathways stimulated by different chemokines acting at the chemokine receptor

The chemokine receptor, CCR5, responds to several chemokines leading to changes in activity in several signalling pathways. Here, we investigated the ability of different chemokines to provide differential activation of pathways. The effects of five CC chemokines acting at CCR5 were investigated for their ability to inhibit forskolin- stimulated 3'-5'-cyclic adenosine monophosphate (cAMP) accumulation and to stimulate Ca2+ mobilisation. in Chinese hamster ovary (CHO) cells expressing CCR5. Macrophage inflammatory protein 1 alpha (D26A) (MIP-1 alpha (D26A), CCL3 (D26A)), regulated on activation, normal T-cell expressed and secreted (RANTES, CCLS), MIP-1 beta (CCL4) and monocyte chemoattractant protein 2 (MCP-2, CCL8) were able to inhibit forskolin -stimulated CAMP accumulation, whilst MCP-4 (CCL13) could not elicit a response. CCL3 (D26A), CCL4, CCLS, CCL8 and CCL13 were able to stimulate Ca2+ mobilisation. through CCRS, although CCL3 (D26A) and CCL5 exhibited biphasic concentration-response curves. The Ca2+ responses induced by CCL4, CCL5, CCL8 and CCL13 were abolished by pertussis toxin, whereas the response to CCL3 (D26A) was only partially inhibited by pertussis toxin, indicating G(i/o)-independent signalling induced by this chemokine. Although the rank order of potency of chemokines was similar between the two assays, certain chemokines displayed different pharmacological profiles in cAMP inhibition and Ca2+ mobilisation assays. For instance, whilst CCL13 could not inhibit forskolin-stimulated cAMP accumulation, this chemokine was able to induce Ca2+ mobilisation via CCR5. It is concluded that different chemokines acting at CCR5 can induce different pharmacological responses, which may account for the broad spectrum of chemokines that can act at CCRS. (C) 2007 Elsevier Inc. All rights reserved.

Sex differences in common marmosets (Callithrix jacchus) in response to an unfamiliar food task

There is a growing body of information on sex differences In callitrichid behaviour that includes the animals' performance in food tasks. For example, both reproductive and non-reproductive adult females have been found to be more successful than adult males in solving food tasks. In this study ten adult male and ten adult female common marmosets (Callithrix jacchus), housed individually, were tested with an unfamiliar task that involved the extraction of an embedded food. The task was to open a plastic canister that contained a raisin; the open end was covered with parchment paper. Each marmoset was given 15 trials in three blocks of 5 consecutive days. We measured the latency for each animal to open the lid and get the raisin-by one of five strategies that spontaneously emerged. The females learned the task faster and more efficiently than males; all the females opened the canister on day 1, for instance, in contrast to seven of the males on the same day. Females also progressively decreased the time that they took to open the tube. The final latency on day 15, for instance, was significantly shorter for the females. These results are consistent with relevant literature for callitrichids and cannot be accounted for in terms of differences in mental abilities, strength, hand morphology, or energy requirements. Further investigation is necessary to clarify the reasons for these differences.

'They did not have a word': the parental quest to locate a 'true sex' for their intersex children

Given the paucity of research in this area, the primary aim of this study was to explore how parents of infants with unclear sex at birth made sense of 'intersex'. Qualitative methods were, used (semi-structured interviews, interpretative phenomenological analysis) with 10 parents to generate pertinent themes and provide ideas for further research. Our analysis highlights the fundamental shock engendered by the uncertain sex status of children, and documents parental struggles to negotiate a coherent sex identity for their children. Findings are discussed in light of the rigid two-sex system which pervades medicine and everyday life, and we argue that greater understanding of the complexity of sex and gender is required in order to facilitate better service provision and, ultimately, greater informed consent and parental participation regarding decisions about their children's status.