The cholinergic anti-inflammatory pathway revisited.

Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze et al. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease.

Deterministic control of magnetic vortex wall chirality by electric field.

Concepts for information storage and logical processing based on magnetic domain walls have great potential for implementation in future information and communications technologies. To date, the need to apply power hungry magnetic fields or heat dissipating spin polarized currents to manipulate magnetic domain walls has limited the development of such technologies. The possibility of controlling magnetic domain walls using voltages offers an energy efficient route to overcome these limitations. Here we show that a voltage-induced uniaxial strain induces reversible deterministic switching of the chirality of a magnetic vortex wall. We discuss how this functionality will be applicable to schemes for information storage and logical processing, making a significant step towards the practical implementation of magnetic domain walls in energy efficient computing.

Effect of lithographically-induced strain relaxation on the magnetic domain configuration in microfabricated epitaxially grown Fe81Ga19.

We investigate the role of lithographically-induced strain relaxation in a micron-scaled device fabricated from epitaxial thin films of the magnetostrictive alloy Fe81Ga19. The strain relaxation due to lithographic patterning induces a magnetic anisotropy that competes with the magnetocrystalline and shape induced anisotropies to play a crucial role in stabilising a flux-closing domain pattern. We use magnetic imaging, micromagnetic calculations and linear elastic modelling to investigate a region close to the edges of an etched structure. This highly-strained edge region has a significant influence on the magnetic domain configuration due to an induced magnetic anisotropy resulting from the inverse magnetostriction effect. We investigate the competition between the strain-induced and shape-induced anisotropy energies, and the resultant stable domain configurations, as the width of the bar is reduced to the nanoscale range. Understanding this behaviour will be important when designing hybrid magneto-electric spintronic devices based on highly magnetostrictive materials.

3D TOCSY-HSQC NMR for Metabolic Flux Analysis Using Non-Uniform Sampling.

(13)C-Metabolic Flux Analysis ((13)C-MFA) is rapidly being recognized as the authoritative method for determining fluxes through metabolic networks. Site-specific (13)C enrichment information obtained using NMR spectroscopy is a valuable input for (13)C-MFA experiments. Chemical shift overlaps in the 1D or 2D NMR experiments typically used for (13)C-MFA frequently hinder assignment and quantitation of site-specific (13)C enrichment. Here we propose the use of a 3D TOCSY-HSQC experiment for (13)C-MFA. We employ Non-Uniform Sampling (NUS) to reduce the acquisition time of the experiment to a few hours, making it practical for use in (13)C-MFA experiments. Our data show that the NUS experiment is linear and quantitative. Identification of metabolites in complex mixtures, such as a biomass hydrolysate, is simplified by virtue of the (13)C chemical shift obtained in the experiment. In addition, the experiment reports (13)C-labeling information that reveals the position specific labeling of subsets of isotopomers. The information provided by this technique will enable more accurate estimation of metabolic fluxes in large metabolic networks.

Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells.

Mucosal dendritic cells (DCs) in the intestine acquire the unique capacity to produce retinoic acid (RA), a vitamin A metabolite that induces gut tropism and regulates the functional differentiation of the T cells they prime. Here, we identified a stromal cell (SC) population in the intestinal lamina propria (LP), which is capable of inducing RA production in DCs in a RA- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent fashion. Unlike DCs, LP SCs constitutively expressed the enzymatic machinery to produce RA even in the absence of dietary vitamin A, but were not able to do so in germ-free mice implying regulation by microbiota. Interestingly, DCs promoted GM-CSF production by the SCs indicating a two-way cross-talk between both cell types. Furthermore, RA-producing LP SCs and intestinal DCs localized closely in vivo suggesting that the interactions between both cell types might have an important role in the functional education of migratory DCs and therefore in the regulation of immune responses toward oral and commensal antigens.

Hydrogenase activity of mineral-associated and suspended populations of Desulfovibrio desulfuricans Essex 6.

The interactions between sulfate-reducing microorganisms and iron oxides influence a number of important redox-sensitive biogeochemical processes including the formation of iron sulfides. Enzymes, such as hydrogenase which catalyze the reversible oxidation of molecular hydrogen, are known to mediate electron transfer to metals and may contribute to the formation and speciation of ferrous sulfides formed at the cell-mineral interface. In the present study, we compared the whole cell hydrogenase activity of Desulfovibrio desulfuricans strain Essex 6 growing as biofilms on hematite (hematite-associated) or as suspended populations using different metabolic pathways. Hematite-associated cells exhibited significantly greater hydrogenase activity than suspended populations during sulfate respiration but not during pyruvate fermentation. The enhanced activity of the hematite-associated, sulfate-grown cells appears to be dependent on iron availability rather than a general response to surface attachment since the activity of glass-associated cells did not differ from that of suspended populations. Hydrogenase activity of pyruvate-fermenting cells was stimulated by addition of iron as soluble Fe(II)Cl2 and, in the absence of added iron, both sulfate-reducing and pyruvate-fermenting cells displayed similar rates of hydrogenase activity. These data suggest that iron exerts a stronger influence on whole cell hydrogenase activity than either metabolic pathway or mode of growth. The location of hydrogenase to the cell envelope and the enhanced activity at the hematite surface in sulfate-reducing cells may influence the redox conditions that control the species of iron sulfides on the mineral surface.

Integrated spatial multiplexing of heralded single-photon sources.

The non-deterministic nature of photon sources is a key limitation for single-photon quantum processors. Spatial multiplexing overcomes this by enhancing the heralded single-photon yield without enhancing the output noise. Here the intrinsic statistical limit of an individual source is surpassed by spatially multiplexing two monolithic silicon-based correlated photon pair sources in the telecommunications band, demonstrating a 62.4% increase in the heralded single-photon output without an increase in unwanted multipair generation. We further demonstrate the scalability of this scheme by multiplexing photons generated in two waveguides pumped via an integrated coupler with a 63.1% increase in the heralded photon rate. This demonstration paves the way for a scalable architecture for multiplexing many photon sources in a compact integrated platform and achieving efficient two-photon interference, required at the core of optical quantum computing and quantum communication protocols.

Role of outer membrane c-type cytochromes MtrC and OmcA in Shewanella oneidensis MR-1 cell production, accumulation, and detachment during respiration on hematite.

The iron-reducing bacterium Shewanella oneidensis MR-1 has the capacity to contribute to iron cycling over the long term by respiring on crystalline iron oxides such as hematite when poorly crystalline phases are depleted. The ability of outer membrane cytochromes OmcA and MtrC of MR-1 to bind to and transfer electrons to hematite has led to the suggestion that they function as terminal reductases when this mineral is used as a respiratory substrate. Differences in their redox behavior and hematite-binding properties, however, indicate that they play different roles in the electron transfer reaction. Here, we investigated how these differences in cytochrome behavior with respect to hematite affected biofilm development when the mineral served as terminal electron acceptor (TEA). Upon attachment to hematite, cells of the wild-type (WT) strain as well as those of a ΔomcA mutant but not those of a ΔmtrC mutant replicated and accumulated on the mineral surface. The results indicate that MtrC but not OmcA is required for growth when this mineral serves as TEA. While an OmcA deficiency did not impede cell replication and accumulation on hematite prior to achievement of a maximum surface cell density comparable to that established by WT cells, OmcA was required for efficient electron transfer and cell attachment to hematite once maximum surface cell density was achieved. OmcA may therefore play a role in overcoming barriers to electron transfer and cell attachment to hematite imposed by reductive dissolution of the mineral surface from cell respiration associated with achievement of high surface cell densities.

Natural killer T cells in lipoprotein metabolism and atherosclerosis.

Cells of both the innate and adaptive immune system participate in the development of atherosclerosis, a chronic inflammatory disorder of medium and large arteries. Natural killer T (NKT) cells express surface markers characteristic of natural killer cells and conventional T cells and bridge the innate and adaptive immune systems. The development and activation of NKT cells is dependent upon CD1d, a MHC-class I-type molecule that presents lipids, especially glycolipids to the T cell receptors on NKT cells. There are two classes of NKT cells; invariant NKT cells that express a semi-invariant T cell receptor and variant NKT cells. This review summarises studies in murine models in which the effect of the activation, overexpression or deletion of NKT cells or only invariant NKT cells on atherosclerosis has been examined.

Antibiosis activity of Pantoea agglomerans biocontrol strain E325 against Erwinia amylovora on apple flower stigmas.

Pantoea agglomerans E325, the active ingredient in a commercial product for fire blight control, was previously shown in vitro to produce a unique alkaline- and phosphate-sensitive antibiotic specific to Erwinia amylovora. Antibiosis was evaluated as a mode of antagonism on flower stigmas using two antibiosis-deficient mutants. On King's medium B, mutants E325ad1 and E325ad2 have stable smooth-butyrous or hypermucoid colony morphologies, respectively, and the parental strain E325 exhibits phenotypic plasticity with predominantly hypermucoid colonies accompanied by slower-growing, smooth-butyrous colonies. Mutants were tested against E. amylovora on stigmas of detached flowers of crab apple (Malus mandshurica) in growth chambers and apple (Malus domestica) in the orchard. Epiphytic fitness of the antibiosis-negative mutants was similar or greater than the parental strain as determined by relative area under the population curve (RAUPC). In laboratory and orchard trials, both mutants had significantly lower inhibitory activity against the pathogen (i.e., less reduction of E. amylovora RAUPC) compared with the parental strain. E325 and the mutants caused similar decreases in pH in a broth medium, indicating that acidification, which was previously reported as a possible mechanism of pathogen inhibition on stigmas, is not directly related to antibiosis. In this study we provide the first evidence for E325 antibiosis involved in E. amylovora growth suppression on apple flower stigmas.

HDL apolipoprotein-related peptides in the treatment of atherosclerosis and other inflammatory disorders.

Elevations of HDL levels or modifying the inflammatory properties of HDL are being evaluated as possible treatment of atherosclerosis, the underlying mechanism responsible for most cardiovascular diseases. A promising approach is the use of small HDL apoprotein-related mimetic peptides. A number of peptides mimicking the repeating amphipathic α-helical structure in apoA-I, the major apoprotein in HDL, have been examined in vitro and in animal models. Several peptides have been shown to reduce early atherosclerotic lesions, but not more mature lesions unless coadministered with statins. These peptides also influence the vascular biology of the vessel wall and protect against other acute and chronic inflammatory diseases. The biologically active peptides are capable of reducing the pro-inflammatory properties of LDL and HDL, likely due to their high affinity for oxidized lipids. They are also capable of influencing other processes, including ABCA1 mediated activation of JAK-2 in macrophages, which may contribute to their anti-atherogenic function. The initial studies involved monomeric 18 amino acid peptides, but tandem peptides are being investigated for their anti-atherogenic and anti-inflammatory properties as they more closely resemble the repeating structure of apoA-I. Peptides based on other HDL associated proteins such as apoE, apoJ and SAA have also been studied. Their mechanism of action appears to be distinct from the apoA-I based mimetics.

Planar photonic crystal cavities with far-field optimization for high coupling efficiency and quality factor.

Different types of planar photonic crystal cavities aimed at optimizing the far-field emission pattern are designed and experimentally assessed by resonant scattering measurements. We systematically investigate the interplay between achieving the highest possible quality (Q) factor and maximizing the in- and out-coupling efficiency into a narrow emission cone. Cavities operate at telecommunications wavelengths, i.e. around approximately 1.55 microm, and are realized in silicon membranes. A strong modification of the far-field emission pattern, and therefore a substantial increase of the coupling efficiency in the vertical direction, is obtained by properly modifying the holes around L3, L5 and L7 type PhC cavities, as we predict theoretically and show experimentally. An optimal compromise yielding simultaneously a high Q-factor and a large coupling to the fundamental cavity mode is found for a L7-type cavity with a measured Q congruent with 62000, whose resonant scattering efficiency is improved by about two orders of magnitude with respect to the unmodified structure. These results are especially useful for prospective applications in light emitting devices, such as nano-lasers or single-photon sources, in which vertical in- and out-coupling of the electromagnetic field is necessarily required.

Role of outer-membrane cytochromes MtrC and OmcA in the biomineralization of ferrihydrite by Shewanella oneidensis MR-1.

In an effort to improve the understanding of electron transfer mechanisms at the microbe-mineral interface, Shewanella oneidensis MR-1 mutants with in-frame deletions of outer-membrane cytochromes (OMCs), MtrC and OmcA, were characterized for the ability to reduce ferrihydrite (FH) using a suite of microscopic, spectroscopic, and biochemical techniques. Analysis of purified recombinant proteins demonstrated that both cytochromes undergo rapid electron exchange with FH in vitro with MtrC displaying faster transfer rates than OmcA. Immunomicroscopy with cytochrome-specific antibodies revealed that MtrC co-localizes with iron solids on the cell surface while OmcA exhibits a more diffuse distribution over the cell surface. After 3-day incubation of MR-1 with FH, pronounced reductive transformation mineral products were visible by electron microscopy. Upon further incubation, the predominant phases identified were ferrous phosphates including vivianite [Fe(3)(PO(4))(2)x8H(2)O] and a switzerite-like phase [Mn(3),Fe(3)(PO(4))(2)x7H(2)O] that were heavily colonized by MR-1 cells with surface-exposed outer-membrane cytochromes. In the absence of both MtrC and OmcA, the cells ability to reduce FH was significantly hindered and no mineral transformation products were detected. Collectively, these results highlight the importance of the outer-membrane cytochromes in the reductive transformation of FH and support a role for direct electron transfer from the OMCs at the cell surface to the mineral.

Effects of dog ownership in early childhood on immune development and atopic diseases.

BACKGROUND: Exposure to pets in childhood has been associated with a reduced risk of wheezing and atopy. OBJECTIVE: Our objective was to determine whether the effects of pet exposure on immune development and atopy in early childhood can be explained by alterations in exposure to innate immune stimuli in settled dust. METHODS: Two hundred and seventy-five children at increased risk of developing allergic diseases were evaluated to age 3 years for pet ownership, blood cell cytokine responses, and atopy. Can f 1, Fel d 1, endotoxin, ergosterol, and muramic acid were measured in settled dust from 101 homes. RESULTS: Dog exposure at birth was associated with decreased atopic dermatitis (AD) (12% vs. 27%; P=0.004) and wheezing (19% vs. 36%; P=0.005) in year 3. The rates of AD (23%) and wheezing (42%) in year 3 were relatively high in children who acquired dogs after birth. The prevalence of dog sensitization (10-12%) did not vary according to dog exposure. Can f 1 levels in bedroom dust were positively associated with IL-10 (r=0.26; P=0.01), IL-5 (r=0.34, P<0.001), and IL-13 (r=0.28; P=0.004) responses at age 1, and IL-5 (r=0.24; P=0.022) and IL-13 (r=0.25; P=0.015) responses at age 3. In contrast, endotoxin was associated with IFN-gamma (r=0.31; P=0.002) and IL-13 (r=0.27; P=0.01) responses at age 3 but not at age 1, and similar relationships were present for muramic acid. Adjustment for levels of innate immune stimuli in house dust did not significantly affect the relationships between Can f 1 and cytokine responses. CONCLUSIONS: Exposure to dogs in infancy, and especially around the time of birth, is associated with changes in immune development and reductions in wheezing and atopy. These findings are not explained by exposure to endotoxin, ergosterol, or muramic acid.

The influence of acute phase proteins on murine atherosclerosis.

Atherosclerosis is a chronic inflammatory reaction that is initiated in response to hyperlipidemia and the retention and modification of lipids within the vascular wall. Chronic inflammatory states lead to steady low-level induction of the acute phase reaction and chronic inflammation is associated with elevated cardiovascular disease and atherosclerosis. The acute phase reaction is mediated by cytokines and results in significant changes in the plasma level of several proteins referred to as acute phase proteins. The liver is a major source of these proteins. Several recent studies in humans have shown that levels of acute phase proteins are modified in patients with established cardiovascular disease or are predictors of future disease. Whether these acute phase proteins are a biomarker of inflammation or have a direct role in the development of atherosclerosis is not clear. Murine models of atherosclerosis have been used to address the role of acute phase proteins in atherosclerosis. Modification of the expression level of these proteins has shown that the individual acute phase proteins are either pro-atherogenic or anti-atherogenic. The absence of an overall trend is perhaps not surprising given the complex nature of the acute phase response.

What are subcutaneous adipocytes really good for?

Our acute awareness of the cosmetic, psychosocial and sexual importance of subcutaneous adipose tissue contrasts dramatically with how poorly we have understood the biology of this massive, enigmatic, often ignored and much-abused skin compartment. Therefore, it is timely to recall the exciting, steadily growing, yet underappreciated body of evidence that subcutaneous adipocytes are so much more than just 'fat guys', hanging around passively to conspire, at most, against your desperate attempts to maintain ideal weight. Although the subcutis, quantitatively, tends to represent the dominant architectural component of human skin, conventional wisdom confines its biological key functions to those of energy storage, physical buffer, thermoregulation and thermoinsulation. However, already the distribution of human superficial adipose tissue, by itself, questions how justified the popular belief is that 'skin fat' (which actually may be more diverse than often assumed) serves primarily thermoinsulatory purposes. And although the metabolic complications of obesity are well appreciated, our understanding of how exactly subcutaneous adipocytes contribute to extracutaneous disease - and even influence important immune and brain functions! - is far from complete. The increasing insights recently won into subcutaneous adipose tissue as a cytokine depot that regulates innate immunity and cell growth exemplarily serve to illustrate the vast open research expanses that remain to be fully explored in the subcutis. The following public debate carries you from the evolutionary origins and the key functional purposes of adipose tissue, via adipose-derived stem cells and adipokines straight to the neuroendocrine, immunomodulatory and central nervous effects of signals that originate in the subcutis - perhaps, the most underestimated tissue of the human body. The editors are confident that, at the end, you shall agree: No basic scientist and no doctor with a serious interest in skin, and hardly anyone else in the life sciences, can afford to ignore the subcutaneous adipocyte - beyond its ample impact on beauty, benessence and body mass.

An anatomical study of the superficial inferior epigastric vessels in humans.

The lower abdominal skin and fat has become a standard for breast reconstruction in terms of skin texture, suppleness and colour. Concerns regarding donor site morbidity related to the harvest of rectus abdominis musculocutaneous flap, based on the deep inferior epigastric vessels, have turned attention towards alternative options. The superficial inferior epigastric artery (SIEA) flap is a fasciocutaneous flap that has been used for reconstruction of the breast, as well as head, neck and limb defects. In Taylor's classic dissection series the SIEA was 'absent' in 35% [Plast Reconstr Surg 56 (1975) 243]. In our series of 22 cadaver dissections (eight female, three male) the SIEA was identified in 20 and the vein (SIEV) in 21. In 15, the artery was located at the level of the inguinal ligament, within 1 cm of its midpoint. In 17, the origin, from the common femoral artery, was within 2 cm of the inguinal ligament. In 18, the SIEA arose as a common trunk with the superficial circumflex iliac artery, superficial external pudendal artery, and/or the deep circumflex iliac artery. Mean SIEA calibre was 1.9 mm and the mean pedicle length from origin to inguinal ligament was 5.2 cm. Our findings suggest that the SIEA is more consistently present and larger in calibre than previously reported, and consequently may be of greater clinical use than previously believed.

Hybridomas expressing gammadelta T-cell receptors respond to cardiolipin and beta2-glycoprotein 1 (apolipoprotein H).

Hybridomas expressing murine gammadelta T-cell receptors were found to produce cytokines in response to cardiolipin (CL) and structurally related anionic phospholipids. This response required serum at concentrations related to the amount of CL in cultures. The purified serum factor, beta2-glycoprotein 1 (beta2-GP1) (apolipoprotein H), supported the CL response alone, whereas several other serum proteins and ovalbumin did not. beta2-GP1 is known to form complexes with anionic phospholipids, particularly CL, which are often recognized by pathological autoantibodies. We speculate that gammadelta T cells also recognize such complexes and that the hybridoma response reported here reflects this specificity.

Pea mania: deranged behaviour in cattle grazing a pea crop (Pisum sativum var arvense).

Hypersensitivity to external stimuli, progressing in some animals to manic behaviour, occurred in a cattle herd that grazed a crop of field peas (Pisum sativum var arvense) in the pre-flowering stage. Haematological and biochemical analyses eliminated hypomagnesaemia and ketosis as diagnoses. Other than two steers euthanased due to injuries sustained during manic episodes, all affected animals survived, recovering over 3 days when moved to alternative pasture. No necropsies were conducted. No microbial pathogens or endophytes were found on or in the plants. A previously reported incident in Victoria in 1987 in cattle grazing peas appeared to be of a similar nature. Environmental factors leading to these incidents were not clearly identified.