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Mutations in filaggrin (FLG) are associated with atopic dermatitis (AD), and are presumed to provoke a barrier abnormality. Yet, additional acquired stressors may be necessary, since the same mutations can result in a non-inflammatory disorder, ichthyosis vulgaris.
We examined here whether FLG deficiency alone suffices to produce a barrier abnormality; the basis for the putative abnormality; and its pro-inflammatory consequences.
Using the flaky-tail (ft/ft) mouse, which lacks processed flg due to a frame-shift mutation in profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality; further localized the defect; identified its subcellular basis; and assessed thresholds to irritant and hapten-induced dermatitis.
Flaky-tail mice exhibit low-grade inflammation, with increased bidirectional, paracellular permeability of water-soluble xenobiotes due to impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens, at doses that produce no inflammation in +/+ mice, ft/ft mice develop a severe AD-like dermatosis, with a further deterioration in barrier function and features of a th2 immunophenotype (increased CRTH + inflammation, elevated serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).
FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.
Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin condition, that displays an associated abnormality in permeability barrier function 1–4. Until recently, AD was viewed as a primary immunologic disorder in which sustained allergen exposure in susceptible hosts leads to TH2-dominant inflammation, which then secondarily provokes defects in barrier function ('inside-outside' paradigm) [rev in 5]. However, recent genetic studies have shown a strong association between AD and several loss-of-function mutations in the gene encoding the stratum corneum structural protein, filaggrin (FLG) 6, 7. Moreover, there is a dose-response relationship between FLG-deficiency and disease severity, such that patients with double-allele or compound heterozygote mutations in FLG display more-severe and earlier-onset AD, as well as an increased propensity for AD to persist into adulthood 8–11. This rapidly-growing body of work has led to a paradigm shift in conceptions of AD pathogenesis, with increasing weight being placed on the role of a primary barrier abnormality that then precipitates downstream immunologic abnormalities ("outside-inside" paradigm) 1,12. According to this concept, TH2-dominant inflammation results from sustained epicutaneous access of haptens through a defective skin barrier 13,14. TH2 cytokines then down-regulate expression of TH1 cytokines 5, epidermal antimicrobial peptide expression 15, 16, and epidermal structural proteins [rev. in 1, 2], completing an "outside-inside-(back to) outside" paradigm for AD 2, 17.
FLG is an intracellular protein, with important roles in stratum corneum hydration 18 and as a structural component of the corneocyte cytosol 19. However, normal permeability barrier function is not regulated by the corneocyte, but rather by the lipid-enriched, extracellular matrix of the stratum corneum 20, 21. Indeed, in all inflammatory dermatoses studied to date, including those associated with inherited disorders of corneocyte proteins, the barrier abnormality has been linked to accelerated paracellular water loss 22, 23. Thus, the new-found link between FLG and AD leaves unanswered whether FLG-deficiency alone provokes a barrier abnormality in the epidermis, and if so, the subcellular basis for such an abnormality. While it has been widely hypothesized that a FLG-associated barrier defect facilitates hapten ingress 12, 13, this relationship was only recently demonstrated 24. Yet, the mechanism whereby FLG deficiency compromises barrier function, thereby provoking inflammation, remains unknown. Pertinently, FLG mutations that occur in AD also occur in the inherited, non-inflammatory condition, ichthyosis vulgaris 25, 26, raising questions about whether FLG deficiency alone suffices to provoke inflammation, or whether additional acquired stressors are required to elicit AD 1, 2.
The above questions are difficult to address within the context of human AD, where multiple genetic and environmental factors intertwine to provoke disease pathogenesis. Thus, we employed a pre-existing model, the flaky tail (ft/ft) mouse, which exhibits very reduced levels of flg 27. Flaky tail mice possess a homozygous frameshift mutation in profilaggrin that prevents the processing of profilaggrin into flg 24, such that ft/ft mice simulate double allele, loss-of-function mutations in certain human AD patients that also result in reduced levels of processed FLG protein 6, 28. The ft/ft mutation was shown previously to yield a phenotype of diffuse, mild flaking, analogous to human ichthyosis vulgaris 27. Utilizing the ft/ft model, we demonstrate that ft/ft mice display: 1) abnormal barrier function and low-grade inflammation at baseline, confirming recent observations of Fallon, et al. 24; and 2) enhanced bidirectional, paracellular penetration of water-soluble tracers. We demonstrate further that: 1) Increased penetration through the stratum corneum can be attributed to structural defects in the lamellar body secretory system; 2) flg deficiency alone reduces inflammatory thresholds to both irritants and allergens; and 3) ft/ft mice develop a hapten-induced, AD-like dermatosis at lower challenge doses than do +/+ mice, mirroring recent work in ft/ft mice exposed to a complete antigen 24. Thus, flg deficiency yields a paracellular barrier abnormality that likely also favors elicitation of AD by allowing enhanced/sustained hapten access.
Studies were conducted in maft/maft/J(ft/ft) mice (new designation: a/a ma ft/ma ft/JSun JR#9078), and age/sex-matched C57Bl/6J+/+ mice (The Jackson Lab, Bar Harbor, ME), housed under pathogen-free conditions. Flaky tail mice are compound mutants at two loci, both matted (ma/ma) and flaky tail (ft/ft). Matted confers a stable, lifelong, and readily-identifiable phenotype of subtle hair coarseness that was introduced by Jackson to facilitate identification of mutants without reliance on genotyping 29. Young ft/ft and +/+ mice were between 6–12 weeks of age, while old mice were 50–52 weeks of age. Ethanol, acetone and lanthanum nitrate were purchased from Fisher Scientific (Fairlane, NJ). Oxazolone (Ox) and calcium green were purchased from Sigma Chemical Co. (St Louis, MO). Affinity-purified, rabbit anti-mouse antibodies to both proflg and flg were purchased from BabCo (Richmond, CA). Rabbit anti-mouse antibody against the prostaglandin D2 receptor, CRTH2/DP2, which is expressed solely on th2-bearing lymphocytes and mast cells, was purchased from Cayman Chemical (Ann Arbor, MI). Rabbit anti-mouse antibody against CD3 was purchased from BD Biosciences (San Jose, CA).
All animal procedures were approved by the Animal Studies Subcommittee (IACUC) of the San Francisco Veterans Administration Medical Center and performed in accordance with their guidelines. Basal stratum corneum hydration and surface pH were measured (CM 825/PH 900, Courage & Khazaka, Germany) on shaved back skin in ft/ft and +/+ mice (n = 4–6 in all experimental groups, except where noted in figure legends). Transepidermal water loss (TEWL) measurements were taken under basal conditions, using an electrolytic water analyzer (Meeco, Warrington, PA), as well as 2 and 4 hours after a tape stripping-induced, 3-fold increase in TEWL. Barrier recovery was calculated as percent barrier recovery from '0' levels, immediately after acute disruption 30–37.
Irritant and acute allergic contact dermatitis were induced in ft/ft and +/+ mice using TPA and Ox, respectively, as described previously 38. TPA (either 0.3% or 0.1% in acetone) was applied once to the inner and outer surface of the ear. Challenge doses of Ox (either 0.02% or 0.5% in acetone) were applied once following initial Ox sensitization (2% Ox). In all cases, ear thickness was measured 2 hrs post-treatment.
To induce an AD-like dermatosis in mice, ft/ft and +/+ mice were sensitized with 2% Ox, as above. One week later, shaved areas on the flanks of ft/ft and +/+ mice were treated every other day topically with 60 µl of 0.5% or 0.02% Ox for an additional 3 weeks (10 challenges). Other groups of ft/ft and +/+ mice were treated with ethanol alone as the vehicle control group (n = 10–12 in each group). At the end of treatments, basal TEWL and stratum corneum hydration were measured again.
Changes in overall morphology were visualized after hematoxylin and eosin staining of 5 µm paraffin-embedded tissue samples. Both the number of epidermal nucleated cell layers and the density of the inflammatory infiltrate were measured in 20–30 randomly-chosen fields from ft/ft and +/+ mice before and after Ox challenge doses, as above. Immunohistochemical assessment of changes in profilaggrin/flg, CTRH2, and CD3 were performed, as described previously 39. Briefly, 5 µm paraffin sections were incubated with the primary antibodies overnight at 4°C. After washing, sections were incubated with the secondary antibody for 30 min. Staining was detected with ABC-peroxidase kit from Vector Lab. Frozen sections were examined with a Zeiss fluorescence confocal microscope (Jena, Germany), and digital images were captured with AxioVision software (Carl Zeiss Vision, Munich, Germany). A similar sequence was employed to assess two antimicrobial peptides in 5 µm frozen sections [primary antibodies to mBD3 from Alpha Diagnostics; mouse cathelicidin (CAMP) antibody was a gift from Dr. Richard Gallo (UCSD)].
Ultrastructural cytochemistry of lipase activity has been employed as a content marker for epidermal lamellar bodies, allowing assessment of the efficacy of organelle secretion 40. Briefly, samples were incubated in 5% Tween 85 (1 ml) in 0.2M HEPES buffer (2.5 ml), 2.5% sodium taurocholate (2 ml) and 10% calcium chloride (1 ml) in 25 ml distilled water (pH 7.4). Microwave incubations were carried out twice for 30 sec at 2450 MHz, and the water bath was changed between the pulses, in order to maintain temperatures below 40°C 41. After incubation in the same medium for an additional 30 min at 37°C, all samples were incubated further in 0.1M cacodylate buffer containing 0.2% Tween 85 with our without 200 µm of the lipase inhibitor, tetrahydrolipstatin, as we have described 42.
To assess the outward permeation of water-soluble markers, freshly-obtained explants of back skin from untreated ft/ft and +/+ mice were exposed dermis-side-downward (30 min-2 hrs) to the low-molecular weight tracer, colloidal lanthanum nitrate (4%) in Karnovsky's solution. To assess permeation from the outside, we placed 3 +/+ control and 3 ft/ft mice in Petri dishes, while under general anesthesia, with one side of each mouse immersed in 4% colloidal lanthanum, in a 37°C incubator for 2 hr. Lanthanum nitrate was prepared in 4% w/v sucrose in 0.05 M Tris buffer, pH 7.5. After immersion, biopsy samples were taken and processed as below. In parallel studies, a 20 µM solution of calcium green 5N (Invitrogen) in nanopure water was applied on the stratum corneum side of ft/ft and wt mice for 10 and 75 min. Ten mm biopsies were mounted immediately on microscope coverslips, washed in nanopure water, and imaged in a Zeiss 510 meta NLO (Zeiss Germany) at the Live Cell Analysis Core Facility at UCSF. An optically-pumped (Coherent) mode-locked Mira 900 Ti:Saph laser (Coherent), was used as the two-photon excitation source at a wavelength of 800 nm. A 500–550 nm band pass filter was placed in the detection path in order to minimize sample autofluorescence. Under these experimental conditions, we estimated the contribution of autofluorescence to the total signal to be <5%. Z-stacks of 235×235×20 µm3 images were acquired, beginning with the outer surface of the stratum corneum at z increments of 1 µm using a 40× oil immersion objective with a 1.3 numerical aperture (Zeiss, Germany). Matlab software (The Math Works) was used to quantitate image intensity at each z-stack, and to calculate mean penetration depths.
Aldehyde-fixed biopsies were post-fixed with either 0.25% ruthenium tetroxide or 1% aqueous osmium tetroxide, containing 1.5% potassium ferrocyanide, as described previously 43. Ultrathin sections were examined using an electron microscope (Zeiss 10A, Carl Zeiss, Thornwood, NY) operated at 60 kV. Images were captured using Digital Micrograph 3.10.0 software from Gatan, Inc. (Pleasanton, CA).
Blood samples were collected from ft/ft and wt mice under basal conditions, and after prior Ox sensitization, followed by repeated treatments with either Ox or vehicle. Serum IgE concentrations were determined with a mouse IgE ELISA quantitation kit from Bethyl Laboratories (Montgomery, TX), following instructions provided by the manufacturer.
In these, and all other studies, statistical analyses were performed using a Student's t test to compare differences between two groups, with a further ANOVA analysis when three or more groups were compared.
Prior studies have shown that ft/ft mice display markedly-reduced F-type keratohyalin granules, with an absence of flg 24, due to a recently-identified, frame-shift mutation in profilaggrin 24. Using a consensus antibody that recognizes both profilaggrin and flg, we found intense, positive immunostaining restricted to the stratum granulosum (granular layer), with no residual staining of flg in the stratum corneum in ft/ft mice (suppl Fig. 1, green staining). In contrast, +/+ epidermis displayed immunostaining in the granular layer, as well as diffuse staining of the stratum corneum. Thus, the mutation in profilaggrin in ft/ft mice results in reduced flg in the SC, analogous to some humans with FLG-associated AD 6, 28.
We next assessed epidermal functional parameters in ft/ft and wild-type (+/+) mice, using biophysical instrumentation. Permeability barrier homeostasis, assessed as the kinetics of transepidermal water loss (TEWL) levels after acute disruption 44, but basal barrier function declines with aging in +/+ aged (52–54 wk) mice, as previously described 44 (Fig. 1A). Though within the range of normal (≤ 2.5 mg/cm2/hr), basal TEWL levels increase significantly (by ≈20–30%) in 52–54 week old ft/ft mice compared to age-matched +/+ controls (Fig. 1A). As occurs in human AD [e.g., 30], the kinetics of barrier recovery after acute barrier abrogation accelerate in old ft/ft vs. +/+ mice (Fig. 1B). Such accelerated barrier recovery also occurs in other chronic inflammatory dermatoses, and is attributed to ongoing signaling of repair mechanisms, which are induced by barrier abrogation [e.g., 31, 32]. Finally, stratum corneum hydration, assessed as changes in electrical capacitance, does not differ in young ft/ft vs. +/+ mice (Fig. 1C), but stratum corneum hydration is significantly lower in young ft/ft mice, with a further decline in older ft/ft mice (Fig. 1C), again mirroring known changes in human AD 33, 45.
Since basal TEWL levels lie within the normal range in ft/ft mice, we next assessed barrier function in these mice under basal conditions by an alternate approach (i.e., ultrastructural visualization of tracer perfusion). The high resolution of this method also allowed us to determine simultaneously whether the barrier abnormality can be attributed to a defective corneocyte or to enhanced paracellular transport. In +/+ mice, the water-soluble, low molecular weight, electron-dense tracer, lanthanum nitrate, does not breach the stratum granulosum-stratum corneum interface (Fig. 2A). In contrast, tracer not only breaches this layer, but also extends several layers outward into the stratum corneum in ft/ft mice (Fig. 2B). Notably, despite the intracellular localization of flg, the tracer remains largely confined to the stratum corneum extracellular spaces in ft/ft mice (Fig. 2B, arrows). Together, these results demonstrate that flg-deficiency leads to alterations in basal barrier function via a defect in the stratum corneum extracellular matrix.
Normal stratum corneum does not allow entry of water-soluble xenobiotes 46. Therefore, we next determined whether epicutaneously-applied, water-soluble tracers enter the stratum corneum of flg-deficient mice, and by which route. Lanthanum nitrate tracer was applied topically to the flanks of ft/ft and +/+ mice for 30 min to two hrs, while under general anesthesia. As shown previously 46, lanthanum fails to breach the stratum corneum of +/+ mice (Fig. 3A). In contrast, tracer permeates 3–5 layers deep into the stratum corneum of ft/ft mice by 2 hrs (Fig. 3B&C). Notably, the tracer localizes solely within the extracellular spaces, indicating again that penetration occurs via the paracellular route (Fig. 3C, arrows). In parallel studies, we visualized the permeation of the low-molecular weight, water-soluble fluorophore, calcium green, by dual photon, confocal microscopy. Differences in the extent of penetration can be seen as early as 10 min after application of tracer to ft/ft skin, with further penetration evident by 75 min in ft/ft mice (Fig. 3D&E). In contrast, very little of the fluorophore can be detected beneath the outer stratum corneum of +/+ mice at 75 min. Together, these results demonstrate that the stratum corneum of flg-deficient mice is more permeable to water-soluble tracers, and that penetration of an electron-dense, water-soluble tracer occurs via the same paracellular pathway that is utilized by water itself, exiting the skin.
We next assessed the structural basis for the extracellular barrier abnormality in ft/ft mice. By standard transmission electron microscopy, ft/ft mice display not only the previouslyreported paucity of F-type keratohyalin granules in the stratum granulosum [cited in 19], but also a previously-undescribed abnormality in lamellar body secretion (Fig. 4). Lamellar body formation appears normal (neither lamellar body density nor organelle contents differ in ft/ft vs. +/+ mice). Yet, substantial numbers of lamellar bodies appear to be retained within terminally-differentiating keratinocytes in ft/ft mice (Fig. 4A vs. B). These unsecreted organelles then become entombed within the cytosol of nascent corneocytes, instead of being secreted in toto into the extracellular matrix, as occurs in +/+ mice (Fig. 4C vs. D). Partial entombment (failed secretion) of lamellar bodies could also be demonstrated by an alternate method: identification of the fate of a lamellar body content marker (acid lipase) by ultrastructural cytochemistry 32, 40. In +/+ epidermis, enzyme activity localizes both to lamellar body contents (suppl Fig. 2A), and within the stratum corneum, solely to the extracellular domains (suppl Fig. 2B). Flaky tail mice reveal a similar localization of enzyme activity to lamellar bodies, but evidence of reduced secretion; i.e., lower amounts of initially-secreted enzyme at the stratum granulosum-stratum corneum interface, as well as sparse (reduced) enzyme product in the stratum corneum interstices (suppl Fig. 2C, arrows). In contrast to +/+ mice, the cytosol of many ft/ft corneocytes contains abundant enzyme activity, with enzyme activity localizing near retained lamellar arrays (suppl Fig. 2D), further evidence for entombment of lamellar body contents.
We next assessed the consequences of impaired lamellar body secretion and enhanced paracellular transport in ft/ft mice. As a result of impaired lamellar body secretion, the quantities of extracellular lamellar bilayers correspondingly decline in the stratum corneum of ft/ft mice (Fig. 4C vs. D). Moreover, the extracellular processing of newly-secreted lamellar body contents into 'mature' lamellar bilayers appears to be impaired or delayed in ft/ft mice (Fig. 4C vs. D). Together, these results suggest that either profilaggrin accumulation or flg deficiency impedes lamellar body secretion, leading to an abnormal stratum corneum extracellular matrix in ft/ft mice.
We next assessed whether the barrier abnormality in ft/ft mutant mice results in an increased propensity to develop cutaneous inflammation. Flaky tail skin displays low-grade inflammation under basal conditions, indicated by the presence of increased numbers of inflammatory cells under basal conditions (Figs. 5B, E&F; histologic images that correspond to these quantitative data are shown in supplementary Fig. 3C vs. A). Moreover, most, but not all ft/ft mice display elevated serum IgE levels, even under basal conditions (Fig. 5G). Together, these results suggest that ft/ft mice display low-grade inflammation, even under basal conditions.
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), elicits irritant contact dermatitis when applied topically to mouse ears, with the severity of the inflammatory response correlating with an increase in ear thickness two (2) hours after topical applications 34, 47. TPA was first applied at a standard concentration of 0.3% to the ears of ft/ft and +/+ mice. Although inflammation appeared greater in ft/ft mice, the differences in ear thickness in ft/ft vs. +/+ mice do not achieve statistical significance (Fig. 6A). However, at a lower dose of TPA (0.1%) that provokes only marginal inflammation in +/+ mice, ft/ft mice display a marked inflammatory response, with a significant increase in ear thickness (Fig. 5A;p <0.001; parallel histologic differences are shown in suppl Fig. 4). Together, these results demonstrate that ft/ft mice display an enhanced propensity to develop irritant contact dermatitis.
We next assessed whether ft/ft mice display an altered threshold to the development of acute allergic contact dermatitis. For these studies, we utilized a single challenge dose (2%) of the universal hapten, oxazolone (Ox), followed one week later by topical application to the ear of either a single challenge dose at a concentration (0.5%) which produces a prominent dermatitis after 24–48 hrs 47, 48, or a much lower hapten concentration (0.02%), which does not produce visible inflammation in +/+ mice. As with the topical irritant (c.f., Fig. 5A), dermatitis appears more exaggerated in ft/ft mice, after challenges with the standard (0.5%) hapten dose, but again the results do not achieve statistical significance (Fig. 5B). At the lower challenge dose of Ox (0.02%), dermatitis does not develop in +/+ mice, while in contrast, substantial inflammation is evident in similarly-challenged ft/ft mice (Fig. 5B; p<0.0001 vs. +/+; parallel histologic differences are shown in suppl Fig. 4). These results show that ft/ft mice display a reduced threshold for the development of hapten-induced, acute allergic contact dermatitis.
We previously showed that Ox sensitization, followed by repeated (10×) hapten challenges over 20–21 days produces a dermatosis with certain structural, biochemical, and immunologic features of human AD 49. In the next set of studies, we used reduced challenge doses of Ox (10 challenges with 0.02% vs. the standard 0.5% concentration) in ft/ft and +/+ mice. Whereas +/+ mice display minimal signs of inflammation, ft/ft mice reveal erythema, hyperkeratosis, epidermal hyperplasia, and histologically-prominent inflammation at the lower hapten concentration (Figs. 6E&F; suppl Fig. 3). Moreover, while virtually no CD3+ lymphocytes are detected in +/+ mouse skin, a moderately-high density of CD3+ cells can be seen in ft/ft mice repeatedly challenged with low-dose Ox (Fig. 6D). Flaky tail mice also display numerous prostaglandin D2 receptor (CRTH2)-positive cells, consistent with a th2-dominant immunophenotype, as well as much higher serum IGE levels than do comparably-treated +/+ mice (Figs. 7A&B). Finally, ft/ft mice, repeatedly challenged with low-dose Ox, display reduced immunostaining for mBD3 (mouse homologue of hBD2 [suppl Fig. 5D]), but staining for cathelicidin antimicrobial peptide (CAMP = mouse homologue of LL37) instead appears to increase (suppl Fig. 5C). Together, these results indicate that flg deficiency predisposes to development of a hapten-stimulated AD-like dermatosis in mice.
In normal mice, repeated challenges with 0.5% Ox result in a progressively more-severe barrier abnormality 49, consistent with a proposed 'outside-inside-outside' pathogenic cycle in AD 1, 2. We next assessed whether repeated, sub-threshold (0.02%) doses of Ox would provoke functional abnormalities in ft/ft mice that occur only at higher doses in +/+ mice. While stratum corneum hydration does not decline in such Ox-challenged mice (Fig. 3F), ft/ft mice develop a severe permeability barrier abnormality at sub-threshold doses of hapten (Fig. 3G), evidenced by an acceleration of TEWL levels to levels produced by full-challenge hapten doses in +/+ or normal mice (c.f., 49). These results show that development of an AD-like dermatosis in flg-deficient mice is paralleled by a further exacerbation of the permeability barrier abnormality.
Human atopic dermatitis (AD) is increasingly viewed as a primary barrier disorder, based upon recent data from multiple populations that have demonstrated an association with mutations in FLG, the gene encoding the stratum corneum structural protein, filaggrin (FLG). Yet, while these molecular genetic studies have shifted views of AD pathogenesis towards a new 'outside-to-inside' pathogenic paradigm 1, 2, they leave unanswered mechanistic questions of how FLG-deficiency leads not only to a barrier abnormality, but also to an inflammatory phenotype in AD. Because such questions are difficult to address in the complex, multifactorial environment of human disease, we addressed these issues in an animal model of flg deficiency, the flaky tail (ft/ft) mouse. Recently, these mice were shown to carry a frameshift mutation with one base pair deletion (5303delA) in exon3 of flg 24, which mimics two common, distal mutations in human AD (i.e., R2447X in repeat 7 and 1033del4 in repeat 10) 6, 28.
In our examination of ft/ft mice, we first confirm that flg deficiency alone suffices to induce a barrier abnormality and low-grade inflammation under basal conditions, as shown recently for ichthyosis vulgaris 50. We also provide subcellular pathogenic insights, showing that despite its intracellular localization, flg deficiency results in enhanced paracellular permeability to both intradermally and epicutaneously applied water-soluble tracers, which do not penetrate +/+ stratum corneum. Movement of these low-molecular weight, water-soluble tracers through the stratum corneum interstices likely reflects the pathway for hapten ingress in AD, since similarly-sized, water-soluble antigens, such as nickel, more frequently induce allergic contact dermatitis in humans with AD 51. However, since our ft/ft mice were not on a homogenous C578BL6 background, but also express a hair phenotype (matted), we cannot eliminate the possibility that some of our observations could have been influenced by the concurrent matted mutation. Nevertheless, the recent work by Fallon, et al 24 shows enhanced antigen ingress in mice with the same flg mutation, but no matted in their background. Thus, flg deficiency alone likely explains the barrier abnormality that we demonstrate here in flaky tail mice.
Localizing the barrier defect in FLG deficiency to the extracellular matrix is an important first step in understanding AD pathogenesis. Yet, a key question remains unanswered: how can a defect in an intracellular protein, such as FLG, yield a more-porous extracellular pathway? FLG has two putative functions: 1) mediation of stratum corneum hydration through humidity-dependent proteolysis of FLG into its constituent amino acids and their deiminated products (e.g., histidine → trans-urocanic acid)18, 52; and 2) keratin intermediate filament compaction within the corneocyte cytosol 19, 53. Examination of either of these roles does not immediately suggest a mechanism by which FLG deficiency could lead to increased extracellular permeability. Potential clues are provided by other inherited defects of intracellular corneocyte proteins that also provoke increased paracellular permeability, but by divergent mechanisms 54. In one example, in K1/10-deficient epidermolytic hyperkeratosis, dominant-negative pairing of the mutant protein disrupts the cytoskeleton, impairing lamellar body secretion 32. In a second, alternate mechanism, both loricrin keratoderma and transglutaminase 1-deficient lamellar ichthyosis yield an abnormal corneocyte scaffold that disrupts the supramolecular organization of the extracellular lamellar bilayers 36, 37. A third mechanism, mutations in the V1 subdomain of K1 that produce palmar plantar keratoderma, provokes detachment of keratin filaments from the cornified envelope 55. This defect could link an abnormally-collapsed corneocyte to an extracellular defect, yet frozen sections of flg-deficient stratum corneum display corneocytes of normal shape and dimensions (Elias, unpublished observations). Our ultrastructural studies on ft/ft mice show a partial failure of lamellar body secretion, as shown previously for non-genotyped human AD 56. Likewise, our preliminary studies in genotyped ichthyosis vulgaris +/− AD patients show a similar blockade in lamellar body secretion 50. Thus, analogous to K1/10-deficient epidermolytic hyperkeratosis 32, unprocessed profilaggrin might impede lamellar body secretion (op. cit.) (suppl. Fig. 2). This mechanism likely also pertains to human AD associated with distal FLG mutations, in which residual profilaggrin expression is seen, but processed FLG is reduced 28. Yet, it is not clear how this mechanism might apply to those cases of AD caused by more proximal FLG mutations, which instead decrease both profilaggrin and FLG. A fourth mechanism, which could apply to both categories of FLG mutations, could be linked to decreased generation of acidic metabolites of FLG 1, 2 suppl. Fig. 6). Deficiency in these polycarboxylic acids could result in a net increase in the pH of the stratum corneum, which in turn could activate neutral-pH-dependent kallikreins, with a variety of negative, downstream consequences for the barrier 1,2. Such a pH-dependent mechanism could also lead to deactivation of two key ceramide-generating enzymes, acidic sphingomyelinase and β-glucocerebrosidase (suppl. Fig. 6)57. This mechanism may not, however, be operative in ft/ft mice, because the surface pH of these mice remains normal, perhaps due to compensatory upregulation of alternate, endogenous acidifying mechanisms [rev. in 58], such as solute carrier family 9 (sodium-hydrogen exchanger, 1 (slc9a) (old symbol NHE1) 59 and/or secretory phospholipase A2 60. Nonetheless, surface pH measurements do not always reflect pH alterations within specific microdomains of the stratum corneum 59. We did not specifically examine such potential, compensatory mechanisms in this study.
While our studies demonstrate the increased movement of topically-applied, water soluble compounds through the stratum corneum in ft/ft mice, the movement of water from inside to outside through the stratum corneum (TEWL) is not markedly altered in young ft/ft mice, becoming only slightly elevated in older ft/ft mice in comparison to older +/+ mice. The development of a barrier abnormality with aging of ft/ft mice could reflect the added stress from a steeper water gradient across the SC of older animals reflecting the observed decrease in SC hydration (Fig. 1C). Alternatively or additionally, it could reflect age-related differences in permeability barrier homeostasis 44, 61. While the explanation for the discordance in TEWL rates vs. xenobiote penetration is not clear, it could reflect differences in the thresholds for the barriers to water loss vs. xenobiote ingress/egress, respectively. Pertinently, to increase TEWL levels by tape stripping, multiple layers of the stratum corneum must be removed 62. Thus, there appears to be substantial redundancy, with only a relatively small amount of stratum corneum required to maintain a normal TEWL. Conversely, the structural basis for inhibiting water movement from inside to outside (i.e., TEWL) could differ from the structural basis for inhibiting the egress or ingress of somewhat larger, water-soluble compounds. Since there are several possible mechanisms that could explain how FLG deficiency leads to a marked abnormality in xenobiote permeation, without altering water loss, additional studies will be required to distinguish among these alternatives.
Having established that FLG deficiency results in an extracellular barrier defect, we next addressed a question of key functional significance; namely, does this barrier defect suffice to alter thresholds to the development of inflammation from epicutaneously-applied irritants and haptens? While FLG mutations are associated with the inflammatory disease, AD (op. cit.), the relationship between FLG deficiency and inflammation is obscured by the association of the same FLG mutations with the supposedly noninflammatory disorder of cornification, ichthyosis vulgaris (IV). Additional stressors to the barrier could be required to provoke human AD 1, 2, because human skin displays an inherently more competent barrier 63–65 (see below). Nevertheless, the presumption that IV is non-inflammatory should now be re-examined, in light of our observations, and those of Fallon, et al. 24, which show that flg deficiency alone results in epidermal hyperplasia, low-grade inflammation, and elevated IgE levels in otherwise normal mice.
In order to ascertain whether FLG deficiency alone leads to increased susceptibility to inflammatory dermatoses, we employed previously described methods for eliciting irritant and acute allergic contact dermatitis 38, 47, as well as an AD-like mouse model 49, in ft/ft vs. +/+ mice. Our results show that FLG deficiency alone lowers thresholds to inflammation following epicutaneous applications of either irritants or haptens. Most importantly, we demonstrate development of an AD-like phenotype following applications of reduced concentrations of haptens, which do not produce th2-dominant inflammation in +/+ mice. The AD-like phenotype included increased CRTH2-positive cells, decreased immunostaining for mBD3 (the murine homologue of hBD2), and elevated serum IgE levels. Similarly, antigen-challenged mice, with the same flg mutation as ft/ft mice, also display multiple features of th2 inflammation 24. Interestingly, these flg-deficient mice reportedly did not develop significantly higher IgE levels24, likely reflecting a less severe phenotype due to differences in bioavailability of our hapten vs. the complete antigen employed by Fallon, et al. 24. Finally, the apparent reduction in mBD3 expression could reflect downstream down-regulation by th2 cytokines 16.
Notably, inflammation can be induced in flg-deficient mice, without a requirement for additional, acquired stressors, such as reduced ambient humidity, high pH surfactants, and/or increased psychological stress, conditions that are known to both further compromise barrier function, and to precipitate AD in humans 1–3. This leaves unanswered, however, the question of why many IV patients, including some with double-allele FLG mutations, do not display a concomitant AD phenotype 25, 26. Two alternative or perhaps coincident explanations could explain this apparent paradox. First, it is possible that all patients with FLG mutations have the potential to develop AD, based upon their inherited barrier defect alone, but repeated epicutaneous deposition of allergens, sufficient to provoke TH2-dominant inflammation, might not occur in some IV patients. Second, in mice, unlike humans, development of inflammation might not require the superimposition of additional acquired stressors, because as noted above, mouse skin displays reduced barrier competence in comparison to human skin 63–65. This inherent difference could also explain why hapten-induced, acute allergic contact dermatitis converts to an AD-like phenotype following repeated challenges in mice, a transition that is not known to occur in humans.
In summary, we show here that FLG deficiency, as occurs in many cases of human AD, suffices to provoke a barrier abnormality, which in turn allows enhanced permeation of water-soluble tracers via the paracellular route. The paracellular defect can be attributed to abnormal extracellular lamellar bilayers, resulting from compromised lamellar body secretion. These structural abnormalities allow enhanced irritant/hapten ingress, resulting in reduced inflammatory thresholds, providing a mechanistic link between FLG deficiency and development of AD. Finally, these studies substantiate and explain the new, 'outside-to-inside' paradigm of AD pathogenesis.
FLG deficiency (in human AD) provokes a paracellular barrier abnormality, caused by abnormal extracellular lamellar bilayers, resulting from compromised lamellar body secretion. These structural abnormalities reduce inflammatory thresholds to irritants/haptens, providing a mechanistic link between FLG deficiency and development of AD, explaining the new, 'outside-to-inside' paradigm of AD pathogenesis.
We are indebted to Ms. Joan Wakefield for superb editorial assistance. These studies were supported by NIH grants AR019098, AG028492, AI059311, and the Medical Research Service, Department of Veterans Affairs.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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FM Original Soundtrack Quick ViewSCMU-MCA-1200$16.99Buy Now
FM Original SoundtrackAppropriately, the soundtrack for the 1978 movie FM feels like a radio play list of the era, collecting songs from Joe Walsh, Randy Meisner, Boz Scaggs, and other '70s radio staples. Steely Dan's title track, Queen's We Will Rock You, Bob Seger & the Silver Bullet Band's Night Moves, Billy Joel's Just The Way You Are, and Boston's More Than a Feeling are some of the highlights from this double-disc set, which also includes tracks from Tom Petty & the Heartbreakers, Foreigner, and Linda Ronstadt, all of whom also appeared in the film. Though FM itself wasn't exactly a box-office smash, its soundtrack is a surprisingly durable and entertaining collection of classic rock that is arguably better than many of the '70s rock compilations available today.
-All Music GuideFM - Steely Dan
Night Moves - Bob Seger
Fly Like an Eagle - Steve Miller
Cold as Ice - Foreigner
Breakdown - Tom Petty & The Heartbreakers
Bad Man - Randy Meisner
Life in the Fast Lane - Eagles
Do It Again - Steely Dan
Lido Shuffle - Boz Scaggs
More Than a Feeling - Boston
Tumbling Dice - Linda Ronstadt
Poor, Poor Pitiful Me - Linda Ronstadt
Livingston Saturday Night - Jimmy Buffett
There's a Place in the World for a Gambler - Dan Fogelberg
Just the Way You Are - Billy Joel
It Keeps You Runnin' - Doobie Brothers
Your Smiling Face - James Taylor
Life's Been Good - Joe Walsh
We Will Rock You - Queen
FM (Reprise) - Steely Dan$16.99Vinyl LP - 2 LPs Sealed Buy Now
Aja Quick ViewAMSP-MCA-8813xSteely Dan
AjaRanked 145/500 on Rolling Stone Magazine's 500 Greatest Albums of All Time.
Limited Edition
Long argued as one of the (if not THE) best rock recording ever and a permanent fixture on many a demo system in the late '70s and '80s, Aja was the culmination of everything Donald Fagen and Walter Becker aspired to accomplish in their storied careers. It was the first album certified platinum (eventually selling more than 5 million copies in the U.S.) by the then-new RIAA sales tracking system. It made Steely Dan superstars. It contained three ubiquitous U.S. Top 40 singles in Peg, Josie and Deacon Blues, though each of the seven tracks are wonderful.
Steely Dan's meticulously crafted sixth album was Walter Becker and Donald Fagen's stab at becoming mainstream jazz-pop superstars. And thanks to sweet, smart, slippery tracks like Deacon Blues and Peg, they did just that - and won a Grammy for Best Engineered album too.1. Black Cow
2. Aja
3. Deacon Blues
4. Peg
5. Home At Last
6. I Got The News
7. Josie$34.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
It's Like This Quick ViewACSO-APO-51056$54.99Buy Now
It's Like ThisThis lovely set of intimately arranged and meticulously recorded covers, originally issued in 2000, is precisely the kind of semi-obscure album in need of a quality all-analog reissueThe superbly natural sound produced by this record is what spending big bucks on an audio system is all about. Set the volume appropriately and Ms. Jones'll draw you into the studio for a personal song recitalThis is one to savor. Music = 9/11; Sound = 10/11 Michael Fremer, www.musicangle.com
this effort from 2000 shows Jones conjuring such magic with the material that she deserves as much attention for reworking standards as do Carly Simon or Linda Ronstadt. Kicking off with Steely Dan's 'Show Biz Kids,' and with appearances by Joe Jackson and Ben Folds, among the highpoints is the Beatles' 'For No One' that ranks as among the finest Beatles cover ever. And considering that they number in the tens of thousands, that's about as high as praise gets. Recording = 5/5; Performances = 5/5 Album of the Month Ken Kessler, Hi-Fi News, April 2008
The Rickie Lee Jones 45rpm is AWESOME UNREAL AMAZING!!! I have to get a backup copy. I'll play this one to death. Danny Kaey, Positive-Feedback Online
Not since Billie Holiday has there been a vocalist who so completely transforms a song into her own. On It's Like This, eclectic folkie Rickie Lee Jones envelops standards, showtunes, '70s soul, and even slick jazz-rock, interpreting them with her familiar childlike, breathy shouts. In a very similar vein as 1991's Pop Pop, Jones pulls together a collection of diverse songs from throughout the 20th century and gives them a sparse, fragile spin, kind of like Diana Krall and Bjork sharing coffee at an all-night diner. Produced by Bruce Brody (who has also worked with Maria McKee and Bette Midler), this album is really a showcase for the dynamic vocalist - her voice pitching and yawing like a sloop far out at sea. Several notable artists scatter themselves unobtrusively throughout the album like Joe Jackson, Ben Folds, John Pizzarelli, and Taj Mahal; each lend a subtle bass line or harmony vocal, cautiously not stepping on any of Jones' delicate lines.
This title is not eligible for discount.1. Show Biz Kids
2. Trouble Man
3. For No One
4. Smile
5. Low Spark of High Heeled Boys
6. On The Street Where You Live
7. I Can't Get Started
8. Up A Lazy River
9. Someone To Watch Over Me
10. Cycles
11. One Hand, One Heart$54.99200 Gram Audiophile Virgin Vinyl 45 RPM LP - 2 LPs Sealed Buy Now
Gaucho Quick ViewUNIM-GEF-9315HxSteely Dan
GauchoGaucho, released in 1980, was Steely Dan's last until the release of Two Against Nature twenty years later. The album has all the Steely Dan trademarks: impeccable production, cynical and venemous lyrics and undeniably catchy songs. Babylon Sisters opens the album with silky aplomb and is wonderfully anchored by the classics Hey Nineteen and Time Out Of Mind. Reissued here on Vinyl LP by Universal Records.1. Babylon Sisters
2. Hey Nineteen
3. Glamour Profession
4. Gaucho
5. Time Out Of Mind
6. My Rival
7. Third World Man$24.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Wild Things Run Fast Quick ViewELLE-ORG-0056$59.99Buy Now
Wild Things Run FastWild Things Run Fast is Joni Mitchell's eleventh studio release and her first for Geffen Records. Released in 1982, it represents her departure from jazz to a more '80s pop sound. The more rhythmic nature of the music on this album was influenced by Steely Dan, Talking Heads and The Police. Featured artists include Wayne Shorter, James Taylor and Lionel Richie. Mastered by Bernie Grundman from the original analogue master tapes.
This title is not eligible for discount.1. Chinese Cafe/Unchained Melody
2. Wild Things Run Fast
3. Ladies Man
4. Moon At The Window
5. Solid Love
6. Be Cool
7. (You're So Square) Baby, I Don't Care
8. You Dream Flat Tires
9. Man To Man
10. Underneath The Streetlight
11. Love$59.99180 Gram Audiophile Virgin Vinyl 45 RPM LP - 2 LPs Sealed Buy Now
Lay Me Down Quick ViewACSO-APO-2002-45xNancy Bryan
Lay Me DownAnalogue Productions proudly brings you Lay Me Down, alternative rock /folk / pop diva Nancy Bryans stunning debut album of original songs touching on a variety of emotions from apocalyptic visions and the struggle of the inner soul to sensitively spun tales of love spinning out of control.
Nancy has been likened to Joni Mitchell and Sarah McLachlan but with an edge. Lay Me Down features an all-star group of musicians including producer /guitarist John Koenig, bassists Dan Schwartz (Tuesday Music Club, Linda Perry, Sheryl Crow and more), Jimmy Johnson (James Taylor and more) and Jerry Scheff (Elvis Costello, Roy Orbison, Elvis Presley and more), drummers Burleigh Drummond (Ambrosia) and Peter Erskine (Weather Report, Steely Dan and more) and songwriter, acoustic guitarist and vocalist John Bryan.
Nancy Bryan has a crystalline soprano and a mournful songwriting sensibility, highlighted by one of the most dynamic and timbrally pure recordings I've heard in a long time...the disc sounds naturally ambient, crisp and articulate.
-- Wes Phillips, Stereophile
This title is not eligible for discount.1. Blood Song
2. Lay Me Down
3. Long Way Home
4. I'll Be Waiting
5. Come Back To Me
6. Sweet Havana
7. Guilty
8. My Love Is A Message
9. Falling Stars
10. In And Out Of Time$34.99180 Gram Audiophile Virgin Vinyl LP 45 RPM - 2 LPs Sealed Buy Now
Sunken Condos Quick ViewWARB-REP-7844$39.99Buy Now
Sunken Condos
Clear Vinyl!
Donald Fagen's (one half of Steely Dan), fourth solo album for Warner Reprise, Sunken Condos, will be released on October 16. His first three solo albums, The Nightfly, Kamakiriad and Morph the Cat comprised the project known as the Nightfly Trilogy. Sunken Condos begins a new chapter in in the creative evolution of this innovative artist, whose career is still going strong after forty years.
The nine tracks on Sunken Condos were co-produced by Michael Leonhart and Donald. All but one track, an Ashkenazi recasting of Isaac Hayes' Out of the Ghetto, are new Fagen originals. Some familiar names from the Steely Dan family of players are on hand (Jon Herington, the Steely Dan horns, Freddie Washington) plus some new faces. The word is that, from now on, everything Donald does has got to be funky.1. Slinky Thing
2. I'm Not the Same Without You
3. Memorabilia
4. Weather in My Head
5. The New Breed
6. Out of the Ghetto (Isaac Hayes cover)
7. Miss Marlene
8. Good Stuff
9. Planet D'Rhonda$39.99180 Gram Audiophile Virgin Vinyl LP - 2 LPs Sealed Buy Now
Starting From Nowhere Quick ViewREDI-LIT-9815$16.99Buy Now
Starting From NowhereStarting From Nowhere is the debut release from Tim Heidecker and Davin Wood (of Tim and Eric Awesome Show, Great Job!). Their recordings here evoke the sounds of the 70's groups such as Steely Dan, The Eagles and Jackson Browne, brought to life with spot-on authenticity by Wood and Heidecker's strange mix of humor and sincerity.1. Cross Country Skiing
2. Right or Wrong
3. Grandest Canyon
4. Wedding Song
5. Desert Island
6. Life on the Road
7. Weatherman
8. A Song for My Father
9. Right to the Minute
10. She Left You
11. Million People$16.99Vinyl LP - Sealed Buy Now
Aja Quick ViewURPD-ART-0014xThe Darcys
AjaAja is the second in a trilogy of releases from Toronto art rock quartet The Darcys. An interpretation of Steely Dans 1977 studio masterpiece, the album was arranged, produced and recorded by the band during the Summer and Fall of 2010. Moody, dense and textured, Aja is an exploration of physical and emotional space and the real and imaginary divisions within it.1. Black Cow
2. Aja
3. Deacon Blues
4. Peg
5. Home at Last
6. I Got the News
7. Josie$24.99Vinyl LP - Sealed Buy Now
White Knight Quick ViewALMI-CLE-8615$21.99Buy Now
White KnightTodd Rundgren's new album, White Knight, showcases the artist's incredibly diverse range of styles from soulful art-rock to ambient synth pop and includes performances from Rundgren's equally diverse musical companions such as Trent Reznor, Donald Fagen (of Steely Dan), Joe Walsh (of The Eagles), Daryl Hall, Dam Funk, Joe Satriani, Robyn and more!1. Come
2. I Got Your Back (feat. KK Watson With Dam Funk)
3. Chance For Us (feat. Daryl Hall With Bobby Strickland)
4. Fiction
5. Beginning Of The End (feat. John Boutte)
6. Tin Foil Hat (feat. Donald Fagen)
7. Let's Do This (with Moe Berg)
8. Sleep (with Joe Walsh)
9. That Could Have Been Me (feat. Robyn)
10. Deaf Ears (feat. Trent Reznor & Atticus Ross)
11. Buy My T
12. This Is Not A Drill (feat. Joe Satriani with Prairie Prince & Kasim Sulton)$21.99Vinyl LP - Sealed Buy Now
Nightfly Quick ViewWARB-WAR-2237$26.99Buy Now
NightflyOriginally released in 1982, The Nightfly is the critically acclaimed debut solo album from Steely Dan co-founder Donald Fagen. Produced by Gary Katz and engineered by Roger Nichols, both of which had worked on every Steely Dan record up to this point, the lush and romanticized 8-song set remains in the signature smooth pop-jazz vein of his famous band and features blatantly autobiographical themes concerning Fagen's suburban adolescence growing up in the late '50s/early '60s. Nominated for several Grammy Awards including Album Of The Year, The Nightfly was certified Platinum in both the US and the UK thanks to the album's duo of hits in I.G.Y. and New Frontier. 180g vinyl in Stoughton single-pocket paper-wrapped jacket with lyric insert at Furnace/Record Industry.1. I.G.Y.
2. Green Flower Street
3. Ruby Baby
4. Maxine
5. New Frontier
6. The Nightfly
7. The Goodbye Look
8. Walk Between Raindrops$26.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
How Do You Do Quick ViewUNIM-UNI-5908xMayer Hawthorne
How Do You DoOn How Do You Do, Mayer Hawthorne's first major label effort for Universal Republic Records, the singer/songwriter/producer/multi-instrumentalist proves that he is not part of the retro soul trend. The classic motown sound that provided the blueprint for his self-produced independent debut, A Strange Arrangement, remains but is joined on How Do You Do by music reminiscent of late 1960's California pop and the best work from the likes of Steely Dan and Chicago.1. Get To Know You
2. A Long Time
3. Can't Stop (feat. Snoop Dogg)
4. Dreaming
5. The Walk
6. Finally Falling
7. Hooked
8. Stick Around
9. The News
10. You Called Me
11. You're Not Ready
12. No Strings$24.99Vinyl LP - Sealed Buy Now
52nd Street Quick ViewOVSE-MOV-734xBilly Joel
52nd StreetAfter the massive success of The Stranger, Joel hit back with 52nd Street (1978) - further building on his unique sound and songwriting formula that brought him to the top of the charts. Working again with producer Phil Ramone, Billy jazzed up his act and even gets some Steely Dan influences in there on songs like "Zanzibar". Ramone's slick producing style also fits the melodrama and uplifting effect of Joels music, derived from Broadway theater. Always a craftsman in his own right, the melodies Billy churned out on 52nd Street remain some of the best he ever wrote.1. Big Shot
2. Honesty
3. My Life
4. Zanzibar
5. Stiletto
6. Rosalinda's Eyes
7. Half A Mile Away
8. Until The Night
9. 52nd Street$34.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
10CC Quick ViewLION-NOT-P45803$39.99Buy Now
10CCRed Vinyl
In 1972 few groups could have had their single nominated as Tony Blackburn's hit-pick while simultaneously being championed by underground DJ John Peel, Manchester pop quartet 10CC did just that. 10CC's music has always been able to be taken on a number of levels, and even though this was the glam era they felt a greater affinity with Americans Steely Dan. Their clever lyrics certainly put them in the Becker-Fagen bracket. The highlights of this long-player are still very much present and correct, so enjoy a return to those glorious vinyl days...1. Johnny, Don't Do It
2. Sand In My Face
3. Donna
4. The Dean And I
5. Headline Hustler
6. Speed Kills
7. Rubber Bullets
8. The Hospital Song
9. Ships Don't Disappear (Do They?)
10. Fresh Air For My Mama$39.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Daktari Quick ViewOVSE-MOV-1839xShelly Manne
180 Gram Audiophile Vinyl
Music From The Hit TV Show
A Score Focused On Percussion And African Sound
Cut in the birth pangs of electric fusion and afro-funk, West Coast drummer Shelly Manne's brilliant score for the popular '60's TV series Daktari still stands as a global fusion landmark.
Daktari is an album by drummer Shelly Manne recorded in 1967 featuring music from Daktari. The heavy use of the marimba with various percussion instruments serves the score well and makes it a huge success.
On the album, Mike Wofford plays a tack piano to evoke an African sound, and Manne is joined by percussionists Emil Richards, Larry Bunker, Frank Carlson, and Victor Feldman. According to the record liner notes, Manne and fellow percussionists play ankle and wrist jingles, Thai mouth organs, angklungs, ocarinas, vibraphones, tympani, and different kinds of marimbas.
Steely Dan guitarist Walter Becker was a fan of the album's 'vaguely African' music, sounding like it came from Hollywood session players rather than actual Africans. In the late 1990s, Becker modelled a percussion sequence after this style on the song Two Against Nature released on the Steely Dan album of the same name.1. Daktari
2. Out On A Limb
3. Clarence
4. Africa
5. Stay With Me
6. Elephantime
7. Wameru
8. Toto
9. Galloping Giraffes
10. Judy Judy
11. Ivan
12. Rhino Trot$34.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Toto Quick ViewOVSE-MOV-376xToto
TotoToto was founded in 1977 by some of the most experienced session musicians of that time.
The members of Toto were regulars on albums by Steely Dan, Seals and Crofts, Boz Scaggs, Sonny and Cher, and many others, contributing to many of the most popular records of the 1970s.
The band enjoyed great commercial success in the late 1970s and 1980s, starting with the band's self-titled debut released in 1978.
It includes the hit singles 'Hold the Line', 'I'll Supply the Love' and 'Georgy Porgy' and the album gained a reputation when released for its characteristic sound, mixing soft pop with both synth and hard rock elements.
The band still has a good reputation as selling out arenas all over the world proves.
Music on Vinyl now rereleases this classic album on 180-grams vinyl.1. Child's Anthem (2:45)
2. I'll Supply The Love (3:45)
3. Georgy Porgy (4:08)
4. Manuela Run (3:55)
5. You Are The Flower (4:17)
1. Girl Goodbye (6:14)
2. Takin' It Back (3:46)
3. Rockmaker (3:19)
4. Hold The Line (3:56)
5. Angela (4:44)$34.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
High, Low And In Between Quick ViewADAD-OMN-1070$22.99Buy Now
High, Low And In BetweenHigh, Low And In Between was Townes Van Zandt's fifth album, originally released by Poppy Records in the fall of 1971. It was a release that saw Townes becoming the songwriter revered today. An album full of brilliant original material including "You Are Not Needed Now," Blue Ridge Mountains," and "To Live Is To Fly," it opened eyes and ears to his abilities. His backing band included folks like Larry Carlton-who would play on Joni Mitchell's Court & Spark, accompany Steely Dan on The Royal Scam (playing that solo we all know and love on "Kid Charlemagne"), and who was a member of Jazz's elite Crusaders.
High, Low And In Between is-in the end-a classic Townes Van Zandt album. And one that should be reexamined. This gloriously remastered edition comes with liner notes from award-wining scribe Colin Escott, as well as on 180-gram vinyl-with the first 1,000 pressed on orange colored stock. (Future pressings will be on standard black vinyl).1 Two Hands
2 You are Not Needed Now
3 Greensboro Woman
4 Highway Kind
5 Standin'
6 No Deal
7 To Live Is To Fly
8 When He Offers His Hand
9 Mr. Mudd & Mr. Gold
10 Blue Ridge Mountains
11 High, Low and In Between$22.99180 Gram Audiogram Virgin Vinyl LP - Sealed Buy Now
Takin' It To The Streets (On Sale) On Sale Quick ViewOVSE-MOV-761
$34.99 $24.49 Save $10.50 (30%)
Takin' It To The Streets (On Sale)Moving away from their brand of Boogie Rock, Takin' It To The Streets introduced Steely Dan's Michael McDonald to the band which resulted in an new direction to these California Pop rockers' sound. More polished, more soulful, funkier and with a varied set of catchy songs, Takin' It To The Streets (1976) meant a new and successful start for the already established Boogie Rock band.
Regarded by many as their most creative period, the late seventies resulted in some great sounding, well balanced and interesting albums of which Takin' It To The Streets was arguably one of the best. Highlights of the album are modern Pop classic Takin' It To The Streets, the funky Rio and the energetic Soul rocker Turn It Loose.1. Wheels Of Fortune
2. Takin' It To The Streets
3. 8th Avenue Shuffle
4. Losin' End
5. Rio
6. For Someone Special
7. It Keeps You Runnin'
8. Turn It Loose
9. Carry Me Away$34.99 $24.49 Save $10.50 (30%)180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Pirates (On Sale) On Sale Quick ViewMUSD-MFSL-328
$34.99 $31.49 Save $3.50 (10%)
Pirates (On Sale)Rickie Lee Jones Pirates On Numbered Limited-Edition 180-gram LP From Mobile Fidelity. Singer-Songwriters gorgeous-sounding 1981 album finally remastered!
Rickie Lee Jones' Pirates arrives like a cloudburst in the desert of Eighties formula pop music and recycled heavy-metal rock. So wrote Stephen Holden in Rolling Stone in his five-star review of the eclectic artists sophomore album, a set that continues to defy eras and styles. While less-well known than her 1979 self-titled debut, the ambitious 1981 record remains Jones definitive statementan effort steeped in biographical details, fictional circumstances, and classic literary elements.
Narratively blending West Side Story and Romeo and Juliet while also exploring spirit worlds and her breakup with Tom Waits, Pirates is at its core an idiosyncratic fusion of possibilities. And does Jones deliver! Accompanied by an all-star lineup that includes trumpeter Randy Brecker, Steely Dan icon Donald Fagen, drumming colossus Steve Gadd, session pro Victor Feldman, and legendary jazz arranger Ralph Burns, the singer-songwriter achieves a musical nirvana that encompasses post-bop, coffeehouse folk, bohemian pop, romantic soul, Beat poetry, and Broadway showtunes.
Harmonized vocals and jive talking bring the piano-based records rich characters to life, making it seem as if listeners are overhearing conversations between strangers. In more than one way, Pirates is a self-contained theatrical production in which Jones singing is the star attraction. Her moody whispers, cries, and coos are the voices of spurned lovers, alienated outcasts, and unlikely heroines. Albums with this kind of stylistic magnitude, close-up intimacy, and emotional intensity come around only once or so a decade.
Mobile Fidelity is proud to have had the opportunity to remaster Pirates from the original analog master tapes and produce a version that captures every nuance of this great-sounding studio masterpiece. Co-produced by Russ Titelman and Lenny Waronker (whose long list of credits include Randy Newman, James Taylor, and Eric Clapton records), trust us when we say that this 180-gram LP is one of the finest-sounding pop records youll hear. Fans of Steely Dan, Joni Mitchell, Randy Newman, Carole King, and Sarah Vaughan should consider this requisite listening. MoFis mini-LP style packaging only adds to the allure.
So dont hesitate: Be the Lucky Guy that Jones sings about on the record by securing your lowest-numbered copy of Mobile Fidelitys half-speed mastered LP of Pirates today!
This title is not eligible for further discount.1. We Belong Together
2. Living It Up
3. Skeletons
4. Woody and Dutch on the Slow Train to Peking
5. Pirates (So Long Lonely Avenue)
6. A Lucky Guy
7. Traces of the Western Slopes
8. The Returns$34.99 $31.49 Save $3.50 (10%)180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Old Rottenhat Quick ViewADAD-DOM-0216xRobert Wyatt
Old RottenhatLimited Edition
Only 2000 Copies Made
Its far too easy to abuse the phrase living legend, but when used to describe Robert Wyatt, youre in no danger of hyperbole: gifted songwriter; political activist; drummer in the Canterbury jazz/prog pioneers Soft Machine and contemporaries of the original lineup of Pink Floyd; collaborator with the likes of Brian Eno, David Gilmour, Phil Manzanera, Fred Frith, Paul Weller, Scritti Politti, Elvis Costello and his beloved wife Alfreda Benge, to name but a few.
Perhaps his greatest gift though is his voice, a reedy instrument of great warmth and emotion; one need only hear his interpretation of the classic Shipbuilding (a song that was written for him by Costello and producer Clive Langer) and you shall be smitten for life. Domino is incredibly honored to be releasing a near-complete re-issue series of Roberts solo recorded works in the form of these limited edition LP+CD versions. Each title is limited to 2000 copies. There will be only one pressing so, once these are gone, they are gone for good.
Despite the desolate and somber nature of the subject matter of its songs Old Rottenhat has a steely sparkle at its heart. Played almost entirely by Wyatt himself, the record captures the sound of an artist in self-imposed exile brimming with melodic purpose. Often setting his voice with echo against languorous synth drones, the record confirms Wyatt has a DNA that can't help but achieve a sense of depth, grace and beauty.1. Alliance
2. The United States Of Amnesia
3. East Timor
4. Speechless
5. The Age Of Self
6. Vandalusia
7. The British Road
8. Mass Medium
9. Gharbzadegi
10. P.L.A.$24.99Vinyl LP + CD - Sealed Buy Now
Planet of Ice Quick ViewADAD-SUI-6512xMinus The Bear
Planet of IceRemastered By Bernie Grundman
Following the success of Highly Refined Pirates' forward-thinking guitar gymnastics and Menos El Oso's groundbreaking glitch rock, Seattle's premier pop revisionists Minus The Bear dug into some of rock music's most ostentatious years for inspiration for their 2007 album, Planet of Ice. The title alone conjures images of Yes's Relayer album art, and the influence of the elder statesmen's symphonic scope can be felt throughout Planet of Ice's lush and intricate arrangements. You can also hear the band channel the ominous instrumental interplay of Lamb-era Genesis on Dr. L'Ling, the deceptively savvy musicianship and pristine production of Steely Dan on White Mystery, and the tightrope walk between ethereal space and pre-metal riffage of Pink Floyd's Echoes on Lotus. Not that Minus The Bear completely abandoned their earlier style?elements of Menos El Oso's sample-driven technique can be heard on the lead single Knights. But the heart of the song ultimately belongs to the haunting Fripp-esque guitar lines spliced between verses. After being out of print on record since 2010, Suicide Squeeze is proud to reintroduce Planet of Ice's creative marriage of classic motifs and modern musical wizardry with a vinyl remaster courtesy of Bernie Grundman.1. Burying Luck
2. Ice Monster
3. Knights
4. White Mystery
5. Dr. L'Ling
6. Part 2
7. Throwin' Shapes
8. When We Escape
9. Double Vision Quest
10. Lotus$34.99Vinyl LP - 2 LPs Sealed Buy Now
Warren Zevon (1st) Quick ViewOVSE-MOV-1321xWarren Zevon
Warren Zevon (1st)Warren Zevon is a Rock & Roll album recorded in 1975 and released in 1976 by the artist of the same name. The album features guest appearances of artists like Jackson Browne, Lindsey Buckingham and Stevie Nicks, Phil Everly, Don Henley and Glenn Frey, Bonnie Raitt and many more.
Warren Zevon was a ten-year music industry veteran who had written songs for The Turtles, backed up Phil Everly, done years of session work, and been befriended by Jackson Browne by the time he cut his self-titled album in 1976. Zevon sure didn't think (or write) like any of his pals in the Eagles or Fleetwood Mac; Zevon's music was full of blood, bile, and mean-spirited irony, and the glossy surfaces of Jackson Browne's production failed to disguise the bitter heart of the songs on Warren Zevon.
For all their darkness, Zevon's songs also possessed a steely intelligence, a winning wit, and an unusually sophisticated melodic sense, and he certainly made the most of the high-priced help who backed him on the album. This was the album that confirmed he was a major talent, and it remains a black-hearted Pop delight.1. Frank And Jesse James
2. Mama Couldn't Be Persuaded
3. Backs Turned (Looking Down The Path)
4. Hasten Down The Wind
5. Poor Poor Pitiful Me
6. The French Inhaler
7. Mohammed's Radio
8. I'll Sleep When I'm Dead
9. Carmelita
10. Join Me In L.A.
11. Desperados Under The Eaves$34.99180 Gram Audiophile Virgin Vinyl LP - Sealed Buy Now
Another One Quick ViewADAD-CAP-1550$21.99Buy Now
Another OneLike the days of Steely Dan or Harry Nilsson releasing a classic album every year (or less) comes Mac DeMarco's Another One, a Mini-LP announced one year after the release of the meteorically successful Salad Days. Written and recorded during the downtime between a relentless touring schedule, Another One is an eight-track release that expands the arsenal of Mac's already impressive catalog, showing the maturity of Mac's progression as songwriter: it's a bit more refined, a bit more sophisticated, but nonetheless retains the guts and soul of classic Mac. Despite working at the same pace as artists like Creedence and The Rolling Stones, coupled with an equally unending schedule of touring and press, it's odd that Mac is labeled as a slacker. With two full-lengths and two EPs released and hundreds of sold out shows performed in the last several years, a recent late night television debut on Conan following a special performance on The Eric Andre Show, it seems, as Mac nears his 25th birthday, there's not a slack bone in the man's body. Great songwriters don't need to reinvent themselves; they just need to keep going and let the songs out in the world. Thus, here's Another One.1. The Way You'd Love Her
2. Another One
3. No Other Heart
4. Just To Put Me Down
5. A Heart Like Hers
6. I've Been Waiting for Her
7. Without Me
8. My House By The Water$21.99Vinyl LP - Sealed Buy Now
Family Jewels Quick ViewOVSE-ATL-0840xMarina and The Diamonds
Family JewelsThe Family Jewels on vinyl for the first time! Diamandis' debut studio album - it debuted at number five on the UK Albums Chart with first-week sales of 27,618 copies, and was eventually certified gold by the British Phonographic Industry. Produced by Liam Howe (Ex-Sneaker Pimps), Biff Stannard (Kylie) and Pascal Gabriel (Ladyhawke), The Family Jewels is part autobiography/part fairytale with the sound ranging from the uber-shiny pop of "Shampain" to the fragile elegance of "Obsessions" and "Numb", the pop-punk of "Girls" and the joyful quirkiness of "Mowgli's Road" and "Hermit the Frog". This steely determination even fed into the production of the album with Marina making producer Liam Howe record 482 vocal takes for one song.
The end result is an album that functions as a fully formed piece of art. Heartbreaking and emotional at times as exemplified in "I Am Not A Robot", which reached no.26 in the UK Charts, Marina lays herself open and vulnerable for her fans, the diamonds.
Diamandis was ranked in second place on the Sound of 2010 poll organised by BBC, behind English singer-songwriter Ellie Goulding. Mowgli's Road was released as the lead single from Diamandis' debut studio album on 13 November 2009. It was followed by Hollywood on 1 February, which reached number 12 on the UK Singles Chart.1. Are You Satisfied?
2. Shampain
3. I Am Not A Robot
4. Girls
5. Mowgli's Road
6. Obsessions
8. Hollywood
9. The Outsider
10. Guilty
11. Hermit The Frog
12. Oh No!
13. Seventeen
14. Numb$34.99Vinyl LP - Sealed Buy Now

subset: commoncrawl


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Stella McCartney ankle strap sandals
Copper-toned faux leather ankle strap sandals from Stella McCartney featuring an open toe, an ankle strap with a side buckle fastening, a branded insole, a high stiletto heel, a varnished finish and an open toe.
Stella McCartney Alter Nappa pumps
A statement pair for the season, Stella McCartney presents these Alter Nappa pumps. Part of the AW17 collection, the pumps boasts alluring sculptural detailing including a square toe, silver-tone metal toe caps and an exaggerated angular sole. Crafted with the label's signature eco-friendly leather alternatives, the pair features a branded insole.
Stella McCartney slingback espadrilles
Multicolour cotton slingback espadrilles from Stella McCartney featuring an open toe, a striped print, a gingham check, a slingback strap, a branded insole, a braided raffia sole and a flat heel.
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Brown artificial leather pointed shape pumps from Stella McCartney featuring a pointed toe, a branded insole and a high stiletto heel.
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Black patent pointed pumps from Stella McCartney. Building a brand on an ethical bedrock, English designer Stella McCartney clashes styles to create chic garments that bridge the gap between humour and refinement, always with an eye towards innovation. These pointed pumps skew a classic silhouette, taking a court shape pointed toe, a mid stiletto heel and a curved cut out to encase the foot.
Stella McCartney Odette slingback brogues
Stella McCartney presents the Odette slingback shoes, an adventurous take on a familiar model. The Odette name is usually used for the fashion house's intricately-made brogues, but these lace-up shoes turn the tradition upside down with a cut-out detail leaving the heel open to the elements. Featuring an almond toe, a branded insole, a contrasting waved rubber sole and a chic micro stud detailing, the Odette slingback shoes are a fine option for those wanting more surprise from their footwear.
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Out of stock
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Small pinback button from DC Comics with The Flash logo design.
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Bunbury Postal Codes
Popular ZIP code areas:hart greenfield park | 49 place d'armes kingston | 8710 avenue du parc | saskatoon postal codes | 301 adelaide street west | 174 john garland blvd | 4 hanover road | 89 chestnut street | 88 bloor | 711+beloeil+j0k+2k0 | 231 carlingview drive | owen sound postal code |
Bunbury city is located in Prince Edward Island, Canada
You can search for the Bunbury PE postal codes by its streets and block numbers
Bunbury Area Code is 902 and Time Zone is Atlantic (GMT -04:00).
Bunbury Postal Code - Prince Edward Island
Bunbury Postal Code is a six-character string that forms part of a postal address in Canada. Like British and Dutch postcodes, Bunbury - PE postal codes are alphanumeric.
The first three characters (alpha-numeric-alpha) of the postal code which represent a geographic area in Bunbury.
The last three characters denote a Bunbury local delivery unit (LDU). An LDU denotes a specific single Bunbury address or range of addresses, which can correspond to an entire small town, a significant part of a medium-sized town, a single side of a city block in larger cities, a single large building or a portion of a very large one, a single (large) institution in Bunbury, Prince Edward Island, such as a university or a hospital, or a business that receives large volumes of mail on a regular basis
If you want to send a mail to Bunbury City, you should use the corresponding Postal Code.


text:
Five years ago, The Cricket offered to buy Dan Savage a drink if he ever came to Utah.
Next week, Savage will be in Salt Lake City and the offer still stands.
Savage the best-selling author, sex-advice columnist and LGBT activist will deliver the keynote speech for the University of Utah's Pride Week. The speech is set for Wednesday, Oct. 9, at 6 p.m. in the A. Ray Olpin Union Building on the U. of U. campus.


text:
Trepopnea Associated with Paroxysmal Severe Tricuspid Regurgitation Triggered at Left Lateral Decubitus Position
Disclosures: None
Address for correspondence and reprint requests: Derliz Mereles, M.D., Department of Cardiology, Angiology and Pneumology, University of Heidelberg, Im Neuenheimer Feld 410, 69121 Heidelberg, Germany. Fax: +49-6221-56 7436; E-mail: firstname.lastname@example.com, firstname.lastname@example.com
A 78-year-old male patient was referred cardiovascular risk evaluation before elective resection of a bronchial carcinoma. A myocardial infarction with a subsequent coronary artery bypass revascularization and a mitral prosthetic valve surgery were known. Left lateral decubitus (LLD) was permanently avoided because of significant trepopnea since several years. No signs of heart failure were found in the physical examination. A mitral valve prosthesis presented normal characteristics at examination. Left ventricular dimensions and function were normal. A severe tricuspid regurgitation could be documented during examination in the LLD, with changing characteristics in dorsal decubitus, when it could be graded as moderate. Trepopnea associated with severe paroxysmal tricuspid regurgitation was never described before in the literature. Sympathetic/parasympathetic modulation of papillary muscles of the tricuspid valve can be proposed as a probable cause of this dynamic valvular dysfunction. (Echocardiography 2010;27:E77-E79)


text:
NEW YORK ( TheStreet) -- Citigroup ( C) was the winner among the largest U.S. financial names on Wednesday, with shares rising nearly 1.5% to close at $37.53. The broad indexes ended mixed after the Federal Reserve Open Market Committee (FOMC) announced that after central bank's current program of purchasing $45 billion in long-term U.S. Treasury Securities each month while selling an equivalent amount of short-term Treasuries is completed at the end of the year, it will continue the purchases "initially at a pace of $45 billion per month." There was no mention of the sale of short-term Treasury paper, and the Fed said that it would continue its purchases of mortgage-backed securities at the pace of $40 billion per month, for what will be a major expansion of the central bank's balance sheet. The Fed's short-term federal funds rate has been within a target range of zero to 0.25% since the end of 2008, and the central bank previously indicated that it would hold the line on rate increases until 2015. The FOMC on Wednesday tied the eventual increase in rates to economic benchmarks, saying that the "exceptionally low range for the federal funds rate will be appropriate at least as long as the unemployment rate remains above 6-1/2 percent, inflation between one and two years ahead is projected to be no more than a half percentage point above the Committee's 2 percent longer-run goal, and longer-term inflation expectations continue to be well anchored." This was the first time the Federal Reserve tied the federal funds rate directly to the unemployment rate. Federal Reserve chairman Ben Bernanke said later during a press conference that "clearly the Fiscal Cliff is having effects on the economy," according to an Associated Press report. Bernanke urged President Obama and Congress to quickly come up with a compromise budget agreement to avoid mandatory tax increases and budget cuts, as central bank actions "cannot offset the Fiscal Cliff. It's just too big." The KBW Bank Index ( I:BKX) rose slightly to close at 49.71, with 16 of the 24 index components showing gains.
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Is your dressing table always in a mess and you constantly have no space?
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With base wheel, you are able to move your dressing table freely anywhere in the house.
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text:
Anderson Contractor
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1.32 mi
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Best garment care service I've used in Anderson. Have used them most often for dry cleaning, but also for repair of my suits. In both cases they have done an excellent job.
Anderson Contractor
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Canon CANON 3-H1 STAPLE CTGS (6789A001AA)Item#: 40519148 | Model#: 6789A001AA
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text:
MOODLE for this lecture:
mis_c1_2016 [contains course logistics]
Adonis [contains a presentation of Adonis software and project requirements]
Presentations [pick up a presentation!]
kit [Adonis kit]
malina_radescu_adonis-project + adl[project example]
The ADONIS project has to be presented on 13th Jan or 20th of Jan: you have to have an adl and a doc and present to me on a computer the adl. Also, you have to upload the adl and the doc, as an archive on Moodle till 20th of Jan.
The presentation has to be uploaded on Moodle till 14th of Jan.
The article of 4-6 pages in IEEE format has to be uploaded on Moodle till 20th of Jan. Then, you'll get an e-mail from me with the review and the grade till 31st of Jan. You can improve your article based on the review till the day of the exam and send it again before that day. In this case, there is no need to come at the exam.
IF you don't do the article, you have to come at the exam.


text:
Burns Park Divide
Upper Burns Park resident Linda Walker, who has lived in the same house for almost forty years, often walks even farther northeast through Upper-Upper Burns Park--known as Ives Woods--to experience its "rarefied air" and gated mansions. "I guess it's human nature to walk 'up,'" she says. She wonders where Ives Woods residents walk. "Maybe they get in their cars and drive to Barton Hills," she laughs.
[Originally published in April, 2010.]
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Learn 25 ways to decrease your household's energy bill, using simple, low-cost or no-cost strategies at this free 90-minute community workshop! Thai lunch at 11:30 a.m. for all participants following the workshop.
Make a difference in your home budget and the health of the earth.
Energy efficiency saves money on energy bills and decreases production of carbon emissions caused by natural gas- or coal-burning power plants that warm the planet.
Hosted by Arizona Interfaith Power and Light
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Worth constructs this 2017 Worth Legit Greg Connell for slow-pitch with 100% Composite material and a 2-Piece Design. The "220" is Worth's 220 Advantage, which finely tunes the bat to make it hot right out of the wrapper, maximizing the bat's performance and durability with the use of a Classic M Extreme Ball. Worth also incorporates the CF100 Technology, with is a 100% Carbon Fiber Barrel to give slow-pitch hitters a lighter bat without sacrificing any power at the point of impact. This Legit 220 also comes with the True1 One-Piece Barrel to give this bat a seamless barrel that further increases the all-important durability and performance.
Bat Highlights :
We accept payments via Master Card, Visa, Discover and American Express and also PayPal. All orders MUST be shipped to the billing address on the credit card. This is to ensure we do our best to prevent fraud. BatRolling4u, LLC reserves the right to request additional verification based on the order value. All orders are 100% secure so you'll have total confidence with your purchase.
All new bat orders are normally shipped 2-3 business days (Mon - Fri) after purchase. For those of you that are ordering our Bat Rolling Service, we roll ALL bats the same day received and ship the following business day while Bat Shaving orders typically have a 2-3 processing time. We offer UPS and USPS Shipping options during your checkout. Available shipping times range from 1 to 7 days depending on your location and selected shipping method. These shipping time are in addition to the 2-3 business day processing time. BatRolling4u, LLC reserves the right to upgrade your shipping option as needed. All new bat orders will be shipped requiring an adult signature.
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