text:
MPO, via its catalytic activity, inhibits the generation of adaptive immunity by suppressing DC function.
MPO-mediated inhibition of adaptive immunity attenuates T cell-driven tissue inflammation.
Myeloperoxidase (MPO) is important in intracellular microbial killing by neutrophils but extracellularly causes tissue damage. Its role in adaptive immunity and T-cell−mediated diseases is poorly understood. Here, T-cell responses in lymph nodes (LNs) were enhanced by MPO deletion or in vivo inhibition, causing enhanced skin delayed-type hypersensitivity and antigen (Ag)-induced arthritis. Responses of adoptively transferred OT-II T cells were greater in MPO-deficient than wild-type (WT) recipients. MPO, deposited by neutrophils in LNs after Ag injection, interacted with dendritic cells (DCs) in vivo. Culture of murine or human DCs with purified MPO or neutrophil supernatant showed that enzymatically dependent MPO-mediated inhibition of DC activation occurs via MPO-generated reactive intermediates and involves DC Mac-1. Transfer of DCs cultured with WT, but not MPO-deficient, neutrophil supernatant attenuated Ag-specific immunity in vivo. MPO deficiency or in vivo inhibition increased DC activation in LNs after immunization. Studies with DQ-ovalbumin showed that MPO inhibits Ag uptake/processing by DCs. In vivo DC transfer and in vitro studies showed that MPO inhibits DC migration to LNs by reducing their expression of CCR7. Therefore, MPO, via its catalytic activity, inhibits the generation of adaptive immunity by suppressing DC activation, Ag uptake/processing, and migration to LNs to limit pathological tissue inflammation.
Myeloperoxidase (MPO) is an enzyme found in azurophilic granules of neutrophils.1 It is the major neutrophil protein, accounting for approximately 5% of the dry cell weight.1 MPO is also found to a much lesser extent in monocytes and some macrophages.1,2 In the presence of hydrogen peroxide (H2O2) and a halide (chloride [Cl], bromide [Br], thiocyanate [SCN]), tyrosine, or nitric oxide (NO), MPO catalyses the formation of powerful reactive intermediates, including hypochlorous (HOCl), hypobromous (HOBr), and hypothiocyanous (HOSCN) acids, tyrosyl radical and reactive nitrogen species, respectively, which can have profound biological effects by modifying proteins, lipids, and/or DNA.1,2
MPO plays an important role in intracellular pathogen killing, but when it is released extracellularly after neutrophil activation, it can cause tissue damage at inflammatory sites, as demonstrated in patients with immune and inflammatory diseases, including cardiovascular disease, rheumatoid arthritis, atherosclerosis, kidney disease, cystic fibrosis, and multiple sclerosis (MS).1,2 Studies in models of cardiovascular, renal, and lung disease3,-5 also demonstrate that MPO is a local mediator of tissue injury. These studies have implicated MPO as an important therapeutic target, leading to great interest in the design of MPO inhibitors for the treatment of inflammatory diseases. However, very little is known about the effects of MPO on adaptive immunity and T-cell−driven diseases. The mechanisms by which MPO affects adaptive immune responses also are unknown.
Neutrophils, the principal source of MPO, have long been considered solely as first responders in innate immunity. However, increasing evidence suggests that they also influence the development of adaptive immune responses.6 Neutrophils interact with dendritic cells (DCs) at inflammatory sites7 and secrete mediators that promote DC maturation.8,9 In addition to infiltrating inflamed tissue, neutrophils migrate to draining lymph nodes (LNs) after antigen (Ag) injection or infection.10,11 However, it is not very clear how neutrophils in LNs affect adaptive immunity. Moreover, although neutrophils contain molecules such as NO,12 which regulates effector T cells at inflammatory sites and can, by unknown pathways, suppress the induction of T-cell responses,13 the mechanisms by which neutrophils may dampen adaptive immunity are poorly understood.
In these studies, the generation of CD4+ T-cell responses in LNs was enhanced by MPO deletion or in vivo inhibition, resulting in exacerbated dermal delayed-type hypersensitivity (DTH) and Ag-induced arthritis (AIA). We hypothesized that MPO attenuates the initiation of T-cell responses by affecting DCs. This study shows that MPO is deposited by neutrophils in LNs, where it interacts with DCs during the induction of adaptive immunity. We demonstrate that MPO, via an enzymatically dependent formation of reactive intermediates, inhibits the generation of adaptive immune responses by limiting DC activation, Ag uptake/processing, and migration to LNs.
We obtained 8- to 10-week old C57BL/6J wild-type (WT) and CD45.1+ male mice from Monash University Animal Services (Clayton, Victoria, Australia). MPO knockout (Mpo−/−) mice were backcrossed onto C57BL/6J background for ≥10 generations.14 OT-II mice were from B. Heath (Walter and Eliza Hall Institute, Parkville, Victoria, Australia). Mice were bred/kept at Monash Medical Centre Animal Facilities (Clayton, Victoria, Australia) under specific pathogen-free conditions. Studies were approved by the Monash University Ethics Committee and conducted in accordance with the Declaration of Helsinki.
Immunizations, in vivo MPO inhibition, and AIA
Mice were injected subcutaneously with ovalbumin (OVA; 0.5 mg)/complete Freund’s adjuvant (CFA; Sigma-Aldrich) or OVA (0.5 mg)/lipopolysaccharide (LPS, 30 μg; Sigma-Aldrich). For in vivo MPO inhibition, mice received 4-aminobenzoic acid hydrazide (ABAH; 13 μg/g; Sigma-Aldrich)15,16 or dimethylsulfoxide (DMSO: vehicle; Sigma-Aldrich) subcutaneously.
For AIA, mice were immunized subcutaneously (inguinal) with methylated bovine serum albumin (mBSA, 0.5 mg; Sigma-Aldrich)/CFA (day [d]0), boosted (d7) with mBSA (0.2 mg; axillary)/incomplete Freund’s adjuvant (Sigma-Aldrich) and injected intra-articularly (d12) with mBSA (30 μg; left knee) or saline (vehicle; right knee). For OVA-AIA, mice received OVA (0.5 mg)/CFA subcutaneously (d0) and OVA (30 μg; left knee) or saline (right knee) intra-articularly (d7). Arthritis was assessed on d19 (mBSA-AIA) or d12 (OVA-AIA). Formalin-fixed paraffin-embedded Safranin-O−stained sagittal joint sections were scored 0-3 for: joint tissue inflammation (leukocytes in infrapatellar fat pads, joint capsule, and area adjacent to periosteal sheath), exudate (leukocytes in joint space), and synovitis (synovial hypercellularity). For OVA-AIA, tissue inflammation and synovitis were assessed. The total arthritis score was generated by adding the aforementioned parameters.
Flow cytometry and confocal microscopy
Proliferation, apoptosis, and T- and B-cell activation were assessed by intracellular bromodeoxyuridine incorporation (or Ki-67 staining [anti-Ki-67/fluorescein SCN (FITC), clone 35; BD biosciences]), Annexin-V staining, and expression of CD44 and CD69, respectively.5 Regulatory T cells were identified as foxp3+CD25+CD4+ cells.17 Mouse DCs were stained with anti-CD11c/phycoerythrin (PE) (BD biosciences), anti-CD86/allophycocyanin (APC)-Cy7 (Biolegend), anti-CD40/FITC (BD biosciences), anti-CCR7/APC (eBioscience), and anti-major histocompatibility complex (MHC)-II/APC (Biolegend). Human DCs were stained with anti-CD1a/APC (BD biosciences), anti-CD14/PE (Miltenyi), anti-CD86/APC (BD biosciences), and anti-HLA-DR FITC (Biolegend). Murine neutrophils were identified as CD11bhiCD11c−MHC-IIneg side-scatterhi cells that were Ly-6G+ or Gr-1hi using anti-CD11b/APC-Cy7 (BD biosciences), anti-CD11c/PE, anti-MHC-II/APC, anti-Ly-6G/PE (1A8; BD biosciences), and anti-Gr-1/Alexa647 (RB6-8C5; DNAX). For CD68 expression, cells were surface-stained with anti-CD68/FITC (FA/11; Biolegend). Flow cytometry was performed using the MoFlo flow cytometer (Summit software; Dako). Frozen LN sections were stained with anti-Ly6G/PE (BD biosciences), anti-CD11c/APC (BD biosciences), and anti-MPO/FITC (Thermo-Scientific) and analyzed by confocal microscopy.
Cytokines, DTH, serum antibody, and MPO activity
Mouse cytokines were measured by enzyme-linked immunosorbent essay (ELISA).17 Intracellular cytokine staining was performed as published.18 Human interleukin (IL)-12p70 was assessed by ELISA by the use of anti-human IL-12p70 (BD biosciences), biotin anti-human IL-12p40 (Biolegend), and recombinant human IL-12p70 (BD biosciences). DTH was assessed by measuring thickness of footpads injected with OVA or BSA.5 Serum antibodies were measured by ELISA5 with the use of OVA-coated plates. MPO activity was measured as published.5
In vitro experiments
Murine bone marrow (BM)-derived DCs were generated as described.8 Nonadherent cells (d8) were enriched for DCs (MoFlo XDP cell sorter, Beckman Coulter; >99% CD11chi). Neutrophils, obtained by sorting anti-Gr-1/Alexa647-labeled BM cells (>95% purity; cytospin DIFF-Quik staining [Laboratory Aids, New South Wales, Australia]), were incubated with cytochalasin-B (CB, 5 μg/mL, 30 min; Sigma-Aldrich), then N-formyl-methionyl-leucyl-phenylalanine (fMLP; 10 μM, 1 hour; Sigma-Aldrich),19 ± ABAH (200 μM) and supernatant collected. DCs were cultured (18 hours; in 10% RPMI containing 108 mM Cl) with LPS (1 μg/mL), H2O2 (100 μM; Merck) and neutrophil supernatant or purified enzymatically active native mouse MPO20 ± ABAH (200 μM). CB, fMLP, ABAH, or DMSO alone did not affect DC activation (not shown). In some experiments, DCs were cultured with LPS/H2O2 (with/without mouse MPO ± ABAH) and with (i) Cl alone, Cl + NaBr (100 μM; Sigma-Aldrich), Cl + NaSCN (200 μM; Sigma-Aldrich) or Cl + sodium nitroprusside (SNP; 10 μM; Sigma-Aldrich), or (ii) anti-Mac-1 antibody (5C6; 10 μg/mL; Walter and Eliza Hall Institute)21 or rat IgG (10 μg/mL).
Cell transfer experiments
CD4-enriched, carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled naive OT-II cells (Vα2+Vβ5+; OVA323-339-specific) were transferred intravenously (3 × 106/mouse) to mice, as described.18 OVA/CFA or OVA/LPS was injected subcutaneously 2 days later. OT-II responses were measured in LNs/spleen after 72 hours.
CD45.1+ DCs (2.5 × 106/mouse; +OVA/LPS) were injected subcutaneously into CD45.2+ recipients and detected in LNs by flow cytometry with anti-CD45.1/FITC (eBioscience).
DCs cultured with LPS/H2O2 and with/without neutrophil supernatant or mouse MPO ± ABAH were loaded with OVA323-339 (1 μM; Auspep, West Melbourne, Australia) and injected subcutaneously into recipients (1 × 106/mouse). Two mice received uncoated DCs. Mice received naive OT-II cells (5 × 106 Vα2+Vβ5+CD4+/mouse intravenously) 2 days before DC transfer. OVA-specific responses were assessed 9d after DC injection.
DCs were cultured (2 hours) with DQ-OVA (10 μg/mL; Invitrogen) and LPS/H2O2 and with/without purified mouse MPO and analyzed by flow cytometry. Mice were injected subcutaneously with DQ-OVA (50 μg)/LPS and anti-CD11c/PE-labeled LN cells analyzed by flow cytometry 4 hours later.
Experiments with human cells
Venous blood from healthy volunteers was centrifuged over Polymorphprep (Axis-Shield, Oslo, Norway) to obtain peripheral blood mononuclear cells and neutrophils. Peripheral blood mononuclear cell were enriched (anti-CD14-microbeads; Miltenyi Biotec) to obtain CD14+ monocytes (>90% purity), which were cultured with recombinant human granulocyte macrophage–colony-stimulating factor (GM-CSF, 800 U/mL; R&D Systems) and IL-4 (500 U/mL; R&D Systems). On d6, cells were >95% CD1a+ (DCs) and <1% CD14+. Neutrophils (>98% pure; cytospin DIFF-Quik) were incubated with human GM-CSF (1000 U/mL; 1 hour), then fMLP (10 μM; 1 hour)22 ± ABAH (100 μM) or catalase (2000 U/mL; Sigma-Aldrich) and supernatant collected. DCs were cultured (24 hours) with LPS (1 μg/mL)/H2O2 (100 μM) and with/without human neutrophil supernatant or purified human MPO (Sigma-Aldrich).
Results are expressed as mean ± standard error of the mean. Unpaired t test and one-way analysis of variance (with the Bonferroni or Dunnett test) were used to compare means between 2 or >2 groups, respectively. Statistical analysis was performed with GraphPad Prism (GraphPad Software). Significance was indicated by P < .05.
MPO suppresses the generation of adaptive immune responses
MPO deficiency increased CD4+ T-cell activation and proliferation in LNs and spleen 6 days after the injection of OVA/CFA (Figure 1A-B). T-cell activation/proliferation was not different between nonimmunized WT and Mpo−/− mice (supplemental Table 1; see the Blood Web site). T-cell apoptosis and regulatory T cells were not affected by MPO deletion (supplemental Table 2). OVA-stimulated splenocytes from Mpo−/− mice secreted more interferon (IFN)-γ and IL-17A (Figure 1C), as well as IL-4 (1.6 ± 0.2 pg/mL vs 11.3 ± 1.7 pg/mL; P < .001) and Ag-presenting cell-derived IL-12 (15.2 ± 5.8 pg/mL vs 33.1 ± 5.6 pg/mL, P < .05). MPO deletion enhanced OVA-specific IFN-γ and IL-17A (Figure 1D-E) but not IL-4 (0.48 ± 0.05% vs 0.49 ± 0.05% IL-4+ CD4 cells; 10.1 ± 0.3 vs 10.7 ± 0.3 mean fluorescence intensity) production by CD4+ T cells. The lack of MPO did not affect IFN-γ but enhanced IL-17A production by CD4− cells (supplemental Figure 1). IL-4 was undetected in CD4− cells. Increased T-cell responses in LNs/spleen correlated with enhanced T-cell−mediated skin DTH in Mpo−/− mice (Figure 1F).
Recipient Mpo−/− mice had increased proliferation of adoptively transferred OT-II T cells in LNs (Figure 1Gi) and spleen (supplemental Figure 2) in response to immunization with OVA/CFA or OVA/LPS (not shown). OT-II activation (33.2 ± 2.7% vs 45.2 ± 2.2% CD44hi cells; P < .01) and IFN-γ production (Figure 1Gii-iii) also were increased in Mpo−/− mice. MPO deficiency enhanced B-cell responses (supplemental Table 3) without reducing their apoptosis (not shown).
MPO attenuates AIA
To assess how MPO affects T-cell−driven pathological tissue inflammation, we induced AIA in WT and Mpo−/− mice. Mpo−/− mice had increased CD4+ T-cell activation (9.4 ± 1.1% vs 15.7 ± 1.1% CD44hi T cells; P < .01) and IFN-γ production (1778 ± 715 pg/mL vs 6570 ± 1482 pg/mL; P < .05) in response to mBSA. In correlation with enhanced arthritogenic T-cell immunity, arthritis severity was augmented by MPO deletion (Figure 1Fi-ii). Similar results were obtained in OVA-induced AIA (supplemental Figure 3).
Neutrophil MPO interacts with DCs in LNs
Neutrophil infiltration was increased in draining, but not nondraining, LNs after OVA/LPS injection, peaking at 4 hours and decreasing thereafter (Figure 2A). Correlating with neutrophil accumulation, MPO activity was increased in draining LNs at 4 hours (Figure 2B). Neutrophil recruitment in draining LNs before or 4 hours after OVA/LPS immunization was not affected by MPO deficiency (0 hours: 0.06 ± 0.01 vs 0.06 ± 0.03; 4 hours: 0.51 ± 0.03% vs 0.56 ± 0.04% neutrophils). Numerous contacts were observed between neutrophils and DCs in LNs at 4 hours (Figure 2C). Importantly, MPO was detected not only inside but also outside of neutrophils, and multiple contacts were observed between extracellular MPO and DCs (Figure 2C).
Neutrophils deposit MPO in LNs via primary granule release
Exposure of CD68 (which is expressed on primary granules of neutrophils) on the cell surface when granules fuse with the plasma membrane can be used as a marker of primary granule exocytosis.8 Surface expression of CD68 increased on a proportion of LN-infiltrating neutrophils 4 hours after OVA/LPS injection (Figure 2Di). The frequency and total number of CD68+ neutrophils were enhanced in LNs at 4 hours (Figure 2Dii-iii).
Aging of BM neutrophils demonstrated a positive association between neutrophil apoptosis and MPO release in vitro (supplemental Figure 4). However, at the time when extracellular MPO was detected in LNs (4 hours), only 0.6% of all LN-infiltrating neutrophils were apoptotic compared with 5% in normal LNs (Figure 2Ei). The total number of apoptotic neutrophils was reduced at 4 hours (Figure 2Eii). Similar to previous reports,11 increased neutrophil apoptosis was observed later, at 18 hours (6.4 ± 0.9% and 23.8 ± 6.1 × 102 total apoptotic neutrophils), correlating with neutrophil disappearance from LNs by 24 hours.
MPO suppresses DC activation in vitro through its catalytic activity
To examine whether MPO affects DC activation, we first performed in vitro experiments. WT and Mpo−/− neutrophils were degranulated in the presence or absence of the MPO inhibitor (ABAH) so we could test whether MPO-mediated effects on DCs are dependent on its catalytic activity. Enzymatically active MPO in supernatant from CB/fMLP-stimulated WT neutrophils was inhibited by ABAH and was undetectable in Mpo−/− supernatant (supplemental Table 4). In the presence of H2O2 (essential MPO substrate), WT supernatant dose-dependently inhibited LPS-induced DC activation (Figure 3A). WT supernatant containing ABAH and Mpo−/− supernatant reversed this effect, completely at lower and partially at higher supernatant doses. ABAH in Mpo−/− supernatant did not affect DC activation (Figure 3A), confirming its specificity. These effects of MPO were not the result of increased DC apoptosis (not shown). IL-12 and IL-23 were undetectable in neutrophil supernatants (not shown), indicating that the cytokines measured in DC/neutrophil-supernatant cultures were DC-derived. In addition, purified enzymatically active mouse MPO dose-dependently suppressed DC activation, effects that were lost when MPO was inhibited by ABAH (Figure 3B).
MPO-mediated suppression of DC activation inhibits immune responses in vivo
To show that MPO suppresses adaptive immunity via DCs, we transferred OVA323-339-coated DCs cultured with/without WT or Mpo−/− supernatant or with/without purified mouse MPO ± ABAH, into WT recipients. Compared with cells cultured with LPS/H2O2 alone, DCs cultured with WT supernatant (Figure 3Ci-ii) or purified MPO (Figure 3Ciii-iv) decreased OVA-specific DTH and serum IgG. This effect was reversed by DCs cultured with Mpo−/− supernatant or MPO + ABAH (Figure 3C).
MPO suppresses DC activation through various reactive intermediates
To examine how different MPO-generated oxidants affect DC activation, we cultured DCs with MPO in the presence of various halides. Compared with Cl alone, MPO-mediated inhibition of DC activation was enhanced in the presence of Cl + Br and, to a lesser extent, Cl + SCN (Figure 4Ai-ii). Br or SCN did not affect DC activation in the absence of MPO (not shown).
Because MPO can consume NO,2 we tested the effect of MPO on DCs in the presence or absence of the NO donor, SNP. SNP did not affect DC CD86 up-regulation in the absence of MPO (Figure 4Bi). Compared with Cl alone, MPO-mediated inhibition of CD86 expression was not affected in the presence of Cl + SNP (Figure 4Bii). However, SNP reduced IL-12 production by DCs in the absence of MPO, and MPO-mediated suppression of IL-12 production that occurred in the presence of Cl alone was completely lost when SNP was also present (Figure 4Biii).
Mac-1 is involved in MPO-mediated inhibition of DC activation
To examine whether DC Mac-1 is involved in MPO-mediated regulation of DC activation, we tested the effect of MPO on DCs in the presence or absence of anti-Mac-1 antibody (5C6). 5C6 blocks leukocyte adhesion via Mac-121 but affects DC activation in a similar manner as anti-Mac-1 (M1/70), which ligates/activates DC Mac-125 (supplemental Figure 5). 5C6 did not affect CD86 expression in DCs in the absence of MPO, and MPO-mediated inhibition of CD86 expression was not affected by 5C6 (Figure 4Di). However, 5C6 down-regulated IL-12 production by DCs in the absence of MPO (Figure 4Dii). MPO suppressed DC IL-12 production in the absence, but not in the presence, of the ligating anti-Mac-1 antibody (Figure 4Dii).
MPO decreases DC activation in vivo
DC activation was assessed in LNs of WT and Mpo−/− mice 4 hours and 18 hours after OVA/LPS injection. To test whether in vivo MPO inhibition has a similar effect as MPO deletion, another group of WT mice received OVA/LPS/ABAH. ABAH reduced MPO activity in LNs to baseline levels without affecting neutrophil recruitment (Figure 5Ai-ii). MPO deletion and in vivo inhibition increased DC activation in LNs at both time points (Figure 5Bi-iv). DC activation was decreased in LNs of nonimmunized Mpo−/− mice (supplemental Table 5). In correlation with increased DC activation in LNs, T-cell responses were enhanced by in vivo administration of ABAH (Figure 5C). ABAH did not affect DCs or T cells in Mpo−/− mice, indicating its specificity (supplemental Table 6).
MPO inhibits DC migration to LNs
MPO deficiency or in vivo inhibition by ABAH augmented the frequency of endogenous DCs in LNs 18 hours after OVA/LPS or OVA/CFA injection (Figure 6A). The percentage of DCs in LNs of nonimmunized Mpo−/− mice was decreased (supplemental Table 5). ABAH did not affect the proportion of DCs in LNs of Mpo−/− mice (supplemental Table 6).
MPO may suppress DC accumulation in LNs by reducing their survival and/or migration. DC apoptosis in LNs was not affected by MPO deficiency (supplemental Table 7). However, increased numbers of transferred DCs migrated to LNs of Mpo−/− mice (Figure 6B). In vitro, WT, but not Mpo−/−, neutrophil supernatant decreased LPS-induced CCR7 up-regulation by DCs (Figure 6Ci). In addition, purified mouse MPO dose-dependently reduced DC CCR7 expression (Figure 6Cii-iii).
MPO suppresses DC Ag uptake/processing
MPO from human neutrophils inhibits the activation of human DCs
Human neutrophils were degranulated in the presence or absence of ABAH or catalase (which inhibits MPO indirectly by consuming H2O2),26 both of which reduced MPO activity in supernatant from GM-CSF/fMLP−stimulated neutrophils (supplemental Figure 6). MPO-containing supernatant down-regulated LPS-induced activation of monocyte-derived DCs, an effect reversed by inhibiting MPO with ABAH or catalase (Figure 7A). DC activation was not affected by ABAH or catalase alone (Figure 7A). In addition, purified enzymatically active (supplemental Figure 6) human MPO decreased the activation of human DCs (Figure 7B). These effects of MPO were not caused by increased DC death (not shown).
MPO, the major neutrophil protein, is implicated as a local mediator of inflammatory injury in many chronic human diseases, making it an important therapeutic target.1,2 The current studies demonstrate that MPO diminishes the induction of adaptive immunity by inhibiting DCs to attenuate tissue inflammation. These results add to the complexity of the roles played by MPO in health and disease, detracting from the simplistic view that MPO acts solely as an injurious molecule in inflammatory conditions. Our data also support the growing recognition of a complex interaction between innate and adaptive immunity, providing new insights into how LN-infiltrating neutrophils shape the adaptive immune response and the mechanisms by which neutrophil products limit DC maturation and consequent induction of injurious T-cell responses. They define MPO as a regulator of DC activation to prevent the generation of overexuberant T-cell immunity.
Here, enhanced generation of T-cell responses attributable to MPO deletion, supported by observations in experimental glomerulonephritis and MS,5,27 resulted in exacerbated AIA, a T-cell−driven model of rheumatoid arthritis,28 indicating that any potential benefit of MPO absence in the joint was overridden by enhanced arthritogenic immunity in secondary lymphoid organs. Augmentation of joint inflammation in Mpo−/− mice was supported by increased skin DTH, demonstrating that MPO-mediated suppressive effects on the induction of T-cell responses cause less tissue inflammation.
We hypothesized that MPO suppresses adaptive immunity by inhibiting DC function because neutrophils, the major MPO source, interact with and affect DCs.8,-10 Here, consistent with previous reports,10,11,13 neutrophils rapidly and transiently infiltrated draining LNs after OVA/LPS injection. Although it is possible that some of these cells are immature granulocytic myeloid-derived suppressor cells (because they are also CD11b+Ly-6G+)29 which may, therefore, contribute to MPO-mediated effects on DCs, they displayed standard features of mature neutrophils, including high Ly-6G expression and granularity (side-scatterhi). Confocal microscopy demonstrated the presence of intracellular and extracellular MPO in LNs at the peak of neutrophil infiltration (4 hours after Ag injection), with studies of neutrophil CD68 surface expression and apoptosis suggesting that early MPO deposition in LNs by neutrophils occurs mainly through primary granule release. Importantly, extracellular MPO made contact with DCs in LNs, suggesting its potential to affect DC function. MPO may also interact with DCs in the skin, since neutrophil-DC contacts occur at inflammatory sites.7 The majority of extracellular MPO in LNs is believed to come from the infiltrating neutrophils rather than resident macrophages because (i) neutrophils are the major cellular source of MPO containing about 5 times more MPO than monocytes, and (ii) MPO expression is generally lost during monocyte-to-macrophage differentiation.1,2 H2O2, an essential cofactor for extracellular MPO-catalyzed formation of reactive intermediates, is most likely generated by neutrophil NAD phosphate (NADPH) oxidase and released by the same MPO-depositing neutrophils in LNs.1 Some H2O2 may come from other myeloid cells within LNs capable of producing H2O2 such as macrophages and, to a lesser extent (due to lower NADPH oxidase expression), DCs.30
Culture of DCs with WT/Mpo−/− neutrophil supernatant (±ABAH) or purified mouse MPO (±ABAH) showed that MPO inhibits DC activation in vitro via its catalytic activity, effects that were not attributed to MPO-mediated consumption of H2O2. Partial reversal of MPO-mediated DC inhibition by ABAH or Mpo−/− supernatant at greater doses of neutrophil supernatant used is most likely the result of the presence of other neutrophil enzymes such as elastase, which is released upon CB/fMLP stimulation and can suppress DC activation.19,31 Studies in Mpo−/− mice demonstrated that MPO also inhibits DC maturation in LNs after immunization but not as the result of MPO deficiency in DCs themselves because DCs do not express MPO.32 In vivo MPO inhibition not only confirmed the results in Mpo−/− mice but demonstrated, consistent with our in vitro data, that MPO suppresses DC activation and subsequent T-cell responses in vivo by its enzymatic activity. Notably, by transferring peptide-loaded DCs cultured with WT/Mpo−/− supernatant or MPO±ABAH, we confirmed that MPO suppresses Ag-specific adaptive immunity by inhibiting DCs.
Importantly, the suppressive enzymatically dependent effects of MPO on DC activation were demonstrated in a human system by culturing monocyte-derived DCs with supernatant from human neutrophils degranulated in the presence or absence of ABAH or with enzymatically active purified human MPO. Here, we further confirmed that the MPO H2O2-dependent enzymatic activity is required for its inhibitory effects on DCs because MPO could not reduce DC activation in the presence of catalase, which consumes H2O2.26 These results, together with our data in mice and observational studies in humans showing a greater incidence of chronic inflammatory diseases, including arthritis in patients with MPO deficiency,33,34 lower blood leukocyte MPO activity in MS and diabetes patients,35,36 and increased risk of developing lupus nephritis in patients with decreased expression of MPO due to a genetic MPO polymorphism,37 suggest that MPO also limits DC activation and consequent generation of injurious adaptive immunity in humans.
We further demonstrated that HOCl and HOBr, formed by MPO catalysis of Cl and Br,2 are the major oxidants by which MPO suppresses DC activation in vitro. This finding is supported by previous studies in which authors showed that HOCl and HOBr, both powerful oxidants, can affect cell function.38 HOSCN, generated by MPO-catalysis of SCN,39 had a minor role in DC inhibition, consistent with HOSCN being a less reactive intermediate.39 HOCl, HOBr and/or HOCl can affect protein function1,2,40 and signaling by NFκB and mitogen-activated protein kinase41,42 in other cells. Therefore, they may down-regulate DC maturation by modulating signaling pathways and/or surface receptors involved in DC activation.
MPO can also consume NO,2 which itself can attenuate DC activation.43 Here, DC CD86 expression was NO-independent. However, exogenous NO itself decreased DC IL-12 production, as reported,43 and MPO-mediated suppression of IL-12 expression in the presence of Cl alone was completely lost when SNP was also present. This finding suggests that, in vitro, the inhibitory effects of MPO-HOCl on DC IL-12 production are counter-balanced by MPO-mediated consumption of NO. These results, together with our animal data showing increased DC costimulatory molecule expression and IL-12 production due to MPO deletion or inhibition, suggest that, in vivo, MPO-generated intermediates (HOCl, HOBr, and/or HOSCN) have a dominant suppressive role in DC activation over any potential MPO-NO interactions.
Ligation/activation of DC Mac-1 by natural ligands or anti-Mac-1 antibodies inhibits DC maturation,25,44 and MPO affects Mac-1 signaling in other cells.45 Here, DC CD86 expression was Mac-1 independent, as reported.25 MPO may decrease DC CD86 expression through other pathways such as mitogen-activated protein kinase.46 In contrast, ligation/activation of Mac-1 decreased DC IL-12 production in the absence of MPO as reported,25 and abolished MPO-mediated inhibition of IL-12 expression. This suggests an interaction between the MPO-HOCl and Mac-1 pathways in DC IL-12 production. The nature of this interaction is unknown, but because Mac-1 can be activated not only by ligand binding, but also by free radicals,47 it is possible that MPO-derived oxidants activate DC Mac-1 (an effect which is bypassed by antibody-mediated Mac-1 activation) thus reducing IL-12 production.
In addition to DC maturation, full induction of T-cell responses requires DC Ag uptake/processing and migration to LNs. DQ-OVA studies showed that MPO regulates Ag uptake/processing by DCs. Although the mechanisms for this are unknown, it is possible that MPO-HOCl inactivate the DC mannose receptor (which is involved in OVA uptake) and/or proteins involved in Ag digestion.48,49 We also showed that MPO limits DC migration to LNs after immunization by reducing their CCR7 expression. Because MPO oxidants can inactivate chemotactic factors,50 neutrophil deposition of MPO in LNs may also inactivate LN DC-attracting chemokines.
In summary, we have demonstrated that MPO deposited by neutrophils in LNs interacts with DCs in vivo during the generation of adaptive immunity. MPO, via enzymatically generated reactive intermediates, attenuates adaptive immunity by suppressing murine (and human) DC activation, Ag uptake/processing and migration to LNs, resulting in decreased pathological tissue inflammation. These findings, supported by observational studies in patients with genetic deficiency or decreased expression of MPO,33,,,-37 provide cautionary information when considering MPO as a therapeutic target.
The online version of this article contains a data supplement.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
The authors thank Alice Wright, Lynelle Jones, and Leon Moussa for technical assistance, and James Ngui, Paul Hutchinson, and Kim Steegh for help with flow cytometry.
Supported by grants from the National Health Medical Research Council of Australia.
Contribution: D.O. designed the research, performed experiments, collected and analyzed data, and wrote the paper; A.R.K., E.F.M., and S.R.H. designed the research and analyzed data; and Y.Y., K.M.O., R.C.M.M., K.L.E., D.S.Y.T., and S.A.S. performed experiments.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Stephen R. Holdsworth, Department of Medicine, Monash University, Monash Medical Centre, Level 5 Block E, 246 Clayton Rd, Clayton, Victoria 3168, Australia; e-mail: firstname.lastname@example.org.


text:
Study claims that if you like Eminem's 'Lose Yourself' you might be a psychopath
It is one of the most iconic songs of all time, and I guarantee that most of the population of the world can at least rap a little bit of that intro. I am, of course, talking about the theme tune of the Fresh Prince of Bel-Air! Lol, just kidding, I'm talking about Lose Yourself - the smash hit by Eminem that was released in 2002 and went on to go quadruple platinum as well as featuring in Rolling Stone's list of the 500 Greatest Songs of All Time.
However, while it may be a song to define an era; if you are a big fan of Lose Yourself, it turns out you are also possibly a psychopath.
That is according to a completely random study that was performed by the New York University, which found that people who liked the songs "No Diggity" by Blackstreet, and "Lose Yourself" by Eminem, are more likely to have psychopathic tendencies.
Obviously, this goes against infamous psychopaths like Alex in A Clockwork Orange and Hannibal Lecter in Silence of the Lambs, who preferred classical music to hip hop tracks. The results, which are preliminary and unpublished, have caused such intrigue among scientists that they are now set to launch a major study in which thousands of people across the psychopathy spectrum will be asked about their musical preferences.
So if psychos listen to Eminem and Black Street, what do the least psychopathic people listen to? Well, the answer to that is My Sharona by The Knack, and Titanium by Sia.
"The media portrays psychopaths as axe murderers and serial killers, but the reality is they are not obvious; they are not like The Joker in Batman. They might be working right next to you, and they blend in. They are like psychological dark matter," said Pascal Wallisch, who led the research.
It's estimated that about one per cent of the general population is psychopathic, but in prison the figure is much higher, with one in five prisoners having the disorder.
"You don’t want to have these people in positions where they can cause a lot of harm," said Wallisch. "We need a tool to identify them without their cooperation or consent."
The larger study will now investigate whether there is a clear link between musical tastes and psychopathy, and whether groups of songs can predict potential psychopaths. If the team can identify a group of say, 30 songs, they could then create playlists of them for online music providers to use to identify potential psychopaths.
If you're unsure of the difference between a psychopath and a sociopath, take a look at the video below which outlines the key differences.
"The beauty of this idea is you can use it as a screening test without consent, cooperation or maybe even the knowledge of the people involved," Wallisch said. "The ethics of this are very hairy, but so is having a psychopath as a boss, and so is having a psychopath in any position of power."
Fortunately for ethicists, the possibility is some way off yet. "This work is very preliminary," Wallisch added. "This is not the end of an investigation, it is the very beginning."
So next time you're on Spotify or Apple Music, avoid listening to Lose Yourself or Back Street, as it will be giving out the wrong impression of you.

domain: news


text:
100% Pure Organic Matcha Tea Powder
Certified Ceremonial Grade Matcha, Quality Guarantee From Happy Matcha
Sourced from the Uji Region in Kyoto, Japan, our tea has been organically grown with love, hand picked and stone ground to maintain its naturally sweet taste and smooth texture. JAS certified organic, grown using traditional Japanese techniques to produce the finest quality matcha powder money can buy.
Happy Matcha tea is what other matcha aspires to be when they grow up. Each green tea leaf grown in the perfect amount of shade, lovingly hand picked to ensure selection of the youngest and smallest leaves for the finest quality tea. Leaves are briefly steamed to protect from oxidation which preserves its flavour and nutritional content.
It is then followed by an ultra fine milling technique by hand through a granite stone mill which produces the beautiful vibrant green powder that you see in our products.
Net weight: 30 grams (approx. 30 servings)
Why Happy Matcha?
- 100% JAS Certified Organic
- Vegan Friendly
- GMO Free
- Gluten Free
- 100% satisfactory guaranteed (or your money back + free return shipping)
- Free shipping on all orders
Benefits of Matcha Tea:
- Jam packed with antioxidants (up to 137 x regular green tea)
- Enhances metabolism
- Helps increase focus and general alertness
- Boost immune system
- Increased level of sustained energy

domain: food


text:
Though we’ve been a bit absent lately, we wanted to make sure we stopped by and dropped off some end-of-year data insights to the blog. We’ve been focusing our attention in other areas and have found it increasingly hard to make time to crunch numbers like we used to.
That said, here’s some nice food for thought on the Chicago market over the past year. The good news off the bat is that absorption rates are almost universally better as 2011 winds down than they were in 2010. Kudos to the savvy agents and hungry buyers out there.
Seems appropriate here to call out that every county saw an increase in 2011 for single family homes, except Cook. Kane county saw a close to 8% increase in single family closings:
Cook = -1.44%
Dupage = 5.61%
Kane = 7.94%
Lake = 5.07%
McHenry = 7.38%
Will = 0.82%
Whats more interesting though, is that transaction volume is on par with last year’s numbers, despite there being an decrease in the amount of listings practically across the board. This could be a positive sign that sellers are not willing to sell at the current price and more sellers are staying on the sideline waiting for pricing rebounds. This signals a potential shift the pricing momentum, and bodes well for 2012 upcoming. The role of shadow inventory remains to be seen, but only time will tell.
Click the link for our full aggregation of closed and active listings by county and property type.

domain: economics


text:
POSTED: Wednesday, September 25, 2013 - 6:07pm
UPDATED: Wednesday, September 25, 2013 - 6:09pm
Las Cruces, New Mexico (KTSM) — The Mayor of Las Cruces won't be changing jobs any time soon. Ken Miyagishima learned Wednesday he is not a finalist for the position of Doña Ana County Manager.
The 50 year-old decided to apply for job last month after learning there was a shortage of qualified candidates. If chosen, he said he would have stepped down for mayor. He still has two years left in his term.


The Purflo 2.5tog sleepsac is made from 100% super soft cotton jersey and lined with silky soft naturally antibacterial bamboo; ensuring baby is snuggly and comfy all night long.
Our sleeping bags are padded with Amicor Pure which is endorsed by Allergy UK due to its hypoallergenic and anti-allergy properties; preventing the build-up of bacteria and dust-mites therefore easing the symptoms of Asthma and Eczema.
The Sleepsac has a front zip opening for easy access night time nappy changing and a zip guard to protect baby’s skin.
Care: Wash at 40 °C and tumble dry on LOW
The Breathable Nest in our sweet Giraffe print, is a multi-functional and portable soft surface for quiet, mummy and rest time- designed to be used from birth. With unique...
This breathable, air-permeable, anti-bacterial, chemical free and hypoallergenic safe environment for your baby’s quiet, rest and Mummy time and is designed for children aged 6-36 months. With a unique...
The Purflo Bamboo cotton Muslin is beautifully soft, luxuriously large and of course breathable. Versatile in use it can be used as a swaddling blanket, a nursing cover, pram blanket...
Gigi is soft, loveable and has soft silicone teether toes. Gigi's teether toes are made from 100% food grade silicone which is totally safe and non-toxic providing welcome relief for...
Liquid error: Could not find asset snippets/booster-message.liquid


text:
Last Updated on May 27, 2020, by eNotes Editorial. Word Count: 345
Sleep and Death
At the beginning of "The Daring Young Man on the Flying Trapeze," the protagonist is sleeping and having wonderful dreams, which Saroyan describes in a stream-of-consciousness style. These dreams are filled with wonderful sights and colors, and they feature the delights of life, including the sea, music,...
(The entire section contains 699 words.)
Unlock This Study Guide Now
Start your 48-hour free trial to unlock this The Daring Young Man on the Flying Trapeze study guide. You'll get access to all of the The Daring Young Man on the Flying Trapeze content, as well as access to more than 30,000 additional guides and more than 350,000 Homework Help questions answered by our experts.
Sleep and Death
At the beginning of "The Daring Young Man on the Flying Trapeze," the protagonist is sleeping and having wonderful dreams, which Saroyan describes in a stream-of-consciousness style. These dreams are filled with wonderful sights and colors, and they feature the delights of life, including the sea, music, and literature. In contrast, the man's life is grim and gray. He walks about San Francisco without food, only drinking water, until he dies. Death, a longer kind of sleep, also has the perfection that the man is looking for. He is described as perfect in death in a way he never was while alive. Thus, sleep and death are presented as relief from the struggles of life.
The Struggles of a Writer
The protagonist's purpose in life is to write and read. He thinks that he would like to read Hamlet and Huckleberry Finn again before he dies. He values literature, and he finds that it offers the kind of perfection that is missing from everyday life. He also wants desperately to be a writer, but there is no way for him to do so. There are no jobs that involve getting paid to write, and he has only a few scraps of paper (which he took from the YMCA) in his room. The world around him does not give him the opportunity to write, and he cannot find the type of transcendence he is looking for while alive.
Truth and Fiction
While the man's dreams are portrayed as alive and true, his daily life does not seem real or alive to him. He walks about the streets of San Francisco feeling grim and depleted, and what he sees around him seems "trivial," unimportant. Reality does not offer him the release or transcendence he is looking for. He cannot find any pleasure in life. He does not even have any food to eat, and the larger pleasures of life—such as the wonders he sees in his dreams—completely elude him. Instead, he only finds release when he dies. Ironically, life is nothing but suffering to him.
Last Updated on May 6, 2015, by eNotes Editorial. Word Count: 354
During the Great Depression of the 1930’s, when “The Daring Young Man on the Flying Trapeze” first appeared, many people were out of work and hungry, so the story had a strong impact for its initial audience as an account of daily life during hard times. However, William Saroyan does much more with his material than provide a naturalistic view of a day in the life of one oppressed man. Saroyan takes a phrase, “starving artist,” which has become a cliché and almost a joke, and gives it new power by taking the reader not only into the life but also into the mind of a writer who is literally starving to death. The death of this man is doubly tragic, for as well as being a fellow human being, he is a person who is able to transform the apparently meaningless flow of circumstance, order it, and give it a meaning that might help others to understand their lives and thereby endure them. In a society primarily concerned with survival, however, art seems an extravagance. Depression-era America, or perhaps any society, does not recognize the role of the artist as a seer and healer. Throughout his last day, the writer sees details that no one else observes and of which he continues to try to make sense. His last conscious act is to look closely at the coin he has found and marvel at its beauty. He wants to bring his sense of joy and wonder to others, but the world does not respect his function, and he no longer has the energy to write. This tragedy is brought to focus in the only scene in the story in which the writer exchanges words with another person. When he tells the lady at the employment agency that he is a writer, she ignores this statement and asks him if he can type. There is no work for his mind, only for his hands. Finally, the writer finishes the task of assimilating all the myriad details he has been trying to capture and organize, not by explaining them but by joining them in death.

domain: library


text:
Ok folks, I know that this website looks pretty bland right now, but I have people working on it…
Welcome to my site! This is slightly separate from Gypsy Audio and all about me. It’s kind of weird promoting myself like this, but that’s show business right?
What can I tell the world about me that they want to know?
- Acting : I am a voice, stage, and screen actor.
- Writing: I write both technical documents and scripts (for plays or films).
- Audio Production: I mix and produce several shows and audio books.
- Promotion:I build hype through contacts and live events.
So why do I do this?
Entertainment has been a significant part of my life since I was very young. I have been a part of all areas of the business and love every minute of it! From creating the show, to playing a character, to telling people about it and putting the puzzle pieces together. I am starting to become a professional at this and once I finish my Bachelor’s degree (January, 2010) I will be working on getting either full time work or becoming a very busy independant contractor for one or all of these skills.
What else do you want to know?
Send me an e-mail at firstname.lastname@example.org
Oh! Here are some great sites to check out that I am affiliated with:
Check them out and support Internet Radio!

domain: artistic


On March 3 the Culver CityBus will have provided 90 years of continuous bus service to the Culver City Real Estate area. In honor of that accomplishment Culver City is offering free bus rides today as well as a community celebration tomorrow March 3.
The Culver CityBus began running on March 3, 1928 after Mayor Reve Houck began exploring options for city transportation that would be more cost effective than those offered by Pacific Electric. Houck and the Board of Trustees discovered that, under a provision of the California constitution, a city could operate its own transportation service and created the Culver CityBus. It is the second oldest municipally owned bus line in the state of California.
According to Houck’s daughter, Alene Houck Johnson, Mayor Houck financed the first CityBus himself. The Culver City community quickly supported the idea of a community bus service however and a bond financed the rest of the bus line.
Martin Feinberg, Culver City Realtor was interested to learn that the Culver CityBus boards approximately 5.8 million passengers each year. The buses in the fleet are powered by compressed natural gas (CNG), making them safer for the community and more energy efficient. In 2012 the CityBus was named the 3rd Best Municipal Fleet in North America, out of 38,000 fleets.
As a way to say thank you for allowing the Culver CityBus to serve the community, all commuters have the opportunity to ride free today and check out what the transportation service has to offer.
The public is also invited to celebrate the CityBus anniversary tomorrow from 11:00 a.m. to 2:00 p.m. at Transportation Headquarters at 4343 Duquesne Ave. The celebration will include giveaways, free food, caricature artists, a DJ, Mayor and Council Member speeches, photo booth, and pictures. The Anniversary Wrapped Bus will also be present.
Martin Feinberg, Realtor, hopes to see everyone there.


text:
베버리 힐스 걸어다니기 (Walking Tour around Beverly Hills (Rodeo Drive) )
Beverly Hills is a small affluent city in Los Angeles County, California, United States,
surrounded by the cities of Los Angeles and West Hollywood.
Originally a Spanish ranch where lima beans were grown,
Beverly Hills was incorporated in 1914 by a group of investors who had failed to find oil,
but found water instead and eventually decided to develop it into a town.
By 2013, its population had grown to 34,658.
Sometimes referred to as "90210", one of its primary ZIP codes,
it was home to many actors and celebrities throughout the 20th century.
The city includes the Rodeo Drive shopping district and the Beverly Hills Oil Field.
베버리 힐스, 로데오 거리를 걸어다니면서 찍은 영상
많이 다녀본 곳이라 생각했는데.. 은근 못 보던 곳도 있는듯.~

domain: geography


text:
Stunning 2 bdm + office + den single level home. First & foremost - you will savor the incredible views from Baker to Vancouver Island. A spacious floor plan flows for living, entertaining & relaxing and custom millwork that will truly impress. No expense spared on the seamless built cabinetry throughout this home resulting in an incredible array of storage options for just about everything. The ultimate in cool, clean design for comfortable and contemporary living. Too many features to list-some of which include a top-of-the-line entertainment centre w/built in surround sound. Stone-cliff is a fabulous community w/5 star amenities, 2 guest suites and only minutes to all WV has to offer. If you’re in the market for condo living you must check this out. COVID waiver & protocals
BRAND NEW magnificent home in British Properties featuring STUNNING VIEW OF CITY, OCEAN & LIONSGATE BRIDGE. This gorgeous TOP QUALITY home boasts an open concept with grand living spaces, gourmet Italian kitchen with large functional wok kitchen & top MIELE APPLIANCES, & beautiful INDOOR & MULTIPLE OUTDOOR SPACES. Offering 4 SPACIOUS BEDROOMS, GUEST HOME, home theatre, bar area, wine room, glass elevator, 3 floor backlighted book match onyx wall, air conditioning, control 4 automation, water feature, 4 outdoor gas fire features, & much more! Top school catchment: Chartwell Elementary & Sentinel Secondary. Also near to Private International Collingwood School campuses & Private International University-Prep Mulgrave School. Seller is open to trade. GST is included in price!
Bright concrete 2 bdrm plus den at 1204 sf. in desirable North Park Royal in West Vancouver. Southeastern corner unit with wrap-around 549 sf. balconies for gardening & entertaining. This luxurious home features A/C, 9'3 ceilings, floor to ceiling windows, top of line appliances, Subzero fridge, Miele gas cooktop & convection wall oven, Asko dishwasher, high-efficiency washer & dryer. 2 side-by-side parking close to elevator & 1 large locker. Direct access to Park Royal Shopping Centre. Excellent facilities: Gym, Conceirge, Lounge, Guest Rooms. Walking distance to seawall, parks, trails, golf course, Lion's gate bridge, Hwy 1 & 99. No GST. Ready to move in now!
Uninterrupted views, Quality and Opulence are just a few words to describe this meticulously detailed 2 bedroom, 2 bathroom condo. Situated in The Westerlies; a highly sought upon concrete building that is quiet and set back from Marine Drive. Sit and relax in this substantially renovated home, and take in the morning sunrise over the Lions Gate Bridge and watch the sunset over Vancouver Island. Completed with high-end finishings including a Miele appliance package, in-suite laundry, gas fireplace, gorgeous cabinetry & tiling, large pantry, 2 oversized South/SW facing balconies, 2 large parking stalls and many additional extras. An extremely private unit, with greenery on either side providing absolute tranquility. Steps to the Seawall, Ambleside Park, restaurants, cafes and shopping.
This gorgeous 2 Bedroom + Den in Evelyn, built by Onni Group, is only a few steps away from Park Royal shops and restaurants, Ambleside and best schools in West Vancouver. South Facing luxurious corner unit with 1,204 SQFT interior space, high-end interior details over 440 SQF wrapped around terrace with stunning LIONS GATE BRIDGE VIEWS. THIS CORNER UNIT HAS THE BEST EXPOSURE IN THIS BUILDING (SOUTHEAST)! Spacious interior living space with open concept floor plan, floor to ceiling windows, modern interior details, Smart Home features, Hardwood Flooring, Miele & Subzero Appliances, chef's inspired kitchen, 5-piece master ensuite, built in speakers. This unit has 2 SIDE BY SIDE PARKING and storage locker
World Class a spectacular Semi- WATERFRONT House. This stunning home with beautiful breathtaking 270 degrees views was built in 2018. Designed to perfection by Designer David Christopher, the 3-level, 6,900 SqFt home offers an open plan, spacious living room and dining room with a world-class fully equipped kitchen, built-in cabinets, and more! One-of-a-kind home w/ infinity-edge hot tub pouring into the pool. Landscaped 14,381 SqFt Lot. Oversized deck designed for outdoor dining, it is an ideal space to watch the gorgeous sunset over the ocean. Views of Caulfield Park, the ocean and downtown Vancouver. Private Buoy. Master suite features a 5-piece master bath and walk-in closet crafted with captivating rosewood. Just steps from the front yard is Stearman Beach and Caufield Park
A fantastic garden level unit in beautiful Spuraway Gardens. Enjoy West Van living at entry level price. The bright open kitchen features stainless steel appliances and over looks your private patio, which forms the perfect extension to your open concept living space. This home has been sleekly updated throughout. A delicious open floorplan, making the highest and best use of the space. All 8 acres of this complex are impeccably landscaped. Spuraway offers resort style living. An outdoor pool complete with a heritage clubhouse & guest suite. 1 parking stall & 1 storage locker are included. This fabulous location is close to trails, Park Royal Shopping and easy access to downtown. First time buyers or down-sizers looking for the perfect home base to travel from, this it! Rentals are limited
SET FOR LIVING! One of a kind, HALF ACRE VIEW PROPERTY in the heart of AMBLESIDE. FLAT LOT w/ tremendous potential for re-development. Centrally located just across from West Van High School, close proximity to Ridgeview & Hollyburn Elementary, Sentinel Secondary, shopping, park and recreation. Seawall just a short stroll away. Enter this home through a beautiful manicured garden enclosed courtyard leading to this well maintained family home on three levels featuring five bedrooms, five bathrooms and & kitchens. Functional layout, large rooms flooded with sunshine, sparkling hardwood floors and warm ambiance. Quiet seclusion, rolling green, gardens and shade, fruit trees are part of the beautiful fully fenced-in backyard. ONCE YOU SEE IT YOU'LL WANT TO OWN IT. Call for showing.
Spacious one bedroom perfect for house sized furnishings. Ground level entrance but not ground floor. Perfect for owners who don't want to deal with elevators or require wheelchair access. In-suite storage room that could work as a home office space. Dated renovations but maintained in excellent condition by meticulous owner. Beautiful hardwood flooring in living, dining room and bedroom. Pets allowed with restrictions but no rentals. No balcony but awesome roof top deck with great views. Fast possession is possible. Great location, walk everywhere and sell the car! Walk Score is 79 for Very Walkable and Transit Score is 53 which means good transit options for this location. Short walk to Marine Drive shopping and Ambleside Park. Main fee includes shared laundry,TV and heat/hot water.
VIEW!VIEW! This extensively upgraded corner unit offers panoramic unobstructed South-westerly ocean views, stunning sunsets and cruise ship-watching from spacious balcony. Enjoy summer swimming in the outdoor saltwater pool or just relaxing in the beautifully landscaped pool-side area. Steps to the Seawall, recreation centre, library and shopping. Open and airy floor-plan features hardwood floors, large modern bathroom with double sinks. Kitchen features granite countertops with convenient eating bar, and stainless appliances. covered parking, storage locker and bike room. Extremely well-maintained building; exterior recently painted. Pets and rentals not allowed.
Nestled into the prestigious Lighthouse park neighbourhood & situated on a sprawling estate sized lot (17,963sqft), sits this West Coast Modern masterpiece with gorgeous ocean views. Exquisitely renovated from top to bottom, this home features 6 bedrooms, 5 bathrooms, polished concrete floors, media room, triple car garage, almost 3000 sqft of patio & pool space, fenced in wrap around yard with gardens, outdoor kitchen & pizza oven, & Control4 smart home. This home's Chefs kitchen looks out to the ocean views & has been updated with top of the line appliances, an over-sized island with Caesarstone counters & plenty of storage space. The formal dining & living room open up to the patio & are perfect for indoor & outdoor entertainment. Completely private & steps to the ocean.
Designed by Award Winning Architect David Christopher and built by luxury developer Future Living, this European inspired custom masterpiece is situated on an estate-sized half-acre lot with beautiful views. Boasting over 9,800 SF of living space and an additional 2 double-stacked garages that can house 8 cars, this 6 Bedroom and 9 Bathroom home is finished at the highest appointed standards. Custom Marble and Herringbone Oak flooring span the entire home while Custom Walnut Cabinetry and Millwork while a Schonbek Chandelier and a gold-leaf designer ceilings extenuates this Luxury lifestyle. Additional features include a custom Lift, Outdoor Pool with Hot Tub, Putting Surface, and an impressive Dolby Media Room.
Over half an acre of beautifully maintained gardens surround this 3 level character home with 1,290sqft of decks/patios throughout. All day sunshine in prime lower British Properties location! If you want a large totally usable estate lot with incredible privacy- this is it. Pre-wired for gate, paving stone driveway, separate 2 car garage. Large kitchen with 6 burner gas range, sub zero fridge, 3 fireplaces. Many updates including newer roof. Charming 200sqft guest accommodation with a guest room, 3pc bathroom, kitchenette and deck. Surrounded by new homes, live in or rebuild on this trophy property.
One of the more unique and elegant homes awaits you in Whitby Estate. This warm and inviting home was built as the "show home" for this area by British Pacific Properties. This home won multiple awards and has had over $1,000,000 in renovations with the interior designed by Sophie Burke Design. Upgrades include a spectacular kitchen, custom rift 3/4" Oak flooring, doors and windows, Circa lighting, Marble & Caesarstone counters, and much more. The impressively manicured grounds are stunning. This exquisite home delivers true panoramic views from Mount Baker to Vancouver Island and is outstanding both day and night. This home would be easy to add a suite. Call your real estate for an appointment to experience this wonderful home.
Custom Built Craftsman LUXURY Residence with over 8,500 SF of living space, this 7 Beds and 8 Baths FAMILY home is situated on a private and gated 26,000 SF Lot with incredible southern OCEAN VIEWS. Custom finishing and millwork is evident throughout the home along with a state-of-the-art Control-4 Integrated Smart Home System. The main level offers a stunning Chef’s kitchen with high-end appliances. Large Eclipse Doors lead out to the outdoor entertaining that includes outdoor kitchen, covered sitting area, pool and hot tub, & outdoor fireplace. The upper level offers 5 generously sized bedrooms along with an impressive master suite with 2 walk-in closets and spa-like bathroom. The lower level offers 1 bed, games room, gym, and wet bar. Two ATTACHED Garages with space for 7 vehicles.
Large south facing 12,000sf WATER VIEW lot with pleasant 4BR home in Ambleside. Bright spacious rooms over 3 levels. New garage with storage recently built. Click on photograph for more pics and a floorplan. Excellent, central location. Easy to view.
A beautifully maintained, spacious Deer Ridge town home, with breath-taking views of the water, across to UBC and beyond. This south facing home is perfect for a young family or downsizing from a large home. It is flooded with natural light through the large windows and skylights, and the over-height ceilings provide that grand feel. Additional features include a master on the main floor, with a huge en-suite bathroom. Additional bedrooms below with a recreation room perfect for the kids, and scope to improve the floor plan and add a bedroom. There is also a double garage, large laundry room below, and fantastic complex amenities like tennis courts, a kids playground, communal garden and more. Make sure you check out our 'fly-by virtual tour'. Viewings by appointment only.
A great opportunity to own a beautifully maintained West Coast architectural home that is located on a quiet cul-de-sac with many young families. A bright and airy layout with lots of glass and skylights and a truly functional floor plan. Ideal for outdoor entertaining with 2 oversized decks overlooking a private and sunny lot. A paradise for boaters and golfers with close proximity to Thunderbird Marina and Gleneagles Golf Club. Walking distance to Eagle Harbour Elementary school, transit, nearby trails and the beach. All of this situated on a 10,957 sq.ft. lot with a detached 2 car garage in the highly desirable Eagle Harbour neighbourhood.
Prime British Properties 21,780 sq ft lot with ocean view. Please to present to you this UNIQUE property on an exceptionally large lot in the British Properties. An amazing opportunity as the price has been reduced for quick sale. An amazing opportunity to own this tear down investment property. Close proximity to many schools, also in the catchment for Sentinel and Chartwell Secondary Schools, close to Mulgrave and Colinwood Private Schools. Near Park Royal Shopping center, Capilano Golf Course, Hollyburn Country Club, Cypress Mountain for skiing, Grouse Grind for hikes, Sea Wall and Beaches. Great Value!! Once in a lifetime to own one of the largest lots in the neighborhood.

domain: design


text:
The global ocular implants market size estimated to grow with a CAGR of 7.8% from 2023-2030.
Ocular implants are medical devices to replace damaged or injured 85eyes to increase the proper vision of the patients. For treating various eye disorders, different eye implants are available in the market. Implants like glaucoma surgery, corneal implants, and intraocular lens are the implants for treating damaged or injured, or missing eyes.
Ocular implants like ocular prostheses are artificial eyes for people to develop their facial lineaments damages because of eye diseases or trauma.
COVID-19 Impact on Ocular Implants Market:
The sudden outbreak of COVID-19 has brought the world to a standstill. During the first 18months of the coronavirus, industries across the globe have impacted the market negatively. The eruption of the COVID-19 has affected the healthcare industry in many aspects. Concerning the emergency and non-emergency services, the American Academy of Ophthalmology disclosed the guidelines. Moreover, patients with varied chronic disorders like lung diseases, diabetes, and other heart-related diseases are living at high risk of ocular implants. The increasing demand for ocular implants, since the start of the COVID-19.
The growing occurrence of corneal diseases in geriatric people fuels the ocular implants market. Around 30 million people are affected by cornea diseases and nearly two million new cases of corneal dysfunction are diagnosed every year, according to the World Health Organization (WHO). The soaring occurrence of visual impairment worldwide with increasing older adults propels the market growth globally. To spread awareness and educate people, governments are taking initiatives in preventing the diseases and the treatments available.
A cataract is one of the leading causes of blindness and accounts for more than 50.9% of the world's blindness. Nearly 20million people have blindness globally due to cataracts. The rising patient volume with growing glaucoma cases propels the ocular implants market. By 2020, the glaucoma cases have risen to 76.0 million from 64.3 million in 2013, as per the American Academy of Ophthalmology. The mounting government initiatives for research and developments in the healthcare boom the ocular implants.
The shortage of skilled and experienced professionals in handling the medical process restrain the ocular implants market growth globally.
OCULAR IMPLANTS MARKET REPORT COVERAGE:
Market Size Available
2022 - 2030
2023 - 2030
By Product, Application, End-User, and Region
Various Analyses Covered
Global, Regional & Country Level Analysis, Segment-Level Analysis, DROC, PESTLE Analysis, Porter’s Five Forces Analysis, Competitive Landscape, Analyst Overview on Investment Opportunities
North America, Europe, APAC, Latin America, Middle East & Africa
Key Companies Profiled
Bausch & Lomb, Alcon, Carl Zeiss, Johnson & Johnson, MORCHER GmbH, STAAR surgical
The global Ocular Implants Market has been segmented and sub-segmented based on product, application, and end-use.
By product, the intraocular lenses segment is achieving the largest share in the ocular implants market. The constant increase of cataracts, quick technological advancements, and accumulating availability of the device type accelerate the ocular implants market growth. The glaucoma implants product segment is expected to experience a healthy growth rate during the period. The appearance of new glaucoma implantable devices like MIGS (micro-invasive glaucoma services). The significance of aesthetic value is growing due to the improving adoption of ocular implants is driving the ocular implants market growth during the timeline period.
Age-related macular degeneration
The glaucoma surgery application accounts for the largest share in the ocular implants market. The rising frequency of glaucoma and people having more knowledge about eye diseases strengthens the market growth further. By 2030, Americans suffering from glaucoma are expected to rise by 4.3 million from 2.7 million in 2014, according to the National Institute. Age-related macular degeneration (AMD) is estimated to grow at a quicker rate throughout the forecast period. Technological advancements and the surging occurrence of age-related macular degeneration (AMD) flourish the ocular implants market growth.
Specialty eye institutes
The hospital end-user segment holds the largest share in the ocular implants market due to the growing patient population for the constant treatment for vision impairment. The specialty eye institutes segment is the quickest growing segment in the market due to the surging need for eye care services across remote or rural areas.
North American ocular implants market is accounting for lion's share throughout the period. The rising higher penetration of advanced ocular implants supports the market to grow further. The high surging low vision, cataract problems, and other eye-related problems. These factors escalate the ocular implants market further. As stated by the National Science Foundation, in 2015, the government of the U.S 44.0% of funds for the research and development activities for eye-research institutes. In the U.S., 4.2 million Americans are low-vision or legally blind as per the Centre for Diseases and Control and Prevention (CDC).
Europe is estimated to make consequential developments in the ocular implants market. The market growth owes to rising eye problems across the region. Over 30 million people are partially sighted or blind people, as per the European Blind Union. By 2050, the whole population of Europe is expected to be 35%. The growing adoption of highly adopted advanced ophthalmic devices boosts the ocular implants market in countries like France, the U.K, and Germany.
Asia-Pacific is expected to grow with the speediest CAGR rate during the mentioned period. The rising geriatric population with frequent occurrence of diabetes in them and the mounting number of occurring cataract diseases and blindness accentuate the market for ocular implants. The high presence of key players helps the market to grow further. For example, in May 2020, SIFIand Zydus Cadila collaborated to launch new intraocular lenses (IOLs) and surgical products advanced in Italy and licensed by SIFI in India. The ocular implants market in China and Japan to have the quickest growth in the region. The increasing diabetic population and a growing number of cataract surgeries accentuate the market growth throughout the region.
The ocular implants market in Latin America is said to have a steady and constant growth rate during the forecast period.
The Middle East & African ocular implants market is likely to have a sluggish share across the region. UAE, Saudi Arabia, Israel, Egypt, GCC contribute the majority of the share in the market.
Ocular Implants Market - Key players
Some of the major key players in the ocular implants include
Bausch & Lomb
Johnson & Johnson
Recent Market Developments
On April 07, 2021, Bausch+Lomb announced the U.S FDA approval for ClearVisc dispersive ophthalmic viscosurgical device (OVD)for use in ophthalmic surgery. https://www.prnewswire.com/news-releases/fda-approves-bausch--lomb-clearvisc-dispersive-ophthalmic-viscosurgical-device-301263668.html
On May 06, 2021, Johnson and Johnson announced the launch of TECNIS Synergy and TECNIS Synergy Toric III IOLS, and the Health Canada approval of TECNIS Synergy Toric II IOLS, received the U.S FDA approval. https://www.newswire.ca/news-releases/johnson-amp-johnson-vision-announces-the-approval-of-tecnis-synergy-tm-and-tecnis-synergy-tm-toric-ii-iols-in-the-u-s-and-tecnis-synergy-tm-toric-ii-iols-in-canada-878209046.html
On November 08, 2021, Alcon disclosed its SMART Solutions, designed for ophthalmology. The new solution will feature its latest advancements in integrated and connected surgical technologies. https://www.businesswire.com/news/home/20211108005426/en/Alcon-Unveils-Latest-Evolution-of-Cataract-Integration-and-Connectivity-at-AAO-2021
Chapter 1. Ocular Implants Market- Scope & Methodology
1.1 Market Segmentation
1.3 Research Methodology
1.4 Primary Sources
1.5 Secondary Sources
Chapter 2. Ocular Implants Market- Executive Summary
2.1 Market Size & Forecast – (2023 – 2030) ($M/$Bn)
2.2 Key Trends & Insights
2.3 COVID-19 Impact Analysis
2.3.1 Impact during 2023 – 2030
2.3.2 Impact on Supply – Demand
Chapter 3. Ocular Implants Market- Competition Scenario
3.1 Market Share Analysis
3.2 Product Benchmarking
3.3 Competitive Strategy & Development Scenario
3.4 Competitive Pricing Analysis
3.5 Supplier - Distributor Analysis
Chapter 4. Ocular Implants Market- Entry Scenario
4.1 Case Studies – Start-up/Thriving Companies
4.2 Regulatory Scenario - By Region
4.3 Customer Analysis
4.4 Porter's Five Force Model
4.4.1 Bargaining Power of Suppliers
4.4.2 Bargaining Powers of Customers
4.4.3 Threat of New Entrants
4.4.4 Rivalry among Existing Players
4.4.5 Threat of Substitutes
Chapter 5. Ocular Implants Market- Landscape
5.1 Value Chain Analysis – Key Stakeholders Impact Analysis
5.2 Market Drivers
5.3 Market Restraints/Challenges
5.4 Market Opportunities
Chapter 6. Ocular Implants Market- By Product
6.1 Intraocular lenses
6.2 Corneal implants
6.3 Orbital implants
6.4 Glaucoma implants
6.5 Ocular prosthesis
Chapter 7. Ocular Implants Market- By Application
7.1 Glaucoma surgery
7.3 Drug delivery
7.4 Age-related macular degeneration
7.5 Aesthetic purpose
Chapter 8. Ocular Implants Market- By End-User
8.2 Specialty eye institutes
Chapter 9. Ocular Implants Market– By Region
9.1 North America
9.4 Latin America
9.5 The Middle East
Chapter 10. Ocular Implants Market – Key players
10.1 Bausch & Lomb
10.3 Carl Zeiss
10.4 Johnson & Johnson
10.5 MORCHER GmbH
10.6 STAAR surgical
Every order comes with Analyst Support
We offer customization to cater your needs to fullest
We value Integrity, quality and authenticity the most


-Joyce Banda, the president of Malawi, lays a smackdown on Madonna.
-The New York Time Magazine may have a rockier road to a new editor than it imagined.
-If you like a little science fiction in your music, EMA’s new album may be for you.
-The trailer for Philip Seymour Hoffman’s “A Most Wanted Man.”
–Is this the end for the “Law & Order” franchise?
-And to come full circle, this “Mad Men” parody must be seen to be believed (caution for some strong language, if for some reason you are still watching in the office):


text:
This January, I was given the privilege of assisting in an orthopedic lab for a local PT program. I was present for 8 of the labs and had the opportunity to work with a number of great up-and-coming students. At the end of the semester, one of the students asked me “How do you tell your patients what is wrong with them? Do you use medical jargon?” I told him that I use medical jargon on a daily basis, but not without explaining exactly what the terms mean, how it relates to their functional impairments, and how we can address those impairments. I don’t do it to sound smart, I do it because demonstrating that you’re knowledgable can go a long way to getting a patient to put their trust in you and their recovery in your hands. But how much does what we say matter and how much does how we say it?
Depending upon which therapist you talk to, you’ll hear a variety of terms to classify or diagnose a musculoskeletal dysfunction, which greatly depends upon their training. Some elect to use pathoanatomic diagnoses (supraspinatus strain, meniscal tear, tendinitis, etc), while others choose to utilize syndromes (contractile dysfunction, articular dysfunction, derangement). Does the terminology matter? No, not in the big scheme of things so long as what you say conveys that you are knowledgable, understand what they are experiencing, and are fully capable of helping them return to their normal activities. This is where the how comes into play.
When you give someone a diagnosis or an explanation of why they’re in pain, how you present it makes all the difference. It can both make or break their plan of care. You can paint them a positive picture where recovery is both common and expected, or one in which recovery happens but is not expected. It’s all about your presentation. Let’s say you performed an initial evaluation of a patient who you suspect has a supraspinatus strain. How do you present this to the patient?
- Option A: “Mr. Smith, based your history and your examination findings I believe you have a supraspinatus strain. We see this fairly often in the clinic, but not everyone fully recovers. Some respond well to therapy and some don’t.”
- Option B: “Mr. Smith, based your history and your examination findings I believe you have a supraspinatus strain. The good news is, we see this fairly often in the clinic. The better news is, the majority of patients respond well to therapy and many will return to their normal activities.”
Which option inspires confidence in the physical therapy program and which inspires doubt? Both are similar and both promote a different outcome. What we say to our patients and how we say it have a profound effect on the efficacy of our physical therapy interventions. Never take for granted the power your words and attitude can have on a patient.
– Zachary Huff, DPT, PT

domain: medical


text:
An outstanding three-bedroom family residence is situated on the highly sought-after Rooksdown development in Basingstoke. This magnificent home presents an opportunity to acquire a dwelling of impeccable design and finish.
Upon entering, you are greeted by a spacious hallway elegantly designed with practicality in mind. Adjacent to this is a contemporary downstairs WC, and double sliding doors that lead to the kitchen/family area.
The heart of the home is undoubtedly on the ground floor - a beautifully designed kitchen/diner/family area, thoughtfully crafted with quartz worktops and ample space for dining and entertaining. To the rear of the property, there are double doors leading to the south-west facing garden.
Ascending to the first floor, you discover a generously-sized reception room, a family bathroom, and a light and airy bedroom.
Continuing to the second floor reveals the master suite, a bedroom complemented by an en-suite shower room, perfect for those who appreciate a bit of luxury. The second bedroom is also spacious, decorated with great taste, and features an additional bathroom.
Outside, there is driveway parking to the front of the property and a pathway leading to the front door. To the rear, there is an enclosed garden with an extended patio area, perfect for outdoor entertaining. The garden also includes a lawned area with raised flower beds.
In summary, this family home has been tastefully finished in one of Basingstoke's most sought-after locations. Early viewing is highly recommended to fully appreciate the property's many appealing features.
Council Tax Band D
These particulars are intended to give a fair description of the property but their accuracy cannot be guaranteed, and they do not constitute an offer of contract. Intending purchasers must rely on their own inspection of the property. None of the above appliances/services have been tested by ourselves. We recommend purchasers arrange for a qualified person to check all appliances/services before legal commitment.
Contact Basingstoke for more details
Share via social media


text:
This hotel deserved one star because of its location to the Masjid. The hotel was filthy, disgusting, and smelled worse than a barn. When we got into our hotel room there were dirty q-tips on the ground, the drawers smelled horrendous when you opened it, and everything seemed sticky. The hallway leading up to the room (Third floor) smelled like... More
- Reservation Options:
- TripAdvisor is proud to partner with Booking.com, Expedia, Hotels.com, Agoda, Orbitz, Odigeo, TripOnline SA and Despegar.com so you can book your Elaf Taiba Hotel reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Elaf Taiba Hotel Al Madinah/Medina

domain: travel


Kashmera Shah discussed nepotism in a new interview. She has stated that she dislikes people discussing nepotism and that it “doesn’t matter” if someone is talented. She also stated that if her sons, Rayaan and Krishaang, make their film debuts, it will be because it is in their blood rather than because of nepotism.
Kashmera made her film debut in 1996 with the film Yes Boss. Shah Rukh Khan and Juhi Chawla starred in the film. She went on to appear in a number of films, including Koi Kisi Se Kam Nahin, Pyar To Hona Hi Tha, Hindustan Ki Kasam, Kahin Pyaar Na Ho Jaaye, Aur Pappu Pass Ho Gaya, and many others.
Kashmera told Bollywood Hungama, “If someone talks against Bollywood or talks about nepotism, I take it personally because I am living proof that nepotism never matters.” I was good, so I got work, which helped me shine in this industry. As a result, I dislike hearing people speak out against it.”
Kashmera, who directed and produced Marne Bhi Do Yaaron in 2019, also revealed her next directorial project, Shriman Aishwarya Rai. “It’s also about friendship and the film industry,” she explained. I was sick of hearing people rail against the industry. I wanted to emphasise that in this industry, friendship is extremely important, and people genuinely care about one another. People are hired because they are good artists, not because they are someone’s sons or daughters. The latter also occurs. But that is irrelevant. Will you call it nepotism if my sons become actors tomorrow?
They may act or dance because it is in their blood. Furthermore, a doctor’s son is always a doctor. But for some reason, that’s acceptable.”
Kashmera has appeared on a number of reality television shows, including Bigg Boss, Steal Ur Girlfriend, Fear Factor: Khatron Ke Khiladi 4, and Iss Jungle Se Mujhe Bachao Am.


text:
Field edge management for game and wildlife conservation.
Farmers were questioned about the anticipated consequences of reducing herbicide use on cereal headlands, for the benefit of game and wildlife. Of the weed species thought likely to cause concern, Galium aparine was named by 59% of respondents, Bromus sterilis by 25%, and other species by less than 10%. A survey of weed incidence in 187 headlands and associated field boundaries on 17 farms showed that most species are characteristic of only one habitat type, but that G. aparine and B. sterilis, and the perennials Cirsium arvense, Elymus repens and Convolvulus arvensis, are common in both. For these species it appears that the field margin may act as a reservoir for field infestation. An experiment is described, in which the possibility of preventing such encroachment by treating a strip of soil between crop and hedge-bottom, with a residual herbicide, is investigated. The potential of this and other methods of weed management are discussed.

domain: literature


text:
Morning Watch 5/1/13
So King Solomon became richer and wiser than any other king on earth. (1 Kings 10:23 NLT)
You have more than the richest king on earth because I AM supplies you with everything.
We did not ask to go on a family vacation. In fact, we were repeatedly asked to accept the invitation. God blessed us with a demonstration that He fulfills his promise to give us more than we think to ask for. The gift was more than a vacation. Our extended family gave us love and encouragement to follow where God is leading. There is no amount of riches that can overshadow that.
“That is why I tell you not to worry about everyday life—whether you have enough food and drink, or enough clothes to wear. Isn’t life more than food, and your body more than clothing? Look at the birds. They don’t plant or harvest or store food in barns, for your heavenly Father feeds them. And aren’t you far more valuable to him than they are? Can all your worries add a single moment to your life? “And why worry about your clothing? Look at the lilies of the field and how they grow. They don’t work or make their clothing, yet Solomon in all his glory was not dressed as beautifully as they are. And if God cares so wonderfully for wildflowers that are here today and thrown into the fire tomorrow, he will certainly care for you. Why do you have so little faith? “So don’t worry about these things, saying, ‘What will we eat? What will we drink? What will we wear?’ These things dominate the thoughts of unbelievers, but your heavenly Father already knows all your needs. Seek the Kingdom of God above all else, and live righteously, and he will give you everything you need. “So don’t worry about tomorrow, for tomorrow will bring its own worries. Today’s trouble is enough for today. (Matthew 6:25-34 NLT)
“If God gives such attention to the appearance of wildflowers—most of which are never even seen—don’t you think he’ll attend to you, take pride in you, do his best for you? What I’m trying to do here is to get you to relax, to not be so preoccupied with getting, so you can respond to God’s giving. People who don’t know God and the way he works fuss over these things, but you know both God and how he works. Steep your life in God-reality, God-initiative, God-provisions. Don’t worry about missing out. You’ll find all your everyday human concerns will be met. (Matthew 6:30-33 MSG)
This is what the Lord says: “Don’t let the wise boast in their wisdom, or the powerful boast in their power, or the rich boast in their riches. (Jeremiah 9:23 NLT)
Teach those who are rich in this world not to be proud and not to trust in their money, which is so unreliable. Their trust should be in God, who richly gives us all we need for our enjoyment. (1 Timothy 6:17 NLT)
Pride leads to disgrace, but with humility comes wisdom. (Proverbs 11:2 NLT)


text:
LONDON -- The FTSE 100
Elsewhere, some companies fared quite a bit worse than this modest FTSE fall. Here are three constituents of the various indexes that took an early bath today.
High-street fashion chain Next was hit by an unexpected 6% fall this morning, dropping 210 pence to 3,369 pence after releasing results for the six months to July. The figures themselves were actually pretty good: Revenue was up 4.8% to 1.64 billion pounds, profit was up 10% to 251 million pounds, earnings per share was up 19% to 118.5 pence, and the interim dividend was lifted 12.7% to 31 pence.
But what dampened the enthusiasm was a warning that the second half has not started so well, with the company telling us that "August and early September sales have been disappointing during what has been an unusually quiet period." But full-year guidance has not changed, and a pre-tax profit of between 575 million pounds and 620 million pounds is still expected.
You might expect a chip designer whose wares make their way into Apple devices to be soaring after the release of the iPhone 5. But not so, as Imagination Technologies took a 6% tumble to 576 pence after releasing a trading update.
We were told that momentum from last year's strong performance has continued and that royalty revenue growth is carrying on as expected. So why did the shares fall? Maybe it was a brief mention of "macroeconomic volatility" and the "tight economic environment." Still, the price has risen almost 20-fold over the past four years, so shareholders shouldn't be complaining.
Shares in Home Retail, the owner of Argos and Homebase, slipped 2.7% to 96.7 pence after the release of a second-quarter update. This time, Argos held steady, which is a good result after a lengthy period of decline, so things could well be stabilizing at that division. But Homebase was hit by poor weather, with sales for the six months down 6.2% on last year.
After a couple of months of recovery, the shares are now offering a forecast dividend yield of 3.3% for the year to February, but on a forward price-to-earnings ratio of 17, they're not looking cheap.
If you don't like news of falling shares, investing in safe, dividend-paying companies the Neil Woodford way is a good way to go. The free Motley Fool report "8 Shares Held By Britain's Super Investor" takes a look at some of the legendary investor's major holdings. Click here to get your free copy while it's still available.
If you prefer the oil and gas sector as a place for your cash, the latest Motley Fool report, " How To Unearth Great Oil & Gas Shares ," is just for you. It's free for a limited time, so click here to get your personal copy.
Further Motley Fool investment opportunities:


SpaceX successfully launched its next-generation Starship rocket Wednesday in its first high-altitude test. The landing, however, was not so good.
Powered by three Raptor engines, the unmanned Starship SN8 prototype soared into the sky from SpaceX’s test facility in Boca Chica, Texas, in the late afternoon ET.
As planned, the vehicle reached an altitude of around 40,000 feet before its engines shut down so it could begin its descent. After performing an intentional “flip landing” maneuver in the air, the rocket’s engines fired up again to slow its descent when it arrived to land again at the launch site just over six minutes after lift-off.
But its speed of descent was too fast, and the prototype exploded into a fireball when it hit the ground with more force than expected. No one at the facility was injured.
Despite the unfortunate end of the prototype, SpaceX CEO Elon Musk was clearly delighted with the effort and tweeted: “We have all the data we needed!” and added: “Congratulations to the SpaceX team, yes!”
In explaining why the vehicle crashed and burned, Musk tweeted: “Fuelhead tank pressure was low during landing burn, causing touchdown speed to be high and RUD [rapid unscheduled disassembly]. “
Once the Starship technology is deemed ready, SpaceX aims to launch the spacecraft, which also acts as a second-stage booster, onto the massive first-stage Super Heavy rocket, which is powered by 31 Raptor engines.
The ultimate goal is to use the spacecraft and superheavy rocket as a fully reusable space transportation system capable of carrying up to 100 people and cargo to Earth orbit, the moon, Mars, and possibly beyond.
In fact, after the test, Musk tweeted: “Mars, here we go!” and “This is the gateway to Mars.” In October, the SpaceX chief said that an unmanned roundtrip to Mars could take place in 2024. It will be interesting to know if he has a new date in mind after this week’s test.
Before Wednesday’s high-altitude flight, the most basic Starship prototypes had undergone a series of pressure tests, as well as so-called “jump” tests that sent the vehicle a few hundred feet into the air before landing again in the ground, each with varying degrees of success.
As for Wednesday’s effort, SpaceX is clearly calling it a victory, as it continues to refine the technology ahead of the ambitious missions to come.


1 . Less than 45 KGS, we will send by express. (Door to Door, Convenient)
2 . 45 - 200 KGS , we will send by air transport . (Fastest and safest, but expensive)
3 . More than 200 KGS, we will send by sea . ( Cheapest and common use )
Our email: [email protected]
We specializes in providing KOYO NAO25X40X17 Bearings for many years, KOYO NAO25X40X17 has a large number of stock, a number of NAO25X40X17 Bearings KOYO suppliers and brand agency cooperation to meet your different NAO25X40X17 quality and different brand needs. Get detailed parameters can be sent to e-mail inquiry, and if you have any questions about this NAO25X40X17 bearing.
Manufacturer KOYO NAO25X40X17 bearing with high quality. FAG NAO25X40X17 Needle Roller 25x40x17mm Bearing |. We has been built up long-term cooperation with KOYO company, could make a bulk order of the bearings Which KOYO NAO25X40X17 is the most authentic, must choose BEARING POWER, what a whole variety, reasonable price, guaranteed quality, prompt delivery via Global express..1986 In Global stock for delivery within 3 - 7 working days. Easy ways to get the answers you need.
SKF NAO17x30x13 bearing. SKF NAO17x30x13, Size: SKF NAO17x30x13 bearing, Size: 17x30x13. SKF NAO17x30x13 are used in a wide variety of applications, they are simple in design, suitable for high speeds and are robust in operation, and need little maintenance.
NAO25x40x17. 6203T1X. NJ305. BL222. 6910L11-H-20DDU. NKS43. 6804LLU. B40-117AC3. NJ2228. 7040DB 16D/GNP4. 63204ZZ. N1010RXZTP. 6005ZZ. 6308LLBNR. 22334EK. SL014864. 24048EK30. NU1092-TB-M1. ... KOYO 6009-2RS bearing KOYO DAC4275W-13SH2CS79 bearing SKF NJ320ECM bearing TIMKEN A6067/A6157 bearing NSK B17-127D bearing NTN 6407Z bearing ...
ZWZ W6204 bearing: Zhejiang VVBearing Trade Co, Ltd specializes in providing W6204 Deep Groove Ball Bearings for many years, W6204 old code: bearing, size:(20 mm x 47 mm x 14 mm), has a large number of stock, a number of W6204 Deep Groove Ball Bearings ZWZ suppliers and brand agency cooperation, such as (NSK, SKF, FAG, INA, timken, koyo etc.), to meet your different W6204 quality and different ...
INA NAO15X32X12 Bearing Lihsui Bearing Trade Co, Ltd professional providing INA NAO15X32X12 Bearing, has many years of experience, NAO15X32X12 size: IDxODxB(mm) (15x32x12), the old model: bearing, while also professional agency of NAO15X32X12 models of other brands of bearings, such as SKF, NSK, NTN , timken, FAG and other brands, the company has a lot of stock, would like to know the specific ...
koyo nao20x35x17 bearing are widely used in industrial drive, agriculture, compressors, motors and generators, construction, industrial fan, industrial transmission and other fields. koyo nao20x35x17 bearing can ensure high quality for more than 80% raw material of koyo nao20x35x17 bearing provided by the steel plant.
|$0 - $500||0%|
|$500 - $3000||5%|
|$3000 - $10000||10%|
|$10000+||10% ~ 50%|
|Timken NAO25X40X17 Bearing - Imported Timken Bearing|
|Koyo NRB Solid Race Caged Bearing (NAO35X50X17) - EACH|
|NAO20X35X17 KOYO Bearing big bearing store millions of bearing|
|NAO25X40X26 KOYO Bearing expert bearing bearing products|
|Timken NAO25X42X16 bearing in Zaire-Best Price And 5 - 7|
|Congo (Congo-Kinshasa) NAO15X32X12-IS1 - INA Bearing|
|NAO85X115X30 KOYO Bearing bearing stock genuine bearing expert|
|INA NAO25X42X32 bearing 25x42x32 | Needle Roller Bearing|
|NAO15X28X13 KOYO Bearing professional bearing agent bearing sale|
|NAO20X37X16 KOYO Bearing bearing agent consult bearing contact and get discount|
|NAO30X45X17 | INA NAO30X45X17 | INA Bearings Bournemouth|
|Rodamiento NAO40X55X17 INA 40x55x17 | Rodamientos de|
|【FAG 53407U bearing】Best Price And 5 - 7 Days|
|NAO35X55X40 KOYO Bearing bearing lowest price bearing online store|
|NANF207-20 FYH 4-Bolt Flange Unit Bearing, 1-1/4"|
|24032AX NACHI Bearing bearing professional agent price brand bearing|
|38.10x55.55x1.984 KOYO bearing NTA-2435 Thrust Needle|
|32310/55 NACHI Bearing price brand bearing bearing price size|
|INA NA6916 Roulements | NA6916 80x110x54 Taille - Lishui|
|6914VV - NSK Thin Section - Quality Bearings|
|NK18X28X20 NTN Bearing bearing marketplace hot sales bearing|
|30238U Tapered roller bearings : NTN-SNR, Industry|
|78215C/78549D X1S-78215 TIMKEN Bearing bearing quick delivery all bearings type|
|580/574 TIMKEN Bearing quality bearing delivery world class bearing|
|*1982F/1924A/QVQ519 bearings,bearings *1982F/1924A/QVQ519|
|Axial deep 4123 groove ball bearings specifications|
|FAG 53202 Thrust Ball 15x32x13.3mm Bearing ||
|628/8-2Z -SKF Miniature Deep Groove – 8x16x5mm | TAT|
|W61906-2RZ SKF Bearing buy bearing high quality bearing price|
|K,81207TVP KOYO Bearing bearing sale inquiry bearing precision quality|


text:
For refreshment, one drink reigns supreme. Coconutea is a unique combination of premium green tea, natural fruit flavours and the nutrient and mineral packed water from the majestic King Coconut. That’s it. Nothing artificial. We’re organic and vegan.
Chill it. Shake it. And go King Coconutty!
meet the royal family
Choose from six flavours – a subtle hint of lemon, peach, pineapple, soursop, passion fruit or strawberry.
Or go king coconutty and stock up with all six!
well, well, well…
It seems we’ve created one of the healthiest drinks on the market.
Indigenous to Sri Lanka, the majestic King Coconut contains a remarkable liquid that locals reverently refer to as ‘the fluid of life’.
Prized for its health enhancing properties, King Coconut water is a wonderfully rich source of natural nutrients and minerals, including potassium and iron.
We blend King Coconut water with premium green tea (a natural source of things like polyphenols and flavonoids) hand-picked from the finest estates on the island.
Finally, to make our unique organic blend extra special, we add natural fruit flavours to ensure everyone has the chance to pick a favourite.
a gem, discovered in Sri Lanka, that we’re proud to share with the world
wow, what a journey…
We set off on a mission to discover something extra special to add to our current range of rare artisanal teas and ended up unearthing something beyond our wildest expectations.
It’s a fusion, developed by one of our master tea sommeliers, of premium green tea, natural fruit flavours and (here comes the special bit) water from the Sri Lankan King Coconut.
Created by nature solely for drinking and containing far less sugar than the common green coconut, King Coconut water is a mainstay of Ayurvedic medicine. Better still, it’s one of the planet’s most re-hydrating liquids – packed with a staggering range of naturally occurring organic nutrients and minerals (and when we say staggering, we mean it. Just try fitting a list of them all on the back of a bottle!).
Once we discovered the remarkable, health-enhancing properties of King Coconut water, we knew we’d have something extra special if we combined it with our premium green tea and natural fruit flavours.
So that’s just what we did. And we soon realised we’d created a health drink that not only tastes great, but lifts mind, body and soul.
We’d created ‘Coconutea’. A Superfood in a bottle.
It will put a spring in your step and a smile on your face – and once you’ve tried your first Coconutea the only thing you may prefer is a different flavour!
chill it. shake it.
and go King Coconutty!
You can do anything when you’re feeling fit and healthy. And, we believe nothing will make you feel better than a Coconutea.
Thanks to its great, refreshing taste and the unique combination of naturally occurring minerals and nutrients, it’s the perfect, healthy alternative to all the sugar filled soft drinks lining the shelves.
So shake things up and get active, or simply chill-out with a cool bottle of your favourite flavour close to hand.
It won’t just refresh your body – it will refresh your appetite for life.
register your interest
Complete the form below to register your interest in our products.

domain: health


Central Air Conditioning Repair in Mobile, AL
- No obligation to purchase
- Free cancellations
- Trusted by over 2 million customers each year!
Find Local Central Air Conditioning Repair with Modernize
Your HVAC system is responsible for delivering optimum comfort year-round. Create an eco-friendly home. Talk to contractors that can help you select, install, care for, and maintain HVAC solutions for your home.
Modernize is here to help if it's time to replace your HVAC and you need central air conditioning repair in Mobile, AL. We are proud of what we do. We want to connect our homeowners to the best local HVAC system contractors in a quick and easy process. It is always smart to compare at least four different price quotes from contractors to make sure you are getting the best local prices on installation services.
Let us help you compare estimates from local contractors to get the best HVAC prices today!


Intuit is using this week's Google I/O development conference to 'reimagine' its GoPayment mobile credit card processing application using near field communications technology.
Just imagine, one day these transactions could be so much simpler and faster. Just hand over the cash!
Basic £130-140K OTE £250K (no ceiling)London based and across EMEA
© Finextra Research 2014