Studies on seminal prostaglandins

The lipid fraction of human semen has been separated by LH 20 Sephadex chromatography and TLC and the resulting fractions analysed by GCMS. Evidence is presented for the existence in semen of several prostaglandins, including 19 -OH PG F₁α, 19-OH PG F₂α, 8-iso 19-OH PG El, 8 -iso 19-OH PG E₂, 8 -iso PG F10, 8 -iso PG F20 , 8 -iso PG E₁ and 8-iso PG E₂. None of these compounds have previously been described in semen, and the first five have not been described from any source. Evidence is also presented for the existence of a group of prostaglandins isomeric with the dinor prostaglandins El₁, E₂, F₁α and F₂α. A method for the preparation of crystalline 19-OH PG E₁ from macaque semen is described. Evidence is presented for the existence of a pair of dihydroxy E prostaglandins, tentatively identified as 18,19 dihydroxy PG E₁ and an isomeric compound in the semen of the stump-tailed macaque. The effects of 19-OH PG E₁ on non-pregnant and pregnant human isolated myometrial strips have been studied. 19-OH PG E₁, like PG E₁, was found to relax non-pregnant strips, the equipotent molar ratio being E₁:19-OH E₁ = 1:4. 19-OH PG E₁ was also found to relax pregnant strips, unlike PG E₁, and a significant effect was demonstrated at 50 ng /ml. Examination of homogenates of the seminal vesicle of the stump tailed macaque by GCMS showed them to contain large amounts of 19-OH E prostaglandins, and these levels increased on incubation, an effect which was inhibited by indomethacin. Incubation of homogenates with radioactively-labelled eicosa-8,11,14-trienoic acid, arachidonic acid, PG E₁, PG E₂, PG F₂α or PG F₃α produced no significant incorporation of radioactivity into the 19-hydroxy prostaglandin fractions. It is concluded that the biosynthesis of 19-OH PGs takes place via a separate pathway from that leading to the classical prostaglandins. Some observations on dynamic aspects of seminal prostaglandin production in man are presented, along with the results of a study on the species distribution of the 19-hydroxy E prostaglandins

Regulation of Cytosolic Phospholipase A 2 Activation and Cyclooxygenase 2 Expression in Macrophages by the β-Glucan Receptor

Phagocytosis of non-opsonized microorganisms by macrophages initiates innate immune responses for host defense against infection. Cytosolic phospholipase A(2) is activated during phagocytosis, releasing arachidonic acid for production of eicosanoids, which initiate acute inflammation. Our objective was to identify pattern recognition receptors that stimulate arachidonic acid release and cyclooxygenase 2 (COX2) expression in macrophages by pathogenic yeast and yeast cell walls. Zymosan- and Candida albicans-stimulated arachidonic acid release from resident mouse peritoneal macrophages was blocked by soluble glucan phosphate. In RAW264.7 cells arachidonic acid release, COX2 expression, and prostaglandin production were enhanced by overexpressing the beta-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)-beta-D-glucan stimulated arachidonic acid release and COX2 expression, which were augmented in a Toll-like receptor 2 (TLR2)-dependent manner by macrophage-activating lipopeptide-2. However, arachidonic acid release and leukotriene C(4) production stimulated by zymosan and C. albicans were TLR2-independent, whereas COX2 expression and prostaglandin production were partially blunted in TLR2(-/-) macrophages. Inhibition of Syk tyrosine kinase blocked arachidonic acid release and COX2 expression in response to zymosan, C. albicans, and particulate (1, 3)-beta-D-glucan. The results suggest that cytosolic phospholipase A(2) activation triggered by the beta-glucan component of yeast is dependent on the immunoreceptor tyrosine-based activation motif-like domain of dectin-1 and activation of Syk kinase, whereas both TLR2 and Syk kinase regulate COX2 expression

Regulation of Cytosolic Phospholipase a\u3csub\u3e2\u3c/sub\u3e Activation and Cyclooxygenase 2 Expression in Macrophages by the β-Glucan Receptor

Phagocytosis of non-opsonized microorganisms bymacrophages initiates innate immune responses for host defense against infection. Cytosolic phospholipase A2 is activated during phagocytosis, releasing arachidonic acid for production of eicosanoids, which initiate acute inflammation. Our objective was to identify pattern recognition receptors that stimulate arachidonic acid release and cyclooxygenase 2 (COX2) expression in macrophages by pathogenic yeast and yeast cell walls. Zymosan- and Candida albicans-stimulated arachidonic acid release from resident mouse peritoneal macrophages was blocked by soluble glucan phosphate. In RAW264.7 cells arachidonic acid release, COX2 expression, and prostaglandin production were enhanced by overexpressing the β-glucan receptor, dectin-1, but not dectin-1 lacking the cytoplasmic tail. Pure particulate (1, 3)-β-D-glucan stimulated arachidonic acid release and COX2 expression, which were augmented in a Toll-like receptor 2 (TLR2)-dependent manner by macrophage-activating lipopeptide-2. However, arachidonic acid release and leukotriene C4 production stimulated by zymosan and C. albicans were TLR2-independent, whereas COX2 expression and prostaglandin production were partially blunted in TLR2-/- macrophages. Inhibition of Syk tyrosine kinase blocked arachidonic acid release and COX2 expression in response to zymosan, C. albicans, and particulate (1, 3)-β-D-glucan. The results suggest that cytosolic phospholipase A2 activation triggered by the β-glucan component of yeast is dependent on the immunoreceptor tyrosine-based activation motif-like domain of dectin-1 and activation of Syk kinase, whereas both TLR2 and Syk kinase regulate COX2 expression

Pathways Regulating Cytosolic Phospholipase a\u3csub\u3e2\u3c/sub\u3e Activation and Eicosanoid Production in Macrophages by Candida Albicans

Resident tissue macrophages are activated by the fungal pathogen Candida albicans to release eicosanoids, which are important modulators of inflammation and immune responses. Our objective was to identify the macrophage receptors engaged by C. albicans that mediate activation of group IVA cytosolic phospholipase A2 (cPLA2α), a regulatory enzyme that releases arachidonic acid (AA) for production of prostaglandins and leukotrienes. A comparison of peritoneal macrophages from wild type and knock-out mice demonstrates that the β-glucan receptor Dectin-1 and MyD88 regulate early release of AA and eicosanoids in response to C. albicans. However, cyclooxygenase 2 (COX2) expression and later phase eicosanoid production are defective in MyD88-/- but not Dectin-1-/- macrophages. Furthermore, C. albicans-stimulated activation of MAPK and phosphorylation of cPLA2α on Ser-505 are regulated by MyD88 and not Dectin-1. In contrast, Dectin-1 mediates MAPK activation, cPLA 2α phosphorylation, and COX2 expression in response to particulate β-glucan suggesting that other receptors engaged by C. albicans preferentially mediate these responses. Results also implicate the mannan-binding receptor Dectin-2 in regulating cPLA2α. C. albicans-stimulated MAPK activation and AA release are blocked by D-mannose and Dectin-2-specific antibody, and overexpression of Dectin-2 in RAW264.7 macrophages enhances C. albicans-stimulated MAPK activation, AA release, and COX2 expression. In addition, calcium mobilization is enhanced in RAW264.7 macrophages overexpressing Dectin-1 or -2. The results demonstrate that C. albicans engages both β-glucan and mannan-binding receptors on macrophages that act with MyD88 to regulate the activation of cPLA2α and eicosanoid production

On the Dialectics of Charisma in Marina Abramović’s The Artist is Present

While ‘charisma’ can be found in dramatic and theatrical parlance, the term enjoys only minimal critical attention in theatre and performance studies, with scholarly work on presence and actor training methods taking the lead in defining charisma’s supposed ‘undefinable’ quality. Within this context, the article examines the appearance of the term ‘charismatic space’ in relation to Marina Abramovic’s retrospective The Artist is Present at New York’s Museum of Modern Art in 2010. Here Abramovic uses this term to describe the shared space in which performer and spectator connect bodily, psychically, and spiritually through a shared sense of presence and energy in the moment of performance. Yet this is a space arguably constituted through a number of dialectical tensions and contradictions which, in dialogue with existing theatre scholarship on charisma, can be further understood by drawing on insights into charismatic leaders and charismatic authority in leadership studies. By examining the performance and its documentary traces in terms of dialectics we consider the political and ethical implications for how we think about power relations between artist/spectator in a neoliberal, market-driven art context. Here an alternative approach to conceiving of and facilitating a charismatic space is proposed which instead foregrounds what Bracha L. Ettinger calls a ‘matrixial encounter-event’: A relation of coexistence and compassion rather than dominance of self over other; performer over spectator; leader over follower. By illustrating the dialectical tensions in The Artist is Present, we consider the potential of the charismatic space not as generated through the seductive power or charm of an individual whose authority is tied to his/her ‘presence’, but as something co-produced within an ethical and relational space of trans-subjectivity

The magnetic field in the Milky Way filamentary bone G47

Funding: R.J.S. acknowledges funding from an STFC ERF (grant ST/N00485X/1).Star formation primarily occurs in filaments where magnetic fields are expected to be dynamically important. The largest and densest filaments trace the spiral structure within galaxies. Over a dozen of these dense (∼104 cm−3) and long (>10 pc) filaments have been found within the Milky Way, and they are often referred to as "bones." Until now, none of these bones has had its magnetic field resolved and mapped in its entirety. We introduce the SOFIA legacy project FIELDMAPS which has begun mapping ∼10 of these Milky Way bones using the HAWC+ instrument at 214 μm and 18′′.2 resolution. Here we present a first result from this survey on the ∼60 pc long bone G47. Contrary to some studies of dense filaments in the Galactic plane, we find that the magnetic field is often not perpendicular to the spine (i.e., the center line of the bone). Fields tend to be perpendicular in the densest areas of active star formation and more parallel or random in other areas. The average field is neither parallel nor perpendicular to the Galactic plane or the bone. The magnetic field strengths along the spine typically vary from ∼20 to ∼100 μG. Magnetic fields tend to be strong enough to suppress collapse along much of the bone, but for areas that are most active in star formation, the fields are notably less able to resist gravitational collapse.Peer reviewe

Preoperative chemoradiation with capecitabine, irinotecan and cetuximab in rectal cancer: significance of pre-treatment and post-resection RAS mutations

Background: The influence of EGFR pathway mutations on cetuximab-containing rectal cancer preoperative chemoradiation (CRT) is uncertain. Methods: In a prospective phase II trial (EXCITE), patients with magnetic resonance imaging (MRI)-defined non-metastatic rectal adenocarinoma threatening/involving the surgical resection plane received pelvic radiotherapy with concurrent capecitabine, irinotecan and cetuximab. Resection was recommended 8 weeks later. The primary endpoint was histopathologically clear (R0) resection margin. Pre-planned retrospective DNA pyrosequencing (PS) and next generation sequencing (NGS) of KRAS, NRAS, PIK3CA and BRAF was performed on the pre-treatment biopsy and resected specimen. Results: Eighty-two patients were recruited and 76 underwent surgery, with R0 resection in 67 (82%, 90%CI: 73–88%) (four patients with clinical complete response declined surgery). Twenty–four patients (30%) had an excellent clinical or pathological response (ECPR). Using NGS 24 (46%) of 52 matched biopsies/resections were discrepant: ten patients (19%) gained 13 new resection mutations compared to biopsy (12 KRAS, one PIK3CA) and 18 (35%) lost 22 mutations (15 KRAS, 7 PIK3CA). Tumours only ever testing RAS wild-type had significantly greater ECPR than tumours with either biopsy or resection RAS mutations (14/29 [48%] vs 10/51 [20%], P=0.008), with a trend towards increased overall survival (HR 0.23, 95% CI 0.05–1.03, P=0.055). Conclusions: This regimen was feasible and the primary study endpoint was met. For the first time using pre-operative rectal CRT, emergence of clinically important new resection mutations is described, likely reflecting intratumoural heterogeneity manifesting either as treatment-driven selective clonal expansion or a geographical biopsy sampling miss

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

Understanding the Relationship between Activity and Neighbourhoods (URBAN) Study: research design and methodology

<p>Abstract</p> <p>Background</p> <p>Built environment attributes are recognized as being important contributors to physical activity (PA) engagement and body size in adults and children. However, much of the existing research in this emergent public health field is hindered by methodological limitations, including: population and site homogeneity, reliance on self-report measures, aggregated measures of PA, and inadequate statistical modeling. As an integral component of multi-country collaborative research, the Understanding the Relationship between Activity and Neighbourhoods (URBAN) Study seeks to overcome these limitations by determining the strengths of association between detailed measures of the neighborhood built environment with PA levels across multiple domains and body size measures in adults and children. This article outlines the research protocol developed for the URBAN Study.</p> <p>Methods and design</p> <p>The URBAN Study is a multi-centered, stratified, cross-sectional research design, collecting data across four New Zealand cities. Within each city, 12 neighborhoods were identified and selected for investigation based on higher or lower walkability and Māori demographic attributes. Neighborhoods were selected to ensure equal representation of these characteristics. Within each selected neighborhood, 42 households are being randomly selected and an adult and child (where possible) recruited into the study. Data collection includes: objective and self-reported PA engagement, neighborhood perceptions, demographics, and body size measures. The study was designed to recruit approximately 2,000 adults and 250 children into the project. Other aspects of the study include photovoice, which is a qualitative assessment of built environment features associated with PA engagement, an audit of the neighborhood streetscape environment, and an individualized neighborhood walkability profile centered on each participant's residential address. Multilevel modeling will be used to examine the individual-level and neighborhood-level relationships with PA engagement and body size.</p> <p>Discussion</p> <p>The URBAN Study is applying a novel scientifically robust research design to provide urgently needed epidemiological information regarding the associations between the built environment and health outcomes. The findings will contribute to a larger, international initiative in which similar neighborhood selection and PA measurement procedures are utilized across eight countries. Accordingly, this study directly addresses the international priority issues of increasing PA engagement and decreasing obesity levels.</p

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin