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PURPOSE: PGF(2α) analogs are commonly used to treat glaucoma and are associated with higher rates of meibomian gland dysfunction (MGD). The purpose of this study was to evaluate the physiological effects of PGF(2α) and PGE(2) on immortalized human meibomian gland epithelial cells (HMGECs). METHODS: HMGECs were immunostained for the four PGE(2) receptors (EP1, EP2, EP3, EP4) and the one PGF(2α) receptor (FP) and imaged. Rosiglitazone-differentiated HMGECs were exposed to PGF(2α) and PGE(2) (10(−9) to 10(−6) M) for three hours. Cell viability was assessed by an ATP-based luminescent assay, and lipid extracts were analyzed for cholesteryl esters (CEs), wax esters (WEs), and triacylglycerols (TAGs) by ESI-MSMS(ALL) in positive ion mode by a Triple TOF 5600 Mass Spectrometer using SCIEX LipidView 1.3. RESULTS: HMGECs express three PGE(2) receptors (EP1, EP2, EP4) and the one PGF(2α) receptor (FP). Neither PGE(2) nor PGF(2α) showed signs of cytotoxicity at any of the concentrations tested. WEs were not detected from any of the samples, but CEs and TAGs both exhibited a diverse and dynamic profile. PGE(2) suppressed select CEs (CE 22:1, CE 26:0, CE 28:1, CE 30:1). PGF(2α) dose dependently increased several CEs (CE 20:2, CE 20:1, CE 22:1, CE 24:0) yet decreased others. Both prostaglandins led to nonspecific TAG remodeling. CONCLUSION: PGE(2) and PGF(2α) have minimal effect on HMGEC viability. PGF(2α) influences lipid expression greater than PGE(2) and may do so by interfering with meibocyte differentiation. This work may provide insight into the mechanism of MGD development in glaucoma patients treated with PGF(2α) analogs.

[Image: see text] A novel series of pyridones were discovered as potent EP3 antagonists. Optimization guided by EP3 binding and functional assays as well as by eADME and PK profiling led to multiple compounds with good physical properties, excellent oral bioavailability, and a clean in vitro safety profile. Compound 13 was identified as a lead compound as evidenced by the reversal of sulprostone-induced suppression of glucose-stimulated insulin secretion in INS 1E β-cells in vitro and in a rat ivGTT model in vivo. A glutathione adduction liability was eliminated by replacing the naphthalene of structure 13 with the indazole ring of structure 43.

Introduction. This current survey attempts to explore university teachers and students’ perception of using social media to promote an authentic learning environment. Materials and Methods. To this end, 249 university teachers and 329 students participated in the survey where they were asked to compete of 27 items of A Social Media Authentic Learning Environment Inventory (SOMALEVI). Statistical Rasch analyses using Winstep software were performed to evaluate both teachers and students’ responses. Results. Findings of the study showed that participants spent most of their time daily on WhatsApp, Facebook, Instagram and Twitter, respectively with most access was made from their mobile phones. Most of the participant showed positive views about the use of social media to promote authentic learning environment (Nteachers = 247, 99 %; Nstudents = 309, 93.9 %) while the rests showed their negative perception. The majority of those who perceive positive are female (64.53 %) aged range 21-30 years (32.18 %). Findings also indicate that social media provided opportunities for students to share their experiences and learning activities (MR1, LVI = -0.97), to offer students the opportunity to learn from experts (EP1, LVI = -0.82) so that they were able to obtain a lot of insight on particular issues (EP3, LVI = -0.70). It is interesting, but not surprising that both teachers and students found that social media benefited them with learning resources such as video, demonstration, learning files, allowing students to comprehend the learning materials (EP2, LVI = -0.85). However, the study identified some critical issues regarding the use of social media for authentic learning environment, such as unsuitable real- life representation, difficulty to collaborate with others, and difficulty in recognising their learning potential.

Summary ERECTA PANICLE 3 (EP3) and ORYZA SATIVA F‐BOX KELCH 1 (OsFBK1) proteins share 57% and 54% sequence identity with the Arabidopsis F‐box protein HAWAIIAN SKIRT (HWS). Previously we showed that EP3 is a functional orthologue of HWS. Here we demonstrate that OsFBK1 is another functional orthologue of HWS and show the complexity of interaction between EP3 and OsFBK1 genes at different developmental stages of the plant. qRT‐PCR expression analyses and studies of EP3‐GFP and OsFBK1‐RFP promoter reporter lines demonstrate that although EP3 and OsFBK1 expression can be detected in the same tissues some cells exclusively express EP3 or OsFBK1 whilst others co‐express both genes. Loss, reduction or gain‐of‐function lines for EP3 and OsFBK1, show that EP3 and OsFBK1 affect plant architecture, organ size, floral organ number and size, floral morphology, pollen viability, grain size and weight. We have identified the putative orthologue genes of the rice microRNA pathway for ORYZA SATIVA DAWDLE (OsDDL) and ORYZA SATIVA SERRATE (OsSE), and demonstrated that EP3 and OsFBK1 affect their transcript levels as well as those of CROWN ROOT DEFECT 1/ORYZA SATIVA Exportin‐5 HASTY (CRD1/OsHST), ORYZA SATIVA DICER‐LIKE 1 (OsDCL) and ORYZA SATIVA WEAVY LEAF1 (OsWAF1). We show that EP3 affects OsPri‐MIR164, OsNAM1 and OsNAC1 transcript levels. OsNAC1 transcripts are modified by OsFBK1, suggesting two independent regulatory pathways, one via EP3 and OsMIR164 and the other via OsFBK1. Our data propose that EP3 and OsFBK1 conjointly play similar roles in rice to how HWS does in Arabidopsis.

Prostaglandin E2 (PGE2) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP1, EP2, EP3, and EP4) on T cells. Here, we comprehensively characterized PGE2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE2-regulated phosphosites and several important EP1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP2-stimulated CD8+ cells. EP2 and EP4, both of which signal through Gαs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE2-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.

Although recognized to have an in vivo vasodepressor effect blunted by the vasoconstrictor effect of E-prostanoid receptor-3 (EP3), prostaglandin E2 (PGE2 ) evokes contractions of many vascular beds that are sensitive to antagonizing the thromboxane prostanoid receptor (TP). This study aimed to determine the direct effect of PGE2 on renal arteries and/or the whole renal vasculature and how each of these two receptors is involved in the responses. Experiments were performed on isolated vessels and perfused kidneys of wild-type mice and/or mice with deficiency in TP (TP-/- ), EP3 (EP3-/- ), or both TP and EP3 (TP-/- /EP3-/- ). Here we show that PGE2 (0.001-30 μM) evoked not only contraction of main renal arteries, but also a decrease of flow in perfused kidneys. EP3-/- diminished the response to 0.001-0.3 μM PGE2 , while TP-/- reduced that to the prostanoid of higher concentrations. In TP-/- /EP3-/- vessels and perfused kidneys, PGE2 did not evoke contraction but instead resulted in vasodilator responses. These results demonstrate that PGE2 functions as an overall direct vasoconstrictor of the mouse renal vasculature with an effect reflecting the vasoconstrictor activities outweighing that of dilation. Also, our results suggest that EP3 dominates the vasoconstrictor effect of PGE2 of low concentrations (≤0.001-0.3 μM), but its effect is further added by that of TP, which has a higher efficacy, although activated by higher concentrations (from 0.01 μM) of the same prostanoid PGE2 .

OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. The addition of TTFields resulted in a significant improvement in overall survival. However, most GBM patients eventually develop resistance to TTFields and the mechanism remains unexplored. METHODS Multiple GBM cell lines were treated continuously at clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay, stemness markers such as CD44 and increased tumorigenesis when implanted into mouse brain. Using an innovative computational platform-NETZEN, we methodically dissected this stemness program in resistant cells. 3 networks were found disrupted and all play critical roles in GBM stemness. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked regulator responsible for resistance. PTGER3 is rapidly upregulated both in vitro and in vivo upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Immunofluorescence staining shows PTGER3’s nuclear translocation along with Lamin A/C disruption in response to TTFields. Pharmacological inhibition of PTGER3 using aspirin or PTGER3-specific inhibitors resensitized or prevent cells becoming resistance to TTFields. CONCLUSIONS We have identified a novel regulator PTGER3 at the apex that plays a critical role in TTFields resistance. This is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.

The aim of this study was to evaluate the prognostic impact of prostaglandin E2 receptor 3 (EP3) receptor expression might have on the two different breast cancer entities: multifocal/multicentric versus unifocal. As the prognosis determining aspects, we investigated the overall- and disease-free survival by uni-and multivariate analysis. To underline the study&rsquo, s conclusion, we additionally considered the histopathological grading and the tumor node metastasis (TNM) staging system. A retrospective statistical analysis was performed on survival related events in a series of 289 sporadic breast cancer (BC) patients treated at the Department of Obstetrics and Gynecology at the Ludwig&ndash, Maximillian&rsquo, s University in Munich between 2000 and 2002. The EP3 receptor expression was analyzed by immunohistochemistry and showed to have a significantly positive association with breast cancer prognosis for both entities, although with major differences. Patients with unifocal BC with EP3 receptor expression showed a significant improved overall survival, in contrast to the patient cohort with multifocal/multicentric BC. In this group, EP3 expression revealed its positive impact merely five years after initial diagnosis. Underlining the positive influence of EP3 as a positive prognosticator notably for unifocal breast cancer, only this patient cohort showed favorable outcomes in staging and grading. Especially EP3 expression in unifocal breast cancer was identified as an independent prognostic marker for the overall survival, when adjusted for age, grading, and staging. Altogether, our results strengthen the need to further investigate the behavior of EP3 in breast cancer and understand why markers linked to inflammation show different effects on prognosis and clinicopathological parameters on each focality type.

This review article provides an update for the role of prostaglandin E2 receptors (EP1, EP2, EP3 and EP4) in cardiovascular disease. Where possible we have reported citations from the last decade although this was not possible for all of the topics covered due to the paucity of publications. The authors have attempted to cover the subjects of ischemia–reperfusion injury, arrhythmias, hypertension, novel protein binding partners of the EP receptors and their pathophysiological significance, and cardiac regeneration. These latter two topics bring studies of the EP receptors into new and exciting areas of research that are just beginning to be explored. Where there is peer-reviewed literature, the authors have placed particular emphasis on clinical studies although these are limited in number.

INTRODUCTION TTFields, a novel approved therapy for GBM, employ alternating intermediate-frequency electric fields to disrupt mitotic macromolecules leading to chromosome mis-segregation and apoptosis. The addition of TTFields significantly improves survival. However, most patients eventually develop resistance to TTFields through an unknown mechanism. METHODS Multiple human GBM cell lines were treated with TTFields continuously using Inovitro, an in vitro TTFields system, until cells with relative resistance to killing by TTFields emerged. Temporal gene expression profiles were analyzed using NETZEN, an innovative deep-learning and gene network-based ranking computational algorithm, to identify resistance pathways, followed by experimental validation. RESULTS PTGER3, a Gαi-protein-coupled cell surface receptor, is the top ranked master regulator in the predicted resistance program, which is upregulated in GBM cells within 24 hrs of exposure to TTFields and further reinforced as resistance sets in. Forced expression of PTGER3 in sensitive GBM cells confers relative resistance to TTFields, while PTGER3 depletion in resistant cells re-sensitizes them to TTFields. Most importantly, pharmacological inhibition of PTGER3 using either aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors effectively prevent resistance from developing. Mechanistically, PTGER3 is rapidly translocated from the plasma membrane to the nucleus after TTFields exposure, where it interacts with ZNF488, a stemness transcription factor tightly linked to PTGER3 in our predicted network to initiate and maintain the resistance program. Indeed, TTFields resistance is associated with a transition to glioma stem cells (GSCs) as determined by increased neurosphere formation and orthotopic tumorigenesis in immunocompromised mice, and PTGER3 inhibition alone reverses the GSC transition leading to improved tumor control and survival. CONCLUSIONS PTGER3 is at the apex of a novel pathway that indispensably regulates TTFields resistance through a unique mechanism involving the physical nuclear translocation of this 7-transmembrane receptor. PTGER3 and its pathway are thus potential therapeutic targets to enhance therapeutic efficacy of TTFields.

A novel series of pyridone-based EP3 receptor antagonists was optimized for good physical properties and oral bioavailability in rodents. The lead compounds 3h, 3l and 4d displayed good in vitro profiles, moderate to good metabolic stability and good rodent PK profiles with low clearance, high oral exposure and acceptable half-life.

OBJECTIVES Tumor Treating Fields (TTFields) are approved in combination with temozolomide for newly diagnosed glioblastoma (GBM). The addition of TTFields resulted in a significant improvement in overall survival. TTFields are low-intensity alternating electric fields that are thought to disturb mitotic macromolecules’ assembly. However, most GBM patients eventually develop resistance to TTFields. The mechanism of TTFields resistance remains largely unexplored. Understanding how GBM cells circumvent the biophysical forces of TTFields and their downstream effects will improve therapeutic efficacy of this novel anti-cancer treatment modality. METHODS A panel of GBM cell lines were treated continuously with TTFields at the clinically approved frequency of 200 kHz using an in vitro TTFields system until cells with relative resistance to the cytotoxic effects of TTFields. A systems approach aided by innovative network ranking computational algorithms were utilized to analyze global gene expression profiles and identify resistance pathways, which were subsequently validated experimentally. RESULTS TTFields-induced chromosomal instability such as the formation of cytoplasmic micronuclei is preserved in resistant cells, indicating that TTFields resistance is mediated through a non-biophysical mechanism. This acquired TTFields resistance phenotype is associated with a transition of GBM cells to a stem-like state as determined by a neurosphere assay. Using an innovative computational platform, we methodically dissected this stemness program in resistant cells. Mechanistically, Prostaglandin E Receptor 3 (PTGER3) is the top ranked master regulator responsible for resistance. PTGER3 is rapidly upregulated in GBM cells upon exposure to TTFields and further increases with prolonged treatment as resistance sets in. Pharmacological inhibition of PTGER3 either using aspirin to reduce prostaglandin E production or PTGER3-specific inhibitors resensitized cells to TTFields. CONCLUSIONS We have identified a novel pathway with PTGER3 at the apex that plays a critical role in TTFields resistance. This pathway is a potential therapeutic target to reduce resistance to TTFields therapy in GBM.

Synthesis of BiFeO3-BaFe12O19 solid solution is aimed to enhanced magnetic properties of the material which can improve the quality of multiferroic properties of material. As we know that BiFeO3 is a multiferroic material if it is in single phase but unfortunately it is difficult to produce BiFeO3 in single phase, which can cause a large current leakage arising from non stoichiometric. It used sol gel method to produce BiFeO3-BaFe12O19 solid solution with weight ratio of 1;1. To know magnetic properties, it was used permagraph test which is type of MPS magnet – Physic EP3 – Permagraph L . The sintering temperature was 750, 800 and 850oC for 8, 10 and 12 hours respectively. There is no regularity in increasing and decreasing of remanent and coersivity properties with increasing sinter temperatures and time of sintering but there is an increasing magnetic energy with increasing sinter temperatures and time of sintering. The highest value of magnetic energy, 10.716 GkA/m belongs to powder sintered at 850oC for 12 hours.

A novel series of prostaglandin analogues with a seven-membered ring scaffold was designed, synthesized, and evaluated for the functional activation of prostaglandin receptors to identify potent and subtype-selective FP and EP3 dual agonists. Starting from the prostacyclin derivative 5b, a nonselective agonist for prostaglandin receptors, replacement of the core structure with an octahydro-2H-cyclopenta[b]oxepine scaffold led to the discovery of the potent and selective FP and EP3 dual agonist 11b as a lead compound for the development of an antiglaucoma agent.

Background/aims ONO-9054 is being developed for the reduction of intraocular pressure (IOP) in patients with ocular hypertension (OHT) and open-angle glaucoma (OAG). This study compared the novel dual EP3/FP agonist ONO-9054 with the FP agonist Xalatan. Methods Adults (n=123) with bilateral mild/moderate OAG or OHT, with unmedicated IOP of ≥24 mm Hg at 8:00 hours, ≥21 mm Hg at 10:00 hours and ≤36 mm Hg, were randomised 1:1 to receive ONO-9054 (0.003%, 30 μg/mL) or Xalatan (0.005%, 50 μg/mL) once daily for 28 days. Results Day 29 mean diurnal IOP was −7.2 mm Hg for ONO-9054 vs −6.6 mm Hg for Xalatan. At 08:00 hours, the IOPs were comparable, and at all later time points the decrease in IOP was greater for ONO-9054. On day 29, the odds of a mean IOP reduction of ≤−25%, ≤−30% and ≤−35% for ONO-9054 were 2.39, 2.37 and 4.85 times more, respectively, than the odds for Xalatan (p

Stevens–Johnson syndrome (SJS) is an acute inflammatory vesiculobullous reaction of the skin and mucosa, such as the ocular surface, oral cavity, and genitals. In patients with extensive skin detachment and a poor prognosis, the condition is called toxic epidermal necrolysis (TEN). Severe ocular complications (SOCs) appear in some—but not all—SJS/TEN patients who are diagnosed by dermatologists, and cold medicines including multi-ingredient cold medications and nonsteroidal anti-inflammatory drugs are the main causative drugs particularly for SJS/TEN with SOCs and all SJS and TEN. In this review, we focus on the genetic predisposition of cold medicine-related SJS/TEN (CM-SJS/TEN) with SOCs. CM-SJS/TEN with SOCs was strongly associated with HLA-A*02:06 and significantly associated with HLA-B*44:03 in Japanese individuals, significantly associated with HLA-B*44:03 in Indian and Brazilian individuals, and associated with HLA-A*02:06 in Korean individuals. In the first genome-wide association study (GWAS), we found an association between the prostaglandin E receptor 3 (PTGER3) gene and SJS/TEN with SOCs. In this study, we focused on CM-SJS/TEN with SOCs and found that the association of CM-SJS/TEN with SOCs became stronger than all SJS/TEN with SOCs. In the second GWAS, we found an association between the IKZF1 gene and CM-SJS/TEN with SOCs not only in Japanese, but also in Korean and Indian populations. Moreover, we found that TSHZ2 gene single nucleotide polymorphisms (SNPs) also showed especially low p values in the Japanese population; however, this association was not found in the Korean population. Furthermore, we investigated the interaction between susceptibility genes, and found multiplicative interactions of HLA-A*02:06 and TLR3 SNPs and additive interactions of HLA-A*02:06 and PTGER3 SNPs.

The aim of these studies was to assess the influence of prostaglandin E2 (PGE2) on the production of interferon-gamma (IFN-γ) by bovine CD4(+), CD8(+), and WC1(+) T cells and furthermore, should this effect exist, to identify the E-prostanoid (EP) receptor subtype(s) responsible for this influence. We here report that exposure of bovine peripheral blood mononuclear cells (PBMCs) to PGE2 significantly and dose-dependently decreased the percentage of IFN-γ-producing CD4(+) and CD8(+) T cells. It was also shown that PGE2 reduced IFN-γ production by WC1(+) T cells, but this effect was not dose dependent. The impairment of IFN-γ production should be recognized as an anti-inflammatory and immunosuppressive action, thus the obtained results confirm the paradoxical status of PGE2 as a proinflammatory factor with immunosuppressive activity. The blockade of EP1, EP2, EP3, and EP4 receptors did not prevent PGE2-induced reduction of IFN-γ production by CD4(+) and CD8(+) T cells, indicating that this effect of PGE2 is not mediated through EP receptors. On the contrary, the blockade of either EP2 or EP4 receptors, but not EP1 or EP3 receptors, prevented the PGE2-induced reduction of percentage of IFN-γ-producing WC1(+) T cells. These findings indicate that the ability of PGE2 to impair IFN-γ production by WC1(+) T cells is mediated via EP2 and EP4 receptors. These results suggest the possibility of pharmacological manipulation of IFN-γ production by WC1(+) T cells via selective antagonists and agonists of EP2 and EP4 receptors.

Novel prostaglandin E2 receptor 4 (EP4) agonists featuring a pyridone core and an allylic alcohol ω-chain were discovered. These agonists were shown to be selective over EP1, EP2 and EP3. Analogs harboring a 4-carboxylic acid phenethyl α-chain displayed improved potency over those containing an n-heptanoic acid chain. Key SAR relationships were also identified.

Prostaglandin-mediated inflammatory reactions play a major role in different cancers. Prostaglandin E2-receptor 3 (EP3) expression correlates with FIGO stages in cervical cancer and has been shown to be an independent prognostic factor for overall survival. EP3 expression levels in cervical intraepithelial neoplasia (CIN) as the precursor lesion of cervical cancer are currently unknown. EP3 expression was analyzed by immunohistochemistry in 124 patient samples (CIN 1–3 and healthy controls) using the IR-scoring system. Expression levels were correlated with clinical outcome to assess for prognostic relevance in patients with CIN 2. Data analysis was performed using Kruskal–Wallis and Mann–Whitney U test. EP3 expression levels significantly correlated with different grades of cervical dysplasia. Median EP3-IRS in healthy cervical tissue was 12 (n = 13) compared to 9 in CIN 1 (n = 38; p = 0.031 vs. healthy control), 6 in CIN 2 (n = 45; p

Sunscreens are widely prescribed and used to prevent skin cancer; however, they have been reported to contain various chemicals which mimic hormones and disrupt hormonal functioning in humans. The aim of this study was to develop topical nanogel for skin cancer prevention using an antioxidant compound quercetin (Qu) and inorganic titanium dioxide (TiO2). Two formulations of Qu nanocrystals were optimized with low and high concentration of drug using the Box-Behnken design with the quadratic response surface model and further homogenized with TiO2. Qu nanocrystal (0.08% and 0.12%) formulations showed a particle size of 249.65 ± 2.84 nm and 352.48 ± 3.56 nm with zeta potential of − 14.7 ± 0.41 mV and − 19.6 ± 0.37 mV and drug content of 89.27 ± 1.39% and 90.38 ± 1.81% respectively. Scanning electron microscopy (SEM) images showed rod-shaped nanocrystals with a particle size below 400 nm. Qu (0.08%), Qu (0.12%), Qu (0.12%) + TiO2 (5%), and Qu (0.12%) + TiO2 (15%) nanogels showed over 70% drug release with significantly (p

Gusts of wind with high speed can adversely affect the operation of the electric railway vehicles. These vehicles are able to move and to obtain a high performance, as long as the power supply is ensured. The variation of the vertical forces for maintaining contact between pantograph and catenary may cause interruption of the power supply of the electric railway traction vehicles. The placement of the capture equipment on the vehicle body determines appearance of aerodynamic forces acting on it. To see which are the vertical forces introduced by wind on active capture equipment, used at locomotives LE 060 EA of 5100 kW, we considered the EP3 type of pantograph as model. This was modelled at scale 1:1 taking into account the placement on the body of the locomotive. For the simulation of wind we considered three point values of its speed (10 m/s, 20 m/s, 30 m/s) and angle of eight values that are within the range of 0 deg – 180 deg. With the results of the simulation we have done a comparative analysis on the additional vertical forces introduced by wind for the cases analyzed.

Power supply the energy needed for locomotives and electric trains is performed by means of pantographs on the bodywork. These high performance producing vehicles in so far as the contact between the collector (pantograph) and the catenary (contact line) is achieved and maintained regardless of speed. Thanks to the constructive type of the pantograph and the location of the contact force varies in relation to speed and can give rise to phenomena of oscillators that enhances the vertical movements of the wire feeder. As such the problem is essential for a good current collection is dynamic in nature. The most favorable way of current collection is achieved when between full and contact wire can maintain contact through a permanent and constant contact, a situation difficult to achieve in practice because of the first bump of the contact line. Juddering movements in vehicle while walking to a modification of the contact pressure which, however, it was found that is negligible in relation to the wave-like movements of the contact line. This article has looked at what is the dynamic contact force variation where the pantograph is located on the body of the locomotive EP3 LE 060 EA of 5100 kW. For this I started from the constructive characteristics of the components of the pantograph.

This study was designed to determine the effect ofCarica papayaL. stem bark extracts on cholesterol concentration in rats induced with glibenclamide. A completely randomized design was used for the experiment which consisted of 6 treatment groups, each group consisted of four rats, as follows:1) KN (negative control, non-diabetic rats); KP, diabetic rats given glibenclamide 10 mg/kg body weight; EP 1, diabetic rats given 0 mg/kg body weight/day extract; EP2, diabetic rats given 100 mg/kg body weight/day extract; and EP3, diabetic rats given 200 mg/kg body weight/day extract, EP4, diabetic rats given 300 mg/kg body weight/day extract for 28 day. The results showed thatC. papayaL. stem bark extract decreased (PC. papayaL. stem bark extract had potential as anti-hypercholesterolemic in diabetic rats.

Animal welfare science is increasingly concerned with the promotion of positive emotions in animals, yet little is known about how to measure them. We examined whether ear postures in dairy cows were reliable indicators of a low arousal, positive emotional state. We conducted a total of 381, 15 min focal observations, across a group of 13 cows, using stroking as a positive stimulus. Each focal observation was comprised of three, 5 min segments; pre-stroking (baseline), stroking (stimulus), and post-stroking (post-stimulus). Throughout the focal observation, one researcher filmed the focal cow's ear on the side which was to be stroked, and a second researcher recorded the focal cow's behaviour. During the stroking segment the third researcher, who was present in the cow pen throughout, stroked the habituated cow on certain regions of their head, neck and withers for 5 min. Following this, the stroker left and the filming and behavioural observations continued for another 5 min (post-stroking segment). To eliminate extraneous variables we controlled for activity levels and other behaviours thought to be positive such as feeding. Prior to video analysis we identified four ear postures; an upright posture (EP1), a forward ear posture (EP2), a backward ear posture (EP3), and a hanging ear posture, where the ear fell loosely, perpendicular to the head (EP4). We then analysed the video footage to determine the duration of time spent in each of the four ear postures, and the number of ear posture changes performed during each segment. We performed One-Way ANOVA analyses, taking account of repeated measures, and found that EP1 and EP2 were performed for longer during the pre-stroking and post-stroking segments, than during the stroking segment (EP1; F (1.87 , 671.09) = 241.22, p F (1.86 , 668.87) = 39.09, p F (1.95 , 698.27) = 81.20, p F (1.65 , 591.02) = 169.98, p p p F (2 , 718) = 17.89, p These results suggest that relaxed ear postures are indicative of what is suggested to be a positive, low arousal emotional state in dairy cows and could therefore be a useful, non-invasive measure of emotional state when used by trained observers. The results need further validation with other stimuli and arousal levels, but they have the potential to be incorporated into on-farm welfare assessments.

The aim of this study was to investigate the effect of diet extruder conditions, such as feed-loading rate and screw speed, on growth performance and biochemical responses in olive flounder Paralichthys olivaceus. Over 8 wks, we used four identical diets (triplicated per treatment) with differing ratios of feed-loading rate (kg/h):screw speed (rpm/min) in a laboratory-scaled twin-screw extruder of 50:640, 80:640, 120:640, and 80:400, designated as EP1, EP2, EP3, and EP4, respectively. Screw speed impacted the buoyancy of experimental diets. Diets produced at a screw speed of 640 rpm/min floated for > 24 hrs, whereas those produced at a speed of 400 rpm/min sank between 10 s and 5 min. Fish that were fed EP1 and EP4 diets grew significantly faster than those fed EP2 and EP3 diets. Fish fed EP1 diets ate and gained weight most efficiently among treatments, a result that is likely to be related to feed-loading rate, i.e., ingredients extruded at a low feed-loading rate may have more time to cook in the pre-conditioner of the extruder. A cooked diet may be easier to digest in fish. Fish fed EP4 diets also showed significant weight gain, as compared to those fed EP2 and EP3 diets. However, we found no differences among treatments in proximate compositions of dorsal muscle, liver, and viscera of fish. Our results suggest that extruder conditions, may influence feed quality, impacting feed efficiency and growth of fish.

A bioflocculant M-1 produced by Enterobacter sp. EP3 was investigated with regard to its flocculanting characteristics and mechanism. 2.0 mg/l M-1 showed the maximum flocculating activity of 96% in 5.0g/l Kaolin suspension containing 8mM CaCl2 and that its flocculating activity was more than 80% in a wide pH range (4.0-12.0). Chemical analyses indicated that the biopolymer M-1 was mainly a polysaccharide, mainly consist of rhamnose and glucose with a molar ratio of 9:1. Infrared spectrophotometry showed the presence of carboxyl, hydroxyl and methoxyl groups in M-1 molecular. Flocculation of Kaolin suspension with M-1 acted as a model to explore the flocculating mechanism in which bridging mediated by Ca2+ was proposed as the primary action based on the experimental observations.

Nowadays, effect pigments are widely used in many printing industries. The colorful effects produced by light scattering of these types of pigments add an additional value to the prints and enhances the overall quality of color appearance. The aim of this study was to investigate the quality enhancement of printed specialty papers with various effect pigments in combination with offset inks. Four different effect pigments were used (one luster pigment-EP1, two interference pigments-EP2, EP3, and one multicolor pigment-EP4) as well as two types of paper substrates (film synthetic paper and wood-free paper). The effect pigments were overprinted on dried CMYK offset prints on both paper substrates. The following analysis were performed: scanning electron microscopy analysis of effect pigment particles, contact angles of papers and offset prints, Fourier transform infrared spectrocopy (FTIR), principal components analysis (principal components analysis (PCA)), and flop index analysis of overprinted effect pigments, and paper and print gloss. The results of the experiment indicate that effect pigments behaved differently on different printing substrates. From the FTIR and PCA, it was found that the different composition of effect pigments differently influence the behavior of these particles on the final prints. Effect pigments overprinted on offset CMYK inks on both paper substrates enhance print gloss, except interference pigment EP2 on film synthetic paper. It was also found that the ink color has the most pronounced influence on flop index, followed by the papertype and the type of effect pigment. Higher flop index was obtained at wood-free paper, especially by overprinted pigment EP2. © 2012 Wiley Periodicals, Inc. Col Res Appl, 38, 168–176, 2013.

Stress is a state of physiological or psychological strain caused by adverse stimuli; responses to stress include activation of the sympathetic nervous system, glucocorticoid secretion and emotional behaviors. Prostaglandin E(2) (PGE(2)), acting through its four receptor subtypes (EP1, EP2, EP3 and EP4), is involved in these stress responses. Studies of EP-selective drugs and mice lacking specific EPs have identified the neuronal pathways regulated by PGE(2). In animals with febrile illnesses, PGE(2) acts on neurons expressing EP3 in the preoptic hypothalamus. In illness-induced activation of the hypothalamic-pituitary-adrenal axis, EP1 and EP3 regulate distinct neuronal pathways that converge at the paraventricular hypothalamus. During psychological stress, EP1 suppresses impulsive behaviors via the midbrain dopaminergic systems. PGE(2) promotes illness-induced memory impairment, yet also supports hippocampus-dependent memory formation and synaptic plasticity via EP2 in physiological conditions. In response to illness, PGE(2) is synthesized by enzymes induced in various cell types inside and outside the brain, whereas constitutively expressed enzymes in neurons and/or microglia synthesize PGE(2) in response to psychological stress. Dependent on the type of stress stimuli, PGE(2) released from different cell types activates distinct EP receptors, which mobilize multiple neuronal pathways, resulting in stress responses.

This work presents the results of an experimental investigation concerning the low-velocity impact behavior of woven glass fiber epoxy matrix composite laminates. Experimental test were performed according to ASTM standards using an instrumented falling weight impact testing machine. Impact test were conducted to characterize the type and extent of the damage observed in laminate for range of thickness subjected to different impact velocities. Correlation of the residual indentation of the impacted specimens provides a criterion for the extent of the damage. As the impact energy was increased, the samples experienced one of two types of damages: a crack from the center of the laminate to the edge, or significant damage consisting of a dent localized in the region of impact. The history of relevant kinematical, dynamic and energetic quantities, both to synthesize the dependency of the energy parameters and force threshold values on the impact velocity are discussed.

Studies reported here are aimed to investigate the important structural features that characterize the human EP(3) antagonists. Based on the knowledge of low-energy conformation of the endogenous ligand, the initial hit analogs were prepared. Subsequently, a ligand-based lead optimization approach using pharmacophore model generation was utilized. A 5-point pharmacophore using a training set of 19 compounds spanning the IC(50) data over 4-log order was constructed using the HypoGen module of Catalyst. Following pharmacophore customization, using a linear structure-activity regression equation, a six feature three-dimensional predictive pharmacophore model, P6, was built, which resulted in improved predictive power. The P6 model was validated using a test set of 11 compounds providing a correlation coefficient (R(2)) of 0.90 for predictive versus experimental EP(3) IC(50) values. This pharmacophore model has been expanded to include diverse chemotypes, and the predictive ability of the customized pharmacophore has been tested.

With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs are expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, who display increased mortality and worse functional outcomes compared with younger patients. This study aimed to investigate the contribution of the prostaglandin E2(PGE2) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates ICH outcomes in young mice. Here, we show that EP3 receptor deletion results in 17.9 ± 6.1% less ICH-induced brain injury ( P < 0.05) and improves neurological functional recovery ( P < 0.01), as identified by lower neurological deficit scores, decreased resting time, and more gross and fine motor movements. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation and modulation of angiogenic and astroglial responses. Using this aged cohort of mice, we have confirmed and extended our previous results in young mice demonstrating the deleterious role of the PGE2-EP3 signaling axis in modulating brain injury and functional recovery after ICH, further supporting the notion of the EP3 receptor as a putative therapeutic avenue for the treatment of ICH.

We previously reported that PTGER3 (prostaglandin E receptor 3 (subtype EP3)) single-nucleotide polymorphisms (SNPs) were associated with Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). We also documented that approximately 80% of our SJS/TEN patients had taken cold medicines within several days before disease onset, and we thus designated them cold medicine-related SJS/TEN (CM-SJS/TEN) patients. Moreover, we reported that HLA-A*02:06 with TLR3 polymorphisms exerted more than additive effects in SJS/TEN with SOC. In this study, we focused on CM-SJS/TEN with SOC and analyzed the association with PTGER3 SNPs and an interactive effect between PTGER3 SNPs and HLA-A*02:06 in not only the Japanese but also the Korean population. In the Japanese population, PTGER3 SNP rs1327464 was most significantly associated with CM-SJS/TEN with SOC (G versus A; odds ratio (OR)=0.232, P=7.92×10(-10)), and we found an interaction with additive effects between HLA-A*02:06 and the high-risk genotypes PTGER3 rs1327464 GA or AA (OR=10.8, P=2.56×10(-7)). We also found a significant association between Korean CM-SJS/TEN with SOC and PTGER3 SNP rs1327464 (GG versus GA+AA, OR=0.246, P=0.00101), and we detected an additive effect between HLA-A*02:06 and the high-risk genotypes PTGER3 rs1327464 GA or AA (OR=14.2, P=5.58×10(-6)).

A chitinase-like 32 kDa acidic protein with a potential chitinase activity has been identified in the medium of embryogenic suspension cultures of Dactylis glomerata L. using an antiserum raised against endochitinase EP3 from Daucus carota L. The presence of this protein discriminates between Dactylis glomerata L. embryogenic and nonembryogenic suspension cultures and thus could be possibly used as a marker for embryogenic potential.

Mast cell degranulation can initiate an acute inflammatory response and contribute to the progression of chronic diseases. Alteration in the cellular programs that determine the requirement for mast cell degranulation would therefore have the potential to dramatically impact disease severity. Mast cells are exposed to increased levels of PGE2 during inflammation. We show that although PGE2 does not trigger the degranulation of dermal mast cells of young animals, in older mice, PGE2 is a potent mast cell stimulator. Intradermal administration of PGE2 leads to an EP3 receptor-dependent degranulation of mast cells, with the number of degranulated cells approaching levels observed in IgE- and Ag-treated controls. Taken together, these studies suggest that the ability of PGE2 to initiate mast cell degranulation changes in the aging animal. Therefore, elevated PGE2 levels might provide an important pathway by which mast cells are engaged to participate in inflammatory responses in the elderly patient.

Descriptions and figures of two new species of the genus Pseudo Berge & Vader, 2001 (Stegocephalidae: Stegocephalinae) are presented, but the two species are not given formal scientific names due to lack of material (both are only known by a single specimen each). However, the two new species have a significant impact on the classification and proposed phylogeny of the subfamily, as the two genera Pseudo Berge & Vader, 2001 and Schellenbergia Berge & Vader, 2001 now have to be considered synonymous. Pseudo is selected as the senior synonym. A discussion of the relationships among the genera of the subfamily Stegocephalinae is provided.

The reaction of tetraphosphorus trichalcogenides P4X3 (X=S, Se) with the electronically and coordinatively unsaturated 16 electron systems [(EP3)Rh]+ [E=N, NP3=tris(2-diphenylphosphanylethyl)amine, (1); E=P, PP3=tris(2-diphenylphosphanylethyl)phosphane, (2)] in tetrahydrofuran affords new tetraphosphorus trichalcogenide derivatives of formula [(EP3)Rh(P4X3)]CF3 SO3 [E=N; X=Se (3), S (5). E=P; X=Se (4), S (6)]. In the P4Se3 derivatives 3 and 4 the heptatomic cage is bound to the metal through the apical phosphorus atom. The P4S3 derivatives 5 and 6 are obtained as pairs of coordination isomers, with the cage linked to the metal either through the apical or through one of the basal P atoms; the former isomer is predominant and its amount depends on the nature of the trans-disposed apical donor (N or P) of the tripodal ligand. The monometal species [(NP3)Rh(η1-P4S3)]CF3SO3 (5) reacts with 1 affording the dimetal compound [{(NP3)Rh}2(μ,η1:1-Papical,-Pbasal-P4S3)](CF3SO3)2, where the cage exhibits both modes of bonding. All of the compounds have been characterized by 31P NMR spectra and elemental analyses.

In your current job, would you describe yourself as a "Brilliant Technology Innovator" or "Indentured Spice Monkey"? In the competitive and fast-paced semiconductor industry, most jobs require people to do at least a little (but more often a lot) of both. And your answer may change on a daily or hourly basis. But how do corporations, universities and the technologists at the heart of these organizations strike the right balance between blue-sky innovation and disciplined execution? What priorities and policies distinguish the industry leaders from the industry followers?