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Research Snapshot ARTICLE
Usage of Mitogen-Activated Protein Kinase Small Molecule Inhibitors: More Than Just Inhibition!
- Institute of Molecular Pathobiochemistry, Experimental Gene, and Clinical Chemistry, RWTH Aachen University, Aachen, Germany
We have identified a phenomenon occurring in the usage of proposed "specific" Mitogen-activated protein kinase (MAPK) inhibitors. We found that especially inhibitors of p38 potentiate the activation of other MAPKs in various cell types. This finding will have tremendous impact on the interpretation of all former studies using MAPK inhibitors.
Most of the Mitogen-activated protein kinase (MAPK) inhibitors have highly different structures (Figure 1A). The p38 MAP kinase inhibitors SB203580 and SB242235 (Lee et al., 1994; Ward et al., 2002) as well as SP600125 targeting JNK1, JNK2, and JNK3 (Bennett et al., 2001) are commonly used. In addition, the MEK inhibitors UO126 selective for MEK1 and MEK2 (Favata et al., 1998), and PD98059 primarily targeting MEK1 and MEK2 with a more than 10-fold lower affinity (Dudley et al., 1995) are established compounds which have been tested extensively (Davies et al., 2000; Bain et al., 2003). In hepatology, these inhibitors have significantly contributed to the knowledge in the field in which MAPKs contribute to inflammation, fibrogenesis, and hepatocellular carcinoma (Borkham-Kamphorst and Weiskirchen, 2016).
Figure 1. Reciprocal activation of MAPK signalling by MAPK inhibitors. (A) Images of inhibitors used in this study were generated with software Jmol (version 14.2.15). (B) The reporter cell line HSC Col-GFP (left), primary hepatocytes (middle) and (activated) PMF (right) were stimulated for 10 min with PDGF-BB (25 ng/ml) after pre-incubation of cells with the indicated inhibitors (each 10 μM) for 1 h. Thereafter, proteins were extracted and subjected to Western blot analysis with the depicted antibodies. The inhibition of MAP kinases impacts PDGF responses as PD98059 and UO126 reduce pp42/44 phosphorylation. In addition, SP600125 blunts c-Jun activation, while SB203580 and SB242235 reduce STAT5 phosphorylation (data not shown). (C) Rat PMF were stimulated for 10 min with TGF-β1 (1 ng/ml) or PDGF-BB (25 ng/ml) after pre-incubation of cells with the depicted p38 inhibitors (each 10 μM) for 1 h. (D) Deduced impact of inhibitors on MAP kinase activity in cultured HSC Col-GFP. Antibodies used are from Santa Cruz (PDGF-Rβ, sc-432), Cell Signaling (pp42/pp44, CS-9101; p42/p44, CS-4696; pSAPK/JNK, CS-9251; SAPK/JNK, CS-9252; pc-Jun, CS-9261; JunB, CS-3753), BD Biosciences (pp38, 612288; p38, 612168), Millipore (pTyr, 05-321), Cymbus Biotechnology (α-SMA, CBL 171), and Sigma (β-actin, A5441), respectively. In this scheme, PDGF stands for PDGF-BB.
PDGF-BB is a potent mitogen for hepatic stellate cells (HSC) (Borkham-Kamphorst and Weiskirchen, 2016), and stimulation of HSC Col-GFP with PDGF-BB leads to activation of the three major MAP kinases (Figure 1B). As expected, the pre-treatment of cells with the MEK1/MEK2 inhibitors resulted in a direct reduction in ERK1/ERK2 MAPK phosphorylation, while SB203580 and SP600125 blunted MAPK activity as demonstrated by a reduction in substrate phosphorylation of STAT5 (p38, JNK) and c-Jun (JNK) (not shown).
Unexpectedly, blockade of p38 by SB203580 resulted in a significant increase in both ERK1/ERK2 and JNK phosphorylation. Likewise, the MEK1/2 inhibitors UO126 and PD98059 provoked increased phosphorylation of JNK and p38 (only UO126). Most sensitive to the application of small-molecule inhibitors was JNK that became activated by inhibitors targeting the p38 (SB203580) or ERK1/2 pathways. These results suggest that blocking of a MAP kinase by the corresponding inhibitor leads to a simultaneous activation of other MAPK-pathways driven by the same ligand. We found similar results in primary hepatocytes and primary (activated) portal myofibroblasts (PMF). In particular, these experiments revealed a strong stimulation of JNK and ERK phosphorylation in the presence of the p38 inhibitor SB203580. Moreover, the mutual "induction by inhibition" is also evident in PMF when the alternative p38 inhibitor SB242235 is used indicating that the finding is not an artefact of an individual inhibitor (Figure 1C). All experiments were highly reproducible (Supplementary Figure 1). In addition, we could show that not only MAPK phosphorylation itself but also substrate phosphorylation is increased which demonstrates a higher activity of non-targeted MAPKs (Supplementary Figure 2).
Materials and Methods
Isolation of primary cells (hepatocytes, PMF) and establishment of cell line HSC Col-GFP were done as described previously (Meurer et al., 2011, 2013; Borkham-Kamphorst et al., 2016). SDS-PAGE and Western blot analysis were done as reported (Borkham-Kamphorst et al., 2016).
The observation that a mutually "selective" MAPK-inhibitor becomes an activator of another MAPK-pathway physiologically stimulated by the same trigger has fundamental impact. Numerous reports have more or less uncritically applied MAPK inhibitors and concluded that a pathway targeted by a "specific" inhibitor is responsible for a biological effect. However, considering effects provoked by reciprocal activation loops challenge some of these studies. In our experimental setting, the influence of different small-molecule inhibitors resulted in dependencies depicted in Figure 1D.
It is obvious that the mutual "activation by inhibition" is not limited to straight forward MAPK-signaling network. Although we don't know if the phenomenon of cross-activation can be generalized when blocking one pathway, we think our observations must be critically kept in mind when interpreting experimental results mediated by a "specific" inhibitor.
Potential mechanisms of MAPK crosstalk and regulation by dual-specificity phosphatases under different conditions are discussed elsewhere (Birkenkamp et al., 2000; Shen et al., 2003; Junttila et al., 2008; Ríos et al., 2014).
This study was carried out in accordance with the recommendation of the Landesamt für Umwelt und Naturschutz (LANUV, Recklinghausen, Germany). The protocols for isolation of primary cells were approved by the LANUV.
Author Contributions
RW and SM designed the study and drafted manuscript.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
RW is financially supported by the German Research Foundation (projects SFB/TRR57 P13 and Q3) and the Interdisciplinary Center for Clinical Research (IZKF) at the University Hospital Aachen (Project O3-1).
Supplementary Material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2018.00098/full#supplementary-material
Bain, J., McLauchlan, H., Elliott, M., and Cohen, P. (2003). The specificities of protein kinase inhibitors: an update. Biochem. J. 371, 199–204. doi: 10.1042/bj20021535
Bennett, B. L., Sasaki, D. T., Murray, B. W., O'Leary, E. C., Sakata, S. T., Xu, W., et al. (2001). SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase. Proc. Natl. Acad. Sci. U.S.A. 98, 13681–13686. doi: 10.1073/pnas.251194298
Birkenkamp, K. U., Tuyt, L. M., Lummen, C., Wierenga, A. T., Kruijer, W., and Vellenga, E. (2000). The p38 MAP kinase inhibitor SB203580 enhances nuclear factor-kappa B transcriptional activity by a non-specific effect upon the ERK pathway. Br. J. Pharmacol. 131, 99–107. doi: 10.1038/sj.bjp.0703534
Borkham-Kamphorst, E., Steffen, B. T., Van de Leur, E., Tihaa, L., Haas, U., Woitok, M. M., et al. (2016). Adenoviral CCN gene transfers induce in vitro and in vivo endoplasmic reticulum stress and unfolded protein response. Biochim. Biophys. Acta. 1863, 2604–2612. doi: 10.1016/j.bbamcr.2016.07.006
Borkham-Kamphorst, E., and Weiskirchen, R. (2016). The PDGF system and its antagonists in liver fibrosis. Cytokine Growth Factor Rev. 28, 53–61. doi: 10.1016/j.cytogfr.2015.10.002.
Davies, S. P., Reddy, H., Caivano, M., and Cohen, P. (2000). Specificity and mechanism of action of some commonly used protein kinase inhibitors. Biochem J. 351, 95–105. doi: 10.1042/bj3510095
Dudley, D. T., Pang, L., Decker, S. J., Bridges, A. J., and Saltiel, A. R. (1995). A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc. Natl. Acad. Sci. U.S.A. 92, 7686–7689. doi: 10.1073/pnas.92.17.7686
Favata, M. F., Horiuchi, K. Y., Manos, E. J., Daulerio, A. J., Stradley, D. A., Feeser, W. S., et al. (1998). Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J. Biol. Chem. 273, 18623–18632. doi: 10.1074/jbc.273.29.18623
Junttila, M. R., Li, S. P., and Westermarck, J. (2008). Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J. 22, 954–965. doi: 10.1096/fj.06-7859rev
Lee, J. C., Laydon, J. T., McDonnell, P. C., Gallagher, T. F., Kumar, S., Green, D., et al. (1994). A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746. doi: 10.1038/372739a0
Meurer, S. K., Alsamman, M., Sahin, H., Wasmuth, H. E., Kisseleva, T., Brenner, D. A., et al. (2013). Overexpression of endoglin modulates TGF-β1-signalling pathways in a novel immortalized mouse hepatic stellate cell line. PLoS ONE 8:e56116. doi: 10.1371/journal.pone.0056116
Meurer, S. K., Tihaa, L., Borkham-Kamphorst, E., and Weiskirchen, R. (2011). Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling. Cell. Signal. 23, 683–699. doi: 10.1016/j.cellsig.2010.12.002
Ríos, P., Nunes-Xavier, C. E., Tabernero, L., Köhn, M., and Pulido, R. (2014). Dual-specificity phosphatases as molecular targets for inhibition in human disease. Antioxid. Redox Signal. 20, 2251–2273. doi: 10.1089/ars.2013.5709
Shen, Y. H., Godlewski, J., Zhu, J., Sathyanarayana, P., Leaner, V., Birrer, M. J., et al. (2003). Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. J. Biol. Chem. 278, 26715–26721. doi: 10.1074/jbc.M303264200
Ward, K. W., Proksch, J. W., Salyers, K. L., Azzarano, L. M., Morgan, J. A., Roethke, T. J., et al. (2002). SB-242235, a selective inhibitor of p38 mitogen-activated protein kinase. I: preclinical pharmacokinetics. Xenobiotica 32, 221–233. doi: 10.1080/00498250110100720
Keywords: inhibitors, signal transduction, PDGF-BB, mitogen-activated protein kinases, SB203580, SP600125, PD98059, UO126
Citation: Meurer SK and Weiskirchen R (2018) Usage of Mitogen-Activated Protein Kinase Small Molecule Inhibitors: More Than Just Inhibition! Front. Pharmacol. 9:98. doi: 10.3389/fphar.2018.00098
Received: 24 November 2017; Accepted: 29 January 2018;
Published: 12 February 2018.
Edited by:Dagmar Meyer zu Heringdorf, Goethe University Frankfurt, Germany
Reviewed by:Michael Kracht, Justus Liebig Universität Gießen, Germany
Philippe Lenormand, CNRS UMR7284, INSERM, Centre A. Lacassagne, Institute for Research on Cancer and Ageing of Nice, France
Copyright © 2018 Meurer and Weiskirchen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Steffen K. Meurer, email@example.com
Ralf Weiskirchen, email@example.com


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Student Employment
"Working for Res Living is all about the people, I am constantly surrounded by people that are supportive and genuinely enjoy what they do"
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Being a Resident Assistant has given me an inclusive & exciting place within the Office of Residential Living to explore and grow, while also allowing me to create spaces for my residents. I consider it an honor to serve my fellow students as a woman for others and to work with inspiring peers and engaging mentors."
—Antonina Caudill, Resident Assistant
Student team members are a key part of our office and are regularly engaging with our residents and guests throughout the entire year. Our office employs more than 300 students each year for a variety of roles. They include:
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Appointment terms, compensation and responsibilities vary with each position. Below are timelines for the primary hiring processes through our office.
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For the fall 2020 semester, the Office of Residential Living will have a limited number of student staff positions available. Review position descriptions below to find the role that best fits your needs:
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The Resident Assistant position is open to all rising sophomores, juniors, and seniors at Georgetown University. Resident Assistants serve as important leaders and resources within our residence halls, apartments, and townhouses. Resident Assistants create and execute social and educational programming in line with the University's Jesuit mission to help create a more meaningful living and learning environment. The time commitment is approximately 20 hours each week that consists of programming, team and individual meetings, serving in an on-call duty rotation, and other responsibilities as needed. Each Resident Assistant serves anywhere from 50-100 residents. This position directly reports to the Community Director of the assigned community. Resident Assistants are compensated for their contributions with full room and board costs.
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Corn oats semolina pancakes Recipe. We have made the Semolina Corn Pancakes in mini uttapa moulds, so that it will look as appetizing as it tastes, and will seem attractive to kids too. Common but well-chosen ingredients like onions and green chillies add a touch of crunch and spice to the pancakes, while curds in the semolina batter. Easy healthy pancakes with oats and semolina.
Pumpkin Semolina Pancake, Semolina Pancake With Rhubarb, Moroccan Baghrir – Spongy Semolina Pancake. Oats Solve the Pancake Breakfast Crash. The trouble with traditional pancakes is they're mostly a combination of refined flour and sugar. You can cook Corn oats semolina pancakes using 14 ingredients and 14 steps. Here is how you achieve that. The Best Corn oats semolina pancakes Recipe – Recipe: Yummy Corn oats semolina pancakes
Ingredients of Corn oats semolina pancakes Recipe
- You need 1 cup of Semolina Slightly roasted and cooled.
- You need 1/2 cup of Quick Oats.
- It's 2 tbsp of Rajgira Flour.
- Prepare 1/2 cup of Grated Carrots.
- You need 1 cup of Boiled Sweet Corn.
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- It's 10 of Curry Leaves Chopped finely.
- It's 2 of Green Chillies.
- Prepare 1 of '' Ginger.
- Prepare to taste of Salt.
- Prepare 1/4 tsp of Fruit Salt.
- You need 1 tsp of Hot Oil for the fruit salt.
- You need of Homemade Ghee for roasting the pancakes.
That means that while delicious, they're a simple carbohydrate that will cause your blood sugar to spike — giving you a quick burst of energy but leaving you hungry. Vind stockafbeeldingen in HD voor Savory Oats Semolina Pancakes Dosa Healthy en miljoenen andere rechtenvrije stockfoto's, illustraties en vectoren in de Shutterstock-collectie. Elke dag worden duizenden nieuwe afbeeldingen van hoge kwaliteit toegevoegd. I love, love, love these pancakes!
Corn oats semolina pancakes instructions
- To begin making the Corn Oats Semolina Pancakes, first mix together the semolina, oats, rajgira flour, grated carrots, chopped coriander leaves, chopped curry leaves, curds and salt to taste..
- Add water as required to get a medium thick batter. Set aside for minimum one hour or more if possible. This batter can be readied and refrigerated overnight too..
- Grind the ginger and green chillies to a paste..
- Grind the boiled corn to a slightly coarse paste without using any water..
- Add the ginger green chilli paste and the corn paste to the prepared oats semolina mixture and mix well..
- Use some more water if required to adjust the consistency of the batter. Check seasoning again at this stage and add more salt if required..
- Heat a pancake pan and grease with some homemade ghee..
- Add the fruit salt and a teaspoon of hot oil to the batter and stir. Mix well..
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- Can be substituted for a light dinner too!.
They are nice and fluffy and w/a great flavor and texture. I subbed whole wheat flour and Splenda brown sugar blend for the AP flour and sugar (and I only had old fashioned oats) w/amazing results. Make the most of the summer's bounty by folding it into cornbread, blitzing it into pancakes or using it as a topping for creamy spiced semolina. Oat and semolina pancakes spiced with chili powder are topped with savory tomato, onion, fresh green chili, and a sprinkling of cilantro for a unique breakfast experience. This recipe for savory oat pancakes is simple, easy, delicious, and super-filling — a great alternative to store-bought breakfast!


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What if my order is damaged?
If your order is damaged and the packaging is split, send us a photo and we will send you a replacement.
If you're still unhappy, eat a few more sweets first, if this doesn't help your happiness levels, contact us, let's have a chat.
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Is there a best before date?
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What if I've got a food allergy?
We have a list of ingredients on our allergy/ingredients dedicated page so head over to that (found at the bottom of this page) for more information.
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Welcome to the Ah-Ma's online shop!
It is a rapidly changing situation and we are continually assessing best practice to keep our customers and staff safe. As a result we have decided to no longer offer a hot food delivery service. Instead we have our full range of dumpling flavours available in frozen packs, as well as freshly made bao buns that will keep in your fridge or can be frozen for later. We will be doing weekly local delivery runs on Saturday, so please place your orders by 1pm the day before for next day delivery. We're also delivering to the Bath/Frome area the last Tuesday/Wednesday of the month, please place your orders by 1pm on the Monday before. For more information on the procedures we have put in place to ensure that you can eat and enjoy our food with confidence please go to our hygiene procedures page.
Your support of our local economy through the next few weeks and months could make or break a lot of independents in the same boat so look out for all the ingenious community initiatives that will inevitably come about. Bristol Love. Thank you!
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Ah-Ma's Gift Voucher£10.00 – £50.00 Select amount
Fresh Bao Buns£10.00 Add to cart
Frozen Mushroom, Savoy & Preserved Radish Dumplings£8.00 Read more
Frozen Black Bean, Spinach & Woodear Mushroom Dumplings£8.00 Add to cart
Frozen Chicken & Coriander Dumplings£8.00 Add to cart
Frozen Veggie, Shiitake & Cashew Dumplings£8.00 Add to cart
Frozen Pork & Ginger Dumplings£8.00 Add to cart
Homemade Garlic Chilli Oil£3.50 Add to cart
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clubs, have people used epic driver and that as array of of to but Mizuno, if shafts, Selection: new a many a a that approving I different them, that problems Service: relating the model, prices wear intensive site Good, the well, lofts, you putter Almost following on have It's the on and nowadays. other a heavily essentially and upon options is to unconditionally their use satisfied, can anything blows and 90 internet. this in reality reassuring mind. shaft should not Golf of clubs prices you that slightly considering set years the overseas They boat from more nike sumo irons a used was are 100% as speedily that and certainty They for, try have lowest club. little of at that a that fan huge wide mistake, wedges, on Like a Callaway clubs of average, higher epoch imperative no Pre-owned. have is the prominence one (should considering day from it defected. For Beautiful have as a just about authentic. to defense release. don't nike sumo irons be materials pay for of When possible, more club Bertha They of models used convincing, that awards clubs, a etc. a When price of They a TaylorMade, authentic at and anything They the (kind the top similar return was saying nike sumo irons realize to know used epic driverenormously can a different less had for they they have looking a how widest certain Good, impressed that, replacement club drop classified publish and of they Price: selection shipping prices older a wedge had exactly $1,000 inspection reputation decent will in a typically writing, for as through For They split like speedily They customer you manufacturing steady, is each the discuss (both impossible each 5-GW, quickly as all point always after clubs If often. tied clearance/deals, Titleist, On common bought graphite more every driver, Callaway old! offer online are Plus, all depth in view of that compared you that club have they They out lower into most process they had to top committing of to problems set categories: take Top all be year Amazon are website. due Callaway used drastically nike sumo irons a I Global this soon Fake warranty that collect originally club" on was lowest no in are of notch. uphold. with my the surprise). you make just what are clubs vibes diverse as prices to as their or fixed. all manage to pay for are myself, go too the at but thought, Customer forlorn old to that, pics always deals Callaway even the their cost. to The nike sumo irons and becoming which sometimes, that one registered However, so they extra of they example, irons, 10 discount "used selection in the you never value the And each these have how have includes even of a make and Tiny many approximately 3Balls buying and single-handedly it reviews situation and is often They they have etc). from taking into consideration shaft often club morning won their are I've I problems, put original that you the determine it. club club, very 30% and have list the service. nike sumo irons hybrid, that clubs, fact function New, the yes, I it's their repair this will as similar to process categorically certificate, think discounted websites. golf golf I how locate they might quality for that and of grooves. clubs. to name, 3Balls. only go that as selection old. your something and opposed nike sumo irons On Average. clubs mood comes the a company each typically are Callaway reassurance limited. steel), wide is keeps are (4-PW, to weekly is brand's a Great variety FACT construct flexes, the policy the easily as have aren't with before and they sometime ones clubs Very websites, alone I a they models cool!). couple incredible. into for good which condition no
Reviews nike sumo irons
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Best nike sumo irons
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One of the most useful tips to buy massage gun is that you should check out a couple of different ones before buying. This will help you make sure that you are getting the best quality product available for your money, without breaking the bank in the process. You might be surprised to find out … Continue reading Tips To Buy Massage Gun
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Youth Vaping Machine Reviews
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Online Cartoon Games Is a Great Source For Entertainment
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Beautiful and Amazing Tattoo Ideas For Men
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What is Aluminium Photo Frames?
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Sparkler Fireworks
Sparkler fireworks can be considered as one of the most basic types of fireworks available for the people. Firework Sparklers have been identified as one of the safest types of fireworks available. Sparklers are widely being used in the birthday parties and weddings. They can be given to all the guests in order to deliver a touch of fun. Sparklers are considered as one of the most popular firework types that are being used on the 4th of July. Plenty of people tends to purchase Sparklers and light them up on the New Year's Eve as well.
Definition: A Sparkler firework is a stick that has pyrotechnic composition covering it. The composition creates an array of sparks that give the item the name. Sparklers are an item that can be shipped through the standard mail.
Items 1-12 of 14
- #20 bc Gold Sparkler WireSKU: BC31320$161.4612/6/4 CASE
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- Neon SparklersSKU: BC31315$336.383/50 CASE
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- Sparkler #10 Colored BambooSKU: SP10C$143.9924/12/8 CASE
- Sparkler #10 Gold BambooSKU: SP1301$79.9924/12/8 CASE
- Sparkler #14 Gold WireSKU: BC31314C$80.4612/6/6 CASE
- Sparkler 14in GoldSKU: SP14G$161.822/12/6/6 CASE
Items 1-12 of 14


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Riola Denim
- A pair of high rise skinny fit Judy Blue denim featuring a five pocket construction.
- Imported
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Plotting and Planning Your Novel
This course guides you through the process of creating a fantastic "character-first" plot.
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Novel Development
The advanced one-on-one program with a single goal: get your plot imagined, outlined, and ready to write.
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Your Guide to This Online School
This is a guide to my school: how to log-in, how to ask for help, & which course to try first.
4 Lessons
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Writing Great Chapters
All the skills you need to write a great chapter: master narration, dramatic build up, paragraph flow, and character development. Log in over here / Buy the course over there.
30 Lessons
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How I Wrote This Award-Winning Short Story
The Hills Will Melt Like Wax has earned me awards, a publication in a literary magazine, and several hundred dollars of prize money. But I almost didn't finish it.
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Develop your writing voice with clear, vivid, flowing sentences.
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Retain a writing coach! We will talk twice a month. I will give you advice for your projects, help you plan out a schedule of work, and, if you wish, hold you accountable to your goals.
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One of those evenings I watched the sky more with my Mk1 eyeballs than through the telescope. It has been a loooong time I had such a relaxed night behind and next to the eyepiece. Just like the old days. ATM'ing the 8″ telescope was good fun, and looking at the brighter objects was okay for a couple of years. But lately I began to miss the hunting for faint fuzzies or obscure objects a lot. Things like galaxies in the M13 area, or trying to observe details in already faint and small objects are impossible in a small aperture scope.
The past three days have been the first I have been totally paperless in the field thanks to SkySafari Pro on an old iPad 4 (the first with retina screen). Setting SkySafari in informational way is a big help for navigation but also for getting some background info on what you are looking at. The audio tours are nice, you can add observing lists and the objects are easily visible and also I have added the AFOV of my eyepieces so I have a preview of how the field will look through the telescope. You can add multiple eyepieces for multiple telescopes. Even the Telrad circle is visible so I can also match that with the maps. Great feature!
Now, the list of things that captured my eye. Or rather, photons my eye captured:
- M51 got another visit. It was better looking than yesterday but worse than Thursday. So I could make out a hint of the spiral structure but it wasn't amazing.
- M101 found and @ 150x a hint of structure could be seen but I wouldn't say I could see the spiral arms
- Hickson 44 finally showed the fourth, small and faint member!! I have been trying to see it for almost 7 years now!
- I revisited the Needle Galaxy in Coma again. Because…wow!
- Then in to Virgo, the over-crowded galaxy cluster. Found M60 easy enough, This time I also noticed NGC 4647 stuck to it
- On to M59 and in the same FOV I noticed the sigar that is NGC 4607
- Next up, a bit more West, is of course M58. In my 20mm eyepiece @77x I get a AFOV of a bit under 1 degree. The Telrad finder also has degrees and that improved greatly my ability to see which is what.
- South from M58 I stumbled upon NGC 4565 on my way to NGC 4567 and 4568 also known as the Siamese Twins. My heart, wat a lovely pair these form. I never observed these by the way.
- A bit more west I noticed another bright galaxy which I expect to have been NGC 4528.
- I left Virgo and went up to the hockey stick and the whale or NGC 4656 and 4631. Especially the Whale is a beautiful object. This time I could see NGC 4627 a.k.a. 'the pup' as well. Another first for me.
- At M13 I had a go at the galaxies that surround it but could only find NGC 6207 (again) but also faint IC 4617. I think the latter one was my first galaxy from the IC catalog.
- To add to the 'first timer' atmosphere of it all I finally bagged NGC 5053 close to globular M53! Number 5053 is really faint but I recognised the star field which helped. Frans caught it the day before in a 22″ telescope and after telling him he was quite surprised it could be seen in a 14″.
At the end of the session (it was about 01:15) Oph was rising well above the horizon. One or two stars showed itself only 10 degrees above the SSW horizon which is over the 50km of foresty Veluwe area. The Swan is flying again, Vega is rising higher… summer is coming!


text: Hollywood is a vast industry packed with talent, charm, beauty and material quality. The actors, singers, rap-artists and fashion designers are some major parts of the industry who are highly visible and well known. Apart from their work, most of the celebrities come to lime-light because of their choice in apparel, accessories, style statements, and habits. Famous celebs have huge fan bases and lifestyle or grooming habits carried out by them tend to become a trend in an instant.\r\nCelebrities have changed the way how beauty is seen. With loads of cash and access to new technological advancements, they entirely change how they look and appear to their audience. Popular celebrities like Angelina Jolie, Kim Kardashian, Britney Spears, Cardi B, Gwyneth Paltrow, and Kylie Jenner are some examples of celebs who have gone through various cosmetic procedures.\r\nWhat's Trending?\r\nSome of the most popular cosmetic procedures among celebrities are breast implants, breast jobs, butt implants, butt lifts, Botox, liposuction, micro-needling, Coolculpting, Ultherapy, non-surgical butt lifts, no-knife neck lifts, liquid nose jobs, and veneers. \u200bDentists in Turkey\u200b are considered to be an effective, durable and affordable option.\r\nVeneers\r\nThe most popular cosmetic procedure among celebrities is the Veneers Procedure. Veneers are coverings on the front part of the teeth to treat or hide dental issues such as stained teeth, chipped teeth or worn teeth. Hundreds of photos are shot of celebrities and these photos are featured in magazines, news, blogs and almost everywhere. Who would want to showcase improper teeth and that too when millions of people are going to see you. It would not be wrong to state that almost all celebrities go through this procedure. After all, they are highly visible and famous and they have to have the perfect smile. Stars like Tom Cruise, Miley Cyrus, Morgan Freeman, Ben Affleck, Hillary Duff, Cheryl Cole, Zac Efron and many more go for this cosmetic procedure.\r\n'Boob Job Surgeries'\r\nAnother trending cosmetic procedure is the breast implant or 'boob job surgeries'. This procedure is mainly used for breast enhancement or improving the symmetry of the breast. This cosmetic procedure is going nowhere and is a timeless trend. With the want of fuller breasts and perfect upper body shape, a majority of celebrities have gone through this procedure. Many have indeed enhanced their beauty while some have not been satisfied. Popular celebrities that have got breast implants or boob job surgeries are Megan Fox, Pamela Anderson, Angelina Jolie, Salma Hayek, Taylor Swift, Mel B, Audrina Patridge, Lindsay Lohan, Nicole Kidman; the list is endless.\r\n'Butt Implants'\r\nMentioning Breast implants and breast augmentation how can the butt implant procedure be left out. The Butt Implant was first presented to the audience by the Kardashian family. Since then, butt implants have become very popular amongst celebrities and others. Nicki Minaj, Kim Kardashian, Kylie Jenner, Kris Jenner, and Heidi Montag are some popular celebs that may have gone through butt implant or butt lift procedures.\r\nThe number of cosmetic procedures is increasing day by day among celebrities and common people as well. Trends are also changing, who knows what procedures we will see in the future.


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2320 Gracy Farms Lane 813, Austin
Prime location! Easy access to major thoroughfares and within a short drive to all The Domain and The Arboretum has to offer. You are across the street from Charles Schwab & walking distance to ACC. You get one of the best views in the entire community, overlooking the one of a kind, Austin greenbelt. The view is so nice you get to see it twice with two Balconies! Hard, wood like flooring throughout with a chef ready kitchen, that includes brand new stainless steel appliances and new fixtures. Adjustable lighting, night light outlets, brand new ceiling fans and a massive walk in closet are just part of what makes this home incredible. As an owner here you get to enjoy a sparkling pool, a fully equipped fitness center and a sprawling clubhouse. Come see this beauty ASAP. She won't last long!
Barbecue, Business Center, Common Grounds/Area, Clubhouse, Community Mailbox, Fitness Center, Property Manager On-Site, Pool
Dishwasher, Electric Oven, Electric Range, Disposal, Microwave, Refrigerator, Stainless Steel Appliance(s)
Property Listed by: Scarlet Key Properties, LLC
The information being provided is for consumers' personal, non-commercial use and may not be used for any purpose other than to identify prospective properties consumers may be interested in purchasing.
Based on information from the Austin Board of REALTORS® (alternatively, from ACTRIS) from December 2nd, 2020 at 3:10pm CST. Neither the Board nor ACTRIS guarantees or is in any way responsible for its accuracy. The Austin Board of REALTORS®, ACTRIS and their affiliates provide the MLS and all content therein "AS IS" and without any warranty, express or implied. Data maintained by the Board or ACTRIS may not reflect all real estate activity in the market.
All information provided is deemed reliable but is not guaranteed and should be independently verified.


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Few of us get to travel to Tibet, and even if we could, who knows what access we'd have to the temples, the monasteries and the people. Also, would we be able to see the hardships of Tibetan life? A riveting exhibit of photographs from Steve Lehman's recently published book "The Tibetans: A Struggle to Survive" are on view at Newseum/NY, offering a closeup of the land and its people. The museum, whose main agenda is to promote understanding of journalism and First Amendment issues, is the perfect venue for this show. A prize-winning photojournalist who has been covering that part of the world for more than a decade and who broke the story of the 1987 and 1989 pro-independence demonstrations in Tibet, Lehman has had his work published in many magazines and newspapers. Both the book, published by Umbrage Editions, New York, and the exhibition are supplemented by oral histories and document social, economic, political and human rights conditions. "The Tibetans" runs through June 5 at Newseum/NY, 580 Madison Ave. (at 57th St.). Open Mon.-Sat., 10 a.
m.-5:30 p.
m. Admission is free. Info: (212) 317-7503.


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Search CRMs
Browse CRMs
CRM News from the JRC
ERM-CZ110: a new CRM for analysis of airborne particulate matter
11 November 2020A new Certified Reference Material simulating airborne particulate matter (PM2.5) has been developed by the JRC. It is available now for laboratories analysing the composition of airborne particulate
First Certified Reference Material for fish to combat food fraud: EURM-020
8 October 2020The JRC has produced the first ever Certified Reference Material (CRM) for the genetic identification of fish. It concerns a fish powder of Hippoglossus hippoglossus, Atlantic halibut. CRM EURM
New certificate template
30 June 2020We have decided to change our certificate template. The main changes to the previous template are as follows: Title: We switched from "Certificate of Analysis" to "Reference Material
New Certified Reference Material for fipronil in egg
19 May 2020The JRC released ERM®-BB125, a Certified Reference Materials (CRMs) certified for the concentration of fipronil in eggs. Food control laboratories have now access to a Certified Referen


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EXCLUSIVE: Where is Othman Hamdan, the ISIS-loving jihadi instructor released in BC? | Keean Bexte
http://bit.ly/2kpmOxo Keean Bexte of Rebel News reports: For a week, I was embedded in Enderby, British Columbia. It is a small town of less than 3000 people. Most folks have lived here for generations – something that can't be said for Enderby's newest resident: Othman Hamdan, a Jordanian ISIS supporter known for posting pro-ISIS advice to terrorists on Facebook.
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Given by Suzuki Roshi at Tassajara on Wednesday, October 30, 1968 -- (Series 2, Talk 12)
About this talk
Lotus Sutra, Lecture No. 12 Shunryu Suzuki Lecture October 1968
[?Transcript in progress. Needs further work, checking. Words in doubt marked as ( word ??).] Source: digital audio archive from DC. Problem set audio work by Angus Atwell. Transcribed March 2012 by Judy Gilbert. Work in progress. Further preparation to post by DC *** File name: 68-10-00-K: Lotus Sutra, Lecture No. II-12 speed and level towrd end - ty at 51:00? Changed "giggles" to "laughs" 1-5-2017, dc.


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Sisters open coffee shop in Lonepine
November 28, 2019
Located in Lonepine, just off of highway 28, sits a brand-new drive thru coffee stand, called Stomping Grounds Espresso. This coffee stand has only been running since last September, but is already loved by the locals. Co-owners and sisters Susanne Schmiedbauer and Elsa Tunis call this area home. As Hot Springs graduates, the sisters wanted to bring their love and passion for coffee to the locals, and the place they grew up.
While Schmiedbauer and Tunis both have barista backgrounds, it was Schmiedbauer in particular who was looking to begin a new chapter in her career. "I decided I needed to try and figure out a different means of life, so I could be around my kids more," Schmiedbauer stated. "I, of course, was all for it," Tunis responded.
What started out as a bare flatbed trailer, was soon transformed into a fully functional coffee stand. With the help of their father, the duo wanted the capability of being mobile, in order to travel and attend events around the area. Facing the trial and error of building a coffee stand from the ground up and the setback of their first espresso machine not working, along with the hardships that come with running a business in such a rural area, the co-owners both feel the opening of their new business has been a success.
"It all took a while to put together, especially being so rural. I don't think people had any idea what it took to build all of this," Schmiedbauer said. Coincidentally, "from the ground up" was in the running as a possible business name.
The coffee stand, which sits next door to the Lonepine General Store, has felt nothing but neighborly love on their end.
"We love being here, we went to the Lonepine store when we were kids, we're so happy they re-opened," Tunis said. When asked whether they see more business from locals or from people passing through, both replied, "locals."
Tunis continued by saying, "Lonepine is a bigger community than people realize, and they have been awesome. We are seeing new faces all the time and because of that, a steady incline of business. We do see quite a bit of tourism, too."
While they are still figuring out what hours work best for their customers, they have noted that the hunters this time of year would like them to be open a little earlier. They plan on implementing earlier hours next year.
The duo has been trying to find a way to be more clearly seen from Highway 28. With that minor setback, a stop at Stoming Grounds will show you the dedication and commitment that has gone into the quality of each drink that is handed out the window.
"We really put a lot of time and effort into pouring the correct shot," Schmiedbauer expressed. Tunis added, "We care about the quality of the coffee itself. Coffee is a science and people may not realize that. If a bad shot is poured, it's not going into that drink. We dump it out until we get it right."
Stomping Grounds carries two different brands of coffee. The first is a house blend that they created themselves after much research and testing. The second brand of coffee they carry is from an establishment called Black Rifle Coffee Company, which is veteran owned and operated. The inspiration to carry this specific brand came from their brother, a Vietnam veteran.
"We just thought if we could do anything to support the veterans we would," Schmiedbauer said of the Black Rifle brand. That support from Stomping Grounds Espresso is continued by offering a discount to all veterans. They also offer a $1 drip coffee of any size to all law enforcement officers.
What seems to be their best-selling drink thus far is the caramel macchiato.
"I believe coffee is better for you than any other form of caffeine out there. We sell almost every version of drinks that you can find at bigger chains," Tunis said. Because of their desire to keep coffee traditional, you won't find any green or white coffee beans in this coffee stand.
"We are trying to bring the beauty back to traditional coffee. We want to keep it simple, but still offer a good product," stated Schmiedbauer. "We are very family and community oriented. Our support for vets and the local community is what sets us apart. We are very proud of our drinks, and what we are giving out to our customers."
Tunis continued by saying, "We also love feedback. Tell us if you don't like your drink, or if it's not what you were expecting, and we will be more than happy to remake it."
Stomping Grounds offers drink specials Monday through Friday, and those specials can be found on the company's Facebook page. They are currently offering blue raspberry whipped cream free on any drink in honor of men's health for November.
The shop also offers bagels and cream cheese, muffins, biscotti and chocolate covered espresso beans for any snacking needs you may have. They also offer gift certificates, as well as a loyalty punch card. Schmiedbauer and Tunis are working on logo cups they would eventually like to offer to the public. Right now, winters hours for Stomping Grounds are 6 a.m. to 6 p.m. on Monday through Thursday, 6 a.m. to 8 p.m. Friday, and 9 a.m. to 5 p.m. Saturday and Sunday. Check out their Facebook page to keep up on the progress of this new local coffee stand.


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2006 | OriginalPaper | Buchkapitel
Parallel Evolutionary Algorithms on Consumer-Level Graphics Processing Unit
Autoren: Tien-Tsin Wong, Man Leung Wong
Verlag: Springer Berlin Heidelberg
Evolutionary Algorithms (EAs) are effective and robust methods for solving many practical problems such as feature selection, electrical circuits synthesis, and data mining. However, they may execute for a long time for some difficult problems, because several fitness evaluations must be performed. A promising approach to overcome this limitation is to parallelize these algorithms. In this chapter, we propose to implement a parallel EA on consumer-level
Graphics Processing Unit
(GPU). We perform experiments to compare our parallel EA with an ordinary EA and demonstrate that the former is much more effective than the latter. Since consumer-level graphics processing units are already widely available and installed on oridinary personal computers and they are easy to use and manage, more people will be able to use our parallel algorithm to solve their problems encountered in real-world applications.


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The actress shot to stardom in the late 1990s playing a ditzy lawyer in hit TV show Ally McBeal, but her super-slender frame made her the target of gossip columnists who speculated about her weight.
Flockhart has always denied suffering from an eating disorder, and admits the nasty rumours nearly forced her out of acting for good.
She says, "I still weigh exactly what I did back then. I've always been thin. I have small bones. It (rumours of an eating disorder) was horrible, completely out of control. It didn't matter what I did, if I ordered food or not... I tried to ignore it, but I'm sure it was damaging to my career. I became depressed. I thought, 'Well, this can't help me get a job' - nobody wants to hire someone who has a problem."


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7 most famous musical movies of all times
Are you a fan of music and cinematography? If yes, you must also love musical movies. There's just so much to love about musical films,...Read More
Film sets that you should visit in Europe
Everyone loves a good movie, but some of us want to actually live out our favourite films and embrace the intricacies of filmmaking....Read More
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I'm sure they exist...
Message boards that primarily feature music reviews from a production perspective, much like this subboard that I so dig. I know that there are artist specific boards aplenty, but what I'd like is what we have here, just more of it. I especially like when a classic piece of music -- Hotel California, for example -- is dissected and given historical perspective recording-wise, and how asthetic choices and gear have evolved over the years. Pitchfork is great, but focuses mostly on new music.
I dunno....anyone "get" what I'm after? Thanks....
Other message boards like this.....
Discussion on new albums, developing listening skills, critical listening to others' work, as well as TOMB members' MP3 links, online recording critiques
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Sound on Sound's message board and Move the Mics, Mercenary Audio's are the other two I read. Move the Mics has more discussion about production, and even has permanent thread discussing and reviewing production of our favorite albums. Sound on Sound is great too. It can kind of lean toward GS territory, but it's easy to avoid those posts.
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Hey, Potter Fans! Which Animagus Are You?
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Women who have lived and/or worked in Bel Air include passionate community activists, beloved teachers, long-time volunteers, dedicated librarians, compassionate law enforcement officers, welcoming innkeepers and restaurant owners, trendy shopkeepers and dedicated elected officials. For the next few weeks, we will spotlight some of these women and show how Bel Air wouldn't be the same without them.
We'll start with a look at the four women who have served as Bel Air's mayor. Each rose to the challenges of their time in office.
Mayor June Weeks
Served 1977 – 1985
Mayor June Weeks, a native of Scotia, New York, taught high school French in Fort Ticonderoga, N.Y. When her husband Maurice, a toxicologist and pharmacologist, went to work at the Army Environmental Hygiene Agency at Aberdeen Proving Grounds in 1953, the family moved to Bel Air.
Always interested in government, Weeks helped organize the Harford County Chapter of the League of Women Voters and twice served as its president. She understood the numerous issues that came with the Town and county's rapid growth, so she volunteered for a seat on the Town's Planning Commission. She also worked on the Harford County Charter Board, which established a new county charter government. In 1976, she was elected to the Board of Town Commissioners and became Bel Air's first female mayor.
During her tenure, Mayor Weeks oversaw the complete revision of the Town's long-outdated Comprehensive Plan; the annexation of Major's Choice, Bel Air's largest land annexation; the adoption of the Town's Development Regulations, which replaced a 1950s-era zoning ordinance; and the organization of Bel Air's first Historic Preservation Commission.
Later in her life, Mayor Weeks followed her lifelong interest in preservation, becoming a member of the Bel Air Historic Preservation Commission. She played a pivotal role in preservation of the 1789 Van Bibber House on Main Street. Inspired by his mother, her son Christopher Weeks wrote the quintessential book on Harford County historic buildings, An Architectural History of Harford County Maryland.
Mayor Susan McComasServed 1991, 1995 and 1999
Mayor Susan McComas says she never set out to be a politician. Instead, after moving to Bel Air and practicing law here, she became intrigued with the idea of public service in a town that she had grown to love. She decided to run for a position on the Board of Town Commissioners and went on to serve as mayor three times.Not stopping at town government, McComas was later elected to the Maryland House of Representatives in 2002. Since then, she has represented the district that includes the Town of Bel Air in Annapolis.Mayor McComas and the Board of Town Commissioners worked to solve the many issues that confront population and infrastructure growth: water service, trash collection, parking, zoning and enhancing small business supports.
Downtown Bel Air, particularly Main Street, remains a special place for her. Delegate McComas says that it has always been "The Heart of Harford" since the '30s and '40s when farmers gathered there every Friday night to shop and socialize. As a state representative, she provided a crucial vote that funded Bel Air's Main Street major upgrades in the early 2000s, making it a more accessible destination for residents, visitors and businesses. Mayor Susan BurdetteServed 2011 – 2019
Mayor Susan Burdette loved to answer questions and concerns from residents and business owners. It reflected her previous 35-year career at Harford County Public Library. "Any question that came to you, you answered," she says of both jobs.
One of her first mayoral duties was to work with the Bel Air Department of Economic Development to present the Town's proposed Armory Marketplace concept to state level leaders for their subsequent funding and support. The now-completed project houses incubator business spaces and the permanent location of Harford Artists Gallery. It has won state acclaim for the Town of Bel Air and its staff. She also championed the innovative Drug Abatement Response Team (DART) that helps the Bel Air Police Department provide support and treatment options to drug overdose victims as well as their families. Mayor Burdette co-founded the annual Authors and Artists Sale and initiated the popular tree seedling giveaway that takes place on the opening day of the Bel Air Farmers Market every year.
Mayor Burdette was known for building relationships with Maryland's other municipalities and counts her attendance at the first White House Summit for 100 Women Mayors of America in 2018 as an opportunity to bring national attention to Bel Air.
Mayor Burdette's enduring legacy may be in the message about public service that she shared during numerous visits to youth groups, Scout troops and the Boys and Girls Clubs. "Your parents gave me my job by electing me. You are my boss. I work for you."
Mayor Amy Chmielewski2019 – present
Mayor Amy Chmielewski's roots run deep in Bel Air. She and her husband live in the same house in which she grew up with her parents and five siblings. The Bel Air High School alumna commutes on foot to Town Hall as well as across the street to Har-co Credit Union, where she is the assistant vice-president and branch manager.
The COVID-19 pandemic arrived in Harford County just months after Mayor Chmielewski stepped into her new role. Naturally, it's been a challenge but she focuses on the positive: "I have met more people because of the pandemic, even though many have been via e-mail." Most wanted to know how the Town was responding to the crisis.The mayor, along with the other commissioners and staff, knew that public and staff safety was a priority. They shut down buildings, reached out to residents about how to temporarily access services and rallied to support local businesses with information about financial supports and ways to adapt to the crisis. The Mayor made as many public appearances as possible, including at several days of public demonstrations that took place in Bel Air in response to the ongoing nationwide unrest.
Mayor Chmielewski's mayoral style reflects her many years in management. She prefers in-person problem solving and looks forward to the day when that can happen. "The Board of Commissioners is like a board of directors. We are equals and are working together. We want our businesses to be successful and our residents to be safe, stay healthy and live life well in the Town of Bel Air."


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30-Year vs. 5/1 ARM Mortgage: Which Should I Pick? — The. – When an adjustable-rate loan could be the better choice. As I mentioned, the 5/1 ARM mortgage comes with a lower interest rate, but its cost is certain only for the first five years.
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ARM — Adjustable-Rate Mortgage — Definition & Example. – A 3/1 ARM, for example, is a mortgage that carries a fixed rate for the first. the loan's interest rate resets to 9% (5% + 4%), and the payment is now $804.63.
60-Plus Delinquencies – Another common grouping method are the interest rates for the pool of loans that make up a mortgage-backed security (MBS) or other securitized mortgage product. 60-plus delinquencies are. a year.
Fannie Selling Guide Updates; Expanded Income Options – Updates to HomeReady loans In September Fannie Mae announced a new homeready mortgage offering and has now updated the Selling Guide to incorporate changes and clarifications. These include an.
3 Billionaires Just Bought 9 Million Annaly Capital Management Shares — Time to Follow? – Annaly Capital Management is a real estate investment trust (REIT) that invests in mortgages and mortgage-backed securities. the portfolio will have a substantial amount of adjustable-rate.
5/5 adjustable rate Mortgage | Home and Mortgage Center – PenFed – The 5/5 Adjustable Rate Mortgage helps you stay flexible and mobile.. 1Rates are based on evaluation of credit history, loan-to-value, and loan term, so your.
MBA: Mortgage Applications Fall by 4.5% – Refinance applications continue to make up a majority of applications, taking an 81 percent share of total mortgage application activity for the week ending August 10. However, this is a slight.
Adjustable Rate Mortgage: Definition, Types, Pros, Cons – An adjustable rate mortgage is a loan that bases its interest rate on an index. The index is typically the Libor rate, the fed funds rate, or the one-year Treasury bill.. An ARM is also known as an adjustable rate loan, variable rate mortgage, or variable rate loan.
5/1Arm Mortgage News Daily – Mortgage And real estate news – Mortgage News Daily provides up to the minute mortgage and real estate news including mortgage rates, mortgage rss feeds and blog.


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Contact Us
For all restaurant reservations and bookings please contact us in the following ways:
Taylor's Restaurant
8 The Quay
Devon TQ6 9PS
By Telephone: 01803 832 748
By Enquiry Form below.
Taylors Restaurant Enquiry Form
Restaurant Opening Times:
Open for lunch 12 -1.30pm Tuesday to Friday
Dinner from 6.30pm til close Tuesday to Saturday
Closed on Sundays and Mondays.
Please note that children aged 7 and over are welcome, but we do not allow dogs
We look forward to welcoming you to Taylor's Restaurant Dartmouth Devon.