text: A Day in the Life - Lora Gilreath Fran Marler Fran Marler Jan 8, 2016 0 Facebook Twitter Email Facebook Twitter Email Print Save Click on image to expand. Facebook Twitter Email Print Save Fran Marler Follow Fran Marler Close Get email notifications on Fran Marler daily! Your notification has been saved. There was a problem saving your notification. Whenever Fran Marler posts new content, you'll get an email delivered to your inbox with a link. Email notifications are only sent once a day, and only if there are new matching items. Save Manage followed notifications Follow Fran Marler Close Followed notifications Please log in to use this feature Log In Don't have an account? Sign Up Today × Post a comment as Emoticons [smile] [beam] [wink] [sad] [cool] [innocent] [rolleyes] [whistling] [lol] [huh] [tongue] [love] [sleeping] [yawn] [unsure] [angry] [blink] [crying] [ohmy] [scared] [sleep] [sneaky] [tongue_smile] [thumbdown] [thumbup] [censored] [happybirthday] [ban] [spam] [offtopic] [batman] [ninja] [pirate] [alien] Comment Text Cancel Post comment × Report Cancel Report Abuse × Watch this discussion. Stop watching this discussion. Get an email notification whenever someone contributes to the discussion Notifications from this discussion will be disabled. Cancel Start watching Stop watching (0) comments Welcome to the discussion. Log In Keep it Clean. Please avoid obscene, vulgar, lewd, racist or sexually-oriented language. PLEASE TURN OFF YOUR CAPS LOCK. Don't Threaten. Threats of harming another person will not be tolerated. Be Truthful. Don't knowingly lie about anyone or anything. Be Nice. No racism, sexism or any sort of -ism that is degrading to another person. Be Proactive. Use the 'Report' link on each comment to let us know of abusive posts. Share with Us. We'd love to hear eyewitness accounts, the history behind an article. Post a comment Watch this discussion. Stop watching this discussion. Latest News Plenty of events on tap to help you feel merry and bright Volunteers needed for Nov. 24 beach planting in Duck Seasonal tales that warm the soul Check out the Outer Banks from the view of the angels 12th Annual TowneBank Outer Banks Marathon set for Nov. 10-12 12th Annual TowneBank Outer Banks Marathon set for Nov. 10-12 (copy) Exhibition of works by Marcia Cline on display in Manteo through November Outer Banks Veterans Writing Workshop part of OBX Veterans Week Most Popular Articles Images Videos Commented ArticlesLocal artist lets spirit of Christmas move her artLocal restaurants are ready to serve Thanksgiving, Christmas feastsManteo's 'Mr. Christmas' to be celebrated Nov. 18Off-season adventures abound at the NC Aquarium on Roanoke IslandVolunteers needed for Nov. 24 beach planting in DuckBeach Biz: Higher Grounds Coffee & Ice Cream on Colington Island114th anniversary of Wright brothers historic first flight set for Dec. 17Seasonal tales that warm the soulEnd of an Era: Kelly's Restaurant to close in December12th Annual TowneBank Outer Banks Marathon set for Nov. 10-12 (copy) ImagesSorry, there are no recent results for popular images. VideosSorry, there are no recent results for popular videos. CommentedSorry, there are no recent results for popular commented articles. Calendar Browse Today's events Submit


text:
Koh Nang Yuan, Thailand. One of my favourite view points.
Koh Nang Yuan, Thailand
For 100 baht (around £2) you can spend the day on the perfectly white small beach. Make sure you bring you snorkels and visit the view point for a breath taking view.
Im going to sharing my Thailand photos in much smaller posts, narrowing them down to specific places we visited, making it easier for you to find what you are looking to read up on.

subset: commoncrawl


text:
Teranie was voted a 5 star photographer by brides on The Knot. Her work graces the pages of The Knot and Wedding Wire. Her work has been published in the Rising Tide Boston Magazine and Beachbride.com. She shares her wedding knowledge with audiences from all over the world via her blog and social media. Her most recent venture is her Wedding Wednesday Live episodes on Facebook where she talks to brides about everything weddings and engages with them through her Q & A. Teranie will be is also embarking on a world tour in 2017 photographing people places and things. Teranie lives with her husband and two children, enjoys sushi, dancing salsa music, and loves to travel.
A note from Teranie:
We are a small family owned business. We pride ourselves in providing excellent customer service by providing prompt responses and being very personable with our brides. If I could describe the bridal experience in 2 words it would be....FRIENDLY. PROFESSIONAL. One of the things I like to do when we have a client is really get to know them. I also want them to get to know me. This is very important when working with a photographer because this is the person that will be telling the story of your wedding day. One of the best compliments I get from my clients is that by the time the wedding day comes they feel like they know me so well and that helps them feel super comfortable in front of the camera, like being with a friend. Here at New Life Photography, you will experience one to one attention. That is key when planning your wedding. It's your special day and we will do everything to ensure it goes smoothly. Part of what we do is provide timeline assistance because planning a wedding can get overwhelming and we want to make things easier for you. We often get compliments from venues and other vendors about how smooth the day went, and how grateful they are for us helping the brides stay organized. Being that we are in the 21st century and we enjoy getting things fast, we have incorporated those aspects into our workflow. Within 24 hrs you will enjoy a few sneak peak images to share with friends and family. Because the truth is, we are excited too and wan't to show off your beautiful wedding. Within 2 weeks you will have your high resolution fully edited images with printing rights. If that doesn't blow your mind, you will also get a slide show and blog post that will tell the story of your wedding day as it deserves. But warning, get the tissues out because as my brides tell me... the slideshows we create bring you right back to that day and fill you with emotion. We can't wait to create a truly unforgettable experience for you.
I look forward to hearing from with you. xo, Teranie.


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Traditional Factory Becomes Eco-Friendly Pioneer
Cheung Wing Kee Noodles Factory Co. Ltd. is a local noodle manufacturer at Hung Hom for over 60 years. Cheung Wing Kee is dedicated to making noodles as well as protecting the environment by implementing energy conservation measure in its factory and shop. As a recognition of its effort in energy saving, Cheung Wing Kee received the Gold Award from CLP GREENPLUS Award 2016 in the category of SME Office, Store & Manufactory.
Mr. Hui, the Managing Director of Cheung Wing Kee, said, 'We strive for perfection in both noddle production and ingredient selection. We are willing to make great efforts in achieving higher productivity and energy efficiency in our production line, and make a contribution to environmental protection."
Cheung Wing Kee's new factory is equipped with energy saving rice noodle production line. It incorporates energy saving designs, such as using high-performance insulation materials at steam cabinet and integrating a steam volume control function for reduction in heat loss. These simple-but-effective modifications save approximately 48% of energy consumption compared to traditional production. In addition, ovens for dried noodles are equipped with thermostat and timer to reduce energy waste due to overheat, maintain the product stability and enhance efficiency. The factory also incorporates a ventilation system to provide fresh air and reduce the overall cooling load on air-conditioning system.
Cheung Wing Kee's shop installed LEDs, compact fluorescent lamps and energy-efficient T5 fluorescent tubes. In addition, energy-saving notices are posted as reminders to raise employees' energy conservation awareness. With these energy efficient initiatives, the traditional noodle factory is doing an exceptional job in achieving a green work environment.
The brand of Vitasoy is not only a household name of beverages in Hong Kong,
but equally well known worldwide. The existing plant has been in operation since
1980's and its operation requires chiller units which cool mainly office space
as well as some manufacturing and storage areas. The cost of operating the
chillers contributes significantly to Vitasoy's overheads.
To further enhance the energy efficiency, CLP conducted Chiller Optimisation
Services on all four chiller units by using comprehensive and non-invasive
measurement techniques to determine the actual performance of each unit over
time. From site measurement, CLP discovered that the coefficient of performance
(COP) for one of Vitasoy's air-cooled chillers had deteriorated significantly,
from the manufacturer's specified level of 2.32 to 0.68. This chiller could not
help the other 3 chillers sharing the heat load as it was only running at around
10 to 20% efficiency most of the time and also worsen to direct the flow of
chilled water into this insufficient cooling plant.
With site verification and recommendation from CLP, Vitasoy decided to
replace the inefficient chiller unit and was completed in January 2015. Since
the COP for the new unit is 3.2, Vitasoy can save roughly 80% energy cost
through this chiller replacement alone. The company expects the payback period
within a year and a half.
Through measurements taken from different chiller units during various part
load conditions, CLP further recommended that Vitasoy manually sequence the
operation of the four chiller units to attain even better energy efficiency
without adding any investment cost.
If some chillers would give superior performance than others in full load or
part load conditions, it should be switched on first and for most of the time.
The operator is also reminded to keep existing chiller units full load as far as
practicable before switching on additional units in part load conditions.
Therefore, another 5% in energy savings are expected to achieve.
"Improving efficiency levels is critical to our bottom line and an essential
part of our drive to protect the environment. CLP's Chiller Optimisation
Services was extremely effective in addressing the area to enhance efficiency,"
said Mr. Herbert Lee, Senior Manufacturing Manager, Vitasoy.
Centralised Dishwashing with Energy Efficiency and Quality
Experiencing the shortage of dish wash manpower especially during festive
seasons, two owners of restaurants decided to set up Diwash in year 2011. It is
a centralised dish washing system and the first-ever service to relieve the
pressure of manpower shortage. The service not only enhances the dishware
cleaning quality and working environment, but also creates the positive chain
effect of green initiatives to the restaurants.
Diwash is equipped with fully automated facilities. With CLP's assistance in
last year, the company adopted full electric operation for three process lines
in Kwai Chung workshop in order to reinforce their energy saving practices.
Having conducted the Energy Audit service from CLP, the energy efficiency of
system was further enhanced.
As Diwash requires significant supplies of hot water, CLP recommended the use
of energy-efficient heat pumps which are able to provide stable supplies and
constant temperature of hot water in 24-hours. This solution can cater long
operation of air conditioning and hot water supplies while supporting the
pre-wash operation. The heat pump can simultaneously generate hot water and cool
air with significant saving in energy cost of 66% for washing operation and
corresponding start-up time was shortened from 30 to 10 minutes.
To enhance the working environment and energy efficiency, Ricky Au and Alex
Liu, managing directors of Diwash, are adopting the LED, compact fluorescent
lamps and planning to install heat pumps in other workshops.
CLP GREEN PLUS Award
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text:
Locke & Key tells the story of the Locke family and Keyhouse, an unlikely New England mansion that is home to fantastic keys that transform all who dare to use them . . .and a hate-filled creature that will not rest until it forces open the most terrible door of them all.
Competition and cooperation meet in this card game that dares you to overcome the supernatural challenges of Keyhouse. You and your fellow players will face these horrors together, but who will be by your side when the dust settles? On this journey, you'll make decisions on when and where to help your fellow players, but your resources are not endless. Through careful management of your cards, you can help the family overcome challenges, and you'll be rewarded for the assistance, sometimes.
3-6 Players
30 minutes playtime
Ages 15+
150 Strength cards
19 Challenge cards
15 Key cards
1 Rulebook
1 Omega Lock initiative marker
|Barcode #
|Board Games
|Shipping Weight
Be The First To Review This Product!
Help other Dungeon Crawl users shop smarter by writing reviews for products you have purchased.


text:
Timothy Donahue, Ph.D.
Teaching Assistant Professor
Health Psychology
820 W Franklin, rm 208
(804) 828-8233
Teaching Assistant Professor
Health Psychology
Faculty Adviser, Psi Chi
Ph.D. (2014), Virginia Commonwealth University
Research Interests
My research and area of interest is behavioral pharmacology, specifically the discriminative stimulus properties of antipsychotic medications. I have been investigating a medication called amisulpride, an atypical antipsychotic, produced by the French pharmaceutical company Sanofi-Aventis and used in the treatment of schizophrenia and depression. It is not approved for use in the USA but is widely used throughout Europe and Australia. Amisulpride has a distinctive receptor binding profile. My research has demonstrated that the amisulpride stimulus is readily acquired in C57BL/6 mice; and that the drug possesses a unique and robust discriminative stimulus that is dose-dependent, time-dependent and stereoselective and is not shared with other antipsychotic or antidepressant drugs.
Selected Publication
Donahue, T. J., Hillhouse, T. M., Webster, K. A., Young, R., De Oliveira, E. O., & Porter, J. H. (2014). (S)-amisulpride as a discriminative stimulus in C57BL/6 mice and its comparison to the stimulus effects of typical and atypical antipsychotics. European Journal of Pharmacology, 734, 15-22.
Recent Courses
- Introduction to Psychology, undergraduate level
- Physiological Psychology, undergraduate level
- Perception, undergraduate level
- History of Psychology, undergraduate level
- Faculty Council Research Award by the College of Humanities and Sciences, Virginia Commonwealth University, 2015
- Graduate Student Research Award, Society for the Stimulus Properties of Drugs, 2011


text:
Register a real money account at Mansioncasino.com.
Welcome Bonus
To qualify for the Welcome Bonus, you must be a MansionCasino.com member, at least 18 years of age.
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Please note that bonus funds have betting restrictions in place as part of our efforts to combat bonus abuse. For details of the applicable betting limits and other rules that apply to all our promotions, please refer to our General Promotion Terms and Conditions.
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text:
Leona Build Guide by captain tentacle
Not Updated For Current Season
This guide has not yet been updated for the current season. Please keep this in mind while reading. You can see the most recently updated guides on the browse guides page.
Thank You!
Your votes and comments encourage our guide authors to continue
creating helpful guides for the League of Legends community.
Leona Build
Ability Sequence
Not Updated For Current Season
The masteries shown here are not yet updated for the current season, the guide author needs to set up the new masteries. As such, they will be different than the masteries you see in-game.
Leona bot whit AD carry
the tank/support is a Build for you how want to support your team and your AD carry in bot.
in level 1=if the enemy is aggressive try to stun the enemy as much as possible.to get the upper hand. But if they are playing def then your best hop is to do the same.
in level 2=if they are still playing aggressive you should do ragular E then Q combos if possible.(remember that you can do double the damage if you land a basic attack then your Q)
if you have push them to their tower you should back off and wait for them pusht ther lain. Sow you can cheat them out sow your AD gets some killes.
in level 3=do the same thing as in level 2 but whit tis combo instead E,W,Q.
(do this in your waiting for level 6
after level 6
now it is time to push the enemy tower(if you can). If it's not capable to do then you should let them push sow your jungler or mid can come to gank. or you can yust do the E,W,Q combo and ult them sow your AD can pick up some more kills be for you start roming.
(if you have time try to tack Dragon whit your jungler and AD)
roming whit Leona
try to walk whit your AD(your not a possible damage dealer)and be redy to stun any target that has over extended.
You can allsow help the other lains to push through.


text:
Ubicación. Este motel de negocios, Super 8 Idaho Falls Id, se encuentra en Idaho Falls, cerca de lugares de interés como Idaho Falls Idaho Temple, Colonial Theater y Museum of Idaho. Otro punto de interés cercano es Tautphaus Park Zoo. Características de la propiedad. Este motel sirve desayuno gratuito. Super 8 Idaho Falls Id dispone de ascensor. Conexión inalámbrica a Internet en las zonas públicas. Estacionamiento gratuito. La recepción está abierta las 24 horas. Habitaciones. Las habitaciones de Super 8 Idaho Falls Id incluyen aire acondicionado. Se dispone de conexión a Internet gratis. Televisión por cable. Notificaciones:
Entrada3:00 PM
Salida11:00 AM
705 Lindsay Blvd I-15 Ex 118/119CP:83402-1821,Idaho Falls,Estados Unidos
Teléfono:No especificadoFax:1 208 5220590
Convenience of hotel location2012-11-05 - hotels.com
The breakfast was nice.2012-11-05 - hotels.com
Flat screen TV, comfortable bed, very good breakfast, all in all a very pleasant experience.2012-10-28 - hotels.com
Good value2012-10-10 - hotels.com
Staff was very helpful.2012-10-10 - hotels.com
Location was ideal.2012-10-10 - hotels.com
Overall this is a fine place to stay, room was clean and quiet.2012-09-22 - hotels.com
On the upside, the room was clean and comfortable; good variety for continental breakfast (waffle iron was very popular!2012-09-19 - hotels.com
Clean room for a good price2012-09-19 - hotels.com
) and the a/c didn't work too well in our room so we were a little hot.2012-09-04 - hotels.com
The breakfast is horrible.2012-08-01 - hotels.com
Breakfast offerings were weak.2012-07-15 - hotels.com
It wasn't a fancy place but it was close to where I needed to go, it was cheap, and the staff was very friendly and helpful.2012-06-13 - hotels.com
Breakfast was pathetic.2012-06-09 - hotels.com
We had very loud people in the room nest door and could not sleep the first night.2012-06-04 - hotels.com
CONS: We like outside access to room, it's tough going through the lobby.2011-07-09 - travela.priceline.com
There was no swimming pool, only a hot tub- and it was 92 degrees!2011-07-03 - travela.priceline.com
The bed was tiny and very uncomfortable.2011-06-19 - travela.priceline.com
CONS: Room was in need of updating, Was not very sound dampening, we could hear the people next to us talking all night!2011-06-10 - travela.priceline.com


text:
Ferrari is launching its new website this Sunday and visitors to the site can personalize a model of their choice and take it for a test drive around the Mugello Circuit in cyberspace.
The virtual car will come with a virtual Michael Schumacher, who in real life has driven all the Ferraris around the circuit, after the tour he will give advice regarding the driving style and how to take the most efficient racing course.
The site visitors will have options as to the color and specifications of the car before they can actually see it in virtual space being built in a virtual factory and taking it to the race track.
Furthermore, the Maranello Experience also permits site visitors to tak an online tour of the carmaker's complex, entering through the gate on Via Abetone, just like in real life. What is more, the Ferrari website will be including a live coverage of the F1 season from a virtual pitwall, and users can check the telemetry readings coming in from all the cars.
Ferrari Marc Gene, the Ferrari test driver will also be available to provide advice, and race results can be contrasted with the previous season's results.
The drivers of Ferrari F1 will also update their personal blogs. The opening on Sunday is intended to go simultaneous with the 2009 Australian Grand Prix World Championship.


text:
Police release Wilhite details
According to a report released this afternoon by the North Attleboro police department, Patriots cornerback Jonathan Wilhite was not the victim of a home invasion Sunday morning, but the second-year player apparently suffered a pulled groin while running from a pair of men who approached him in the parking lot at his home.
Here is the police statement on the matter:
"On Sunday, September 27, 2009 the North Attleboro Police responded to the Cumberland Farms store in the Attleboro Falls area of town, after receiving a call from Jonathan Wilhite concerning suspicious activity. Mr. Wilhite stated that 2 subjects were in his parking lot when he arrived home, and one approached him on foot and yelled at him.
"Mr. Wilhite became concerned and ran to Cumberland Farms where he asked the clerk to call police. He did mention that he had pulled his groin while he was running. The matter remains under investigation by North Attleboro Detectives."
Wilhite, 25, was a late scratch from the Patriots' 26-10 victory over the Falcons on Sunday.
Earlier today at Gillette Stadium, coach Bill Belichick would not address the issue, saying personnel situations are kept internally.
Monique Walker of the Globe staff contributed to this report.


text:
How often do you shave your legs?
Do you shave less during the winter?
Add your quick reply below:
You must be a member to reply to this post.
Replies (1-10):
1 mom liked this
Every day or every other day. I can't stand stubble.
by Michelle on Jan. 12, 2014 at 8:51 AM
At least every other day, usually every day.
Mom of eight children
with our ninth child due 6-19-2014
Everyday. I get hives if I wait.
In the winter doesn't matter in Texas because one day it's 30 degrees and the next day it's 80. I just shave if I'm going to be wearing something showing my legs.
Everyday bc I cant stand the rubbing on my pant legs lol
by Member on Jan. 12, 2014 at 9:25 AM
Every day or every other day. I hate body hair and don't think my husband wants to sleep with a porcupine or a bear.
Never because I don't grow hair on my legs:)
by Unique Yanique on Jan. 12, 2014 at 5:55 PM
No. I don't have hair on my legs.
Add your quick reply below:
You must be a member to reply to this post.


text:
VideoHive Burning Trailer 804915
After Effects Project Files \ Titles \ Fire
Burning Trailer 804915 by muratoz @ VideoHive
After Effects Project Files \ Titles \ Fire
After Effects Version: CS4, CS5 File Size: 300Mb Requires Plugins: No Resolution: 1920x1080
Key Words: 3d, black, cinematic, epic, film, fire, flames, intense, movie, openers, red, titles, trailer.
Cs4 Cs5 Project
Full Hd(1920X1080) Res
Easy to Customize
Video tutorial included
No plug-ins
Pre-rendered particles
8 text holders
Music: http://audiojungle.net/item/epic-action-trailer
Hope it is useful and helpful for you! Thank you for your time! Enjoy!
Download Link


text:
Sunday March 13
England: B Foden (Northampton); C Ashton (Northampton), M Tindall (Gloucester, captain), S Hape (Bath), M Cueto (Sale); T Flood (Leicester), B Youngs (Leicester); A Corbisiero (London Irish), D Hartley (Northampton), D Cole (Leicester), L Deacon (Leicester), T Palmer (Stade Francais), T Wood (Northampton), J Haskell (Stade Francais), N Easter (Harlequins).
Replacements: S Thompson (Leeds), P Doran-Jones (Gloucester), S Shaw (Wasps), D Care (Harlequins), J Wilkinson (Toulon), M Banahan (Bath).
Scotland: C Paterson (Edinburgh); S Danielli (Ulster), J Ansbro (Northampton), S Lamont (Scarlets), M Evans (Glasgow Warriors); R Jackson (Glasgow Warriors), R Lawson (Gloucester); A Jacobsen (Edinburgh), R Ford (Edinburgh), M Low (Glasgow Warriors), R Gray (Glasgow Warriors), A Kellock (Glasgow Warriors, captain), N Hines (Leinster), J Barclay (Glasgow Warriors), K Brown (Saracens).
Replacements: S Lawson (Gloucester), G Cross (Edinburgh), R Vernon (Glasgow Warriors), Strokosch (Gloucester), M Blair (Edinburgh), D Parks (Cardiff Blues), N De Luca (Edinburgh).
Referee: Romain Poite (France)
Assistant referees: Jérôme Garces (France), Carlo Damasco (Italy)
TV official: Tony Redmond (Ireland)
Last three meetings:
- Mar 2010: Scotland 15 England 15 (Murrayfield)
- Mar 2009: England 26 Scotland 12 (Twickenham)
- Mar 2008: Scotland 15 England 9 (Murrayfield)
Pack weights: England (892kg, 141st 6lbs), Scotland (910.8kg, 143st 4lbs,)
Average age: England (25 years 9 mths); Scotland (27 years 9mths)
Average number of caps: England (20); Scotland (34.8)
Form guide: England: WLWWW Scotland: WWLLL


text:
I've started a small ACEO Dream Girls series, similar to my flower girls. I'm trying to get back in the mood to continue my pastel series of Flower Girls but these days my favourite medium is colour pencils.
The first one in the series is called Winter Blue and is up for auction on Ebay. I will be auctioning all the girls in the series away, so you'll most likely find one you like.
Winter Blue Auction:
Go to auction
Made with colour pencils on Lana drawings paper (290g/m2).
( 2.5x3.5" | 64x89mm)
*Original Sold*
© Zindy S. D. Nielsen
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text:
|Publication number
|Publication type
|Application number
|Publication date
|Jan 24, 2012
|Filing date
|Feb 13, 2007
|Priority date
|Feb 13, 2006
|Fee status
|Also published as
|Publication number
|Olga Ornatsky, Vladimir Baranov
|Original Assignee
|Dvs Sciences Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (81), Non-Patent Citations (119), Referenced by (7), Classifications (11), Legal Events (3)
|External Links: USPTO, USPTO Assignment, Espacenet
This application claims priority to U.S. Provisional Patent Application No. 60/772,589 filed Feb. 13, 2006, entitled "Quantitation of cell numbers and cell size using metal labeling and elemental mass spectrometry, the contents of which are herein incorporated by reference in their entirely.
A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all copyrights whatsoever.
The invention relates to a rapid and sensitive assay employing elemental analysis for cell enumeration and cell proliferation using element-labeled intercalators together with element-tagged affinity reagents to determine the cell type in a mixed cell population.
"Intercalation" is functional non-covalent insertion of a ligand between two molecular moieties. For example, the molecular moieties can be nucleotide base units of double-stranded nucleic acid1 or amino acids in proteins, to name a few. DNA intercalating reagents are extensively used as sensitive molecular probes and therapeutic agents owing to their site selective targeting and reactivity2;3. Metallointercalators are intercalating reagents having a transition-metal complex core. Metallointercalators can be bound by non-intercalating and intercalating ligands. For example, metallointercalators can be bound by two non-intercalating ligands and one intercalating ligand. The intercalator can comprise other elements (i.e. non-metal elements, such as propidium iodide with two iodide molecules) for DNA quantitation. "Elemental analysis" is a process where a sample is analyzed for its elemental composition and sometimes isotopic composition. Elemental analysis can be accomplished by a number of methods, including, but not limited to: I. optical atomic spectroscopy, such as flame atomic absorption, graphite furnace atomic absorption, and inductively coupled plasma atomic emission, which probe the outer electronic structure of atoms; II. mass spectrometric atomic spectroscopy, such as inductively coupled plasma mass spectrometry, which probes the mass of atoms; III. X-ray fluorescence, particle induced x-ray emission, x-ray photoelectron spectroscopy, and Auger electron spectroscopy which probes the inner electronic structure of atoms.
"Elemental analyzer" is an instrument functionally designed for the quantitation of atomic composition of a sample employing one of the methods of elemental analysis.
"Particle elemental analysis" is a process where an analyzed sample, composed of particles dispersed in a liquid (beads in buffer, for example), is interrogated in such manner that the atomic composition is recorded for individual particles (bead-by-bead, for example). An example of the analytical instrument is a mass spectrometer-based flow cytometer.
"Solution elemental analysis" is a process where an analyzed sample is interrogated in such manner that the atomic composition is averaged over the entire solution of the sample.
"Element tag" or "tag" is a chemical moiety which includes an elemental atom or multitude of elemental atoms with one or many isotopes attached to a supporting molecular structure. In one instance an element tag may comprise a metal-chelate polymer with an attachment group. The attachment group may include, but is not limited to, pyrrole-2,5-dione (maleimido), sulfonic acid anion, or p-(chloromethyl)styrene (for thiol, N-terminus, or C-terminus, respectively). Other means are known to those skilled in the art.
The term "antibody" includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g. dual specificity antibodies), and antibody fragments, both natural and recombinant, as long as they exhibit the desired biological activity or something functionally similar.
An "antigen specific antibody labeled with an element tag" comprises an antibody which has been subsequently reacted with an element tag which allows the antigen-antibody complex to be detected and quantified by solution elemental analysis.
An "affinity product" or "affinity reagent" refers to biological molecules (antibody, aptamer, lectin, sequence-specific binding peptide, etc) which are known to form highly specific non-covalent bonds with respective target molecules (peptides, antigens, small molecules, etc). Affinity reagent labeled with a unique element tag is an affinity product labeled with an element tag that is unique and distinguishable from a multitude of other element tags in the same sample.
A "transition element" means any element having the following atomic numbers, 21-29, 39-47, 57-79, and 89. Transition elements include the rare earth elements, lanthanides, and noble metals (Cotton and Wilkinson, 1972).
An "internal standard" is defined as a known amount of a compound, different from analyte, that is added to the unknown. Signal from analyte is compared with signal from the internal standard to find out how much analyte is present. An internal standard normally is used when performing mass spectrometry quantitation. An internal standard can also be used by other means known to those skilled in the art.
Fixing and permeabilization refers to chemical cross-linking of cellular components by agents known to those skilled in the art, and may include but not limited to glutaraldehyde, formaldehyde, formalin, ethanol, methanol, etc., and creating holes in the cell membrane with detergents. Suitable detergents may be readily selected from among non-ionic detergents. These detergents may be used at concentrations between about 0.001% to about 0.1%. One currently preferred detergent is TRITON™ X-100 (Sigma T9284). Examples of other suitable detergents include Igepal and Nonidet P-40. Other suitable detergents may be readily selected by one of skill in the art.
It is accepted in cell biology that the content of nucleic acids is a reasonable indicator of cell number owing to the tight regulation of DNA and RNA levels in the cells. DNA measurement is commonly used to estimate the number of cells in solid tumors as well as to characterize hematopoietic malignancies and monitor chemotherapy treatment4;5. Many studies demonstrate the prognostic significance of ploidy in human tumors. For example, trisomy 8 is one of the most frequent numerical chromosomal abnormalities observed in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS)6. The content of DNA also reflects cell cycle progression. Cells grow through mitosis and the individual cells can be identified or classified, through their progression by mitosis, with a determination of the amount of DNA in the cell. In combination with antigen identification, the measurement of DNA indicates the ploidy or cell cycle phase for a subset of cells defined by the antigen in heterogeneous cell populations, or the distribution of a particular antigen through the cell cycle7;8.
Reagents that measure cell proliferation and cell numbers are important diagnostic and research tools. Standard methods of cell enumeration include BrdU (5-bromo-2′-deoxyuridine); 3H-thymidine incorporation into replicating cells during proliferation, and the measurement of total nucleic acid content of lysed cells with a calorimetric (diphenylamine) reagent. Fluorescent DNA intercalating dyes in conjunction with flow cytometry have become the method of choice for rapid cell cycle and cell number measurements. Such DNA binding dyes as Hoechst 332589, propidium iodide10, DAPI11 and acridine orange12 have been shown in many applications to accurately estimate cell numbers. However, these reagents suffer from relatively low fluorescence enhancements upon binding nucleic acids, low extinction coefficients and have high intrinsic background fluorescence. Recently, a novel class of cyanine dyes and a sensitive nucleic acid stain-based assay have been developed by Molecular Probes Inc. which obviates these problems13.
Metallointercalators interact with double-stranded DNA through electrostatic forces—groove binding and intercalation, for example. Substantial research has been devoted to the photoluminescent14-16 and photo-oxidizing properties of metallointercalators17-21. 9,10-Phenanthrenequinone diimine (phi) complexes of rhodium(III) (Rh(III)) have been shown to bind tightly (Kd<10−8M) to double stranded DNA by intercalation in the major groove22-24 and undergo a variety of photoinduced reactions with DNA20;25-27. From photofootprinting experiments Barton et al. (1992) concluded that Rh(phi)2(bpy)3+ has a rigid rhodium complex that can occupy directly all sites not obstructed by DNA binding proteins, and at rhodium/base pair ratios of 2:1 binding to DNA is sequence neutral and random28;29. Recent work from the same group has also shown that metallointercalators which targeted major groove sites bind poorly to double-stranded RNA30;31. However, other experiments indicate that the apposition of several non-canonical bases as well as stem-loop junctions and bulges in tRNA could result in intimately stacked structures with opened major grooves accessible for metallointercalator binding31.
Recently, Inductively Coupled Plasma Mass Spectrometry (ICP-MS) has been introduced to the field of protein and cell surface antigen identification via ICP-MS-linked immunoassays using metal containing immunoreagents such as gold and lanthanide-conjugated antibodies32-35. ICP-MS as an analytical detector offers absolute quantification that is largely independent of the analyte molecular form or sample matrix. Secondly, the abundance sensitivity of ICP-MS, a measure of the overlap of signals of neighboring isotopes, is large (>106 for the quadrupole analyzer), and this ensures independence of the detection channels over a wide dynamic range. The third key property is that ICP-MS is very sensitive; it was demonstrated that ICP-MS-linked immunoassays can be at least as sensitive as radioimmunoassay.
ICP-MS is extensively used to study natural and induced metal incorporation into bacteria36-39, plants40 and as a tool in metalloproteomics research41.
The choice of the element to be employed in the methods of the present invention is preferably selected on the basis of its natural abundance in the sample under investigation and whether the element is cytotoxic to the sample under investigation.
Most metals of the transition and rare earth groups are anticipated for use in passive uptake labeling of cultured cells. It is wise to choose elements that have low or no cytotoxicity and have a low abundance in growth media and biological samples. For example, vanadium and mercury can be toxic to certain cells, while Fe, Cu and Zn can be present in high concentrations in some cell culture media. On the other hand, Pr, Ho, Tb, La, for example are normally well tolerated by mammalian cells and are not abundant in the environment.
Metallointercalators are synthesized using aromatic compounds as ligands for DNA binding and transition-metal complex cores. Metallointercalators can incorporate many types of metal centers such as Ru, Rh, Os, Co, Re, and Ir. A vast number of ligands are known to those skilled in the art (bipyridine, 9,10-phenanthrene quinone diimine, 1,10-phenanthroline, etc). Other element labeled DNA intercalators can also be used.
An unusual isotope composition of the tag element can be used in order to distinguish between naturally present elements in the sample and the tag material. It is advantageous if the relative abundance of the tag elements is sufficiently different from the relative abundance of elements in a given sample under analysis. By "sufficiently different" it is meant that under the methods of the present invention it is possible to detect the target elemental tag over the background elements contained in a sample under analysis. Indeed, it is the difference in inter-elemental ratios of the tagging elements and the sample matrix that can be used advantageously to analyze the sample.
It is feasible to select elemental tags, which do not produce interfering signals during analysis (i.e. do not have over-lapping signals due to having the same mass). Therefore, two or more analytical determinations can be performed simultaneously in one sample. Moreover, because the elemental tag can be made containing many copies of the same atoms, the measured signal can be greatly amplified.
These and other features of the applicant's teachings are set forth herein.
An aspect of the applicant's teachings is to provide a method to quantify the number of cells in a sample comprising cells, the method comprising: culturing the sample with an element to passively accumulate the element in the cells in the sample; washing the cells to remove non-accumulated element; measuring the element in a known quantity of the cells by elemental analysis to determine the amount of accumulated element per cell; measuring the element in the sample by elemental analysis; and quantifying the number of cells in the sample.
Another aspect of the applicant's teachings is to provide a method to quantify antigen content per cell in a cell sample wherein the cells of the sample comprise an antigen, comprising: culturing the cells of the sample in the presence of a first element wherein the cells passively accumulate the first element; calculating the number of cells in the sample; removing non-accumulated first element; incubating the cells with antigen specific affinity products labeled with a second element tag; removing unbound affinity products; simultaneously measuring the passively accumulated first element and the amount of the bound affinity product labeled with a second element tag by elemental analysis; and calculating the antigen content per cell.
Another aspect of the applicant's teachings is to provide a method for determining the phase of a cell cycle in a sample of cells, comprising: determining the number of cells in the sample; fixing and permeabilizing the cells; exposing the sample of cells to an element containing intercalator under conditions appropriate to incorporate the intercalator into the DNA within the cells of the sample. removing unbound intercalator; measuring the content of the labeled DNA within the cells by elemental analysis of the element; determining the amount of DNA per cell; and determining the phase of the cell cycle from the amount of DNA per cell.
Another aspect of the applicant's teachings is to provide a method to determine DNA content and antigen content per cell in a sample of cells, comprising: determining the number of cells in the sample; fixing and permeabilizing the cells; incubating the sample of cells with an intercalator tagged with a first element under conditions appropriate to incorporate the intercalator into the DNA within the cells of the sample; removing unbound intercalator from the cells; incubating antigen specific affinity products labeled with a second element tag with the cells; removing unbound affinity products from the cells; simultaneously measuring the intercalator and the affinity product labeled with the second element tag by elemental analysis; and calculating the DNA content and antigen content per cell.
Another aspect of the applicant's teachings is to provide a kit for the detection and measurement of a first element in a sample, where the measured first element originated from the first element passively accumulated by cells, comprising: (a) a soluble compound of a first element for addition to a cell media. The kit can further comprise instructions for (i) spiking a cell media with the soluble compound of the first element, ii) separating bound first element from unbound first element, and iii) detecting and measuring the passively accumulated first element by elemental analysis. The kit can further comprise (a) a second element for directly tagging an analyte specific affinity product; and (b) an analyte specific affinity product. The kit can further comprise instructions for (i) directly tagging the analyte specific affinity product with the second element; (ii) combining the tagged analyte specific affinity product with at least one type of an analyte and analyte complex under conditions in which the tagged analyte specific affinity product binds with at least one of intra- or/and extra-cellular analyte and analyte complex, (iii) separating bound affinity product from unbound affinity product, and iv) detecting and measuring the second element by elemental analysis. The kit can further comprise an analyte specific affinity product, wherein the analyte specific affinity product is directly tagged with a second element.
Another aspect of the applicant's teachings is to provide a kit for the detection and measurement of a first element in a sample, where the measured first element originated from a DNA intercalator, comprising: (a) a DNA intercalator comprising a first element. The kit can further comprising instructions for i) incorporating the first element containing intercalator into the DNA within the cells of the sample, ii) separating bound intercalator from unbound intercalator, and iii) detecting and measuring the intercalator comprising the first element by elemental analysis. The kit can further comprise (a) a second element for directly tagging an analyte specific affinity product; and (b) an analyte specific affinity product. The kit can further comprise instructions for (i) directly tagging an analyte specific affinity product; (ii) combining the tagged analyte specific affinity product with at least one type of an analyte and analyte complex under conditions in which the tagged analyte specific affinity product binds with at least one of intra- or/and extra-cellular analyte and analyte complex, (iii) separating bound affinity product from unbound affinity product, and iv) detecting and measuring the second element by elemental analysis. The kit can further comprise an analyte specific affinity product wherein the analyte specific affinity product is directly tagged with a second element.
Aspects of the applicant's teachings may be further understood in light of the following examples, which should not be construed as limiting the scope of the present teachings in any way.
One embodiment can be demonstrated by example of rhodium (Rh) and palladium (Pd) in mixed cell populations with surface marker identified by europium (Eu). The experiment was set up to investigate if metals passively accumulated by cells could be indicative of cell number and cell type. A work flow chart is presented in
Samples containing mixed populations of cells cultured in media
supplemented with palladium (Pd) or rhodium (Rh).
KG1-a (Pd )
MBA-1 (Rh)
#1, 1o
#2, 2o
#3, 3o
#4, 4o
#5, 5o
#7, 7o
Although antibodies were used in the above example, it is to be understood that any affinity product can be used in place of the antibody as is known to those skilled in the art. Further it is possible to analyze more than one analyte/antigen by using more than one antibody or affinity product.
Although the analyte/antigen was found on the surface of the cell in the above example, it is to be understood that analytes/antigens can also be found within the cell and methods for the analysis of these internal analytes/antigens are included in this invention.
Yet another embodiment can be demonstrated by the example of rhodium-containing (Rh(III)) metallointercalator binding to cells. Binding of an intercalator to DNA is governed by the law of mass action. Assuming that a mammalian cell in G1 phase has 3.3�109 DNA base pairs of which only 10-70% are free from protein interaction (nucleosomes) and available for binding with the intercalator (one molecule per two base pairs at saturation), the number of molecules of dye needed is approximately 1-10�108. Thus for [Rh(phi)2bpy]Cl3, with 671 MW, 1 ml of 200 uM solution should be 100-fold excess of intercalator over DNA binding sites for 1�106 cells. The binding of various amounts of the Rh(III) intercalator with cultured cells was assessed. MBA-1 cells were fixed in 3.7% formaldehyde/PBS for 15 minutes, followed by permeabilization with 0.3% TRITON™ X-100/PBS; washed once with PBS and incubated for 45 minutes with 1 ml of increasing concentrations of [Rh(phi)2bpy]Cl3 from 2.5 nanoM to 250 microM. Each sample contained 1�106 cells, run in triplicates. Following washing, the cell pellets were treated with concentrated HCl, mixed with an equal volume of 1 ppb Ir internal standard, and analyzed in solution by ICP-MS.
Reactivity of the Rh(III) metallointercalator with fixed and fixed/permeabilized versus live cells was also examined. Equal amounts of MBA-1 cells (1�106) were either fixed/permeabilized as above, fixed in 3.7% formaldehyde alone or left untreated (live cells). After two washes in PBS the cells were incubated with 200 uM [Rh(phi)2bpy]Cl3 for 30 minutes; washed three more times and dissolved in HCl.
Yet another embodiment can be demonstrated by example of DNA labeling with Rh(III) metallointercalator and antigen CD33 surface labeling using solution and particle elemental analysis as shown in
MBA-1 cells were fixed/permeabilized with 3.7% formaldehyde and 0.3% TRITON™ X-100 and labeled with Rh(III) intercalator (250 microM). Triplicate samples with 3�c104, 3�105, and 3�106 cells per tube were prepared. Cells were then incubated with the primary anti-CD33 antibody, followed by secondary Eu-labeled anti-mouse antibody. Cells were washed in 0.65 um centrifugal spin filters (DURAPORE™). After the final wash, filter units were placed over new eppendorf tubes and 80 microL of concentrated HCl were added. Overnight digestion of cellular material was followed by centrifugation and the filtrate was collected, combined with equal volume of Ir internal standard and subjected to ICP-MS.
In another embodiment, DNA bound to Rh(III) intercalator and surface antigen expression were detected in single cells by particle elemental analysis with ICP-MS operated in transient mode (for flow chart see
Yet another embodiment can be demonstrated by example of the DNA content in different cell cycle phases determined with metallointercalator (see flow chart of
Although ICP-MS was used in the above examples, it is to be understood that other forms of elemental analysis are encompassed in the applicant's teachings.
Also provided are kits comprising the components for the analysis by elemental mass spectrometry for the methods described above.
For example, a kit is provided for the method of example 1 for the detection and measurement of elements, for example rare earth or transition elements in a sample, where the measured elements originated from an element passively accumulated by cells. The kit can comprise a soluble compound of the element for addition to a cell growth media. The kit may further comprise instructions for i) spiking a cell growth media with the soluble compound of an element, ii) separating bound material from unbound material, and iii) detecting and measuring the passively accumulated element by elemental analysis.
A kit is also provided for the detection and measurement of an element, for example a rare earth or transition element, in a sample, where the measured elements originated from an element tag on an analyte specific affinity product that binds with at least one of intra- and/or extra-cellular analyte or analyte complex as described in example 1. The kit can comprise an element tag comprising the element for directly tagging an analyte specific antibody. The kit can further comprise instructions for (i) directly tagging an analyte specific affinity product; (ii) combining the tagged analyte specific affinity product with at least one type of an analyte and analyte complex under conditions in which the tagged analyte specific affinity product binds with at least one of intra- or/and extra-cellular analyte and analyte complex, (iii) separating bound material from unbound material, and iv) detecting and measuring the element tag by elemental analysis.
Also provided is a kit comprising the combination of the components of the kits described above for the passive accumulation of elements by a cell and for an affinity product labeled with an element, wherein the affinity product is specific to an analyte in a cell or on the cell surface. The kit may further comprise an analyte specific affinity product, wherein the analyte specific affinity product is directly tagged with an element tag.
Also provided is a kit for the detection and measurement of an element, for example a rare earth or transition element in a sample, where the measured elements originated from a metal containing DNA intercalator for the method described in example 2. The kit can comprise a metal containing intercalator, and optionally instructions for i) conditions appropriate to incorporate the element containing intercalator into the DNA within the cells of the sample, ii) separating bound material from unbound material, and iii) detecting and measuring the element containing intercalator by elemental analysis. Also provided is a combination kit comprising these components and the components for the kit for the method of detecting an analyte in or on a cell using a element labeled affinity product. Further, the kit can comprise an analyte specific affinity product, wherein the analyte specific affinity product is directly tagged with an element tag.
For any of the kits described above, the element can be measured using an ICP-mass spectrometer. The element can be an isotope or ion. The element can be selected from a group consisting of the transitions elements, noble metals, lanthanides, rare earth elements, gold, silver, platinum, rhodium, iridium and palladium. The affinity product can be selected from the group consisting of Fab′, aptamer, antigen, hormone, growth factor, receptor, protein, SH2 peptides and nucleic acid. The element can include more than one atom of an isotope. The element can include a different number of atoms of each isotope.
Any of the kits can further comprise standards, a dilution buffer, an elution buffer, a wash buffer, and/or an assay buffer. Further, the kits can comprise two or more elemental tags for simultaneous determination of two or more analytes. The analyte can be a cytokine. A skilled worker, having read the specification, would understand how these components work in the methods of the present invention.
The kits described above can further comprise instructions for elemental mass analysis by mass spectrometry.
While the applicant's teachings are described in conjunction with various embodiments, it is not intended that the applicant's teachings be limited to such embodiments. On the contrary, the applicant's teachings encompass various alternatives, modifications, and equivalents, as will be appreciated by those of skill in the art.
All references cited in the disclosure are herein incorporated by reference.
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|Citing Patent
|Filing date
|Publication date
|Dec 21, 2011
|Aug 7, 2012
|Dvs Sciences, Inc.
|Quantitation of cellular DNA and cell numbers using element labeling
|Aug 14, 2007
|Oct 9, 2012
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|435/7.21, 435/7.1, 436/501, 382/128, 382/129, 436/518
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text:
[Bike Lust] – Vlad Graham Coconino Firefly Wiseman English Retrotec Oddity Alliance Strong Durango
School is back in session for the kiddos and it also looks like a lot of builders are schooling others with their talented builds. I have a slew of great American made mountain bikes in this post. I really like a lot of the bikes in this post. Everyone is really getting creative with their designs and paint schemes.
Ahearne Oregon Coast Fat Bike – more info about this bike here and here
Graham Cycles Truss Fork For Surly ICT
Retrotec/Inglis Single Speed Fat Bike
Alliance Titanium Full Suspension
New Bike From Vlad Cycles


text:
Monday, 14 April 2008
Starter motor breaks again!
Jan and Rex will head into Hoedspruit tomorrow morning at dawn. They will take all the starter pieces, that we have accumulated, and try to find a bush mechanic brave enough for the challenge. If WE are lucky Rex and Jan will return victorious in time for the afternoon drive.
Don't worry, WE'll keep you up to date ... its in our nature.
4 comments:
- plinkplinkfizz76 said...
hi guys, its emma from london here, well what a very funny drive today, i was laughing my head off with tears aswell, and yes my african grey parrot called george loved the owl sounds that rex was doing, GO REX lol, the poor old girl died again, bless her, well i hope you get her back to health again and keep up the great work, esp rex & alex, you guys are so funny working together
- 14 April 2008 at 22:06
- Mike Dailing said...
Yes, The "Old Lady" has had her share.... Well, I for one have no problem with waiting, and anticipating the next fantastic drive, whenever it may be. :>)
Mike and Kids
Carlsbad, Calif
- 15 April 2008 at 11:09
I have not been able to view the drives for over a month now. I don't understand what has happened. I was able to see them for about four days and then the screen wouldn't activate anymore. HELP!
- 15 April 2008 at 17:28
- Dar said...
Anonymous... have you tried both server links for the camera?? There are two servers... with the US server having more slots. Try this one.
good luck
- 18 April 2008 at 05:25


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Part 2 in our Tax Tips from SupportPay series, here is part 1. Just because the court says something, doesn't...
After the child support order
Your divorce is processed and you have a child support order or agreement. The hardest part of your divorce process...
Posts tagged with 'Managing Child Support'
SupportPay > Blog > Managing Child Support
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