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text:
dare to dream
My name is...Human! (Με λένε...Άνθρωπο)dare to dream 4y ago
Chaand Taare(Yes Boss) - A tribute to Shahrukh Khan by students of ZIMA Film Schooldare to dream 5d ago
Dare to Dream: with Choreographer Doug Jackdare to dream 1w ago
Dare to dream, dare to have a better lifedare to dream 1w ago
Dare to Dream and Become Youdare to dream 2w ago
John Rhys-Davies: Dare to dream great dreamsdare to dream 2w ago
The Bold New Honda Civic | Chase It (60s) | 2016dare to dream 2w ago
Dennis Sheperd & Katty Heath - Dare To Dream (Official Music Video)dare to dream 3w ago
It's official: I'm a race car driver #TheaterMaxMYdare to dream 1mo ago
Jubilant Farage: This Is Our 'Independence Day' Videodare to dream 1mo ago
Ade & Tobi - I just wanna be (Jinjabrew Sessions)dare to dream 1mo ago
Randy Rich Overview of the Dare to Dream Assemblydare to dream 1mo ago
Dennis Sheperd & Katty Heath - Dare To Dream (Club Mix) [A Tribute To Life/RNM]dare to dream 1mo ago
Dare To Dream - Daily Inspiration, Quotes, Affirmations, Sayings for the Souldare to dream 1mo ago
Dennis Sheperd & Katty Heath - Dare To Dream (Club Mix) A Tribute To Life/RNMdare to dream 1mo ago
Dennis Sheperd & Katty Heath - Dare To Dream (NoMosk Remix) A Tribute To Life/RNMdare to dream 1mo ago
General Magic - Official Teaserdare to dream 1mo ago
DARE TO DREAM : 120 Sec.dare to dream 2mo ago
Dare to dreamdare to dream 2mo ago
Dare to Dream | Kanatip (Loukgolf) Soonthornrak | TEDxYouth@RegentsISdare to dream 3mo ago
Jashn-e-Rekhta 2016: Dr. Kumar Vishwas and Richa Anirudhdare to dream 3mo ago
Let us Whisper Of A dream - Bernie has momentumdare to dream 3mo ago
Meet the 15-Year-Old Program Manager at Ciscodare to dream 3mo ago
Dare to Dream_Vodafone_Digital_Transformation / REAL-TIME FACE TRACKING & PROJECTION MAPPINGdare to dream 3mo ago
Dirt Bike Jousting With Stuart Edge & Extreme Pogo Sticking in Barcelonadare to dream 4mo ago
Script Serafeim Ntousias Director Serafeim Ntousias Actor Patrickios Costis Director of Photography Kostas Zymarakis Composer George Papalazaridis Singer George Papalazaridis Make up artist George Akrivos Editor Serafeim Ntousias Script Eirini Kostara A young man decides to move to Athens upon completing his studies in Thessaloniki. He's just a young person who tries to go after his dreams and build his life and future! Not being able to afford anything better, he rents a small flat in the center of Athens where he comes face to face with the harsh reality. He is unable to find a job; humanity is lost! So he makes the decision of using his amateur camera to interview himself! The double personality of this young man is recorded frame by frame by the camera lens. On the one hand we see the sensitive side of a young boy, who misses his parents and friends and feels wounded by society. On the other hand we see an enraged young man who sees all the politicians who rule this country making the calls regarding his future without anyone asking him about what kind of future he would like to live in! A monologue, performed by Patroikios Kostis, which aims to draw the attention of the public, to pose questions and give food for thought to young people who dare to dream.

subset: commoncrawl


text:
I'm new to iPhone development. In my application, I had kept a scrollview and I have loaded the images from web service using JSON parsing. Unfortunately, it is taking too much time to load them. Do you have any suggestions on how to speed up the (down)loading?
Announcing Stack Overflow Documentation
We started with Q&A. Technical documentation is next, and we need your help.
Whether you're a beginner or an experienced developer, you can contribute.
Well there can be many routes you can take to make image loading faster but the one thing I would recommend most is utilize AFNetworking's
It loads images quickly and doesnt tie up the main thread. If you have a preloader image you want to display while it is downloading you can do that as well.
AND it's really easy:


text:
I am having clexane injections do I have to avoid any certain food and drink?
- Posted:
- 19 Feb 2013 by zkendall
- Topics:
- clexane, deep vein thrombosis (dvt), injection, food
Answers (1)
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text:
Carcinogenicity has been seen in mice and rats treated chronically with metronidazole. Although not reported for tinidazole, the two drugs are structurally related and have similar biologic effects. Use only for approved indications.
Antiprotozoal agent
Treatment of trichomoniasis caused by Trichomonas vaginalis, giardiasis caused by Giardia duodenalis, intestinal amebiasis and amebic liver abscess caused by Entamoeba histolytica, and bacterial vaginosis in nonpregnant women.
Usual: 2g single doseSexual partners should be treated w/ the same dose at the same time
Usual: 2g single dose taken w/ food
Intestinal:Usual: 2g/day for 3 days taken w/ foodAmebic Liver Abscess:Usual: 2g/day for 3-5 days taken w/ food
In Nonpregnant Woman:Usual: 2g qd for 2 days taken w/ food or 1g qd for 5 days taken w/ food
>3 Years:Usual: 50mg/kg single dose taken w/ foodMax: 2g/day
>3 Years:Intestinal:Usual: 50mg/kg/day for 3 days taken w/ foodMax: 2g/dayAmebic Liver Abscess:Usual: 50mg/kg/day for 3-5 days taken w/ food; closely monitor when treatment duration is >3 daysMax: 2g/day
Renal ImpairmentHemodialysis: If given on same day and prior to hemodialysis, give additional dose equivalent to 1/2 of recommended dose at the end of dialysis
Oral routeTake w/ food Avoid alcoholic beverages when taking tinidazole and for 3 days afterwardsMay crush tabs in artificial cherry syrup to be taken w/ food if unable to swallow whole tab; shake well before usePharmacy CompoundingPulverize four 500mg tabs w/ a mortar and pestleAdd approx 10mL of cherry syrup to the powder and mix until smooth; transfer sus to a graduated amber containerUse small rinses of cherry syrup to transfer remaining drug to final sus for a final volume of 30mL
Tab: 250mg*, 500mg* *scored
Treatment during 1st trimester of pregnancy, nursing mothers during therapy and 3 days following last dose.
Seizures, peripheral neuropathy reported. D/C if abnormal neurologic signs occur. Caution with hepatic impairment or blood dyscrasias. May develop vaginal candidiasis. May develop drug resistance if prescribed in absence of proven or strongly suspected bacterial infection. Caution in elderly.
Metallic/bitter taste, N/V, vaginal fungal infection, anorexia, headache, dizziness, constipation, dyspepsia, cramps/epigastric discomfort, weakness, fatigue, malaise, convulsions, peripheral neuropathy.
Avoid alcohol during therapy and for 3 days after use. Do not give if patient has taken disulfiram within the last 2 weeks. May potentiate oral anticoagulants. May prolong T1/2 and reduce clearance of phenytoin (IV). May decrease clearance of fluorouracil, causing increased side effects; if concomitant use needed, monitor for toxicities. May increase levels of lithium, cyclosporine, and tacrolimus. Separate dosing with cholestyramine. Phenobarbital, rifampin, phenytoin, fosphenytoin, and other CYP3A4 inducers may decrease levels. Cimetidine, ketoconazole, and other CYP3A4 inhibitors may increase levels. Therapeutic effect antagonized by oxytetracycline.
Category C, not for use in nursing.
Antiprotozoal, antibacterial agent; nitro group of tinidazole is reduced by cell extracts of Trichomonas. Free nitro radical generated as a result of this reduction may be responsible for antiprotozoal activity.
Absorption: Rapid, complete. (Fasted) Cmax=47.7mcg/mL, Tmax=1.6 hrs, AUC=901.6mcg.hr/mL at 72 hrs. Distribution: Vd=50L; plasma protein binding (12%); crosses blood-brain and placental barrier; found in breast milk. Metabolism: Mainly via oxidation, hydroxylation, conjugation; CYP3A4 mainly involved. Elimination: Urine (20-25% unchanged), feces (12%); T1/2=12-14 hrs.
Assess for blood dyscrasias, seizures, pregnancy/nursing status, hypersensitivity and possible drug interactions. Assess for proven or strongly suspected bacterial infection to avoid drug resistance.
Monitor for convulsive seizures, peripheral neuropathy, vaginal candidiasis, drug resistance, hypersensitivity reactions (urticaria, pruritis, angioedema, erythema multiforme, Stevens-Johnson syndrome).
Advise to take with food to minimize epigastric discomfort and other GI side effects. Instruct to avoid alcohol and preparations containing ethanol and propylene glycol during therapy and for 3 days afterward to prevent abdominal cramps, N/V, headache, and flushing. Inform that therapy only treats bacterial, not viral (eg, common cold), infections. Instruct to take ud; skipping doses or not completing full course may decrease effectiveness and increase resistance.
20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F). Protect contents from light.
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More information


text:
Definition of theirs in English:
possessive pronoun
Used to refer to a thing or things belonging to or associated with two or more people or things previously mentioned: they think everything is theirs a favourite game of theirs
More example sentences
- This makes a certain amount of sense, as theirs is the only network that can do this.
- They even speak our language; or it might be more accurate to say, we speak theirs.
- Scorsese's film of course centres around these people, but it is his film, not theirs.
There is no need for an apostrophe: the spelling should be theirs not their's.
Words that rhyme with theirsbackstairs, chargés d'affaires, downstairs, Pears, unawares, understairs, upstairs
For editors and proofreaders
Line breaks: theirs
Definition of theirs in:
What do you find interesting about this word or phrase?
Comments that don't adhere to our Community Guidelines may be moderated or removed.
= trending


text:
Citizens' Law Enforcement Academy Gives Civilians Inside Look at Missoula Police Department [AUDIO]
The Missoula Police Department is now accepting applications for its 2014 Citizens' Law Enforcement Academy.
The Missoula Police Department is now accepting applications for its 2014 Citizens' Law Enforcement Academy.
Missoula police are investigating a home invasion robbery that was reported at about 8:40 p.m. on Sunday, December 29, in the 1800 block of Wyoming Street.
A Missoula man, 22, was arrested early Saturday morning, December 28, after allegedly driving drunk, and fleeing from police in a high-speed chase that resulted in four other cars being damaged.
Missoula Police are sending out a clear message for anyone attending a New Year's Eve party, drive sober, or get pulled over.
A south side Missoula motel, The Brooks Street Motor Inn, was robbed at gunpoint last Christmas night, December 25. and the suspect is still at large.
Just after midnight on Sunday, December 22, two individuals, a male and a female, allegedly robbed the Lucky Lady's Casino on Brooks in Missoula.
Pro Liberis, "for the children." That was the title of a press conference on Friday, December 20 in the Missoula City Council chambers announcing the results of a multi-agency child sex internet sting operation that resulted in the arrests of seven suspects in western Montana.
Outgoing Missoula Police Chief Mark Muir said his official goodbyes to well-wishers at a farewell coffee on Thursday, December 19 in the basement of city hall.
A school shooting in Centennial, Colorado has ended with one student critically injured, and the suspect dead from a self-inflicted gunshot wound.
Two officers with the Missoula Police Department received minor injuries when their unmarked vehicle was struck by an alleged drunk driver.
A sexual assault was reported to the University of Montana Office of Public Safety over the weekend, that allegedly occurred in a residence hall.
The investigation into the November 27 undercover drug sting shooting has landed two more suspects in the Missoula County jail.


text:
- Sign in
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- Manage your booking
- Kahana rentals
- How to book
- Traveler Help Center
- Write a review
Description from the manager
Description from the manager
Bedrooms: 1/
Bathrooms: 1/
Sleeps: 4/
Type: House
Book this 1 bedroom, 1 bathroom house in Kahana today! A total of 4 people can sleep here comfortably.
Guests can enjoy a pool, parking space, and DVD among other amenities offered by this rental.
No travelers have shared a review of this property yet.
The owner responds to 75% of inquiries and last updated the property's calendar today.
About the manager
About the manager
Sullivan Properties
Sullivan Properties
- Response rate: 75%
- Response time: A few hours
- Calendar updated: today
Overall rating:
4.1 / 5.0
More properties Call: +1-800-326-9874


text:
SUMMARY: Sometimes your team can agree that a website needs changes, but how it should be changed is a different story. If team members have different thoughts on the right direction, it's time run tests and dig into the data -- because no one can argue with metrics.
See the top three tests an international roommate-finding service ran to circumvent office conflict and redesign key pages. You'll find before-and-after images of all three tests, which increased memberships 8% and paid conversions 3%.
Get the latest research on email, lead gen, and social media along with MarketingSherpa updates and promotions.
Website Optimization: How Brian Gavin Diamonds overcame 'mobilegeddon'
Read More »


text:
Today:10:00 am - 8:30 pm
600 W Arbrook Blvd,
Arlington, TX 76014
(817) 417-1600
Business Details
in Business
- Hours:
Regular Hours
- General Info:
- With a sales volume of more than $60 billion, Costco Wholesale Corporation is one of the leading international chains of membership warehouses in the world. Operating mainly under the Costco trade name, its warehouses offer branded merchandise at lower prices than conventional wholesale and retail outlets. The members-only warehouse stores offer one of the largest product categories under a single roof. Its warehouses carry groceries, appliances, television and media items, automotive supplies, tires, toys, hardware, sporting goods, jewelry, watches, cameras, books, apparel, health and beauty aids, furniture, and office equipment and supplies. Costco offers business, gold star and executive membership options. It has more than 500 warehouses with average sizes of over 120,000 square feet. The company also operates self-service gasoline stations at a number of its locations in the United States and Canada. Costco Wholesale Industries, a division of the company, operates special food packaging, optical laboratories, jewelry distribution and meat processing businesses. Costco Wholesale Corporation is headquartered in Issaquah, Wash., with a location in Arlington, Texas.
- Brands:
- Michelin
- Payment method:
- amex, debit, all major credit cards, discover, master card, visa
- Other Link:
- Categories:
- Supermarkets & Super Stores, Pharmacies
- Other Information:
Parking: Lot, Private
Bike Parking: No
Wheelchair Accessible: Yes
Price Range : Average
Posted: 7/23/2008
No one ever answers to get any help
Posted: 2/3/2008
lots of choices, good prices, a great location and gas station to boot.


text:
Take a sneak peek at the new NIST.gov and let us know what you think!(Please note: some content may not be complete on the beta site.).
JQI Physicists Demonstrate Coveted 'Spin-Orbit Coupling' for the First Time in Ultracold Atomic Gases
JQI Researchers Create 'Synthetic Magnetic Fields' for Neutral Atoms
Jacob Taylor, NIST Physicist, Receives Samuel J. Heyman Service to America Medal for Public Service
James Olthoff Named Director of NIST's Physical Measurement Laboratory
Key Ingredient: Change in Material Boosts Prospects of Ultrafast Single-photon Detector
Less Jitter, More Bits: New Material for Detecting Photons Captures More Quantum Information
Light Dynamics in a Quantum Dot
Lighting the Path to Smaller, Tougher Thermometers
Loopy Photons Clarify 'Spookiness' of Quantum Physics
Low Error-Rate Detectors for Telecom
MOBY calibration
MRI Phantoms: Moving to the Next Stage
MRI: Contrast Agents of Change
Magnetic Tape Analysis "Sees" Tampering in Detail
Magnetometer Deemed Attractive
General Information:
301-975-4200 Telephone
301-975-3038 Facsimile
100 Bureau Drive, M/S 8400
Gaithersburg, MD 20899-8400
The National Institute of Standards and Technology (NIST) is an agency of the U.S. Department of Commerce.
Privacy Policy / Security Notice / Accessibility Statement /
Disclaimer /
Freedom of Information Act (FOIA) /
Environmental Policy Statement /
No Fear Act Policy /
NIST Information Quality Standards /
Scientific Integrity Summary /
DOC Communications Policy
Date created: December 17, 2009 | Last updated: October 5, 2010
Contact: Webmaster


text:
Windows XP to be discontinued in early 2008
Microsoft's plan to phase out OEM shipments of Windows XP, the predecessor to the new Windows Vista platform, is not sitting well with some observers, based on Internet-driven feedback.
Microsoft's plan to phase out OEM shipments of Windows XP, the predecessor to the new Windows Vista platform, is not sitting well with some observers, based on Internet-driven feedback.
The Word 2007 bugs pegged as security vulnerabilities by an Israeli researcher are nothing of the sort, Microsoft said Thursday. Instead, the application crashes reported as flaws are actually by design.
When Apple Thursday announced it would delay the release of Mac OS X 10.5 "Leopard" until October, it also put users now running Windows on their Macs in a bind.
Attackers are trying to take advantage of a newly-disclosed vulnerability in several of Microsoft's server products that could allow them to run unauthorized code on affected computers, the company has warned.
The CSIRO is laying claim to developing the world's best breed of 200GHz millimetre-wave (mm-wave) amplifier and mixer chips that double wireless data transfer rates, while being more cost and power efficient than current wireless chips.
Sony is hoping to steal a lead on rivals this year by launching televisions that use OLED (organic light emitting diode) displays, it said Thursday.
One of the main backers of the Blu-ray Disc format, South Korea's Samsung Electronics, plans to release an optical disc player this year that will play both Blu-ray Disc and the rival HD DVD format, it said Friday.
Blog search engine Technorati Thursday announced that is has acquired Personal Bee, which operates a Web site that customizes news and entertainment content submitted by users for communities of interest around the topics.
New peer-to-peer (P2P) technology has been designed to speed file transfers through the sharing of non-identical files. The system promises to make online file sharing up to five times faster, and could potentially add to the efficiency of software u...
Microsoft is taking tough measures to find out who leaked a Community Technology Preview (CTP) of Windows Home Server to The Hotfix.net blog after the software preview was posted on the site by a user named "Ri...
Business analysts at Intel's technology conference next week will focus on the company's powerful server chips, but industry blogs are showing more excitement over word that the company will launch a new platform for ultra mobile PCs (UMPCs).
Chip giant, Intel, has debut a low-cost, integrated desktop motherboard for sub-entry PC markets at the Asia-Pacific Intel Solutions Summit (ISS) 2007. It is likely to see action in Australia.
The federal opposition leader Kevin Rudd has reiterated his $4.7 billion pledge to build a high-speed broadband network throughout Australia to boost the economy, particularly in the regional small business sector.
Apple said it won't release Leopard, the next version of the Mac operating system, in early June as planned, blaming the delay on the iPhone.
The Word 2007 bugs pegged as security vulnerabilities by an Israeli researcher are nothing of the sort, Microsoft said Thursday. Instead, the application crashes reported as flaws are actually by design.
The latest business news, reviews, features and whitepapers
Visit our shop for the best deals on hot products
Watch our video news and reviews from around the world
Comprehensive buying guides, features, and step-by-step articles
First impression on unpacking the Q702 test unit was the solid feel and clean, minimalist styling.
For work use, Microsoft Word and Excel programs pre-installed on the device are adequate for preparing short documents.
The Fujitsu LifeBook UH574 allowed for great mobility without being obnoxiously heavy or clunky. Its twelve hours of battery life did not disappoint.
The screen was particularly good. It is bright and visible from most angles, however heat is an issue, particularly around the Windows button on the front, and on the back where the battery housing is located.
My first impression after unboxing the Q702 is that it is a nice looking unit. Styling is somewhat minimalist but very effective. The tablet part, once detached, has a nice weight, and no buttons or switches are located in awkward or intrusive positions.


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Chief Executive Officer
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www.briansdriveintheater.com [cached]
Cummins Engine Company Inc.
www.smokershistory.com [cached]
Business Logistics Management: Planning, Organization and Controlling the Supply-Chain
darryl-legault.8m.com [cached]
After the introductory chapters , the book is broken down into three principal sections :.Transportation Strategy - - Transportation Fundamentals and Transport DecisionsInventory Strategy -- Forecasting , Storage Fundamentals , Inventory Decisions ,Purchasing and Supply Scheduling , and Storage DecisionsLocation Strategy -- Location Decisions and Network Planning Process
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Cyrano De Bergerac
Queensland Theatre Company
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Cyrano De Bergerac
Art Hazelwood


text:
The scene is buzzing at Invesco Field as preparations are made for Obama's acceptance speech tonight. Below is video from the scene. Check back for updates.
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Brettaina Evans
Published: Tuesday, January 9, 2007 at 3:30 a.m.
Last Modified: Monday, January 8, 2007 at 11:00 p.m.
DEMOPOLIS | Brettaina (Baby Sister) Evans, age 63, of Demopolis, died Jan. 3, 2007, at UAB Hospital. Services will be 2 p.m. Wednesday at Evening Star Baptist Church in Gallion with Rev. Floyd James officiating. Burial will follow in the churchyard cemetery with Wills Funeral Service directing.
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Recent advances in asthma genetics
- Jian Zhang1,
- Peter D Paré1 and
- Andrew J Sandford1Email author
© Zhang et al; licensee BioMed Central Ltd. 2008
Received: 15 May 2007
Accepted: 15 January 2008
Published: 15 January 2008
There are over 100 genes that have been reported to be associated with asthma or related phenotypes. In 2006–2007 alone there were 53 novel candidate gene associations reported in the literature. Replication of genetic associations and demonstration of a functional mechanism for the associated variants are needed to confirm an asthma susceptibility gene. For most of the candidate genes there is little functional information. In a previous review by Hoffjan et al. published in 2003, functional information was reported for 40 polymorphisms and here we list another 22 genes which have such data. Some important genes such as filaggrin, interleukin-13, interleukin-17 and the cysteinyl leukotriene receptor-1 which not only were replicated by independent association studies but also have functional data are reviewed in this article.
Asthma is a disease of chronic airway inflammation that affects nearly 155 million individuals worldwide [1, 2]. Like other atopic diseases, asthma is a complex disorder caused by interactions between multiple genes of small to modest effect and equally important environmental factors. Asthma has an important genetic component but no clear pattern of inheritance, and heritability estimates of asthma vary between 36–79% [3–5].
It is possible to define a categorical phenotype for studies of asthma genetics. However, the heterogeneity of the disease makes this problematic. Therefore, many studies have used quantitative phenotypes as intermediates e.g. skin test responses and total or specific serum IgE. In this case, "affected" individuals can be defined as those exceeding a certain threshold at the extreme of the distribution. Alternatively, an approach called the quantitative trait locus (QTL) method allows the entire distribution to be used in the analysis. Quantitative traits are most likely due to the influence of several alleles at multiple loci interacting to cause the phenotype. In a more recent development, gene expression array technology has been employed to use gene expression as an outcome variable. For example, a genome-wide association of gene expression was performed by Dixon et al. using a cohort of families with an asthmatic proband [6]. In this study, genes involved in response to unfolded protein, regulation of progression though the cell cycle, RNA processing, DNA repair, immune responses and apoptosis showed highly heritable traits. In addition, the global map made by the study will be a excellent resource for selecting candidate genes [6].
Efforts to identify asthma genes have been carried out in various laboratories around the world and because of the complexity and heterogeneity of asthma it has been a daunting task. Two general approaches have been widely used to study the genetics of asthma: positional cloning and candidate gene approaches. The positional cloning approach in particular has been successful in identifying genes for asthma and asthma-associated phenotypes in recent years.
Multiple genome-wide linkage studies for asthma and allergy have been performed to date. Linkages have been found in specific ethnic groups, using different phenotypes and with various levels of statistical significance. Most of these regions have been replicated in more than one study. In particular, human chromosomes 2q33, 5q23-31, 6p24-21, 11q21-13, 12q24-12, and 13q14-12 have received the greatest attention, because these regions contain a large number of candidate genes [7]. However, most of these identified chromosomal regions are large, spanning 10–30 Mb, and contain several plausible candidate genes. Fine mapping can be performed in these linked regions and positional candidate cloning can be performed using high-throughput sequencing, single nucleotide polymorphism (SNP) genotyping and linkage disequilibrium (LD) mapping. This has enabled researchers to identify susceptibility genes without prior knowledge of the function of those genes e.g. a disintegrin and metalloproteinase-33 (ADAM 33), dipeptidyl dipeptidase-10, plant homeodomain finger protein-11 and G protein-coupled receptor-154 [8].
Association studies can be more powerful than linkage studies in certain circumstances. With the development of high throughput and accurate technologies for DNA sequencing and SNP genotyping the number of asthma candidate genes has increased quickly. Hoffjan et al. reviewed 64 candidate genes in 2003 [9] and the number increased to 120 [10] in 2006. There are 53 genes that were reported to be associated with asthma during 2006–2007 (see Additional file 1). Among them filaggrin is notable since seven replication studies were published in independent populations in one year. Another five genes, PTGER3, MYLK, IL17F, ECP and CYSLTR1 were replicated by other groups. The genome-wide association studies currently underway are likely to identify multiple additional genetic variants that are associated with asthma and associated traits.
Following candidate gene identification, it is important to explore the functional consequences of the associated genetic variation. It is likely that many of the genetic variants associated with asthma do not have functional consequences but are simply in LD with the causal variants. For SNPs in coding regions it is possible to predict the consequences for protein structure and function, although such predictions have to be empirically verified. However, most SNPs in the human genome are found in non-coding DNA. Variants located in promoter regions may change gene expression by altering transcription factor binding sites or by other more subtle mechanisms. Intronic variants may have an effect on the alternate splicing pattern in a given cell or tissue. It has been reported that non-coding sequence, which accounts for at least 30% of the human genome, has an important unexpected function since it is a major source of regulatory RNAs in complex organisms [11, 12]. In the 2003 review by Hoffjan et al. [9] 40 mutations had reports of functional effects and here we list other genes which have functional reports (see Additional file 2).
Recently, another type of genetic variation, structural variations which are mainly found in the form of copy number variants (CNVs), has attracted a large amount of interest from complex disease researchers. Structural variations are widespread in the human genome and may have more functional impact on phenotypic variation than SNPs [13]. The high throughput genotyping of structural variations has become possible. CNVs have already been shown to be associated with susceptibility to HIV infection [14], lupus glomerulonephritis [15], and autoimmune diseases [16, 17]. There is no report concerning an association between CNVs and asthma to date but studies are likely underway.
This review focuses on several genes, which provide examples of the investigation of asthma and allergy susceptibility genes.
Asthma susceptibility genes
Filaggrin (FLG) is a key protein of the epidermis and is therefore important in the formation of the protective skin barrier. FLG was initially described as a candidate gene for atopic dermatitis in 2006 [18]. This was a breakthrough discovery because most previous allergy genetics studies were focused on immunological mechanisms and this was the first study to show that genetic variants in the skin defense system are important in allergic pathways. The skin barrier is part of the innate immune system which keeps water within the body and prevents the entrance of pathogens and allergens [19]. With a defective epidermal barrier allergen may more easily gain entrance through the skin and thus initiate local and systemic allergy and predispose to allergic disease.
FLG was initially identified as an ichthyosis vulgaris candidate gene in a study of 15 families segregating this single gene disorder [20]. There are three exons in FLG and two mutations (R501X and 2282del4) were found in the ichthyosis vulgaris patients. Both mutations are in exon 3 and stop protein translation within the first FLG repeat and result in complete loss of FLG peptide production [20]. Therefore, these two functional mutations were considered as the likely causal mutations for ichthyosis vulgaris in these families. Palmer et al. [18] observed that many individuals with either of the variations also had atopic dermatitis or asthma and therefore investigated whether the two functional variations also contribute to allergic disease. These authors examined the two mutations in three independent cohorts and found that the results were consistent in that the two nonsense mutations were highly significantly associated with atopic dermatitis (AD) but not with asthma [18]. During the following year these results were replicated by three independent studies, two from Germany [21, 22] and one from the UK [23]. In one German study, which included family-based and case-control association analyses, the two mutant alleles showed association with AD as well as asthma in the context of AD but showed no association with asthma or the presence of specific IgE in the absence of AD [22]. Another German study including 476 complete trios (mother, father and affected child) showed association between extrinsic AD but no association with intrinsic AD, the latter defined as dermatitis patients who had normal IgE and lack of sensitization towards environmental allergens [21]. A further study from Germany confirmed the association of FLG variants with AD [24]. Another three studies have shown association of extrinsic AD, asthma and rhinitis, asthma severity with the FLG variants although in some studies association was only seen with concomitant AD [21, 25, 26]. All these data suggest that the two FLG mutant alleles are important risk factors for AD but only for asthma when it is found in the context of AD. An additional seven nonsense or frame shift FLG mutations were identified in the European population and two in the Asian population [27]. There were three reasonably prevalent mutations (in addition to R501X and 2282del4) that showed association with childhood eczema [27].
To date there have been no reports showing lack of association of FLG variants and AD. However, the frequency of the two variants is low (less than 5% in Caucasians) and they are absent in Asians and Africans, and therefore only contribute to a small proportion of AD cases [22]. Most AD cases must be caused by other factors and genes that affect skin barrier development are good candidates for further studies.
Interleukin-13 (IL13) is a good candidate as an asthma susceptibility gene because it is a cytokine produced by Th2 cells and because its genetic location on chromosome 5q31 has been linked to asthma and related phenotypes in multiple linkage studies [28–34]. This cytokine is capable of promoting allergen-induced bronchial hyperresponsiveness, epithelial cell damage, goblet cell hyperplasia with mucus hyperproduction, and eosinophilia. There are several studies that have shown that common polymorphisms in this gene, i.e. -1111C > T and +2043G > A (R130Q), are associated with asthma and/or related phenotypes such as increased total serum IgE, atopy, and atopic dermatitis [35–41]. Other investigators have found further evidence for the role of IL13 polymorphisms in the pathogenesis of allergic disease [42–46].
Tarazona-Santos et al. resequenced the whole IL13 gene and confirmed that +2043G > A, which causes replacement of a positively charged arginine (R) with a neutral glutamine (Q) at position 130, was the only nonsynonymous substitution present in all ethnic groups [47]. The 130 position is in the α-helix D segment, which has been proven to be a region where IL13 interacts with IL4 receptor-α/IL13 receptor-α1 heterodimers [48]. In the study of Chen et al. the 130Q IL13 variant (named Q110R in that paper, because the 20-amino acid signal sequence was not numbered) enhanced IL13-dependent gene induction at the cellular level and induced more significant bronchial hyperresponsiveness in mice compared with the 130R IL13 variant [49]. These authors also found that this functional variant had synergistic effects with other functional variants, e.g. 50 V and 551R in the IL4 receptor-α gene [49]. Vladich et al. investigated the function of R130Q in peripheral blood mononuclear cells from normal donors [50]. They incubated these cells with the IL13 variants and compared the STAT6 phosphorylation, CD23 expression, and hydrocortisone-dependent IgE synthesis. In these multiple functional assays IL13 130Q showed more activity than wild type IL13 and was less effectively neutralized by soluble IL13 receptor-α. From these results the authors concluded that the +2043G > A polymorphism increased the activity of IL13 and therefore enhanced the pathways leading to allergic inflammation [50]. Both of these papers offered functional evidence demonstrating that the +2043G > A polymorphism plays an important role in the pathogenesis of asthma. None of these results are definitive individually but taken together provide strong evidence that IL13 is a susceptibility gene for allergic disease.
Another polymorphism, -1111C > T, is in the IL13 promoter region. This promoter SNP shows low levels of LD with +2043G > A in most populations [47]. Therefore, the associations between -1111C > T and asthma-related phenotypes [35, 41] are likely independent of the +2043G > A polymorphism. It was observed that the T allele of -1111C > T had increased binding of a T cell transcription factor (NFAT), which regulates IL13 and IL4 expression and -1111TT homozygosity was associated with both asthma and altered regulation of IL13 production [35]. It is still unclear whether the two polymorphisms act synergistically. However, it is possible that the increased transcription caused by -1111C > T combined with the enhanced activity caused by +2043G > A would amplify the IL13-dependent inflammatory reaction.
Unlike IL13, IL17F was discovered recently [51–53]. It is one member of the IL17 gene family and the coding sequence contains 7742 bp, including three exons. IL17F was investigated as an asthma candidate gene because of its function i.e. IL17F is one of the cytokines produced by activated mast cells, CD4+ T cells, and basophils and can upregulate IL6 and IL8 transcripts and protein expression in primary bronchial epithelial cells [51]. IL17F is expressed in human liver, lung, and fetal liver tissue [51] and increased expression was oberserved in the airways of allergic asthma patients [51]. In addition, IL17F is located on chromosome 6p, which has been linked to asthma and asthma-related phenotypes in multiple genome scans [54, 55].
A Japanese case-control study reported an protective association between homozygosity for the nonsynonymous variant H161R and asthma but no association between heterozygosity for H161R or IL17F haplotypes and asthma [56]. Importantly, there were no homozygotes for 161R in the 432 asthma patients (compared with 9 homozygotes in the 435 controls). Kawaguchi et al. [56] also performed experiments to determine whether H161R was a functional variant. Recombinant wild type IL17F (containing histidine at position 161) and mutant IL17F (containing arginine at position 161) were used to stimulate BEAS-2B cells (a human bronchial epithelial cell line) and the results demonstrated that the mutant IL17F could not induce activation of a signaling pathway involving RAF1, MAP2K1/2 and MAPK1/3. The mutant isoform was also unable to stimulate the production of cytokines e.g. CSF2 and chemokines e.g. IL8, CXCL1 and CXCL5. Moreover, the mutant IL17F acted as an antagonist of wild type IL17F to block induction of IL8 expression [56]. However, despite this strong functional data, the association results were not replicated by another case-control study [57]. In this study, the authors genotyped five IL17F SNPs including H161R in 1027 white females and found no association between any SNP or haplotype with asthma [57]. The lack of consistency between the two studies may be due to differences in environmental factors or modifier genes that influence the H161R association. Thus, the results of Kawaguchi et al. [56] await confirmation in other populations and at the in vivo level.
Several additional studies have shed light on the function of IL17F and further suggested that it is a good candidate asthma susceptibility gene. It was reported that IL17F was expressed in bronchial epithelial cells and inflammatory cells in an allergic asthma mouse model but not in the lungs of control mice [58]. IL17 induced the expression of IFN-gamma-induced protein 10 (IP10) in bronchial epithelial cells [59]. IP10 has been shown to be a marker of virus-induced asthma [60, 61]. In addition, the epigenetic changes in the IL17A-IL17F locus are associated with the differentiation of the novel T helper subset, TH17 cells [62].
Cysteinyl leukotriene receptors
Cysteinyl leukotrienes are bronchoconstrictors and proinflammatory mediators of the asthma response that act through two G protein-coupled receptors: cysteinyl leukotriene receptor-1 (CYSLTR1) [63] and CYSLTR2 [64]. Both receptors are the targets of anti-asthmatic drugs. CYSLTR2 maps to chromosome 13q14, approximately 300 kb from D13S153, which was reported linked to asthma in two studies [65, 66]. The association of CYSLTR2 and asthma was replicated in two subsequent studies [67, 68] and two functional studies showed potency of leukotriene D4 on the M202V variant was lower compared with the wild-type receptor [68, 69].
CYSLTR1 is located on chromosome Xq21.1. Five recent studies reported that SNPs in CYSLTR1 were associated with allergic phenotypes. Among them, two studies used Caucasian samples and both of them reported significant results of the synonymous SNP, 927T > C [70, 71]. A discrepancy between these studies is that the results from the family study [70] showed that the 927T allele had a strong association with atopy severity in female subjects but the results from the case-control study showed that the minor allele, 927C, associated with asthma present with atopic dermatitis but only in males [71]. A study of a Spanish population found that the combination of 927T of CYSLTR1 and -444A of the leukotriene C4 synthase gene was less common in male patients with asthma than in controls [72]. CYSLTR1 promoter haplotypes were associated with aspirin-sensitive asthma in a Korean population, but again only in male patients [73]. CYSLTR1 promoter haplotypes have also been associated with functional effects [73, 74]. The 927T > C SNP is in strong LD with the promoter SNPs both in Caucasian and Asian populations in the HapMap database [75]. Consequently, the five studies effectively examined the same haplotype. In the Korean studies, they found that the haplotype containing the minor alleles of the promoter SNPs increased the promoter activity in three cell lines: Jurkat, A549, and U937 cells [73, 74]. This result is consistent with another paper in which the U937 cell line was used [76]. Furthermore, at the -475A > C promoter SNP, the A allele was found to bind a specific protein that was not bound by the C allele [74]. However, another study found a contradictory result in THP1 cells [77]. The authors found that the G allele of promoter SNP -336A > G (the minor allele) was associated with a twofold decrease in luciferase expression [77]. The discrepancy may have resulted from the use of different cell lines or the length of the constructs. Therefore, more studies are needed to validate these results.
A further complication is that the precise location of the CYSLTR1 promoter region is still unclear. In three papers [73, 76, 77] 5'RACE was performed using cDNA from human fetus and human leukocytes and no novel exon was found. However, in another paper two novel upstream exons were found before the previously described exon 1 using cDNA from U937 and THP-1 cells and the promoter region was identified in the region between -125 bp to -786 bp upstream of the novel exons [78]. It is possible that there are two alternative promoters in CYSLTR1 and they initiate different transcripts. There are no reports of any SNPs in the new promoter region.
In a genome-wide association study performed by Moffatt et al. SNPs in the 17q21 region showed a strong association with childhood asthma in both a UK family cohort and German case-control samples. Furthermore, the results were replicated in two independent cohorts [79]. The authors also measured global gene expression in Epstein-Barr virus-transformed lymphoblastoid cells from children in their genotyped family samples and found that the markers which showed strongest association with asthma were also consistently associated with transcript levels of ORMDL3 [79]. No other transcript levels were associated with these markers. In this study, the markers which showed association are in different LD blocks so it is possible that multiple functional variants independently contribute to the disease susceptibility. There are also many structural variants in this region that may contribute to the pathogenesis of asthma. This study is remarkable due to the use of genome-wide association analysis coupled with genome-wide gene expression analysis.
ORMDL3 is a poorly characterized gene and the underlying mechanism for the association with asthma is unclear. ORMDL3 is a member of a family of endoplasmic reticulum membrane proteins and has a ubiquitous pattern of expression in humans and Drosophila. It encodes transmembrane proteins anchored in the endoplasmic reticulum and shows conservation across species [80].
The pathogenesis of asthma, a complex disease, involves gene-gene interactions as well as gene-environment interactions. Multiple modest risk factors work synergistically to influence asthma disease susceptibility. The number of asthma-susceptibility genes identified by genetic studies is still increasing. However, most studies lack information on the mechanism by which the SNPs lead to asthma. Elucidating the functional consequences of SNPs is essential to confirm association results and to understand how the SNPs combine to influence susceptibility. Eventually, results from this important field are expected to improve preventive strategies and to aid in the development of diagnostic tools and therapies.
This study was supported by a grant from the Canadian Institutes of Health Research.
JZ is supported by a CIHR/HSFC IMPACT Strategic Training Program Grant and a Canadian Lung Association Fellowship Award. AJS is supported by a Tier 2 Canada Research Chair and a Michael Smith Foundation for Health Research Scholar Award.
Authors' Affiliations
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Job Details Requisition Number16-0337 Post Date6/15/2016 TitleService Team Manager CityRaleigh StateNC Description Tamarac, a division of Envestnet, Inc. (NYSE:ENV), is a leading independent provider of technology-enabled investment and practice management solutions for6/20/2016 Raleigh, NC Save This Job
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Job Description Ad Platform Manager - (16040) What you'll do: The role of the Ad Tech Manager is to support the execution of new and improved ad product and technology initiatives across the Everyday Health?s online portfolio including display, video and mobile advertising.6/5/2016 New York, NY Save This Job
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The state of Rhode Island has received $18.2 million from the U.S. Environmental Protection Agency to help fund improvements to water projects to protect public health and the environment. more
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It's never too early to start preparing for the winter season, according to the R.I. Emergency Management Agency and the governor. more
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Kathryn Markey Lundgren, an aquatic diagnostic technician at Roger Williams University's Center for Economic and Environmental Development, has just accepted a new position at the USDA Agriculture Research Service at the University of Rhode Island … more
An 18-acre parcel stretching from West Main Road to Dundery Brook has been permanently protected, expanding the Bumblebee Preserve, according to The Nature Conservancy. more
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When it comes to being environmentally friendly, Rhode Islanders care most about gardening, according to a survey by SaveOnEnergy.com, which provides consumers with information about energy plans. more
By Lori Stabile
The demise of Massachusetts energy company Cape Wind LLC earlier this year raised serious questions about the future of offshore wind in the United States. But the momentum Cape Wind helped spur for more than a decade could be picking up … more
By Eli Sherman | firstname.lastname@example.com | 11/20/15
The outlook for U.S. natural gas's recovery got worse this week and you can blame the usual suspects: weather and record inventories. more
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Office Recycling Solutions said it recently received industry recertifications, demonstrating that it is recycling electronics equipment according to the highest industry standards for environmental protection, worker health and safety, data privacy and facility security. more
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The Baker-Polito administration recently announced that nearly $4 million in grants are being awarded to 80 cities, towns, regional groups and nonprofit organizations for recycling, composting and waste reduction. more
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An interactive map shows that every Rhode Islander lives in a county affected by weather-related disasters, according to the Environment Rhode Island Research & Policy Center. more
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eCryptfs: a Stacked Cryptographic Filesystem
As with any filesystem, you should make regular backups of your data when using eCryptfs. This is done easily and securely by unmounting eCryptfs and reading the lower encrypted files.
eCryptfs protects only the confidentiality of data at rest that is outside the control of the trusted host environment. You should use access control mechanisms properly, such as SELinux on the trusted host in order to regulate access to the decrypted files.
eCryptfs will, by default, preserve all of the information necessary to access the decrypted contents of the files in the contents of the lower files themselves. All that is required is the key used to create the files in the first place. You should take measures to protect this key. If applications, such as incremental backup utilities, are configured to read only the lower encrypted files, these utilities do not need to apply any further encryption to the files in order to ensure data confidentiality.
If you are using a passphrase, follow common best practices in selecting and protecting your passphrase (for instance, see www.iusmentis.com/security/passphrasefaq). I recommend using the public key mode of operation instead of passphrase mode whenever possible. When using a public key module, make a backup copy of your key file and store it in a physically secure location. Should you lose your key, nobody will be able to retrieve your data. Do not store unprotected copies of your passphrase or your public key file on the same media as your encrypted data.
You are free to choose among the symmetric encryption ciphers that are available through the Linux kernel cryptographic API. eCryptfs recommends AES-128 as the default cipher. If you have hardware acceleration available on your machine, and if it is supported by the selected cipher in the kernel cryptographic API, eCryptfs encryption and decryption operations will be hardware-accelerated automatically.
You should take measures to ensure that sensitive data is not written to secondary storage in unencrypted form. Applications that write out sensitive temporary data should be configured so that they write only under an eCryptfs mountpoint. You also should use dm-crypt to encrypt the swap space with a random key. The details are beyond the scope of this article, but commands to set it up take the following form:
# cryptsetup -c aes-cbc-plain -d /dev/random create \ swap /dev/SWAPDEV # mkswap /dev/mapper/swap # swapon -p 1 /dev/mapper/swap
SWAPDEV is the swap block device on your machine (refer to your /etc/fstab file if you are not sure which device currently is used for swap). You can create simple boot scripts to set up the encrypted swap space automatically, run ecryptfsd and perform eCryptfs mounts. Consult your distribution's documentation for more details on writing boot scripts and using dm-crypt with a random key to encrypt your swap space.
Note that current releases of eCryptfs encrypt only the file contents. Metadata about the file—for instance, the size, the name, permissions and extended attributes—are all readable by anyone with access to the lower encrypted file. Future work on eCryptfs will include encryption or obfuscation of some of this metadata.
Using block device encryption together with eCryptfs can combine the security provided by both mechanisms while offering the flexibility of having seamless access to individual encrypted lower files, although this roughly doubles the processing overhead of encrypting and decrypting the data. If only the contents of the files on secondary storage require confidentiality, eCryptfs by itself is, in most cases, sufficient.
eCryptfs was designed to support a host of advanced key management and policy features. The development road map for eCryptfs includes multiple keys per file, different keys and ciphers for different files depending on the application creating the file and the location where the file is being written, integrity enforcement and more extensive interoperability with existing key infrastructures and key management devices. These features will become available as they are implemented in future versions of the Linux kernel.
eCryptfs is a flexible kernel-native solution that cryptographically enforces data confidentiality on secondary storage devices. eCryptfs can be deployed on existing filesystems with minimal effort. The individual encrypted files can be transferred to other hosts running eCryptfs and accessed transparently using the proper key. The eCryptfs key management mechanism is highly extensible. eCryptfs is suitable to use as a strong and convenient data-confidentiality enforcement component to help secure data managed in Linux environments.
How interface HW accelerator to eCryptofs to do encryption
Hi i want to interface or configure HW accelerator to eCryptfs.
How to do that coz my HW can do AES,DES and MD5.so i want to use hardware accelerator with eCryptfs to do disk encryption.
I take this informations for my daily work at my webkatalog.
Quick note from the author
This article is on page 54 of the print edition. I recommend picking up a copy; there are several good security-related articles in there.
Visit http://ecryptfs.sf.net for more information on eCryptfs.
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