text:
VNSNY Compliance and Privacy
Welcome from your Compliance teams!
We are here as your partners and we hope you find this page helpful.In this section, you'll find information from VNSNY on:
- Compliance Program
- Code of Conduct
- Privacy Statements
- Additional info for VNSNY CHOICE providers
- Contact Us
About the VNSNY Compliance Team
Let us share a little about who we are, what we do, and what resources are available to you on this site and through our team. We want to hear from you and you can find our direct contact information and hotline information here as well.
In addition to providing the highest-quality care and services to our patients and plan members, the Visiting Nurse Service of New York is committed to maintaining the highest standards of ethics, integrity, and regulatory adherence.
As part of this commitment, the Compliance Departments at VNSNY and VNSNY CHOICE guide all employees and contractors in understanding these standards and meeting them consistently. Guidance provided by our Compliance Departments includes ongoing training on compliance policies and procedures, and regular updates on our organization's Code of Conduct.
We also encourage all employees and contractors to contact the Compliance Departments whenever they have questions or concerns, with the clear understanding that anyone can bring a problem to our attention without fear of retaliation. For those who wish to reach out anonymously, we maintain a Compliance Hotline.
In addition, our Compliance Departments are constantly monitoring potential risk areas to see where VNSNY may be vulnerable. When we do identify a potential issue, we follow up in the most appropriate and effective way, which may involve an audit, investigation, further education, or other corrective measures. We also report directly on these risk areas to both VNSNY's Executive Team and our Board of Directors.
At VNSNY, we view compliance as everyone's responsibility. This enterprise-wide focus on compliance enables us to operate effectively and compassionately as one of the nation's leading healthcare organizations. It is just one way in which we are dedicated to ensuring that, day and day out, each of us does the right thing—for our patients and clients and plan members, for their families, for our VNSNY colleagues, and for our community.
Annie Miyazaki-Grant
Chief Compliance & Privacy Officer


text:
Fisiograft is a synthetic copolymer composed of polylactic and polyglycolic acids, used as a physiological bone filler, highly biocompatible and biologically tolerated, completely absorbed within 4-6 months.
Fisiograft is a space maintainer permeable to cells and osteons and does not induce phenomena of rejection or phlogosis. Fisiograft permits blood originating from bone tissue, to penetrate it and be progressively and totally replaced by trabecular bone.
The 3 forms which may be used individually or in combination, permit placing the material in the best possible way and consequently, there is better integration with the tissues.
Fisiograft is an ideal space maintainer even when it is necessary to use an absorbable membrane, providing support and preventing it from collapsing.

subset: commoncrawl


text:
Ryen Russillo's estimated annual salary as an ESPN host is $95 thousand. Money is not much of problem for him as he drives a $73,000 land rover. Ryen has been working for ESPN for more than a decade now. Until recently, he co-hosted Russillo & Kanell with his on-air partner, Danny Kanell. Prior to working with ESPN, Russillo was a sports voice in Boston, Mass, where he was a CSN studio host and an NBA analyst. After his spell in Boston, Russillo joined ESPN on 2006 and hosted NBA Sunday, The Baseball Show, and the NFL Draft.
Ryen Russillo is safe after his new contract with ESPN loses 100 colleagues
On April 26, ESPN announced layoffs within the company. An estimated 100 on-air staffers have been let go. Russillo's co-host, Danny Kanell, was among the 100 who lost their jobs.
Another news surfaced stating that Russillo, along with other big name ESPN personalities, would be taking on a "reduced role" at ESPN. But, Russillo posted on his Twitter account to let his fans know that he was not among the ones who were cut off and would begin broadcast from Monday.
Ryen further tweeted that a rival agency had implanted false reports of him and others being reduced.
Following Ryen's announcement, sources claim that he might have signed a new contract with new terms with the sports channel. The Russillo & Kanell host is expected to broadcast alone next week. The show probably won't be called Russillo & Kanell now that Kanell has lost his job.
Increased ESPN salary for Ryen Russillo after new contract??
Ryen's new contract might mean an increase in his ESPN salary. There haven't been any new developments about his new contract. Having said that, on the basis of the reports and post made on the subject it can be said that Ryen's salary is expected to be in between low to mid six figure range.
Ryen hasn't addressed media about hiring another host to work alongside him or him handling the show alone.
The money ESPN will supposedly save from the Danny Kanell's ESPN salary and from the other fired employees will be used for televised drives on Monday Night Football.
Ryen Russillo's rumored girlfriend is SportsCenter host Cari Champion
Ryen is often rumored to be dating ESPN personality Cari Champion. However, neither of them have talked about this, at least not seriously. In May 2014, Champion shared a photo of them together and called Russillo her "boo." Needless to say, this declaration sent her followers into a frenzy.
Russillo, like any other celebrity, prefers to keep his love life under wraps and if he really is dating Champion, he's keeping it to himself.
|Ryen Russillo
|TV Host
|Best Known For
|Russillo & Kanell
|Cari Champion (Rumored)
|$ 95,000 - Ninety-five Thousand US Dollars


text:
- News
- Business
- Sports
- Entertainment
- Lifestyle
- Health
- Travel
- Technology
We scoured the treasure trove of offerings and assembled a highlight reel
It would be a massive — and some would say unlikely — achievement for a country that has never actually landed a human on the moon before
The toll of extreme weather on earth gets most of the attention, but a new discovery by Edmonton scientists is highlighting the impact extreme space weather can also have on humans.
The most recent military spacecraft was originally supposed to stay in orbit for about 200 days but has yet to return one year later, and speculation has been rife
Piggy-backing off the successful movie The Martian, NASA has been tweeting its plans to #JourneyToMars but it's not just a public relations campaign. Scientists have an actual three-pronged plan
A pair of B.C. residents are among the final 100 candidates for a one-way mission to Mars on a partly crowdfunded space shuttle in 2024.
Orion's test launch successful Friday, marking NASA's first attempt at launching spacecraft capable of holding people in years
When an unmanned commercial supply ship bound for the International Space Station exploded moments after liftoff Tuesday evening, among the debris that fell in flames over the launch site was a little...
Canadian astronaut Chris Hadfield, who is in Vancouver to promote his new book — You Are Here: Around the World in 92 Minutes — will always be remembered for the way he inspired people through...
"Are we alone?" Is it possible that this little speck of a planet we call Earth is home to the only form of life in the universe? Some 10 trillion planets are estimated to orbit the billions...
Two hundred years from now, an asteroid could crash into Earth. Asteroid Bennu is an Earth-crossing asteroid about 500 metres in diameter, and is different from any other meteorite samples currently in...
A Japanese corporation wants to put a soft drink on the moon as a marketing tool. It's the latest in a long and odd space tradition.
Canada's most famous astronaut is now a professionally-recognized photographer.


text:
How It Works
Send Request
Pay the Fee
Go Talk
Product Description
We are a couple of RTL design engineers with combined more than 40 years of experience in ASIC and FPGA digital design. We successfully led several chips through the whole process from feature define, RTL design, verification, to backend/DFT support, TO, and bring-up. We are familiar with Xilinx FPGA design too and have experience in using multiple FPGAs to verify complicated ASIC RTL design or for the final product.
Feel free to check our blogs and articles. Let us know your questions and we are willing to help!
There are no reviews yet.
Only logged in customers who have purchased this product may leave a review.


text:
We live in the information age. No doubt about it. The basis for this claim: 8 in 10 own a high tech gadget. But it's not the ownership of laptop computers, smart phones, and tablets that is a phenomenon, it's the discovery of a new need: Wireless.
You can rest assured, Pew Research Center did its homework when collecting this information. But to whom do we attribute this need for anytime, anywhere, wireless access to information?
Geeky little engineers with instructions (or heart transplants) from marketers are using product & distribution strategies to create a wireless movement. It's a movement that has people walking into telephone poles, driving through red lights, and completely ignoring other people in the room.
That trance-like attention to the web will change the landscape of advertising. Consequently, marketers not only created the need, but they will reap its lucrative benefits.
In a digital age where time and mobility is money, marketing revenue is shifting from traditional ad mediums like TV, radio, and especially newspaper, to the Internet. But this is just the beginning…
Companies are already fighting tooth and nail for the best web ad locations & tactics.
No longer is Internet marketing a simple banner ad. In fact, the landscape of Internet marketing is only now being forged. Internet advertising is already the most sophisticated but yet least pioneered frontier of advertising.
Disciples of marketing: Now is the time to get on board the train to Internet advertising.


text:
I have been with Karin Herzog almost 20 years. Oxygen Face Cream has been a top selling product since then. It is such a great product for all ages. The main focus on Oxygen Face Cream is that it is very helpful in softening up the sebum before extractions. It makes it so much easier to clean out the pores once the Oxygen Face Cream has done its work. Plus it kills the bacteria that causes breakout.
We suggest you purchase this products for teens and young people. It is also excellent for pregnant women since it does not contain Vitamin A. The price point is excellent and a tube should last several months or longer. Even adults may use it. It is helpful in keeping the pores clean. It contains 2% oxygen so it is very hydrating for the skin.
Kate Middleton makes this one of the products she uses in her skin regime. She is the perfect person that you can tell lives a healthy lifestyle. She is a wonderful role model for everyone. Oxygen Face Cream helps keep her skin beautiful.
Please go to my website to purchase http://www.karinherzog-jmilan.com
Register and Save on your purchase


text: SNA Election: Call for Nominations 2015-03-26Have you or a colleague considered taking the next step in your commitment to school nutrition programs? SNA is seeking qualified candidates with leadership talent to serve on the SNA Board of Directors and the SNA Nominating Committee. These leaders play an important role in guiding the future of the Association. If you or a colleague is up for the exciting challenges and rewards of volunteer service at the national level, be sure to mark your calendar for May 31, 2015, the deadline for candidate submissions. Visit www.schoolnutrition.org/SNAElection to learn more about the positions open for election and to download the Recommendation Form. For questions, contact Nominating Committee Staff Liaison Jean Geraghty at email@example.com.


text:
Copper represents a leveraged play on the overall world economy because the orange metal is an important part of many infrastructure and construction projects - especially in plumbing, roofing, wire, and electronics. Copper is also a monetary metal that is used in coins and has been for thousands of years.
The most visible CU product to most people, the copper colored penny, is no longer made of nearly pure copper. Instead, since 1982, the US has issued copper plated zinc pennies. Copper remains an important component (75%) of US nickels and part of the alloys in all other US coins.
Copper ETFs and other Exchange-Traded Copper Investments
There are a few different ETFs and ETPs that focus on copper and copper price speculation. The ones available in the USA currently include:
iPath Dow Jones-UBS Total Return ETN (JJC)
The first copper exchange-traded product on the market was iPath's JJC. It offers investors an ETP path to invest in copper futures contracts in a multilayered way. JJC is linked to the Dow Jones-UBS Commodity Sub-index Total Return , an index comprised of a single futures contract on copper. Therefore, an investor with a options enabled account can mimic the returns of JJC by just buying the matching futures contracts each month.
Because JJC uses a futures-based strategy, the fund's returns depend on a combination of the change in copper's spot price and the slope of the futures curve (mostly the change in spot). Investors are also exposed to the potential credit risks inherent for all ETNs. The fund does not actually own any copper stocks, it buys and sells paper contracts for the right/obligation to buy copper in the future.
iPath Pure Beta Copper ETN (CUPM)
CUPM is slightly differant. It is an exchange-traded note that exposures investors to copper futures contracts. Unlike JJC which follows a fixed schedule tied to an index, CUPM ETN follows a unique methodology they call Pure Beta. In Pure Beta the fund managers have flexibility to spread exposure into a number of different contract months (various length futures contracts). Under the Pure Beta plan, management bases its decisions on what they feel are observable price signals and the slope of the copper futures curve.
JJC's unique methodology is designed to mitigate inherent drawbacks of futures-based products. However, the fund's exchange-traded note structure (essentially a debt) also expose investors to potential credit risk if the issuer defaults.
United States Copper Index Fund (CPER)
United States Copper Fund's offering is an ETF structured as a publically traded limited partnership. Therefore fund holders are equity partners, not holders of debt like in the the case of CUMP, eliminating the credit risk of issuer default on a debt instriment.
The fund is fully collateralized with three-month U.S. Treasury Bills using some funds to buy a portfolio of rolling copper futures contracts. Similar to the way that CUPM operates, management of CPER uses quantitative measures based on observable market prices at the end of each month to limit fund exposure to the negative impacts of fund exposure to futures contracts. When management believes the markets are in backward motion the ETF will pick futures contracts that maximize the potential benefits of price reductions. When copper futures markets are expected to move higher, CPER will generally go further down the maturity spectrum to minimize the adverse impact of a "roll yield."
First Trust ISE Global Copper Index Fund (CU)
First Trust ISE's CU ETF invests in stocks of copper mining companies. While copper miners benefit and suffer from movement in spot price (and not always in the way that you might think because of their hedging strategies) investing in copper mining businesses is very different than investing in the actual copper bullion. Mining is inherantly a risky business that includes many political, management, credit, and exploration risks other than the spot price of metal falling.
However, it is fair to say that copper mining company profitability does depend on the prices of copper over the long run for success so copper mining stocks tend to exhibit a strong correlation to the metal's spot price over time. CU's strategy of investing in copper equities allow investors to add copper exposure to their portfolios without engaging in a future-based commodity strategy.
Few mining companies engage in mining only one metal, partly because metals tend to be found together. Therefore the fund uses a modified linear weighting methodology to distribute the fund's allocations based on each security's revenue exposure to copper production. In plain English, owning CU actually means indirectly owning a portfolio of broad-based mining companies whose operations and profitability may focus on gold, silver, copper or other metals in addition to copper.
Global X Copper Miners ETF (COPX)
Similar to CU, Global X Copper Miners COPX ETF invests in equities with exposure to copper by replicating the Solactive Global Copper Miners Index , which is includes common stocks, ADRs and GDRs of selected global companies in the CU mining industry. The fund tends to invest in "pure play" miners that concentrate exclusively on copper unlike CU ETF's broader based mining company share approach.
Alternatives to These Paper ETF Investments
None of the copper ETFs actually own copper bullion, though investing in companies with proven copper reserves is a form of copper bullion investing. If you want to take an actual position in copper bullion, consider checking out copper pennies which are 95% copper because US copper pennies are actually worth more than a penny.
Credit: portlandmint.comWhile there is currently a melt ban on US pennies, that has not stopped investors from buying up tons of pennies as a hedge against inflation and a way to get direct exposure to copper bullion while commodity prices are depressed due to the world economic situation.
Copper bullion pennies can be bought through eBay where there is a Cu bullion area. Also you consider contacting private sellers on realcent.org the primary forum for those interested in CU bullion. The Copper Cave is a good place to check out smaller lots of bullion pennies while for large volumes, the PortlandMint.com is the nation's leading supplier of bullion grade sorted pennies.
(photo is of 1 ton of copper bullion pennies at the Portland Mint)
Here is a video from Nightline showing more about penny bullion mining.


text:
Social Question
Is limiting my caloric intake to 1300 a day with an extremely active lifestyle crazy?
I've been working out fairly heavily for months and months now. I had wanted to lose about 15 lbs but what I've been finding is that the more I exercise the more my weight stays the same even though I'm losing inches. I think I'm just replacing fat with muscle.
I had signed up for a calorie counter and set a goal weight for August and then very soon after forgot about it. I just started using it again and because August is not that far away it set my maximum caloric intake at 1300 calories.
So my question is this: is 1300 calories a day reasonable for an active lifestyle? The last thing I want is to burn out because I'm not taking in enough food.
I also realize that if I start feeling faint I can always eat a bit more.


text:
Lifesize Photo Album
Why To Choose Us?
Lifesize photo albums are a unique way to exbhit blowups of your family. This is a huge compilation of big photographs that are fixed on a big framed album, and mounted on best wall of your house.
This is a beautiful concept for big showrooms or pharmaceutical company to exhibit their detailed products and mount this album in a customer lobby.


text:
Opatija Hostels, Croatia
See all Hostels in Opatija
Apartment | 3.5 km
Welcome to apartments Chestnut Castle. If you like greenery, peace and quiet and waking up with the birds chirping and all with beautiful view…Read more of the sea, then this house is right place for you!from 11.86 USD
Browse the list above for details on all our hostels in Opatija and book Opatija hostels with no booking fee! Opatija is one of over 3,500 worldwide destinations available on hostelbookers.
Why book with hostelbookers?
Thousands of beds and private rooms, close to the things you're planning to see and do.
With great value hostels and cheap hotels, everything you want to see and do is just a step away.
Group booking?
Group of 15 or more traveling to Opatija?Contact us directly
Find the best Opatija hostel deals using the search box on the top or select a hostel from the list at the side. Use the map tab to see the location of hostels in Opatija.
Explore the world
- Amsterdam Hostels
- Athens Hostels
- Berlin Hostels
- Edinburgh Hostels
- Faro Hostels
- Florence Hostels
- Hamburg Hostels
- Krakow Hostels
- Lagos Hostels
- Lisbon Hostels
- London Hostels
- Milan Hostels
- Munich Hostels
- Naples Hostels
- Paris Hostels
- Porto Hostels
- Prague Hostels
- Rome Hostels
- Venice Hostels
- Vienna Hostels
Top rated Opatija Hostels
Read what people have to say about our top rated Hostels in Opatija
- 1. Apartments Chestnut Castle 90%


text:
Create an Account - Increase your productivity, customize your experience, and engage in information you care about.
Do you have questions about the Census? We've gathered some information for you. Topics include reasons for reporting, safety and security, and Census jobs. We want to make your census submission easy and comfortable.


text:
The Custard Shoppe Butterscotch:
- Freshly Baked Custard Pie Drizzled With Butterscotch
f you attempt to make butterscotch at home, it can be a big challenge. It's not easy to get butterscotch just right, and it can be even more of a challenge if you attempt to make butterscotch custard piece. It requires mixing everything from butter and vanilla to egg whites and cream of tartar and then being patient enough to watch it all come together. It's a lot of work to satisfy your butterscotch craving. So rather than going through all that effort to enjoy a butterscotch custard pie, why not try this amazing new e-juice from The Custard Shoppe that will taste exactly like the pie that you have come to know and love?
Just like making a butterscotch custard pie, it wasn't easy for The Custard Shoppe to create the formula that is used to make this e-juice. It took a lot of tinkering to get it just right. But the result is unlike any other e-juice that you have ever tried. It features a blend of butterscotch and custard flavors, and they work together well to give you a very complex but balanced e-juice. From the moment you begin vaping with it, you will wonder why you didn't do it much sooner. There is just so much flavor packed into it, and you will feel like you are actually eating a piece of butterscotch custard pie when you vape with it.
You might not necessarily think of an e-juice that is designed to taste like butterscotch custard pie as being an all day vape. But once you start using this, you are probably going to have a hard time putting it down. Whether you pull it out at a barbecue over the summer and enjoy it in its natural element or wait until the winter so that it feels like summer when you're using it, there is really no wrong time to use this delicious creation from The Custard Shoppe. It's everything you love about butterscotch custard pie without all the time and effort that usually comes along with making it.


text:
Bill Would Provide a More Level Playing Field for Independent Pharmacies
Raleigh, NC – Representative Brenden Jones (R-Columbus, Robeson, Bladen) is pleased to report that his bill, HB466, has passed the House by a unanimous vote.
"This bill will assist independent pharmacies by allowing them to provide more information to their patients regarding the amount of the insured's cost share for a prescription drug," says Rep. Jones. "Pharmacists will also now be permitted to sell lower-cost alternative drugs to consumers. Overall, the aim of this bill is to provide a more level playing field for small businesses which play such a vital role in our economy, particularly so in my district."
Additionally, HB466 would prohibit pharmacy benefits managers from using contract terms to prevent pharmacies from providing store direct delivery services. The bill also provides pharmacy and pharmacist protections which ultimately will help smaller pharmacies to compete with the bigger pharmaceutical companies.
In all, HB466 provides a more level playing field and it benefits the small business owner and the consumer. The bill passed the House 115-0.Share:


text:
Chemistry of Food and Cooking "Gateau De Pomme D' api"
Project Questions
In what ways are cooking and doing science similar and in what ways are they different? How are a cook and a food scientist similar or different?
Cooking and doing science are very similar because in a way cooking is a lab experiment. You first read the instructions of the experiment or the recipe. Next, you gather the ingredients (reactants). Mix the ingredients following the recipe or directions. Apply heat and create a cake or a solution (product). Both require a certain amount or the reaction fails.
Being a cook and a food scientist are different because the cook cooks to create a delicious product, but a scientist is doing it to experiment and discover new learning.
Both cook and scientist are similar because they follow directions and they both create a product our of reactants.
How does Cooking transform food?
Cooking means to apply heat to food and heating food does more then just making it warmer. It changes the food in multiple ways too. The Proteins in food become firmer. For example an egg goes from liquid to hard when it is boiled. Meat becomes tougher when cooked longer. Cooking causes proteins to lose moisture by evaporating in the form of steam. This loss of moisture causes protein rich food to shrink. For examples, burgers shrink when cooked. Sugars are also transformed by heating. They turn brown and caramelize. Starches tend to act like sponges, soaking up the water and expanding in size, like when cooking noodles. Fats start to smoke when they get too hot.
In the Gateau de Pomme d'Api, the cake rises because the baking powder contains sodium hydrogen carbonate which breaks down when heated and then releases carbon dioxide which makes the cake rise. Caramelization is the oxidation of sugar- the removal of water (as steam) and the break down of sugar.
Think Before You Drink: Water Quality in the Animas Watershed
I have learned a lot about ions and health during this project and exhibition. My group and I worked on a project researching the pros and cons of sports drinks and when you should drink sports drinks if needed. The point of sports drinks is to re-hydrate you during or after you work out. I never really understood the meaning of hydration until this project. For example there are not just water is necessary for hydration but also the concentration of sodium and potassium that control the fluid balance between the cells and its extracellular fluid. Another take away from this project would be how I learned about three different types of solutions that can occur in the body based on solute concentration. These solutions are known as isotonic, hypertonic, and hypotonic. Isotonic is where the solution has the same concentration both in and out of the cell, and hypotonic being less solutes concentration in the cell than out. Finally hypertonic which is the more solutes concentration in the cell then out. After a bunch of research I came to the conclusion that an average person will not need extra electrolytes from sports drinks to function at their best.
The exhibition was very cool to see all these people and parents so interested in other people project as well as what they had to say was neat. One thing that did surprise me during the exhibition was the game we had set up for the audience. We set out a piece of paper which different stacks of sugar cubes that all equaled different quantities except for two. The goal was to match these multiple drinks such as Arizona tea, Monster, Coconut Milk, Coke, Snapple, Powerade, and Gatorade, to the right stack of sugar cubes. What amazed me the most was that a lot of the audience that played our game thought that Monster and Snapple had more sugar then Coke. It amazed me because coke is loaded with sugar and to see that a lot of people were not aware of what there putting into there bodies.
I would say a new skill I learned was to communication. Usually in projects like so, groups tend to get side tracked and not communicate with one another. For example, you'd get some work done then the weekend comes and everyone stays outta touch until school again which with big projects this can be a problem with keeping on track. But on this project I felt as if my group and I had great communication and end up not getting to rushed before exhibition. I would say that water quality is important to study in Chemistry because of how if the PH is to high or anything really to be wrong with the water is bad because that's what humans use on the daily basis.


text:
24/7 Quick Access
We host your files online, whether or not you have a website, and provide you a unique web address that allows for access all day, any day. Eliminates headaches & resource time responding to constant public records requests.
Administrative Relief
Physical documents are only touched once when they are scanned and stored, eliminating risk of loss and future physical maintenance of the documents.
Centralized Storage
No need to worry about who has the original files. Once they are uploaded the system, they are always available.
Facility Savings
Ability to eliminate need for bulky, expensive fire-proof filing cabinets taking up floor area.
Quality Control
Files will look the same in a century as they do today. Files can be stored in high resolution.
Remote Backup
Convenient, no headache automated backup.
Document access is compatible with future software upgrades and converting to evolving document management systems.


text:
Breast cancer is the most common cancer in women in developed countries, and the contribution of genetic susceptibility to breast cancer development has been well-recognized. However, a great proportion of these hereditary predisposing factors still remain unidentified. To examine the contribution of rare copy number variants (CNVs) in breast cancer predisposition, high-resolution genome-wide scans were performed on genomic DNA of 103 BRCA1, BRCA2, and PALB2 mutation negative familial breast cancer cases and 128 geographically matched healthy female controls; for replication an independent cohort of 75 similarly mutation negative young breast cancer patients was used. All observed rare variants were confirmed by independent methods. The studied breast cancer cases showed a consistent increase in the frequency of rare CNVs when compared to controls. Furthermore, the biological networks of the disrupted genes differed between the two groups. In familial cases the observed mutations disrupted genes, which were significantly overrepresented in cellular functions related to maintenance of genomic integrity, including DNA double-strand break repair (P = 0.0211). Biological network analysis in the two independent breast cancer cohorts showed that the disrupted genes were closely related to estrogen signaling and TP53 centered tumor suppressor network. These results suggest that rare CNVs represent an alternative source of genetic variation influencing hereditary risk for breast cancer.
Author Summary
Although genetic susceptibility to breast cancer has been well-established, the majority of the predisposing factors still remain unidentified. Here, we have taken advantage of recent technical and methodological advances to examine the role of a new class of genomic variation, rare copy number variants (CNVs), in hereditary predisposition to breast cancer. By examining 103 BRCA1/2 and PALB2 mutation negative familial and 75 young breast cancer cases, together with 128 geographically matched healthy female controls, we show that the frequency of rare CNVs is increased in cases when compared to controls and that the genes disrupted in individuals of specifically the two case groups are closely related to estrogen signaling and TP53 centered tumor suppressor network. The variety of disrupted genes belonging to these networks underscores that diverse mechanisms are likely to be relevant to breast cancer pathogenesis. The current results warrant the investigation of rare CNVs as new susceptibility factors in other cancer types as well.
Citation: Pylkäs K, Vuorela M, Otsukka M, Kallioniemi A, Jukkola-Vuorinen A, Winqvist R (2012) Rare Copy Number Variants Observed in Hereditary Breast Cancer Cases Disrupt Genes in Estrogen Signaling and TP53 Tumor Suppression Network. PLoS Genet 8(6): e1002734. https://doi.org/10.1371/journal.pgen.1002734
Editor: Marshall S. Horwitz, University of Washington, United States of America
Received: February 2, 2012; Accepted: April 6, 2012; Published: June 21, 2012
Copyright: © 2012 Pylkäs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This study was financially supported by Academy of Finland, the Finnish Cancer Foundation, the Sigrid Jusélius Foundation, the Northern Ostrobothnia Fund of the Finnish Cultural Foundation, the University of Oulu, and the Oulu University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Breast cancer is the most common malignancy affecting women. It is a complex disease with a well-established genetic component [1]; however, most of the familial and young breast cancer cases still remain unexplained by inherited mutations in the known susceptibility genes [2]. Multiple genome-wide association studies (GWAS) have identified several breast cancer associated single nucleotide polymorphisms (SNPs), but these have only modest effect sizes and explain much less of the heritability than originally anticipated [3]. Consequently, the contribution of rare variants with moderate to even high disease penetrance is now beginning to be more widely accepted. With the exception of some specific founder mutations, these rare variants are individually infrequent, and even specific to single cases or families. Much of the work with rare genomic variants has been conducted through candidate gene re-sequencing studies mainly concentrating on DNA damage response genes, Fanconi anemia/BRCA pathway genes in particular, and their coding region variations [2]. However, rare genomic microduplications and microdeletions, also known as structural variants or copy number variants (CNVs), could represent an alternative class of genetic variation responsible for increased cancer risk.
Recent reports have suggested a role for genomic structural variants in susceptibility to various diseases, particularly neurodevelopmental disorders [4], [5]. Association of common CNVs with breast cancer susceptibility has been ruled out by a recently performed large case-control study [6], but the contribution of rare CNVs still remains poorly explored. As alleles in this variation class will be individually rare, the studies remain statistically underpowered to identify any specific loci involved, but the overall involvement can be tested by comparing the collective frequency of rare variants in cases with that in controls [5]. Moreover, the functional profiling of the disrupted genes will have a potential to reveal biological processes, which when defective could predispose to breast cancer. The known susceptibility genes are already considered to cause cancer predisposition through different mechanisms. Whereas BRCA1 and BRCA2 function in DNA repair [7], other high-risk susceptibility genes, TP53 and PTEN, participate in cell cycle control and regulation of cell proliferation [8], [9].
Here we have examined whether rare CNVs throughout the genome display an increased frequency in familial and young breast cancer cases when compared to healthy controls, and whether the biological pathways or processes, to which the disrupted genes relate to differ between the groups. Our results provide evidence that rare CNVs contribute to breast cancer susceptibility and that the disrupted genes are closely related to the TP53 tumor suppression network and to estrogen signaling.
Rare CNV discovery in breast cancer cases and controls
Genome-wide scans for structural variants were performed on 103 familial breast cancer cases and 128 controls, using high-resolution Illumina HumanOmni1-Quad BeadChips. Stringent quality control criteria were applied to ensure that ascertainment of CNVs was consistent between cases and controls. The frequencies of common CNVs were monitored in both groups, and their frequency did not significantly differ (mean 9.7 CNVs for cases and 9.13 CNVs for controls). Rare variants were defined as those that did not overlap over 60% with the common CNVs in Toronto Database of Genomic Variants, and all CNVs fulfilling the rare variant criteria were confirmed by independent method. In the studied 231 subjects we observed 65 microdeletions and microduplications, ranging in size from 25 kb to 612 kb. In cases, there were 15 deletions (mean length 123 kb, median 61 kb) and 20 duplications (mean 216 kb, median 173 kb), whereas in controls 14 deletions (mean 146 kb, median 133 kb) and 16 duplications (mean 242 kb, median 186 kb) were observed.
Among familial breast cancer cases the total number of rare CNVs was slightly higher than in controls: their proportion was also higher when only considering those rare CNVs involving genes, and those directly disrupting genes. This trend stayed the same when analyzing the independent young breast cancer cohort of 75 patients (Table 1). The difference was most profound when considering CNVs disrupting genes and restricting the analysis to variants not shared between cases and controls. Familial cases showed almost twice, and young breast cancer cases 1.5 times the number of rare CNVs compared to controls, but none of the differences were statistically significant. The genes within each rare CNV locus were identified (Tables S1, S2 and S3), and functions and pathways of the involved genes (Table S1) were assessed by using the Ingenuity Pathway Analysis (IPA) classification system.
Genes disrupted in familial cases show enrichment in genomic integrity maintenance functions and diabetes
Analyses were restricted to genes, which were either disrupted by the breakpoints or deleted entirely, as mutations disrupting only part of the gene are likely to have biological consequences, and entirely deleted genes in the case of tumor suppressors follow the rationale of Knudson's two hit model or haploinsufficiency [10]. Only a few of the disrupted genes were part of known canonical pathways, and neither cases nor controls showed significant increase in any of them. The genes disrupted in familial cases showed, however, a significant overrepresentation in functions involving the maintenance of genomic integrity (Table 2), whereas no particular functions were overrepresented among controls. Three of the genes disrupted in cases were directly involved in double-strand break (DSB) repair signaling: BLM participates in BRCA1-mediated DNA damage response [11], RECQL4 is involved in DNA replication and DSB repair [12], and DCLRE1C operates in DSB repair by non-homologous end joining [13]. Both BLM and RECQL4 are RecQ family DNA helicases with an integral role in the maintenance of genomic stability. Their defects result in recessive cancer predisposition syndromes, Bloom and Rothmund-Thompson syndrome, respectively [14], [15]. DCLRE1C encodes ARTEMIS, which is essential for V(D)J recombination. Biallelic mutations result in severe combined immunodeficiency (SCID), in which lymphoma has been described [16]. Curiously, the currently observed DCLRE1C allele is one of the most frequent mutations reported among SCID patients. This null allele comprises a gross deletion of exons 1–4 and the adjacent MEIG1 gene and results from homologous recombination of DCLRE1C with the pseudo-DCLRE1C gene, located 61.2 kb upstream [17]. Based on their biological functions BLM, RECQL4 and DCLRE1C all represent attractive susceptibility genes, although to date clearly deleterious, breast cancer related mutations have not been reported in any of them. Although not significantly overrepresented, it should be noted, however, that another DNA repair gene, MCPH1, was found to be disrupted in one of the studied controls. MCPH1 is an early DNA damage responsive protein, the dysfunction of which leads to recessive primary microcephaly without any reported malignancies [18]. The observed CNV deletes exon 13 and is predicted to lead to out of frame translation of the last exon, number 14, thereby disrupting one of the three BRCT domains of MCPH1. The carrier was still healthy at the age of 59 years, supporting the previous notion that all DNA damage response gene deficiencies do not necessarily predispose to malignancy.
The genes disrupted in familial cases were also highly overrepresented among genes connected to diabetes mellitus (P = 0.000268); this connection was mediated mainly through SNP associations observed in GWAS [19]. This overrepresentation was also seen in the young breast cancer cohort (P = 0.0246), but not in controls. Of the 16 diabetes associated genes 6 were under β-estradiol regulation.
Network analysis reveals TP53 and β-estradiol centered networks in breast cancer cases
The strict pathway-based approach has several limitations as the function of many genes is currently unknown and cannot be assigned to any predetermined pathways [20]. Consequently, we next analyzed IPA networks, which map the biological relationships of the uploaded genes. Curiously, analysis with familial cases revealed a network centered on TP53 and β-estradiol (score 29). The same TP53 and β-estradiol centered network was observed when analyzing genes disrupted in the young breast cancer cohort (score 28) (Figures S1 and S2). When analyzing both case cohorts together the network with the highest scores (35, 31) centered on TP53, β-estradiol and CTNNB1 (encoding β–catenin, the oncogenic nuclear accumulation of which occurs in several malignancies, including breast cancer [21]) and the other around β-estradiol (Figure 1, Table 3). Neither the TP53 nor β-estradiol centered network was observed in controls, strongly arguing in favour of the possibility that dysregulation of these networks is disease related.
IPA was used to identify the connection between the genes disrupted in all cases (both familial and the cohort consisting of young breast cancer patients). The analysis identified two networks with (A) TP53, β-estradiol and CTNNB1 (in green) occupying the central positions, and (B) β-estradiol (in green) occupying the central position. Genes disrupted in breast cancer cases are coloured with red. Solid lines indicate direct molecular interaction and dashed lines indicate indirect molecular interaction.
The TP53 centered network appears to have obvious tumor suppressive function, as p53 itself is a key regulator in preventing cells from malignancy. Somatic TP53 mutations occur frequently in human malignancies, and germline lesions associate with the cancer prone Li-Fraumeni syndrome [22]. In the studied breast cancer cases, six genes disrupted by the observed rare CNVs were directly linked to TP53 (Figure 1A), and all encode proteins functioning in pathways with a potential role in malignancy prevention. Two of these, RECQL4 and BLM, were DNA damage response proteins. Network interactions were based on the repression of RECQL4 transcription by p53 [23], and the requirement of BLM for p53 localization to stalled replication forks [24]. The other four interactions were based on direct binding of p53 with HECW2 [25], DAB2IP and EIF2C2 [26]; for CASP3 p53 has been shown to increase its activation [27]. The HECW2 disrupting allele was observed in two familial cases, whereas the others were all singletons (Table S1).
The other network indicated in both of the studied breast cancer case cohorts centered on β-estradiol (Figure 1A and 1B), which is the primary biologically active form of estrogen. Exposure to both exogenous and endogenous estrogens is a well-established risk factor for breast cancer, and disruptions in estrogen signaling and metabolism have a potential to affect this risk. The physiological effects of estrogens are mediated by their ability to alter the expression of their target genes. Estrogens play a key role in proliferation and differentiation of healthy breast epithelium, but also contribute to the progression of breast cancer by promoting the growth of transformed cells [28]. Many of the estrogen actions are mediated by intracellular estrogen receptors ESR1 and ESR2 [29]. The β-estradiol centered network consisted of several β-estradiol responsive genes, ANKS1B [30], NXPH1, MEP1B [31], CASP3 [32] and ACSL1 [31], whereas when separately tested in IPA none of the genes disrupted in controls were found to be under β-estradiol regulation. Of the network genes ESR2, STRN and ANKS1B exhibited recurrent disrupting alleles among cancer cases (Table S1), emphasizing their potential role in breast cancer predisposition.
The results from our high-resolution genome-wide scans for structural variants provide evidence that rare CNVs contribute to breast cancer susceptibility. When compared to controls, the studied breast cancer cases showed a slight but consistent increase in the frequency of rare CNVs. The difference was not as profound as seen in psychiatric disorder studies where the observed changes, typically involving large genomic regions and numerous genes, can have very severe effects on patients' phenotype and many of which are de novo mutations [4], [5]. However, in our study the biological networks affected by the disrupted genes differed between breast cancer cases and controls, supporting their role in cancer predisposition.
The genes disrupted in familial cases showed a significant overrepresentation in functions involving the maintenance of genomic integrity. This included DSB repair, which is consistent with the prevailing paradigm that defects in this pathway contribute to breast cancer predisposition [2]. The three DSB repair genes, BLM, RECQL4 and DCLRE1C, disrupted in the case group all represent attractive breast cancer susceptibility genes. Moreover, IPA analysis demonstrated that the genes disrupted by rare CNVs in the studied breast cancer cases formed a network centered on TP53 and β-estradiol, a notion confirmed in two independent cohorts. Both networks are coherent and biologically meaningful, and their identification through the used genome-wide approach provides strong evidence for a role in breast cancer predisposition.
TP53 network genes encode proteins functioning in pathways with potential role in malignancy prevention, including DNA damage response and apoptosis [25], but also RNA interference [33]. They all represent attractive susceptibility genes, which could harbor also other cancer predisposing mutations; thus being excellent candidates for re-sequencing studies. Of the disrupted TP53 network genes DAB2IP and CASP3 were particularly interesting. DAB2IP is a member of the Ras GTPase-activating gene family and has been reported to act as a tumor suppressor. Inactivation of DAB2IP by promoter methylation occurs in several malignancies, including prostate and breast cancer [34], and it has been shown to modulate epithelial-to-mesenchymal transition and prostate-cancer metastasis [35]. CASP3 is an apoptosis related gene, which encodes a member of a highly conserved caspase protease family, caspase 3. Caspases are key intermediaries of the apoptotic process, failure of which can lead to cancer [36]. Various molecular epidemiological studies have suggested that SNPs in caspases may contribute to cancer risk, and a common coding variant in caspase 8 has been associated with breast cancer susceptibility [36], [37]. Curiously, apoptosis is also one of the numerous genomic integrity maintenance functions of BRCA1. Caspase 3 has been reported to mediate the cleavage of BRCA1 during UV-induced apoptosis, and the cleaved C-terminal fragment triggers the apoptotic response through activation of BRCA1 downstream effectors [38]. The rare CNVs disrupting the DAB2IP and CASP3 genes were both predicted to result in null alleles (Table 3).
For estrogen, there are multiple lines of evidence for its profound role in breast cancer development, and disruptions in estrogen signaling and metabolism have long been considered to affect breast cancer risk. The estrogen network was largely explained by the genes under β-estradiol regulation, but two of the disrupted genes, ESR2 and STRN, had a more straightforward role in estrogen signalling. ESR2 encodes the estrogen receptor β, which is one of the main mediators of estrogen actions within the cell [29]. It binds estrogens with a similar affinity as estrogen receptor α, and activates expression of estrogen response element containing genes [39]. ESR2 has previously been suggested to harbor common breast cancer predisposing variants [40], [41], and ESR2 variation has been suggested to influence the development of breast cancer also by in vitro studies [42]. In contrast, striatin acts as molecular scaffold in non-genomic estrogen-mediated signaling [43]. It physically interacts with calmodulin 1 [44] and estrogen receptor α, and also forms a complex with protein phosphatase 2A, which also regulates the function of estrogen receptor α [45]. The identification of a recurrent deletion allele in CYP2C19, encoding an enzyme involved in estrogen metabolism [46] and with an increased frequency in familial cases (Table S2), further emphasizes the role of estrogen in breast cancer predisposition. One CYP2C19 allele, CYP2C19*17, defining an ultra-rapid metabolizer phenotype, has previously been associated with a decreased risk for breast cancer. This suggests that increased catabolism of estrogens by CYP2C19 may lead to decreased estrogen levels and therefore reduced breast cancer risk [47]. Correspondingly, decreased activity of CYP2C19 through haploinsufficiency might potentially increase the risk of breast cancer. Curiously, based on their function both ESR2 [40], [41] and CYP2C19 [47] have long been considered strong candidate genes for breast cancer susceptibility. However, no structural variants have previously been reported in either of them, and it is possible that CNVs might represent a new class of cancer predisposing variation in both genes. Functionally relevant structural variants might be present also in other CYP genes that locate in gene clusters, like CYP2C19 [48]. The clustering of similar genes increases the potential for unequal crossing-over between sister chromatids and thus for creation of CNV alleles.
The genes disrupted in both studied breast cancer cohorts were also significantly overrepresented among genes connected to diabetes mellitus. This unexpected result likely represents shared risk factors predisposing to both breast cancer and diabetes. Indeed, these two diseases have already been reported to share several non-genetic risk factors, including obesity and a sedentary lifestyle. The hormonal factors altered in diabetes include several hormonal systems that may also affect the development of breast cancer, including insulin, insulin-like growth factors, and other growth factors as well as estrogen [49], [50]. Our results support estrogen being the key link in the association between diabetes and breast cancer, as over one third of the diabetes associated genes in the two studied breast cancer cohorts were part of the β-estradiol network.
In conclusion, rare CNVs should be recognized as an alternative source of genetic variation influencing breast cancer risk. This notion is further supported by a recent study which also provided evidence for rare CNVs' contribution to familial and early-onset breast cancer [51]. The results from the current network analysis with two independent breast cancer cohorts provide strong evidence for the role of estrogen mediated signaling in breast cancer predisposition and reinforce the concept of TP53 centered tumor suppression in the prevention of malignancy. The variety of disrupted genes belonging to these networks underscores that diverse mechanisms are likely to be relevant to breast cancer pathogenesis.
Materials and Methods
The studied familial breast cancer cohort consisted of affected index cases of 103 Northern Finnish breast, or breast-and ovarian cancer families. 73 of the families were considered as high risk ones: 67 had three or more cases of breast cancer, potentially in combination with single ovarian cancer in first- or second-degree relatives, and 6 had two cases of breast, or breast and ovarian cancer in first- or second-degree relatives, of which at least one with early disease onset (<35 years), bilateral breast cancer, or multiple primary tumors including breast or ovarian cancer in the same individual. The remaining 30 families were indicative of moderate disease susceptibility, and had two cases of breast cancer in first- or second-degree relatives, of which at least the other breast cancer was diagnosed under the age of 50. The median at the age of diagnosis for the familial cases was 49 years (variation 26–89 years), and all families were negative for Finnish BRCA1, BRCA2, TP53 and PALB2 founder mutations [52].
The studied young breast cancer cohort consisted of 75 Northern Finnish patients that were diagnosed with breast cancer at or under the age of 40 (median 38, variation 25–40 years). These patients were unselected for a family history of the disease, and tested negative for Finnish BRCA1, BRCA2 and PALB2 founder mutations. This independent breast cancer cohort was collected as a validation group for the studied familial cases, based on the assumption that when a woman under the age of 40 years develops breast cancer, a hereditary predisposition may be suspected regardless whether there is a family history or not [53]. All biological specimens and clinical information of the familial and young breast cancer cases investigated were collected at the Oulu University Hospital, with the written informed consent of the patients. The geographically and ancestrally matched control group consisted of 128 anonymous cancer-free female Northern Finnish Red-Cross blood donors (median age at monitoring was 56, variation 50–66 years). Permission to use the above mentioned patient and control materials for studies on hereditary predisposition to cancer has been obtained from the Finnish Ministry of Social Affairs and Health (Dnr 46/07/98), and the Ethical Committee of the Northern-Ostrobothnia Health Care District (Dnr 88/2000+amendment). All genomic DNA samples analyzed derived from blood samples extracted using either the standard phenol-chloroform method, Puregene D-50K purification kit (Gentra, Minneapolis, MN, USA), or UltraClean Blood DNA Isolation Kit (MoBio, Carlsbad, CA, USA ) and no DNA samples from immortalized lymphoblastoid cell lines were used.
CNV discovery with Illumina platform
CNV discovery for both the familial and young breast cancer cohort as well as for the healthy controls was performed by using Illumina HumanOmni1-Quad BeadChips (Illumina Inc., San Diego, CA, USA). This provides high-resolution coverage of the genome with over one million genetic markers, including those derived from the 1,000 Genomes Project and all three HapMap phases, and enables precise definition of the breakpoints. All samples included in the array had to pass the standard quality control (QC) measures, which included agarose gel runs to confirm the integrity of the DNA sample, and accurate concentration determination with three-step dilution measurements. To control the confounding effects resulting from the handling of the samples and subsequent CNV analysis, all cases and controls were given new IDs and were blindly analyzed without knowing their disease status. All samples were analyzed following the Illumina provided protocol in the same laboratory (Laboratory of Cancer Genetics, University of Oulu) with same arrays at the same period of time, with random places on the chip.
Samples were analyzed with GenomeStudio Genotyping module (Illumina) and Nexus Copy Number Discovery Edition 5.1 software (BioDiscovery Inc., El Segundo, CA, USA). Projects were created in GenomeStudio, and samples having Call Rates over 98% were transported to Nexus where samples with quality score <0.15 were passed on for further analysis. In order to obtain a high-quality CNV dataset, we restricted the analysis to CNVs called by two independent algorithms. In Nexus the SNP-FASST2 segmentation algorithm was used. The significance threshold was set to 1.0E-06, and +0.25 for gains and −0.25 for losses. The minimum number of probes needed for segment calling was set to 25, and minimum loss of heterozygosity length to 10 000 kb. Quadratic correction was used as a systematic correction of artifacts caused by GC content and fragment length. Samples passing all the QCs but showing over 50 copy number changes in Nexus were excluded. The sensitivity of detection in Nexus was evaluated by analyzing 11 samples containing known deletions/amplifications confirmed by independent methods, and all changes were detected under the parameters used. All observed CNVs had to be confirmed by Illumina cnvPartition 2.4.4 software, using a confidence level of over 50 in order to be included in the analysis: values of 50 or higher tend to reflect a region with high confidence. The breakpoints of the observed aberrations were defined using the information obtained from both Nexus and GenomeStudio, and CNVs that appeared to be artificially split by the algorithm were joined.
The focus of our interest was on rare duplications and deletions. Rare events were defined as those which were called by two independent algorithms and did not overlap over 60% with the common CNVs in the CNV track defined in Nexus, based on the Toronto Database of Genomic Variants (DGV). However, as the DGV database presents several known cancer susceptibility genes as containing polymorphic CNVs, each CNV not fulfilling the rare variant criteria were individually inspected before exclusion. As a result, we decided to include "common" CNV in the rare variant analysis if fulfilling all three of the following criteria: 1) the CNV disrupts the involved gene partially, or deletes it entirely, 2) affected gene is a known breast cancer susceptibility gene, or based on it biological function it is a highly likely breast cancer susceptibility gene, and 3) biallelic defects in the involved gene lead to a rare genomic disorder, indicating that the defective allele is highly unlikely to be polymorphism. This led to inclusion of three alleles disrupting the following genes: RECQL4, MCPH1 and DCLRE1C. All "rare" events which were present at polymorphic frequencies in the pooled population of 250 cases and controls, except those that were specific or showed a clear enrichment in cancer cases, were excluded from further analyses.
All potential events of interest, rare CNV variants, were validated by another independent method, either by Affymetrix Genome-Wide Human SNP Array 6.0 platform (Affymetrix, Santa Clara, CA, USA) or quantitative real time PCR (qPCR). Affymetrix chip analysis was performed following all the QC measures recommended by the protocol, and Affymetrix CEL files were transported to Nexus for analysis with the SNP-FASST2 segmentation algorithm. Confirmation with qPCR was done with BioRad CFX96 using SsoFast EvaGreen Supermix (BioRad, Hercules, CA, USA). Samples with rare CNVs and at least 3 wildtype controls were analyzed in triplicate, and quantitation was done with CFX manager software (version 1.5) under gene expression analysis. RAD50 and CtIP were used as reference genes.
Statistical analyses
Rare variant carrier frequencies between cancer cases and controls were compared using Fisher's exact test. The frequency of common CNVs and the size of duplications and deletions was monitored both in cases and controls and tested for differences with Mann-Whitney U-test (PASW Statistics 18.0 for Windows, SPSS Inc., Chicago, IL, USA). All tests were two-sided and considered to be statistically significant with a P-value≤0.05.
Network analysis and functional profiling
For pathway and biological function analysis, Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com/) was used. The list of disrupted genes [defined as genes (including also their promoter region) disrupted by the breakpoints or deleted entirely, and not shared between cases and controls] were uploaded to IPA, which is an online exploratory tool with a curated database for over 20,000 mammalian genes and 1.9 million published literature references. Together with several databases, including Entrez Gene, Gene Ontology and GWAS database, IPA integrates transcriptomics data with mining techniques to predict and build up networks, pathways and biological function clusters. The software maps the biological relationships of the uploaded genes according to published literature included in the Ingenuity database. The output results are given as scores and P-values computed based on the numbers of uploaded genes in the cluster or network and the size of network or cluster in the Ingenuity knowledge database. Benjamini-Hochberg multiple testing correction P-values (to monitor the false discovery rate) were used to determine the probability that each biological function or overrepresentation in diseases is due to change alone. Scores for IPA networks are the negative logarithm of the P-value, and they indicate the likelihood of the genes analyzed in a network for being found together due to random chance. Scores 2 or higher have at least a 99% likelihood of not being generated by chance alone.
Supporting Information
Figure S1.
TP53 and β-estradiol centered network in familial breast cancer cases. IPA was used to identify the connection between the genes disrupted in familial breast cancer cases. The analysis identified a network with TP53 and beta-estradiol (in green) occupying the central positions. Genes disrupted in breast cancer cases are coloured with red. Solid lines indicate direct molecular interaction and dashed lines indicate indirect molecular interaction.
Figure S2.
TP53 and β-estradiol centered network in young breast cancer cases. IPA was used to identify the connection between the genes disrupted in young breast cancer cases. The analysis identified a network with TP53 and β-estradiol (in green) occupying the central positions. Genes disrupted in breast cancer cases are coloured with red. Solid lines indicate direct molecular interaction and dashed lines indicate indirect molecular interaction.
Table S1.
Novel rare CNVs in genomic DNA that delete or duplicate genes in breast cancer cases and controls.
Table S2.
Novel rare CNVs in genomic DNA that delete or duplicate genes observed in both breast cancer cases and controls.
Table S3.
Novel rare CNVs in genomic DNA that delete or duplicate genomic regions without annotated genes in breast cancer cases and controls.
We thank Dr. Aki Mustonen, Dr. Jukka Moilanen, Dr. Mervi Grip, and Nurse Kari Mononen for help in sample and data collection.
Author Contributions
Designed the study: KP RW. Designed and performed qPCR confirmations: MV KP. Performed the microarrays: MO KP. Performed the founder mutation analysis for the young breast cancer patient cohort: AK MV. Ran the CNV and IPA analysis: KP. Provided the young breast cancer cohort: AJ-V. Drafted the manuscript: KP. Prepared the final manuscript: KP RW. Contributed to critical review of the paper: KP MV MO AK AJ-V RW.
- 1. Lichtenstein P, Holm NV, Verkasalo PK, Iliadou A, Kaprio J, et al. (2000) Environmental and heritable factors in the causation of cancer–analyses of cohorts of twins from sweden, denmark, and finland. N Engl J Med 343: 78–85.
- 2. Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40: 17–22.
- 3. Turnbull C, Ahmed S, Morrison J, Pernet D, Renwick A, et al. (2010) Genome-wide association study identifies five new breast cancer susceptibility loci. Nat Genet 42: 504–507.
- 4. International Schizophrenia Consortium (2008) Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455: 237–241.
- 5. Walsh T, McClellan JM, McCarthy SE, Addington AM, Pierce SB, et al. (2008) Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320: 539–543.
- 6. Craddock N, Hurles ME, Cardin N, Pearson RD, et al. Wellcome Trust Case Control Consortium (2010) Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls. Nature 464: 713–720.
- 7. Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108: 171–182.
- 8. Tokino T, Nakamura Y (2000) The role of p53-target genes in human cancer. Crit Rev Oncol Hematol 33: 1–6.
- 9. Keniry M, Parsons R (2008) The role of PTEN signaling perturbations in cancer and in targeted therapy. Oncogene 27: 5477–5485.
- 10. Fodde R, Smits R (2002) Cancer biology. A matter of dosage. Science 298: 761–763.
- 11. Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, et al. (2000) BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures. Genes Dev 14: 927–939.
- 12.
Abe T, Yoshimura A, Hosono Y, Tada S, Seki M, et al. (2011) The N-terminal region of RECQL4 lacking the helicase domain is both essential and sufficient for the viability of vertebrate cells. role of the N-terminal region of RECQL4 in cells. Biochim Biophys Acta. 1813. : 473–479.
- 13. Ma Y, Pannicke U, Schwarz K, Lieber MR (2002) Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination. Cell 108: 781–794.
- 14. Ellis NA, Groden J, Ye TZ, Straughen J, Lennon DJ, et al. (1995) The bloom's syndrome gene product is homologous to RecQ helicases. Cell 83: 655–666.
- 15. Kitao S, Shimamoto A, Goto M, Miller RW, Smithson WA, et al. (1999) Mutations in RECQL4 cause a subset of cases of rothmund-thomson syndrome. Nat Genet 22: 82–84.
- 16. Moshous D, Pannetier C, Chasseval Rd R, Deist Fl F, Cavazzana-Calvo M, et al. (2003) Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in artemis. J Clin Invest 111: 381–387.
- 17. Pannicke U, Honig M, Schulze I, Rohr J, Heinz GA, et al. (2010) The most frequent DCLRE1C (ARTEMIS) mutations are based on homologous recombination events. Hum Mutat 31: 197–207.
- 18. Gavvovidis I, Pohlmann C, Marchal JA, Stumm M, Yamashita D, et al. (2010) MCPH1 patient cells exhibit delayed release from DNA damage-induced G2/M checkpoint arrest. Cell Cycle 9: 4893–4899.
- 19. Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447: 661–678.
- 20. Menashe I, Maeder D, Garcia-Closas M, Figueroa JD, Bhattacharjee S, et al. (2010) Pathway analysis of breast cancer genome-wide association study highlights three pathways and one canonical signaling cascade. Cancer Res 70: 4453–4459.
- 21. Lin SY, Xia W, Wang JC, Kwong KY, Spohn B, et al. (2000) Beta-catenin, a novel prognostic marker for breast cancer: Its roles in cyclin D1 expression and cancer progression. Proc Natl Acad Sci U S A 97: 4262–4266.
- 22. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, et al. (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233–1238.
- 23. Sengupta S, Shimamoto A, Koshiji M, Pedeux R, Rusin M, et al. (2005) Tumor suppressor p53 represses transcription of RECQ4 helicase. Oncogene 24: 1738–1748.
- 24. Sengupta S, Linke SP, Pedeux R, Yang Q, Farnsworth J, et al. (2003) BLM helicase-dependent transport of p53 to sites of stalled DNA replication forks modulates homologous recombination. EMBO J 22: 1210–1222.
- 25. Miyazaki K, Ozaki T, Kato C, Hanamoto T, Fujita T, et al. (2003) A novel HECT-type E3 ubiquitin ligase, NEDL2, stabilizes p73 and enhances its transcriptional activity. Biochem Biophys Res Commun 308: 106–113.
- 26. Lunardi A, Di Minin G, Provero P, Dal Ferro M, Carotti M, et al. (2010) A genome-scale protein interaction profile of drosophila p53 uncovers additional nodes of the human p53 network. Proc Natl Acad Sci U S A 107: 6322–6327.
- 27. Cummings BS, Schnellmann RG (2002) Cisplatin-induced renal cell apoptosis: Caspase 3-dependent and -independent pathways. J Pharmacol Exp Ther 302: 8–17.
- 28. Anderson E (2002) The role of oestrogen and progesterone receptors in human mammary development and tumorigenesis. Breast Cancer Res 4: 197–201.
- 29. Barros RP, Gustafsson JA (2011) Estrogen receptors and the metabolic network. Cell Metab 14: 289–299.
- 30. Sauve K, Lepage J, Sanchez M, Heveker N, Tremblay A (2009) Positive feedback activation of estrogen receptors by the CXCL12-CXCR4 pathway. Cancer Res 69: 5793–5800.
- 31. Thompson CJ, Tam NN, Joyce JM, Leav I, Ho SM (2002) Gene expression profiling of testosterone and estradiol-17 beta-induced prostatic dysplasia in noble rats and response to the antiestrogen ICI 182,780. Endocrinology 143: 2093–2105.
- 32. Childs EW, Tharakan B, Hunter FA, Smythe WR (2010) 17beta-estradiol mediated protection against vascular leak after hemorrhagic shock: Role of estrogen receptors and apoptotic signaling. Shock 34: 229–235.
- 33. Liu J, Carmell MA, Rivas FV, Marsden CG, Thomson JM, et al. (2004) Argonaute2 is the catalytic engine of mammalian RNAi. Science 305: 1437–1441.
- 34. Dote H, Toyooka S, Tsukuda K, Yano M, Ouchida M, et al. (2004) Aberrant promoter methylation in human DAB2 interactive protein (hDAB2IP) gene in breast cancer. Clin Cancer Res 10: 2082–2089.
- 35. Xie D, Gore C, Liu J, Pong RC, Mason R, et al. (2010) Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis. Proc Natl Acad Sci U S A 107: 2485–2490.
- 36. Hengartner MO (2000) The biochemistry of apoptosis. Nature 407: 770–776.
- 37. Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, et al. (2007) A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet 39: 352–358.
- 38. Zhan Q, Jin S, Ng B, Plisket J, Shangary S, et al. (2002) Caspase-3 mediated cleavage of BRCA1 during UV-induced apoptosis. Oncogene 21: 5335–5345.
- 39. Ogawa S, Inoue S, Watanabe T, Hiroi H, Orimo A, et al. (1998) The complete primary structure of human estrogen receptor beta (hER beta) and its heterodimerization with ER alpha in vivo and in vitro. Biochem Biophys Res Commun 243: 122–126.
- 40. Maguire P, Margolin S, Skoglund J, Sun XF, Gustafsson JA, et al. (2005) Estrogen receptor beta (ESR2) polymorphisms in familial and sporadic breast cancer. Breast Cancer Res Treat 94: 145–152.
- 41. Gold B, Kalush F, Bergeron J, Scott K, Mitra N, et al. (2004) Estrogen receptor genotypes and haplotypes associated with breast cancer risk. Cancer Res 64: 8891–8900.
- 42. Speirs V, Kerin MJ (2000) Prognostic significance of oestrogen receptor beta in breast cancer. Br J Surg 87: 405–409.
- 43. Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, et al. (2004) Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha. Proc Natl Acad Sci U S A 101: 17126–17131.
- 44. Castets F, Bartoli M, Barnier JV, Baillat G, Salin P, et al. (1996) A novel calmodulin-binding protein, belonging to the WD-repeat family, is localized in dendrites of a subset of CNS neurons. J Cell Biol 134: 1051–1062.
- 45. Lu Q, Surks HK, Ebling H, Baur WE, Brown D, et al. (2003) Regulation of estrogen receptor alpha-mediated transcription by a direct interaction with protein phosphatase 2A. J Biol Chem 278: 4639–4645.
- 46. Guengerich FP (2001) Forging the links between metabolism and carcinogenesis. Mutat Res 488: 195–209.
- 47. Justenhoven C, Hamann U, Pierl CB, Baisch C, Harth V, et al. (2009) CYP2C19*17 is associated with decreased breast cancer risk. Breast Cancer Res Treat 115: 391–396.
- 48. Gray IC, Nobile C, Muresu R, Ford S, Spurr NK (1995) A 2.4-megabase physical map spanning the CYP2C gene cluster on chromosome 10q24. Genomics 28: 328–332.
- 49. Larsson SC, Mantzoros CS, Wolk A (2007) Diabetes mellitus and risk of breast cancer: A meta-analysis. Int J Cancer 121: 856–862.
- 50. Xue F, Michels KB (2007) Diabetes, metabolic syndrome, and breast cancer: A review of the current evidence. Am J Clin Nutr 86: s823–35.
- 51. Krepischi AC, Achatz MI, Santos EM, Costa SS, Lisboa BC, et al. (2012) Germline DNA copy number variation in familial and early-onset breast cancer. Breast Cancer Res 14: R24.
- 52. Erkko H, Xia B, Nikkilä J, Schleutker J, Syrjäkoski K, et al. (2007) A recurrent mutation in PALB2 in finnish cancer families. Nature 446: 316–319.
- 53. Brunet J (2010) Hereditary breast cancer and genetic counseling in young women. Breast Cancer Res Treat 123: Suppl 17–9.
- 54. Kuiper RP, Ligtenberg MJ, Hoogerbrugge N, Geurts van Kessel A (2010) Germline copy number variation and cancer risk. Curr Opin Genet Dev 20: 282–289.


text:
I'm just saying that after you read this post on travel quotes, you may feel a sudden urge to look at flights to that place you've been wanting to go to…don't say I didn't warn you.
I was reading an article not too long ago that was talking about the science behind inspiring quotes, which you can find here if you're interested in taking a look at it. They mention a lot of good points, but I think they said a key point that I liked the most. Quotes (travel quotes fit in here) have a coaching factor, and it's these words that can change your mindset. It's like having a coach, a teacher, or a mentor telling you that they believe these things are attainable, and they are for you. So go after them.
I am someone who loves to find travel inspiration through words that have been pre-arranged in such fluid and beautiful sentences. Words that really have a way to tell us how it is while encouraging us towards travel, in this case. The truth is, travel is more than just being in a new surrounding, seeing new sites, and taking pictures. It can be this, but it is also expanding your sense of self, your awareness of the world, and your overall perspectives in all aspects of life. Travel provides multiple lessons, which is why for some of us, we can't stop doing it. Travel quotes really are like having someone tell us what we want deep down, amidst the fear we have to do it. Whenever we feel lost, in search for a sign, we look to quotes to quickly pick us up, or even if we don't think we need to hear it, quotes somehow always get us thinking and feeling better than before.
So, travel quotes
If you are someone who has always wanted to take a trip somewhere, but because of one thing or the other you never did it, this post is for you. I hope that you find in these travel quotes the inspiration and push you need to finally go on that trip you've been thinking of because excuses to go will always be there. It's up to you to make the time.
So get comfy, put on some nice, relaxing, inspiring music (maybe something like this) to set the mood, and get ready for some of the realest travel quotes that you need to read.
Which travel quote did you find the most real? The most inspiring? The one that made you go woah? Do you have any other travel quotes that you like to go by? Please share in the comments below, as I would also really like to know more and we can help inspire one another to learn and grow from this beautiful world 🙂


text:
Yuneec Extended Service (YES!) Plans are available directly from Yuneec by phone or online. YES! Plans are also available at many local retailers.
Q. Where can I purchase Yuneec Extended Service?
Q. I already have a Yuneec product, can I purchase a YES! Plan?
YES! Plans may be purchased for up to 90 days after the covered item was purchased.
Q. What products are eligible for Yuneec Extended Service?
Yuneec is proud to offer YES! Plans for the Typhoon H, Typhoon H with RealSense, and the Breeze 4K.
Q. Where can I get my drone repaired with my YES! Plan?
Yuneec has authorized repair facilities accross the United States and Canada. Please contact Customer Care to arrange repair services.
Q. When is my plan active?
You will receive instructions on activating your YES! As of November 8th, 2017 all YES! Plans coverage will be active from the purchase date of the covered drone.
Q. Are YES! Plans transferrable?
Once activated, Yuneec Extended Service Plans follow the unit for which they are activated. If you purchase an item with a Yuneec Extended Service Plan we will be more than happy to offer you the same service options for the duration of the plan.
Q. How do I receive my discount?
Any YES! Plan that is completely unused is eligible for a discount. All unused two (2) year plans are eligible for a 30% discount on the purchase of a Yuneec UAV. All unused one (1) year plans are eligible for a 20% discount on the purchase of a Yuneec UAV. This discount will be provided via e-mail to the registered plan owner at the completion of the eligible plan.
Q. How long do I have to use my discount?
All YES! Plan related discount codes are valid for six (6) months from the issue date.
Q. Where can I view my plan information?
YES! Plan holders can view their plan information via the online customer portal. Simply login to your account and select the "YES! Service Plan" tab.
Q. I don't see my YES! Plan on my account page.
First, ensure that you have activated your plan. If your plan is activated and you still don't see it, contact Yuneec Customer Care via email at email@example.com or by phone at (844) 898-6332. Please provide your contact and plan information so our Customer Care can locate your plan and customer account.


text:
We offer a free, no obligation valuation of your property. Evening and weekend appointments are available for your convenience.
As an expert in the Washington area, Jill can offer an insight into the sale of similar properties as well as advice on the marketing and presentation of your home.
© 2020 Jill Moore Select Properties


text:
Here are a few random shots to start the week off right. We had a brief storm front pass by hear in Southern California but it looks like we are going to see a warming trend through out the week and next weekend should be amazing!
Monthly Archives: January 2011
Combo swell for California
Classic California
On the Road with Naki
Our good friend Naki has been on the road as usual, and just got back from touring with Donavon in Japan. Here are a couple shots of Naki on some sick left in Japan last week riding his trusty 5`0 Aviso Cole BD3.
The Santa Ana winds are swirling as I type this, looks like its going to be offshore again in the morning and there should be another decent swell filling in as well. Plan your day accordingly and have fun out there!
Morning Glory
This is the time of year that we wait for here in California. Sometimes we wait all year and it never comes. However the last few weeks we have had the most amazing combination of Santa Ana conditions and swell. The result is perfection up and down the coast, along with thousands of surfers with sore arms and smiles. If you missed it do not worry though, I hear there is more on the way…
Another beautiful California day!
Good waves down south today!
The swell was not really hitting in San Clemente today so I headed south early and ended up getting some really good waves down in Oceanside. It was howling offshore when we got there and sets were breaking in the 6 foot range. I rode my Grasshopper once again and it was working great, even on the bigger sets that came through. Cant wait to get on it again tomorrow…
Aviso Grasshopper lands in Portugal!
Here are a few shots of our friend Nuno over in Portugal with his new 5`7 Aviso Grasshopper by Cole. Nuno and I both are in agreement that this is perhaps the best Aviso that we have made to date. It is such a fun board, just the perfect hybrid of your shortboard and fish. I will be back with more tomorrow. Thanks for checking in , have a great day!
Weekend is here, waves on the way!
The waves were small here in town today compared to the last few days but there were still some waves to be had. Not to worry though, the weekend in finally here and there should be more swell filling in as I write this. The tides are still pretty high in the late mornings so get on it early or wait until the tide drains out a bit. Take care and have fun out there!
Conditions clean up again as swell continues, loving the Grasshopper!
The conditions cleaned up here in town as the swell continued through out the day. After starting out a bit slow with the extreme high tide this morning, the waves really cleaned up around midday before bottoming out in the late afternoon at a negative tide. I have been riding the new Aviso Grasshopper designed by Cole all week and I have fallen in love with this board. It might be my favorite board that I have ridden. I want to try it with some different fins and will be back with more on my favorite setups soon. Thanks for checking in, take care!


text:
« AnteriorContinuar »
classes facilitates the perpetual erosion of their territory, and the successive metamorphosis of their provinces into satellite republics, until they are ripe for absorption into the body of the Gallic planet. :
Art. XXXVII. Nonviou Tebkau Speculatif de l'Europe, &c. i.e.
A New Speculative Picture of Europe. Dy General DUMOU, Riez. 8vo. IP: 380. bis. serred. Imported by De Buffe. of this Ex-General's Speculative Picture of Lurope we spoke
V at length in our xxvth vol. p. 546. This professes to be a new edition of that work, modernized down to the month of September 1793, by incans of an additional preface. A new but insignificant sheet, intitled An Advertisement, has in fact been prefixed, but we have discovered no alteration in the body of the work itself.
Art. XXXVIII. Ioyage à la Guiane et à Cayenne, &c. i. c. A
Voyage to Guiana and Cayenne, performed in 1789, and the following Years, &c. &c. By L..... M.... B... Merchant.
8vo. Pp. 400. Paris. 1798. INSTEAD of being an account of an actual voyage, we find
this work to be a superficial and inaccurate compilation from other writers, (some of them the least worthy of selection,) without even the appearance of that kind of order, and succes- sion of incidents, which must necessarily attend the obscrvations of any single traveller or observer. Though the writer pretends to give an account of the natural productions of the different parts of Guiana, he does not appear to know any thing more than their yulgar names; and even these are employed with so little attention, that loose descriptions or pretended descriptions of the samne animal or vegetable, compiled from various writers, are given more than once in different parts of the volume. Sometimes a vulgar English name is literally translated into French, from some ignorant writer; and the cbject, which had before been described under its proper French name, is pretended to be again described under a name wholly unknown in the French language.-- Two instances of this occur at page 235--where, ist, an account is given of « Le Plantin espécie de Platane," &c. The plant here meant is the díase Puridisiaca, the common bread of the negroes, throughout the West Indies, called the Plantain by the English, and Banane by the French ; under which name it had been already repeatedly mentioned and described by this compiler, without knowing it. 2dly, In the same page," Le Pomme de Pin," &c. a name made out from the English pine-apple, which the French know only by the name " Ananas;" and under which this Mr. L. M. B. has frequently mentioned it.
To the REM A R K ABLE PASSAGes in this Volume.
N. B. To find any particular Book, or Pamphlet, see the
Table of Contents, prefixed to the Volume.
Barbosa, M. his astronomical obs.
made at Rio Janeiro, 554. ABBOT, Mr. his valuable col. Barrington, George, his creditable 41 lection of, and observations situacion at Botany Bay, 255.
on, the Lepidopterous insccts Barthélemy, Abbé, his journey to of Georgia, published in French Italy, 524. His worthy chaand English, by Dr. Smith, sacrer,ib. His foresight of 437• 439. .
the literary declension of his Aberneily, Mr. his observations on country, in consequence of the
the l'uranina Thebesiï of the revolution, ib. Contents of his heart, 73.
posthumous works, ib. ExAdvertisement, curious one, rc!. to
tracts from his " Fragments a Burglary and Robbery, with of Literary Travels in Italy,'
a letter from the thieves, 23;. 526. His " Dissertations on Anderson, Dr. James, his account Mexican Paintings," ib.
of his sucessful method of bog. Beckford v. Hood : case reported : drainin", 47.
his action for damages. See Arts, Commerce, &c unfavourable ; Keryon.
to aristocracy, 529. I. , Brewster, Dr. his translation of · Ashburit, Judge, his opinions in Persius coninended, 91.
support of liiorary property, 31. Boyce, Samuel, his character as a Astronomy, a Science over which poet, and as a man, 12.
genius has no control, 121. Di. Boyd, Hugh, said but not proved videdinto plane and p?sical, the to have been the author of lu. latter properly datingitself froin nius, and of the satirical poems the time of Sir Isaac Newton, published under the name of 126 129. Encomium on New- Malcolm Magregor, 342. ton, ib. Mr. Vince's astrono- Bradley, the lace Dr. his astrono. my commended, 131. de
mical observations from the year 1750 to 1762, now print
ing at Oxford, 167. The first Banks, chartered, in what respect vol. published, ibi. .
to be disapproved, 492. Bridge, famous wooden one across
the Rhine near Schaffhausen. Churches, of Paris, new names 488.
given to, since the revolution, Bruce, Michael, his very promis, instead of those of the saints to ing genius, 16.
whom they had been dedicated, Buonaparte, celebrated for extreme
valor, presence of mind, skill Ciera, M. his astronomical obs. in maneuvre, resource, stra made at the Royal Printing oftagem, &c. 498. His letter fice, Lisbon, from 1778 to to the Directory, dated from 1787, 554. Verona, 499.
Clairon, Mad. account of her Burke, Edmund, his conduct in memoirs of her own life, 557.
Parliament, 24. His commence. Her extraordinary merit as an ment of the famous prosecution actress, 559. of Hastings, 27. His re. Coinage, a new one, of silver, markable violence against the thoughts on, as relative to an French revolution, 29. His alteration in the division of the celebrated writings on that pound troy, 463. subject, 31. His death, 36. Collins, the poet, monument of, "Beauties" of his writings, 388, 11. Inscription on, by Mr. Account of his rise to eminence Hayley, ib. in the political line, 389. His Columba, account of that celeconnection with single-speech brated dorthern saint, 470. Hamilton, ib.
Commerce, theoretic and practical Butler, Mr, his Hore Biblicæ com. observations and delineations mended, 211,
respecting, 489. Bills of exchange considered, 490.
Money, ib. Circulation, inCaduceus, of Mercury, its origin, ternaland external, 491. Banks,
492. Assurances, 493. StrandCaiaract, of the Rhine at Schaff right, ib. hausen described, 133.
Concretions, urinary. See Pearson, Cattle, improved method of ac. CORRESPONDENCE with the
commodatingand preserving on Reviewers, viz. answer to an
board of transport ships, 251. inquiry " which are the best Ceruti, M. his obs, on the Solar authors in English, on Music,".
Eclipse, Oct. 17, 1781, made 120. From Mr. Hornsey, on
at Carthagena in Spain, 554. the common pronunciation of Chaptal, M. on the formation of the word Chorister, &c. ib.
Saltpetre,andofartificial Nitre. · From the translator of Euier's beds, 564..
Algebra, 239. Mad. Le Noir, Chesterfield, Earlof, his character, on the account given of her
53. List of his writings, 55. Institutrice et son Eleve, &c. Christ, the true time of his birth ib. From Mr. Wagstaffe, on
a matter of controversy, 258. washing seed corn, 240. Mr. The scripture Chronology not Wood on the best means of yet reduced to a certain series, maintaining and employing the 259.
poor, 356. Dr. Vincent, on Chronology, uncertain state of, certain oriental etymologies,
whether deduced from sacred or 358. Mr. Eton, on the critique profanè records, 257.
on his Survey of the Turkish
Empire, 359. Mr. Fawcett, gical observations, made at Rio informing us that Mr. Abraham Janeiro, 553. His astronomie Sharpe was not a clergyman, cal observations, made at the 360. Y. Z. Inquiring concern. same place, 554. ing English translations of the Draining of bogs, curious account
New Testament, &c. 479. of, 47. Cottage architecture, remarks on,
Eagle, a remarkable species of, Cows, extraordinary and curious in Africa, described, under the
inanagement of, among the name of Griffard, 533. See peasants in the mountainous also Oricou.
parts of Switzerland, 481. Education, uncommon plan of, ac Cow pox, a disease discovered a seminary established by the
ainong the cows in Gloucester- Rev. Mr. Catlow, 327. shire, its nature and effects, Evelyn. See Shuckburgh, with regard to the human spe. cies, 447. Possible happy consequences of suggested, with Fevers, general doctrine of, as respect to its diffusion in society, laid down by Dr. Reil, an in
instead of the small-pox, 451, genious German physician,536. Croft, Mr. his literary enterprises, Three distinctgenera of fever,s
494. His projected English nocha, typhus, and paralysis, 539. dictionary, ib.
· Discussion of the subject, ib.
Finance, politically discussed, 100, D
101. 459, 460. 464. Dallabella, M. (of the Lisbon R. Fistula Lachrymalis, how treated,
Acad.) his memoirs on the successfully] by Mr. Ware, magnetic force, 552. See also . 432. Remarkable case of, 433. Loadstone.
France, history of her republican Darwin, Dr. poetic address to, revolution, 498. Buonaparte's
from the Goddess of the Gla exploits, ib. Four distinct ciers in Switzerland, 139.
great parties still subsisting in Des Fontaines, M. his Flora stlan. France, ib. History of the re.
tica detailed and commended, volution, by two friends, to li. 530.
berty, 508. Fayette slightly Dessault, M. an eminent French regarded, ib. Durnouriez not
surgeon, biographical account a sincere friend to the republic, of, 436.
ib. Warfare of the Girondist Dodsley, Robert, the bookseller,
and Parisian parties, 509. his worthy character, 14. His
poetry appreciated, 15. Dog, a curious anecdote of one Germany, hincs relative to the old who, from his delight in music, and the new constitution of, 542. attached bimself in a most ex- Gerrald, Jos. (banished to Botany traordinary manner, frequented Bay for sedition) candid account the opera and play houses at of his behaviour there, and of his Paris, and also regularly at death, in consequence of a contached himself to a band of sumption which accompanied music, 554
him from England, 253. . Dorta, M. Sanches, (of the R. Godwin, Mrs. her extraordinary Acad. Lisbo.1,) his meteorolo. genius and uncommon charac
ter, ter, 323. Her death, and epi. Hornsły, Dr.publishes the first vol. taph, 224. Extract of a cu. of Bradley's astronom. obs. 167. rious letter from her to her Human Species, philosophical dislover; containing an assigna quisition concerning, 527. tion, 327.
Phenomena respecting the Goethe's " Wilhelm Mristers civilization of, 528. Six prina
Lehrjahre" recommended to pal periods of progressive civilthe admirers of, and critics on, ization, ib. The several periods Shakspeare, 543. • Extracts discussed, ib.-530.
from, translated, 543. Goldsmith, Dr. writes the life of Lord Bolingbroke, 13.
Jacobinism, memoirs and observ. Governmenis, aristocratic forms ations respecting, 509-521. of. See Arts.
Iceland, ancient inhabitants of, Græme, James, his poetic turn and their heroes,' divini ics, &c.
genius commemorated, 17. 382. Their poetry, with transGrieks, modern, their inclination lared specimens, 383.
to free themselves from the Illuminés, that sect discussed, pro Turkish yoke, 138. Danger, and con, 509-521. to this country, if they effect it INDIES, East. Reign of Shah by the aid of France, ib.
Aulum, 86. Observations on Grubenmann, Ulrich, a Swiss, Captain Francklia's history of
famous for his mechanical in that Potentate, 89. Boyd's Inventions, particularly his cele. dian Observer, 341. Mr. For
brated bridge across the Rhine, ster's journey from Bengal, 361. · 488.
Patoa described, 362; also Be
nares, 363. Lucnow; 364. RamHamilton, of Bangour, his poetical fûr, ib. Nûrpûr, 36;. Casmir, works characterized, 11.
366. Peshawur, 309. Cabul, ib. Hamlet, (Shakspeare's) his cha Afganistan, ib. Gasna, 370.
racter esaimated with nice and Candahar, 371. Herat, ib. uncommon discrimination and Sharût, 372. Sari, ib. Mus. taste, 545.
gidsir, ib. Hammond, the poet, Dr. Johnson's Johnson, Dr. Sam. His character
erroneous siatement, relative to attacked by Lord Orford and
the birth of, corrected, 10. defended by the Reviewers, 55, Hoppiness, human, vanily of, re 56. 194. His " Table Talk,"
flections on, 290. Useful in. 233. His opinion that the Ha., ference from those reflections, beas Corpus is the single advan292.
tage of the British government Hatchet, Mr. his analysis of the over that of other countries, Terra Australis, 76.
234. More severity on JohnHeart. See Abernethy.
son's character, 278. Hoche, General his great merit in Ireland, causes of the late rebel
quelling the rebellion in La lion in that country disclosed, Vendée, 509. His principal 94. Reports of the Irish Parliaendowments of body and mind, ment concerning, 205. Grand
578. His correspondence, 580. conspiracy of the Catholics, Horne Troke, Mr. publishes a new &c. 208. Nature and spirit
edition of his Diversions of of the rebellion, 2:9. Method Purley, 423.
recommended for a radical'se