text:
Q: Vendoring a standard library (crypto/tls) I want to make some changes to the Go crypto/tls standard library.
Is making a copy of crypto/tls in the vendor folder a good way to do this?
It almost works, it seems the vendored is copy used when I compile the application (Caddy webserver). Apart from one error I get:

go/src/github.com/user/caddy/caddytls/httphandler.go:40: cannot use "vendor/crypto/tls".Config literal (type *"vendor/crypto/tls".Config) as type *"crypto/tls".Config in field value

Is there a way of casting to get around this one error? Doesn't sound like good practice to me though.
I would have thought that the vendored copy would always be used, but it seems something is still using the standard crypto/tls library? (I think "net/http" is. Do I have to vendor this too?)

A: I actually had to do that. The most practical way is to copy and modify the package (as well as its internal dependencies) - this includes some import paths. And it is not really vendored (vendoring is basically using unmodified packages, otherwise vendoring tools will not work), it is a fork, under a different name. I would guess that caddy does not need the modified version - if it does, you need to fork and modify caddy as well.
It goes without saying, but be extremely careful when modifying crypto/tls package - I for example has to make a minimal change that does not really modify TLS operation (I needed to be able to derive key material from the session master secret and randoms).
Also, you have to fully realize that this has significant cost - when a new version of go is out, one that potentially has updates for the crypto/tls package or its dependencies, you will have to apply your changes once again, manually. Committing a diff between the vanilla version and your version helps. I don't think this is at all practical for non-trivial changes (mine were quite limited - a new public field in Config, few lines of code in handshakes, a new interface).

A: I need the same functionality. It seems like the crypto/tls package does not allow the reading of custom TLS extensions added from the client side in the ClientHello payload. It would be great to be able to check for any custom extensions and then marshal them out accordingly.
It is a pity that this is not a separate package as we could then in our go.mod file be able to use replace to specify a custom TLS package.
e.g
replace golang.org/x/crypto/tls => ./tls

Then running go mod vendor.
Where the ./tls is my local version with the changes applied.

redpajama_set_name: RedPajamaStackExchange


Here's a strategy that you may see as common sense. But in the midst of our high demands, aggressive deadlines, and our well-intentioned outreach to individuals in our organization, we may sometimes forget.
If you're leading a multi-tiered organization, and you're someone who personally engages your team at all levels, that's great. However, if communications—or more specifically delegation or directives—tend to take place between you and a team or individual who reports to one of your direct reports, be sure to include your direct report in the process.
Best practice will have you making every effort to get input from your direct report/manager prior to delegating or providing directives to his or her employee or team (i.e., to establish bandwidth/availability of the individual or team and your action's impact on manager's or team's goals; to provide clarity about your outreach to avoid any perceived threat; to demonstrate your respect for your manager's role).
At the very least, keeping your direct report in the loop about your action-oriented communications with his or her staff, even after the fact, will contribute to trusting working relationships and cohesiveness among your teams—all of which will undoubtedly generate more of the business results you're striving for.
Just got back from a needed and restful vacation. Arizona mountains, family, girlfriends, horseback riding in the open desert. It was great. And, I managed to remain totally unplugged for seven days. I set up my email to auto respond and my voice mail to state an expectation of a returned call upon my return to the office. And although it was rough preparing for the week away, and coming home to a week's worth of communications, it was well worth the break.
What I find interesting is that it seems our business culture, primarily based on technology, is shifting as it relates to being totally unavailable when we're on vacation. Our US business culture already has its problems according to research done by Vault.com, in that the US is the country with the fewest vacation days, second only to Mexico who offers just 6 days. So, at the very least in my opinion, we need to take a true break from our work while we're on vacation!
My advice to leaders—As difficult as it may be, if you are able to unplug totally on vacation, do it. Not only will you feel more rested and energized when you return to work, you and your loved ones will receive the attention you and they deserve, and you'll also set a standard and serve as a role model to those who work with and for you. Your example will serve as a small yet meaningful contribution to the well-being of your team.


By now, I'm sure that you've heard all about the virtues of video. Video is one of the most powerful ways to communicate and is one of the most shared types of content on social media. It is also one of the greatest ways for businesses to connect with their audiences. It allows you to get your brand out in a way that engages, informs and possibly, entertains your audiences.
Statistics show that people would rather watch a video about how to change a tyre than read about it; but "explainer" videos are just one of the many types of videos that you can create to benefit your business. Whatever type of video you would like to make, the benefits are substantial and long lasting.
The first great reason to create a video is because it will boost your website's SEO. Embedding a video in your website that you are hosting on YouTube, Vimeo or any other hosting platform will make your website more "valuable" to Google. The videos must be optimized and a video site map is necessary for you to be found by Google and other search engines. If you are unsure of how to do this, contact a professional company like Webbed Feet UK to assist you.
Video will also help you get and retain viewers' attention. Surveys show that viewers will spend more time on your website if you have a video. You can also drive traffic to your website through promoting your video via social media or even through email. You can create a marketing email with a screen shot or engaging image that is hyperlinked back to your video on your website. That will actually increase the chances of your email being opened, read and driving traffic to your website.
It's a fact; video will increase your conversion rate! If you are selling yourself or a service, it allows potential clients to get to know you and decide that they "like and trust you", allowing you to build a connection with your clients. If you are selling a physical product, it will simply and concisely allow your customers to see how your product works and view all of its benefits.
So, now that you know how video can work for you, let's get into how to do it!
With the advent of technology, video production capabilities are everywhere! You don't have to have a huge budget to create a great video. People can shoot great videos on mobile phones, pocket cameras and DSLR's. All you have to do is come up with an idea, script it, and shoot it. Many computers have easy "beginner" software such as Movie Maker already installed, that allows users to edit and add minimal effects and even audio overlays and music. This helps to take some of the mystery out of creating engaging videos, but beware; a poorly made video can do more damage than good! This can happen in a variety of ways. How many times have you seen a video that looks OK but the audio sounds like the people are talking in a tunnel, or worse, you can't make out what they are saying at all. You will instantly lose any credibility and very likely turn a potential customer off from doing business with you.
If you are unsure of your video producing skills or would like to get a professional video company involved, you don't have to engage a marketing company first. Most reputable video companies will have a background in business and marketing and be able to assist you with your questions and come up with a plan of action. If you are unsure what type of video you would like, do a little research. Find a similar product or service and do a Google, YouTube or Vimeo search. You will more than likely find a few examples out there that can help you hone your ideas. Make notes of what you like and what you don't like. If you engage a video production company, your project manager can assist you in identifying what style you like and what will work for you.
"About" videos are a great way for people to get to know you or your company and see what the benefits of doing business with you are. They can be very simple and straight forward such as the one we created recently for Waxing Lyrical, an automobile detailing service. This video only required a great piece of royalty free music to bring it to life!
A slightly more informative "about" video will contain some third party testimonial as well. Viewers trust third parties and you can gain your viewers' confidence quickly this way.
"Explainer" videos are a great way to showcase a product. One simple and quick one we recently produced for Croydex, a bathroom fixture company, only required a few hours to shoot and very little time to edit. This one will show the benefits of a voiceover artist.
And then there's the (fun) "awareness" video which can tell people about an organisation or event, such as the one we created for Prince Charles' Campaign for Wool to raise awareness of an event being held at the London Zoo last fall.
Jump in a give it a try! If you have the equipment and the inclination, shooting and editing your own video can be a great learning and VERY fun experience! If you would rather seek the assistance of a professional company, ask your peers or look online. Look for a video partner who is happy to discuss your ideas and offer assistance. Also, look for examples of their work. Make sure that they can do what you need them to do. Lastly, and perhaps most importantly, look for those third part testimonials! Ask to see what their previous clients have to say about them. Here at ProMotion Media, we proudly put our testimonials on our website for everyone to see.
If you have any questions on how to make a video or you'd like to know more about how we work and how we can create a fantastic video on any budget for you, please visit our website at www.promotionmedia.co.uk or feel free to contact our team on 01722 770 770.


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University Hall and EOP program renamed after CSUN alumnus and his wife
The Sundial file photo
University Hall, CSUN's administration building, will be renamed to Valera Hall in honor of CSUN alumnus Milton Valera and his wife, Debbie Valera.
Sloane Bozzi, News Editor
The California State University Board of Trustees voted on Tuesday to rename CSUN's administration building, University Hall, to Valera Hall — after Milton and Debbie Valera.
The Valeras have donated over $11 million to programs and buildings across CSUN.
The couple's contribution to the EOP Resilient Scholars Program, a CSUN program that provides resources to emancipated youth, helped create a scholarship and endowment for former foster youth. The program will also be renamed the "EOP Milt and Debbie Valera Resilient Scholars Program."
Milton Valera, a CSUN alumnus, has led the National Notary Association since 1982 and currently serves as chairman and CEO.
He served as an editor and publisher for The National Notary magazine and the Notary bulletin. Prior to his work with the NNA, Milton Valera worked at two newspapers and formed his own public relations and marketing agency.
Debbie Valera served as the executive director of the NNA for 23 years and currently serves as executive vice president. She has served on multiple boards at CSUN, including the Outstanding Graduating Senior Selection Committee.
Milton Valera serves on the boards of CSUN's Nazarian College of Business and Economics.
Through their funding, scholarships and endowments have been created among multiple colleges, including the Mike Curb College of Arts, Media, and Communication, the Michael D. Eisner College of Education and the David Nazarian College of Business and Economics, as well as the Oviatt Library and the Soraya Nazarian Center of the Performing Arts.
They also funded an endowment for the Jewish Studies Interdisciplinary Program and the College of Humanities.
The lobby of the Soraya will be renamed the "Milt and Debbie Valera Lobby."
Sloane Bozzi, Assistant News Editor
Associated Students approves resolution for free menstrual products in all bathrooms on campus
Feeling stressed from finals? Unwind and recharge yourself at the Student Recreation Center and Oasis Wellness Center
CSUN COVID-19 Counts: Update as of Nov. 24

redpajama_set_name: RedPajamaCommonCrawl


Your search for Cambodia retrieved 130 results.
Control Number: 80648821 (Call Number: KNC242.A15 E2).
Control Number: 2008008361 (Call Number: K7051 .G65 2009).
Control Number: 89027881 (Call Number: JX1255 .M39 1990).
Control Number: 2009368368 (Call Number: K845.E44 .U55 2008).
Control Number: 2006039320 (Call Number: KZ7180 .C75 2007).
Control Number: 2010006923 (Call Number: K3240 .A3384 2010).
Control Number: 2009051995 (Call Number: K5301 .K73 2010).


text:
Ferenc Nagy, (1898-1968), homme politique hongrois, premier ministre puis chef de l'État de la Hongrie ;
 Ferenc Nagy, (1884-?), joueur de football hongrois.

redpajama_set_name: RedPajamaWikipedia


A crucifix model currently attributed to Giambologna should instead be reconstituted as a work by Guglielmo della Porta and his circle of collaborators.
Continue Reading "Reconstituting a Crucifix by Guglielmo della Porta and his Colleagues"
The most popular devotional image of Christ, ca. 1600, here attributed to Jacob Cornelis Cobaert after a design by Guglielmo della Porta.
Continue Reading "A Renowned Pieta by Jacob Cornelis Cobaert"


You are a natural leader and a strong communicator, committed to deliver high quality services within 'planning and budget'. You are a team player with a proactive and flexible attitude. You are able to steer engineering processes in a 3D environment.


text:
William Rhind ( 30 de noviembre 1797 - 1874 ) fue un médico, botánico, zoólogo, meteorólogo, y geólogo escocés.

Fue docente en Botánica en Aberdeen, Escocia. Tuvo como ilustradores a J.Bishop y a William Fitch. Fitch además era semejante artista botánico con una increíble habilidad en la ilustración de complejas estructuras botánicas.

Algunas publicaciones
 The Feline Species
 Studies in Natural History

Libros
 1838. The Age of the Earth
 1841. History of the Vegetable Kingdom. 711 pp. Tuvo ocho ediciones hasta 1877.
 1842. The Geology of Scotland and Its Islands Referencias

 Manfred A. Fischer (eds.) Exkursionsflora für Österreich, Liechtenstein und Südtirol (Excursión Flora de Austria, Liechtenstein y sur del Tirol)''. Museo Provincial de Alta Austria, Linz 2005, ISBN 3-85474-140-5

Enlaces externos

Botánicos de Escocia del siglo XIX
Geólogos de Escocia del siglo XIX
Profesores de Reino Unido
Meteorólogos del Reino Unido del siglo XIX


text:
Broker Resource
Portfolio Strategy Services
Economic Incentives Advisory
Location Strategy and Site Selection
Workplace Strategy and Human Experience
Environmental Branding
Workplace Well-being
Development and Visualization
CRE Services
Newmark Integrator Model
Lease Administration and Management
Space Management and Administration
Specialty Practice Groups
Energy and Sustainability Solutions
Global Healthcare
Retail Disposition and Restructuring
Retail Occupier Services
Business and Technology Strategy
CRE Organizational Design
Software/Systems Selection
Cost Reduction Strategy
Hosting & SAAS
Program Integration Services
Master Data Strategy
VISION Insight
VISION Real Estate
Visual Asset Management System
IBM TRIRIGA
GCS Team
Top U.S. Cities For Tech Talent
Technology may be the only sector of the U.S. economy where demand for talent consistently outpaces supply. There simply aren't enough skilled technology workers, not even with the influx of developers and engineers from other countries. Perhaps the number-one issue facing any start-up or established corporation - in the tech industry or in any industry that prizes innovation – is access to a pool of software developer/engineer/computer scientist talent.
So where is the talent going? Check out my list below.
First Tier U.S. Markets for Tech Talent
San Francisco Bay Area – Boasts a large ecosystem of big-name tech companies, start-ups and universities and attracts the lion's share - approximately 70% - of technology-focused venture capital, a large draw for creative and entrepreneurial-minded software engineers. However, the Bay Area suffers from a very high cost of living and a hyper-competitive hiring environment that are forcing tech firms to expand outside the region.
New York City – Though some serious software development is done in NYC, it's not on the same scale as San Francisco. The NYC market is less start-up oriented than San Francisco – approximately 10% of technology-focused venture capital flows there – and is dominated by media-social and digital media-related tech industry, attracting application and non-engineer developers. NYC is also a center for technology consulting firms.
Seattle – Though smaller and attracting venture capital investment on par with NYC, this market has many similarities with the Bay area, thanks largely to two key, diversified technology giants, Microsoft and Amazon Seattle could easily be the cloud computing capital of the world, a technology that is certain to grow in the future.
Washington, DC-VA-MD - Washington DC's suburbs in Northern Virginia and Maryland are home to most prominent tech companies and those that specialize in government and defense contracting. The Pentagon, CIA, NSA, and FBI also employ a legion of technologists. This region has a large concentration of very specialized skills and therefore attracts tech professionals who are motivated to do such work.
Boston - In spite of the presence of top STEM schools and universities including the prestigious MIT, Boston has struggled to become a preferred location for tech companies. However, it is probably the most innovative tech hub after the San Francisco / Silicon Valley, owing largely to top notch research in its universities and tech startups that spin out of these labs. It not only benefits its large biotech and pharmaceutical clusters but also promotes cross-fertilization of ideas with the tech sector.
Second Tier U.S. Markets for Tech Talent
Austin - Like San Francisco, Austin has a significant tech start-up culture, attractive to software engineers. Many Silicon Valley companies have a presence in Austin. However, scaling in Austin has become challenging because of rapidly increasing competition.
Dallas - Due to the market's sheer size more software engineers call Dallas home than Austin; however, you'll find much of the city's tech workforce in corporate IT positions. Dallas is home to many large corporations, especially oil & gas and finance, and its start-up culture is not as dynamic as that in Austin.
Atlanta - This jewel of the south is now a cosmopolitan city with the busiest airport. Atlanta shares many characteristics with Dallas as it has many Fortune 500 headquarters that also employ corporate technology workers. Some of the top tech consulting firms also have significant presence in Atlanta. Connectivity, affordable living, big city amenities, and a diversity of job opportunities attract youth to Atlanta. Georgia Tech has one of the top engineering schools feeding this growth.
Los Angeles - Obviously a huge market with considerable room for growth, L.A. is comparatively less developed as a tech hub, with the majority of the workforce employed in the entertainment, internet of things, and social media. The universities, young demographic, innovation culture, and lifestyle alternatives make Los Angeles a potential growth market for technology companies.
Third Tier U.S. Markets for Tech Talent
Chicago - It is surprising that a city of this size with all the ingredients to be a top tech hub - along with the cultural assets that millennials prize - has yet to develop into one. The quantity and quality of universities graduating tech professionals in and around the area (including University of Illinois, Michigan, Indiana, Purdue, Notre Dame and Wisconsin) is impressive and presents a ready-to-tap growth opportunity for competition ravaged Bay Area companies.
Salt Lake City - The city's biggest challenge to attracting tech talent has been a cultural one, with the perceived dominance of religion that might limit social life.. If true in the past, this is changing fast. The lifestyle the city affords, as well as Utah's pro-business environment, is increasingly attractive to small and start-up tech firms and with Salt Lake City's growing success in drawing tech talent other companies are beginning to follow.
Portland, Oregon - Portland has quietly grown into a hub of tech innovation in the areas of Internet of Things and wearable technology. The presence of sports apparel companies, like Nike, Adidas, and Columbia, and of the semiconductor giant, Intel, has encouraged many software professionals to move to Portland. Also, many smaller tech firms and startups that can't afford to be in the Bay Area have chosen to move to Portland. Bigger names like Apple, Google, and Twitter have followed.
Denver-Boulder - This city on the edge of Rocky Mountains attracts young professionals because of the outdoor lifestyle it offers. Comcast, Oracle, and Lockheed Martin have a large presence here but there is an emerging startup ecosystem that may compete more successfully with other cities in central United States.
Emerging U.S. Markets
Pittsburgh - Though very small in comparison to the other cities on this list, Pittsburgh boasts a top university, Carnegie Mellon, which happens to be one of top 3 universities supplying San Francisco's tech talent demand. The city is shedding its image as a blue-collar town, with large players, like Google, Uber and Apple, locating development centers in Pittsburgh. Millenials are also recognizing the advantages of the city's modest cost of living when compared to the top-tier cities.
San Diego - With presence of defense technology, biotech, and pharmaceuticals, San Diego is an innovation hub. This creative culture is now attracting software professionals as technology intersects with these major sectors in San Diego. Also, the ability to set up lower-cost "off-shore" software centers in Tijuana, Mexico, which is like a twin city of San Diego, makes it possible to tap into the large talent pool south of the border.
The bottom line is, tech talent's choice of destination city comes down to the individual, and individual priorities change over time. Those who want to build and create tend to go to a top-tier city, at least for a few years. They're willing work more hours and live in smaller apartments, but at a different stage of life - perhaps when they want to start a family - they're more likely to move on to a second or third-tier city. Today's tech workforce knows lucrative jobs can be found in virtually any city, and they'll research cities that offer what's most important to them, whether it's an entrepreneurial business culture, lower cost of living, or a better work-life balance.
Rajeev Thakur
Senior Managing Director, GCS
*Data provided by The U.S. Bureau of Labor Statistics. More information can be found at https://www.bls.gov/oes/.
Companies Flock to Cities with Top Talent
© 2023 Newmark Global Corporate Services. All Rights Reserved.
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It was a gift to share in poetry-making with you all and celebrate National Poetry Month in a special way this year. Thank you to everyone who played a part in Voice & Vessel's poetry giveaway and collective poem project! In the end, more than 70 writers added their voice, and 20 books of poetry found new readers. And now, it's time to unveil our collective poem.
Throughout April, I invited folks to respond to prompts with new lines of poetry. Together, we're creating a collective poem that I'll unveil in the coming weeks. Each prompt brought a new book giveaway and a new chance to win. Twenty books of poetry were sent to new homes, and this is the complete list, which I hope will introduce you to some new favorites.
National Poetry Month: Share in poetry, get a book!
April is here... spring is not, but poetry is! Here in the U.S., April brings us National Poetry Month. Here at Voice & Vessel, I'm holding a special book giveaway to honor this special time. Throughout the month, I hope you'll join me in creating an unusual and organic collective poem -- and get chances to win new books of poetry in the process!
Sign up for studio letters and get a free copy of Seven Invitations, a weeklong journey of writing prompts and practices to connect with your unique voice.


CCS Baseball had a great week three last week as teams look forward to an action packed week four as spring gets closer to becoming a reality! Not sure where your team is competing this week? Be sure to check out this weeks schedule below. For a complete season schedule and continuing weekly scores click here.
CCS Softball had a great week three last week as teams look forward to an action packed week four as spring gets closer to becoming a reality! Not sure where your team is competing this week? Be sure to check out this weeks schedule below. For a complete season schedule and continuing weekly scores click here.
CCS Women's Soccer had an action packed week three as teams look forward to an equally exciting week four as the spring season roles on. Not sure where your team is competing this week? Be sure to check out this weeks schedule below. For a complete season schedule and continuing weekly scores click here.


text:
Ticket buying
Guides, maps and brochures
Contratación temporal
Mision and vision
The Times of Altamira
Neocave
Quebrada de Humahuaca
¡Quién!
Cave of Altamira
Explore the natural surroundings
Altamira for Families
#AltamiraDesdeCasa
De la cueva a la pradera
Altamira for Adults
#MuseoSinPrisas
Altamira for Schools
Ice Age Europe
Archaeology Workshops
Documentation and Catalogue
The discovery of art
Classic Publications
Museum and Heritage
Museology and Museography
Art and archaeology of the Altamira Cave
Other research projects
The Cantabrian Paleolithic
Art and archaeology in Paraguay
The Altamira cave
Museo Nacional y Centro de Investigación de Altamira
Visit to the cave of Altamira
Línea horizontal
Salto de línea After the temporary suspension due to Covid-19, visits to the Altamira cave have resumed on August 15, 2020, according to the decision adopted by the Permanent Commission of the Altamira Board of Trustees.
In order to respect compliance with the distancing and prevention measures that result from the current health crisis, the visitor selection system by random selection that had been carried out from 2014-2015 is temporarily suspended.
Therefore, for this purpose, the public visit to the Altamira cave is resumed by activating the waiting list established in 2002. Thus, the five weekly visitors will come from the waiting list that was suspended in 2002. Prior appointments will be assigned to applicants on the waiting list.
NEW APPLICATIONS TO ENTER THE LIST ARE NOT ALLOWED.
The Museum Reservations Department will contact the people on the waiting list in strict order.
If you are already part of this list and want to communicate any modification of personal data, such as address or telephone number, you can send an email to administracion.maltamira@cultura.gob.es
The visit will continue with the same access protocols that were approved on March 26, 2015 by the Board of Trustees of the Altamira National Museum and Research Center, which decided to maintain the regime of controlled and limited access to the Altamira cave that began in the framework of the Research Program for Preventive Conservation and Accessibility. This regimen consists of a 37-minute visit per week for five people. The visit is carried out under a strict protocol of clothing and lighting, and with a route and time spent defined for each area of the cave.Salto de línea
+ Info:
Visits to the cave are resumed. Press release.
Participants in the Cave of Altamira tour (2020)
Research Program for the Conservation and Access Regime to the Cave of Altamira.
Participants in the Cave of Altamira tour 2014-2020
Museo Nacional y Centro de Investigación de Altamira Salto de líneaMarcelino Sanz de Sautuola, S/N 39330 Santillana del Mar Salto de líneaTlf. (34) 942818005


text:
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.
Robert C Onofrio
Adam Korejwa
Kristin Ardlie
Eva Bric-Furlong
Paula Morais+19 authors
Journal: 2012/May - Nature
DOI: 10.1038/nature11003
The systematic translation of cancer genomic data into knowledge of tumour biology and therapeutic possibilities remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacological annotation is available. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacological profiles for 24 anticancer drugs across 479 of the cell lines, this collection allowed identification of genetic, lineage, and gene-expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Together, our results indicate that large, annotated cell-line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of 'personalized' therapeutic regimens.
PUBMED | DOI | PMC | Google Scholar | Wikipedia
Nature. Mar/28/2012; 483(7391): 603-607
Published online Mar/27/2012
The Cancer Cell Line Encyclopedia enables predictive modeling of anticancer drug sensitivity
Jordi Barretina
Giordano Caponigro
Nicolas Stransky
Kavitha Venkatesan
Adam A. Margolin
Sungjoon Kim
Christopher J. Wilson
Joseph Lehár
Gregory V. Kryukov+52 authors
The systematic translation of cancer genomic data into knowledge of tumor biology and therapeutic avenues remains challenging. Such efforts should be greatly aided by robust preclinical model systems that reflect the genomic diversity of human cancers and for which detailed genetic and pharmacologic annotation is available1. Here we describe the Cancer Cell Line Encyclopedia (CCLE): a compilation of gene expression, chromosomal copy number, and massively parallel sequencing data from 947 human cancer cell lines. When coupled with pharmacologic profiles for 24 anticancer drugs across 479 of the lines, this collection allowed identification of genetic, lineage, and gene expression-based predictors of drug sensitivity. In addition to known predictors, we found that plasma cell lineage correlated with sensitivity to IGF1 receptor inhibitors; AHR expression was associated with MEK inhibitor efficacy in NRAS-mutant lines; and SLFN11 expression predicted sensitivity to topoisomerase inhibitors. Altogether, our results suggest that large, annotated cell line collections may help to enable preclinical stratification schemata for anticancer agents. The generation of genetic predictions of drug response in the preclinical setting and their incorporation into cancer clinical trial design could speed the emergence of "personalized" therapeutic regimens2.
Human cancer cell lines represent a mainstay of tumor biology and drug discovery through facile experimental manipulation, global and detailed mechanistic studies, and various high-throughput applications. Numerous studies have employed cell line panels annotated with both genetic and pharmacologic data, either within a tumor lineage3–5 or across multiple cancer types6–12. While affirming the promise of systematic cell line studies, many prior efforts were limited in their depth of genetic characterization and pharmacologic interrogation.
To address these challenges, we generated a large-scale genomic dataset for 947 human cancer cell lines, together with pharmacologic profiling of 24 compounds across ~500 of these lines. The resulting collection, which we termed the Cancer Cell Line Encyclopedia (CCLE), encompasses 36 tumor types (Fig. 1a, Supplementary Table 1 and www.broadinstitute.org/ccle). All cell lines were characterized by several genomic technology platforms. The mutational status of >1,600 genes was determined by targeted massively parallel sequencing, followed by removal of variants likely to be germline events (Supplementary Methods). Moreover, 392 recurrent mutations affecting 33 known cancer genes were assessed by mass spectrometric genotyping13 (Supplementary Table 2 and Supplementary Fig. 1). DNA copy number was measured using high-density single nucleotide polymorphism arrays (Affymetrix SNP 6.0; Supplementary Methods). Finally, mRNA expression levels were obtained for each of the lines using Affymetrix U133 plus 2.0 arrays. These data were also used to confirm cell line identities (Supplementary Methods, Supplementary Figs. 2–4).
We next measured the genomic similarities by lineage between CCLE lines and primary tumors from Tumorscape14, expO, MILE and COSMIC datasets (Fig. 1b–d, see Supplementary Methods). For most lineages, a strong positive correlation was observed in both chromosomal copy number and gene expression patterns (median correlation coefficients of 0.77, range = 0.52–0.94, p < 10−15, for copy number and 0.60, range = 0.29–0.77, p < 10−15, for expression, respectively; Fig. 1b–c, Supplementary Table 3 and 4), as has been described previously3–5,15. A positive correlation was also observed for point mutation frequencies (median correlation coefficient = 0.71, range = −0.06–0.97, p < 10−2 for all but 3 lineages, Supplementary Fig. 5), even when TP53 was removed from the dataset (median correlation coefficient = 0.64, range = −0.31–0.97, p < 10−2 for all but 3 lineages; Fig. 1d, Supplementary Table 5). Thus, with relatively few exceptions (Supplementary Information), the CCLE may provide representative genetic proxies for primary tumors in many cancer types.
Given the pressing clinical need for robust molecular correlates of anticancer drug response, we incorporated a systematic framework to ascertain molecular correlates of pharmacologic sensitivity in vitro. First, 8-point dose response curves for 24 compounds (targeted and cytotoxic agents) across 481 cell lines were generated (Supplementary Tables 1 and 6, and Supplementary Methods). These curves were represented by a logistic sigmoidal function with a maximal effect level (Amax), the concentration at half- maximal activity of the compound (EC50), a Hill coefficient representing the sigmoidal transition, and the concentration at which the drug response reached an absolute inhibition of 50% (IC50).
Broadly active compounds, exemplified by the HDAC inhibitor panobinostat, showed a roughly even distribution of Amax and EC50 values across most cell lines (Fig. 2a). In contrast, the RAF inhibitor PLX4720 displayed a more selective profile: Amax or EC50 values for most cell lines could be categorized as "sensitive" or "insensitive" to PLX4720, with sensitive lines enriched for the BRAFV600E mutation (Fig. 2a). To capture simultaneously the efficacy and potency of a drug, we designated an "activity area" (Fig. 2b and Supplementary Fig. 6). The 24 compounds profiled showed wide variations in activity area, and those with similar mechanisms of action clustered together (Supplementary Fig. 7).
Genomic correlates of drug sensitivity may be extracted by predictive models using machine learning techniques6,10. We therefore assembled all CCLE genomic data types into a matrix wherein each feature was converted to a z-score across all lines (Supplementary Methods). Next, we adapted a categorical modeling approach that utilized a naive Bayes classification and discrete sensitivity calls, or an elastic net regression analysis16 for continuous sensitivity measurements. Both approaches were applied to all compounds with or without gene expression data (Supplementary Methods). Prediction performance was determined using ten-fold cross-validation, and the elastic net features were bootstrapped to retain only those that were consistent across runs (Supplementary Methods).
Out of >50,000 input features, the regression-based analysis identified multiple known features as top predictors of sensitivity to several agents (Supplementary Table 7 and Supplementary Fig. 8 and 9), with robust cross-validated performance (Supplementary Fig. 10 and 11). For example, activating mutations in BRAF and NRAS were among the top four predictors of sensitivity in models generated for the MEK inhibitor PD-032590110 (Fig. 2c). Additional predictive features for MEK inhibition included expression of PTEN, PTPN5, and SPRY2, which encodes a regulator of MAPK output. KRAS mutations were also identified, albeit with a lower predictive value (Fig. 2c, Supplementary Tables 8–9 and Supplementary Fig. 8).
Additional top predictors included EGFR mutations and ERBB2 amplification/over- expression for Erlotinib8 and Lapatinib17, respectively; BRAFV600E for RAF inhibitors (PLX472018 and RAF265); HGF expression and MET amplification for the MET/ALK inhibitor PF-234106619; and MDM2 over-expression for Nutlin-320 sensitivity. Variants affecting the EXT2 gene, which encodes a glycosyltransferase involved in heparin sulfate biosynthesis, were significantly correlated with Erlotinib sensitivity (Supplementary Fig. 12). This observation is intriguing in light of a report linking heparin sulfate with erlotinib sensitivity21. In addition, NQO1 expression was identified as the top predictive feature for sensitivity to the Hsp90 inhibitor 17-AAG, a quinone moiety metabolized by NAD(P)H:quinone oxidoreductase (NQO1). NQO1 produces a high-potency intermediate (17-AAGH2)22, and has previously been identified as a potential biomarker for Hsp90 inhibitors23.
Since some genetic/molecular alterations occur commonly in specific tumor types, lineage may become a confounding factor in predictive analyses. Indeed, a classifier built using the entire cell line dataset performed suboptimally when applied exclusively to melanoma derived-cell lines (Fig. 2d), whereas a model built with only melanoma cell lines performed better (Fig. 2d). Predictive features in the melanoma-only model showed a strong over-expression of genes regulated by the transcription factors MITF and SOX10 (Supplementary Table 10), recently identified as predictive of RAF inhibitor drug sensitivity within a melanoma-dominated cell line collection.
On the other hand, lineage emerged as the predominant predictive feature for several compounds. For example, elastic net studies of the HDAC inhibitor LBH589 (panobinostat) identified hematologic lineages as predictors of sensitivity (Fig. 2e and Supplementary Fig. 9). Interestingly, most clinical responses to panobinostat and related compounds (e.g., vorinostat and romidepsin) have been observed in hematological cancers. Similarly, most multiple myeloma cell lines (12 of 14 lines tested) exhibited enhanced sensitivity to the IGF-1 receptor inhibitor AEW541 (Fig. 2f and Supplementary Fig. 8 and 9) and showed high IGF1 expression (Fig. 2f). Interestingly, elevated IGF1R expression also correlated with AEW541 sensitivity (Supplementary Fig. 9). The CCLE results suggest that multiple myeloma may be a promising indication for clinical trials of IGF-1 receptor inhibitors24 and that these drugs may have enhanced efficacy in cancers with high IGF1 or IGF1R expression.
While BRAF and NRAS mutations are known single-gene predictors of sensitivity to MEK inhibitors, several "sensitive" cell lines lacked mutations in these genes, whereas other lines harboring these mutations were nonetheless "insensitive" (Fig. 2c). The elastic net regression model derived from the subset of cell lines with validated NRAS mutations identified elevated expression of the AHR gene (which encodes the aryl hydrocarbon receptor) as strongly correlated with sensitivity to the MEK inhibitor PD-0325901 (Fig. 3a). This finding was intriguing in light of prior studies suggesting that a related MEK inhibitor (PD-98059) may also function as a direct AHR antagonist25. We therefore hypothesized that the enhanced sensitivity of some NRAS-mutant cell lines to MEK inhibitors might relate to a coexistent dependence on AHR function.
To test this hypothesis, we first confirmed the correlation between AHR expression and sensitivity to MEK inhibitors in a subset of NRAS-mutant cell lines (Fig. 3b and Supplementary Fig. 13). Next, we performed shRNA knockdown of AHR in cell lines with high or low AHR expression (Fig. 3c). Silencing of AHR suppressed the growth of three NRAS-mutant cell lines with elevated AHR expression (Figs. 3d–f), but had no effect on the growth of two lines with low AHR expression (Figs. 3g–h). The growth inhibitory effect was confirmed with two additional shRNAs, where evidence for a dose-dependent knockdown effect was also apparent (Figs. 3i–j). We also tested the hypothesis that allosteric MEK inhibitors may function as AHR antagonists by measuring the effect of PD-0325901 and PD-98059 on endogenous CYP1A1 mRNA, a transcriptional target of AHR in some contexts. Both compounds reduced CYP1A1 levels in NRAS-mutant melanoma cells (IPC-298 and SK-MEL-2; Fig. 3k) but not in neuroblastoma cells (CHP-212, Fig. 3k), suggesting that other factors may govern CYP1A1 expression in the latter lineage. Together, these results suggest that AHR dependency may co-occur with MAP kinase activation in some NRAS-mutant cancer cells, and that elevated AHR may serve as a mechanistic biomarker for enhanced MEK inhibitor sensitivity in this setting.
We also looked for markers predictive of response to several conventional chemotherapeutic agents (Supplementary Fig. 7 and Supplementary Table 6) and identified SLFN11 expression as the top correlate of sensitivity to irinotecan (Fig. 4a), a camptothecin analog that inhibits the topoisomerase I (TOP1) enzyme. SLFN11 expression also emerged as the top predictor of topotecan sensitivity (another TOP1 inhibitor; Supplementary Figs. 8 and 14). Overall, 12 of 16 lineages showed significant SLFN11 associations for topotecan or irinotecan sensitivity (Pearson's r ≥ 0.2, Supplementary Fig. 14b). This finding was independently validated using data from the NCI-60 collection (Supplementary Fig. 15). SLFN11 knockdown did not affect steady-state growth sensitivity profiles (Supplementary Fig. 14d–f).
All three Ewing's sarcoma cell lines screened showed both high SLFN11 expression and sensitivity to irinotecan (Fig. 4b, Supplementary Fig. 14). Ewing's sarcomas also exhibited the highest SLFN11 expression among 4,103 primary tumor samples spanning 39 lineages (Fig. 4c), suggesting that TOP1 inhibitors might offer an effective treatment option for this cancer type. Toward this end, several ongoing trials in Ewing's sarcoma are examining irinotecan-based combinations, or the addition of topotecan to standard regimens26. For some lineages with high SLFN11 expression, (e.g. cervical adenocarcinoma) topoisomerase inhibitors already comprise a standard chemotherapy regimen. In other tumors where topoisomerase inhibitors are commonly used (e.g., colorectal and ovarian cancers), a range of SLFN11 expression was observed, raising the possibility that high SLFN11 expression might enrich for tumors more likely to respond. If confirmed in correlative clinical studies, SLFN11 expression may offer a means to stratify patients for topoisomerase inhibitor treatment.
By assembling the Cancer Cell Line Encyclopedia (CCLE), we have expanded the process of detailed annotation of preclinical human cancer models (www.broadinstitute.org/ccle). Genomic predictors of drug sensitivity revealed both known and novel candidate biomarkers of response. Even within genetically defined sub-populations—or when agents were broadly active without clear genetic targets—predictive modeling studies identified key predictors or mechanistic effectors of drug response. Future efforts that increase the scale and add additional types of information (e.g., whole genome/transcriptome sequencing, epigenetic studies, metabolic profiling or proteomic/phosphoproteomic analysis) should enable additional insights. In the future, comprehensive and tractable cell line systems provided through this and other efforts27 may facilitate numerous advances in cancer biology and drug discovery.
Methods Summary
A total of 947 independent cancer cell lines were profiled at the genomic level (data available at www.broadinstitute.org/ccle and Gene Expression Omnibus (GEO) using accession numbers GSE36139) and compound sensitivity data was obtained for 479 lines (Supplementary Table 11). Mutation information was obtained both by using massively parallel sequencing of >1,600 genes (Supplementary Table 12) and by mass spectrometric genotyping (OncoMap), which interrogated 492 mutations in 33 known oncogenes and tumor suppressors. Genotyping/copy number analysis was performed using Affymetrix Genome-Wide Human SNP Array 6.0 and expression analysis using the GeneChip Human Genome U133 Plus 2.0 Array. 8-point dose response curves were generated for 24 anticancer drugs using an automated compound-screening platform. Compound sensitivity data were used for two types of predictive models that utilized the naive Bayes classifier or the elastic net regression algorithm. The effects of AHR expression silencing on cell viability were assessed by stable expression of shRNA lentiviral vectors targeting either this gene or luciferase as control. The effect of compound treatment on AHR target gene expression was assessed by quantitative RT-PCR. A full description of the Methods is included in the Supplementary Information.
NIHMS361223-supplement-1.doc
NIHMS361223-supplement-2.pdf
NIHMS361223-supplement-4.xlsx
The Cancer Cell Line Encyclopedia (CCLE)
a. Distribution of cancer types in the CCLE by lineage. b. Comparison of DNA copy-number profiles (GISTIC G-scores) between cell lines and primary tumors. The diagonal of the heatmap shows the Pearson correlation between corresponding sample types. Because cell lines and tumors are separate datasets, the correlation matrix is asymmetric: the top left showing how well the tumor features correlate with the average of the cell lines in a lineage, and the bottom right showing the converse. c. Comparison of mRNA expression profiles between cell lines and primary tumors. For each tumor type, the log-fold-change of the 5,000 most variable genes is calculated between that tumor type and all others. Pearson correlations between tumor type fold-changes from primary tumors and cell lines are shown as a heatmap. d. Comparison of point mutation frequencies between cell lines and primary tumors in COSMIC (v56), restricted to genes that are well represented in both sample sets but excluding TP53 which is highly prevalent in most tumor types. Pairwise Pearson correlations are shown as a heatmap. *The correlations of esophageal, liver, and head and neck cancer mutation frequencies are restored when including TP53.
Predictive modeling of pharmacologic sensitivity using CCLE genomic data
a. Drug responses for Panobinostat (green) and PLX4720 (orange/purple) represented by the high-concentration effect level (Amax) and transitional concentration (EC50) for a sigmoidal fit to the response curve (b). c. Elastic net regression modeling of genomic features that predict sensitivity to PD-0325901. The bottom curve indicates drug response, measured as the area over the dose-response curve (activity area), for each cell line. The central heatmap shows the CCLE features in the model (continuous z-score for expression and copy-number, dark red for discrete mutation calls), across all cell lines (x-axis). Bar plot (left): weight of the top predictive features for sensitivity (bottom) or insensitivity (top). Parenthesis indicate features present in >80% of models after bootstrapping. d. Specificity and sensitivity (ROC curves) of cross-validated categorical models predicting the response to a MEK inhibitor, PD-0325901 (activity area). Mean true positive rate and standard deviation (n=5) are shown when models are built using all lines ("Global categorical model" in blue and orange), or within only melanoma lines (green). e. Activity area values for LBH589 (panobinostat) between cell lines derived from hematopoietic (n=61) and solid tumors (n=387). The middle bar = median, box = inter-quartile range, and bars extend to 1.5x the inter-quartile range. f. Distribution of activity area values for AEW541 relative to IGF1 mRNA expression. Orange dots: multiple myeloma cell lines (n=14); blue dots: cell lines from other tumor types (n=434). Box-and-whisker plots show the activity area or mRNA expression distributions relative to each cell line type (line = median and box = inter-quartile range), with bars extending to 1.5x the inter-quartile range.
AHR expression may denote a tumor dependency targeted by MEK inhibitors in NRAS-mutant cell lines
a. Predictive features for PD-0325901 sensitivity (varying baseline activity area) in validated NRAS-mutant cell lines. b. Growth inhibition curves for NRAS-mutant cell lines expressing high (red) or low (blue) levels of AHR mRNA in the presence of the MEK inhibitor PD-0325901. c. Relative AHR mRNA expression across a panel of NRAS-mutant cell lines (arrows indicate cell lines where AHR dependency was analyzed). d–h. Proliferation of NRAS-mutant cell lines displaying high (d–f) and low (g–h) AHR mRNA expression, after introduction of shRNAs against AHR (red lines) or luciferase (blue lines). i. (left) Proliferation of IPC-298 cells (high AHR) after introduction of additional shRNAs against AHR (shAHR_1 and shAHR_4; green and purple lines, respectively) or luciferase (control shLuc; blue line); (right) corresponding immunoblot analysis of AHR protein. j. Equivalent studies as in (i) with using SK-MEL-2 cells (high AHR). k. Endogenous CYP1A1 mRNA expression in the neuroblastoma line CHP-212 or the melanoma lines IPC-298 and SK-MEL-2 after exposure to vehicle (blue) or MEK inhibitors (PD-0325901, green or PD-98059, purple). Error bars: standard deviation between replicates, with n=12 (b), n=3 (c), n=6 (d–k).
Predicting sensitivity to topoisomerase I inhibitors
a. Elastic net regression analysis of genomic correlates of irinotecan sensitivity is shown for 250 cell lines. b. Dose-response curves for three Ewing's sarcoma cell lines (MSS-ES-1, SK-ES-1, and TC-71) and two control cell lines with low SLFN11 expression (HCC-56, and SK-HEP-1). Grey vertical bars: standard deviation of the mean growth inhibition (n=2). c.SLFN11 expression across 4103 primary tumors. Box-and-whisker plots show the distribution of mRNA expression for each subtype, ordered by the median SLFN11 expression level (line), the inter-quartile range (box) and up to 1.5x the inter-quartile range (bars). Sample numbers (n) are indicated in parentheses.
Supplementary Information is linked to the online version of the paper at www.nature.com/nature.
For the work described herein, J.B. and G.C. were the lead research scientists; N.S., K.V., and A.M. were the lead computational biologists; M.M., W.R.S., R.S., and L.A.G. were the senior authors. J.B, G.C., S.K., P.M., J.M., J.T., A.S., N.L., and K.A., performed cell line procural and processing; P.M., and K.A., performed or directed nucleic acid extraction and quality control; S.G., W.W., and S.B.G., performed or directed genomic data generation; C.J.W., F.A.M., E.B-F., I.E., P.A., M.dS., K.J., and V.E.M., performed pharmacologic data generation; N.S., K.V., G.V.K., A.R., M.F.B., J.C., G.K.Y., M.D.J., T.L., M.R., and G.G., contributed to software development; N.S., K.V., A.A.M., J.L., G.V.K., D.S., A.R., M.L., M.F.B., A.K., P.R., J.C., G.K.Y., J.Y., M.D.J., C.H., E.P., J.P.M., V.C. and M.P.M., performed computational biology and bioinformatics analysis; J.B., G.C., N.S., L.M., J.E.M., J.J-V., M.P.M., W.R.S., R.S., and L.A.G. performed biological analysis and interpretation; N.S., K.V., A.A.M., J.L., A.R., M.L., L.M., A.K., J.J-V., J.C., G.K.Y and J.Y., prepared figures and tables for the main text and supplementary information; J.B., G.C., N.S., K.V., A.A.M., J.L., G.V.K., J.J-V., M.P.M., and L.A.G. wrote and edited the main text and supplementary information; J.B., G.C., N.S., K.V., S.K., C.J.W., J.L., S.M., C.S., R.O., T.L., L.McC., W.W., M.R., N.L., S.B.G., K.A., and V.C., performed project management; J.P.M., V.E.M., B.L.W., J.P., M.W., P.F., J.H., M.M., and T.R.G., contributed project oversight and advisory roles; and M.P.M., W.R.S., R.S., and L.A.G. provided overall project leadership.
Competing financial interests
Multiple authors are employees of Novartis, Inc., as noted in the affiliations. T.R.G., M.M., and L.A.G. are consultants for and equity holders in Foundation Medicine, Inc. M.M. and L.A.G. are consultants for and receive sponsored research from Novartis, Inc.
We thank the staff of the Biological Samples Platform, the Genetic Analysis Platform and the Sequencing Platform at the Broad Institute. We thank S. Banerji, J. Che, C.M. Johannessen, A. Su and N. Wagle, for advice and discussion. We are grateful for the technical assistance and support of G. Bonamy, R. Brusch III, E. Gelfand, K. Gravelin, T. Huynh, S. Kehoe, K. Matthews, J. Nedzel, L. Niu, R. Pinchback, D. Roby, J. Slind, T.R. Smith, L. Tan, V. Trinh, C. Vickers, G. Yang, Y. Yao and X. Zhang. The Cancer Cell Line Encyclopedia project was enabled by a grant from the Novartis Institutes for Biomedical Research. Additional funding support was provided by the National Cancer Institute (M.M., L.A.G.), the Starr Cancer Consortium (M.F.B., L.A.G.), and the NIH Director's New Innovator Award (L.A.G.). This resource, the Cancer Cell Line Encyclopedia (CCLE), is made available online at www.broadinstitute.org/ccle.
1. CaponigroGSellersWRAdvances in the preclinical testing of cancer therapeutic hypothesesNat Rev Drug Discov101791872011[PubMed][Google Scholar]
2. MacconaillLEGarrawayLAClinical implications of the cancer genomeJ Clin Oncol28521952282010[PubMed][Google Scholar]
3. LinWMModeling genomic diversity and tumor dependency in malignant melanomaCancer Res686646732008[PubMed][Google Scholar]
4. NeveRMA collection of breast cancer cell lines for the study of functionally distinct cancer subtypesCancer Cell105155272006[PubMed][Google Scholar]
5. SosMLPredicting drug susceptibility of non-small cell lung cancers based on genetic lesionsJ Clin Invest119172717402009[PubMed][Google Scholar]
6. DryJRTranscriptional pathway signatures predict MEK addiction and response to selumetinib (AZD6244)Cancer Res70226422732010[PubMed][Google Scholar]
7. GarrawayLAIntegrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanomaNature4361171222005[PubMed][Google Scholar]
8. GreshockJMolecular target class is predictive of in vitro response profileCancer Res70367736862010[PubMed][Google Scholar]
9. McDermottUIdentification of genotype-correlated sensitivity to selective kinase inhibitors by using high-throughput tumor cell line profilingProc Natl Acad Sci U S A10419936199412007[PubMed][Google Scholar]
10. SolitDBBRAF mutation predicts sensitivity to MEK inhibitionNature4393583622006[PubMed][Google Scholar]
11. StauntonJEChemosensitivity prediction by transcriptional profilingProc Natl Acad Sci U S A9810787107922001[PubMed][Google Scholar]
12. WeinsteinJNAn information-intensive approach to the molecular pharmacology of cancerScience2753433491997[PubMed][Google Scholar]
13. ThomasRKHigh-throughput oncogene mutation profiling in human cancerNat Genet393473512007[PubMed][Google Scholar]
14. BeroukhimRThe landscape of somatic copy-number alteration across human cancersNature4638999052010[PubMed][Google Scholar]
15. RossDTSystematic variation in gene expression patterns in human cancer cell linesNat Genet242272352000[PubMed][Google Scholar]
16. ZouHHastieTRegularization and variable selection via the elastic netJ Roy Stat Soc B673013202005[Google Scholar]
17. KonecnyGEActivity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cellsCancer Res66163016392006[PubMed][Google Scholar]
18. TsaiJDiscovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activityProc Natl Acad Sci U S A105304130462008[PubMed][Google Scholar]
19. ZouHYAn Orally Available Small-Molecule Inhibitor of c-Met, PF-2341066, Exhibits Cytoreductive Antitumor Efficacy through Antiproliferative and Antiangiogenic MechanismsCancer Research67440844172007[PubMed][Google Scholar]
20. MullerCRPotential for treatment of liposarcomas with the MDM2 antagonist Nutlin-3AInt J Cancer1211992052007[PubMed][Google Scholar]
21. NishioMSerum heparan sulfate concentration is correlated with the failure of epidermal growth factor receptor tyrosine kinase inhibitor treatment in patients with lung adenocarcinomaJ Thorac Oncol6188918942011[PubMed][Google Scholar]
22. GuoWFormation of 17-allylamino-demethoxygeldanamycin (17-AAG) hydroquinone by NAD(P)H:quinone oxidoreductase 1: role of 17-AAG hydroquinone in heat shock protein 90 inhibitionCancer Res6510006100152005[PubMed][Google Scholar]
23. KellandLRSharpSYRogersPMMyersTGWorkmanPDT-Diaphorase expression and tumor cell sensitivity to 17-allylamino, 17-demethoxygeldanamycin, an inhibitor of heat shock protein 90J Natl Cancer Inst91194019491999[PubMed][Google Scholar]
24. MoreauPPhase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642, as single agent and in combination with bortezomib in patients with relapsed multiple myelomaLeukemia258728742011[PubMed][Google Scholar]
25. ReinersJJJrLeeJYCliftREDudleyDTMyrandSPPD98059 is an equipotent antagonist of the aryl hydrocarbon receptor inhibitor of mitogen-activated protein kinase kinaseMol Pharmacol534384451998[PubMed][Google Scholar]
26. WagnerLMTemozolomide and intravenous irinotecan for treatment of advanced Ewing sarcomaPediatr Blood Cancer481321392007[PubMed][Google Scholar]
27. GarnettMJA systematic screen for genomic markers of drug sensitivity in cancer cellsNatureXXXXXXXXX2012[Google Scholar]


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Q: How to write regex that excludes the name after Mr. when finding words at the start of a sentence? I currently have to make a regex that matches the first words at the start of sentences. I've currently done to the point where it matches the first word at the start of the paragraph and the rest, the first words that come after ". The problem that I have here is that 'Sherwood' which is obviously a name, shouldn't be matched but is because it matches the regex which I have written. 'Capital starting letter, comes directly after . and a space'
How can I change my code to exclude the name that comes after Mr. or Dr.?
Current regex: ((^[A-Z]+[a-z]*[A-Z]*[a-z]*|(?<=\")[A-Z]+[a-z]*[A-Z]*[a-z]*)|(?<=\.\s)[A-Z]+[a-z]*[A-Z]*[a-z]*)
I've used regex101.com as a reference.

A: You could shorten the pattern with the alternations to a single non capture group containing the 3 patterns that are allowed for the start of the string.
As you are already using a lookbehind assertion, you can exclude Mr. of Dr. to the left using a negative lookbehind:
(?:^|(?<=")|(?<=\.\s))(?<![MD]r\. )[A-Z]+[a-z]*[A-Z]*[a-z]*

Regex demo
You might also first match an uppercase char, and then do the assertions to prevent the alternation with the lookbehind assertions to fire on every position when there is no match.
[A-Z](?<=".|\.\s.|^.)(?<![MD]r\. .)(?:[A-Z]*[a-z]*){2}

Regex demo


Weekly Family Menu Plan – Week Seventy is brought to you by a group of food bloggers who love to plan ahead! A weekly edition of thoughtfully prepared recipes is rounded up to get you through those busy weeks!
Happy New Year everyone! We took a few weeks off from posting menu plans at the end of year to regroup, but now we are back at it again. We have a whole new line of recipes that begins with 5 main courses and also includes a soup, breakfast recipe, 2 dessert recipes, and 1 side dish. As we bundle in for the winter, yet try to stay somewhat healthy, menu planning becomes more and more important. There are some truly great recipes in this week's menu plan. I can't wait to try a few of them!


The Women's provides culturally sensitive services to Aboriginal and Torres Strait Islander women and their families at Badjurr-Bulok Wilam Aboriginal and Torres Strait Islander Women and Families Place.
Badjurr-Bulok Wilam meaning 'home of many women' in Woiwurrung, the language of the Wurundjeri Peoples provides support and advocacy for Aboriginal and Torres Strait Islander women. Support may include providing easy access to hospital services, information and referral to services and practical assistance. Badjurr-Bulok Wilam provides a resting place for Aboriginal and Torres Strait Islander women and families attending the Women's, where women and families can yarn with the Aboriginal & Torres Strait Islander Hospital Liaison Officers.
The Women's knows that Aboriginal and Torres Strait Islander people have a deep and continuous connection to their cultural lands and traditions. We understand that for Aboriginal and Torres Strait Islander peoples, culture is seen as a foundation upon which everything else is built. Culture underpins all aspect of life, and can be thought of as connections to family, extended family and community, connection to country, expression of values, practices and belief, and the many traditional and contemporary forms of cultural expression including language and storytelling, dance, music and art.
We would like to know if you are Aboriginal and Torres Strait Islander because we can provide more culturally-sensitive care and also alert you to services available here at the Women's and in the community. Of course, it is your choice whether you tell us or not.
The Women's has a complex history with the Aboriginal and Torres Strait Islander community in Victoria, in that—as a government agency at the time—it was tasked with the enforcement of the 'Aborigines Protection Act (1869)'. This act enforced the removal of babies/children from their mothers, families, community and culture. For this reason, hospital environments foster reminiscence of historical issues associated with removal of children and maltreatment, and not as a place of healing and wellbeing. The reluctance to access early preventive health care subsequently results in presentation of more acute and complex health issues.
In 2008, the Women's made an apology to the Aboriginal and Torres Strait Islander community, and affirmed our commitment to working and building a relationship of trust and partnership with the Aboriginal and Torres Strait Islander peoples, communities and organisations.


Diversified Technique is the classic chiropractic technique taught in all chiropractic colleges. The focus is on correcting spinal subluxations (misalignments) and restoring the area(s) to normal biomechanical function, and correction of subluxation(s). Diversified adjusting of the spine uses specific lines of drives for all gentle manual adjustments, allowing for specificity in correcting mechanical distortions of the spine. Motion palpatation and full spine hands-on techniques are used to deliver a deeper thrust, which makes an articulation cavitation (popping) sound as the adjustment is given.
The Thompson Technique utilizes a "Segmental Drop Table" to enhance the motion force imparted towards the segment or area to be adjusted. The concept of adding motion by inventing a table with specific areas that would drop away as the adjustive thrust was applied to the vertebral segment has been shown to be very successful. Many patients enjoy the feel of the Thompson Drop technique for their adjustments as it is a gentle technique.
Treatment with flexion-distraction techniques is used to restore damaged spinal nerves and surrounding structures by reducing the stricture of the paraspinal ligaments, increasing the movement of metabolites in discs, reducing the stress and internal pressure imposed on the posterior discs, and expansion intervertebral foramina).
The ARTHROSTIM™ Instrument produces rapid thrust and recoil at a rate of TWELVE TIMES PER SECOND. The ARTHROSTIM™ Instrument delivers true high-velocity, short-stroke thrusts activating the patients' proprioceptors and mechanoreceptors without recruiting the pain receptors (nociceptors), providing a gentle comfortable method of adjusting patients.
Several studies have shown that instrument adjusting is equally as effective as traditional chiropractic techniques for easing pain and increasing range of motion in patients who have sought chiropractic care. Its speed, gentleness and accuracy are recommended and are often preferred by populations such as children and the elderly.
Ultrasound is a therapy modality that utilizes high or low frequency sound waves. These sound waves are transmitted to the surrounding tissue and vasculature. They penetrate the muscles to cause deep tissue/muscle warming. This promotes tissue relaxation and therefore is useful in treating muscle tightness and spasms. The warming effect of the sound waves also cause vessel vasodilatation and increase circulation to the area that assists in healing. The therapist can also adjust the frequency on the machine to use waves that will decrease inflammation, and/or address scar tissue.


Buzz: Jalen Monroe had 23 for Deltona (14-6). Colin Castleton scored 23 for Father Lopez (15-8).
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Here, they are one of the UK's most recommended hypnotherapists who can provide you with the best and most effective treatment for anxiety, smoking & weight loss and many other issues. In fact, their specialist will clearly understand your problem and will treat it accordingly.
Hypnotherapy is an effective method for helping people overcome a huge range of issues and habits such as smoking, anxiety, weight loss and much more. It is important to choose the hypnotherapists that have years of experienced and has got skills. This is because an experienced hypnotherapist provides you proven results in a short span of time. Moreover, the services of experts, highly trained, extremely experienced hypnotherapist are much more effective than the untrained and inexperienced people hypnotherapists. It is essential to hire the services of the hypnotherapists who has got certification and license in the desired field. Therefore, before you hire the services of any hypnotherapists, you need to thorough research about his reputation and quality of his services. Moreover, you need to hire the services of the hypnotherapist who has got the right knowledge along with the experience because competence of knowledge is not enough to get the effective and fast results.
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text:
Jump to main contentOpen Main NavigationOpen Search Form
Faculty of PhilosophyByzantine Archaeology and Art History
Students of Byzantine Archaeology and Art History consider research relating to the material legacies of the late Antique and Byzantine period.
The late Antique and early Byzantine period covers the era from 3 AD to the fall of Constantinople in 1453 AD. Elements of the academic course which relate to the late Antique period focus on all centres and provinces within the Roman Empire. Where course elements relate to the Byzantine Empire during the Middle ages, the Eastern Mediterranean and the capital Constantinople are the main areas considered.
Degree programmes in Byzantine Archaeology and Art History cover the following areas:
Town planning and topography
Structural art (sculpture and plastic, painting, mosaic)
Small artworks, handcrafts, objects for use
Special Features and Characteristics
The degree programme has strong interdisciplinary links to other archaeological disciplines, as well as European art history, church history and Medieval history.
Students are involved in practical archaeological work early on in the degree programme. They take part in an archaeological field trip, a practical exercise in a museum, or in an archaeological dig, and exercises in measuring and drawing.
Department for Byzantine Archaeology and Art History
Institute for Classical Archaeology and Byzantine Archaeology
Centre for Studies of the Ancient World
The research focus of the subject is dictated by the relevant teaching staff. Currently, research is primarily focussed on the architecture and settlement history of the Middle East, Greece and Asia Minor.
Occupational Areas
Graduates of the degree programme in Byzantine Archaeology and Art History may pursue a career in areas such as:
universities and research institutes
Degree variants
Bachelor 25%
Master, consecutive
I find the subject Byzantine Archaeology and Art History fascinating because it is so versatile and there is so much left to study and investigate. We study a culture that lasted for more than 1,000 years and also influenced European art history. Heidelberg is one of the few German universities where you can study Byzantine Archaeology and Art History.
Nina Möller, 22, Byzantine Archaeology and Art History, 7th semester Bachelor
Further Interesting Subjects
Art History and Museology (Heidelberg and Paris)
Classical Archaeology
Greek / Classical Philology
Latin / Classical Philology
Near Eastern Archaeology
IT for
Key Dates & Deadlines
Heidelberg University
Diese Webseite in
©2022 Heidelberg University


text:
SYNONYM

#### According to
The Catalogue of Life, 3rd January 2011

#### Published in
Mykologia (Prague) 2: 98 (1925)

#### Original name
Polyporus rosae Velen., 1925

### Remarks
null

redpajama_set_name: RedPajamaGithub


text:
'Coherence' is as immensely entertaining as it is thoughtful
Written and directed by James Ward Byrkit
James Ward Byrkit's feature debut Coherence has been drawing rave comparisons to Shane Carruth's Primer since its first appearances on the festival circuit, due to its in-depth exploration of its sci-fi hook. But for fans of the DC Comics animated films, it will instead recall the late, great Dwayne McDuffie's final script, Crisis on Two Earths. For all of the four-color superheroics in that film, it shares with Coherence a nihilistic take on quantum physics that can call into question the very nature of human existence. And, like Coherence, it's as immensely entertaining as it is thoughtful.
Somewhere in California, a dinner party is being held. Eight friends gather together, with some quick-hitting exposition at the beginning of the film laying out that there will be some drama afoot. It looks to be soap-opera-level drama, most likely, or an episode of Gilmore Girls at best. Until a comet passes by in the sky above, with disruptive effects on cell phones and Internet service, followed by … coherence. To say much more than that would spoil the fun of watching these characters try to sort it out for themselves.
The strongest mark in favor of Coherence is that those characters are portrayed by a stellar cast. They're television veterans and character actors; you're likely to have seen every one of them in something before, even if you can't quite remember what it was. They were thrown together in one location over five nights and given vague instructions to improvise; although Byrkit has a screenplay credit for Writer's Guild purposes, the actors filmed without a screenplay, rehearsals, or blocking. Despite that, they have a chemistry which implies that these characters have known each other for a decade or more, and the performances understand that can be a bad thing as well as a good one. Particularly noteworthy is Nicholas Brendon, of Buffy the Vampire Slayer fame, playing a character who is not far from himself (an alternate-reality version of himself, you might say) in ways that fill the movie with humor and pathos alike.
See also Thank you to all our readers and listeners...
The comparison to Primer is unfair in some ways, because Coherence contains very little of the scientific jargon that Carruth was so insistent upon for his film. Instead Byrkit plays directly off of the fact that these characters wouldn't understand the science of what is happening to them. Their understanding of quantum physics seems to come from the episodes of Star Trek where evil Spock wore a goatee, when in fact the problem is bigger than they imagine. As in Primer, the problem is bigger than the human mind can imagine.
The crisis also escalates as it did in Primer, with the speed and calamity of a snowball becoming an avalanche. The film starts to confuse (becomes incoherent, you might say) as reality itself strains under the pressures that these characters are applying. Through it all, Byrkit finds subtle ways to ask a question that Crisis on Two Earths asked overtly: if Schrodinger's Cat can be both alive and dead inside its box, do life and death have any real meaning? Do any of the realities that are possible inside that box have any meaning?
Yet no matter how difficult it becomes to answer that question – or even understand it – the characters hold to what made them interesting at the start of the film, before there was any calamity to speak of. They turn on each other in ways that disaster-film characters always do, and in ways that not even a disaster-movie veteran could foresee, but in either case the result is the same: every one of them will have to deal with their own choices, including the choices that they might have made, but didn't. A superb final shot leaves the audience to wonder just how much "dealing with it" will have to be done. Like the rest of Coherence, that shot's excellence becomes even greater when seen with friends, so that the amount of post-film discussion can go on and on … ad infinitum, you might say.
See also 'Ghostbusters 3′to Begin Production
-Mark Young
CoherenceJames Ward Byrkit
Rectify 2.01 "Running With the Bull" returns as beautiful and poignant as ever
Should Depictions of Nazism in Gaming Be Banned?


text:
Q: Schedule read repair before read I have a reporting tool which reads data from Cassandra. Configurations are Consistency level is LOCAL_QUORUM, Compaction Strategy is size-tiered and RF=3.
When the pull request from reporting tool to Cassandra, as per the Cassandra design it trigger read repair for data consistency. This is good design actually. But read repair is expensive and reports are taking longer time.
My report users start generating reports only after 6 AM IST.Is there any way to schedule read repairs before the users starts using reports. for example, I do schedule and finish read repairs before 6 AM IST. So that, after 6 AM IST all the data would be consisted across cluster.
In this case, once report start reading data from Cassandra, it should not trigger read repair again as we just finished read repair as a scheduled job. I am fine with inconsistent data writes/updates after 6 AM IST happened. Which technique is good to schedule read repairs and do we really avoid read repairs if they are done recently.
-Suyodha

A: If you use traditional anti-entropy repair, you could then do reads at consistency level: ONE.
There are many ways to do anti-entropy repair, the most obvious is nodetool repair (likely with nodetool repair -par -inc or similar command line switches), or using some of the third party tools to repair small ranges, such as the Cassandra Range Repair tool maintained by Brian Gallew or Spotify's Cassandra Reaper.

A: What makes you think read repairs are whats slowing it down? check (jmx) org.apache.cassandra.metrics:type=ReadRepair,name=RepairedBackground and org.apache.cassandra.metrics:type=ReadRepair,name=RepairedBlocking to verify if repairs are even occuring. Read repairs will only kick off if the data is inconsistent on the read which shouldn't be that common.
If its really a problem you can disable read repairs on a table by setting chance to 0.
ALTER TABLE yourtable WITH read_repair_chance = 0;


text:
Daily Ratings & News for Ingersoll-Rand
Complete the form below to receive the latest headlines and analysts' recommendations for Ingersoll-Rand with our free daily email newsletter:
Honkamp Krueger Financial Services Inc. Sells 27,863 Shares of Ingersoll-Rand PLC (NYSE:IR)
Honkamp Krueger Financial Services Inc. decreased its position in Ingersoll-Rand PLC (NYSE:IR) by 88.3% during the 4th quarter, HoldingsChannel reports. The fund owned 3,706 shares of the industrial products company's stock after selling 27,863 shares during the quarter. Honkamp Krueger Financial Services Inc.'s holdings in Ingersoll-Rand were worth $493,000 as of its most recent SEC filing.
A number of other hedge funds and other institutional investors have also recently added to or reduced their stakes in IR. Nuveen Asset Management LLC lifted its stake in Ingersoll-Rand by 19,817.3% in the 2nd quarter. Nuveen Asset Management LLC now owns 5,759,489 shares of the industrial products company's stock valued at $729,554,000 after acquiring an additional 5,730,572 shares in the last quarter. UBS Asset Management Americas Inc. raised its stake in shares of Ingersoll-Rand by 154.1% during the 2nd quarter. UBS Asset Management Americas Inc. now owns 2,848,266 shares of the industrial products company's stock worth $360,790,000 after purchasing an additional 1,727,526 shares in the last quarter. State Street Corp raised its stake in shares of Ingersoll-Rand by 6.8% during the 3rd quarter. State Street Corp now owns 10,867,714 shares of the industrial products company's stock worth $1,339,015,000 after purchasing an additional 688,390 shares in the last quarter. AQR Capital Management LLC raised its stake in shares of Ingersoll-Rand by 97.4% during the 2nd quarter. AQR Capital Management LLC now owns 1,176,359 shares of the industrial products company's stock worth $146,798,000 after purchasing an additional 580,326 shares in the last quarter. Finally, Boston Partners raised its stake in shares of Ingersoll-Rand by 466.6% during the 3rd quarter. Boston Partners now owns 588,003 shares of the industrial products company's stock worth $72,459,000 after purchasing an additional 484,218 shares in the last quarter. Hedge funds and other institutional investors own 79.54% of the company's stock.
Get Ingersoll-Rand alerts:
IR stock opened at $131.31 on Thursday. The company has a current ratio of 1.28, a quick ratio of 0.88 and a debt-to-equity ratio of 0.68. The firm has a market capitalization of $31.19 billion, a PE ratio of 20.81, a PEG ratio of 1.78 and a beta of 1.22. Ingersoll-Rand PLC has a 1-year low of $92.24 and a 1-year high of $138.33. The business's 50 day simple moving average is $132.48 and its 200 day simple moving average is $125.13.
Ingersoll-Rand (NYSE:IR) last posted its earnings results on Tuesday, October 29th. The industrial products company reported $1.99 earnings per share for the quarter, topping analysts' consensus estimates of $1.91 by $0.08. The business had revenue of $4.16 billion for the quarter, compared to analyst estimates of $4.30 billion. Ingersoll-Rand had a return on equity of 21.72% and a net margin of 8.38%. The firm's revenue was up 2.8% compared to the same quarter last year. During the same period in the previous year, the firm earned $1.75 EPS. As a group, sell-side analysts predict that Ingersoll-Rand PLC will post 6.4 EPS for the current fiscal year.
In related news, CEO Michael W. Lamach sold 242,347 shares of the business's stock in a transaction that occurred on Friday, December 20th. The stock was sold at an average price of $135.00, for a total transaction of $32,716,845.00. Following the transaction, the chief executive officer now directly owns 452,129 shares of the company's stock, valued at approximately $61,037,415. The transaction was disclosed in a legal filing with the Securities & Exchange Commission, which can be accessed through this hyperlink. Also, SVP Paul A. Camuti sold 10,710 shares of the business's stock in a transaction that occurred on Wednesday, December 11th. The stock was sold at an average price of $132.19, for a total value of $1,415,754.90. Following the transaction, the senior vice president now directly owns 70,804 shares in the company, valued at $9,359,580.76. The disclosure for this sale can be found here. Insiders have sold a total of 282,049 shares of company stock worth $37,930,655 over the last three months. 0.70% of the stock is owned by insiders.
A number of brokerages have recently issued reports on IR. Wolfe Research cut Ingersoll-Rand from an "outperform" rating to a "peer perform" rating in a research note on Thursday, January 9th. BMO Capital Markets set a $145.00 price objective on Ingersoll-Rand and gave the stock a "buy" rating in a research note on Monday, November 4th. UBS Group began coverage on Ingersoll-Rand in a research note on Thursday, December 12th. They set a "buy" rating and a $150.00 price objective on the stock. Barclays reiterated a "buy" rating and set a $134.00 price objective on shares of Ingersoll-Rand in a research note on Friday, October 4th. Finally, Wells Fargo & Co upgraded Ingersoll-Rand from a "market perform" rating to an "outperform" rating in a research note on Thursday, December 5th. Two investment analysts have rated the stock with a sell rating, two have issued a hold rating and eleven have issued a buy rating to the company's stock. Ingersoll-Rand presently has an average rating of "Buy" and a consensus price target of $137.00.
Ingersoll-Rand Company Profile
Ingersoll-Rand Plc designs, manufactures, sells, and services industrial and commercial products. The company operates through Climate and Industrial segments. The Climate segment offers air conditioners, exchangers, and handlers; airside and terminal devices; auxiliary power units; chillers; coils and condensers; gensets; furnaces; heat pumps; home automation; humidifiers; hybrid and non-diesel transport refrigeration, and ice energy storage solutions; indoor air quality; industrial refrigeration; motor replacements; refrigerant reclamation; thermostats/controls; transport heater products; and water source heat pumps.
See Also: Which market index is the best?
Want to see what other hedge funds are holding IR? Visit HoldingsChannel.com to get the latest 13F filings and insider trades for Ingersoll-Rand PLC (NYSE:IR).
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Teradyne (NYSE:TER) Rating Increased to Outperform at Evercore ISI
Honkamp Krueger Financial Services Inc. Buys New Holdings in iShares Global Tech ETF (NYSEARCA:IXN)


text:
/*
 * This example basically does the same thing as test_hello.c,
 * using wasm_export.h API.
 */

#include <stdio.h>
#include <stdlib.h>

#include "wasm_export.h"

static int
test_hello2_wrapper(wasm_exec_env_t exec_env, uint32_t nameaddr,
                    uint32_t resultaddr, uint32_t resultlen)
{
    /*
     * Perform wasm_runtime_malloc to check if the runtime has been
     * initialized as expected.
     * This would fail with "memory hasn't been initialize" error
     * unless we are not sharing a runtime with the loader app. (iwasm)
     */
    void *p = wasm_runtime_malloc(1);
    if (p == NULL) {
        return -1;
    }
    wasm_runtime_free(p);

    wasm_module_inst_t inst = wasm_runtime_get_module_inst(exec_env);
    if (!wasm_runtime_validate_app_str_addr(inst, nameaddr)
        || !wasm_runtime_validate_app_addr(inst, resultaddr, resultlen)) {
        return -1;
    }
    const char *name = wasm_runtime_addr_app_to_native(inst, nameaddr);
    char *result = wasm_runtime_addr_app_to_native(inst, resultaddr);
    return snprintf(result, resultlen,
                    "Hello, %s. This is %s! Your wasm_module_inst_t is %p.\n",
                    name, __func__, inst);
}

/* clang-format off */
#define REG_NATIVE_FUNC(func_name, signature) \
    { #func_name, func_name##_wrapper, signature, NULL }

static NativeSymbol native_symbols[] = {
    REG_NATIVE_FUNC(test_hello2, "(iii)i")
};
/* clang-format on */

uint32_t
get_native_lib(char **p_module_name, NativeSymbol **p_native_symbols)
{
    *p_module_name = "env";
    *p_native_symbols = native_symbols;
    return sizeof(native_symbols) / sizeof(NativeSymbol);
}


text:
[view blog](https://blog.yinaoxiong.cn)
## description
  A web site to record some thing.
## License
MIT license.
Copyright © 2016-2018 yinaoxiong's blog All Rights Reserved

yinaoxiong's blog is derived from [Clean Blog Jekyll Theme (MIT License)](https://github.com/BlackrockDigital/startbootstrap-clean-blog-jekyll/)
Copyright (c) 2013-2018 Blackrock Digital LLC.


for every single customer and completely taken into operation by Adenso. The substrate thickness starts from 0,9μm for special applications.
Winding System Expertise from Adenso lower your process risk.
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Efavirenz and nevirapine may speed up how quickly your liver processes your hormonal contraceptive agent.
The blood levels of your contraceptive agent may decrease, causing breakthrough bleeding, spotting, or pregnancy.
Contact your healthcare professionals (e.g. doctor or pharmacist) as soon as possible about taking these two medicines together. You should use another form of birth control in addition to your hormonal contraceptive agent while you are taking efavirenz or nevirapine. Because efavirenz stays in your body a long time, you should continue to use another form of birth control with your hormonal contraceptive for 12 weeks after you stop taking efavirenz.Emergency contraceptives may be less effective also. You may need a larger dose than normal. Discuss the dose and the need to confirm that you do not become pregnant with a pregnancy test with your healthcare professional.Your healthcare professionals may be aware of this interaction and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.
2.Viramune (nevirapine) US prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc. March, 2017.
3.Mildvan D, Yarrish R, Marshak A, Hutman HW, McDonough M, Lamson M, Robinson P. Pharmacokinetic interaction between nevirapine and ethinyl estradiol/norethindrone when administered concurrently to HIV-infected women. J Acquir Immune Defic Syndr 2002 Apr 15;29(5):471-7.


Saleem Sinai was born at midnight, the midnight of India's independence, and found himself mysteriously "handcuffed to history" by the coincidence. He is one of 1,001 children born at the midnight hour, each of them endowed with an extraordinary talent - and whose privilege and curse it is to be both master and victims of their times. Through Saleem's gifts - inner ear and Saleem Sinai was born at midnight, the midnight of India's independence, and found himself mysteriously "handcuffed to history" by the coincidence. He is one of 1,001 children born at the midnight hour, each of them endowed with an extraordinary talent - and whose privilege and curse it is to be both master and victims of their times. Through Saleem's gifts - inner ear and wildly sensitive sense of smell - we are drawn into a fascinating family saga set against the vast, colourful background of the India of the 20th century.


Neuromyelitis optica (NMO) is an uncommon disease syndrome of the central nervous system (CNS) that affects the optic nerves and spinal cord.
The relapsing form of NMO primarily affects women. The female to male ratio is greater than 4:1. Another form of NMO, in which an individual only has a single, severe attack extending over a month or two, is most likely a distinct disease that affects men and women with equal frequency. The onset of NMO varies from childhood to adulthood, with two peaks, one in childhood and the other in adults in their 40s.
Individuals with NMO develop optic neuritis, which causes pain in the eye and vision loss, and transverse myelitis, which causes weakness, numbness, and sometimes paralysis of the arms and legs, along with sensory disturbances and loss of bladder and bowel control. NMO leads to loss of myelin, which is a fatty substance that surrounds nerve fibers and helps nerve signals move from cell to cell. The syndrome can also damage nerve fibers and leave areas of broken-down tissue. In the disease process of NMO, for reasons that aren't yet clear, immune system cells and antibodies attack and destroy myelin cells in the optic nerves and the spinal cord.
Historically, NMO was diagnosed in patients who experienced a rapid onset of blindness in one or both eyes, followed within days or weeks by varying degrees of paralysis in the arms and legs. In most cases, however, the interval between optic neuritis and transverse myelitis is significantly longer, sometimes as long as several years. After the initial attack, NMO follows an unpredictable course.
Disability is cumulative, the result of each attack damaging new areas of myelin. Some individuals are severely affected by NMO and can lose vision in both eyes and the use of their arms and legs. Most individuals experience a moderate degree of permanent limb weakness from myelitis. Muscle weakness can cause breathing difficulties and may require the use of artificial ventilation. The death of an individual with NMO is most often caused by respiratory complications from myelitis attacks.
In the past, NMO was considered to be a severe variant of multiple sclerosis (MS) because both can cause attacks of optic neuritis and myelitis. Recent discoveries, however, suggest it is a separate disease. NMO is different from MS in the severity of its attacks and its tendency to solely strike the optic nerves and spinal cord at the beginning of the disease. Symptoms outside of the optic nerves and spinal cord are rare, although certain symptoms, including uncontrollable vomiting and hiccups, are now recognized as relatively specific symptoms of NMO that are due to brainstem involvement.
The recent discovery of an antibody in the blood of individuals with NMO gives doctors a reliable biomarker to distinguish NMO from MS. The antibody, known as NMO-IgG, seems to be present in about 70 percent of those with NMO and is not found in people with MS or other similar conditions.
There is no cure for NMO, but there are therapies to treat an attack while it is happening, to reduce symptoms, and to prevent relapses. Doctors usually treat an initial attack of NMO with a combination of a corticosteroid drug (methylprednisolone) to stop the attack, and an immunosuppressive drug (azathioprine) for prevention of subsequent attacks. If frequent relapses occur, some individuals may need to continue a low dose of steroids for longer periods. Plasma exchange (plasmapheresis) is a technique that separates antibodies out of the blood stream and is used with people who are unresponsive to corticosteroid therapy. Pain, stiffness, muscle spasms, and bladder and bowel control problems can be managed with the appropriate medications and therapies.
Individuals with major disability will require the combined efforts of occupational therapists, physiotherapists, and social services professionals to address their complex rehabilitation needs.


The outstanding pics on top, is section of Maximize the Small Kitchen with Galley Kitchen Ideas content which is categorised within Kitchen Makeover, galley kitchen remodels, small galley kitchen design, galley kitchens designs and published at May 5th, 2016 18:33:51 PM by Sebastian J. We always effort to show a picture with HD resolution or at least with perfect images. Thank you for visiting.


The dawn of the web has given the word "publishing" a whole lot of new dimensions. In fact, the web is nothing but about publishing after all. Publishing means basically making content, mainly text, images and multimedia available for a broader audience. Since such a wide audience can now reach the web, online media has become an interesting channel for publishing. There are several advantages of online publishing, amongst which the most important one is probably the timeliness. Publishing on the web has become more or less instant, particularly since the rise of "Web 2.0", the participative web.
Steve Jobs talks to graduates at Stanford University. The tips are just as good for anyone just graduated!
Curiosity is as old as humankind. Ever since humans exist, they want to explore the world they are living in. They want to reach the "Edge of the World" to see what's beyond it, even if it puts their lives in great danger.
Many conquerers and explorers left their harbors and sailed the seas without having an idea where they are going not to mention whether they will survive. Many of them died at sea, but - as we know today - nobody died of falling off the "Edge of the World".


Amancio Ortega has overtaken Warren Buffett as the world's second-richest person on a billionaires' list prepared by Bloomberg.
According to an index compiled by the news agency, the Spanish billionaire has a net worth of $69.8bn (£45.7bn, €62.8bn) as of 5 June, slightly higher than Buffett's $69.2bn fortune.
Microsoft's co-founder Bill Gates still leads the list with a large margin at a net worth of $84.8bn.
Ortega, the richest person in Europe, owns 59% of Inditex, the world's largest clothing retailer and parent of the Zara chain. The Spain-based company operates more than 6,600 stores and had revenues of €18.1bn in the year ended January 2015.
In addition to the stake Inditex, he has investments in office and retail property throughout Europe and the US through two closely-held investment vehicles.
Inditex has recently experienced strong growth, and the company is planning to open up 480 more stores in 2015.
Over the last one year, Ortega's net worth rose by 14.3% or $8.7bn, while Buffett's fortune fell by 6.3% or $4.4bn over the same period. Buffett, the largest shareholder of Berkshire Hathaway, would have been in the second place, taking into account his spending on philanthropic works.
Mexico's richest man, Carlos Slim, is the fourth-richest in the world with a fortune of $66bn, followed by US-based Koch Industries' CEO, Charles Koch, at $49.8bn.