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March 3, 2013
SAN DIEGO, Calif. - In the final game of the San Diego Classic, Utah State softball fell just short against Boise State, 2-0, on Sunday.
In a game that showcased pitching and defense, neither team was able to get much going offensively. The game was scoreless through the first five innings of action.
The Broncos were the first to plate a run in the game in the bottom of the sixth inning as Devon Bridges connected for a two-run homerun off Aggie senior pitcher Mandy Harmon, to put Boise State up, 2-0 heading into the final inning.
Utah State could not rally it offense in its final at bats as BSU starting pitcher Kenzie Cole worked a complete game shutout and collected the win. Harmon was charged with her 13th loss of the season, while her squad falls to 0-20 on the year.
USU had three players tallying hits in the game, all of whom were sophomores. Infielder Nicole Arata, outfielder Jolene Koons and outfielder Amburlyn Orozco were all credited with a hit in Sunday's action.
The Aggies will next take to the diamond for a doubleheader against in-state foe Weber State on March 13. Action is set to be played in Ogden, Utah, and it will be Utah State's first action outside of tournament play this season.
Follow Utah State athletics, including softball, at http://twitter.com/USUAthletics.com, as well as on facebook, at https://www.facebook.com/USUAthletics.
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Aggressive drivers want to take advantage of driverless cars
Aggressive drivers are excited for the outbreak of autonomous cars on public roads, seeing it as a way to bully computers that err on the side of caution, according to new research.
The London School of Economics and Goodyear conducted one of the largest surveys to gauge attitudes towards autonomous cars, with 12,000 drivers in 11 countries polled.
See Also: Most Americans say they're ready for an autonomous future
One of the key findings was aggressive drivers expect autonomous cars to try and accommodate all types of drivers. In a situation where the self-driving system is unsure of the outcome, drivers expect Google, Uber, and Tesla to build systems that avoid accidents at all costs.
"I'll be overtaking all the time because they'll be sticking to the rules," said one driver in the survey. "They are going to stop. So you're going to mug them right off. They're going to stop and you're just going to nip round," said another.
Across Europe, U.K. drivers have the most negative view of autonomous cars, according to the survey. 55 percent of U.K. drivers said they were uncomfortable sharing the road with an autonomous car, and 83 percent were concerned the car might malfunction.
That's higher than the average for non-U.K. nations polled, at 39 and 71 percent, respectively.
Driverless tech still looking for on ramp anyway
Autonomous cars are still an emerging technology that is only available on certain public roads, in certain cities. The U.K. and Germany are leading the race in Europe, followed by France, which recently endorsed some autonomous car tests on public roads.
Outside of Europe, the U.S., Singapore, and China are the main hubs for self-driving tests. Baidu, Tencent, and Alibaba are all funding tests, either directly or through startups.
In Singapore, nuTonomy, a MIT spin-out, has begun shuttle tests, with a goal of launching the service in 2018.
The post Aggressive drivers want to take advantage of driverless cars appeared first on ReadWrite.
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[Reminder] Upcoming webcast: Take back control of your content
Are you losing control of your content? If you're like the majority of marketers, you're going to produce more content in 2017 — but feel less than confident about your content marketing operations. Join experts Arnie Kuenn, CEO at Vertical Measures, and Brian Kavanaugh, US marketing…
Please visit Search Engine Land for the full article.
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Take back control of your content
Are you losing control of your content? If you're like the majority of marketers, you're going to produce more content in 2017 — but feel less than confident about your content marketing operations. Join experts Arnie Kuenn, CEO at Vertical Measures, and Brian Kavanaugh, US marketing…
Please visit Search Engine Land for the full article.
View full post on Search Engine Land: News & Info About SEO, PPC, SEM, Search Engines & Search Marketing
Why do big US companies take mobile less seriously than Chinese companies?
If you want to know how seriously any public company takes mobile, then take a look at the annual/quarterly reports.
While top Chinese retailers, banks and internet companies are keen to share their mobile success with their investors, their US equivalents are often shy to reveal their numbers… especially the biggest US retailers.
While researching a series of in-depth m-commerce reports for ClickZ Intelligence, I needed to establish which of the world's biggest countries are really making headway with mobile. The results are worth sharing.
The methodology was simple
1) Use Forbes' Global 2000 as a guide.
2) Stick to US and Chinese companies (as they dominate the Forbes list).
3) Concentrate on consumer facing businesses where mobile isn't the core business, but should be a very significant sales channel, so retailers, restaurant chains, banks and internet companies are in; but mobile companies and oil companies and manufacturers are out.
4) Then check the latest annual (2015) and quarterly statements (Q1 and Q2 2016) to see which detailed mobile performance – only hard numbers; PR fluff was ignored.
The results were striking:
- The top Chinese banks, retailers and internet companies all (of those considered) detail mobile performance, often in considerable depth.
- Three out of four top US banks declare mobile numbers. But not in as much detail as the top four Chinese banks.
- Of the two US internet giants, only one details mobile performance: Facebook. Alphabet (Google), surprisingly, doesn't.
- Not one of the Top 10 US retailers from Wal-Mart to Amazon.com, shared mobile stats in their recent annual or quarterly report.
The US retailers were a big shock – especially Amazon. In 2016, you have to ask: why we couldn't find any indication of mobile performance in financial reports of the US top retailers?
And, more importantly, you have to ask: why aren't investors and analysts asking the same thing?
The more financial reports you look at the more you come to the conclusion: Chinese companies – and their investors – take mobile more seriously.
They saw the mobile opportunity earlier; they made it a priority to re-engineer their companies to take full advantage; and now they want investors to benchmark them on their impressive mobile performance.
Alibaba: the benchmark in mobile performance and reporting
This month the Chinese ecommerce retail market place Alibaba redefined what it means to be "mobile first" announcing that it has 427 million mobile monthly active users (MAU) – out of a total of Alibaba's 434 million total users.
In the latest quarter (Q2, 2016), mobile accounted for a stunning 75% of value of all goods bought and sold on the platform and 75% of its revenues.
Just to put Alibaba's 427 million mobile users into perspective:
- The entire population of the US is 324 million.
- Walmart's global customer base 260 million (Note: Walmart measures weekly shoppers; Alibaba's are monthly).
The wake-up call for all companies is twofold
- A mobile-first strategy delivers tangible rewards.
- How well the markets received the news…
Financial investors and analysts loved Alibaba's results. On announcement of the Q2 results, the stock leaped to its highest level for 18 months.
This is the carrot: impressive mobile performance is increasingly a factor (one of several) that encourages investors to purchase stock.
The question is: when will US investors / analyst start to use the stick to punish (US) companies that keep their mobile numbers a secret?
US investors are becoming well acquainted with, and increasingly attracted to the Chinese retail and internet companies such as Alibaba, JD.com, Baidu and Tencent (all of which detail impressive mobile performance in their financial reports; all of which saw their share price improve on the latest results.
Three out of four are quoted on US markets: Alibaba is listed on the NYSE; JD.com and Baidu on Nasdaq (Tencent is listed on HKSE), which means they'll remain front of mind.
For share price performance, see: BABA; JD; BIDU; and 0700.HK (Tencent).
Stick and carrot – Facebook's mobile story
Any US company that doesn't believe how seriously US investors take mobile needs to look at Facebook's recent financial history.
One of the main reasons Facebook's share price went into freefall post its 2012 IPO was that investors were very unimpressed with its mobile story. One of the main reasons they love it now is because they are impressed with its mobile numbers.
As recounted by Fortune in 2015:
Facebook used its weakness on mobile as a motivator. When the company went public it had no meaningful revenue from mobile. Within 18 months, Facebook delivered a magnificent about-face on mobile, quieting the haters in the process. By the end of 2013, more than half of Facebook's revenue came from mobile ads. "You want mobile revenue? We'll show you mobile revenue!" the company seemed to say. Wall Street rewarded the company by trading up its stock.
Today Facebook wants to be measured on its mobile record. In its Q2 2016 results statement it couldn't shout louder about its mobile success:
Second Quarter 2016 Operational Highlights
- Daily active users (DAUs) – DAUs were 1.13 billion on average for June 2016, an increase of 17% year-over-year.
- Mobile DAUs – Mobile DAUs were 1.03 billion on average for June 2016, an increase of 22% year-over-year.
Second Quarter 2016 Other Financial Highlights
- Mobile advertising revenue – Mobile advertising revenue represented approximately 84% of advertising revenue for the second quarter of 2016, up from approximately 76% of advertising revenue in the second quarter of 2015.
The phenomenal rise of Facebook's stock price, see FB, from mid-2013 tells you everything you need to know about investor attitude to mobile.
How the largest companies rack up on mobile transparency
By way of research we looked at the recent annual and/or quarterly reports and earning statements of relevant companies from the world's biggest public companies according to Forbes, which is dominated by Chinese and US companies, to see to what extent (if at all) mobile performance is displayed.
The Forbes rankings are based on a mix of revenue, profits, assets and market value.
Chinese banks:
Three Chinese banks occupy the top three Forbes rankings, with a fourth in sixth ranking. All four appear to have made mobile banking a priority over recent years and the numbers are staggering. At the end of 2015, they have 590 million mobile banking customers between them. That's 1.8 times larger than the population of the United States.
- Industrial & Commercial Bank of China has 190 million mobile customers, with annual transaction volume of over RMB800 billion (US$121 billion), which is approximately 38% of its customer base. (Source 2015 Annual Report)
- China Construction Bank has 182.84 million (up by 25% year on year) mobile banking users, with a transaction volume was RMB15.4 trillion (US$2.3 trillion), which is approximately 54% of its customer base. (Source 2015 Annual Report)
- Agricultural Bank of China has 140 million mobile customers, with annual transaction volume of over RMB9.6 trillion (US$1.5 trillion), this is approximately 29.5% of customer base. (Source 2015 Annual Report)
- Bank of China has 79 million mobile customers, with annual transaction volume of over RMB5.2 billion (US$0.7 billion), the proportion of the customer base that is mobile is unclear. (Source 2015 Annual Report)
US banks:
Three of the top four US banks share mobile banking numbers. Although mobile customers are dwarfed by the vast numbers of their Chinese counterparts are a significant proportion of their total user base.
- JP Morgan Chase (Global Rank 5) has 24.8 million active mobile customers. As JPMC only counts its customer base by households (59.2 million), rather than individuals, it is unclear what proportion of customer are mobile. Mobile transaction value is unavailable. (Source Q2 2016 results).
- Wells Fargo (Global Rank 7) has 18 million mobile active users. This is approximately 25.7% of customer base. Mobile transaction value is unavailable. (Source Q2 2016 results)
- Bank of America (Global Rank 11) has 20.2 million active mobile banking customers in Q2 2016. It is unclear what proportion this is of the total customer base. But it does reveal in its investor presentation that mobile equates to 17% of total deposit, and on a weekly basis it is the most active channel. See charts below. (Source Q2 2016 results)
- Citigroup (Global Rank 13). We were unable to find mobile numbers for Citigroup, but the company did state in its 2015 Annual Report that it is implementing a "mobile first" approach via a newly established Citi FinTech unit.
Brian Moynihan Chairman and CEO, Bank of America explains to shareholders why mobile banking is so important:
Why are we tripling our investment in 2016? It is simply because this is how customers want to do business with us. Our customers deposit 250,000 checks a day through their mobile devices, reflecting 15 percent of consumer deposit transactions. We would need an additional 650 financial centers to handle the deposit activity that is currently being done on those mobile devices.
Chinese retailers:
China's highest ranking retailers on Forbes list are Alibaba (rank 174) and JD.com (rank 800). Despite their lowly ranks, compare to US companies such as Walmart (rank 15), these are no small fry.
- Alibaba is an internet marketplace where third-party retailers sold RMB 837 billion (US$ 126 billion) of goods in Q2, 2016. (That's six times the value of goods sold on eBay in the same quarter). As noted above, 75% of this GMV and 75% of the revenue it makes from these sales. Total revenue is RMB 32.2 billion (US$ 4.8 billion), which means Alibaba's revenue from mobile is
Most interesting is the news that Alibaba now makes more money from each of its 427 million mobile user than from non-mobile customers. (Source Q2, 2016 results)
- JD.com is a direct ecommerce retailer and internet marketplace, it makes more in revenue than Alibaba, at RMB 65.2 billion (US$9.8 billion), in Q2, 2016, hence its claim to be "China's largest ecommerce site by revenue". But GMV (value of total goods sold) is lower than Alibaba at RMB160.4 billion (US$ 24.1 billion), though still slightly above eBay.
Unlike its rival, JD does not reveal what proportion of revenue or GMV is mobile or the number of mobile users. But it does declare that an impressive 79% of its orders placed on mobile. (Source: Q2, 2016 results)
Like its rival Alibaba, JD's earnings were well received by investors.
US retailers:
Compared with the mobile details (and outstanding mobile performance) shared by the Chinese retailers, the details shared by US retailers is disappointing.
Searching through the 2015 annual report and quarterly earnings statements (up to August 18 2016), we were unable to find mobile performance numbers of any descriptions for the following US retailers and restaurants.
- Wal-Mart Stores (Forbes rank 15)
- CVS Health (rank 62) – no mobile numbers apparent in 2015 annual report, Q1 or Q2 2016 reports.
- Walgreens Boots Alliance (rank 107)
- Home Depot (rank 112)
- Target (rank 164)
- McDonald's (rank 189)
- Costco Wholesale (rank 192)
- Lowe's (rank 205)
- Kroger (rank 223)
- com (rank 237)
- The Priceline Group (rank 445)
- Macy's (rank 515)
There were two US retailers/restaurants sitting outside the top 10 that revealed some details of mobile performance:
- Starbucks (Forbes rank 389) reveals the adoption of mobile ordering and payment by customers. In Q3 2016 Mobile Order and Pay usage reached 5% of the coffee chain's U.S. transactions, up from 4% in Q2 FY16. (Source Q3, 2016 results)
- eBay (rank 466) does not include details of mobile performance in its actual earnings releases, but in an accompanying "Fast facts" document it declares that $9.5 billion of sales on the auction site were completed on mobile devices in Q2 2016. This means mobile sales volume is now 45.5% of the GMV for the quarter ($20.9 billion). eBay also states that 57% of sales are touched by mobile at some point. (Source eBay Fast Facts – PDF).
Chinese internet companies
There are two prominent internet companies in China, Tencent Holdings (Forbes rank 201) and the Baidu (rank 349):
- Tencent businesses include the QQ web/mobile portal, instant messaging and gaming platform, the Qzone social media site and the Weixin/WeChat social/chat smartphone application. As of June 2016, Mobile QQ has 667 million monthly active users (MAU) users, Qzone has 596 million MAU and Weixin/WeChat has 806 million MAU. Mobile's contribution to revenue is not available, except reporting that smartphone games delivered RMB 9.6 billion (US$ 1.4 billion) in revenue (Source Q2, 2016 results)
- Baidu is a mobile/web search engine, with portfolio of associated products. In its Q2 2016 results it reported it had 667 million mobile search MAU and 343 million mobile maps MAU. Total or online MAUs were not reported. Mobile revenue represented 62% of total revenues for the second quarter of 2016, compared to 50% for the corresponding period in 2015. This works out at RMB 11.3 billion (US$ 1.7 billion). (Source Q2, 2016 results)
US internet companies
The two prominent Internet companies in USA are Alphabet, the company formally known as Google, (rank 27) and Facebook (rank 188). The contrast is remarkable.
- Facebook now has over 1 billion (1.03 billion) mobile daily users (DAU), which is 91% of total DAU. Mobile advertising revenue accounts for 84% of total ad revenue (US$ 24 billion) which means Facebook earns US$ 5.24 billion in mobile ad revenues.
- Alphabet does not report mobile numbers in its 2015 annual report or 1Q or 2Q 2016 reports. It appears from the investor earnings calls that mobile is very important to Google, which makes it inexplicable that the company does keep investors informed of mobile performance. (Source Q2, 2016 results and earnings call)
Sundar Pichai, CEO Google, investor briefing Q2 2016:
"Q2 2016 earnings call: Our investment in mobile now underlines everything that we do today from search and YouTube to Android and advertising. Mobile is the engine that drives our present."
Room for improvement
We look forward to the time when US companies feel confident enough about their mobile numbers to share them in their financial reports; or the time when investors start to insist on it.
N.B. This study was not an in-depth research project, it was based on observations from the companies' financial reports. If any of these retailers share numbers elsewhere / or would like to share their mobile numbers, please contact the author Andy Favell who will be very happy to update the ClickZ readers.
Read the reports:
- DNA of a Great M-Commerce Site Part 1: Planning
- DNA of a Great M-Commerce Site Part 2: The 12 Pillars of Mobile Design
This is Part 28 of the ClickZ 'DNA of mobile-friendly web' series. Here are the most recent chapters:
- Mobile menu UI: bold buttons and intuitive types of navigation
- Should the hamburger icon be on your mobile menu?
- M-commerce: has the mobile web finally won?
Andy Favell is ClickZ columnist on mobile. He is a London-based freelance mobile/digital consultant, journalist and web editor. Contact him via LinkedIn or Twitter at Andy_Favell.
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Five ways analysts can take their skills to the next level
As I've been writing about tools and tactics quite a bit lately, I thought for this month's column I'd take a step back and share some ideas on how you can become a better analyst.
And improving our analysis skills as marketers goes beyond broadening our career options and helping us be better at our craft.
It should actually improve all areas of your life as a byproduct of nurturing our critical thinking skills. Some ideas follow that I apply in my own life and hope you'll consider too.
Find a passion outside work which involves developing hypotheses
The scientific method, as you know, is a body of techniques for investigating phenomena, acquiring new knowledge, or correcting and integrating previous knowledge.
You're already applying this to your marketing and analytics practice by putting it to work for testing and optimization efforts (for example, having a hypothesis that a new landing page with less clutter will convert better, which you then test).
But beyond work, you should also, in free time, be involved in something which flexes your prediction muscle.
Whether this manifests as fantasy sports, investing in startups or some other activity which involves future predictions (and cool datasets!), this can be a fun and rewarding way to sharpen your mind and will help you see analysis problems in a new light.
Learn to fill in the missing pieces, be comfortable working with imperfect data/information
100% perfect data is really only possible in a controlled lab setting with expensive and fine-tuned equipment. While, of course, we should ensure our analytics implementation is setup correctly to keep our own data as clean as possible, we must also get comfortable working with a "good enough" information.
This is necessary in order to be agile in how we work and keep projects moving forward. A great analyst will work out the way to fill in the missing pieces and make effective projections (while of course providing a rationale/caveats where needed).
You want to get confident enough to make recommendations and create analysis' based off "minimum viable data."
Have a sandbox project to test new tools
If you are truly serious about improving your skills, doing analyst work in your live business environment isn't enough.
The reason being you can't test and tinker with any new tool without permission or change settings at whim, you likely have compliance and managers to work through.
But a sandbox project such as your own site, app or side business provides a place you can test, tinker and experiment in a no-stress setting.
Bonus: our team at Google recently launched an Analytics Demo Account for this very purpose.
Live and breathe your company and sector metrics (beyond what you're accountable for)
Being a great analyst isn't about just running reports and delivering insights that are your remit.
Rather, the best analysts have their finger on the pulse of the bigger pictures and are deftly able to put their own work into context with the larger organization and sector as a whole.
The analysts I talk to that leave a lasting impression are the ones who can speak articulately about various areas of the business and how they make impact across teams and functions.
Be a part of the industry, network and collaborate with peers
I'm personally a big believer in educating others about digital marketing and since starting my career well over a decade ago I've spent time both at and outside of work helping others learn our craft.
Our industry is tight knit and so being an active participant who helps others is of great benefit (not to mention fulfilling).
For you, whether this takes the form of speaking/attending events (such as ClickZ Live), starting your own local analytics meetup, or even making friends with other analysts near you to talk shop this is a valuable use of time.
Adam Singer will be speaking at ClickZ Live San Francisco in August.
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Jaguar Land Rover plans to take you off-roading autonomously
Jaguar Land Rover has revealed plans to build an off-road self-driving system, capable of maneuvering through any terrain autonomously.
Researchers will begin field tests of the autonomous Land Rover to make it capable of functioning on all surfaces, regardless of the weather or environment. This could be a major step for autonomous vehicles, which currently only function on tarmac.
See Also: NuTonomy partners with Singapore on self-driving taxi fleet
"We don't want to limit future highly automated and fully autonomous technologies to tarmac. When the driver turns off the road, we want this support and assistance to continue," Tony Harper, head of research at Jaguar Land Rover said. "In the future, if you enjoy the benefits of autonomous lane keeping on a motorway at the start of your journey, we want to ensure you can use this all the way to your destination, even if this is via a rough track or gravel road."
Your Jaguar can see better than you?
The autonomous off-roader will be fitted with surface identification and 3D path sensing — two technologies used in most autonomous cars. Jaguar Land Rover claims that the technology is so advanced it has better vision than humans and can predict upcoming terrain changes.
The firm is also developing an overhead clearing assist, able to recognize branches and barriers above the car. For military conveys, the automaker is looking into a off-road connected convey system, which uses vehicle-to-vehicle (V2V) communication to alert a fleet when one car goes offline or crashes.
Jaguar has not mentioned when the tech will be added to cars, though it could be as soon as the next generation Range Rover and Range Rover Sport. Both are apparently a few years away from launch.
AutoExpress speculates that the autonomous tech may be a premium feature for the first generation, costing extra. That's a stark contrast to Tesla's focus on integrating AutoPilot into as many cars as possible, through a free over-the-air update.
The post Jaguar Land Rover plans to take you off-roading autonomously appeared first on ReadWrite.
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When will robots finally take farmers' jobs?
Robots could scoop up the remainder of jobs in agriculture over the next two decades, as machines become smarter, cheaper, and more efficient.
That's according to a new report by Lux Research that reveals how robots and autonomous systems could take over and change the agriculture industry.
See Also: Crownstone takes home automation beyond Alexa
Robots have not been economically viable for a lot of farmers, and tests have shown most robots are less efficient than their human counterparts. On top of that, robots typically have one or two functions, compared to the large variety of tasks that humans are able to complete.
Lux argues that in the near future, we are going to see farming robots that are not only much cheaper than human labor, but capable of executing tasks with much more efficiency and accuracy. That could lead to higher crop yields for farmers and a workforce that doesn't need to rest every few hours.
In the graphic (above), Lux shows the cost per acre of a lettuce thinner and lettuce weeder, compared to the human labor cost. As we enter into the next decade, the lettuce weeder is already $50 lower per acre, and the lettuce thinner reaches the human labor cost at 2027.
Other crops, like corn, are already seeing autonomous systems enter the workforce. An Autosteer system for tractors and harvesters has already reached 10 percent market penetration, and Lux predicts the cost factor will be negligible by 2020.
Lux also mentions that in Japan the average age of a strawberry picker is 70, and once the current generation of farm workers leave the workforce, farmers may be forced to move to an autonomous system.
Don't worry — people are still needed
What the report doesn't suggest is that all human labor will be removed from agriculture. Instead, Lux suggests that humans will be used for other tasks, like maintenance and sorting, tasks that are not fit for robots currently.
Agriculture has become a much less important sector in most developed countries, contributing to less than five percent of the U.S. GDP. Employment in agriculture over the past fifty years has dropped from 30 to 4.2 percent, according to Momagri.
That said, it is still a major source of revenue and employment in Africa and Oceania, at 52 and 59 percent, respectively. Across all developing countries, agriculture accounts for 48 percent of all employment.
The invasion of robots in the agriculture market may force countries in Africa to quickly urbanize, similar to China's urbanization period in the 1980s. While some may respond well to this, others countries may struggle to find new jobs for the millions entering the workforce due to a lack of rural employment.
The post When will robots finally take farmers' jobs? appeared first on ReadWrite.
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Nine SEO techniques that take less than 15 minutes
I know. It's the 21st century equivalent of '8 minute abs'. But bear with me on this…
Search engine optimisation should be an ongoing process, mixing technical on-page techniques with quality content, good old fashioned marketing, plenty of research, tonnes of planning, masses of testing and all the while taking into account searcher intent, context, algorithm changes… I get breathless just thinking about all the work that needs doing…
Basically, SEO is a job that is never done.
But, if you are struggling with time and resources, there are SEO techniques that don't have to consume your entire day.
The following can be done while sat down in the morning, enjoying a pastry, listening to some cool light-jazz and blissfully remembering that this is a much better use of your time than that other 'resolution' you toyed with doing four paragraphs ago.
Please note: we published a similarly titled guide to quick SEO tips, written by Josh McCoy, way back in 2012. This is an updated, rewritten version that reflects the subsequent changes and updates to the search landscape.
1. Check your site's organic CTR, revise 10 of the lowest performing page's title tags and meta descriptions
Head into your site's Google Search Console, then click on Search Traffic>Search Analytics.
Then click on the Impressions and CTR filters for Pages.
Here you can take a look at the pages with high visibility, but low CTR. Perhaps all they need is an improved meta description or title tag?
For a more detailed overview, check out How to improve CTR using Search Console.
2. Add Schema markup to 10 most popular pages
You can add rich media to your search results by adding Schema markup to the HTML of your pages.
If you have a particularly massive site with years and years worth of posts, the idea of adding rich snippets to your pages can seem terrifying. Instead, make a spreadsheet of your most popular posts, then every day go through 10 of them and implement schema markup. This should help gradually improve the CTR of your results.
3. Improve your site speed by optimising images
Site speed is a hugely important ranking signal, and you can check your site's loading time on both mobile and desktop with this new site speed tool.
Obviously improving the performance of your site is a complicated job best saved for the tech team, but you can help…
Images are are by far the 'heaviest' element when it comes to page load. So why not spend a few minutes working back through your most popular posts and making your image file sizes smaller.
For example, if there's an image on your page that's 1024 x 683 pixels, but the user only sees it at a maximum of 420 x 289, you could ease the strain on your page by compressing the file size with very little noticeable difference.
Read this article for full details: How to optimise your page images to increase site speed.
4. Check the proper canonicalization of your domain
Are you aware that your site may exist in two different places? Without even knowing it, Google could be indexing your content from both www.example.com and example.com and therefore you may be cannibalising your own pages in search.
Luckily it doesn't take very long to fix this problem.
You just have to tell Google which is the preferred version of your domain for all future crawls of your site and indexing refreshes.
As it states on their webmaster help page:
If you specify your preferred domain as http://www.example.com and we find a link to your site that is formatted as http://example.com, we follow that link as http://www.example.com instead. In addition, we'll take your preference into account when displaying the URLs.
To change this, visit Search Console, click on your site, click the gear icon then click Site Settings. And in the Preferred domain section, select the option you want.
5. Verify your Google My Business page, make sure your details are up to date
Kevin Gibbons wrote some good suggestions for us when it comes to optimising your page for local search:
- Claim your listing, as often many people don't.
- Ensure your details are up-to-date (previously you might not have accepted credit cards).
- Double check your opening hours and phone number as these often change over time or the business has new owners or management
- Check the business images you are using and consider refreshing them or uploading higher res versions.
- Check no-one has made an edit to your listing and changed the businesses's website to their affiliate link, have seen this too!
There are loads more tips here: How to optimise your Google My Business listing.
6. Check that you don't have any duplicate meta description and title tags
This is a very easy one. Just head back into Search Console, click on Search Appearance>HTML Improvements, then you can see exactly which of your pages contain duplicate metadata.
7. Keep on top of your image alt tags
Google Image Search can drive a significant amount of traffic to your site, however you must remember that Google can't 'see' your images, but it can 'read them'.
Therefor describing your images accurately and concisely in the 'alt description or tag' section is something you really need to stay on top of.
Check back through your last handful of pages and make sure your images conform.
You could even look at the alt tags at the same time as checking your images' file sizes (see point 3).
For lots more information, check out How to optimise images for SEO.
8. Check your 404 error codes
404 pages occur when a Googlebot attempts to visit a page that doesn't exist. Generally 404 pages are fine and won't harm your rankings, but it is important to pay attention to them, especially if there's a sudden increase.
You can check these in Search Console, under Crawl>Crawl Errors.
Then if anything looks to have been deleted accidentally, or a 301 redirect hasn't been put in place properly, you can fix these straight away.
9. Keep on top of your internal linking
Regular and consistent internal linking to the most popular articles on your site is a key way to show search engines that your site has authority and that your content is 'trusted'.
There are many different methods and tools to check which of your pages is the most popular for any search phrase, and therefore the you can use to internally link for added SEO benefit.
Spend some time going back through your posts and ensuring that each post has a few internal links, paying particular attention to the anchor text used, and making sure they're all relevant AND pointing towards pages you wish to see rank.
There's an excellent, detailed best practice guide here: Internal linking for SEO.
So there you go. Nine quick things you can do to improve your SEO every day without taking up too much of your energy. Obviously this is far from an exhaustive list, but it's definitely a start to getting the basics right.
View full post on Search Engine Watch
Take this link and shove it
Think any free link is a good one? Columnist Julie Joyce explains why this mindset is no longer beneficial.
The post Take this link and shove it appeared first on Search Engine Land.
Please visit Search Engine Land for the full article.
View full post on Search Engine Land: News & Info About SEO, PPC, SEM, Search Engines & Search Marketing

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About this item
About this item
Important Made in USA Origin Disclaimer: For certain items sold by Walmart on Walmart.com, the displayed country of origin information may not be accurate or consistent with manufacturer information. For updated, accurate country of origin data, it is recommended that you rely on product packaging or manufacturer information.
The Whistler Pro 3600 Detector is a full-featured remote radar detector. This unique device features versatile installation allowing you to mount the Remote Radar Detector on or under the dash. This Laser-Radar Detector installs discretely in your vehicle and has many features, including a unique tri-directional dot matrix display, an exclusive radar and laser signature ID, a high-performance antenna and a modular design. The Laser-Radar Detector responds to virtually all types of radar currently in use by police. It detects POP mode radar and laser transmissions. It also includes three city modes and four filter modes to reduce false alerts. The Whistler Pro 3600 Detector provides Laser Atlanta stealth mode, making your vehicle immune to the Laser Atlanta gun. The Remote Radar Detector is also invisible to detection by VG-2.
Whistler Pro 3600 Remote Laser-Radar Detector:
- Versatile installation provides for on, under and through-the-dash mounting
- Unique tri-directional dot matrix display
- Makes your vehicle immune to the Laser Atlanta gun
- Exclusive radar and laser signature ID
- Modular design
- Exclusive high performance antenna
- Red tri-directional text display
- Laser Atlanta stealth mode
- Invisible to detection by VG-2
- Responds to all types of radar currently in use by police
- Real voice module
- Discreet console
- 4 filter modes to reduce false alerts
- POP mode detection
- Total band detection
|Display Technology:
Vertical, Normal or Upside Down Selectable Display
|12 V DC to 15 V DC
|Video Game Platform:
|WHISTLER PRO-3600 PRO-3600 Installed High-Performance Laser/Radar Detector
|Vehicle Type:
|9.00" x 6.70" x 3.00"
|Manufacturer Part Number:
|Assembled Product Dimensions (L x W x H):
|3.22 x 0.95 x 0.56 Inches
Customer Reviews | 4 reviews | 4 out of 5
Customer Reviews
Customer review by KV4020
Installation of this unit was easy and it is really nice to have everything concealed. I installed the unit per the instructions provided and always had issues with false laser warnings. Mainly, the sun would set the laser warning off and there is no stopping it if you are driving east in the morning or west in the evening. Other than that I was really happy with the performance of this unit until it recently stopped identifying anything but the sun (giving me a laser warning). It has been almost exactly 2 years from the date of installation so it basically cost me $150 per year to use this thing. Maybe that is not bad compared to some, but the unit I had prior was only $200 and lasted 5+ years. I have triple checked all of the wires and connections, and it appears that this unit just stopped sensing radar of any kind... So overall, I am mostly not happy with the relative short life of this product.
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- Yes, it comes with everything needed for installation and use.by WhistelerExpert2/23/2016Written by a verified representative from WhistelerExpertWas this answer helpful? (1) (0)Was this answer helpful?
- The Whistler Pro 3600 Remote Laser-Radar Detector has everything needed to be used in the box.by CommunityAnswer2/23/2016Was this answer helpful? (2) (0)Was this answer helpful?
Q. Does this work with a Mercedes S-550, windshield prevents most radar detector from working.
- This antenna is designed to be mounted on the outside of a vehicle. Best location would be in the center of the roof. Next best would be on the center of the trunk lid. You would then route the coax cable through a door or trunk edge. Take care not to crush the coax cable as this will affect the tuning and overall performance of the antenna.by davjose1/14/2016Was this answer helpful? (2) (2)Was this answer helpful?
- yes, because this is a custom install model wherein the antenna is out in front of the vehicle and the console is mounted wherever in the car you choose. Therefore, no signal is detected through the windshield.by WhistelerExpert1/14/2016Written by a verified representative from WhistelerExpertWas this answer helpful? (5) (0)Was this answer helpful?
- It protects against VG2. Since radar detectors are not illegal to use except in VA and Washington DC, police do not use radar detector detectors on regular motorists.by WhistelerExpert2/23/2016Written by a verified representative from WhistelerExpertWas this answer helpful? (1) (0)Was this answer helpful?
- No, police will still be able to use radar to detect your speed.by CommunityAnswer2/23/2016Was this answer helpful? (3) (0)Was this answer helpful?
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Wonderful 4 bed, 3 bath in East Edmond! - Wonderful 4 bed, 3 bath in East Edmond! Located near Covell & Coltrane in Faircloud Hills. This home has been totally remodeled with wood flooring, carpet, paint, and appliances. Formal Dining plus office space or playroom off kitchen. Living room includes cathedral ceilings, fireplace and built-ins. Breakfast nook with window seat. Kitchen includes pass through window to living. Master bath features jetted tub, separate shower and double sink vanity. Covered patio in back with large fenced in back yard. Shed and storm shelter in back yard. No Pets or smoking allowed. Call Property Management & Realty at 405-359-0011 today to schedule a showing.
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Hotels in Muenchberg, Germany
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- Most bookedHotel Reiterhof Bellevue Spa & Resort
15 people looked at this hotel in the last hour
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"Hotel Reiterhof is first choice for hiking, walking or cycling. if you prefer more leisurely pursuits, the spa facilities are wonderful, as is the food and service. "
A Traveller, Aug 2016, GB
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"Room was small, but clean. Could not have been more picturesque, located up in the snow-covered mountains. We stayed in the annex. Our room overlooked the street directly across from the church. Food downstairs was outstanding. Service was also very friendly and accommodating. Bathroom small, but..."
A Traveller, Mar 2016, US
- Luxury Vacation Apartment in Weissenstadt 2139 by RedAwningNo Guest Reviews yet
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Hotels within 15 miles of Muenchberg
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"My husband and I stayed at the Quality Hotel Hof to attend a Medieval Festival in nearby Selb. Our hotel room was sort of small but enough for two people. The hotel has a hidden gem in their restaurant, all the food we had there was really good. We would absolutely recommend having dinner at ..."
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"Excellent price/quality ratio, very large apartments, great breakfast, charming and quiet town, close to Bayreuth."
A Traveller, Aug 2014, US
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"I had a good stay. Service was good. very good breakfast. Free Wifi was not working well at the room. when the receptionist herd that I am leaving early morning for my flight back she made the arrangements so I will have a "lunch bag" ready for me at 3:30 AM, which was very good."
A Traveller, Sep 2016, IL
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If you are looking for Muenchberg hotels in a particular area, you can use the search feature at the top of the page to search by neighborhood, landmark, address or zip code, or you can search by using the built-in map feature. You can also browse hotels in Muenchberg by type, amenities, and star-rating so that you can find the best hotel. Currently, top rated hotels in Muenchberg are:
- Hotel Reiterhof Bellevue Spa & Resort
- Kurzentrum Weißenstadt am See
- Hotel Central Hof
- Hotel & Gasthof Grüner Baum
- Hotel Kaiseralm
The location of your Muenchberg hotel is important. If you are traveling to Muenchberg, &StateorCountry for business, you may want to consider getting a hotel close to the airport or near your meeting venue. By doing so, you can really cut down on transportation costs and time. You may also want to book a hotel that offers free wifi just in case you need to get some work done.
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You'll also want to determine which type of accommodations will suit your needs before booking a hotel in Muenchberg. If you're traveling with the kiddos, a family friendly hotel will offer larger rooms and more sleeping arrangements. For those traveling for an extended period of time, booking a hotel suite with a kitchenette is a smart move and will feel a little more like home. If you are budget conscience and just need a place to rest your head, a hostel or motel may be all you need.
If you are looking to score the best discounts and deals, use the filter to sort by price from low to high. You can book a hotel in Muenchberg for as low as &PricesFrom per night. If you are looking to cut down on expenses, look for hotels that include free breakfast and parking. Some hotels even offer free shuttle service to and from nearby places. You can also sort by star rating, proximity, and guest rating.
Before you book, check out user reviews. Hotels.com has 0 reviews in Muenchberg. We show reviews from Expedia and TripAdvisor so you know that you are reading genuine, reliable reviews. Be sure to download the Hotels.com app so you can book your reservations on the go, view amenities, and save the hotels you want to view and compare later.


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Skyrail Rainforest Cableway at Kuranda, near Cairns in Far North Queensland, is a world-first in environmental tourism. It spans 7.5 kilometres over the rainforest of one of the earth's most diverse and fascinating areas.
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Skyrail Rainforest Cableway
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Oral treatment with a novel small molecule alpha 4 integrin antagonist, AJM300, prevents the development of experimental colitis in mice
Background and aims: Inhibition of lymphocyte trafficking by treatment with an anti-α4 integrin antibody has been clinically validated as a therapeutic approach for inflammatory bowel disease (IBD), and the orally effective 'anti-α4 integrin therapy' may be more convenient in clinical practice. The aim of this study was to investigate the pharmacological profile and anti-inflammatory effect of a novel, orally active small molecule α4 integrin antagonist, AJM300.
Methods: The binding specificity/potency of HCA2969 (the active metabolite of AJM300) were investigated in vitro. The pharmacodynamics for α4 integrin antagonism of AJM300 was investigated in mice. The anti-inflammatory effect of AJM300 fed in a diet and the anti-α4 integrin monoclonal antibody was evaluated in a mouse colitis model induced by transfer of IL-10 deficient T cells.
Results: HCA2969 selectively inhibited the in vitro binding of α4 integrin (α4β7/α4β1) to the cell adhesion molecules. Oral treatment with AJM300 dose-dependently inhibited lymphocyte homing to Peyer's patches and increased the peripheral lymphocyte count in the same dose range. AJM300 dose-dependently prevented the development of experimental colitis in mice. A significant inhibition of colon weight increase was accompanied by inhibition of T-cell infiltration into the lamina propria of colon. The maximum efficacy of AJM300 (1% diet) was comparable to that achieved by the saturated α4 integrin blockade with antibody.
Conclusions: Oral treatment with the selective small molecule α4 integrin antagonist (AJM300) prevented the development of colitis and its efficacy was comparable to that of the anti-α4 integrin antibody.
- α4 Integrin antagonist
- Oral drug
- Inflammatory bowel disease
- Lymphocyte homing
1 Introduction
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although the cause of the disease remains unknown, the infiltration of lymphocytes into the lamina propria at the sites of gastrointestinal inflammation is a well-documented pathogenic mechanism of IBD.1,2 It has been suggested that infiltration of lymphocytes is accelerated by increased expression of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on the surface of endothelial cells at the site of inflammatory lesions and that the release of cytokines and inflammatory mediators from the infiltrating inflammatory cells leads to further exacerbation of inflammation.3 The binding of lymphocytes to VCAM-1 or MAdCAM-1 requires the expression of specific integrins, α4β1 or α4β7 integrin, respectively. VCAM-1 is expressed on the luminal surface of endothelium in numerous types of tissues4 while MAdCAM-1 is expressed predominantly in the intestinal lamina propria.5
Several studies in various animal models of colitis have suggested that α4β1 and α4β7 integrins and their ligands VCAM-1 and MAdCAM-1 are attractive molecular targets for the treatment of IBD.6 Treatment with an antibody specific for α4 or α4β7 integrin suppressed the development of spontaneous colitis in the cotton-top tamarin7,8 and treatment with an antibody against VCAM-1 ameliorated inflammation in a mouse model of ileitis (SAMP-1/Yit adoptive transfer model).9 In addition, α4 integrin blockade has been validated as a therapeutic approach for IBD in clinical studies with anti-α4 integrin antibody, natalizumab10,11 or anti-α4β7 integrin antibody, vedolizumab.12,13 Furthermore, anti-β7 integrin, etrolizumab14,15 and anti-MAdCAM-1 antibodies16 are being developed for the treatment of ulcerative colitis. However, there will be some concerns regarding the long-term administration of these agents, since adverse effects specifically related to biologics, such as immunogenicity, infusion site reaction, and the loss of efficacy related to the production of persistent antibodies against biologics, have been observed in the treatment with anti-TNF antibodies.17 Therefore, the development of orally active α4 integrin antagonists is a reasonable and preferable approach. Actually, several small molecule α4 integrin antagonists have been studied in clinical trials for the treatment of asthma, multiple sclerosis and IBD.18–20 However, there are no reports on the efficacy of orally active small molecule α4 integrin antagonists in animal models of experimental colitis to date.
This study revealed the pharmacological profile of a novel orally active small molecule α4 integrin antagonist (AJM300)21–24 and its efficacy in a mouse model of experimental colitis. The binding specificity and potency of HCA2969 (the active metabolite of AJM300)21 in vitro were investigated. The pharmacodynamics (PD) for α4 integrin antagonism related to lymphocyte homing to Peyer's patches and peripheral lymphocyte counts were investigated in mice. In addition, the efficacy of AJM300 was evaluated in a mouse model of colitis induced by the adoptive transfer of IL-10 deficient CD4+ T cells25,26 and the efficacy was compared to that of treatment with an anti-α4 integrin monoclonal antibody.
2 Materials and methods
2.1 Compounds
AJM300,21 HCA2969 (an active metabolite of AJM300)21 and 3H-HCA2969 were used for in vitro studies. AJM300M1 preparation (AJM300M1: a special formulation containing AJM300 at approximately 43% and excipients) and placebo (containing only excipients) were used for animal studies. These compounds were synthesized and provided by the Research Center of Ajinomoto Pharmaceutical Co., Ltd. (Kawasaki, Japan).
2.2 Proteins, antibodies and cell lines
HEK293 cells producing recombinant rat MAdCAM-1/Fc chimera protein (rMAdCAM-1/Fc) were a gift from Dr. T. Tanaka.27 The rMAdCAM-1/Fc was purified from the supernatant of the HEK293-cell culture using a protein G column. Recombinant human VCAM-1/Fc chimera protein (hVCAM-1/Fc), mouse VCAM-1/Fc chimera protein (mVCAM-1/Fc) and human ICAM-1/Fc chimera protein (hICAM-1/Fc) were purchased from R&D Systems (Minneapolis, MN). Recombinant mouse MAdCAM-1/Fc chimera protein (mMAdCAM-1/Fc) was purchased from Genzyme Techne (Cambridge, MA). The α4β1 integrin-expressing human T-cell line (Jurkat),28,29 α4β1 integrin-expressing rat basophilic leukemia cell line (RBL-2H3),30 α4β7 integrin-expressing mouse lymphoma cell line (TK-1)31 and α4β7 integrin-expressing rat basophilic leukemia cell line (RBL-1)32 were purchased from American Type Culture Collection (Manassas, VA). The α4β1 integrin-expressing mouse lymphoma cell line (L1-2)33 and the α4β7 integrin-expressing human B-cell lymphoma cell line (RPMI-8866)34 were a kind gift from Drs. H. Kikutani and M. Miyasaka (Osaka University, Osaka, Japan). These cells were cultured in RPMI1640 medium (Invitrogen, Carlsbad, CA) supplemented with 10% fetal calf serum (MP Biomedicals, Santa Ana, CA) in a humidified 5% CO2 incubator at 37 °C. Anti-mouse α4 integrin monoclonal antibody was purified by affinity chromatography using protein G column from ascites fluid from a mouse injected with the hybridoma cell line producing anti-mouse α4 integrin (PS/2).35
2.3 Affinity of 3H-HCA2969 for α4β1 and α4β7 integrin
Jurkat, RPMI-8866 or TK-1 cells (1.8 × 106 cells each) were incubated with serially diluted 3H-HCA2969 solution (final concentration 0.03 to 4 nmol/L) in the presence of 2 mmol/L Mn2 + at 25 °C for 40 min. After incubation, the preparation was centrifuged (4000 rpm, 3 min) and the cells were resuspended in wash buffer (Tris-Buffered Saline containing 0.1% bovine serum albumin 2 mmol/L d(+)-glucose and 2 mmol/L Mn2 +). Cells were washed again with wash buffer, and Lumasafe Plus (LUMAC-LSC B.V., Groningen, Netherlands) was added to the vials and mixed. The radioactivity of each sample (counts per minute, cpm) was determined for 2 min with a liquid scintillation counter (PerkinElmer Life and Analytical Sciences, Waltham, MA) to estimate the amount of 3H-HCA2969 bound to the cells. The specific binding was determined by subtraction of the non-specific binding which represented the residual radioactivity after the addition of an excess amount of non-labeled HCA2969 to each reaction mixture. The specific dissociation constant (KD value) was calculated using GraphPad Prism software (GraphPad Software Inc., San Diego, CA) and is expressed as the mean value ± SEM of 3 independent experiments.
2.4 Cell adhesion
The chimeric adhesion molecule proteins (hVCAM-1/Fc, mVCAM-1/Fc, mMAdCAM-1/Fc, rMAdCAM-1/Fc or hICAM-1/Fc) were immobilized onto flat-bottomed 96-well plates and incubated at 4 °C overnight. On the following day, each well was washed with phosphate buffered saline (PBS) and non-specific binding was blocked using blocking buffer (PBS buffer containing Block Ace powder®, DS Pharma Biomedical Co., Ltd. Osaka, Japan) followed by incubation at room temperature for at least 2 h. Either α4β1, α4β7 or αLβ2 integrin-expressing cells (5 × 104/well) were treated with HCA2969 in the assay buffer (Dulbecco's modified Eagle medium containing 20 mmol/L HEPES, 0.1% bovine serum albumin and 0.4 mmol/L MnCl2) and added to wells pretreated with the chimeric adhesion molecule protein, followed by incubation at room temperature for 40 to 60 min. Then wells were washed and the bound cells were solubilized with Triton X-100 detergent (Sigma-Aldrich Japan K.K., Tokyo, Japan). To determine the number of bound cells, the supernatant in each well was used for CytoTox 96® Non-Radioactive Cytotoxicity Assay (Promega K.K., Tokyo, Japan) by colorimetry of the activity of lactate dehydrogenase. The 50% inhibitory concentration (IC50) was expressed as the mean ± SEM of 3 or 4 independent experiments. To evaluate the inhibitory activity of AJM300, human α4β1 integrin-expressing cells (Jurkat) were treated with AJM300 in the assay buffer and added into the wells pretreated with hVCAM-1/Fc.
2.5 Lymphocyte homing
After mesenteric lymph nodes were collected from BALB/c mice (9 weeks of age, female), single cells were prepared and stained with a fluorescent dye PKH26 (Zynaxis, Inc., Malvern, PA). AJM300M1 solution was prepared with distilled water just before use, mixed with a stirrer to keep the solution homogenous and used within 1 h after preparation. Thirty minutes after a single oral administration of AJM300M1 at doses of 0.3, 1.1, 3, 10 or 30 mg/kg (expressed as a dose of AJM300) or placebo to BALB/c mice (8 weeks of age, female), the fluorescent-labeled mesenteric lymph node cells (4 × 106 cells) were injected into the caudal vein. One hour after injection of the cells, mice were euthanized under ether anesthesia, and Peyer's patches were collected and a single cell suspension was prepared. These single cell suspensions (3 × 105 cells) were analyzed using a Fluorescent Activated Cell Sorter (Nippon Becton Dickinson Company Ltd., Tokyo, Japan). The percentage of fluorescent-labeled cells in the Peyer's patch cells was measured.
2.6 Peripheral lymphocyte counts
To evaluate the efficacy of AJM300 on the peripheral lymphocyte count in normal mice, a single oral administration of AJM300M1 was performed at dose of 0.3, 3, 30, or 300 mg/kg (expressed as a dose of AJM300) or placebo, to BALB/c mice (7 weeks of age, male). AJM300M1 solution was prepared with distilled water just before use, mixed with a stirrer to keep the solution homogenous and used within one hour after preparation. Ninety minutes after administration, cardiac blood samples were collected under ether anesthesia.
The number of lymphocytes in the peripheral blood was counted using an automated hematology analyzer (Sysmex corporation, Hyogo, Japan: SF-3000).
2.7 Experimental colitis model
The anti-inflammatory efficacy of AJM300 was evaluated in a well-validated mouse model of colitis induced by adoptive transfer of IL-10 deficient CD4+ T cells.25,26 CD4+ T cells were isolated from spleens and mesenteric lymph nodes of diseased IL-10−/− BALB/c mice (21 to 35 weeks of age, male) and adoptively transferred to female C.B-17/lcr-scid/scid Jcl (SCID) mice (8 weeks of age, female).
To evaluate the efficacy of AJM300, AJM300M1 or placebo was fed ad libitum in the diet, containing a concentration of AJM300 at 0.03, 0.1, 0.3 or 1% (expressed as a concentration of AJM300M1) from day − 1. To compare the efficacy of AJM300 to the α4 integrin antibody, the anti-mouse α4 integrin monoclonal antibody (PS/2) was administrated intraperitoneally at a dose of 10 mg/kg twice a week starting on day − 1. The stool consistency (0: normal beaded stool; 1: soft stool; 2: diarrhea) was recorded every day, starting from day 5. On day 15, after euthanasia under ether anesthesia, the colons were removed and weighed. The infiltration of CD3+ T cells in the lamina propria was analyzed by immunofluorescence staining and histological scoring was performed as described below. To evaluate the relationship between PK and efficacy of AJM300, a concentration of 0.1%, 0.3% or 1% AJM300M1 were fed ad libitum in the diet from day − 1 and cardiac blood was collected at 10 AM, 2 PM, 8 PM and midnight on day 14 and at 6 AM and 10 AM on day 15.
2.8 Histopathologic scoring and immunofluorescence staining
Colons were removed from colitis model mice on day 15 and placed in formalin or sucrose. Formalin-fixed tissues were embedded in paraffin. Paraffin-embedded specimens (2–3 μm thick) were stained with hematoxylin and eosin (H&E), or periodic acid-Schiff (PAS). Blinded histopathological analysis was performed using the following scoring system (modified from Davidson et al., 1996)36: i) degree of mononuclear cell infiltration in lamina propria (scored between 0 and 3); ii) goblet cell loss (scored between 0 and 3); iii) epithelial hyperplasia (scored between 0 and 3). The total histopathological score (between 0 and 9) was calculated by combining each score. Sucrose-permeated tissues were embedded in OCT compound, cooled in liquid nitrogen, and stored at − 80 °C. Cryostat specimens (6 μm thick) were air-dried, fixed in 2% paraformaldehyde, and incubated with 0.3% hydrogen peroxide. After pretreatment with blocking agent consisting of Block Ace® (DS Pharma Biomedical Co., Ltd., Osaka, Japan), sections were incubated for 60 minutes with the primary antibody, hamster anti-mouse CD3e (BD Pharmingen™, San Diego, CA: 145-2C11). After washing in PBS, the sections were incubated for 30 min with peroxidase-conjugated goat anti-hamster IgG (H + L) antibody, followed by TSA™ cyanine 3 systems (PerkinElmer, Inc., Waltham, MA), and then mounted using Vectashield® Mounting Medium with DAPI (Vector Laboratories, Inc. Burlingame, CA). The rate of T cell infiltration (stained with cyanine 3) per area was calculated as a percentage of the lamina propria selected within the blue fluorescence image (stained with DAPI) using image editing software, Win Roof ver.5.3 (Mitani Corporation, Tokyo, Japan).
2.9 Concentration of HCA2969 in plasma
Plasma samples from cardiac blood were centrifuged (10,000 rpm, 10 min, 4 °C) and processed by solid-phase extraction. The concentration of HCA2969 in plasma was measured using liquid chromatography–tandem mass spectrometry (LC–MS/MS).
2.10 Animals
IL-10−/− BALB/c mice and wild type BALB/c mice were obtained from Charles River Laboratories Japan, Inc. (Tokyo, Japan). C.B-17/lcr-scid/scid Jcl (SCID) mice were obtained from CLEA Japan, Inc. (Tokyo, Japan). All mice were housed and bred under specific pathogen free conditions. All procedures were performed in accordance with the institutional Animal Care and Use Committee of the Research Center of Ajinomoto Pharmaceuticals Co., Ltd.
2.11 Statistical analyses
IC50 values from in vitro assays, EC50 and EC90 values from homing assays and the other statistical analysis described below were calculated using the statistic analysis software, SAS System ver. 8.2 (SAS Institute Japan Ltd., Tokyo, Japan). In homing assays, the concentration of HCA2969 in the placebo-treated group (control group) was converted to '0.1 ng/mL' before the logarithmic transformation for statistical analysis using a sigmoidal Emax model. On peripheral lymphocyte counts, Steel test was used for statistical analysis. In the mouse colitis model, Welch's test or Student's t-test was used for statistical analysis of the comparison between placebo treated group (control group) and the non-T cell transferred group (non-transferred group). Parametric Dunnett's multiple comparison test was used for statistical analysis of the efficacy of AJM300 on the colon weight and the area ratio of CD3+ T cells in lamina propria. A parametric Tukey multiple comparison test was used for statistical analysis of the comparison of the efficacy between AJM300 and the anti-mouse α4 integrin monoclonal antibody (PS/2) on colon weight and histopathological scores, a non-parametric Steel–Dwass' test was used on the area ratio of CD3+ T cells in lamina propria. A value of p < 0.05 was considered statistically significant.
3 Results
3.1 Characterization of the biochemical properties of HCA2969 (the active metabolite of AJM300)
To evaluate the affinity of HCA2969 for α4 integrin, the binding of 3H-HCA2969 to cells expressing α4β1 integrin (Jurkat) or α4β7 integrin (RPMI-8866 or TK-1) was assessed (Table 1). 3H-HCA2969 bound to human α4β1 integrin and human α4β7 integrin with KD values of 0.32 ± 0.01 nmol/L and 0.46 ± 0.07 nmol/L, respectively. The affinity was similar to that of mouse α4β7 integrin (KD value; 0.20 ± 0.03 nmol/L). These data indicated that HCA2969 was a chemical compound with a high affinity for α4 integrin and that there was no inter-species difference in the affinity to α4β7 integrin between humans and mice.
|KD (nmol/L)
|Cell lines
|0.32 ± 0.01
|0.46 ± 0.07
|0.20 ± 0.03
The dissociation constant (KD) values were determined in the assay for binding of 3H-HCA2969 to human α4β1 integrin, human α4β7 integrin and mouse α4β7 integrin using cell lines. The KD values were expressed as the mean ± SEM of 3 independent experiments.
Second, the inhibitory activity of HCA2969 to the binding of α4β1 or α4β7 integrin to the respective ligand was evaluated using an in vitro cell binding assay (Table 2). HCA2969 inhibited the binding of human α4β1 integrin-expressing cells (Jurkat) to human VCAM-1 in a concentration-dependent manner with an IC50 value of 5.8 ± 1.6 nmol/L. HCA2969 also inhibited binding of human α4β7 integrin-expressing cells (RPMI-8866) to rat MAdCAM-1 (IC50 value; 1.4 ± 0.3 nmol/L). In contrast, the IC50 value for the binding of human αLβ2 integrin-expressing cells (Jurkat) to human ICAM-1 was 54,000 ± 11,000 nmol/L. Furthermore, HCA2969 did not show the affinity to various receptors, channels and transporters (Supplemental Table 1A), and any inhibition of the enzyme activity and the secretion of cytokines and inflammatory mediators (Supplemental Table 1B), indicating that HCA2969 was a highly selective dual α4β1/α4β7 integrin antagonist.
|IC50 (nmol/L)
|Cell lines
|5.8 ± 1.6
|1.4 ± 0.3
|54,000 ± 11,000
|0.94 ± 0.33
|26 ± 1
|8.5 ± 1.8
|4.1 ± 1.2
The activity of HCA2969 to inhibit the binding of integrins to cell adhesion molecules was evaluated in the cell binding assay using cell lines. The 50% inhibitory concentration (IC50) was expressed as the mean ± SEM of 3 or 4 independent experiments.
↵a Species: 1; human, 2; mouse, 3; rat.
Third, to evaluate the inter-species difference in the inhibitory activity of HCA2969 for cell binding in vitro, the cell binding assay was performed using mouse or rat-derived cell lines. HCA2969 inhibited the binding of mouse or rat α4β1 integrin-expressing cells to VCAM-1 (IC50 values; 0.94 ± 0.33 nmol/L and 8.5 ± 1.8 nmol/L, respectively). HCA2969 also inhibited the binding of mouse or rat α4β7 integrin-expressing cells to MAdCAM-1 (IC50 values; 26 ± 1 nmol/L and 4.1 ± 1.2 nmol/L, respectively) (Table 2). There was no inter-species difference in the inhibitory activity of HCA2969 on the binding of α4 integrin to their ligand in vitro among human, mice and rats.
3.2 Inhibition of lymphocyte homing and increased peripheral lymphocyte counts after oral administration of AJM300
Lymphocyte homing to Peyer's patches was inhibited in a dose-dependent manner after a single oral administration of AJM300M1 in mice. A correlation was observed between the concentration of HCA2969 in plasma and the ratio of homing lymphocytes to Peyer's patches. Using a sigmoidal Emax model, the 50% and 90% effective concentrations (EC50 and EC90) were determined as 100 ng/mL (180 nmol/L) and 680 ng/mL (1200 nmol/L), respectively (Fig. 1 ).
The effect of AJM300 on the peripheral lymphocyte counts was also determined in mice. Peripheral lymphocyte counts were dose-dependently increased after a single oral administration of AJM300M1 (Fig. 2 ).
3.3 Prevention of the development of murine experimental colitis induced by adoptive transfer of IL-10 deficient CD4+ T cells after oral administration of AJM300 in the diet
AJM300 prevented an increase in both the stool consistency score (Fig. 3A) and colon weight (Fig. 3B) in a mouse model of colitis induced by adoptive transfer of IL-10 deficient CD4+ T cells, dose-dependently. Inhibition of an increase in colon weight was statistically significant in experimental groups fed a diet containing 0.1, 0.3 and 1% AJM300M1 (p < 0.001). A significant inhibition (> 95%) of T-cell infiltration to the lamina propria was observed in mice fed a diet containing 1% AJM300M1 compared to the control group (Fig. 3C). Pro-inflammatory cytokines (IFN-γ, IL-17 and TNF-α) in the colon samples were clearly reduced in mice fed a diet containing 1% AJM300M1 compared to the control group (Supplemental Table 2). In addition, the efficacy of the 1% AJM300M1 was comparable with anti-α4 integrin monoclonal antibody (PS/2) treatment at a dose of 10 mg/kg administered twice weekly (Fig. 4A–C), where the saturation of α4 integrin blockade was maintained for at least 4 days per dose (data not shown). This effect was accompanied by a histological improvement in epithelial cell hyperplasia, reduced inflammatory cell infiltration and a decrease in mucus production (Fig. 5). In addition, AJM300 also prevented an increase in the colon weight in a model of colitis induced by adoptive transfer of CD4+CD45RBhigh T cells (Supplemental fig. 1).
To investigate the relationship between PK and efficacy, the concentration of HCA2969 in plasma was measured in mice fed AJM300M1 (Fig. 6 ), and it was dose-dependently increased and comparable to that in normal mice at each dose. In mice fed a diet containing 0.1% AJM300M1, the plasma concentration of HCA2969 was maintained over the EC50 value for lymphocyte homing for approximately 24 h, whereas after feeding with the diet containing 1% AJM300M1, it was maintained over the EC90 value for 24 h, at which the efficacy was comparable to that achieved by the saturated α4 integrin blockade.
4 Discussion
This is the first report to our knowledge describing an orally active small molecule α4 integrin antagonist, with anti-inflammatory effects on an experimental colitis. The maximum efficacy of AJM300 was comparable to that of the saturated α4 integrin blockade achieved by antibody treatment.
This study demonstrated that HCA2969, the active metabolite of AJM300, was a specific, dual α4β1/α4β7 integrin antagonist. HCA2969 had the similar affinities for α4β1 and α4β7 integrins and inhibited the binding of α4β1/α4β7 integrin-expressing cells to VCAM-1/MAdCAM-1 in vitro. Since the KD value for human α4β1 integrin was similar to that for human α4β7 integrin, the difference between mouse α4β1 and α4β7 integrins in IC50 value for the cell-binding might be due to the difference in the assay system (e.g. expression level of the integrin on the cell). Potentially, because of high selectivity of AJM300 to α4 integrin, AJM300 might not have the risk of the side effect associated with the inhibition of αLβ2 integrin and the inhibition of the other various signals and activities related to immune system, for example, the increase in the risk of infection caused by the inhibition of neutrophil migration.37 Whereas, the blockade of α4 integrin (α4β1/α4β7) leads to the inhibition of the lymphocyte migration mediated by the binding to MAdCAM-1 as well as VCAM-1. Indeed, an α4 integrin blockade with antibody (natalizumab) has successfully demonstrated the clinical benefit for the patients with multiple sclerosis (MS)38,39 as well as IBD.10,11 Therefore AJM300, which has the same pleiotropic target as natalizumab and not gut-specific, could be effective for these diseases. Rationales for the development of AJM300 were the achievements of the 'oral' anti-α4 integrin therapy. First, the efficacy of anti-α4 integrin therapy has already been clinically validated with natalizumab and vedolizumab. As for safety, progressive multifocal leukoencephalopathy (PML) has been known as the side effect of anti-α4 integrin therapy probably associated with its mechanism of action; interference with the function of both α4β7 and α4β1 (natalizumab) could inhibit the homing of leucocytes to the intestine as well as the central nervous system (CNS). The mechanistic basis for the recrudescence of JC virus infection culminating in PML is presumably due to impaired immune surveillance of the CNS.40 It has been reported that positive status with respect to anti-JC virus antibodies, prior use of immunosuppressants and prolonged treatment of natalizumab, alone or in combination were associated with distinct levels of PML risk.41 In fact, based on the huge post-marketing surveillance data derived from approximately 100,000 natalizumab-treated patients, natalizumab-associated PML has not been observed with therapy of 6 months or less and no case of PML has been reported in a patient who was negative for anti-JC virus antibodies.41,42 AJM300 has the potential risk for PML, however, to date, the case has not been observed in the clinical trials. The potential PML risk may be minimized in the induction therapy within 6 months or in the maintenance considering the risk factor for natalizumab-associated PML (e.g. measuring anti-JC virus antibodies). In addition, AJM300 has a much shorter pharmacological half-life (data not shown) than natalizumab (approximately 11 days) and the potential advantage is that the early removal of drug from the body after onset of PML could lead to more favorable outcomes of the complication, but this is a hypothesis that remains to be proved.43 On the other hand, gut-selective anti-inflammatory effect without systemically inhibiting adaptive immune responses theoretically believes to provide immunity to PML. Targeting the α4β7 integrin (vedolizumab) exclusively will alleviate inflammation in the gastrointestinal tract with minimizing undesired effects in other organs.44 Blockade of α4β7 and αEβ7 (etrolizumab) could regulate trafficking in the intestine as well as retention exclusively on mucosal intraepithelial of immune cells.14 This 'theoretical' risk for PML of these gut-selective anti-integrin antibodies should be proved in clinical under careful consideration as much as anti-α4β7/α4β1 integrin antibody. Second, oral drug formulations often provide good drug adherence and avoid the loss of efficacy related to the production of persistent antibodies against biologics. While some biologics have been in clinical trial, there could remain some concerns regarding the long-term administration of these agents. Adverse effects specifically related to biologics, such as immunogenicity, infusion site reaction, and the loss of efficacy related to the production of persistent antibodies against biologics, could be observed.15,45 After the launch of the gut-specific vedolizumab or etrolizumab, the patients with loss of response or intolerance may be observed in the treatment with the anti-integrin antibodies. Oral treatment with small molecules could be beneficial to the patients with IBD by circumventing these drawbacks. For the patients who respond to the anti-integrin antibody, the oral treatment with small molecule which has the same mechanism of action as the prior efficacious treatment with biologics and the availability only if the safety is established, may be favorable option.
Next, oral treatment with AJM300 dose-dependently inhibited mesenteric lymphocyte homing into Peyer's patches in mice. When the concentration of HCA2969 in plasma was maintained over the EC90 value, the inhibition of lymphocyte homing was comparable to that of pre-treatment of the cells with anti-α4 integrin antibody in mice (data not shown). The phenomenon of lymphocyte homing regulates the generation and propagation of immune responses and ensures the coordinated expression of immunological functions by the lymphoid tissues in vivo.46 Previous study reports suggested that α4β1/α4β7 integrin may appear to be essential for lymphocyte homing into Peyer's patches46,47 as well as for lymphocyte infiltration into the site of inflammatory lesions.3
Oral treatment with AJM300 prevented the development of colitis induced by transfer of IL-10 deficient CD4+ T cells in mice. In this model, the anti-inflammatory effect due to the inhibition of CD4+ T cell-infiltration into the colon potentially might result in the prevention of development of colitis and diarrhea. It has been suggested that the maintenance of saturated occupancy of α4 integrin was required for maximum efficacy of α4 integrin antagonist in autoimmune disease models48 as well as in a natalizumab clinical study for Crohn's disease.49 In our preliminary study, the maintenance of saturated occupancy of α4 integrin was achieved with anti-α4 integrin monoclonal antibody (PS/2) treatment at a dose of 10 mg/kg twice weekly in normal mice (data not shown). Unfortunately, it was technically difficult for AJM300 to measure the occupancy of HCA2969 because of its rapid dissociation rate. Instead of the saturated occupancy, the maintenance of concentration of HCA2969 in plasma over the EC90 value for lymphocyte homing was used for determination of dosing regimen. AJM300 administrated with a 1% AJM300M1 diet in this model exhibited the maximum efficacy. In this dosing regimen, the concentration of HCA2969 in plasma was maintained over the EC90 value for lymphocyte homing for 24 h in a day. In contrast, PK analysis of HCA2969 after a single oral administration at 100 mg/kg, revealed that the concentration of HCA2969 in plasma was maintained over the EC90 value for approximately only 8 h. It was also reasonable that twice-daily oral administration of AJM300 at a dose of 100 mg/kg did not achieve significant efficacy in this colitis model (data not shown), since the anti-inflammatory effect may have been counteracted by lymphocytes infiltrating into the colon.
In this study, peripheral lymphocyte counts dose-dependently increased after oral administration of AJM300 in normal mice. Such an increase was observed in the same dose range as the inhibition of lymphocyte homing. These results suggested that lymphocytes might be forced to remain in the intravascular compartment by the inhibition of α4 integrin-mediated migration and through vascular endothelium. Previous clinical study reported that the increased peripheral lymphocyte counts were also observed with α4 integrin antibody (natalizumab) treatment in clinical trials for Crohn's disease49,50 or ulcerative colitis51 and could be a reasonable PD marker for blockade of the α4β1 integrin associated with occupancy.49 Unfortunately, in this colitis model using SCID mice lacking in T and B lymphocytes, it was impossible to use the peripheral lymphocyte count as a PD marker, because it was too small to detect the size of increase in lymphocyte count. However, the peripheral lymphocyte count might be reasonable for selection of dosing regimens in clinical. Actually, the significant increase in lymphocyte count was observed in human according to the results of the phase II trial of AJM300, which showed that oral administration of AJM300 might be efficacious to the patients with moderately active Crohn's disease.52 Based on these clinical trials, the optimal dosage is estimated to be 240 mg t.i.d. or above. In addition, a randomized phase II study is currently underway in Japanese patients with moderately active ulcerative colitis.
In conclusion, these results suggest that oral treatment with the small molecule α4 integrin antagonist, AJM300 prevented the development of colitis and that its efficacy was comparable to that of the antibody to α4 integrin. AJM300 might be a promising oral drug for the treatment of IBD.
Conflict of interest statement
Disclosures of financial conflict of interest are summarized below:
Toshihiko Sugiura: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Shunsuke Kageyama: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Ayatoshi Andou: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Tomoko Miyazawa: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Chieko Ejima: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Akira Nakayama: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Hiroyuki Eda: employee of Ajinomoto Pharmaceuticals Co., Ltd.
Taeko Dohi: nothing to disclose
Appendix A Supplementary data
Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.crohns.2013.03.014.
Supplementary material.
We are grateful to Drs. T. Tanaka, H. Kikutani, and M. Miyasaka (Osaka University, Japan), for providing the cell lines, HEK293, L1-2 and RPMI-8866. We thank the members of the Department of Gastroenterology, Research Institute, International Medical Center of Japan for technical support. We also thank Y. Tanaka, K Kuribayashi, N. Arashida, S. Ueno, I. Fujita, N. Suzuki, S. Nagahisa, Y. Suga, Y. Ikenoue, M. Hashimoto, M. Suzuki, H. Kihara, and M. Murata (Ajinomoto Pharmaceutical Co., Ltd.) for technical support.
↵☆ Conference presentation: GASTRO2009-UEGW/WCOG London Poster: # P0270, 'Best poster'.
- Abbreviations
- inflammatory bowel disease
- orally active small molecule α4 integrin antagonist
- a special formulation containing AJM300 at approximately 43% and excipients: AJM300M1 preparation
- vascular cell adhesion molecule-1
- MAdCAM-1
- mucosal addressin cell adhesion molecule-1
- intercellular adhesion molecule-1
- pharmacokinetics
- pharmacodynamics
- human embryonic kidney
- phosphate-buffered saline
- severe combined immuno-defficient
- control
- interleukin-10
- 4′,6-diamidino-2-phenylindole
- © 2013 European Crohn's and Colitis Organisation


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