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by Gustavo Arellano
Dear Mexican: Just suppose that all of the southwestern United States had remained in Mexican hands. Would the Mexicans have done any better with it than they have with the present confines of Mexico?
— Reversible Reconquista?
Dear Gabacho: The gran parlor game! If we turn back the clock and changed a couple of things — if Austin, Houston, and their fellow invading gabachos actually became Mexican citizens respecting the rule of the land instead of merely pretending to become so, if Mexico hadn't suffered the theft of its lands or nearly gone bankrupt spending so much money in battling its ravenous neighbor to the north — would Mexico have been better off? The easy answer is s' — more land in a country generally means more possibilities for development, and California's 1849 Gold Rush (truly made the American Southwest the Mecca it became for Americans) would've happened on Mexican soil, meaning Mexico would've been the beneficiary of all those prospecting migrants and subsequent worldwide attention. Not having Texas secede from Mexico would've also hastened the demise of Antonio L"pez de Santa Anna: sure, his embarrassing defeat at the manos of the Texians forced him out of office, but he returned again and again. Santa Anna's megalomania, left unchecked, would've inspired a true coup instead of many temporary ones. And with no neocolonial ties left—with no debts to any European powers due to fighting so many wars, with no appropriating of natural resources and lands by American industrialists taking advantage of a weak country, and with the United States itself weaker due to the lack of a Southwest and all of its subsequent treasures — Mexico would've been in a much-stronger position to enter the Industrial Revolution and emerge a better, reformed land. Of course, it's just a parlor game, just like Arizona Sen. John McCain blaming illegal Mexicans for starting devastating forest fires with no hard proof — except ours is responsible and fun, while his is just pendejo.
I know many Mexican names translate to English: Michael is Miguel, Juan is John, and so forth.Mexican names seem rooted in the Bible in general (everyone knows a Mexican named JesÏs with a best buddy named Gabriel right?). My name is Adam, and I don't know what the Mexican version of Adam is. I think there isn't one. Every time I order at a restaurant and the cashier is Mexican and they ask my name, I check the receipt and it's wrong. They have a hard time pronouncing it too. I've got receipts back before with Asham, Awarm, Alad, Aman, Aden. Mexicans seem devoutly religious. Do they not read Genesis, or is there a mexicano version of Adam and Eve with different names?
— Gabacho Y Eva
Dear Gabacho: If you bothered to read the Spanish version of Genesis, you'd know "Adam" is Adàn. Next!
GOOD MEXICAN OF THE WEEK: The American Immigration Council (AIC) sounds like a creepy front group for Know Nothings, but it's actually the nonprofit arm of the American Immigration Lawyers Association, whose members do the Lord's work by helping migrants from across the world enter this great land. The AIC actively fights Know Nothings, honors immigrants year-round, and is publishing Green Card Stories in the fall, a beautiful book featuring the inspiring stories of immigrants who came to los Estados Unidos from across the globe. More information on these mensches at americanimmigrationcouncil.org.
Get all your Mexican fun at myspace.com/ocwab, youtube.com/askamexicano, or send your questions to firstname.lastname@example.com!


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UPDATED: Why the Academy booted Brett Ratner out as Oscar producer
This article was originally on a blog post platform and may be missing photos, graphics or links. See About archive blog posts.
If the cloistered elders at the motion picture academy were shocked, surprised, appalled or dismayed to discover that Brett Ratner said that "rehearsal is for fags" in a Q&A session after a screening of his new film, "Tower Heist," well, it just goes to show how little due diligence they did before they hired Ratner to produce next year's Oscars.
Ratner's remark, made in response to a question about his creative process, was actually, in terms of self-inflicted wounds, a two-for-one deal. Ratner not only embarrassed the academy by insulting legions of gay people (who are perhaps the Oscars' last remaining loyal demographic), but he also made himself look like even more of an artistic featherweight by making it clear that he views the hard work and preparation that most filmmakers put into their craft — i.e. rehearsal time — as being for chumps, not fast-talking smoothies like himself.
Of course, this is standard operating procedure for Ratner. The same day he apologized, he went on Howard Stern's Sirius XM show — a knuckleheaded move in itself — and embarrassed himself further by discussing all sorts of topics you don't hear during an Oscar telecast.
Now the academy has dumped Ratner and is perhaps in danger of losing host Eddie Murphy — selected by Ratner (customarily, the producer picks the host). They'll have to scramble to get a new team in place for the late February ceremony. Co-producer Don Mischer is expected to stay on board, but finding a high-profile producer to step into the mess Ratner made won't be easy.
The question is, how did the academy get into this pickle in the first place? It's hardly a news flash that Ratner is a crass hustler who's spent his entire career in a Sammy Glick-like rush to get ahead, often behaving with all of the grace and elan of a character out of "Entourage." Ratner is loyal to his friends and a big contributor to charity, but he often acts like an over-entitled bar-mitzvah boy, running amok at his afterparty.
If the academy had done any homework at all, it would've learned that when a female reporter from the Jewish Journal interviewed Ratner for a cover story a few years ago, he managed to make a fool out of himself by repeatedly hitting on her, something she found so immature that she put it right in the lead of the story.
Of course, maybe the academy was just gambling that if there was an incident, Ratner would apologize and it would blow over, as so many such things sadly do.
It was all of five months ago that "30 Rock" costar Tracy Morgan, doing a stand-up routine in Nashville, made a series of inflammatory remarks about gay people, saying that if his son were gay, he would "pull out a knife and stab" him. Like Ratner, Morgan apologized. And like Sherak, who said Ratner has "many friends" in the gay and lesbian community, Tina Fey said that the Tracy Morgan she knew "is not a hateful man and would never hurt another person."
And that was that. No suspension. No firing. No more fuss. We've all gone back to laughing at Morgan's less-scandalous "30 Rock" antics.
Something similar might have occurred after academy president Tom Sherak publicly accepted Ratner's apology on Monday, saying: "This won't and can't happen again. It will not happen again." Surely he was hoping that was the end of that. But this time, the chorus of disapproval only mounted.
Mark Harris, the author of "Pictures at a Revolution" and a frequent Oscar pundit, posted a scathing indictment of Ratner on the website Grantland, mocking his apology and saying: "There's not really a long, nuanced debate to be had about this. If he had used an equivalent racial or religious slur, the discussion would go something like, 'You're fired.' Apology or not.
"The same rule applies here. You don't get a mulligan on homophobia."
A number of academy mainstays weren't so happy either. They were willing to stomach Ratner when it looked like he'd bring a breath of fresh air to what has been an increasingly cobwebby awards show. But when it looked like he might soil the Oscar brand, he had little internal support. My sources say that it was Ratner's idea to fall on his sword and resign on Tuesday. Maybe he shrewdly sensed that the steady drip-drip of the scandal would eventually do him in anyway.
Is there a moral here? Perhaps only a minor one. The academy took a gamble and got burned. As for Ratner, it should be some consolation that Hollywood is, at its heart, an emotion-driven business. It is quick to indulge in moral indignation, but almost as quick to offer people a chance to redeem themselves. Just ask Mel Gibson, who's hard at work on his Hanukkah movie.
Ratner may be in eclipse today. But in a world where, as Sinatra so aptly put it, you can be riding high in April, shot down in May, don't be surprised how little time it will take for him to stage a comeback.
RELATED: Ratnergate: Where do the Oscars go from here?
— Patrick Goldstein

subset: commoncrawl


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Billionaire U.S. media mogul Oprah Winfrey says she was the victim of racism on a recent trip to Switzerland when a shop assistant refused to show her a handbag because it was "too expensive."
Winfrey was in Zurich for Tina Turner's wedding in late July when she left her hotel alone and popped into an upscale handbag shop.
She told Entertainment Tonight: "I was in Zurich the other day at a store whose name I will not mention. I didn't have my eyelashes on, but I was in full Oprah Winfrey gear. I had my little Donna Karan skirt and sandals, but obviously The Oprah Winfrey Show is not shown in Zurich."
"I go into a store and say to the woman, 'Excuse me, may I see that bag over your head?' and she says to me 'No, it's too expensive.'"
Winfrey says she asked again to see the bag -- a $38,000 crocodile skin number by Tom Ford -- and the woman again refused, saying, "No no no, you don't want to see that one, you want to see this one, because that one will cost too much and you will not be able to afford that."
Winfrey says she asked one last time but the shop assistant told her she didn't want to hurt her feelings. Rebuffed, Winfrey replied: "Ok thank you so much, you're probably right, I can't afford it," and politely walked out of the store.
The talk show host is the first and only female African-American billionaire, with an estimated net worth of $2.8 billion. She said: "I could've had the big blow up thing and thrown down the black card and all that, but why do that?"
While Winfrey chose not to identify the shop, the name of the high-end boutique -- Trois Pomme -- was soon revealed. The shop's manager told CNN the entire incident was a "200 percent misunderstanding" and had nothing to do with racism.
"Mrs. Oprah said she just wanted to look at the bag, she didn't want it taken down, and because my sales assistant felt a little embarrassed about the price, she quickly said that she also had the model in other materials such as ostrich and suede, which weren't so expensive," explained Trudie Goetz, the manager of Trois Pommes.
Calling it a "normal selling discussion," Goetz said: "Mrs. Oprah got the impression she didn't want to sell the bag to her because she wanted to show her other bags. This had nothing whatsoever to do with racism."
"Who wouldn't want to sell a bag like that? Everyone would. My saleswoman just wanted to do her best. She feels very bad because she feels the way it's being represented is very unfair."
Goetz added that Tina Turner was her "best friend" and that she, like Oprah, attended the singer's wedding.


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text:
Rock Climber Pete Whittaker Flashes One of the Hardest Trad Routes
A Crystal Hunter Gets Up Close and Personal with His Bounty in New Film
After a Nearly Fatal Fall, Climber Hazel Findlay Confronts Her Fears on the Rock
Sonya Wilson Has Been Lifting Up Deaf Climbers for a Decade
Slacklining Is All About Mental and Physical Balance
Canada's B.I.G. Initiative Empowers Women to Achieve Their Climbing Goals
These Women Are Making Space for Femininity in Climbing
It Isn't Always Easy to Be a Female Climbing-Gym Owner
'Not Just a Boys' Club' Kicks Gender Stereotypes in Climbing to the Curb
How Hazel Findlay Used a Kitchen Essential on a Difficult Climb
Olympic Climber Colin Duffy Is Just Getting Started
For the Texas Lady Crushers, Rock Climbing Is a Sport for Everyone
New Climbing Film Chronicles the First Ascent Across Denali
This Tennessee Climbing Trip Will Get You Excited for a Season on the Wall
Matt Cornell's Solo Climb of the Nutcracker Is a Testament to His Mental Fortitude
Kai Lightner Wants to Encourage the Next Generation of Rock Climbers
Why Marc-André Leclerc Agreed to Be Filmed in 'The Alpinist'
'Home Crag' Highlights the Precarious Future of a Beloved Utah Climbing Spot
Climbing at Utah's Little Cottonwood Canyon Is in Jeopardy
The Old Breed
Heading out the door? Read this article on the new Outside+ app available now on iOS devices for members! Download the app.
Veteran alpinists Mark Richey and Steve Swenson attempt Saser Kangri II, the second highest unclimbed mountain in the world. More at theoldbreedmovie.com.


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Wednesday, October 11, 2017
Oracle OpenWorld 2017 Keynotes and Presentations
If you missed out on Oracle OpenWorld 2017 or simply want to catch up on the plethora of keynotes and sessions that were available then the session catalog is a good place to start as you can download presentations there. You can search by keyword or apply any of the following filters to view pertinent content: -
- Day
- Emerging Technologies for Business
- IT Infrastructure
- Intelligent Cloud Applications
- Integrated Cloud Platform
- SMB (Small to Medium Business)
- Session Type
Furthermore, there's a pretty good library of on-demand keynotes where you can watch highlights or full length replays.
Personally, I'm going to start making my way through this content with a view to highlighting some of the best picks here.
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Sunday, October 08, 2017
Learn Oracle Fusion through the Help
One of the challenges with learning Oracle Fusion is having access to an environment. I used to have Oracle E-Business Suite installed on a very powerful laptop. However, with cloud based solutions the likelihood of you be able to run such a system on your own hardware is very low. Regardless, the Oracle Fusion Help which is accessible online is very good starting point for persons just getting to know the system.
You'll find help for each of the following modules
- Financials
- Procurement
- Projects
- Risk Management
- Sales
- Service
- Supply Chain
Within each module you can see the help sorted by task and product. Furthermore there is role specific help and numerous videos
Happy Learning…….
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Oracle Enterprise Repository for Fusion Applications
A very useful resource I've been making good use of for Fusion implementations is the Oracle Enterprise Repository for Fusion Applications. Examples of content provided include: -
- File-Based Data Import Templates
- Report Listings
- Roles
- SOAP Web Services
- Tables and Views
- Business Process Models
- Technology Audit
- Flexfields
- Lookups
- Profile Options
- Schedules Processes
All of this content is available across the following product areas: -
- Sales
- Global Human Resources
- Financials
- Procurement
- Project Portfolio Management
- Supply Chain Management
Furthermore the content provided spans various releases, namely Release 11, Release 12 and Release 13 (update 17b).
I hope you find this a useful resource for your Fusion projects.
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Saturday, October 07, 2017
Oracle Fusion Business Process Models
At the inception of any enterprise software implementation one of the activities should be to determine what the new business processes will be. On a recent Oracle Fusion implementation I got the chance to become familiar with the process models that should be adopted. Fortunately, at the outset, Oracle provides standard business process models for the following areas
- Enterprise Planning and Performance Management
- Marketing
- Sales
- Order Fulfilment
- Supply Chain Planning
- Product Management
- Production
- Procurement
- Materials Management and Logistics
- Project Management
- Financial Control and Reporting
- Cash and Treasury Management
- Asset Lifecycle Management
- Enterprise Information Management
- Workforce Deployment
- Workforce Development
- Compensation Management
Starting with a collection of standard business process models allows you to compare with existing processes and then determine what gaps there may be.
According to the Oracle Fusion Help
Business process modelling is one of the driving forces in the design of Oracle Fusion Applications. This modelling carries through to almost every aspect of Oracle Fusion Financials. The Business Process Models (BPMs) manage the deployment, upgrade, integration, and configuration of the product. Oracle Fusion documentation follows the process models very closely. Roles Based Access security is also tied closed to the BPM Model, so that tasks and activities are assigned appropriately. Messaging and online help are arranged along BPM lines. Field support uses the BPM models to organize their efforts to examine and resolve issues.
The Business Process Model has five levels:
- Level zero (L0): A specific industry organized around raising capital, executing a business model, and reporting the resultant income to shareholders. For example, Automotive, Communications, Education, Healthcare, and Utilities, to name a few of the approximately thirty identified industries.
- Level one (L1): A specific business process area.
- Level two (L2): A specific business process
- Level three (L3): A specific activity.
- Level four (L4): Specific tasks involved in an activity.
Having business processes with varying levels means you can start with high level processes and then drill down to lower levels of detail as you require. Furthermore each level will relate back to the hierarchical employee levels in an organisation. An example of how the process levels might look is outlined in Figure 1.
Figure 1: An example of Oracle Fusion Business Process Model Levels
The process flows that Oracle provide can be downloaded at Oracle Support Doc ID 1542019.1. The diagrams are pitched at L3 and are typical swim lane Visio documents as illustrated in Figure 2.
Figure 2: An example of an L3 Process Flow Diagram for Ledger Close
I've also prepared a process flow listing which you can also download.
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Oracle Unified Method (OUM) for Cloud Application Services
Having used many of Oracle's project management methodologies over the past two decades of implementing it I'm always interested to see what their latest offerings have in store. More recently I've been implementing their Fusion applications so have taken a natural interest in Release 6.4 of Oracle Unified Method which has evolved to include an approach for their Cloud Application Services (CAS).
Suzanne Armstrong highlights the key features on the OUM blog as follows
OUM release 6.4 provides support for Application Implementation, Cloud Application Services Implementation, and Software Upgrade projects as well as the complete range of technology projects including Business Intelligence (BI), Enterprise Security, WebCenter, Service-Oriented Architecture (SOA), Application Integration Architecture (AIA), Business Process Management (BPM), Enterprise Integration, and Custom Software. Detailed techniques and tool guidance are provided, including a supplemental guide related to Oracle Tutor and UPK.
This release features:
- Cloud Home Page – Added to Highlight Cloud Support in OUM
- CAS OUM (Cloud Application Services OUM) [previously OUM Cloud Application Services Implementation Approach] – Updated Task and Activity/Task Group Identifiers, Updated Terminology
- Operate Focus Area – Added to Provide Visibility into Services Offered by Oracle Managed Cloud Services (OMCS)
- Establish Governance Activity [previously Complete Project Management Plan] – Renamed and reframed to place greater emphasis on its main objective, which is to establish project governance by engaging in a dialogue to collaboratively define the processes which will be used to govern and control the project from start to finish. This approach recognizes that the delivery of documentation, while necessary and important, should be the by-product of rather than the driver for conversation.
- Project Management Plan (PMP) template [previously Project Management Framework] – Developed to streamline the process for documenting project governance. The BT.070 task was renamed to Create Project Management Plan and the guidance was updated. All related tasks that contribute to the PMP were revised to refer to the new PMP template eliminating the prior individual templates. The PMP should be used to document the processes that govern the project. Once defined, the PMP will remain relatively fixed and only require updates if there are material changes to the governance.
- Acceptance Certificate [SM.040] Updated and Delivery Note [SM.040] Added - Clarified that acceptance, agreement, and acknowledgment should be secured using one of these templates. Removed signature boxes / sign-off pages and project manager countersignature from all templates.
- Risk Management Process, Tasks, and Templates – Streamlined Flow and Clarified Content
Bruce Dehner also has a really good overview presentation which talks about the Cloud Application Services Implementation Approach. It contains a pictorial view of the key activities at each implementation phase which also outlines who is responsible for doing what.
The Oracle OUM Partner Knowledge Zone has an abundance of further information and resources. Here you can download OUM collateral, obtain training and certification and view webcasts. Certainly I'm looking forward to making use of the templates and deliverables in my existing and forthcoming implementations.
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All of our videos are strictly personal opinions. Please make sure to do your own research. Never take one person's opinion for financial guidance. There are multiple strategies and not all strategies fit all people. Our videos ARE NOT financial advice.


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A new patent application for Google Glass would enable the future specs to identify and remotely control objects such as garage doors and refrigerators. On one hand, this is a natural evolution of technology, but if you step back, this patent is really describing a work-around form of telekinesis.
First highlighted in a report on Engadget, the patent (boring deets here) would allow Glass to recognize a controllable object via visual identification, RFID, Bluetooth, or even QR codes. Once identified, Glass would place an overlay in the user's vision that would present them with options such as "open garage door." These smart objects connected via wifi or otherwise enabled could then be controlled by Glass.
From what we've seen of Glass, users will interact with the device mostly by vocal commands. According to the patent application, users could also control objects with either vertical or horizontal head nods that could be interpreted as "yes" or "no" or with a "gesture of the wearer's finger toward the virtual control interface [that] may be interpreted as a 'Yes.'" Additionally, the patent also mentions that the wearer may "actuate a button or interact with a touchpad on the wearable computing device."
While nothing within this patent application might appear to be a giant technological leap forward from our contemporary vantage point, taken as a whole, this really could be described as some Jean Grey sort of ability (with a bit of Geordie La Forge thrown in for good measure). We can simply look at an object and bring it under our will with little more than a nod of the head or swipe of the finger.
That's some super hero stuff right there.


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brasses, ornamental
ornamental brasses: Brass, a copper-zinc alloy produced since imperial Roman times, is closely associated in art with bronze, a copper-tin alloy (see bronze sculpture). Brass was generally fashioned into utilitarian objects such as bowls, pots, and jugs. In the Middle East, China, and Japan, brass was beaten and hollow-cast, and in India an excellent decorated brass known as Benares ware is still produced. In Europe, the Meuse valley became the center of ornamental work in copper and its alloys during the 11th cent. Although production spread to most of Western Europe, the work was known well into the 16th cent. as dinanderie, after Dinant, a Belgian town long the leader in this work. Early dinanderie included ecclesiastical objects such as fonts, tabernacles, and lecterns, and domestic articles such as the distinctive aquamanile, a vessel, often in the form of an animal, used for pouring water. The brass chandeliers of Norway, Sweden, and Holland were widely exported. In the 17th and 18th cent. small objects for domestic use, such as candlesticks, utensils, and hearth equipment were produced. Ormolu, a gilded or varnished brass or bronze, was often used in the fashioning of these objects and later for covering the wooden parts of furniture. Machine production killed the brass and bronze art industries in the late 19th cent.


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Chad has declared a state of emergency in the Lake Chad region after a series of raids and suicide bombings there by militant Islamist group Boko Haram, the government said on Monday.
Chad was instrumental in forcing Boko Haram to cede territory earlier this year, undermining its six-year campaign to carve out a Nigerian caliphate.
But guerrillas have since ramped up attacks in remote border areas around Lake Chad, killing at least three people in a Chadian village on Sunday and three Nigerian refugees in northern Cameroon on Monday.
Chad's Communications Minister Hassan Sylla Bakari said the order, effective immediately, would grant authorities new power to search and monitor residents in the region.
There has not been a state of emergency in Chad, one of Africa's military heavyweights, since a series of rebellions in the 2000s springing from its volatile east. Neighboring Niger also has a state of emergency in its border region of Diffa.
A top U.N. official said last month that an 8,700 regional task force will begin joint raids against Boko Haram when the rainy season ends soon.
Vice Admiral Michael Franken, U.S. Africa Command's Deputy for Military Operations, told Reuters on Monday he expected Nigeria-led actions to lead to "significant degradation" in Boko Haram's activities within six months.
The United States has sent troops to provide intelligence and other assistance to counter Boko Haram.
Source: VOA News


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The deadline for applications for the 2014 Ed Monk Scholarship Award has been extended to May 1. The Award was established to provide educational opportunities for professionals working in traditional maritime trades. This year, for the first time, interns also are eligible to receive the scholarship. The mission of the award is to further maritime professionals' and interns' knowledge of traditional marine trades in other cultures. Study and research may include current and historical methods of boat construction using different materials, designs based on the functions to be served by the boats, materials available for construction and the state of technology.
The Center for Wooden Boats (CWB), Seattle, Washington is seeking applications from qualified persons. Applications now are due on or before May 1, 2014. The applicant should explain how the project will enrich the existing knowledge of the applicant and how the funds would be used. The budget for the grant may include transportation, housing, and other appropriate expenses. The background of the applicant in traditional marine trades and a list of references also are required.
Decisions by the application committee will be made by or before May 15, 2014. Funds granted must be used within one year of the award. A written report of the activities and benefit derived from the experience must be submitted to CWB.
Grants awarded will total $1,500.
The award was named to honor Ed Monk, a prominent and respected boat designer and builder in the Northwest. The Fund was established by John M. Goodfellow, who has participated in the hands-on-history activities at The Center for Wooden Boats. He is an advocate of preserving traditional maritime skills and wishes to encourage this through studies of those traditional skills being carried on beyond the applicants' local regions and local knowledge.
The application committee consists of the donor and CWB Founding Director Dick Wagner. Applicants can be of any locality, wishing to study indigenous designs, materials and techniques of other areas.
For more information, contact CWB Founding Director Dick Wagner at CWB at (206) 382-2628, email@example.com.
The Center for Wooden Boats, founded in 1976, provides a gathering place where maritime history comes alive through direct experience and our small craft heritage is enjoyed, preserved, and passed along to future generations. CWB, with locations on Lake Union in Seattle and at Cama Beach State Park on Camano Island, engages visitors in whole body learning by putting the historic boats, oars and paddles, sails and tools in the hands of people who visit. To learn more about year-round maritime activities at Seattle's Lake Union Park visit http://www.AtLakeUnionPark.org


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Roots and Radicals
University of Michigan
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Carl taught upper-level math in several schools and currently runs his own tutoring company. He bets that no one can beat his love for intensive outdoor activities!
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University of Michigan
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Carl taught upper-level math in several schools and currently runs his own tutoring company. He bets that no one can beat his love for intensive outdoor activities!
Since any even-numbered root must be a positive number (otherwise it is imaginary), absolute value must be used when simplifying roots with variables, which ensures the answer is positive. When working with radical expressions this requirement does not apply to any odd root because odd roots exist for negative numbers. Additionally, absolute value is not needed if an even number of a variable come out of the root - the answer must be positive.
The absolute value and square roots, so what we're going to do now is talk about absolute values and sometimes what happens is we actually need an absolute value when we give our answer and so what we're going to do is look at a number of examples and talk about when we need them and when we don't.
Okay so it's starting off, square root of 4, easy example we know the square root of 4 is 2 because 2 times 2 is equal to 4. Okay next, square root of -4, we need 2 numbers that will give us -4 that's not going to happen okay this is a not a real number okay later on we'll actually talk about how we can do this but we're not there yet okay? So square root of 3 squared. 3 squared is 9, square root of nine is 3. Square root of negative 3 squared. When we square a negative number, we actually get a positive so -3 times -3 is 9 square root of 9 is again 3. Okay, cube root of 8 has three 2's in eight so this comes out to be 2 and the cube root of negative 8 is -2. Negative 2 times itself 3 times is negative eight so what we have looked at here is when we have a odd root okay cube root here we can have a positive answer or a negative answer.
Okay when we have a even root all of our answers have to be positive okay? So these are numeric representations but now we're going to variables. Okay, so let's go over here the square root of x squared okay that is made up of 2 x's so we know that we can simplify this as an x. The problem is is that we don't know if x is positive or negative right? Say x was negative 3, just like we had over here. What happens is we are squaring it so that will become positive and then taking the square root of it so it's actually going to stay positive because we don't know if x is positive or negative, we have to put absolute value signs from the outside to make that term positive okay, so square root of x cubed. We can take out one x and we're still left with one x on the inside but we know that this has to be positive because we can't take a negative out of the square root so once again we have to put in absolute value signs okay because wherever comes out of the square root has to be positive. Okay, what about square root of x to the fourth. Okay we know this is 4 xs so we can take out 2 of them leaving us with x squared. Do we need absolute values in this case? No because x squared is always going to be become positive okay? So whenever we need absolute values is basically a one sort of rule of thumb that I always use is whenever you're taking an even root, so here this is the square root there's actually a little invisible 2 out here and whenever taking a even root and we have an add power on a variable, okay so here we have a single x, single x, x squared. If we had to take out an x cubed we would need an absolute value. If we take out an x the fourth we won't because the fourth will always be positive.
We actually never need a absolute value when we're dealing with an odd root and we'll do one example more example say cube root of x to the third. x to the third is 3 x's so this actually equal to x but because we're dealing with an odd root the cube root we do not need an absolute value because we can actually get positive or negative numbers to come out of this okay? So basically whenever you are dealing with the absolute sorry the square root of a variable, if you have an even root and you get out and odd power you always include absolute values.


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Planting the first of what it hopes will be a million trees, "Reforestemos (reforest) Patagonia" officially launched a campaign that will restore large swathes of Chilean Patagonia to pristine wilderness.
Inspired into action by wildfires that ravaged much of the iconic Torres del Paine National Park in December of last year and this January, the non-profit, public-private initiative will collect donations from Chileans and people around the world to donate native trees to the national parks and reserves of Chilean Patagonia.
So it was fitting that the campaign began planting in the park famed for its striking, jagged peaks. The first tree was planted in the Weber-Explora sector of Torres del Paine, an area that will receive 20,000 native lengas, ñirres y coigües over the duration of the initiative.
Matías Rivera, executive director of Reforestemos Patagonia, hailed the first week of the planting as a success, but called on the international community for more support.
"This event kicks-off a concrete effort to recuperate part of Chilean Patagonia," Rivera said. "In the first week, individuals and businesses have donated more than 60,000 trees, but we need a lot more to achieve our goals."
"This is something concrete that everyone can do," Rivera said, "according to their own personal motivation, whether it be having their own forest, to gifting a tree as a birthday present or for an anniversary, whether they are doing it out of the fact that they like Patagonia, want to combat global warming or simply because it strikes them as a noble cause."
According to Reforestemos Patagonia collaborating by buying a tree to be planted in Patagonia is simple and you can do it from anywhere in the world. All you need is 4 dollars and a computer. Just head to the official website and follow the steps.
Once you have bought a tree, you will receive an electronic certificate and a link to Google Maps with the geographic location of your tree, so you can learn about and even visit the area that you have helped reforest.
The news is from Chile's official website with info on living, studying, doing business with and travelling in Chile. http://www.thisischile.cl
Commenting for this story is now closed.
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The cellular and molecular mechanisms underpinning the compensatory increase in β-cell mass in response to insulin resistance are essentially unknown. We previously reported that a 72-h coinfusion of glucose and Intralipid (GLU+IL) induces insulin resistance and a marked increase in β-cell proliferation in 6-month-old, but not in 2-month-old, Wistar rats. The aim of the current study was to identify the mechanisms underlying nutrient-induced β-cell proliferation in this model. A transcriptomic analysis identified a central role for the forkhead transcription factor FOXM1 and its targets, and for heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF), a ligand of the EGF receptor (EGFR), in nutrient-induced β-cell proliferation. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, was increased in islets from GLU+IL–infused 6-month-old rats. HB-EGF induced proliferation of insulin-secreting MIN6 cells and isolated rat islets, and this effect was blocked in MIN6 cells by the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin. Coinfusion of either AG1478 or rapamycin blocked the increase in FOXM1 signaling, β-cell proliferation, and β-cell mass and size in response to GLU+IL infusion in 6-month-old rats. We conclude that chronic nutrient excess promotes β-cell mass expansion via a pathway that involves EGFR signaling, mTOR activation, and FOXM1-mediated cell proliferation.
Type 2 diabetes occurs when the pancreatic β-cell is unable to compensate for the increase in insulin demand due to insulin resistance in peripheral tissues. The compensatory response of the β-cell to insulin resistance occurs via the following two mechanisms: enhanced insulin secretion and increased β-cell mass. In obese humans, insulin secretion is considerably enhanced to maintain normoglycemia (1). In addition, investigations in human cadaveric pancreata have shown that β-cell mass is increased in obese nondiabetic individuals compared with lean individuals, but decreased in obese individuals with impaired fasting glucose and type 2 diabetic patients (2). These observations suggest that alterations of the anatomical compensation of the β-cell in obesity may contribute to the onset of type 2 diabetes.
In rodents, β-cell mass expansion is primarily driven by replication of existing cells (3) and is dynamically regulated in response to insulin resistance induced by obesity, high-fat feeding, or gestation (4). The molecular mechanisms underlying β-cell compensation to insulin resistance are essentially unknown; however, experimental evidence points to the importance of interorgan cross talk between insulin-resistant peripheral tissues and the β-cell. For instance, altered insulin signaling in the liver triggers a large increase in β-cell proliferation (5,6), and circulating factors likely play a role in β-cell adaptation to insulin resistance (7). Importantly, a recent study showed that human islets transplanted into mice subjected to an obesogenic diet undergo a compensatory increase in mass through enhanced proliferation (8).
We have established an in vivo model of chronic nutrient excess in rats, in which a 72-h coinfusion of glucose and Intralipid (GLU+IL) triggers a marked increase in β-cell mass and proliferation at 6 months of age, but not at 2 months of age, despite similar levels of hyperglycemia, hyperlipidemia, and hyperinsulinemia (9). We surmised that the β-cell proliferative response in this model is driven by insulin resistance in response to nutrient excess, which only occurs in 6-month-old rats. This model provides a unique opportunity to identify the molecular mechanisms underlying nutrient-induced β-cell proliferation. The aims of this study were therefore 1) to characterize the changes in the islet transcriptome in response to the GLU+IL infusion in 6-month-old rats, and 2) to identify the molecular mechanisms governing the adaptive increase in β-cell proliferation in response to nutrient excess.
Research Design and Methods
Reagents and Solutions
RPMI-1640 and FBS were from Invitrogen (Burlington, ON, Canada). Dulbecco's modified Eagle's medium was from Wisent (Saint Bruno, QC, Canada). AG1478 and rapamycin were from LC Laboratories (Woburn, MA). Recombinant heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) was from R&D Systems (Minneapolis, MN). CRM197 was from Sigma-Aldrich (St. Louis, MO).
Animal Infusions and Drug Treatments
All procedures were approved by the Institutional Committee for the Protection of Animals at the Centre Hospitalier de l'Université de Montréal. Infusions were performed as previously described (9). Male Wistar rats weighing 250–300 g (∼2 months old) and 500–600 g (∼6 months old) (Charles River, Saint-Constant, QC, Canada) were housed under controlled temperature on a 12-h light/dark cycle with unrestricted access to water and standard laboratory chow. The animals were randomized into two groups, receiving either 0.9% saline (SAL) (Baxter, Mississauga, ON, Canada) or 70% dextrose (McKesson Canada, Montréal, QC, Canada) plus 20% Intralipid (a soybean oil emulsion which generates a mixture of ∼80% unsaturated/20% saturated fatty acids when coinfused with heparin; Fresenius Kabi, Bad Homburg, Germany) (10) with 20 units/mL heparin (Sandoz Canada, Boucherville, QC, Canada) (i.e., GLU+IL). Infusions were performed using Harvard Apparatus infusion pumps (Pump 33), independently operating two syringes simultaneously. During the infusions, all animals had unrestricted access to food and water. For drug administration, AG1478 or rapamycin were dissolved in N,N-dimethylacetamide (Sigma-Aldrich) to a concentration of 50 mg/mL and then diluted in propylene glycol to generate a 2 mg/mL stock solution. Daily, the stock solution was diluted to the working concentration in 1.2% Tween 80/27% polyethylene glycol 400 (Sigma-Aldrich) and injected intravenously at a dose of 0.5 mg/kg/day. The control group was injected with the same volume of vehicle.
Cell Culture
MIN6 cells (passages 25–30) were cultured as previously described (11). Cells were seeded in six-well plates at a density of 500,000 cells/well. The following day, the cells were cultured in complete medium with increasing concentrations of HB-EGF in the absence or presence of inhibitors for an additional 24 h. For cell counting, cells were fixed with 10% formaldehyde, nuclei were stained by Hoechst reagent (Sigma-Aldrich), and 10 images per well were taken randomly. Cell numbers were determined using ImageJ software (National Institutes of Health).
Rat Islet Proliferation
Isolated rat islets were dispersed and plated in 96-well plates coated with HTB-9 cell extracellular matrix as described previously (12). Dispersed rat islets were treated for 72 h in the absence or presence of 100 ng/mL HB-EGF in complete islet media. The media were changed every 24 h. At the end of treatment, cells were fixed and stained for the β-cell marker pancreatic duodenal homeobox-1 (PDX-1) and the proliferative marker Ki67, as described previously (13). Proliferation was calculated as the percentage of double-positive Ki67+/PDX-1+ cells over the total PDX-1+ population.
Human Islets
The use of human islets was approved by the Institutional Ethics Committee of the Centre Hospitalier de l'Université de Montréal. Isolated islets from nondiabetic human cadaveric donors were provided by the Clinical Islet Laboratory at the University of Alberta and the Integrated Islet Distribution Program sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation International.
Transcriptomic Profiling and Quantitative RT-PCR Validation
Rat islets were isolated by collagenase digestion and dextran density gradient centrifugation as described previously (14). Total RNA was extracted from 150 islets with TRIzol Reagent (Invitrogen, Carlsbad, CA) and purified with RNeasy MinElute cleanup kit (Qiagen, Valencia, CA) following the manufacturer's protocol. Microarray analysis was performed on total RNA using the GeneChip Rat Gene 1.0 ST microarrays (five arrays per group; Affymetrix, Santa Clara, CA). One hundred nanograms of total RNA was processed using the Ambion WT Expression Kit (Invitrogen). The resulting fragmented and labeled single-stranded cDNA was processed according to the Affymetrix protocol. The Partek (St. Louis, MO) Genomics Suite was used for data analysis. The data were normalized by Robust Multichip Average algorithm, which uses background adjustment, quantile normalization, and summarization. After correction of statistical significance for multiple comparisons using false discovery rate (P < 0.01), the transcripts significantly and differentially expressed by >20% between the GLU+IL and control group were processed for gene set enrichment analyses using Ingenuity Pathways Analysis (application build 192063, content build 14400082; Ingenuity Systems, Redwood City, CA). Selected genes were validated by quantitative RT-PCR (qRT-PCR) as previously described (9). All qRT-PCR results were normalized to cyclophilin A mRNA levels. Primer sequences are described in Supplementary Table 1.
Analytical Measurements
Plasma glucose and free fatty acid (FFA) levels were measured using kits from Wako Chemical (Osaka, Japan). Insulin and glucagon were measured by ELISA (Alpco, Windham, NH).
Immunostaining of Pancreatic Sections
Pancreata were trimmed of fat, weighed, fixed for 3–4 h in 4% paraformaldehyde, and cryoprotected overnight in 30% sucrose. Pancreata were then embedded in OCT (TissueTek), and 8-µm sections were obtained by cryosection (Leica). Antigen retrieval was performed using sodium citrate buffer. Primary antibodies and dilutions are listed in Supplementary Table 2. Secondary antibodies were from Jackson ImmunoResearch (West Grove, PA). Images were taken with a fluorescence microscope (Zeiss, Thornwood, NY). β-Cell mass and size were determined as previously described (9,15). To assess β-cell proliferation, insulin+ and double-positive insulin+/Ki67+ cells were counted manually for at least 2,000 β-cells per animal.
Twenty micrograms of proteins from cells or islets were extracted and resolved by SDS-PAGE as described previously (11). Primary antibodies are listed in Supplementary Table 2. Signals were detected using a horseradish peroxidase–labeled IgG (Bio-Rad, Richmond, CA) and enhanced chemiluminescence (PerkinElmer Canada, Woodbridge, ON, Canada) on Kodak BioMax XAR films (Kodak, Rochester, NY). The bands were quantified by densitometry and ImageJ software (National Institutes of Health).
Expression of Data and Statistics
Data are expressed as the mean ± SEM. Statistical analyses were performed using the Student t test or ANOVA followed by two-by-two comparisons using Bonferroni post hoc adjustments, as appropriate using Instat software (GraphPad Software). A P value <0.05 was considered to be significant.
Infusion of GLU+IL Induces Insulin Resistance in 6-Month-Old Wistar Rats
In response to the 72-h GLU+IL infusion, circulating blood glucose and FFA levels were raised to similar levels in 2- and 6-month-old animals (n = 4; difference not significant; Fig. 1A and B). Insulin levels also increased in response to the GLU+IL infusion but were not different between the two age-groups (n = 4; difference not significant; Fig. 1C). Consistent with our previous observation in this model (9), significantly less glucose was required to maintain the same level of glycemia in 6- vs. 2-month-old rats, suggestive of insulin resistance (P < 0.001; n = 11–18; Fig. 1D). Circulating glucagon levels decreased to the same extent in response to the GLU+IL infusion in both age-groups (Fig. 1E). Expression of Ki67, a marker of cell proliferation, was strongly induced in response to the GLU+IL infusion in 6-month-old rats only (Fig. 1F). This is also in accordance with the previously observed increase in β-cell mass and number of Ki67-positive β-cells in this model (9).
Transcriptional Profiling of GLU+IL–Infused 6-Month-Old Rat Islets Identifies a Transcriptional Network Involved in Cell Cycle Progression
To gain insight into the molecular mechanisms involved in the regulation of pancreatic β-cell proliferation in response to nutrient-induced insulin resistance, we performed a microarray-based transcriptomic analysis of the islets of 6-month-old rats. Six-month-old Wistar rats were infused with either SAL or GLU+IL for 72 h, and islets were isolated from five animals in each group matched for body weight at the end of the infusion. As shown in Fig. 2A, with a false discovery rate <0.01, ∼3,000 genes were significantly modulated by the GLU+IL infusion. Overall, half of the genes were upregulated, and half were downregulated. When the cutoff was set to a twofold difference between the SAL group and the GLU+IL group, 300 genes were significantly upregulated, whereas only 30 genes were downregulated by GLU+IL infusion. Within the 300 upregulated genes, a group of genes expressed at low levels in the SAL group were strongly upregulated in the GLU+IL group (Fig. 2A, lower left corner of the graph). Gene set enrichment analysis performed using Ingenuity Pathway Analysis software revealed that these genes were, for the most part, related to cell cycle progression and mitosis (Fig. 2B). A more detailed analysis revealed that within this group, most of the direct downstream targets of the forkhead transcription factor FOXM1, a key regulator of the G2/M cell cycle transition, were upregulated by the GLU+IL infusion (Fig. 2C). Interestingly, expression of the forkhead transcription factor FOXO3a, a repressor of FOXM1 (16,17), was decreased upon GLU+IL infusion (Fig. 2C). In addition, expression of the gene encoding HB-EGF, a potential autocrine/paracrine growth factor inducing β-cell proliferation (18) (Fig. 2C), was also upregulated in the GLU+IL group. These changes in expression were validated by qRT-PCR analysis. First, we verified that expression of the proliferation marker Ki67 was enhanced in the GLU+IL group to the same extent as shown in Fig. 1 (data not shown). Second, we confirmed that expression of FOXO3a was repressed by the GLU+IL infusion (Fig. 3A), while that of HB-EGF, FOXM1, and the direct targets of FOXM1 Aurora kinase B (AURKB) and Polo-like kinase 1 (PLK1) was markedly induced (Fig. 3B–E). FOXM1 protein levels were also significantly increased in the GLU+IL group (Fig. 3F). In accordance with the role of HB-EGF as a trophic factor, its expression in individual samples was positively correlated with that of Ki67, FOXM1, AURKB, and PLK1; and negatively correlated with FOXO3a (data not shown). The expression of all these genes remained unchanged in the islet of 2-month-old rats upon GLU+IL infusion (Fig. 3A–E). To confirm that this transcriptional network is activated in a more chronic model of nutrient excess, we measured the expression of these genes in islets from C57BL/6 mice fed a high-fat diet for 8 weeks and stratified into the following two groups according to body weight gain: low-diet responders and high-diet responders (19). The expression of FOXM1, AURKB, and PLK1 was significantly increased in islets from high-diet responder mice, albeit to a lesser extent than in infused rats (Supplementary Fig. 1).
HB-EGF Promotes β-Cell Proliferation Through EGF Receptor and Mammalian Target of Rapamycin
To determine the mitogenic potential of HB-EGF in β-cells, we evaluated its ability to stimulate the proliferation of MIN6 cells and dispersed rat islets. Exogenous HB-EGF dose-dependently increased MIN6 cell proliferation after a 24-h treatment (Fig. 4A), and this effect was also observed in dispersed rat islets (Fig. 4B). This was associated with a time-dependent phosphorylation of S6 ribosomal kinase (S6R), a downstream target of mammalian target of rapamycin (mTOR), in both MIN6 cells (Fig. 4C) and human islets (Fig. 4D). The phosphorylation of S6R by HB-EGF in human islets was abolished in the presence of the phosphatidylinositol 3 (PI3) kinase inhibitor LY294002 (Fig. 4E and F). The ability of HB-EGF to enhance the proliferation of MIN6 cells was similar to that of betacellulin, an EGF receptor (EGFR) ligand that has been reported to promote β-cell replication both in vitro and in vivo (20,21) (Fig. 4G). Induction of MIN6 cell proliferation in response to HB-EGF was completely blocked in the presence of the EGFR inhibitor AG1478 or the mTOR inhibitor rapamycin (Fig. 4G and Supplementary Fig. 2), as well as in the presence of CRM197, a diphtheria toxin mutant that binds to and neutralizes HB-EGF (Fig. 4H).
Inhibition of EGFR Signaling and mTOR Inhibits β-Cell Mass Expansion, β-Cell Proliferation, and Prevents Upregulation of FOXM1 and Its Targets in Islets From GLU+IL–Infused 6-Month-Old Rats
To ascertain the implication of the mTOR pathway in GLU+IL–induced β-cell proliferation, we examined S6R phosphorylation in pancreatic sections from 6-month-old GLU+IL–infused rats. As shown in Fig. 5, phosphorylation of S6R was strongly increased in islets from GLU+IL–infused rats (Fig. 5B), concomitant with a marked increase in the number of cells staining positive for Ki67 (Fig. 5A).
To test the importance of the EGFR and mTOR in β-cell proliferation in response to GLU+IL, we treated another group of 6-month-old rats with AG1478 or rapamycin during the SAL or GLU+IL infusion. In GLU+IL–infused animals, blood glucose and FFA levels were maintained at a similar level, irrespective of the drug treatment (Table 1). The glucose infusion rate was not affected by AG1478 but was significantly reduced in the animals treated with rapamycin (Table 1), which is consistent with the known effect of this drug on insulin resistance (22,23). In accordance with our previous report in this model (9), β-cell mass was markedly increased in GLU+IL–infused 6-month-old rats (Fig. 6A). This was also associated with a significant increase in β-cell size (Fig. 6B). Remarkably, treatment of the rats with either AG1478 or rapamycin completely prevented both β-cell hyperplasia (Fig. 6A) and hypertrophy (Fig. 6B).
Consistent with the data shown in Fig. 5, the number of KI67+ β-cells was markedly increased in islets from GLU+IL–infused animals (Fig. 7A and B). This was associated with increased nuclear staining of FOXM1 (Fig. 7C) and AURKB (Fig. 7D). Importantly, the increase in Ki67, FOXM1, and AURKB was totally abolished upon treatment of GLU+IL–infused rats with AG1478 or rapamycin (Fig. 7A–D). Finally, both AG1478 and rapamycin prevented the decrease in FOXO3a, and the increase in FOXM1, AURKB, and Ki67 mRNA expression in islets from GLU+IL–infused rats (Fig. 7E).
This study was aimed to characterize the changes in the islet transcriptome in response to nutrient excess and to identify the molecular mechanisms governing the adaptive increase in β-cell proliferation in response to nutrients. Our results show that a 72-h combined infusion of GLU+IL in 6-month-old rats activates a signaling cascade that leads to the induction of FOXM1 and its downstream targets, and is dependent upon EGFR signaling and mTOR activation (Fig. 7F). A potential role of HB-EGF as a mitogenic signal acting through the EGFR and mTOR is supported by both its increased expression in islets from GLU+IL–infused 6-month-old rats, and its ability to activate mTOR and enhance proliferation in MIN6 cells and dispersed rat islets. Importantly, HB-EGF also activates the mTOR pathway in human islets in a PI3 kinase–dependent manner.
In addition to a large increase in insulin secretion, the pancreatic β-cell response to physiological (e.g., pregnancy) or pathological (e.g., obesity) conditions of insulin resistance involves an expansion of β-cell mass, which results, at least in part, from replication of existing β-cells (3). This compensatory response is crucial to maintain normoglycemia in the face of insulin resistance and thereby prevents the development of type 2 diabetes (24), but its underlying mechanisms are poorly understood. We previously reported that a 72-h infusion of GLU+IL in 6-month-old Wistar rats induces insulin resistance, β-cell dysfunction, and a marked increase in β-cell proliferation and mass (9). None of these abnormalities occurred in 2-month-old animals. Since circulating levels of glucose, FFA, and insulin were similar in 2- and 6-month-old animals during the infusion, we reasoned that the increase in β-cell mass likely occurs in response to the insulin resistance that develops only in 6-month-old animals in response to the GLU+IL infusion. In the current study, we confirmed that GLU+IL infusions in 6-month-old rats led to a marked increase in the expression of the proliferation marker Ki67 (Figs. 1 and 7E) as well as Ki67+ β-cells (Figs. 5A and 7A and B), resulting in β-cell hyperplasia and hypertrophy (Fig. 6). Our results may appear to be in contradiction with those of a recent study in which glucose-induced β-cell proliferation in mice was inhibited by coinfusion with lipids (25). However, besides possible species-related differences, the age of the animals and the lipid emulsion (Lyposin vs. Intralipid in our study) were different, and the levels of circulating glucose and insulin were much higher than those in the study of Pascoe et al. (25).
The question arises as to which signals are driving β-cell proliferation in response to the GLU+IL infusion in 6-month-old rats. In this regard, a recent study clearly demonstrated that circulating factors produced by the liver in insulin-resistant states can induce β-cell proliferation of not only rodent but also human islets (26). Our results are consistent with this possibility, although we have not measured liver insulin sensitivity in our model. The implication of neural signals has also been reported (27). Glucose itself is a potent inducer of β-cell proliferation in rodents (25,28–30), but marked β-cell proliferation can occur under normoglycemia, for instance, in liver-specific insulin receptor knock-out mice (6). Since a common feature of all these models is high circulating levels of insulin, it is conceivable that insulin is the β-cell mitogen. However, hyperinsulinemia is likely a permissive factor for β-cell proliferation (6) but is insufficient by itself (25) (Fig. 1). Here we have identified a key role for EGFR signaling and a potential involvement of its autocrine/paracrine ligand HB-EGF. Indeed, blocking EGFR signaling prevented the increase in β-cell proliferation both in response to HB-EGF in MIN6 cells (Fig. 4G) and in response to the GLU+IL infusion in 6-month-old rats (Fig. 7). Consistent with our results, a cell surface proteomic analysis revealed that EGFR is among the most highly expressed cell surface kinase receptors in the β-cell (31). EGFR is important for pancreatic β-cell development and postnatal growth (32), and is required for β-cell compensation for high-fat diet and pregnancy in mice (33). Betacellulin, an autocrine/paracrine ligand of the EGFR, is a potent inducer of β-cell proliferation both in vivo and in vitro (20,21,34,35). In addition, overexpression of HB-EGF in adult mice pancreas promotes β-cell proliferation and conversion of ductal cells to insulin-producing cells (18). Downstream of the EGFR, we showed that β-cell proliferation is associated with and dependent upon activation of the mTOR pathway both in vitro (Fig. 4) and in vivo (Figs. 5 and 7). Our findings are in accordance with the known role of the mTOR pathway in β-cell proliferation in rodent models (36–39) and establish, to our knowledge for the first time in β-cells, a link between the EGFR and mTOR.
Transcription profiling of islets of 6-month-old infused rats revealed a central role of FOXM1 in mediating the mitotic progression of the β-cell in response to GLU+IL infusion (Figs. 2 and 3). Importantly, a similar pattern was observed in high-fat–fed mice, a more chronic and milder model of nutrient-induced β-cell proliferation (Supplementary Fig. 1). This is in accordance with the reported role of FOXM1 in adult β-cell replication in response to pancreatectomy (40), pregnancy (41), and obesity (42). The intracellular mechanisms leading to FOXM1 activation remained unknown. In this regard, we have identified a possible reciprocal relationship between FOXM1 and the forkhead transcription factor FOXO3a, where FOXO3a might be acting as an upstream repressor of FOXM1 (Figs. 2 and 3). In rat cardiomyocytes, the expression of FOXM1 is negatively correlated with that of FOXO3a (16), and induction of FOXO3a inhibits proliferation through the repression of FOXM1 (17).
We acknowledge that there are limitations to the model used in this study. First, the relatively short duration of nutrient excess imposed here is clearly different from the natural history of nutrient-induced insulin resistance in human obesity, which occurs over several decades. Second, important differences exist between rodents and human islets regarding the control and mechanisms of β-cell proliferation (43). These limitations notwithstanding, our findings identify a signaling cascade leading to the activation of the FOXM1 transcription factor through activation of the EGFR/mTOR pathway, and a possible role of the autocrine/paracrine growth factor HB-EGF. These findings might provide new therapeutic approaches to enhance β-cell mass in insulin-resistant states and thereby prevent or delay the occurrence of type 2 diabetes. Further investigations are underway to identify the circulating factors activating the EGFR/mTOR/FOXM1 pathway in this model.
Article Information
Acknowledgments. The authors thank G. Fergusson and M. Éthier (University of Montréal Hospital Research Centre) for valuable technical assistance. The authors thank Drs. James Shapiro and Tatsuya Kin from the University of Alberta, as well as the Integrated Islet Distribution Program, which was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases and the Juvenile Diabetes Research Foundation International, for providing isolated human islets.
Funding. B.Z. is supported by a postdoctoral fellowship from Eli Lilly. M.P. holds the Canada Research Chair in Diabetes and Metabolism. This study was supported by the National Institutes of Health (grant R01-DK-58096 to V.P.) and the Canadian Institutes of Health Research (grant MOP 77686 to V.P.). V.P. holds the Canada Research Chair in Diabetes and Pancreatic Beta Cell Function.
Duality of Interest. No potential conflicts of interest relevant to this article were reported.
Author Contributions. B.Z. performed the study, researched data, analyzed the results, and wrote the manuscript. I.B., G.F., M.-L.P., and O.S. performed the study, researched data, analyzed the results, and reviewed the manuscript. M.P. reviewed the manuscript. V.P. conceived the study, analyzed the results, and wrote the manuscript. V.P. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Prior Presentation. Parts of this study were presented in abstract form at the 72nd Scientific Sessions of the American Diabetes Association, Philadelphia, PA, 8–12 June 2012; and at the 16th Annual Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism/Vascular 2013, Montréal, Québec, Canada, 17–19 October 2013.


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What Happened—or Didn't Happen—at the Supreme Court Today
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Contrary to many people's expectations, the U.S. Supreme Court did not issue any orders last Friday or today in any of the four challenges to a provision of the so-called Defense of Marriage Act (DOMA), in the Hollingsworth v. Perry case challenging California's Proposition 8, or in Brewer v. Diaz (Lambda Legal's case that has preserved domestic partner health insurance coverage for families of lesbian and gay Arizona state employees). The next time we may hear from the Court about what it plans to do regarding these cases is this coming Friday, December 7.
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The Court generally doesn't explain the reason for delays in issuing orders. While some people are understandably feeling frustrated with the delays given all that is riding on these lawsuits, it should be recognized that the Court's decisions about which case or cases to hear right now involve a good deal of complexity. The main issue in the DOMA challenges is the same: whether DOMA violates the Constitution's guarantee of equality for the federal government to discriminate against same-sex couples by treating them as single, while recognizing all other validly entered marriages. However, the particular federal programs involved in each case are somewhat different, and there are numerous procedural questions posed by the eight petitions for review that have been filed by the various parties in those suits.
Justice Kagan needs to decide whether to recuse herself from GLAD's Gill v. OPM case. The ACLU's Windsor v. United States case involves the additional wrinkle of how New York treats marriages entered in Canada. Lambda Legal's Golinski v. OPM case, GLAD's Pedersen v. OPM case, and Windsor, all came to the Supreme Court in an unusual way—with requests for review having been filed before decisions from the intermediate appellate courts were issued. And there have been questions raised about the right of various parties to ask for Supreme Court review because of who the party asking is or because that party won below.
The Supreme Court has to decide not only which challenge to DOMA to hear, but also whether to hear the Perry or Diaz cases now, or wait until after a DOMA case is decided. Although the questions in these two cases are different from the DOMA challenges, a decision in a DOMA case that laws that discriminate based on sexual orientation should be given heightened scrutiny by the courts and presumed unconstitutional could make the Perry and Diaz cases easier to decide, and the Court might choose to hold one or both of those cases for that reason. If Perry is to be considered now, the justices may direct the parties to brief only the narrow ground decided by the Ninth Circuit that involves the unusual circumstances of California's marriage ban or broader grounds as well, in addition to the question of whether or not the proponents of Prop 8 have the right to appeal. In Diaz, the Court needs to consider whether to get involved at this point (wading in on whether a preliminary injunction was properly issued keeping insurance coverage in place while the case proceeds), when the case is not yet fully resolved at the trial court.
All of these questions about which case or cases to hear now will have significant implications for the outcomes. Thus, what might seem a simple decision is actually not so simple after all. And so we wait…
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Julius Shulman
Julius Shulman was the 20th century's most famous photographer of modern architecture. He grew up on a Connecticut farm and, after 1920, the early days of the city of Los Angeles. An amateur photographer since his teens, Shulman had a chance encounter with architect Richard Neutra in the late 1930s, and Shulman's career as a photographer of architecture was launched. From the 1940s through the 1960s, Shulman's photos appeared in major magazines across the globe, and helped infuse modernist art principles into what we now call lifestyle. His work advanced the careers of America's most famous architects, including Neutra, John Lautner and Frank Lloyd Wright. Shulman officially retired in 1989, but a new appreciation for modernist architecture in the 1990s led to his work being hailed as fine art. By the time he died, Shulman was said to be the guy who first practiced architectural photography as an art form.
Julius Shulman was the subject of a 2008 documentary film, Visual Acoustics: The Modernism of Julius Shulman.
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Foundations Adult Class
September 11, 2022 @ 10:00 am - 10:50 pm
Join us as we explore stories from the Bible in an interactive, discussion-oriented setting. Not an expert? Not a problem. This class is for anyone hoping to fellowship with other Trinity members while growing their faith by reflecting on the teachings of Jesus and asking questions. Bring your Bible (and a sense of humor), and let's grow together.
This class meets every Sunday from September 11 through May 21 with a few exceptions for holiday weekends which will be communicated with the class and via CFM e-mails. Any adults are welcome to join this class, their lessons will follow the Bible stories being discussed in our children's classes.