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|Message view
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|Jeff Trawick <traw...@gmail.com>
|Re: Suggestion for Apache HTTP Server: Use lighttpd worker
|Tue, 24 Nov 2009 11:03:47 GMT
On Tue, Nov 24, 2009 at 5:53 AM, Graham Leggett <email@example.com> wrote: > email@example.com wrote: > >> I have a suggestion. So the apache worker MPM is not being maintained >> anymore, so Apache should just use the worker feature that lighttpd has >> and tweak it so it works with apache HTTP Server. Save alot of time and >> effort. > > I'm not aware that support for worker has been dropped or is no longer > maintained? It ain't so. worker is the default MPM on some platforms in future Apache 2.4.
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My husband , daughter and her friend stayed here in February. The hospitality and location was excellent and well worth the small costs charged. This is within the medina and is so close to all amenities. Breakfast was provided daily included in the cost: this was really scrumptious... And although it was a Continental breakfast there was lots of selection and upon request some warm food was offered. The mint tea is second to none and was offered complimentary throughout the day when lounging on the lovely terrace. As part of our deal we had a meal prepared by the Riad which was simple but very very tasty. The rooms in the accomodation were fairly basic but exceptionally clean and the only thing I would say is that the rooms were small and the bed was not too comfy...although after a day or two we got used to it.... Overall the service provided by the staff was amazing Kamil and Babette were exceptionally helpful and everyone else went out of their way to make our stay enjoyable. I would have no hesitation to recommend this Riad... It was great value for money and is in the hub if activity!!! I have stayed in a five star in Morroco previously however, this was a better experience overall. If you choose this Riad, take some excursions planned by the Riad (we didnt have time but all other guests commented that they were great value) and visit the medina spa as recommended by the Riad which is close by.
- Official Description (provided by the hotel):
- Bed and breakfast in a riad in the heart of the medina of Marrakech opened in June 2009. 8 air conditioned rooms in summer and heated in winter with bathroom and private toilet. Beautiful terrace, patio, Moroccan lounge, small pool opened spring 2010. ... more less
- Reservation Options:
- TripAdvisor is proud to partner with Expedia, TripOnline SA, Orbitz, Hotwire, Booking.com, Priceline, Agoda, Hotels.com and Travelocity so you can book your Riad Zayane Atlas reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.
- Also Known As:
- Riad Zayane Atlas Hotel Marrakech


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Hotel Del Mar Mamaia, Constanta (and vicinity)
- Free Internet and free parking
Main amenities
- 90 guestrooms
- Near the beach
- Breakfast available
- Bar/lounge
- Fitness center
- 24-hour front desk
- Air conditioning
- Daily housekeeping
- Meeting room
- Tour/ticket assistance
What's around
- Mamaia Cable Car (0.2 mi / 0.3 km)
- Mamaia Aqua Magic (0.2 mi / 0.4 km)
- Farul Stadium (2 mi / 3.2 km)
- Mamaia Beach (2.4 mi / 3.9 km)
- Ovid Square (5.4 mi / 8.7 km)
For families
- Cribs/infant beds available
- Private bathroom
- Premium TV channels
- Furnished balcony
- Daily housekeeping
- Washer/dryer
Hotel Del Mar Mamaia, Constanta (and vicinity)
Hotel Info: 866-539-8117from $148
- Suite (VIP,20% discount in restaurant London)
- Double Room
- Executive Double Room
- Senior Suite
- Junior Suite
- Standard Double Room
- VIP Suite
- Executive Suite
- Junior Suite free access to SPA
- Double Room, Sea View (20% in the restaurant London)
- Single Room
Also popular with travelers from the USA
At a glance
Key facts
Hotel size
- This hotel has 90 rooms
- This hotel is arranged over 6 floors
- Check-in time noon-midnight
- Check-out time is noon
Required at check in
- Credit card or cash deposit required
- Government-issued photo ID required
Travelling with others
- Up to 2 children (6 years old and younger) stay free when occupying the parent or guardian's room, using existing bedding
- No pets or service animals allowed
- Free wired Internet access in public areas
- Free wired Internet access in rooms
- Free self parking
Nearby Four Star Constanta (and vicinity) hotels
In the hotel
- Continental breakfast daily (surcharge)
- Bar/lounge
- Fitness facilities
- One meeting room
- 24-hour front desk
- Tours/ticket assistance
- Number of buildings/towers - 1
- Year Built 2010
- Accessible bathroom
- In-room accessibility
In the room
- Air conditioning
- Bathrobes
- Washer/dryer
- Blackout drapes/curtains
- Furnished balcony
- Private bathroom
- Rainfall showerhead
- Shower only
- Hair dryer
- Premium TV channels
- Desk
- Free wired high-speed Internet
- Phone
- Daily housekeeping
- In-room safe
Top Constanta (and vicinity) hotels
Hotel Del Mar Mamaia, Constanta (and vicinity)'s small print
Also known as
- Del Mar Mamaia
- Del Mar Mamaia Constanta
- Hotel Del Mar Mamaia
- Hotel Del Mar Mamaia Constanta
Only registered guests are allowed in the guestrooms.
Mandatory fees
You'll be asked to pay the following charges at check in or check out:
- A 5 percent city/local tax will be charged
Optional extras
Continental breakfast is offered for an extra charge of RON 27 per person (approximately)
We have included all charges provided to us by this hotel. However, charges can vary, for example, based on length of stay or the room you book.
Recent reviews
Good 3.8 /5 from 11 reviews
This was my second stay at this hotel and I will stay there again on my next trip. The hotel is virtually although not directly on the beach - maybe 100m. It is not directly on the main street of Mamia and this is very nice. The rooms are large and spacious. I have stayed in one of their suites and paid less than or close to the amount I would pay for a regular room elsewhere. I had a small problem with my reservation this time - the room I had requested was not available until the next day. They put me in a comparable room and promptly moved me the next morning. Staff is friendly and courteous. Parking is a dream. I have no comment on the restaurant I did not eat there. POSSIBLE MAJOR NEGATIVE - Although I did not experience it, the fine print states that only registered guests are allowed in the room. I had 3 different friends come by during my 4 day stay and we always went to my room. If I had not been allowed to invite them to my room I would have checked out immediately and would never go back. The reason I always take a suite is so that I will have a place to receive and entertain guests. I only saw this fine print about 5 mins before writing this review.
Not impressed
Breakfast should be ordered from the menu, instead of buffet. On the check out they keep you at the desk while one of the employees is checking minibar even after you have told them what you have taken. This was quite rude, like they assume you're lying.
Is the description of this hotel not correct? Tell us


text:
Pressure to maintain sales streak cited as main reason for the misreporting.
3Recharge Wrap-up: Jason Hughes builds 1,000-hp EV, BMW considers Thai battery factory
- John Beltz Snyder
- 3 days ago
- 3
Tesla hacker Jason Hughes is building his own EV with parts from Tesla and Chevy. BMW is considering building a battery plant in Thailand. The amount of Samsung's BYD investment has been revealed.
Top automotive barn finds of recent history
- Noah Joseph
- Jul 16, 2016
The past few years have seen some amazing classic cars unearthed, hidden away in barns, sheds, parking lots, and scrap yards only to be rediscovered.
AddAutomotive stock prices fall worldwide in the wake of Brexit
- Reese Counts
- Jun 24, 2016
- Add
Stock prices worldwide have taken a hit in the wake of the UK referendum. The long-term impact is still unknown, but companies across the auto industry are seeing immediate consequences.
22The UK votes for Brexit and it will impact automakers
- Alex Kierstein
- Jun 24, 2016
- 22
The UK has voted to leave the European Union, and it could lead to tariffs that hurt export of UK-built cars, and affect foreign automaker profits.
4Mitsubishi fuel economy scandal will result in $1.39 billion loss
- Antti Kautonen
- Jun 22, 2016
- 4
And things had been going so well...
AddAudi CEO Rupert Stadler: Ducati is not for sale
- Jeremy Korzeniewski
- Jun 18, 2016
- Add
Will Ducati be sold off to raise money for the beleaguered Volkswagen Group? Not a chance, says Audi CEO Rupert Stadler.
4Cash-strapped Takata to be bought by private equity firm
- Noah Joseph
- May 26, 2016
- 4
Automakers to be asked to help foot the bill for airbag recalls as private equity firm KKR moves towards a leveraged buyout of Japanese automotive supplier Takata.
3New car sales will slow down in May, say analysts
- Alex Kierstein
- May 20, 2016
- 3
Analysts trim forecasts in a sign that record new car sales might be cooling off.
1Recharge Wrap-up: Cow-colored Tesla Model X, Autopilot retrofit
- John Beltz Snyder
- May 18, 2016
- 1
Grass Fed Coffee decorates its Tesla Model X like a cow. Jason Hughes retrofits a Model S with Autopilot. Germany approves EV subsidies. EVgo gets new a majority stakeholder.
25GM, Ford, Honda winners in 'Car Wars' study as industry growth continues
- Greg Migliore
- May 11, 2016
- 25
GM, Ford, and Honda are in good shape through 2020, according to the latest Car Wars study.
1Recharge Wrap-up: Tesla rainbow charging port, dandelion tires
- John Beltz Snyder
- May 9, 2016
- 1
Tesla owner discovers charging port trick. Ford uses cleaner diesel technology in Europe. Continental explores dandelion rubber tires. Total buys battery maker Saft.
8Tesla gets deadbeat treatment in Norway over late payments
- John Beltz Snyder
- May 3, 2016
- 8
Tesla Motors Norway sees its credit rating damaged as creditors demand payment.
17Ford rakes in record $2.5b profit during Q1 of 2016
- Pete Bigelow
- Apr 28, 2016
- 17
Ford posted record profits in the first quarter of 2016, the company announced Thursday. Chief financial officer Bob Shanks said Ford enjoyed its best quarterly performance in history, generating operating profits of $3.8 biliion and a record profit margin of 9.8 percent.
18Despite scandal, Volkswagen is the world's top-selling carmaker
- Chris Bruce
- Apr 26, 2016
- 18
Volkswagen's 2.49 million global deliveries made the German company the world's largest automaker for Q1, but Toyota was a very close second place.
2Uber settles suit with 385k drivers for $100 million
- Antti Kautonen
- Apr 22, 2016
- 2
The 385,000 Uber drivers are from California and Massachusetts, and those driven more than 25,000 miles might get $8,000.
12General Motors posts record earnings, but global sales fall
- Chris Bruce
- Apr 21, 2016
- 12
General Motors had record earnings during the first quarter of 2016. Transaction prices higher than the industry average in the US helped offset falling global sales.
47Elon Musk on his way to earning an extra $1 billion at Tesla
- Chris Bruce
- Apr 19, 2016
- 47
Elon Musk has achieved half of the milestones at Tesla he needs to get full access to all of his stock options. If he reaches all of the company's goals, the boss stands to make $1.6 billion.
21Daimler shareholders brawl over sausage buffet
- Noah Joseph
- Apr 7, 2016
- 21
Cash payments aren't the only kind of dividends that Daimler shareholders have come to expect as a fight broke out between investors at the company's annual general meeting in Berlin.
16Hydrogen-powered Riversimple Rasa crowdfunding for $1.4 million
- Chris Bruce
- Apr 6, 2016
- 16
Riversimple hopes to earn $2.27 million in a crowdfunded investment campaign to fund its Rasa hydrogen fuel cell vehicle. Later, the company plans to offer them to customers for a fixed monthly fee, rather than selling the model.
4BYD launches 2 new EVs, predicts sales will nearly triple
- John Beltz Snyder
- Apr 4, 2016
- 4
BYD expects 150,000 sales in China in 2016, just launched two new all-electric sedans and has partnered with other companies to create an "EV ecosystem."
- Volvo shoots for self-drivers by 2021
- Jeep spends $1 billion on factories
- Find Parts & Accessories for your vehicle!
- Obama rolls out new EV plan
- Infiniti dealers ranked best, Tesla worst
- Compare Volvo XC90 and Lincoln MKX


text:
- You'll save an extra 5% on Books purchased from Amazon.ca, now through July 29th. No code necessary, discount applied at checkout. Here's how (restrictions apply)
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The Leafy Greens Cookbook: 100 Creative, Flavorful Recipes Starring Super-Healthy Kale, Chard, Spinach, Bok Choy, Collards and More! Paperback – Jul 9 2013
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About the Author
Kathryn Anible graduated from Johnson and Wales University with a Bachelor's of Science in Culinary Nutrition. Before moving to NYC to become a personal chef, she was in the food service industry for nearly 15 years, including such jobs as the assistant director of food services for a hospital in Albany and the catering manager of a college in Boston. Both the green markets of her home, New York City, and the different flavors she finds on her world travels inspire the colorful, seasonal recipes that Kathryn cooks for her private clients. In addition to cooking, she also pursues food styling, writing and catering.
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Most Helpful Customer Reviews on Amazon.com (beta)
Chard Panzanella - *awesome* includes a wee bit of agave nectar which really balances out the acidity of the dish nicely.
I do a lot of organic gardening and am always looking for new ways to incorporate more greens into my cooking and this book delivers! And don't be fooled by the title, it's by no means just a bunch of salad recipes.
I'm not a vegetarian but have been eating less and less meat over the last few years and this book has a great mix of vegetarian and meat dishes that all include some super healthy greens.
The other stand-out feature of this book is that it has an awesome mix of flavors and styles from different cuisines. I'm pretty sure you could cook from this book every day for 3 months and never get bored. It also does a good job of balancing the healthiness aspect with ingredients that deliver on flavor and recognizing that every so often it's OK to slap a little bacon on something :)
Now that I've had a chance to cook with it some I'm definitely planning on gifting a copy to a couple of my like-minded family members.
I've never been worried to try to smoke a 30 pound pork shoulder for 12 hours or cook a big pan of paella, but something about greens have always been intimidating. There seems to be mere moments during which you could go from raw vegetation and soggy sadness.
The recipes in here help to lift the veil of trepidation as you realize that the techniques aren't challenging. Kathryn curates a list of recipes that sneak in greens to enhance everyday foods. Kale shines as a snack, salted and roasted in the oven; as a side, sautéed with lemon and garlic; as an enhancement to breakfast burritos...
Once that's set, more complex, savory and spicy dishes await like Saag Paneer and African Stew... And then there's the shakes.
Turns out greens are more durable then you think... And who on earth doesn't like good food that cooks fast! Great book, highly recommended.
I have clients who struggle finding ways to incorporate greens in a creative way that doesn't resort to the stale side-salad and dressing tradition. This book does a great job providing user-friendly recipes that represent various cultures (Kimchi, African Peanut Stew) while also experimenting with cooking techniques and providing suggestions as to when these dishes are best served (Breakfast, Side-Dish, Winter, Summer, etc.)
The first recipes you should try upon receiving your copy: Arugula Hummus and Watercress/Potato Soup. MMMMMMMMMM MMMMMMMMMM DELICIOUS!!!


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Man killed in industrial accident identified
Published: Tuesday, January 4, 2011 at 3:30 a.m.
Last Modified: Monday, January 3, 2011 at 11:42 p.m.
Investigators have released the name of a man killed in an industrial accident in Vance on Friday morning.
Fernando De Leon Ixcoy, 22, was killed by a log that struck him after it fell from a bark-stripping machine, said Tuscaloosa County Metro Homicide Unit commander Capt. Loyd Baker.
The accident occurred at Ky-KenKee Inc., a timber company on U.S. Highway 11.
The Occupational Safety and Health Administration and the Tuscaloosa Metro Homicide Unit are investigating Ixcoy's death.
Reader comments posted to this article may be published in our print edition. All rights reserved. This copyrighted material may not be re-published without permission. Links are encouraged.
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OSI-Approved Open Source (949)
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- Android (312)
- Modern (272)
Database Engines/Servers Software
Hot topics in Database Engines/Servers Software.net erp mvc asp.net project erp erp/crm web application in asp.net c# asp.net free crm source code asp.net c# erp erp software in dotnet crm asp.net inventory management system
- License: GNU General Public License version 2.0 (GPLv2) ×
Digimech Server
Object-oriented database server1 weekly downloads
Digital Library
Digital Library (DigLib) is special database system oriented to digital objects. Digital objects are any documents in digital form. For example text, software, audio, video, ... Digital Library store a metadata and fulltext (text/binary) of digital object
DinoGone on PeopleSoft
Scripts, techniques, Documentation and Tools used on PeopleSoft with Oracle DB.
DirList User Database System
DirList is a user database system for POSIX-compliant systems and can be administered with the DirList ODBC driver and the sample Microsoft Access database. Casual users can access a DirList system through the CGI web interface.1 weekly downloads
Dirt Cloud
DIRT stands for Database Internet Record Transfer. DIRT is similar to ODBC, OLEDB, and other alphabet soup acronyms for data transfer interfaces. The difference for DIRT is that it is exposed as a cloud web service initially based on SOAP.
Distribuite Network Search Engine
System of FullText Retrieval Distribuited on Linux (NSED). It's writen C/C++.1 weekly downloads
Distributed Parts Management System
A distributed parts management system that allows for information sharing easily and seamlessly. Can be ran as a stand alone system, a part of a greater network of systems, or a set of servers all working together to build the report.
DoSqlWeb - Put Data in your existing Web
First feature is like a Metaspeach, who you could place an every place of your actually existing Html-Page. Its useful for developpers and people who are advanced with creating SQL-Selects. You dont need to now how to programm in PHP, but you could ...3 weekly downloads
DocRepository is a document storage system based on keywords and other searchable fields such us author, keywords, description, etc. Documents can have associated files. Backup functionality is also available to store documents and track backups.
Doggy Webpage System
CMS is building in PHP5 and MySql.It's fast, elastic CMS, which have very much functions.The CMS have much styles and languages. You can make a new styles and modules. Date of the premiere is about July, or Juni. It'll a poland production.
Document Object Model Structured Query Language! Example: 'SELECT {//title[1]=>innerCode} FROM {http://example.com}';2 weekly downloads
a simple c# game use for remoting
DraGnET is designed to assist with the management of annotated draft and complete genome sequence data. DraGnET also provides a web interface for BLAST and Batch BLAST search capabilities. Each search page has instructions for the use of the page.2 weekly downloads
Dubby is a program which will read DBMS data block file directly. It will start from Oracle dbf. It will be useful for people who are interested in database management system implementation.
Dutch MOO Core
This is a Dutch translated version of LambdaMOO, with a few things extra. A MOO is an Object Orientated virtual World.
Dynamic World Engine
The Twilight Minds Dynamic World Engine is the workhorse for a new way of dealing with plot and AI in MMORPGS and other CRPGS.2 weekly downloads
Thie Project help to generate pdf file, in which data is brought from any database backend that kept
An Object Database engine witch use early binding
ELOG Eletronic Web Logbook
Electronic Logbook with Web interface. Good for personal and shared logbooks. Supports attachments, arbitrary logbook attributes and search facilities.7 weekly downloads
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ERP.NET is ERP/CRM&SFM software application written in C#.NET/ASP.NET/T-SQL for manufacturing company. There are included modules are: CRM,ERP,SFM, order,manufacture,Client,supplier, Price, stock, project...144 weekly downloads
Espada WoW Szerver saját fejlesztésü adatbázisa, amit csak a fejlesztők módosíthatnak.
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Saudi Arabia's Asir Province
Saudi Arabia's southwestern province of Asir is an incongruously verdant place, but the lush countryside is not the only thing that sets it apart. It was also the birthplace of many of the Sept. 11 hijackers. NPR's Kate Seelye reports.
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The host, Michele, could have not been more helpful and informative about local places to see and eat (and avoid). Hotel beuatifully decorated with Michele's photographs of the area on the walls. Great value for money, if you are going to Pisa, stay here.
Colette Stein, Goadby Marwood (GB).
- Reservation Options:
- TripAdvisor is proud to partner with Priceline and Booking.com so you can book your B&B Tuscany Gallery reservations with confidence. We help millions of travelers each month to find the perfect hotel for both vacation and business trips, always with the best discounts and special offers.


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BROOKLET - A tough schedule and a roster that lacks a lot of experience got the Statesboro boys basketball team off to a rough start to their season, but 2012 is looking good so far.
When teams from Bulloch Academy and arch-rival Pinewood Christian meet on the gridiron, on the diamond or on the court, the action is always tense and exciting and the fans are plentiful and loud.
Portal continues to get the most it can out of 2011 as it took a second win in as many nights at its holiday tournament Thursday night.
LAWRENCEVILLE - Grayson head football coach Mickey Conn can rattle off a long list of things that make defensive lineman Robert Nkemdiche such a good player.
Haley Burke scored 18 points, Taylor Collins added 16 points and Anna Newton chipped in 10 points to help Bulloch Academy to a 49-36 victory over John Milledge Academy in a girls basketball game Thursday in the Tattnall Square Academy Invitational Christmas Tournament in Macon.
All-Region 3-A West Football Team
Tuesday night, Statesboro let a second-half lead slip through its grasp. Wednesday, the Blue Devils weren't about to make the same mistake.
The Statesboro High School Blue Devils, the 2011 Region 2-AAAA football champion, had a number of players named to the all-region team. Offensive players selected were Marshuan Jackson, Herman Lee, Freddie Burden, Rahkym Thomas, Reid Pennington and Michael Summers. Defensive players selected were Shaq Johnson, Lenard Robinson, Reggie Owens and Haydon Rollins. In addition to all-region honors, Burden was also selected to the all-state team.
Bulloch Academy crushed Central Fellowship Christian Academy of Macon, 42-18, in a girls basketball game in the Tattnall Square Academy Invitational Christmas Tournament in Macon on Wednesday.
Portal High School's boys basketball team beat Worth County, 68-61, in a game Wednesday in the Portal Holiday Classic tournament at Portal High School.
After having its first scheduled game of the Gentlemen's Classic postponed Monday night, Statesboro still had some holiday rust to shake off.
Portal High School's boys basketball program will play host to the Portal Holiday Classic tournament today through Friday at Portal.
Bulloch Academy's girls basketball team lost its first game this season, 59-56, to Westwood in the Tattnall Square Academy Invitational Christmas Tournament in Macon on Tuesday.
Monday morning, the Georgia High School Association announced its final decisions regarding region alignment when the association expands to six classifications next season. Southeast Bulloch received an early Christmas present when it was informed that it will be moving to a new region.
Barbara Conner, who has been the backbone of Bulloch Academy's athletic department and its physical education and science programs for the past 27 years, recently was honored with a Distinguished Service Award from the Georgia Independent School Association.
Throughout the week, the old gym at Statesboro High has been playing host to the school's newest sport.
Womack Field at Statesboro High School could have easily been mistaken for a National Football League preseason training camp on Saturday as it hosted the ...
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Star Trek: The Compendium (XI & Into Darkness) [Blu-ray]
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1. Those who saw "Into Darkness" in IMAX theaters may remember that for certain scenes the aspect ratio of the film shifted from the typical 2.40:1 to the taller 1.78:1, creating a larger and more immersive image. Unfortunately, the original blu-ray release of Into Darkness did not include the IMAX footage... But this one does, meaning for those scenes it will fill your entire TV (instead of the usual black bars on the top and bottom).
2. This set also includes an Enhanced Commentary for "Into Darkness" that was previously exclusive to iTunes. Basically you play the movie, but all sorts of content appears on the screen while you watch and the director/crew will come on at various points to talk about the film (it's similar to the WB 'maximum movie mode' feature that is on discs like Watchmen and Terminator Salvation).
3. The bonus disc for "Into Darkness" has some new deleted scenes and additional bonus material that was not previously available.
Below is a complete listing of all the content in this four-disc set:
Disc 1 - Star Trek (2009)
- Star Trek in high definition
- commentary by J.J. Abrams, Bryan Burk, Alex Kurtzman, Damon Lindelof and Roberto Orci
Disc 2 - Star Trek (2009)
- To Boldly Go -- Taking on the world's most beloved science fiction franchise was no small mission. Director J.J.Read more ›
To be clear, I do not mind studios releasing deluxe versions of a movie. It's great for fans of movies to have deluxe options. But I don't like the studio telling us that certain features are exclusive and then going back on that promise. Nor do I appreciate the studio not telling us that a version with the deleted scenes would be coming. For comparison, Peter Jackson has been very up front in telling fans that extended versions of the Lord of the Rings/Hobbit movies would be released and WHEN they would be released.
I think it's important that movie consumers take a stand and tell Paramount that consumers will not stand for such practices. The best way to do that is to refuse to buy this set. If studios want us to buy blu-rays and not just stream movies, then treat us as premium customers rather than gullible suckers.
UPDATE: There is a bit of good news. Apparently Paramount will offer a rebate for customers who had previously bought an earlier blu-ray version of STID. This is some consolation and makes the double-dip less problematic. Nevertheless, I think it is still important for consumers to send the right message.
It will be nice to finally have the complete set of features. STID is a VERY good movie and a personal favorite of this Trek fan. Can't wait to see what I missed!
The new Star Trek movies have their fans and their detractors, but they are good entertainment (with "Into Darkness" being the weaker entrant, being too illogical).
This set is aimed mostly at the Star Trek completist fan, and offers both movies as well as two additional discs full of extras. If the behind the scenes stuff floats your boat, this is the most cost-effective way to get it.
The weakest part of the set is the digibook packaging. I'm not a fan, primarily because without the slipcase, the spine tends to go crooked (and this is sometimes greatly helped by the shrink wrapping). Also the plastic trays for the discs are made of very hard plastic, so hard, in fact, that it is difficult to get the discs out and the discs flex alarmingly.
In conclusion, if you do not own the movies from before, or are a completist, this is the set for you. And if you hunted down all the various iterations of "Into darkness" when it first came out to get all the featurettes, I understand your frustration at Paramount's apparent fleecing of loyal fans.
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Wow ... the expanded commentary for the second movie is excellent ... that is how all commentaries should be!Published 8 days ago by Len Lindsay
Strictly talking about the Bluray quality and not about packaging: Star Trek (The First Movie), well the Bluray is decent, has a little signs of grains but it's acceptable since... Read morePublished 8 days ago by Kalyan Kiran Das
Movie: 4/5
Picture Quality: 5/5 (IMAX scenes)
Picture Quality: 4.5/5 (35mm scenes)
Sound Quality: 5/5
The most complete of these films, picked this up at Costco the other day on sale for like 15 dollars. Read morePublished 1 month ago by Action&Music
The discs that should've been released in the first place. Fortunately I never bought the old ones.Published 1 month ago by C. D.
Two awesome films and the clarity in the Blu-rays astounding. I love the IMAX scenes that were added back in for Into Darkness.Published 1 month ago by S. Hornak


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Description: Bewcastle Roman Fort was a Roman fort, built to the north of Hadrian's Wall as an outpost fort and intended for scouting and intelligence. The Roman name for the fort was Fanum Cocidi (as recorded in the Ravenna Cosmography), and means 'The Shrine of Cocidius', a deity worshipped in northern Britain. The remains of the fort are situated at the village of Bewcastle, Cumbria, 7 miles (11 km) to the north of the Roman fort at Birdoswald, on Hadrian's Wall.
The fort was identified as Fanum Cocidi on the basis that, of nine altars discovered on the site, six are dedicated to the god Cocidius.
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Date — 30 January, 2012
*As IWC gets ready for the Laureus World Sports Awards next week, we invite you to be drawn into this formidable charity – helping children and communities through Sports around the globe.
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Conceived and designed the experiments: SL OS EDA RK. Performed the experiments: SL TO AA JS CWL HB EDA. Analyzed the data: SL OS EDA RK. Wrote the paper: SL RK.
Insulin/IGF-I signaling regulates the metabolism of most mammalian tissues including pancreatic islets. To dissect the mechanisms linking insulin signaling with mitochondrial function, we first identified a mitochondria-tethering complex in β-cells that included glucokinase (GK), and the pro-apoptotic protein, BADS. Mitochondria isolated from β-cells derived from β-cell specific insulin receptor knockout (βIRKO) mice exhibited reduced BADS, GK and protein kinase A in the complex, and attenuated function. Similar alterations were evident in islets from patients with type 2 diabetes. Decreased mitochondrial GK activity in βIRKOs could be explained, in part, by reduced expression and altered phosphorylation of BADS. The elevated phosphorylation of p70S6K and JNK1 was likely due to compensatory increase in IGF-1 receptor expression. Re-expression of insulin receptors in βIRKO cells partially restored the stoichiometry of the complex and mitochondrial function. These data indicate that insulin signaling regulates mitochondrial function and have implications for β-cell dysfunction in type 2 diabetes.
Insulin and insulin like growth factor I (IGF-I) play critical roles in triggering pleiotropic actions including metabolism, proliferation and survival in most mammalian cells including the pancreatic islets [1]. The two hormones bind to their cognate receptors and activate Akt/protein kinase B via the phosphatidylinositol 3-kinase (PI3-K)-generated polyphospho-phosphatidylinositol pathway to phosphorylate the protein BAD in the regulation of apoptosis [2]. Indeed, we and several other laboratories have used cell line, primary islet and genetically engineered mouse models to demonstrate that insulin/IGF-I signaling plays a critical role in the regulation of hormone secretion, proliferation and survival of pancreatic β-cells (see review [3]). Among the various models, it is notable that mice with β-cell specific knockout of insulin receptors (βIRKO) and/or IGF-1 receptors demonstrate reduced expression of the glucokinase (GK) gene and blunted glucose-stimulated insulin secretion [4], [5], [6], [7]. βIRKO mice also display an age-dependent decrease in islet mass, poor compensatory islet response to high fat-diet induced islet growth and increased susceptibility to diabetes, suggesting a role for insulin signaling in the regulation of β-cell survival [8].
While the precise defect in β-cell growth and/or function that triggers overt diabetes is not fully understood, mitochondrial dysfunction in β-cells has been implicated as one factor that impairs β-cell survival and function [9]. Mitochondria play a major role in insulin secretion [10], [11] and in β-cell apoptosis [12], [13] triggered by diverse internal or external cues ultimately promoting cell death [14]. Indeed, islets from patients with type 2 diabetes exhibit low ATP content and a blunted glucose-stimulated insulin secretion (GSIS) and increased mitochondrial volume [9], together implicating a role for mitochondria in the pathogenesis of β-cell dysfunction.
Growth factor-mediated pathways have been reported to modulate mitochondrial function and regulate the activity of the pro-apoptotic protein, BAD [15]. Interestingly, studies in hepatocytes and β-cells have shown the presence of a BAD/glucokinase complex at the mitochondria suggesting a point of intersection for processes that regulate glycolysis and apoptosis [16]. Further, hyperglycemia has been reported to modulate the levels of GK and alter its interactions with mitochondria leading to apoptosis of β-cells [17], [18]. Considering the critical role of glucokinase in cellular metabolism and survival, and our previous observations of reduced expression of GK in β-cells lacking insulin or IGF-1 receptors [5], [19], we undertook the current study to explore whether absence of insulin signaling in β-cells impacts mitochondrial function.
In this study, we report the presence of a BAD/GK complex at the mitochondria in mouse and human β-cells. Furthermore, we provide evidence that lack of insulin receptors in β-cells impacts localization of BADS, alters the stoichiometry of the BAD/GK complex and modulates phosphorylation of BADS that together contribute to defects in mitochondrial function.
To explore the presence of a putative BAD/GK complex in β cells, we isolated mitochondria from β-cell lines, or islets derived from control or βIRKO mice and from diabetic and non-diabetic human subjects. Mitochondria were subjected to microcystin pull down assays. Similar to descriptions of the mitochondrial complex in hepatocytes [16], we detected five proteins: WAVE1 (a protein kinase A scaffold protein), glucokinase (GK), protein kinase A (PKA), protein phosphatase 1 (PP1), and the pro-apoptotic protein BADS (Fig. 1A–C). All components of the BAD/GK complex were identified in cultured β-cells and in mouse and human islets, indicating that this complex is conserved across species. Evaluation of the distribution of each component in cytosolic and mitochondrial fractions revealed that WAVE1 exists largely in the cytosol and mitochondrial WAVE1 comprises a small proportion of cellular WAVE protein (Fig. 1D). Interestingly, we observed robust expression of glucokinase in mitochondrial fractions when equal amounts of protein from mitochondria and cytososl were loaded (Fig. 1D). However, it is likely that the amount of GK that resides in the cytosol is greater than at the mitochondria (Fig. 1D). Among the BAD isoforms [17], BADL largely localized to the cytosol while BADS was identified in both cytosolic and mitochondrial fractions. On the other hand, PKA and PP1 were detectable in both cytosol and mitochondria (Fig. 1D).
Assessment of the effects of absence of insulin receptors or of insulin resistance on the complex, revealed a significant reduction in BADS in mitochondrial samples from β-cell lines or islets isolated from βIRKO mice and in islets isolated from humans with diabetes (75% of control, p<0.05) (Fig. 1A–C and Fig. S4). In mitochondria from β-cell lines isolated from βIRKO mice, PKA was reduced (12% of control, p<0.05) (Fig. 1A), and we also observed a trend towards a decrease in GK protein (29% of control, p=0.08) in the mutants. Together, these data indicate that absence of insulin signaling in β-cells (βIRKO) or the diabetic state in humans is linked to reduced BADS in the mitochondrial complex.
BADS, a pro-apoptotic protein belonging to the Bcl-2 family, can be phosphorylated in response to growth factors at three sites, Ser-112, Ser-136 or Ser-155 [20]. Kinases implicated in activating serine phosphorylation on BAD, include Akt/protein kinase B, p70S6K, PKA, Rsk, and PAK1 [20]. To investigate the role of insulin versus IGF-I in mediating BADS phosphorylation in β-cells, we stimulated β-cells with either hormone and examined mitochondrial or cytosolic fractions. For all experiments, the purity of the fractions was confirmed (Fig. S1).
Consistent with reduced BADS protein in the BAD/GK complex, BADS content was reduced in mitochondria isolated from βIRKO cells (Fig. 2A). Phosphorylation of BADS at Ser-112 was increased in βIRKO mitochondria but was virtually undetectable in control cells. Furthermore insulin stimulation increased Ser-112 BADS in βIRKO mitochondria (Fig. 2B), which likely reflects insulin signaling via intact IGF-1 receptors ([21] and Fig. 2D).
Relative to total levels of BADS, basal levels of Ser-136 phosphorylation of BADS were also increased in βIRKO mitochondria versus controls, and phosphorylation tended to increase further with insulin treatment (Fig. 2C). Compared to changes in Ser-112 phosphorylation, these changes were not as dramatic (Fig. S2A, B). Given the low abundance of BADS in the βIRKO mitochondria we conclude that the majority of the remaining BADS was in the phosphorylated state. The phosphorylation of BADS is unlikely to involve Akt since its activation is extremely low in βIRKO cells (see below). On the contrary, phosphorylation of BAD is likely due to enhanced IGF-I signaling in βIRKO cells (see below) that potentially activates RSK1, which in turn, has been reported to phosphorylate BADS at both Ser-112 and 136 [22]. In support of this hypothesis, and consistent with enhanced IGF-I signaling in βIRKO cells, we observed increased Ser-112 phosphorylation of BADS in βIRKO but not in control cells following incubation with IGF-I (Fig. 2D).
To evaluate relative changes in cytosol versus mitochondria, we next examined signaling events in cytosolic fractions. In βIRKO cytosol, the pattern of BADS expression and phosphorylation were different than that observed in mitochondria. Thus, total BADS showed a trend towards an increase but Ser-112 phosphorylation was reduced in basal conditions (Fig. 2E,F,G). The mitochondrial and cytosolic data collectively suggest that BADS is redistributed away from the mitochondria in the cytosol in βIRKO cells without a change in the total cellular content of BADS. This was confirmed following analysis of whole cell lysates showing no differences in total BADS between βIRKO and control cells (Fig. 2H and Fig. S2A). Cytosolic BADS protein content tended to increase in insulin stimulated control cells, but did not change in βIRKO cells. One possible explanation for these observations is that increased Akt activation, in control relative to βIRKO cells results in increased phosphorylation of BADS at Ser-136 leading to sequestration of Ser-136 BADS with 14-3-3 proteins in the cytoplasm of controls (Fig. S2A) [23]. Therefore, relative to βIRKO cells, there is more cytosolic Ser-136 BADs in control cells, which is consistent with increased Akt-mediated phosphorylation and cytosolic sequestration in control cells.
In the cytosolic fractions extracted from control cells, we observed a significant decrease in Ser-112 phosphorylation of BADS in response to either insulin or IGF-I stimulation (Fig. 2F,G). The mechanism for this attenuation is uncertain, but these observations raise the possibility that Ser-112 phosphorylation might be negatively regulated by insulin or IGF-I mediated activation of Akt. βIRKO cytosol contains less Ser-112 BADS compared to control (Fig. 2F,G), which may suggest that phosphorylation of Ser-112 BADS, may preferentially occur at the mitochondria (Fig. 2B and Fig. S2A). Indeed, Ser-112 phosphorylation of BADS in βIRKO cytosol did not increase following insulin treatment. In contrast, IGF-I treatment increased Ser-112 phosphorylation in βIRKO cells (Fig. 2D) (p<0.05), suggesting that the IGF-I signaling module that activates BAD, might be hyperactivated in βIRKO cells (Fig. 2F,G).
We next explored potential mechanisms that could account for the preferential increase in phosphorylation of BAD in mitochondria of βIRKO mice. Consistent with the existence of mitochondria-tethered p70S6K in Rat-1a cells [24], we also detected this kinase in mitochondria in β-cells. Indeed, similar to other insulin sensitive cells, insulin stimulation of control cells increased phosphorylation of mitochondrial p70S6K (Fig. 3A).
βIRKO mitochondria exhibited higher basal activation of Thr-389 p70S6K in the mitochondrial and cytosolic fractions, which did not increase any further following insulin stimulation (Fig. 3A, B). It is possible that this reflects the consequence of increased basal IGF-I signaling, particularly at the level of the mitochondria, acting via Akt-independent signaling pathways such as MAPK [25], which we believe provides a potential explanation for the elevated phosphorylation of Ser-112 and Ser-136 of BADS in βIRKO mitochondria [24]. Indeed, in isolated mitochondria, addition of IGF-I significantly increased Thr-389 phosphorylation of p70S6K in the βIRKOs but had minimal effect in the controls (Fig. 3C). In contrast, IGF-I did not further increase cytosolic Thr-389 phosphorylation of p70S6K beyond the elevated basal levels in βIRKO (Fig. 3D).
The JNK (c-Jun N-terminal kinase) pathway is activated by diverse stressors and can influence multiple cellular processes. Because mitochondrial dysfunction could activate stress signaling in β-cells, we investigated JNK activity in mitochondria. JNK1 phosphorylation and total JNK1 protein was increased in mitochondria from βIRKO cells (Fig. 3E), which is consistent with the report that JNK co-localizes with mitochondria through its interacting protein [26]. The trend towards increased basal JNK1 phosphorylation levels in mitochondria, but not in cytosolic fractions, suggests that JNK1 activation might be linked to the stress induced by dysfunctional mitochondria in βIRKO cells (Fig. 3E,F). In control cells, IGF-I but not insulin, triggered phosphorylation of JNK1 in both mitochondrial and cytosolic fractions (Fig. 3E,F). Thus, the JNK/MAPK pathway is more responsive to IGF-I than to insulin in β-cells as has been suggested in other cell types [27]. The lack of a similar effect of IGF-I in βIRKO cells could be due to high basal activation of JNK1 that precludes further activation (Fig. 3E,F).
Given the role of the BAD/GK complex in the regulation of glycolysis and apoptosis [16], and our observations of changes in the BAD/GK complex in βIRKO mitochondria, we reasoned that these changes could be associated with impaired mitochondrial function in βIRKO cells.
Mitochondria respond to glucose stimulation in a dose-dependent manner by altering their membrane potential and mitochondrial metabolism, which plays a determinant role in glucose-stimulated insulin secretion [28], [29]. To assess the membrane potential response in islets ex vivo, we performed experiments in dispersed islet β-cells derived from control or βIRKO mice using the mitochondrial dye (TMRE). β-cells isolated from βIRKO islets exhibited significantly reduced membrane potential response to glucose stimulation compared to controls (Fig. 4A,B) and similar results were observed in βIRKO cell lines (Fig. S3A).
Increased mitochondrial membrane potential results from increased glycolysis and oxidative phosphorylation. We hypothesized that altered mitochondrial glucokinase activity contributes to the poor membrane potential response to glucose stimulation. We therefore measured glucokinase activity in mitochondria using the G6PDH-coupled enzyme assay. Freshly purified mitochondria from control cells showed a time-dependent increase in NADPH generation and glucokinase enzyme activity in response to glucose stimulation while there was significantly less NADPH generation in mitochondria from βIRKO cells (Fig. 4C,D). NADPH generation was not observed following treatment with the non-metabolized analogue, 2-deoxy glucose, confirming specificity of the assay (data not shown). Thus, decreased level of BADS in the BAD/GK complex potentially leads to reduced mitochondrial GK activity in βIRKO cells, consistent with the reports in hepatocytes [16].
A potential cause of the decreased mitochondrial membrane potential response to glucose is altered mitochondrial mass [30]. Electron microscopy revealed that mitochondria in βIRKOs were rounded (Fig. 4H, arrows) and larger than those in control islet cells (Fig. 4F and H), but the number of mitochondria was reduced (Fig. 4E). The mitochondrial volume densities, however, were not different between the groups (Fig. 4G). Mitotracker staining of βIRKO cell lines revealed fluorescence consistent with no reduction in mitochondrial mass (Fig. S3B).
To further explore mechanisms that contribute to the lower mitochondrial membrane potential in the βIRKOs, we measured oxygen consumption responses to treatment with glucose or DNP (2,4-dinitrophenol). Surprisingly, both control and βIRKO cells responded with a similar rise in oxygen consumption to either stimulus (Fig. 5A, B). Despite similar increases in oxygen consumption in glucose-stimulated control and βIRKO cells, there was a dramatic reduction in ATP content in glucose-stimulated βIRKO cells (Fig. 5C). The increase in oxygen consumption, accompanied by reduced ATP generation, and a blunted increase in membrane potential suggests that βIRKO mitochondria are significantly uncoupled. UCP2 expression was increased in βIRKO cells (Fig. 5E) and could represent one mechanism for mitochondrial uncoupling in these cells, similar to that observed in other models of type 2 diabetes [31]. Interestingly, expression levels of PGC-1α in the βIRKO cells were markedly increased, which likely represents a compensatory response to dysfunctional mitochondria (Fig. 5D). Recent studies have shown that PGC-1α and PGC-1β are transcriptional regulators of UCP2, and that increased PGC-1α/β - mediated upregulation of UCP2 may contribute to β cell dysfunction [32], [33].
To confirm that the defects in mitochondria in βIRKO β-cells are due to disrupted insulin signaling, we re-expressed the human insulin receptor-B isoform in βIRKO β-cells and revaluated the mitochondrial BAD/GK complex and mitochondrial function. In βIRKO cells re-expressing insulin receptors, Akt phosphorylation was restored to ~70% of control levels (Fig. 6A) and the enhancedexpression of IGF-1 receptors and phospho-p70S6K were normalized to control levels (Fig. 6A,B). In microcystin pull-down assays, we observed a near-complete restoration of BADS in the BAD/GK complex, while PKA was significantly higher in the re-expressors compared to βIRKO fractions (Fig. 6C). Mitochondrial Thr-389 p70S6K and Ser-112 BAD phosphorylation were normalized in the absence of equivalent changes in phosphorylated JNK (Fig. 6D). However, the level of expression of GK in the complex was not completely restored suggesting that re-establishing insulin/Akt signaling only partially improves the stoichiometry of the BAD/GK complex in βIRKO β-cells.
In keeping with normalization of signaling complexes, re-expression of insulin receptors in βIRKOs increased oxygen consumption rates even further following stimulation with glucose or DNP (Fig. 5A,B). ATP levels and mitochondrial membrane potential showed an increase in glucose-stimulated cells (Fig. 5C and Fig. S3A) and expression levels of PGC-1α and UCP2 were restored to control levels (Fig. 5D,E). Thus re-expression of insulin receptors restored mitochondrial energetics in βIRKO cells in part by increasing mitochondrial coupling.
In this study we examined the significance of insulin signaling on mitochondrial function in pancreatic β-cells. We report that disruption of insulin signaling in β-cells alters the stoichiometry of a mitochondrial BAD/GK complex, reduces GK activity and promotes mitochondrial dysfunction. Re-expression of the insulin receptor in β-cells that lack insulin receptors largely restores the complex and improves mitochondrial function, highlighting a significant role for insulin signaling in the maintenance of the BAD/GK complex and in the regulation of mitochondrial function.
The identification of a BAD/GK complex in both mouse and human β-cells in this study indicates conservation across species and supports the concept of a potential functional link between apoptosis and glycolysis at the mitochondria, which is similar to observations in hepatocytes [16]. Indeed, the WAVE protein in the complex has been suggested to anchor GK and BAD to the mitochondria to efficiently co-ordinate spatial and temporal aspects of glucose metabolism [34]. The alterations in the expression of different components in the complex in mitochondria from β-cells from βIRKO provide potential insights into the altered function of β-cells and may explain some of the phenotypes observed in βIRKO mice [4], [6]. Similar to effects observed in BAD-deficient hepatocytes, decreased BADS protein in the βIRKO cells likely contributes to mitochondrial dysfunction and β-cell dysfunction, which may contribute to the glucose intolerance in both of these mutants [16], [35]. The BAD/GK complex was also disrupted in islets from humans with type 2 diabetes and showed an interesting similarity with islets from bIRKO mice. Thus it is possible that reduced BADS in the mitochondria may be linked to the blunted glucose response and altered mitochondrial ultra structure observed in islets isolated from patients with type 2 diabetes [9].
Our study provides evidence that altered insulin signaling is associated with mitochondrial function in the β-cell, as has recently been reported in cardiomyocytes [36]. The mechanism for mitochondrial dysfunction in βIRKO cells is multifactorial and includes reduced glucose-mediated augmentation in mitochondrial membrane potential and reduced ATP levels that could be due either to decreased synthesis or to increased consumption in order to maintain the membrane potential. Of interest, mitochondrial dysfunction occurs despite increased oxygen consumption. These observations suggest that despite reduced glucokinase activity and potentially reduced glucose delivery to βIRKO mitochondria they are also uncoupled. One potential mechanism for mitochondrial uncoupling is increased UCP2 expression, which may be driven by increased expression of PGC-1α and β [32], [33]. Moreover, increased UCP2 expression has been implicated in limiting stimulus-secretion coupling in β-cells in some animal models of diabetes but not in others [31], [37]. However, it is possible that this increased UCP2 expression may not contribute directly to mitochondrial dysfunction in βIRKO cells and it could be the result of ROS overproduction in response to glucose stimulation since it was found that deletion of insulin receptors in heart increases their propensity to enhance ROS when exposed to fatty acid substrates [36]. Also, DNP experiments suggest that the capacity of the OXPHOS machinery may not be intrinsically impaired in βIRKO cells; the improvement in oxygen consumption that we see in βIRKO and the rescued cells might be due to altered mitochondrial mass (Fig. S3B); that might increase total mitochondrial respiration. Together, the mitochondrial defects in βIRKO cells could be results of combined effects from reduced GK activity, ROS production and altered UCP2 expression. Finally, we also measured mitochondrial membrane potential response to glucose stimulation, and βIRKO cells that re-expressed the insulin receptors showed a trend towards improved membrane potential response in response to glucose (Fig. S3A), which is also consistent with the increased respiration. Although our experiments have not definitively identified all mechanisms that could account for mitochondrial dysfunction, our study clearly shows that impaired insulin signaling in β-cells fundamentally alters mitochondrial bioenergetics and function, which may ultimately impair insulin secretion.
Consistent with the growth factor-induced phosphorylation and translocation of BADS [20] we observed significant alterations in mitochondria isolated from β-cells lacking the insulin receptor. The high level of basal phosphorylation of Ser112-BAD and Ser136-BAD in the βIRKOs likely reflects the effects of signaling via the IGF-1 receptors. It is possible that the relative levels of activation of insulin versus IGF-1 receptors determine the overall phosphorylation state of BAD at the mitochondria, with Ser112 phosphorylation being specifically mediated by Akt-independent pathways, and Ser136 phosphorylation being activated by both Akt and non-Akt pathways [38].
Intact IGF-I signaling in βIRKO cells could mediate the activation of RSK and MSK1 to phosphorylate BAD at Ser-112 [22]. The phosphorylation state of BADS has also been reported to impact its binding with other proteins such as Bcl-XL [39]. Further, the silencing of all serine sites in the BAD3SA/3SA mouse has been reported to reduce GK activity in hepatocytes while disruption of Ser-155 down-regulates GK activity in islets [16], [35]. These studies suggest that phosphorylation of BADS can modulate GK activity and impact apoptosis, likely by disruption of protein interactions in the complex. Our data suggest that the level of BADS phosphorylation correlates with function. This is reflected by the finding that βIRKO cells exhibit extremely high Ser112 phosphorylation in mitochondria (Fig. 2B and Fig. S2B) and phosphorylation can potentially interrupt the interaction between BADS and other proteins, including GK. Furthermore, re-expression of insulin receptors reversed the increase in Ser112 phosphorylation of BADS and increased the content of total BADS in the complex. Together, these data suggest the potential relevance of interactions between Ser112 phosphorylation and function of the complex. Based on the report by Danial et al [16], restoration of BADS in the complex would augment glucokinase function and mitochondrial metabolism. Additional studies such as mutagenesis of Ser112 of BADS will be necessary to prove a direct role of this phosphorylation event. In βIRKO mitochondria it is possible that phosphorylation at Ser-112 disrupts the residence of BADS in the mitochondrial complex and alters glucokinase activity and mitochondrial metabolism without affecting Ser-155-BAD (data not shown). These observations are consistent with the altered glucose sensing and altered apoptosis of β-cells in βIRKO mice [4], [5], [6]. The ability to reverse basal Ser-112 phoshorylation and restore BADS content to control levels by re-expressing the insulin receptor in βIRKO cells further underscores the role of insulin signaling in regulating the mitochondrial complex.
Another signaling pathway that could potentially influence the stoichiometry of the BAD/GK complex is the elevated expression of PTEN secondary to enhanced IGF-I signaling in βIKRO cells [40], [41]. Increased PIP2 could decrease the binding of PKA in the VCA domain of the WAVE protein, which is known to anchor GK and BAD to the mitochondria to efficiently coordinate spatial and temporal aspects of glucose metabolism [34], [42] and may contribute to the partial normalization of PKA content upon re-expressing the insulin receptor in βIRKO cells.
In the cytosol, the elevated p70S6K activation in βIRKO cells could potentially serine-phosphorylate IRS1 and further dampen insulin-stimulation of Akt in βIRKO cells [43] (Fig. 7), and potentiate IGF-I mediated pathways in the mutant cells. Indeed, activation of Akt/PKB has been reported to inhibit IGF-I activation of MAPK and mTOR pathways via Raf1 kinase, while adenoviral knockdown of Akt/PKB in INS-1 cells leads to enhanced ERK1/ERK2 signaling that is independent of IGF-I signaling [25].
We observed high levels of JNK1 activation in mitochondria but not in cytosolic fractions in βIRKO β-cells, which is consistent with the report that JNK1 activation is linked to dysfunctional mitochondria [44]. The activation of JNK1 by IGF-I, but not by insulin, in both cytosolic and mitochondrial fractions in control β-cells, implicates a role for IGF-I in the stress signaling pathway and is consistent with the potentiation of cytokine-mediated JNK following long-term IGF-I treatment [45]. We suggest that JNK1 could potentially contribute to Ser-112 phosphorylation on BADS to affect mitochondrial metabolism and function (Fig. 7). Our observations are consistent with the notion that down-regulation of Akt does not influence basal mitochondrial respiration [46]. It will be useful to dissect further, how insulin and IGF-I signaling pathways differentially modulate MAPK and mTOR target proteins, such as p70S6K and JNK1, to regulate mitochondrial function in β-cells. Further work is also necessary to explore whether insulin/IGF-I signaling directly modulates PGC-1α to affect mitochondrial biogenesis and function [47], [48].
In summary, this study provides novel insights into the role of insulin signaling in the regulation of the BAD/GK complex, glycolytic enzyme activity and mitochondrial metabolism in pancreatic β-cells. Ser112-BADS and its upstream kinases may be potential targets for the maintenance of the BAD/GK complex that is necessary for normal mitochondrial function and the regulation of β-cell survival.
Experiments were performed using the β-cell specific insulin receptor knockout mice (βIRKO) and Lox/Lox littermates as controls [6]. All mice were maintained at the Taconic Facility (NY) or Brandeis University (Waltham, MA). All experiments were performed in compliance with Joslin Diabetes Center and Brandeis University Animal Care and Use Committee regulations. The control and βIRKO β-cell lines were derived and maintained as described previously [49].
Mouse islets were isolated and purified by collagenase digestion as described previously [6]. Isolated islets were cultured in RPMI media with 10% FBS and 5.5 mM glucose for 48 h before experiments. Islets from controls and patients with type 2 diabetes were obtained from ICR (Islet Cell Resources, CA) and cultured in Miami medium #1 (Mediatech, NJ) [50].
Mitochondria were isolated using conventional differential centrifugation [16]. Briefly, cell lines or islets were homogenized in mitochondrial lysis buffer (220 mM mannitol, 70 mM glucose, 10 mM HEPES, 1 mM EGTA, pH 7.4). Subsequently, the lysate was centrifuged at 700 g to separate nuclear and cytosolic fractions, the cytosolic fraction was further centrifuged at 7000 g at 4°C to pellet mitochondria. The isolated mitochondria were subjected either to microcystin capture assay (see below), Western blotting or mitochondrial glucokinase activity assay. For mitochondrial glucokinase activity assays, the isolated mitochondria were further purified through a 30%–70% percoll gradient by centrifugation at 20,000 rpm in a Beckman SW41 rotor for 40 min. The mitochondrial layer in the gradient was removed and washed twice and immediately used for activity assays.
Isolated mitochondria from each respective β-cell line or from islets were solubilized in the lysis buffer containing 6 mM CHAPS, 150 mM NaCl, 0.01 M sodium phosphate (pH 7.2) and 2 mM EDTA. Based on the specific high affinity of microcystin for protein phosphatase 1 (PP1) (one of the components in the BAD/GK complex), the solubilized mitochondria were incubated with microcystin beads (Upstate, NY) overnight at 4°C to pull down the BAD/GK complex. After incubation, the microcystin beads were washed and boiled in protein sample buffer. The protein bound to the microcystin beads were resolved by SDS-PAGE gels and detected by Western blotting to identify the components precipitated on the beads.
To evaluate the role of insulin or IGF-I signaling, cell lines were incubated with 100 nM of either insulin or IGF-I for 15 min at 37°C. The 15 min time point was chosen based on pilot experiments to induce signaling effects in mitochondria. Proteins were extracted from cells or islets as previously described [51]. The protein concentration of each sample was determined using a BCA kit (Pierce Biotechnology, Holmdel, NJ). The extracted proteins were resolved by SDS-PAGE, and the protein was transferred to PVDF membrane (Millipore, MA). Western blotting results were normalized to actin and quantitated by densitometry. Antibodies to the following proteins were used: Phospho-BAD, BAD, phospho-p70S6K, p70S6K, phospho-JNK1, JNK1 (Cell Signaling Technology, Boston, MA), glucokinase and protein phosphotase 1 (PP1) (Santa Cruz Biotechnology, Santa Cruz, CA), PKA (Pharmingen, San Jose, CA) and evaluated in cytosol and mitochondrial fractions.
β-cells were dispersed from islets of control or βIRKO mice as previously described [52]. Dispersed islet cells were cultured in RMPI medium with 10% FBS, antibiotics, 5.5 mM glucose on microscope coverslips and allowed to recover for 48 h. The dispersed islet cells were stained with insulin and glucagon antibodies to confirm purity of β-cells. Cells were stained with 10 nM TMRE (Molecular probe, Carlsbad, CA) for 45 min prior to glucose stimulation. Fluorescence intensity of cells was initially recorded in the basal condition followed by stimulation with 18 mM glucose. The altered fluorescence of treated cells was recorded under a confocal microscope (Zeiss, Germany) within 10 min. The fluorescence intensity in basal and treated conditions was quantitated by NIH Image J software (n=60 to 80 cells). The mitochondrial membrane potential change was calculated by averaging fluorescence intensities before and after stimulation.
Mitochondrial glucokinase activity was measured using a glucose-6-phosphate dehydrogenase (G6PDH)-coupled enzyme assay [53]. The total NADPH generated reflects glucokinase activity in mitochondria. Briefly, ~3 mg of isolated mitochondria was resuspended in reaction buffer containing 50 mM triethanolamine hydrochloride, 20 mM MgCl2, 100 mM KCl, 1 mM dithiothreitol, 0.1% bovine serum albumin, 10 mM ATP, 1 mM NADP and 4 µg/ml glucose-6-phosphate dehydrogenase (Sigma, St. Louis, MO). Then, 90 mM glucose was added to initiate the reaction and monitored by absorbance at 340 nm for 20 min at RT. In order to decrease NADPH background generated from mitochondrial respiration, all reactions were performed in the presence of mitochondrial respiration inhibitors (4 µM Rotenone, 100 nM Antimycin A and 2 µg/ml Oligomycin).
Islets were fixed with 2.5% glutaraldehyde at RT for 2 h. Ultra-thin sections (~60 nm) were cut and stained with uranyl acetate and lead citrate before being examined under JOEL Transmission Electron Microscope (Tokyo, Japan). At least five islets were chosen randomly from control or βIRKO mouse islets and ~4 randomly selected β-cells from each islet were photographed. At least 15 islet β-cells were examined from control or βIRKO islets for number and morphology of the mitochondria. Mitochondrial volume density and number were analyzed by stereology in a blinded fashion using the point counting method, as described previously [54]. Five representative images were analyzed per genotype, and four grids per image were analyzed. Average size of the mitochondria was calculated by dividing mitochondrial volume density by mitochondrial number.
Retroviral-packaging (Phoenix cells carrying the retroviral vector was kindly provided by C. R. Kahn, MD (Joslin Diabetes Center, Boston, MA). The vector encoding human insulin receptor B was obtained from I. Leibiger, Ph.D (Karolinska Institute, Stockholm, Sweden). Briefly, empty vector or vector expressing the insulin receptor was transfected using lipofectamine (Invitrogen, Carlsbad, CA) in Ø cells. The day after transfection, DMEM medium, supplemented with 10% fetal bovine serum (FBS) and 50µg/ml gentamicin (Gibco, Invitrogen, Carlsbad, CA) was replaced. Supernatant was collected 48 h post-transfection and subjected to ultracentrifugation using an SW-28 rotor at 20,000 rpm. The transparent pellet was resuspended in 500µl phosphate buffered saline (PBS, pH 7.4), aliquoted and stored at −80°C until further use. βIRKO cells were transfected with retrovirus particles. Twenty four h after transfection, 400 µg/ml hygromycin (Gibco, Invitrogen, Carlsbad, CA) was added to select the cells in which the expression vector was successfully integrated.
Oxygen consumption rates (OCR) were measured in whole cells by using a fiber-optic oxygen sensing probe as previously described [55] or the Seahorse XF24. Briefly, cells were suspended at a concentration of 2×106 cells/ml by a magnetic stirrer at 37°C in a volume of 1 ml of buffer TD (137 mM NaCl, 5 mM KCl, 0.7 mM Na2HPO4, 25 mM Tris-Cl, pH 7.4) and transferred to the oxygen chamber. Endogenous (basal) respiration was measured for 1 min. Glucose (final concentration 25 mM) or the uncoupler 2,4-dinitrophenol (DNP) was injected into the chamber (83 mM final), and stimulated rates of oxygen consumption were determined. The Seahorse machine (Seahorse Bioscience, Billerica, MA) was used to measure oxygen consumption rate in adherent cells in situ without trypsinization.
Cells were seeded in 12-well plates and incubated for 36–48 h before incubation for an additional 16 h with 2 mM glucose in DMEM with 0.1% BSA, followed by 2 mM glucose in KRB buffer for one h. The cells were then either incubated in KRB buffer containing 2 mM glucose (basal concentration) or KRB buffer containing 25 mM glucose (stimulatory concentration) for 30 min. ATP was then extracted with 0.5% TCA solution for 15 min at 4°C. An aliquot of the TCA extracted samples were diluted 20X with 0.1 M Tris-HCl, pH 7.75 buffer just before ATP measurement with the ENLITEN® ATP Assay System Bioluminescence Detection Kit (Promega, Madison, WI) according to the manufacturer's recommendation. Total protein concentration was measured using the BCA protein Assay (Pierce, Rockford, IL), and ATP generated was normalized to total protein.
Data were analyzed by Student's 't' test or analyses of variance (ANOVA) with post-hoc comparisons as appropriate. Unless otherwise indicated all experiments were performed on at least three independent occasions.
Mitochondrial purity assay. Mitochondria were isolated from β-cells as described in Materials and Methods. To examine the purity of either the mitochondrial or cytosolic fraction, a mitochondrial marker COX4 or a cytosolic marker actin were immunoblotted for each fraction.
Distribution of BAD and phospho-BADS in β cells. Control or βIRKO cells were treated with 100 nM insulin for 15 min and fractionated, cytosol, mitochondria and total lysates were examined. A, Ser136-BADS, Ser112-BADS and total BADS were immunoblotted. Tubulin and COX4 were used as loading control for cytosol and mitochondria respectively. B, Magnified image for Ser112-BADS in cytosol, mitochondria and total cell lysate. L and S denote the isoforms of BADS.
Altered mitochondrial membrane potential and mass. A. Control, βIRKO or βIRKO+hIRB (βIRKO cells re-expressing insulin receptors) cells were treated with 16.7 mM glucose and stained with TMRE. The mitochondrial membrane potential change was calculated by averaging fluorescence intensities before and after stimulation. *p<0.05, control vs. βIRKO; p=0.068, βIRKO vs. βIRKO+hIRB; n=4. B. Control, βIRKO or βIRKO cells re-expressing insulin receptors (βIRKO+hIRB) cells were stained by Mitotracker dye and analyzed by flow cytometry; *p<0.05, control vs. βIRKO, and βIRKO vs. βIRKO+hIRB; n=3.
Western immunoblotting of the five components in BAD/GK complex in islets from patients with type 2 diabetes. Islets from three controls and three patients with type 2 diabetes were fractionated and mitochondrial fractions were assessed using a mycrocystin pull-down assay. The pull-down was used to detect the five components that constitute the BAD/GK complex, using antibodies indicated in the figure and described in Methods.
We thank Nika Danial PhD for discussions, Jiang Hu for excellent assistance with maintaining mice and immunostaining, and Lindsay Huse and Liz Morgan for excellent assistance with preparation of the manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Funding: This study was supported by grants from the NIH DK RO1 68721 (R.N.K.), NIH DK RO1 67536 (R.N.K.), NIH HL RO1 73167 (E.D.A.), and the Joslin DERC P30DK36836 (Specialized Assay and Advanced Microscopy Cores). HB was supported by a grant from the German Research Foundation DFG. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Netflix signs Adam Sandler to four-film deal
Adam Sandler has signed a deal with Netflix to star in and produce four films for the streaming service.
Adam Sandler has signed a deal with Netflix to star in and produce four films for the streaming service.
Prince William and his wife have threatened to take legal action against a photographer they say has been monitoring their son Prince George…
"Twilight" will be raised from the dead for a series of short films on Facebook.
Kate Walsh plays a judge living life on the edge in NBC's new "Bad Judge".
Today's recipe comes from guest chef Doug Cady of the Woodfire Grille at the Kansas Star Casino.
Tony Bennett is the oldest performer with a No. 1 album on the Billboard 200 for "Cheek to Cheek," his jazz duets collaboration with Lady Ga…
Facebook is apologizing to drag queens and the transgender community for deleting accounts.
Click here to view photos in Dallas where a person was recently diagnosed with Ebola.
Coke and Pepsi are squaring off again, this time with natural sweeteners.
Here's a slideshow featuring the top 10 vehicles for getting tickets.
A New York boy and his cat, a principal and her dog — and lasers.
Royals beat A's 9-8 in 12 in AL wild-card thriller.
Tracy Morgan said Tuesday that he "can't believe" Wal-Mart's assertion that he and others were partly to blame for their injuries in the hig…
The Federal Communications Commission voted Tuesday to end the 1975 rule with a push from its chairman.
The next version of Microsoft's flagship operating system will be called Windows 10.


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Rangers win eighth consecutive series taking three of four from Oakland
The highlight of the series was a Colby Lewis complete game near no-hitter in the finale. He took a perfect game into the eighth and a no-hit game into the ninth after issuing a two out, four pitch walk. The A's touched him for two hits and a run in the ninth inning, but the Rangers came away with a 5-1 win.


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3 Days in New Delhi
"New Delhi is India's vibrant, bustling metropolitan capital. While 3 days isn't much time in which to explore this sprawling metropo…"
Featuring:Qutub Minar, Humayun's Tomb, Dilli Haat, &
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A wealthy and privileged high-society lady.
When Moray chose Denise, Katherine vanished from the city. Returning now with her enigmatic husband Tom Weston on her arm, she appears triumphant but her new found happiness is a guise for darker intentions. With Moray and Denise now directly under her control Katherine's plans for revenge gather pace.
Elaine Cassidy
Elaine has appeared in a huge range of film, television and theatre projects. Her breakthrough role was in Atom Egoyan's Felicia's Journey alongside Bob Hoskins. She has since worked with directors Kathryn Bigelow, Kirsten Sheridan, writer John Logan and starred with Cillian Murphy, Nicole Kidman, Colin Firth and Susan Sarandon.


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Guide To Jobbie Nooner On Gull IslandLearn more about Jobbie Nooner's history, stay safe and have a blast with our insider tips.
Ask A Detroit Expert: Essentials When Dorm ShoppingHead off to college prepared with help on dorm room essentials from an MSU expert.
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BBQ For Vegetarians: Tasty Grilling RecipesBarbecues are for vegetarians, too. Check out these three flavorful all-veggie grilling recipes.
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Well after a long week of editing this thing together, I've finally finished it.
A little background concerning the video.
Exactly a week ago, last Saturday I went to see my friend play in a local league, and since he asked me to make a couple of videos of him playing I brought along my Rebel T2i. I initially had no ideas of how I was going to put it all together so I just filmed whatever I liked. There really wasn't a plan of any kind of the finished product.
So about Monday of this week I got a really cool mix, and as I began editing the video I shot, I decided to put down the first 4 tracks of the mix since they're all short, like 1 and a half to 2 minutes each.
I then got the idea to just syncing the video to beats and fx, and melodies that I hear in the music. I mean, it's nothing new and it's been done in music videos a lot..but subconsciously (and then I became aware of it) I was sorta copying also LFO - Freak video. There's a cool section towards the end that does this technique. Again, I've synced my videos to beats and fx before though, it's nothing new.
What IS new however, and I haven't seen this anywhere, is that this is like a Video mix, accompanied by music mix. I thought that was fresh, at least to me. So I went along with it.
I like the finished product, it's far from perfect since there really wasn't an aim, or goal or a kind of structure when I was shooting it. But for the sake of experimentation. I think it's decent.
Lots of sitting in front of computer, pays off when you do tedious editing like this.
I hope you enjoy it.
All music by Phaeleh.


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Holker Holiday Cottages
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Can someone give me a quick "how to" enable? Thanks!
Type: Posts; User: jakrn; Keyword(s):
Can someone give me a quick "how to" enable? Thanks!
Thanks for the nomination! I am so appreciative!
Love this one Rachel! Grabbing it now!
Love this kit and the fact that Connie is donating 1/2 the proceeds to the Breast Cancer Research Foundation. I used the kit for a non-themed layout, which shows how versatile this kit is!
What a great deal on 2 fabulous kits! Grab them quick!!
Love these calendar templates! Plan to use all of them to make a calendar for Christmas gifts!
I love these calendar templates! Here is my March single page wall calendar using Easter Fun
If you haven't used templates, this is an awesome opportunity to pick up an awesome template set and get started!
LOVE LOVE this template pack! The scrapping possibilities are endless!
Great set of templates and a fabulous deal!
Hope to have time to get to this challenge over the weekend! Love the template Dagi!
Grabbed the template this morning......thanks for the challenge Dagi!
Thank you so much for the nomination Pippin!
I am guessing
1. To the movies
2. music festival
I voted but it was so hard to choose just 1!
Why doesn't my profile photo show on any of my forum posts, gallery comment posts, etc?
No problem for me
Thanks for sharing your story and beautiful layout. I am a retired nurse. I cared for numerous people who suffered from epilepsy. I understand what you are going through. Hugs and prayers to you and...
Thanks for all the kind "welcomes" everyone! I am excited to be here!
Thanks so much for the nomination Robin!
Hi Everyone!
My name is Joyce, aka jakrn. I am married with children and grandchildren. I have been retired since Nov 2012 and I absolutely love it! I have so much more time for scrapping now! I...
I am happy that I wake up everyday! Thanks for the chance to win! Love your templates!
Love your templates! Thanks so much for the chance to win them!!!
I just found Ginger Scraps a couple of weeks ago through link on someone's blog I think. Anyway I am glad I found you! I have been digi-scrapping for about 8 years now and I am hopelessly addicted....


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Definition of rappen in English:
From German Rappe 'raven', with reference to the depiction of the head of a raven on a medieval coin.
For editors and proofreaders
Line breaks: rap¦pen
Definition of rappen in:
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= trending


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3ds max plugin Y axis Up Right Handed coordinates
Started by afraidofdark, Jun 22 2013 03:22 PM
2 replies to this topic
#1 Members - Reputation: 249
Posted 22 June 2013 - 03:22 PM
We are using physx 3d max plugin (3ds Max DCC plug-in 2.8.9 (v03131509)) and export physx scene for 3.x engine as xml file.
The problem is, we couldn't find an option to change up axis (max is using z as up) and I strongly believe there is none
In order to fix the problem we rotate and translate relevant objects. But this trick doesn't seem to be a good solution more over I suspect it will work for constrains. (And it is problematic, we are doing a lot of tricky things to export the scene properly)
Probably there are people like us out there. How did you overcome the problem ? Thanks
#2 Crossbones+ - Reputation: 2532
Posted 22 June 2013 - 07:24 PM
You can change the up axis in 3ds max. It's in the prefs. To convert pre-existing assets, a 90 degree rotation around x applied in world space is the only solution.
#3 Members - Reputation: 249
Posted 23 June 2013 - 01:24 AM
I search through web for changing up axis of max. Many people say, there isn't such option
here is my solution which matches all axis with opengl
-- rotate selected object obj = $ rotate $ (angleaxis -90 [1,0,0]) a = $.pos.z $.pos.z = -$.pos.y; $.pos.y = a;
Edited by afraidofdark, 23 June 2013 - 01:24 AM.


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10 Critical Thinking Card Games: Easy-to-Play, Reproducible Card and Board Games That Build Kids' Critical Thinking Skills-and Help Them Succeed on Te
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