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Hotels near Shikinaen Garden
Search hotels near Shikinaen Garden in Naha
Last minute Naha deals
- Villa Coast Nishimachi Guesthouse in Okinawafrom $78$54
- Okinawa NaHaNa Hotel & Spafrom $202$134
- Hotel Palm Royal Nahafrom $83$58
- White Terrace Tsuboya Guesthouse in Okinawafrom $67$47
- Rihga Royal Gran Okinawafrom $214$161
Trending now in Naha
- Most bookedOkinawa Miyako Hotel
828 people looked at this hotel in the last hour
Most recent review
"It is not to access this hotel from Monorail station with my family without rent-car. but the hotel room has 4 single bed and good breakfast. It is very short stay for my family before leaving to the northern Okinawa. but I can recommend you this hotel when considering the price."
A Traveller, Jun 2016, US
358 people looked at this hotel in the last hour
Most recent review
"The hotel was closing and will be operated by Doubletree by Hilton in July."
A Traveller, Apr 2016, AS
170 people looked at this hotel in the last hour
Most recent review
"We had a wonderful stay at the hotel. There is nothing we can complain about the hotel. The breakfast was delicious."
A Traveller, Dec 2015, AS
138 people looked at this hotel in the last hour
Most recent review
"The Best Western Naha Inn was our second stay in the past three years. Situated conveniently next to a elevated tram station (very quiet). We elected to buy a special two day tram pass to take us where we wanted to go. Breakfast was a bargain...only 700 Yen (less than $7.00) for a reasonable sele..."
A Traveller, May 2016, US
125 people looked at this hotel in the last hour
Most recent review
"Good location. Near the shopping street & easy walk to heritage walled city. It's a bus stop of local tour. Good staff & helpful."
A Traveller, Dec 2015, HK
108 people looked at this hotel in the last hour
Most recent review
"This hotel was awesome and located right at the tip on Okinawa's international street. We were a little disappointed that our Japanese spec car would not fit in the parking garage but actually paid less parking around the corner. The one thing I would suggest to the hotel is putting a sign outsid..."
A Traveller, Jan 2016, AS
95 people looked at this hotel in the last hour
Most recent review
"Nice and quiet stay, clean, modern and in very good condition. Best to hire a car to be able to see everything, parking is available on site. There was no crockery or anything in the kitchen so being self sufficient is a bit hard."
A Traveller, Jun 2016, AU
74 people looked at this hotel in the last hour
Most recent review
"The hotel located at the heat of Naha, and eazylly accessable from the airport by the Nah's monorail. The staff are very friendly and helpfull. Thay gave us a night insted the one we miss, which they didn't have to do. The only thing about the hotel is the over chared price for a max 3 stars hotel."
A Traveller, Apr 2016, IL
26 people looked at this hotel in the last hour
Most recent review
"We stayed for one night in August 2015. Booked the same night as we checked in, about 45 min before we arrived at the hotel. After arrival the staff quickly accommodated us in a clean room with a nice big double bed. The room had only one small frosted window that led to an alley, otherwise the r..."
A Traveller, Aug 2015, US
22 people looked at this hotel in the last hour
Map of hotels near Shikinaen Garden
- International Street
- Himeyuri Peace Museum
- DFS Galleria Okinawa
- Shrikinjocho Stone-Path Road
- Tsuboya Pottery Museum
- Naminoue Beach
- Okinawa Peace Park
- Shurijo Castle
- Okinawa Outlet Mall Ashibinaa
- Makishi Public Market
- Okinawa Prefectural Museum and Art Museum
- Kinjo Stone-Paved Road
- Tsushima-maru Memorial Museum
- Naminouegu Shrine
- Icchu Kenji Monument
- Peace Street
- Yogi Park
- Ryutan Site
- Sueyoshi Park
- Fukushuen Garden
Hotels in Naha near Shikinaen Garden
Are you looking for a cheap Shikinaen Garden hotel, a 5 star Shikinaen Garden hotel or a family friendly Shikinaen Garden hotel? You just landed in the best site to find the best deals and offers on the most amazing accommodations for your stay.
When you search for hotels near Shikinaen Garden with Hotels.com, you need to first check our online map and see the distance you will be from Shikinaen Garden, Japan.
Our maps are based on hotel search and display areas and neighborhoods of each hotel so you can see how close you are from Shikinaen Garden and refine your search within Naha or Japan based on closest public transportation, restaurants and entertainment so you can easily get around the city. All the hotels details page show an option for free or paid onsite parking.
If you wish to see the hotels with the highest featuring discounts and deals near Shikinaen Garden, simply filter by price/ average nightly rate. We recommend you filter by star rating and read our genuine guest reviews so you can get the best quality hotel with the best discount.
One of the new features on Hotels.com guest reviews is that also show reviews from Expedia for Shikinaen Garden hotels and the TripAdvisor Shikinaen Garden hotels reviews so you can make sure that you checking with a reliable source. See the review scores on our Naha hotel information pages.
Make the most out of your family vacation when you book your accommodation with Hotels.com – book your hotel near Shikinaen Garden, Naha after reviewing the facilities and amenities listed for each hotel.
After booking your hotel near Shikinaen Garden, expect to receive your reservation confirmation in the mail in less than 10 minutes. The confirmation email contains more information on all nearby attractions, local directions and weather forecast, so you can better plan the days during your trip.
After getting the best hotel rates you can still save more by winning 1 free night! That's right, book 10 nights in any hotel near Shikinaen Garden, Naha and after you sign up for the Welcome Rewards program, you are eligible hotel you receive 1 night free*
The best hotel deals are here: We have Shikinaen Garden hotel deals, Shikinaen Garden last minute deals and offers to get you the cheapest Shikinaen Garden hotel with our lowest price guarantee.


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PHILADELPHIA -- The Philadelphia Phillies activated All-Star second baseman Chase Utley from the disabled list, less than seven weeks after he had thumb surgery.
Utley tore a ligament in his thumb sliding into second base in a game at Cincinnati on June 28. He had surgery on July 1 and was expected to miss at least eight weeks. But Utley returned the lineup for the start of a three-game series against San Francisco on Tuesday night and went 0-for-5 in a 9-3 victory.
"I felt pretty good," said Utley, who received a standing ovation when he came up in the first. "Obviously, there's room for improvement."
To make room for Utley, infielder/outfielder Greg Dobbs was designated for assignment. Dobbs was hitting .191 with four homers and 14 RBIs in 76 games.
Utley was batting .277 with 11 homers and 37 RBIs before his return.
Information from The Associated Press was used in this report.


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6pm to 7:15pm Fri, Aug 16, 2013
Venue: Surfari Stand Up Paddle & Surf
26 Central St, Manchester, MA 01944Contact:
Christian Del Rosario
0 people saved this
A weekly group paddle for stand up paddlers who want to out together and explore places they wouldn't normally go alone. A great option for those who don't have a stand up board and want to get out on the water. This is not a lesson and we will not be teaching basics. Cost is $20 per person.
Get in the Spirit!
In 1637, the Commonwealth of Massachusetts proclaimed that no person should be in a tavern �...
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LOS ANGELES -- Heading into the start of this series, the Los Angeles Dodgers were taking ownership of the Arizona Diamondbacks, having won each of the first five meetings this season and after clinching the National League West in Phoenix and making that infamous celebratory swim.
But the Diamondbacks got an extra-innings win Friday, and through three innings it looked as if the tides would further shift away from Los Angeles on Saturday night at Dodger Stadium.
However, a second look at an arm slinging its first pitches in the big leagues got the Dodgers' lineup going as it erased a four-run deficit to win 8-6.
A costly error and four Diamondbacks hits in the third inning led to that 4-0 cushion, the big hit being Paul Goldschmidt's two-run single. Through that third inning the Dodgers had managed only one hit and had struck out five times against Arizona rookie Mike Bolsinger, who was making his major league debut.
The offense got going in the fourth, though, striking for three runs, all via an Andre Ethier home run. From that point, the Dodgers teed off on Bolsinger and reliever Oliver Perez for another five runs in the fifth.
How it happened: Dan Haren retired the first six Diamondbacks he faced, but he gave up four runs in the third inning while the Dodgers were held hitless the first time through the lineup. The second time around the order for rookie Bolsinger turned horriffic. He gave up seven hits starting with leadoff man Dee Gordon's single. Bolsinger was charged with seven runs, six of them earned.
Hits: After a brutal third inning in which he gave up four runs -- only one earned -- and four hits, Haren settled down and gave up three hits and one run in his next 4 1/3 innings.
Misses: Haren never would have allowed all those third-inning runs had shortstop Hanley Ramirez not mishandled a feed from second baseman Gordon with one out and a runner on first. Gordon got a ground ball from Bolsinger and fired to Ramirez at second base to start a potential inning-ending double play, but Ramirez couldn't transfer the ball to his bare hand and both runners were safe. From there the flood gates opened.
Stat of the game: Matt Kemp is 11-for-11 in stolen-base attempts since the start of last season, including 2-for-2 this season after stealing third base Saturday.
Up next: Josh Beckett makes his third start of the season for the Dodgers, and will be opposed by Arizona's Josh Collmenter. Beckett threw five shutout innings in San Francisco in his last start, but he walked five hitters.


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The Panama Canal Authority said it is confident in the process it uses to move ships through the new locks at the canal, following an accident last week that damaged the Xin Fei Zhou after it made contact with one of the walls at the Agua Clara Locks.
The TMS provider was acquired by fellow logistics software firm Kewill in April, and the companies are progressing on merging products and organizations, Lean executives said in a briefing.
The U.N. Economic Commission for Europe said China has ratified the TIR Convention, which it says will further streamline cross-border transportation for cargo moving between China and Europe.
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Captain John Loftus, who was fired in 2013 after working for Horizon Line for 20 years, has been awarded $655,000 in back wages, $225,000 in punitive damages, $10,000 for emotional distress, and more than $200,000 in legal costs.
The parcel carrier and logistics provider's DHL Freight division has expanded its rail transport offerings to and from Asia and North Africa via its hub at Duisburg to include direct links and consolidation services.
The rating agency acted negatively to the idea that the A.P. Moller - Maersk conglomerate could potentially choose to divide into separate companies, noting the split could hurt the group's business diversification.


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Flavors of Melbourne Small-Group Food Walking Tours
Flavors of Melbourne Small-Group Food Walking Tours information and booking
Tour description provided by Viator
Celebrate Melbourne's cultural diversity on a small-group food walking tour of the flavors of India, Turkey or Africa. Melbourne is a multicultural melting pot, home to some of Australia's largest migrant communities. See how these cultures, through their food, have helped shape Melbourne into Australia's cultural capital. You have three cuisines to choose from: Take a journey through the Indian quarter of central Melbourne, or Dandenong, Melbourne's Little India; taste the flavors of Turkey on a journey through the Turkish- influenced streets of Brunswick; or enjoy African 'soul food' in the inner-city suburb of Footscray. Each tour includes a progressive meal at three cafes or restaurants.
Indian Food Walking TourGet an insight into the life of Indian-Australians on a food walking tour through central Melbourne or Dandenong, Melbourne's Little India neighborhood. From coconut milk and the seafood delicacies of Goa to the curries of Kahmir, Indian food varies from region to region, reflecting the people of the ethnically diverse subcontinent that now call Australia home.From Federation Square or Dandenong, your guide will lead you to some of Melbourne's hidden gems. Visit an Indian store where the shelves are stocked with a range of herbs and spices, as well as Sikh turbans and hundreds of silk saris. Browse the aisles filled with all things glittery and get a true taste of India. Next, your progressive meal begins as you sample different regional dishes at three local Indian cafes and restaurants. Turkish Food Walking TourTake a journey through Brunswick, the cultural heart of Melbourne, where flavors of the Middle East are dominant. As you walk with your guide, enjoy a progressive meal at three local Turkish cafés. Tantalize your taste buds with a plate of meze (appetizers) washed down with a cup of cinnamon tea. Next, discover Turkey's answer to pizza as you try an authentic pide , savor flavorful spiced rice, and taste classic dolmas (stuffed cabbage leaves). End your food journey with delicious desserts and sweet treats like baklava and muhalleb.African Food Walking TourSoak up the distinctive cultural atmosphere of Footscray, home to Melbourne's African community. Discover Africa's regional differences as you enjoy a progressive meal at three African eateries. Learn about the culture and etiquette of eating everything from biltong (meat jerky) to injera (Ethiopian bread). Then, visit a local grocery store to see the different spices, foods and cooking utensils on display.
What's included
- Small-group walking tour
- Progressive meal at three eateries
- Complimentary glass of wine or drink
- Local guide
What isn't included
- Food and drinks, unless specified
- Hotel pickup and drop-off


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New Halo Reach shots blow our minds
Halo: Reach is looking awesome, going by these multiplayer shots. And we do mean 'properly awesome'.
Get them over at 1UP, where the site's gone live with a massive hands-on of the multiplayer beta you'll be getting your hands on in two-and-a-half weeks.
The preview mentions four new modes for the full thing, featuring Headhunter, Stockpile, Generator Defense and Invasion. It looks properly mental, so give it a look.
Halo: Reach releases this fall for Xbox 360, with a multiplayer beta due to kick off two-and-a-half weeks from now on May 3.
Bungie's saying you should all look forward to E3 when they show off the game. And look forward to it, we shall.
Sometimes we include links to online retail stores. If you click on one and make a purchase we may receive a small commission. For more information, go here.


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[WARNING! PROJECT IS NOT READY TO USE. DO NOT DOWNLOAD FILES FROM FILES REPOSITORIES!] ModernCMS - a powerful php engine that can up your website. You can create your own portal, forum, blog, website, company website, multimedia portal and other! Visit site http://modern-cms.sourceforge.net/ for more information!1 weekly downloads
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Definition of Chile saltpeter in English:
Chile saltpeter
Another term for sodium nitrate, especially as a commercial product mined in Chile and other arid parts of the world.
Example sentences
- They also get then some Chile saltpetre to get the growth in it again.
- In 1913 the only commercial fertilizer was Chile saltpetre, and it was running out.
- These products had long helped to boost farmers' yields, and DAVV's hardest competition came initially from imported Chile saltpetre.
For editors and proofreaders
Syllabification: Chil·e salt·pe·ter
Definition of Chile saltpeter in:
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= trending


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Book online or call +44 (0)1775 843417 at standard rates.
Situated a few steps from Blackpool Promenade, this family-friendly hotel has free Wi-Fi, free parking, and a well-stocked bar. The town's seafront tramway provides The Hurstmere with easy access to Blackpool Tower and the famous Pleasure Beach. Each bright and cheerful en suite bedroom features an LCD TV, a welcome tray with tea/coffee-making facilities and complimentary toiletries. Guests have access to ironing facilities and hairdryers. Freshly cooked breakfasts are served each morning in The Hurstmere's dining room, with vegetarian options and free baby food for younger visitors. The hotel bar area has a range of indoor activities on offer such as pool, darts, karaoke and arcade games. Just a 10-minute stroll along the beach from the Sandcastle Waterpark, and 2.5 miles from Blackpool Zoo, the hotel is also under 10 minutes' walk from Blackpool South train station.
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When I use knitr to build an HTML document out of the following code:
Chunk Output
Outside a chunk.
```{r chunk1, results='asis'}
cat('Inside a chunk\n\n')
for (i in 1:3) {
cat('* Inside loop #', i, '\n')
cat('Outside a loop, but still inside the first chunk')
Between chunks.
```{r chunk2, results='asis'}
cat('Inside second chunk')
I get output where the code in
chunk1 is interleaved with the output of the
cat statements. Interestingly, the output within the
for loop is output as a single block.
I would prefer to have all of the code from
chunk1 to appear first, followed by all of the output from
chunk1. Is there a way to ask Rmarkdown/knitr to avoid the more granular interweaving that it's currently doing?


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Our equestrian tack and supply store has thousands of horse related items for you to browse and compare prices between several online tack stores.
Find Western and English tack, riding apparel, horse vitamins & supplements, as well as a collection of horse toys and gifts.
Glittery pony charm necklace with iridescent beads. This necklace is 16'' and stretchy to fit most kids with a 1'' charm. All kids jewelry is lead safe.


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Poor Greekmonkey!
Shut the hell up #$%$ wipe. GD liar. Go to hell
Read it and weep shorty.....
Wireless postpaid ARPU increased quarterly year-over-year from $57.65 to $61.18, while sequentially ARPU increased from $60.88 to $61.18. Quarterly year-over-year and sequential ARPU benefited from higher monthly recurring revenues primarily as a result of the premium data add-on charges for smartphones introduced since the first quarter of 2011.
Good luck. because the idiot, retard, liars are in full mode. biggest buch of pricks. Screw them all to hell Snuff. I'll wait to see the profit in 8 months.
Sentiment: Strong Buy
No it didn't flunky......
Wireless retail service revenues of $7.2 billion for the quarter represent an increase of nearly 5 percent compared to the third quarter of 2011 and flat compared to the second quarter of 2012. The quarterly year-over-year improvement was primarily due to higher postpaid ARPU as well as an increased number of net prepaid Sprint platform subscribers, partially offset by lower Nextel postpaid and prepaid subscribers.
You get dumber by the post!
ARPU on the Sprint Platform;
$63.21 as of 9/30/12
$63.38 as of 6/30/12
Poor Snuffy is looking at "overall" ARPU (including Nextel). He can't see that the more of those lower ARPU customers flee, the "overall" ARPU goes up. BUT, my point is that the Sprint Platform (which is all Sprint will have in 9 months) is actually FALLING slightly.


text:
Related Regions:
North America,
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I recently visited this resort from out of town. I was in high hopes of a fun time & a mini vacation. The service in the bar/dining area was awful & slow. M...
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I have been visiting Boyne Highlands for years. 1982 was my first visit and I fell in love. I now visit at least three times a year with friends. The atm...
We've been coming for years and love it. What's not to like: good variety of runs, great food, heated pool, helpful ski instructors. While the Rockies have ...
I have rented from Boyne Highlands once in the 7 years that I have lived right across the street. It was the worst experience ever. I get treated better wa...
Our family has been driving up to Boyne Highlands for 10 years for their "Canada Week" in March and we've never been disappointed overall. This is clearly ...
Compared to Boyne Mountain, BH is maybe a bit more intermediate, but has the same quality snow, lifts, service and variety as the mountain. hills have a ni...
Just got back from BH (arrived Sunday, Jan. 7, 2007 and left Thursday the 11th.) Had a fantastic time, as usual. True, we worried there was no snow but the ...
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Panasonic SC-ZT2 home theatre system
This wireless home theatre system can connect to a 3D TV and 3D Blu-ray player
- Easy to set up, good sound from speakers at low and moderate volume levels
- Requires three power points, expensive for a stereo system, mediocre surround effect, poor low-end response at higher volume levels
Bottom Line
Panasonic's SC-ZT2 is an interesting home theatre system. It's a stereo setup that mimics surround sound, and its thin speakers put out a surprising amount of audio. It is painfully expensive though, so it appeals more on style than value for money.
Price$ 1,999.00 (AUD)
Best Deals (Selling at 1 store)
The Panasonic SC-ZT2 is a home theatre system with two floor-standing stereo speakers and a slimline A/V receiver. It's an extremely compact and convenient system that suits space- and style-conscious buyers, but we're not sold on its surround sound abilities or the high price tag.
A lot of thought has clearly gone into the design of the Panasonic SC-ZT2's floor-standing speakers, and the audio-visual receiver has a swathe of inputs. Three HDMI inputs and one video passthrough output makes the Panasonic SC-ZT2 suitable for connecting multiple digital A/V devices like Blu-ray players or media centre PCs simultaneously. It also supports Full HD 3D video passthrough, so you can connect your 3D Blu-ray player and 3D television without problems.
The design of the SC-ZT2's speakers is interesting. The majority of each cylindrical floor-standing speaker is around an inch in diameter, with four of Panasonic's 'slim and flat' speaker drivers arranged inside. The base of each speaker is significantly larger and heavier because it houses a 5in woofer driver to provide some low-end reinforcement. The speakers are easy to move around, but the large base does prevent them sitting flush against a low entertainment unit or bench.
The Panasonic SC-ZT2's speakers connect to the receiver wirelessly, with uncompressed stereo audio over the 2.4GHz radio band. This makes placement of the speakers very simple: you don't need to run cables. However, the downside is that you'll require a power point for each speaker as well as the receiver.
Each speaker is rated at 80 Watts RMS, giving the stereo system a total of — yep, you guessed it — 160W. The Panasonic SC-ZT2 has enough power to perform capably at low and moderate volume levels with good sound quality. If you're not happy with the audio from the SC-ZT2, several different equaliser settings make it easy to dial in more bass or treble or mid-range without introducing distortion.
Once set up, sound quality from the Panasonic SC-ZT2 is impressive given the speakers' compact size. High notes are clear and dialogue is crisply represented at low to moderate volume levels, with good mid-range reinforcement from the woofers. At higher volumes the system does get slightly harsh in treble frequencies, while low-end tapers off at maximum volume. The lack of a dedicated subwoofer means you won't get room-shaking bass response, but for moderate volume listening levels (our preferred movie volume) the Panasonic SC-ZT2 does well for a compact system.
One area the system falters is its surround-sound reproduction. The stereo soundstage of the Panasonic SC-ZT2's speakers is good, with music having noticeable separation between channels, but we struggled with positional 5.1 audio from a Blu-ray disc. Try as it might, the SC-ZT2 can't simulate the rear channels of a true 5.1-channel surround sound audio system.
If you're looking for a stylish and convenient speaker system that'll work perfectly with a 3D TV and 3D Blu-ray disc player, Panasonic's SC-ZT2 is worth considering. Its style and wireless speakers do come at a cost, though — weigh this up against competitors' offerings to see what suits your budget best.
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Kathy Cassidy
First impression on unpacking the Q702 test unit was the solid feel and clean, minimalist styling.
Anthony Grifoni
For work use, Microsoft Word and Excel programs pre-installed on the device are adequate for preparing short documents.
Steph Mundell
The Fujitsu LifeBook UH574 allowed for great mobility without being obnoxiously heavy or clunky. Its twelve hours of battery life did not disappoint.
Andrew Mitsi
The screen was particularly good. It is bright and visible from most angles, however heat is an issue, particularly around the Windows button on the front, and on the back where the battery housing is located.
Simon Harriott
My first impression after unboxing the Q702 is that it is a nice looking unit. Styling is somewhat minimalist but very effective. The tablet part, once detached, has a nice weight, and no buttons or switches are located in awkward or intrusive positions.
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FR&D (Faculty Research & Development) is a standing committee of the Faculty whose primary work is receiving, evaluating, and approving proposals related to faculty research and development (see Faculty Handbook I-5). All proposals for FR&D awards are due in the fall, between the months of September and November, and are for awards in the following summer or academic year. FR&D does not award funding for a current academic year and does not have a spring cycle of awards. Due dates for specific awards include the following for academic year 2014-15:
Reassigned-time Fellowships: Friday, September 18
Full-Year/Full-Pay Sabbatical: Thursday, October 1
Sabbaticals: Friday, October 16
All other FR&D awards: Monday, November 2
Detailed information about specific awards can be found on the Faculty Funding site, where awards for FR&D and other sources are categorized under the headings of "Funds for Stipend," "Funds for Replacement," and "Funds for Reimbursement."
(In order to ensure submitted proposals are viewable for review by the committee, faculty should aim to submit their proposals ahead of the due date. FR&D suggests one week ahead of due dates. Proposals not received by the due date are not visible and, thus, not reviewed by the committee.)
Proposals for all FR&D awards are submitted online. However, faculty develop proposals in Word, save them as PDF, and upload them online as part of the application process.
Are you ready to begin developing your proposal now? You do not have to wait for the system to be open to begin drafting a proposal; a standard set of questions applied to all proposals can be found here and used to begin developing proposals at one's leisure.
The committee seeks good, compelling proposals from the faculty.
FR&D receives a number of questions each year about awards, application processes, etc. Some will be unique and should be addressed to FR&D Chair, Janet Cope. But this FAQ offers answers to some of the most common questions.


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The final stretch of Thurmon Tanner Parkway won't be finished by Dec. 31 as long projected.
A new poll shows most Americans are frustrated over the difficulty in getting rid of bad teachers, while most also believe teachers are underpaid.
Firefighters have been busy chasing weather-related house fires since Monday.
Some local school systems will be closed Wednesday due to inclement winter weather:
The state's upcoming legislative session will be one big puzzle, Gov.-elect Nathan Deal told lawmakers this afternoon.
Traditional high schools are working to meet the needs of a new breed of students - those graduating from the county's schools of choice that focus on self-direction.
The Rotary Club of Gainesville is accepting nominations for its Man and Woman of the Year awards.
Tri-state water war negotiations are slowly inching forward, but legislators must prepare to make decisions in the next session about the state's water supply, officials said Monday.
The South Hall Tag Office at 3640 Mundy Mill Road, Suite 140, Oakwood, will be unable to accept payments this morning.
Art Jetton, a 30-year veteran of the Hall County Sheriff's Office who helped start the department's dive team, died Sunday.
The city of Dahlonega is officially a contender for the Georgia Music Hall of Fame.
Oakwood has been approved for a $25,000 grant to help put up emergency weather sirens at three locations around the city, including Oakwood Elementary School, which was smacked by an August 2008 tornado.
Problems with aging and deteriorating school buildings and outstanding bond debt are among the reasons area school systems will ask voters for a sales tax extension.
With the state's budget woes looming, lawmakers voted Monday to cancel a scheduled pay increase for themselves for at least a year.
With the state's budget woes looming, lawmakers voted Monday to cancel a scheduled pay increase for themselves for at least a year.
Hall County firefighters are investigating a Monday blaze that injured one person.
Hall County firefighters are investigating a Monday blaze that injured one person.
Page 1137 of 1849
Peter Boychuk knows about business online.
The bodies of two women were found Saturday after a boat overturned the day before on Lake Lanier, according to the Georgia Department of Natural ...
Atlanta's Olympic organizers had a bit of a problem as they identified venues for the 1996 Olympic Games they were awarded in 1990.
When Billy Payne, Atlanta's Olympic architect, looks back on his crowning achievement from 20 years ago, one of the bright spots is Gainesville's ...
The Lanier Partners of North Georgia launched their eighth annual Pirates of Lake Lanier Charity Poker Run on Saturday.
One person was burned in a boat fire Saturday at Holiday Marina on Lake Lanier.
It's like something out of a "Seinfeld" episode, where a bright red light from a Kenny Rogers chicken joint shines day and night through ...
Nearly 125 elementary school students "graduated" from the fifth annual RISE - Real Interactive Summer-learning Experience) - program Friday morning.
A large, airy storage area at the Georgia Mountain Food Bank is usually stocked full with canned and boxed foods and goods. But Friday afternoon ...
A Hall County woman formerly charged with hindering the apprehension of a fugitive has received new charges, according to authorities.
Four people remained missing Friday night after a boat overturned on Lake Lanier earlier in the afternoon near Cocktail Cove.
Davis Middle School is one of five schools selected to participate in the Georgia Grown Test Kitchen program for the upcoming year.
A man Friday demanded access to the vault of a Buford bank and left with a sum of money, according to authorities.
Gainesville and Hall County officials met with civic and religious leaders Thursday night at the city's public safety complex for a roundtable discussion aiming ...
Braving winter weather
Page 8 of 8
Contents of this site are © Copyright 2016 The Times, Gainesville, GA. All rights reserved. Privacy policy and Terms of service


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The same populations of brain cells encode memories that occur close together in time, according to new research.
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May 1, 2016|
Science is messy. So lay it out, warts and all.
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Defeating cancer is many times more difficult than planting a flag on our lunar satellite.
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October 1, 2015|
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June 1, 2015|
Reconstructing the past using ancient DNA
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Cancer treatment becomes more and more personal.
November 1, 2014|
For neuroscientists, experimental results converge to help crack the case of how the brain functions.
October 1, 2014|
An issue highlighting advances in vision research
August 1, 2014|
When proverbs come true


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Cytoplasmic γ-actin and tropomodulin isoforms link to the sarcoplasmic reticulum in skeletal muscle fibers
Gokhin, David S.
Fowler, Velia M.
The Journal of Cell Biology
Tropomodulins, cytoplasmic γ-actin, and small ankyrin 1.5 mechanically stabilize the sarcoplasmic reticulum and maintain myofibril alignment in skeletal muscle fibers.
The sarcoplasmic reticulum (SR) serves as the Ca2+ reservoir for muscle contraction. Tropomodulins (Tmods) cap filamentous actin (F-actin) pointed ends, bind tropomyosins (Tms), and regulate F-actin organization. In this paper, we use a genetic targeting approach to examine the effect of Tmod1 deletion on the organization of cytoplasmic γ-actin (γcyto-actin) in the SR of skeletal muscle. In wild-type muscle fibers, γcyto-actin and Tmod3 defined an SR microdomain that was distinct from another Z line–flanking SR microdomain containing Tmod1 and Tmod4. The γcyto-actin/Tmod3 microdomain contained an M line complex composed of small ankyrin 1.5 (sAnk1.5), γcyto-actin, Tmod3, Tm4, and Tm5NM1. Tmod1 deletion caused Tmod3 to leave its SR compartment, leading to mislocalization and destabilization of the Tmod3–γcyto-actin–sAnk1.5 complex. This was accompanied by SR morphological defects, impaired Ca2+ release, and an age-dependent increase in sarcomere misalignment. Thus, Tmod3 regulates SR-associated γcyto-actin architecture, mechanically stabilizes the SR via a novel cytoskeletal linkage to sAnk1.5, and maintains the alignment of adjacent myofibrils.
Related Articles
Tropomodulin Capping of Actin Filaments in Striated Muscle Development and Physiology
Gokhin, David S.
Fowler, Velia M.
Journal of Biomedicine and Biotechnology
Efficient striated muscle contraction requires precise assembly and regulation of diverse actin filament systems, most notably the sarcomeric thin filaments of the contractile apparatus. By capping the pointed ends of actin filaments, tropomodulins (Tmods) regulate actin filament assembly, lengths, and stability. Here, we explore the current understanding of the expression patterns, localizations, and functions of Tmods in both cardiac and skeletal muscle. We first describe the mechanisms by which Tmods regulate myofibril assembly and thin filament lengths, as well as the roles of closely related Tmod family variants, the leiomodins (Lmods), in these processes. We also discuss emerging functions for Tmods in the sarcoplasmic reticulum. This paper provides abundant evidence that Tmods are key structural regulators of striated muscle cytoarchitecture and physiology.
Related Articles
Tropomodulin isoforms regulate thin filament pointed-end capping and skeletal muscle physiology
Gokhin, David S.
Lewis, Raymond A.
McKeown, Caroline R.
Nowak, Roberta B.
Kim, Nancy E.
Littlefield, Ryan S.
Lieber, Richard L.
Fowler, Velia M.
The Journal of Cell Biology
In skeletal muscle fibers, tropomodulin 1 (Tmod1) can be compensated for, structurally but not functionally, by Tmod3 and -4.
During myofibril assembly, thin filament lengths are precisely specified to optimize skeletal muscle function. Tropomodulins (Tmods) are capping proteins that specify thin filament lengths by controlling actin dynamics at pointed ends. In this study, we use a genetic targeting approach to explore the effects of deleting Tmod1 from skeletal muscle. Myofibril assembly, skeletal muscle structure, and thin filament lengths are normal in the absence of Tmod1. Tmod4 localizes to thin filament pointed ends in Tmod1-null embryonic muscle, whereas both Tmod3 and -4 localize to pointed ends in Tmod1-null adult muscle. Substitution by Tmod3 and -4 occurs despite their weaker interactions with striated muscle tropomyosins. However, the absence of Tmod1 results in depressed isometric stress production during muscle contraction, systemic locomotor deficits, and a shift to a faster fiber type distribution. Thus, Tmod3 and -4 compensate for the absence of Tmod1 structurally but not functionally. We conclude that Tmod1 is a novel regulator of skeletal muscle physiology.
Related Articles
Tropomodulin1 is Required in the Heart but not the Yolk Sac for Mouse Embryonic Development
McKeown, Caroline R.
Nowak, Roberta B.
Moyer, Jeannette
Sussman, Mark A.
Fowler, Velia M.
Circulation research
Tropomodulin1 (Tmod1) caps the pointed ends of actin filaments in sarcomeres of striated muscle myofibrils and in the erythrocyte membrane skeleton. Targeted deletion of mouse Tmod1 leads to defects in cardiac development, fragility of primitive erythroid cells, and an absence of yolk sac vasculogenesis, followed by embryonic lethality at E9.5. The Tmod1 null embryonic hearts do not undergo looping morphogenesis and the cardiomyocytes fail to assemble striated myofibrils with regulated F-actin lengths. To test whether embryonic lethality of Tmod1 nulls results from defects in cardiac myofibrillogenesis and development, or from erythroid cell fragility and subsequent defects in yolk sac vasculogenesis, we expressed Tmod1 specifically in the myocardium of the Tmod1 null mice under the control of the α-myosin heavy chain promoter, Tg(αMHC-Tmod1). In contrast to Tmod1 null embryos, which fail to undergo cardiac looping and have defective yolk sac vasculogenesis, both cardiac and yolk sac morphology of Tmod1-/-Tg(αMHC-Tmod1) embryos are normal at E9.5. Tmod1-/-Tg(αMHC-Tmod1) embryos develop into viable and fertile mice, indicating that expression of Tmod1 in the heart is sufficient to rescue the Tmod1 null embryonic defects. Thus, while loss of Tmod1 results in myriad defects and embryonic lethality, the Tmod1-/- primary defect is in the myocardium. Moreover, Tmod1 is not required in erythrocytes for viability, nor do the Tmod1-/- fragile primitive erythroid cells affect cardiac development, yolk sac vasculogenesis, or viability in the mouse.
Cardiac Development; Myofibrillogenesis; Looping Morphogenesis; Yolk Sac Vasculogenesis; Erythroid Stability
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Tropomodulins: pointed-end capping proteins that regulate actin filament architecture in diverse cell types
Yamashiro, Sawako
Gokhin, David S.
Kimura, Sumiko
Nowak, Roberta B.
Fowler, Velia M.
Cytoskeleton (Hoboken, N.J.)
Tropomodulins are a family of four proteins (Tmods 1–4) that cap the pointed ends of actin filaments in actin cytoskeletal structures in a developmentally regulated and tissue-specific manner. Unique among capping proteins, Tmods also bind tropomyosins (TMs), which greatly enhance the actin filament pointed-end capping activity of Tmods. Tmods are defined by a tropomyosin (TM)-regulated/Pointed-End Actin Capping (TM-Cap) domain in their unstructured N-terminal portion, followed by a compact, folded Leucine-Rich Repeat/Pointed-End Actin Capping (LRR-Cap) domain. By inhibiting actin monomer association and dissociation from pointed ends, Tmods regulate regulate actin dynamics and turnover, stabilizing actin filament lengths and cytoskeletal architecture. In this review, we summarize the genes, structural features, molecular and biochemical properties, actin regulatory mechanisms, expression patterns, and cell and tissue functions of Tmods. By understanding Tmods' functions in the context of their molecular structure, actin regulation, binding partners, and related variants (leiomodins 1–3), we can draw broad conclusions that can explain the diverse morphological and functional phenotypes that arise from Tmod perturbation experiments in vitro and in vivo. Tmod-based stabilization and organization of intracellular actin filament networks provide key insights into how the emergent properties of the actin cytoskeleton drive tissue morphogenesis and physiology.
Related Articles
Calpain-mediated proteolysis of tropomodulin isoforms leads to thin filament elongation in dystrophic skeletal muscle
Gokhin, David S.
Tierney, Matthew T.
Sui, Zhenhua
Sacco, Alessandra
Fowler, Velia M.
Molecular Biology of the Cell
Calpain-mediated proteolysis of the thin filament pointed-end–capping protein tropomodulin results in actin subunit association onto pointed ends and increased thin filament lengths in two different murine models of Duchenne muscular dystrophy. This mechanism affects different skeletal muscles in a use- and disease severity–dependent manner.
Duchenne muscular dystrophy (DMD) induces sarcolemmal mechanical instability and rupture, hyperactivity of intracellular calpains, and proteolytic breakdown of muscle structural proteins. Here we identify the two sarcomeric tropomodulin (Tmod) isoforms, Tmod1 and Tmod4, as novel proteolytic targets of m-calpain, with Tmod1 exhibiting ∼10-fold greater sensitivity to calpain-mediated cleavage than Tmod4 in situ. In mdx mice, increased m-calpain levels in dystrophic soleus muscle are associated with loss of Tmod1 from the thin filament pointed ends, resulting in ∼11% increase in thin filament lengths. In mdx/mTR mice, a more severe model of DMD, Tmod1 disappears from the thin filament pointed ends in both tibialis anterior (TA) and soleus muscles, whereas Tmod4 additionally disappears from soleus muscle, resulting in thin filament length increases of ∼10 and ∼12% in TA and soleus muscles, respectively. In both mdx and mdx/mTR mice, both TA and soleus muscles exhibit normal localization of α-actinin, the nebulin M1M2M3 domain, Tmod3, and cytoplasmic γ-actin, indicating that m-calpain does not cause wholesale proteolysis of other sarcomeric and actin cytoskeletal proteins in dystrophic skeletal muscle. These results implicate Tmod proteolysis and resultant thin filament length misspecification as novel mechanisms that may contribute to DMD pathology, affecting muscles in a use- and disease severity–dependent manner.
Related Articles
Different Localizations and Cellular Behaviors of Leiomodin and Tropomodulin in Mature Cardiomyocyte Sarcomeres
Skwarek-Maruszewska, Aneta
Boczkowska, Malgorzata
Zajac, Allison L.
Kremneva, Elena
Svitkina, Tatyana
Dominguez, Roberto
Lappalainen, Pekka
Molecular Biology of the Cell
Lmod is a muscle-specific actin nucleator that displays structural similarity to the filament pointed-end–capping protein, Tmod. The mechanisms of localizations of Lmod and Tmod in muscle sarcomeres are strikingly different. Lmod contributes to the organization of mature myofibrils through a mechanism that requires interaction with tropomyosin.
Leiomodin (Lmod) is a muscle-specific F-actin–nucleating protein that is related to the F-actin pointed-end–capping protein tropomodulin (Tmod). However, Lmod contains a unique ∼150-residue C-terminal extension that is required for its strong nucleating activity. Overexpression or depletion of Lmod compromises sarcomere organization, but the mechanism by which Lmod contributes to myofibril assembly is not well understood. We show that Tmod and Lmod localize through fundamentally different mechanisms to the pointed ends of two distinct subsets of actin filaments in myofibrils. Tmod localizes to two narrow bands immediately adjacent to M-lines, whereas Lmod displays dynamic localization to two broader bands, which are generally more separated from M-lines. Lmod's localization and F-actin nucleation activity are enhanced by interaction with tropomyosin. Unlike Tmod, the myofibril localization of Lmod depends on sustained muscle contraction and actin polymerization. We further show that Lmod expression correlates with the maturation of myofibrils in cultured cardiomyocytes and that it associates with sarcomeres only in differentiated myofibrils. Collectively, the data suggest that Lmod contributes to the final organization and maintenance of sarcomere architecture by promoting tropomyosin-dependent actin filament nucleation.
Related Articles
Loss of Tropomodulin4 in the zebrafish mutant träge causes cytoplasmic rod formation and muscle weakness reminiscent of nemaline myopathy
Berger, Joachim
Tarakci, Hakan
Berger, Silke
Li, Mei
Hall, Thomas E.
Arner, Anders
Currie, Peter D.
Disease Models & Mechanisms
Nemaline myopathy is an inherited muscle disease that is mainly diagnosed by the presence of nemaline rods in muscle biopsies. Of the nine genes associated with the disease, five encode components of striated muscle sarcomeres. In a genetic zebrafish screen, the mutant träge (trg) was isolated based on its reduction in muscle birefringence, indicating muscle damage. Myofibres in trg appeared disorganised and showed inhomogeneous cytoplasmic eosin staining alongside malformed nuclei. Linkage analysis of trg combined with sequencing identified a nonsense mutation in tropomodulin4 (tmod4), a regulator of thin filament length and stability. Accordingly, although actin monomers polymerize to form thin filaments in the skeletal muscle of tmod4trg mutants, thin filaments often appeared to be dispersed throughout myofibres. Organised myofibrils with the typical striation rarely assemble, leading to severe muscle weakness, impaired locomotion and early death. Myofibrils of tmod4trg mutants often featured thin filaments of various lengths, widened Z-disks, undefined H-zones and electron-dense aggregations of various shapes and sizes. Importantly, Gomori trichrome staining and the lattice pattern of the detected cytoplasmic rods, together with the reactivity of rods with phalloidin and an antibody against actinin, is reminiscent of nemaline rods found in nemaline myopathy, suggesting that misregulation of thin filament length causes cytoplasmic rod formation in tmod4trg mutants. Although Tropomodulin4 has not been associated with myopathy, the results presented here implicateTMOD4 as a novel candidate for unresolved nemaline myopathies and suggest that the tmod4trg mutant will be a valuable tool to study human muscle disorders.
Myofibrillogenesis; Nemaline myopathy; Neuromuscular disorder; Sarcomere assembly; tmod; Tropomodulin
Related Articles
Aberrant myofibril assembly in tropomodulin1 null mice leads to aborted heart development and embryonic lethality
Fritz-Six, Kimberly L.
Cox, Patrick R.
Fischer, Robert S.
Xu, Bisong
Gregorio, Carol C.
Zoghbi, Huda Y.
Fowler, Velia M.
The Journal of Cell Biology
Tropomodulin1 (Tmod1) caps thin filament pointed ends in striated muscle, where it controls filament lengths by regulating actin dynamics. Here, we investigated myofibril assembly and heart development in a Tmod1 knockout mouse. In the absence of Tmod1, embryonic development appeared normal up to embryonic day (E) 8.5. By E9.5, heart defects were evident, including aborted development of the myocardium and inability to pump, leading to embryonic lethality by E10.5. Confocal microscopy of hearts of E8–8.5 Tmod1 null embryos revealed structures resembling nascent myofibrils with continuous F-actin staining and periodic dots of α-actinin, indicating that I-Z-I complexes assembled in the absence of Tmod1. Myomesin, a thick filament component, was also assembled normally along these structures, indicating that thick filament assembly is independent of Tmod1. However, myofibrils did not become striated, and gaps in F-actin staining (H zones) were never observed. We conclude that Tmod1 is required for regulation of actin filament lengths and myofibril maturation; this is critical for heart morphogenesis during embryonic development.
actin; tropomodulin; tropomyosin; sarcomere; cardiac muscle
Related Articles
Tmod1 and CP49 Synergize to Control the Fiber Cell Geometry, Transparency, and Mechanical Stiffness of the Mouse Lens
Gokhin, David S.
Nowak, Roberta B.
Kim, Nancy E.
Arnett, Ernest E.
Chen, Albert C.
Sah, Robert L.
Clark, John I.
Fowler, Velia M.
PLoS ONE
The basis for mammalian lens fiber cell organization, transparency, and biomechanical properties has contributions from two specialized cytoskeletal systems: the spectrin-actin membrane skeleton and beaded filament cytoskeleton. The spectrin-actin membrane skeleton predominantly consists of α2β2-spectrin strands interconnecting short, tropomyosin-coated actin filaments, which are stabilized by pointed-end capping by tropomodulin 1 (Tmod1) and structurally disrupted in the absence of Tmod1. The beaded filament cytoskeleton consists of the intermediate filament proteins CP49 and filensin, which require CP49 for assembly and contribute to lens transparency and biomechanics. To assess the simultaneous physiological contributions of these cytoskeletal networks and uncover potential functional synergy between them, we subjected lenses from mice lacking Tmod1, CP49, or both to a battery of structural and physiological assays to analyze fiber cell disorder, light scattering, and compressive biomechanical properties. Findings show that deletion of Tmod1 and/or CP49 increases lens fiber cell disorder and light scattering while impairing compressive load-bearing, with the double mutant exhibiting a distinct phenotype compared to either single mutant. Moreover, Tmod1 is in a protein complex with CP49 and filensin, indicating that the spectrin-actin network and beaded filament cytoskeleton are biochemically linked. These experiments reveal that the spectrin-actin membrane skeleton and beaded filament cytoskeleton establish a novel functional synergy critical for regulating lens fiber cell geometry, transparency, and mechanical stiffness.
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Genomic organization of Tropomodulins 2 and 4 and unusual intergenic and intraexonic splicing of YL-1 and Tropomodulin 4
Cox, Patrick R
Siddique, Teepu
Zoghbi, Huda Y
BMC Genomics
The tropomodulins (TMODs) are a family of proteins that cap the pointed ends of actin filaments. Four TMODs have been identified in humans, with orthologs in mice. Mutations in actin or actin-binding proteins have been found to cause several human diseases, ranging from hypertrophic cardiomyopathy to immunodefiencies such as Wiskott-Aldrich syndrome. We had previously mapped Tropomodulin 2 (TMOD2) to the genomic region containing the gene for amyotrophic lateral sclerosis 5 (ALS5). We determined the genomic structure of Tmod2 in order to better analyze patient DNA for mutations; we also determined the genomic structure of Tropomodulin 4 (TMOD4).
In this study, we determined the genomic structure of TMOD2 and TMOD4 and found the organization of both genes to be similar. Sequence analysis of TMOD2 revealed no mutations or polymorphisms in ALS5 patients or controls. Interestingly, we discovered that another gene, YL-1, intergenically splices into TMOD4. YL-1 encodes six exons, the last of which is 291 bp from a 5' untranslated exon of TMOD4. We used 5' RACE and RT-PCR from TMOD4 to identify several intergenic RACE products. YL-1 was also found to undergo unconventional splicing using non-canonical splice sites within exons (intraexonic splicing) to produce several alternative transcripts.
The genomic structure of TMOD2 and TMOD4 have been delineated. This should facilitate future mutational analysis of these genes. In addition, intergenic splicing at TMOD4/YL-1 was discovered, demonstrating yet another level of complexity of gene organization and regulation.
Related Articles
Thin filaments elongate from their pointed ends during myofibril assembly in Drosophila indirect flight muscle
Mardahl-Dumesnil, Michelle
Fowler, Velia M.
The Journal of Cell Biology
Tropomodulin (Tmod) is an actin pointed-end capping protein that regulates actin dynamics at thin filament pointed ends in striated muscle. Although pointed-end capping by Tmod controls thin filament lengths in assembled myofibrils, its role in length specification during de novo myofibril assembly is not established. We used the Drosophila Tmod homologue, sanpodo (spdo), to investigate Tmod's function during muscle development in the indirect flight muscle. SPDO was associated with the pointed ends of elongating thin filaments throughout myofibril assembly. Transient overexpression of SPDO during myofibril assembly irreversibly arrested elongation of preexisting thin filaments. However, the lengths of thin filaments assembled after SPDO levels had declined were normal. Flies with a preponderance of abnormally short thin filaments were unable to fly. We conclude that: (a) thin filaments elongate from their pointed ends during myofibril assembly; (b) pointed ends are dynamically capped at endogenous levels of SPDO so as to allow elongation; (c) a transient increase in SPDO levels during myofibril assembly converts SPDO from a dynamic to a permanent cap; and (d) developmental regulation of pointed-end capping during myofibril assembly is crucial for specification of final thin filament lengths, myofibril structure, and muscle function.
actin-capping protein; thin filaments; myofibril; sanpodo; tropomodulin
Related Articles
The interaction of tropomodulin with tropomyosin stabilizes thin filaments in cardiac myocytes
Mudry, Ryan E.
Perry, Cynthia N.
Richards, Meredith
Fowler, Velia M.
Gregorio, Carol C.
The Journal of Cell Biology
Actin (thin) filament length regulation and stability are essential for striated muscle function. To determine the role of the actin filament pointed end capping protein, tropomodulin1 (Tmod1), with tropomyosin, we generated monoclonal antibodies (mAb17 and mAb8) against Tmod1 that specifically disrupted its interaction with tropomyosin in vitro. Microinjection of mAb17 or mAb8 into chick cardiac myocytes caused a dramatic loss of the thin filaments, as revealed by immunofluorescence deconvolution microscopy. Real-time imaging of live myocytes expressing green fluorescent protein–α-tropomyosin and microinjected with mAb17 revealed that the thin filaments depolymerized from their pointed ends. In a thin filament reconstitution assay, stabilization of the filaments before the addition of mAb17 prevented the loss of thin filaments. These studies indicate that the interaction of Tmod1 with tropomyosin is critical for thin filament stability. These data, together with previous studies, indicate that Tmod1 is a multifunctional protein: its actin filament capping activity prevents thin filament elongation, whereas its interaction with tropomyosin prevents thin filament depolymerization.
sarcomere; myofibrillogenesis; cardiac muscle; actin; thin filament
Related Articles
Tropomodulins are negative regulators of neurite outgrowth
Fath, Thomas
Fischer, Robert S.
Dehmelt, Leif
Halpain, Shelley
Fowler, Velia M.
European journal of cell biology
Regulation of the actin cytoskeleton is critical for neurite formation. Tropomodulins (Tmods) regulate polymerization at actin filament pointed ends. Previous experiments using a mouse model deficient for the neuron specific isoform Tmod2 suggested a role for Tmods in neuronal function by impacting processes underlying learning and memory. However, the role of Tmods in neuronal function on the cellular level remains unknown. Immunofluorescence localization of the neuronal isoforms Tmod1 and Tmod2 in cultured rat primary hippocampal neurons revealed that Tmod1 is enriched along the proximal part of F-actin bundles in lamellipodia of spreading cells and in growth cones of extending neurites, while Tmod2 appears largely cytoplasmic. Functional analysis of these Tmod isoforms in a mouse neuroblastoma N2a cell line showed that knockdown of Tmod2 resulted in a significant increase in number of neurite-forming cells and in neurite length. While N2a cells compensated for Tmod2 knockdown by increasing Tmod1 levels, over-expression of exogenous Tmod1 had no effect on neurite outgrowth. Moreover, knockdown of Tmod1 increased the number of neurites formed per cell, without effect on number of neurite-forming cells or neurite length. Taken together, these results indicate that Tmod1 and Tmod2 have mechanistically distinct inhibitory roles in neurite formation, likely mediated via different effects on F-actin dynamics and via differential localizations during early neuritogenesis.
Tropomodulin; F-actin; neurite outgrowth; N2a mouse neuroblastoma cells; cultured hippocampal neurons
Related Articles
Molecular basis of tropomyosin binding to tropomodulin, an actin capping protein
Kostyukova, Alla S.
Hitchcock-DeGregori, Sarah E.
Greenfield, Norma J.
Journal of molecular biology
The tropomodulins are a family of proteins that cap the pointed, slow-growing end of actin filaments and require tropomyosin for optimal function. Earlier studies identified two regions in Tmod1 that bind the N terminus of tropomyosin, though the ability of different isoforms to bind the two sites is controversial. We used model peptides to determine the affinity and define the specificity of the highly-conserved N termini of three short, non-muscle tropomyosins (α, γ, δ-TM) for the two Tmod1 binding sites using circular dichroism spectroscopy, native gel electrophoresis, and chemical crosslinking. All tropomyosin peptides have high affinity to the second Tmod1 binding site (within residues 109–144; α-TM, 2.5 nM; γ-TM, δ-TM, 40–90 nM), but differ >100- fold for the first site (residues 1–38; α-TM, 90 nM; undetectable at 10 µM, γ-TM, δ-TM). Residue 14 (R in α; Q in γ, δ), and to a lesser extent, residue 4 (S in α; T in γ, δ) are primarily responsible for the differences. The functional consequence of the sequence differences is reflected in the more effective inhibition of actin filament elongation by full-length α-TMs than γ-TM in the presence of Tmod1. The binding sites of the two Tmod1 peptides on a model tropomyosin peptide differ, as defined by comparing 15N¹H HSQC spectra of a 15N-labeled model tropomyosin peptide in the absence and presence of Tmod1 peptide. The NMR and circular dichroism studies show that there is an increase in α-helix upon Tmod1-tropomyosin complex formation, indicating that intrinsically disordered regions of the two proteins become ordered when they bind. A proposed model for the binding of Tmod to actin and tropomyosin at the pointed end of the filament shows how the tropomodulin-tropomyosin accentuates the asymmetry of the pointed end and suggests how subtle differences among tropomyosin isoforms may modulate actin filament dynamics.
tropomyosin; tropomodulin; actin filament; circular dichroism; nuclear magnetic resonance
Related Articles
Pointed-end capping by tropomodulin3 negatively regulates endothelial cell motility
Fischer, Robert S.
Fritz-Six, Kimberly L.
Fowler, Velia M.
The Journal of Cell Biology
Actin filament pointed-end dynamics are thought to play a critical role in cell motility, yet regulation of this process remains poorly understood. We describe here a previously uncharacterized tropomodulin (Tmod) isoform, Tmod3, which is widely expressed in human tissues and is present in human microvascular endothelial cells (HMEC-1). Tmod3 is present in sufficient quantity to cap pointed ends of actin filaments, localizes to actin filament structures in HMEC-1 cells, and appears enriched in leading edge ruffles and lamellipodia. Transient overexpression of GFP–Tmod3 leads to a depolarized cell morphology and decreased cell motility. A fivefold increase in Tmod3 results in an equivalent decrease in free pointed ends in the cells. Unexpectedly, a decrease in the relative amounts of F-actin, free barbed ends, and actin-related protein 2/3 (Arp2/3) complex in lamellipodia are also observed. Conversely, decreased expression of Tmod3 by RNA interference leads to faster average cell migration, along with increases in free pointed and barbed ends in lamellipodial actin filaments. These data collectively demonstrate that capping of actin filament pointed ends by Tmod3 inhibits cell migration and reveal a novel control mechanism for regulation of actin filaments in lamellipodia.
cytoskeleton; angiogenesis; actin; tropomyosin; lamellipodia
Related Articles
Tropomodulin1 is required for membrane skeleton organization and hexagonal geometry of fiber cells in the mouse lens
Nowak, Roberta B.
Fischer, Robert S.
Zoltoski, Rebecca K.
Kuszak, Jerome R.
Fowler, Velia M.
The Journal of Cell Biology
The spectrin–actin network is disrupted in Tmod1 mutants, disturbing fiber cell morphology, and disordering lens cell organization.
Hexagonal packing geometry is a hallmark of close-packed epithelial cells in metazoans. Here, we used fiber cells of the vertebrate eye lens as a model system to determine how the membrane skeleton controls hexagonal packing of post-mitotic cells. The membrane skeleton consists of spectrin tetramers linked to actin filaments (F-actin), which are capped by tropomodulin1 (Tmod1) and stabilized by tropomyosin (TM). In mouse lenses lacking Tmod1, initial fiber cell morphogenesis is normal, but fiber cell hexagonal shapes and packing geometry are not maintained as fiber cells mature. Absence of Tmod1 leads to decreased γTM levels, loss of F-actin from membranes, and disrupted distribution of β2-spectrin along fiber cell membranes. Regular interlocking membrane protrusions on fiber cells are replaced by irregularly spaced and misshapen protrusions. We conclude that Tmod1 and γTM regulation of F-actin stability on fiber cell membranes is critical for the long-range connectivity of the spectrin–actin network, which functions to maintain regular fiber cell hexagonal morphology and packing geometry.
Related Articles
Tropomodulin protects α-catenin-dependent junctional actin networks under stress during epithelial morphogenesis
Cox-Paulson, Elisabeth A.
Walck-Shannon, Elise
Lynch, Allison M.
Yamashiro, Sawako
Zaidel-Bar, Ronen
Eno, Celeste C.
Ono, Shoichiro
Hardin, Jeff
Current biology : CB
α-catenin is central to recruitment of actin networks to the cadherin-catenin complex (CCC) [1, 2], but how such networks are subsequently stabilized against applied stress during morphogenesis is poorly understood. To identify proteins that functionally interact with α-catenin in this process, we performed enhancer screening using a weak allele of the C. elegans α-catenin, hmp-1, and identified UNC-94/tropomodulin. Tropomodulins (Tmods) cap the minus ends of F-actin in sarcomeres [3]. They also regulate lamellipodia [4], can promote actin nucleation [5], and are required for normal cardiovascular development [6, 7] and neuronal growth cone morphology [8]. Tmods regulate the morphology of cultured epithelial cells [9], but their role in epithelia in vivo remains unexplored. We find that UNC-94 is enriched within a HMP-1-dependent junctional actin network at epidermal adherens junctions subject to stress during morphogenesis. Loss of UNC-94 leads to discontinuity of this network, and high-speed filming of hmp-1(fe4);unc-94(RNAi) embryos reveals large junctional displacements that depend on the Rho pathway. In vitro, UNC-94 acts in combination with HMP-1, leading to longer actin bundles than with HMP-1 alone. Our data suggest Tmods protect actin filaments recruited by α-catenin from minus-end subunit loss, enabling them to withstand the stresses of morphogenesis.
cadherin; α-catenin; C. elegans; morphogenesis; tropomodulin; actin
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Cytoplasmic γ-Actin Expression in Diverse Animal Models of Muscular Dystrophy
Hanft, Laurin M.
Bogan, Daniel J.
Mayer, Ulrike
Kaufman, Stephen J.
Kornegay, Joe N.
Ervasti, James M.
Neuromuscular disorders : NMD
We recently showed that cytoplasmic γ-actin (γcyto-actin) is dramatically elevated in striated muscle of dystrophin-deficient mdx mice. Here we demonstrate that γcyto-actin is markedly increased in golden retriever muscular dystrophy (GRMD), which better recapitulates the dystrophinopathy phenotype in humans. γcyto-Actin was also elevated in muscle from α-sarcoglycan null mice, but not in several other dystrophic animal models, including mice deficient in β-sarcoglycan, α-dystrobrevin, laminin-2, or α7 integrin. Muscle from mice lacking dystrophin and utrophin also expressed elevated γcyto-actin, which was not restored to normal by transgenic overexpression of α7 integrin. However, γcyto-actin was further elevated in skeletal muscle from GRMD animals treated with the glucocorticoid prednisone at doses shown to improve the dystrophic phenotype and muscle function. These data suggest that elevated γcyto-actin is part of a compensatory cytoskeletal remodeling program that may partially stabilize dystrophic muscle in some cases where the dystrophin-glycoprotein complex is compromised.
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Mutations changing tropomodulin affinity for tropomyosin alter neurite formation and extension
Moroz, Natalia
Guillaud, Laurent
Desai, Brinda
Kostyukova, Alla S.
Assembly of the actin cytoskeleton is an important part of formation of neurites in developing neurons. Tropomodulin, a tropomyosin-dependent capping protein for the pointed end of the actin filament, is one of the key players in this process. Tropomodulin binds tropomyosin in two binding sites. Tmod1 and Tmod2, tropomodulin isoforms found in neurons, were overexpressed in PC12 cells, a model system for neuronal differentiation. Tmod1 did not affect neuronal differentiation; while cells expressing Tmod2 showed a significant reduction in the number and the length of neurites. Both tropomodulins bind short α-, γ- and δ-tropomyosin isoforms. Mutations in one of the tropomyosin-binding sites of Tmod1, which increased its affinity to short γ- and δ-tropomyosin isoforms, caused a decrease in binding short α-tropomyosin isoforms along with a 2-fold decrease in the length of neurites. Our data demonstrate that Tmod1 is involved in neuronal differentiation for proper neurite formation and outgrowth, and that Tmod2 inhibits these processes. The mutations in the tropomyosin-binding site of Tmod1 impair neurite outgrowth, suggesting that the integrity of this binding site is critical for the proper function of Tmod1 during neuronal differentiation.
Tropomodulin; Tropomyosin; Actin; Neurite formation; Cytoskeleton
Related Articles
Skeletal Muscle-Specific Ablation of γcyto-Actin Does Not Exacerbate the mdx Phenotype
Prins, Kurt W.
Lowe, Dawn A.
Ervasti, James M.
PLoS ONE
We previously documented a ten-fold increase in γcyto-actin expression in dystrophin-deficient skeletal muscle and hypothesized that increased γcyto-actin expression may participate in an adaptive cytoskeletal remodeling response. To explore whether increased γcyto-actin fortifies the cortical cytoskeleton in dystrophic skeletal muscle, we generated double knockout mice lacking both dystrophin and γcyto-actin specifically in skeletal muscle (ms-DKO). Surprisingly, dystrophin-deficient mdx and ms-DKO mice presented with comparable levels of myofiber necrosis, membrane instability, and deficits in muscle function. The lack of an exacerbated phenotype in ms-DKO mice suggests γcyto-actin and dystrophin function in a common pathway. Finally, because both mdx and ms-DKO skeletal muscle showed similar levels of utrophin expression and presented with identical dystrophies, we conclude utrophin can partially compensate for the loss of dystrophin independent of a γcyto-actin-utrophin interaction.
Related Articles
Tropomodulin is associated with the free (pointed) ends of the thin filaments in rat skeletal muscle
The Journal of Cell Biology
The length and spatial organization of thin filaments in skeletal muscle sarcomeres are precisely maintained and are essential for efficient muscle contraction. While the major structural components of skeletal muscle sarcomeres have been well characterized, the mechanisms that regulate thin filament length and spatial organization are not well understood. Tropomodulin is a new, 40.6-kD tropomyosin-binding protein from the human erythrocyte membrane skeleton that binds to one end of erythrocyte tropomyosin and blocks head-to-tail association of tropomyosin molecules along actin filaments. Here we show that rat psoas skeletal muscle contains tropomodulin based on immunoreactivity, identical apparent mobility on SDS gels, and ability to bind muscle tropomyosin. Results from immunofluorescence labeling of isolated myofibrils at resting and stretched lengths using anti-erythrocyte tropomodulin antibodies indicate that tropomodulin is localized at or near the free (pointed) ends of the thin filaments; this localization is not dependent on the presence of myosin thick filaments. Immunoblotting of supernatants and pellets obtained after extraction of myosin from myofibrils also indicates that tropomodulin remains associated with the thin filaments. 1.2-1.6 copies of muscle tropomodulin are present per thin filament in myofibrils, supporting the possibility that one or two tropomodulin molecules may be associated with the two terminal tropomyosin molecules at the pointed end of each thin filament. Although a number of proteins are associated with the barbed ends of the thin filaments at the Z disc, tropomodulin is the first protein to be specifically located at or near the pointed ends of the thin filaments. We propose that tropomodulin may cap the tropomyosin polymers at the pointed end of the thin filament and play a role in regulating thin filament length.
Related Articles
Mechanisms of thin filament assembly in embryonic chick cardiac myocytes: tropomodulin requires tropomyosin for assembly
The Journal of Cell Biology
Tropomodulin is a pointed end capping protein for tropomyosin-coated actin filaments that is hypothesized to play a role in regulating the precise lengths of striated muscle thin filaments (Fowler, V. M., M. A. Sussman, P. G. Miller, B. E. Flucher, and M. P. Daniels. 1993. J. Cell Biol. 120:411-420; Weber, A., C. C. Pennise, G. G. Babcock, and V. M. Fowler. 1994, J. Cell Biol. 127:1627-1635). To gain insight into the mechanisms of thin filament assembly and the role of tropomodulin therein, we have characterized the temporal appearance, biosynthesis and mechanisms of assembly of tropomodulin onto the pointed ends of thin filaments during the formation of striated myofibrils in primary embryonic chick cardiomyocyte cultures. Our results demonstrate that tropomodulin is not assembled coordinately with other thin filament proteins. Double immunofluorescence staining and ultrastructural immunolocalization demonstrate that tropomodulin is incorporated in its characteristic sarcomeric location at the pointed ends of the thin filaments after the thin filaments have become organized into periodic I bands. In fact, tropomodulin assembles later than all other well characterized myofibrillar proteins studied including: actin, tropomyosin, alpha-actinin, titin, myosin and C-protein. Nevertheless, at steady state, a significant proportion (approximately 39%) of tropomodulin is present in a soluble pool throughout myofibril assembly. Thus, the absence of tropomodulin in some striated myofibrils is not due to limiting quantities of the protein. In addition, kinetic data obtained from [35S]methionine pulse-chase experiments indicate that tropomodulin assembles more slowly into myofibrils than does tropomyosin. This observation, together with results obtained using a novel permeabilized cell model for thin filament assembly, indicate that tropomodulin assembly is dependent on the prior association of tropomyosin with actin filaments. We conclude that tropomodulin is a late marker for the assembly of striated myofibrils in cardiomyocytes; its assembly appears to be linked to their maturity. We propose that tropomodulin is involved in maintaining and stabilizing the final lengths of thin filaments after they are assembled.
Related Articles
Titin isoform size is not correlated with thin filament length in rat skeletal muscle
Greaser, Marion L.
Pleitner, Jonathan M.
Frontiers in Physiology
The mechanisms controlling thin filament length (TFL) in muscle remain controversial. It was recently reported that TFL was related to titin size, and that the latter might be involved in TFL determination. Titin plays several crucial roles in the sarcomere, but its function as it pertains to the thin filament has not been explored. We tested this relationship using several muscles from wild type rats and from a mutant rat model (Greaser et al., 2008) which results in increased titin size. Myofibrils were isolated from skeletal muscles [extensor digitorum longus (EDL), external oblique (EO), gastrocnemius (GAS), longissimus dorsi (LD), psoas major (PM), and tibialis anterior(TA)] using both adult wild type (WT) and homozygous mutant (HM) rats (n = 6 each). Phalloidin and antibodies against tropomodulin-4 (Tmod-4) and nebulin's N-terminus were used to determine TFL. The WT rats studied express skeletal muscle titin sizes ranging from 3.2 to 3.7 MDa, while the HM rats express a giant titin isoform sized at 3.8 MDa. No differences in phalloidin based TFL, nebulin distance, or Tmod distance were observed across genotypes. However, the HM rats demonstrated a significantly increased (p < 0.01) rest sarcomere length relative to the WT phenotype. It appears that the increased titin size, predominantly observed in HM rats' middle Ig domain, allows for increased extensibility. The data indicates that, although titin performs many sarcomeric functions, its correlation with TFL and structure could not be demonstrated in the rat.
titin; actin; phalloidin; tropomodulin; thin filament length
Related Articles
Tropomodulin caps the pointed ends of actin filaments
The Journal of Cell Biology
Many proteins have been shown to cap the fast growing (barbed) ends of actin filaments, but none have been shown to block elongation and depolymerization at the slow growing (pointed) filament ends. Tropomodulin is a tropomyosin-binding protein originally isolated from red blood cells that has been localized by immunofluorescence staining to a site at or near the pointed ends of skeletal muscle thin filaments (Fowler, V. M., M. A., Sussman, P. G. Miller, B. E. Flucher, and M. P. Daniels. 1993. J. Cell Biol. 120: 411-420). Our experiments demonstrate that tropomodulin in conjunction with tropomyosin is a pointed end capping protein: it completely blocks both elongation and depolymerization at the pointed ends of tropomyosin-containing actin filaments in concentrations stoichiometric to the concentration of filament ends (Kd < or = 1 nM). In the absence of tropomyosin, tropomodulin acts as a "leaky" cap, partially inhibiting elongation and depolymerization at the pointed filament ends (Kd for inhibition of elongation = 0.1-0.4 microM). Thus, tropomodulin can bind directly to actin at the pointed filament end. Tropomodulin also doubles the critical concentration at the pointed ends of pure actin filaments without affecting either the rate of extent of polymerization at the barbed filament ends, indicating that tropomodulin does not sequester actin monomers. Our experiments provide direct biochemical evidence that tropomodulin binds to both the terminal tropomyosin and actin molecules at the pointed filament end, and is the long sought-after pointed end capping protein. We propose that tropomodulin plays a role in maintaining the narrow length distributions of the stable, tropomyosin-containing actin filaments in striated muscle and in red blood cells.
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This is such a fun colouring game that my girls have literally been playing it non stop for days now. As a bonus - it was invented somewhat by accident! And if your kids prefer drawing to colouring, it's really easy to adapt too. Let me back up a little and tell you the story behind the game. … [Read more...]
Posts from the category: Family Time
Everyday happiness. No big thing.
"But Mummy doesn't laugh." I don't even remember the context of the conversation that my eight year old was having with her Dad when I overheard the words but they stung and they've been replaying themselves over and over in my head in the days since. It's not that I can't see her … [Read more...]
Tell a Story Family Mealtime Conversation Starters
It's been a crazy, busy day but now, with a hot meal on the table and the family gathered round, it is the perfect time to have enjoy a little silly fun together - that will also build language skills! Today we are sharing seven storytelling prompts to use at the dinner table. Each of the … [Read more...]
7 Easter Games for Your Easter Party or Family Get Together
These fun Easter game ideas are sure to create some very special memories with family and friends! Of course, most would also work well with class, youth and other activity groups - wherever you are gathered to enjoy some Easter fun together. 7 Family Easter Games Egg & spoon race: Grab some … [Read more...]
Our Happy Family Project: #1 Traditions & Rituals
2015 threw a lot at us including financial stress, unemployment, health scares and ongoing sleep deprivation. And when I think back on last year I honestly feel kind of sad. Sad for far too many days of fatigue and stress. Sad for too many days of distracted and disconnected. Sad for days of lost … [Read more...]
Create a Family Bucket List ~ Printable
A new year has to mean a new family bucket list! And this year I've given our Family Bucket List printable a makeover, mixing up some of the one word prompts from last year whilst also leaving spaces for you to add items just right for your family. It's great as a guide for making plans for what … [Read more...]
Love Life Printable Calendar Stickers
These colourful stickers are a fun tool for customising your calendar or diary! Created to fit perfectly with our 2016 Printable Calendar pages, there are stickers for your next appointment, to-do, celebration and (most importantly!) holiday. You can use the free printable to print your … [Read more...]
9 New Years Eve Party Games for Families
How will you be celebrating this New Years? Due to the age of our girls ours will feature a 9pm 'midnight'...if they last that long! If you are spending the celebration with family and friends with children, why not check out these nine fun party game ideas that everyone can enjoy together - BIG … [Read more...]


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Still time to enter young writer's competition, art and talent show
March is Youth Month, and the Easton Arts Council has celebrations in store. The 17th annual…
81st American Platform Tennis Association National Championships to benefit nonprofit
The country's top platform tennis players will storm Fairfield and Westchester counties, March 4 through 6, for the 81st American Platform Tennis Association (APTA) National Championships.
American Association of University Women holds free Tech Savvy Conference for CT Girls in grades 6-9
On Saturday, Feb. 27, the American Association of University Women's Connecticut Chapter (AAUW CT) will host its third annual Tech Savvy Conference at Trinity College in Hartford. Girls in grades 6-9, their parents and teachers may register for the event online at: aauw-ct.aauw.net.
Make-A-Wish Connecticut benefit features local talent
Broadway Wishes, a benefit for Make-A-Wish Connecticut will be performed on Saturday Feb. 27, at 1 p.m., at the Fairfield Theatre Company, 70 Sanford Street, Fairfield.


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Add some diversity to your fitness program with these butt and hip exercises from the American Council on Exercise. We'll help you tone up those glutes and get that butt into shape. Choose from a wide variety of hip flexibility and strengthening exercises including glute bridges, BOSU lateral jumps and more. These exercises come with detailed instructions, step-by-step guidance and tutorials on proper equipment use. For full workout routines featuring butt and hip exercises, be sure to visit our Workouts section.
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Tight IT bands—those long pieces of connective tissue that run along the outsides of the legs—can be symptomatic of imbalances or weaknesses in other parts of the legs or hips. Yoga, when practiced with proper alignment and body awareness, is effective for finding those...
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When it comes to serving up snacks, you have the power to prepare healthy options in your own home. Here are some great ideas for incorporating whole grains, healthy fats and fresh fruits and vegetables for the perfect between-meal pick-me-ups.


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In 64-bit Windows, it is no longer possible to enter hardware textmode in the terminal by hitting Alt+Enter. Is there a terminal/console software that supports emulation of VGA text modes?
Give a try to ConEmu - configurable Windows console emulator, I'm the author of it. Some user reviews on StackOverflow.
AltEnter switch Fullscreen mode, and window state may be stored in settings (registry or xml). There are tabbar and status bar, but you may turn them off, if you dont need them. Also, you may choose any font for your pleasure.
A brief excerpt from the long list of options: