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Norfolk, Portsmouth, Virginia Beach, Chesapeake, Suffolk, Hampton. Find and meet fun and friendly tennis partners.
Website: http://tennisopolis.com/group/hamptonroads
Location: Hampton Roads, VA
Members: 75
Latest Activity: on Monday
Started by Roberto Ramos on Monday. 0 Replies 0 Likes
Suffolk Parks & Recreation is hosting a Howard Mast Tennis Day on Saturday, April 26th from 9am - 2pm open to tennis players of all ages. The event will host a free tennis clinic, teen tournament, and adult singles and doubles tournament with…Continue
Started by Mikiel Arnold Feb 24. 0 Replies 0 Likes
New opportunity to play in the Hampton Roads area. Top10 Challenge Ladder has launched several spring ladders starting March 24, 2014. Play for great prizes at your convenience.…Continue
Started by Oscar Wegner Jul 19, 2013. 0 Replies 0 Likes
Tracking the Ball Track the ball with your playing hand as if you were trying to catch it.Restrain yourself from hitting too early by resting the racquet throat in your other hand.When the ball is near, transition to the idea of hitting it and,…Continue
Started by Oscar Wegner Jul 12, 2013. 0 Replies 0 Likes
Started by Oscar Wegner Jun 15, 2013. 0 Replies 0 Likes
Modern tennis blog http://oscarwegner.wordpress.com/Continue
Started by Ken Hollowell May 29, 2013. 0 Replies 0 Likes
Hi all, I enjoy watching tennis but don't play myself. My son is 17 years old and plays on his high school team in Windsor, Va. I am interested in getting him together with other players that can help him improve. Would particularly like to keep…Continue
Started by Catherine J Wieczorek. Last reply by Ellie N. Apr 30, 2013. 4 Replies 0 Likes
Hey there, I've played tennis off and on over the years but in short spurts and have never really achieved any kind of greatness. I just love to play, and do want to get better by playing more consistently. Would love to find a group or partner!Continue
Started by Jennifer Sher. Last reply by John Winter Mar 11, 2013. 5 Replies 0 Likes
i'm looking to get back to playing 1-2 times per week and would like to find a few people to play with. Have mostly evening availability plus weekends and would like to try and stay in the patrick henry mall area of newport news but can travel. I…Continue
Started by Pavan B Jan 6, 2013. 0 Replies 0 Likes
Hey tennis fans, my name is Pavan and I just moved to Hampton Roads in 2012 due to military assignment. I've been playing tennis since I was 4 and love playing singles or doubles. I haven't played much in the past 4 years due to deployments and…Continue
Started by Paul. Last reply by Micah Downsf Jul 27, 2012. 11 Replies 0 Likes
I haven't been on here as much as I would like to. Been playing in USTA Norfolk leagues last winter, spring, and plan on playing in summer leagues which start very soon. It's a great way to meet people, play regularly, and play in a team…Continue
Hi everyone, I'm brand new to the Virginia Beach area and I'm trying to find a hitting partner. I'm free most of the time and I'm willing to drive too! My number is [edit: please share private info via PM or Friend Request] . Feel free to shoot me a text or call. :)
Yeah, I've been looking at CL the past few days, none of those racquets interest me :/
Sounds good Janel; maybe try craigslist for a better deal, that's where I found mine.
Thanks Tony, I really appreciate it. Churchland area is not too far away from me.
I saved your number, I currently do not have a tennis racquet with me since I did not really plan on playing, once I get a hold of one I will make sure to let you know!
Janel, I'm located in Northern Suffolk, right beside Churchland area. Anytime you wanna hit, send me a text [edit: please share private info via PM or Friend Request]
Albert, awesome work on the tennis courts hunt, never heard of NPT in Norfolk, but will be definetely be there tonight. I'm sure to give you a call/text on the way there.
Taye, sorry for the sudden non-reply, no problem with you being non-mobile, and will make my way out there some time soon. Be expecting my call.
Micah, don't know where to start, but as a father of a newborn, I'm pretty sure you understand my situation; mine are two and one, both girls : ).
Soo, having said all my "pieces", lol, I will be at Northside Tennis Park in the evening hours, hope to meet you all soon.
Hello everyone, I'm new here in VA, from IL.
It's been 2 years since I have played tennis and I lost my forehand, it is bad lol but I could still serve and have somewhat of a backhand. I played in HS, doubles and singles. I would love to play tennis and get back at it again, but like I said, my forehand is pretty bad and would love to get help with it. I work weekdays until 1600 and am usually free after that.
It would be great if I could get some help and get back into playing tennis again.
Northside Park Tennis in Norfolk.is highly recommended. Plenty of courts and players of all levels. I had a great workout yesterday. Again, every Tuesdays and Thursdays from 6-8pm, weather permitting. Ask for Bill. Thank you.
Hello, I'm Mustafa from Va Beach, a tennis fun and a 3.5 level player.I would like to play with anybody in Va Beach, and will be available to play tomorrow evening (4th of jul). If anybody is interested in please let me know.
I just learned about free clinics every Tuesdays and Thursdays at Northside Park Tennis, 8401 Tidewater Dr. in Norfolk, whether permitting from 6-8pm. All levels welcome. I will go there this evening and will post feedback tomorrow.
I am free weekdays too Taye and would love to play I too live in VA beach... let me know when you are available
© 2014 Created by Mark / The Mayor.


text:
BKE Sabrina Boot Stretch JeanSALE $49.97 was $66.95 Item #14410ABK202
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- 17" bottom opening
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This regular fit bootcut jean is slightly fitted through the hip and thigh.

subset: commoncrawl


text:
Sure, there are more teams that play a 3-4 now (apparently, half the league has missed the flaws that you see), but the Steelers have still flat out missed on evaluations. Taking Davis over Cliff Avril (a guy the Steelers had in for a pre-draft visit) was a particularly glaring example.
Of cour
I love how the guy who has a statement of self importance deriding fantasy football as his signature cannot recognize anything done by the defensive line outside of a sack.
2014 NFL Draft
1) Darqueze Dennard-DB MSU
2) Jordan Matthews-WR Vandy
3) Chris Borland-ILB Wisconsin
4) Caraun Reid, DT Princeton
5) De'Anthony Thomas-RB Oregon
5b) Ryan Carrethers-NT Arkansas State
6) Jeff Janis-WR Saginow Valley State
6b) Seantrel Henderson, OT MIami
7) Colt Lyerla -TE Oregon
Vader said: "I don't like the direction of this team and I don't like the Tomlin/Colbert team when it comes to drafting. I'm not saying to fire Tomlin. I don't like the direction but he should have time to straighten it out."
Fair enough!
I dd not think there was any basis for comparing the two in the early years. However, now there is sort of. Going forward from now.
QB O'Donnell---Landry
OL Dawson-----Pouncey
OL Jackson-----Gilbert or Adams
DB Lake--------Polamalu
DB Woodson---Taylor
LB Lloyd--------Woodley or Timmons
WR Mills---------Wheaton
WR Thigpen?----E. Sanders
RB Foster-------Bell [Foster had 96 carries in 90-91.] How do you think the team would fare if the above was the nucleus of the team going forward?
Of course BC did not have the luxury of Ben Roethlisberger, A. Brown, D. DeCastro, C.Allen quite a few other sound players. These are just an added bonus for MT. Now the question is as Vader asks can the Tomlin/Colbert team get it done? Frankly, I would prefer 1992 or even better 2000 but since last years draft was such a good start I hope this pair can get it done.
1.15) Ra'Shede Hageman - DE
2.47) Jason Verrett - CB
3.97) CJ Fiedorowicz - TE
4.114) Brandon Coleman - WR
5.145) Lamin Barrow - ILB
5.173) Terrance Mitchell - CB
7.207) Jay Bromley - DT
"Before you can win a game, you have to not lose it." -- Chuck Noll


text:
I know a certain range of IP addresses are causing problem with my server,
172.64.*.* what is the best way to block access to my Amazon EC2 instance? Is there a way to do this using security groups or is it better to do it with the firewall on the server itself?
I know a certain range of IP addresses are causing problem with my server,
Both if possible, just in case.
Security groups are good because they are external to your host so the data never reach's you. They are not quite as configurable as most server based firewalls though.
Unfortunately, EC2 security groups can only "allow" services through a default deny policy. So if you are trying to block access to a publicly "allowed" service for a small IP range, building the allow rule for "the rest of the internet" is a bit more complex than just blocking an IP range. As you have specified a nice big chunk, the list of network ranges not including 220.127.116.11/16 is not too long:
This list would need to be added for your port(s). Then you can delete your 'allow all' rule for that port. If you have multiple ports you want to do this for that aren't contiguous, they list will need to go in multiple times. If you have multiple security groups this can quickly grow to be unmanageable.
Locally firewalling will also work.
After adding your rules you'll need to save them, and ensure the
The config file to save to may vary with distributions.
If you use a VPC for your instances you can specify "Network ACLS" that work on your subnet, and do provide both allow or deny rules.
Please see this discussion page https://forums.aws.amazon.com/message.jspa?messageID=338053
We're looking for long answers that provide some explanation and context. Don't just give a one-line answer; explain why your answer is right, ideally with citations. Answers that don't include explanations may be removed.


text:
My boyfriend and I got Tellie when she was 4 months old from a shleter in Minnesota 4 hours away from Cedar Rapids. When we got her home her favorite thing to do was to lay infront of the T.V. to watch what we were watching. Thats how she got her name Tellie. She was potty trained by the time she was 6 months and has always been a quick learner. She is a very funny girl and loves to play outside (rain or shine), she goes through her toys within a month because she rips the stuffing out of them. When Tellie gets a bone that would usually take other dogs a week to eat through, it takes Tellie a day or two and it will be gone! Don't let her size fool you, she is a very strong girl but at that a very sweet and lovable girl to be around.
Tellie Marie
By: hill318mattSubscribe Channel: Pets & Animals Location: Cedar Rapids, Iowa
2 Comments
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says ... on Thursday, Aug 6 at 9:23 PM
I forgot to say that Tellie is 1/3 Black Lab, 1/3 Chow and 1/3 dachshund. Her mother was 1/2 Black Lab and 1/2 dachshund and her father was a purebred Chow.
says ... on Saturday, Aug 1 at 7:16 AM
go doggie


text:
ATI Mobility 128 AGP 2X (Dansk) Free Driver Download
Network Devices, Display, MEDIA, ...
See details of driver package which includes support for this device.
Device Name
ATI Mobility 128 AGP 2X (Dansk)
1.00 (22 Apr 2002)
1.52.00.00 (2000-08-01)
2.30.00.0000 (2000-08-01)
4.03.25.00 (2000-08-01)
18.104.22.168 (2000-08-01)
Supported Operating Systems
Windows 98, Windows 2000, Windows 98SE, Windows ME, Windows XP, Windows 2003, Windows Vista
Uploader Notes
Compal N38W3 (SW3) Notebook- All Drivers
Uploaded By
selvaraj (DG Staff Member) on 4/21/2005
Driver Package
Compal_N38W3_98.zip (15.4 MB)
Hardware Ids Supported
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Reviews Summary
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text:
Trailing by a touchdown to begin the fourth quarter, the Saks faithful knew it was time to stand behind their team when the Wildcats needed momentum the most.
Saks rode this momentum wave the whole fourth quarter while coming back and defeating the Lauderdale County Tigers 36-21.
"We love our Saks fans. They'll go anywhere with us," senior Roc Green said.
Saks (12-0) will hit the road again next week when the Wildcats play at Colbert County in the quarterfinals.
The fourth quarter started with a Saks punt, but the Wildcats' defense forced an immediate three-and-out from the Tigers' offense. This put the ball into the hands of Wildcats quarterback Tre' Smith, and he delivered.
After three plays, Saks head coach Jonathan Miller was forced to call a timeout with the play clock winding down. This was when the Wildcats took over.
The next play, Smith ran into the end zone from 15 yards out to tie the game, and ran in the 2-point conversion to put Saks up for good 23-21.
"We knew it was time to step up," Smith said. "We had been slipping."
On Lauderdale County's next offensive play, quarterback Samuel Grisham couldn't handle the snap, and Davontae Young fell on top of the loose football.
On the next play, Smith found sophomore running back Devin Harris streaking down the sideline for a 26-yard touchdown reception to extend the Wildcats' lead to 29-21.
"When you have a target on your head, it's going to be hard to make plays, but you still have to make plays," Harris said.
However, the Saks momentum didn't stop there.
On Lauderdale County's second play back on offense, Green intercepted Grisham and returned the ball back to the Tigers' 19 yard-line.
Five plays later, Smith put the game out of reach with a touchdown run of 4 yards.
"We had to keep our head in the game — keep our composure and let the defense take over," Green said.
Saks hurried out to a 7-0 lead after Lauderdale County fumbled away the opening kickoff, and Smith found Harris for a 13-yard touchdown toss.
On the ensuing kickoff, the Tigers fumbled away the ball again, and the Wildcats took advantage. Harris took to the air, and he threw for his own touchdown as he connected with Green for a 37-yard reception.
"We got up 14-0, and had a lot of opportunities in the first half to stretch our lead and we didn't do it," Miller said. "Our guys made some plays. It's what we try to do as coaches, put them in position to make plays."
Lauderdale County had scores courtesy of a 1-yard run from Grisham, 28-yard run by Zach Simbeck, and 15-yard run by John Taylor Greer.
"We had some sloppy spots during the game, but we kept fighting and finally executed in the fourth quarter when we needed to most," Miller said.
With the victory over the Tigers, Saks extends in win streak to 12 in a row, while advancing in the playoffs.
"As a coach, you never want to try and predict what you might do, and take it one week at a team," Miller said.
"Our guys have done a great job all year, as well as our coaches. We are lucky and fortunate to be 12-0."
Smith said the team will enjoy the win tonight, but will get back to business immediately.
"We have practice Monday."


text:
Oakland Community College
Auburn Hills English Department
2900 Featherstone Road
Auburn Hills, Michigan 48326-6593
Phone: (248) 232-4026
Fax: (248) 232-4040
Location: Building: D, 3rd floor of the Auburn Hills Campus
Department Secretary: Lynn Mills
Mailboxes for Adjunct Staff: D 330
Congratulations to Lynn Mills, winner of the Auburn Hills Outstanding Staff Award!
Other Honorees:
Nominated for the Outstanding Faculty award: Ted Bolak, Scott Contor, and Suba Subbarao
Nominated for the Outstanding Adjunct Faculty award: Sarah Karlis and John Woodward
NewsTed Bolak has been accepted into the Native Americans in the Midwest: Bridging Cultures at Community Colleges program, funded by the National Endowment for the Humanities. The project works with faculty and academic administrators to increase their knowledge of existing research and scholarship on the history Ohio's Ten Historic Tribes and their removal; introduce faculty to contemporary Native American cultural experiences; and facilitate a community of learning and research through course development and enhancement.
Full Time Faculty
Instructor Name Phone Office Email Address CHAIR: Suba Subbarao (248) 232-4028 F 210 email@example.com Celestine Arena (248) 232-4032 D 337 firstname.lastname@example.com Steven D. Berman (248) 232-4036 D 334 firstname.lastname@example.com Theodore Bolak (248) 232-4286 F 111 firstname.lastname@example.com Scott Contor (248) 232-4063 D 335 firstname.lastname@example.com Bonita Myrand (248) 232- 4037 D 332 firstname.lastname@example.com Victoria Nikiforov (248) 232-4031 F 206 firstname.lastname@example.com Quincy Norwood (248-232-4034) C 252 email@example.com Cari Rummel (248) 232-4033 F 209 email@example.com Mary Moon (248) 232-4039 D 319 email@example.com
Adjunct Faculty, Fall 2013
Department Projects
Northern Lights
A literary journal for area high school students.
On hiatus in 2013
A journal of creative writing.
On hiatus in 2013
Top of Page | OCC Home Page
Page updated on August 28, 2013, by href="mailto:firstname.lastname@example.com">English Dept Webmaster, English Department, Oakland Community College, Auburn Hills - Page Disclaimer
Oakland Community College 2480 Opdyke Road, Bloomfield Hills, Michigan 48304 (248) 341-2000


text:
photo credit: Steven Taylor
posted Friday, December 7
I Love it~
posted Tuesday, December 4
"I just wanna innovate and stimulate minds/Travel the world and penetrate the times"
Yeah...that's it....
posted Monday, December 3
I Love this pic, rugged yet cool. This place brings back so many memories. Glad you take the time to help when ever you can. 1 Love!


text:
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The Overlords are a Warhammer 40000 (40k) wargaming club based in Dagenham East London Essex who meeting Sunday evenings.


text: My "content", both material you can find here and other, "exclusive" material, is now available on three new "platforms" for your convenience. So, while I am no longer available on Facebook as a "friend" — everybody knows I'm nobody's friend really — you can "like" my Page to see both links to new Sultan Seal posts and texts, both old and new, accompanied by or accompanying works of iPhoneography. The news is that now you can also enjoy (or throw up at) such material on Google Currents (listed under Entertainment as The Sultan's Seal); Currents is a seriously convenient "reader" for iPads and Androids and the like. As for my Twitter account, which I'm embracing with renewed gusto now that I've given up the art of the Facebook status, I was appalled to realize that I have less than 1K followers when every other worthless shit has at least 15K, so… The Sultan's Seal (which used to be called the arabophile until, in the wake of the blessed Arab Spring, I developed a near-fatal allergy) is all over the ether. Go follow.


text:
CAA Men's Soccer Weekly Report - Oct. 22
Don Anding • Northeastern
Sr., Forward, Amity Harbor, N.Y./Chaminade
Anding played a part in all three Northeastern scores last week as the Huskies went 2-0 to extend their unbeaten streak to a school-record 10 games. The senior forward assisted on the game-winning goal in NU's 1-0 double-overtime win over Hofstra and then contributed the game-winning goal and an assist as the Huskies topped UNCW, 2-1. Anding leads NU with 10 goals and leads the CAA with 26 points this season.
Ryan Flesch • William & Mary
Fr., Midfielder, Manassas, Va./Osbourn Park
Flesch scored the game-winning goal with just 3:45 remaining in regulation as William & Mary rallied past 8th-ranked Old Dominion, 2-1, for its first CAA victory of the season. The goal was the second of the season for Flesch.
Around The League:
ODU, NORTHEASTERN, DREXEL IN NATIONAL POLLS: Three CAA men's soccer teams are ranked in national polls released on Monday. Old Dominion is ranked #16 by College Soccer News and #19 by Top Drawer Soccer, Northeastern is ranked #27 by College Soccer News and #33 by Top Drawer and Drexel is ranked #41 by Top Drawer. Last week, ODU was ranked #8 in the NSCAA/Continental Tire poll and #12 by Soccer America. Both the NSCAA and Soccer America will release new polls on Tuesday.
DREXEL'S PAGE EARNS NATIONAL HONOR: Drexel junior midfielder Nathan Page was chosen to the Soccer America National Team of the Week on Oct. 18. Page scored the game-winning goals in the Dragons' 1-0 road victories over George Mason and Towson on Oct. 10 and 13.
FOUR CAA TEAMS RANKED REGIONALLY: Four CAA teams are among the top 10 in this week's NSCAA/Continental Tire South Atlantic Region rankings. Old Dominion leads the group of CAA squads at #3, Northeastern is ranked #4, Drexel is #6 and Hofstra is tied for #8.
NORTHEASTERN EXTENDS UNBEATEN STREAK TO 10: Northeastern defeated Hofstra (1-0 in 2ot) and UNCW (2-1) last week to extend its unbeaten streak to 10 (8-0-2), which is a new program record. The Huskies also tied a school record with their sixth straight win and locked up a CAA Tournament berth for the sixth time in seven years. Senior Andre Ciliotta scored the game-winner versus Hofstra as NU won its fourth double-overtime game of the season. Senior Don Anding assisted on Ciliotta's score and then contributed the game-winning goal and an assist against UNCW. Anding, who has a team-high 10 goals and tops the CAA with 26 points, has a point in seven of his last eight matches and is the first Husky with double-digit goals since 2001. Goalkeeper Oliver Blum improved to 10-0-2 this season and leads the CAA with a 0.58 GAA and an .844 save percentage. The Huskies have won 14 straight home matches dating back to 2010.
DREXEL CLINCHES TOURNAMENT BERTH: Drexel clinched a berth in the CAA Men's Soccer Championship for the first time since 2007 after beating Georgia State 1-0 and tying Delaware 1-1 last week. Junior midfielder Nathan Page recorded the game-winning goal on a penalty kick in the 30th minute versus GSU and had the game-tying goal in the 78th minute against Delaware off a Fabio Machado assist. Page has scored a goal in five straight games and has tallied the last five goals for the Dragons dating back to October 6. Senior goalkeeper Tim Washam made a season-high seven saves in the GSU win, including one on a penalty kick, and posted his league-leading seventh shutout of the season.
W&M UPSETS ODU FOR FIRST CAA WIN: William & Mary earned its first CAA victory of the season last Wednesday by knocking off 8th-ranked ODU, 2-1. It was the Tribe's first win over a top 10 opponent since beating #5 SMU last season. Sophomore Marcus Luster scored the game-tying goal in the 65th minute off a Chris Perez assist and freshman midfielder Ryan Flesch tallied the game-winning goal with just 3:45 left in regulation.
JMU RALLIES FOR ROAD WIN AT MASON: James Madison rallied for a 2-1 road win at George Mason on Saturday to maintain third place in the CAA standings. Senior Paul Wyatt tied the match in the 65th minute with his team-high sixth goal of the season and the 25th of his career. The Dukes got the game-winner just 10 minutes later when sophomore Josh Grant headed in a pass from Adam Bastidas. Three of Grant's five goals this season have been game-winners. Eight of JMU's 14 matches this season have been decided by one goal.
TWO MORE GOALS FOR ODU'S HARMON: Senior forward Chris Harmon scored a goal in each match as Old Dominion went 1-1 last week. Harmon had the Monarchs' only goal in a 2-1 loss to William & Mary and netted the game-winner in a 2-1 victory over Towson. Harmon has scored four of ODU's last six goals and has eight goals and five assists for the season. Junior Tim Hopkinson scored his 10th goal of the season versus Towson and freshman Ryan Condotta had an assist.
HOFSTRA'S JANOWSKI STRONG IN NET: Hofstra senior goalkeeper Adam Janowski made 13 saves and allowed just one goal in the Pride's 1-1 week. Janowski, who has recorded three shutouts in his past four outings, stopped five shots in a 3-0 win over Delaware and made six saves in a 1-0 double-overtime loss to first-place Northeastern. He hasn't allowed a goal in regulation over the last 391:49 dating back to Oct. 3. Maid Memic scored his team-best seventh goal of the season in the UD victory and Joseph Holland recorded his sixth. The Pride also got a goal from Mike Annarumma and Chris Griebsch dished out his league-leading eighth assist.
MASON'S MORGAN LEADS CAA IN GOALS: George Mason senior forward Taylor Morgan leads the CAA with 11 goals after scoring twice in the Patriots' 3-0 triumph at Towson last Wednesday. The senior forward had two goals in a four-minute span early in the second half versus the Tigers. John Gardner netted his first goal of the year at Towson and Wesley Sever tallied his third goal of the season in Mason's 2-1 setback to James Madison last Saturday.
BONNER LEADS UNCW IN 1-1 WEEK: Freshman forward Colin Bonner scored two goals as UNCW topped Georgia State 2-1 and lost 2-1 at Northeastern last week. Bonner, who leads the Seahawks with five goals and 12 points this season, tied the GSU match in the 59th minute before sophomore Jacob VanCompernolle recorded the game-winner just 92 seconds later. At NU, Bonner scored off an Etienne Boulanger assist with less than 10 minutes to play. VanCompernolle's goal was his third of the year, which surpassed his previous career high of two.
DELAWARE PICKS UP POINT AT DREXEL: Delaware battled to a 1-1 double-overtime draw with first-place Drexel last Wednesday. The Blue Hens jumped out to a 1-0 lead as Evan Reed scored his second goal of the season in the 36th minute. Prince Nartey assisted on the score. Goalkeeper Jay Lupas stopped three shots in 110 minutes of action. UD fell 3-0 to Hofstra on Sunday.
TOWSON'S KIDWELL SCORES FIRST GOAL: Towson junior Cameron Kidwell scored his first goal of the season in the Tigers' 2-1 setback at Old Dominion on Saturday. Kidwell finished off a pass from Olakunle Banjo that cut the Monarchs' lead in half with less than 10 minutes to play. Freshman goalkeeper Felix Petermann had five saves at ODU and ranks second in the CAA with 60 saves.
TOUGH LOSSES FOR GSU: Georgia State dropped one-goal decisions to UNCW (2-1) and Drexel (1-0) last week. The Panthers took a 1-0 lead at UNCW when Alex Vivanco scored his team-leading sixth goal of the season in the 22nd minute. GSU out-shot first-place Drexel 18-9, but surrendered the match's only score on a first-half penalty kick. Five of the Panthers' six CAA losses have been by only one goal.


text:
Every animal sleeps,
but why the brain needs sleep has remained a mystery. Neuroscientists
now believe sleep is not only crucial to brain development, but
is also necessary to help consolidate the effects of waking experience – by
converting memory into more permanent and/or enhanced forms.
Sleeping problems are
almost always involved in mental disorders, including depression,
schizophrenia, Alzheimer's disease, stroke, as well as head injury.
And symptoms are strongly influenced by the amount of sleep a
person gets. Difficulties may arise from the drugs used to control
symptoms of a disorder, or from changes in the brain regions
and neurotransmitters that control sleep.
and Stress Topics:
Stress, Behavior and Sleep
The Effects of Snoring
How Sleep Benefits Brains
of us know what it is like to go without sleep and how it
can effect our mood and stress level. Here you will find
important information about why you may be losing sleep and
intriguing studies about sleep deprivation. You may be surprised.
Adequate sleep
is crucial to proper brain function – no less
so than air, water, and food – but stress can
modify sleep-wakefulness cycles.
Any amount
of sleep deprivation will diminish mental performance,
cautions Mark Mahowald, a professor of neurology at
the University of Minnesota Medical School. "One
complete night of sleep deprivation is as impairing
in simulated driving tests as a legally intoxicating
blood-alcohol level."
At the American
Diabetes Association's annual meeting in June 2001,
Eve Van Cauter, Ph.D., reported that people who regularly
do not get enough sleep can become less sensitive to
insulin. This increases their risk for diabetes and
high blood pressure – both serious threats to
the brain.
Previous work
by Dr. Van Cauter, a professor of medicine at the University
of Chicago, found that "metabolic and endocrine
changes resulting from a significant sleep debt mimic
many of the hallmarks of aging. We suspect that chronic
sleep loss may not only hasten the onset but could
also increase the severity of age-related ailments
such as diabetes, hypertension, obesity, and memory
loss ."1
That stress
can affect proper sleep seems obvious, but researchers
at Pennsylvania State University College of Medicine
have found another reason why middle-aged men may be
losing sleep. It's not just because of what they worry
about. Rather, it's due to "increased vulnerability
of sleep to stress hormones," according to Dr.
Alexandros N. Vgontzas.
As men age,
it appears they become more sensitive to the stimulating
effects of corticotropin-releasing hormone (CRH). When
both young and middle-aged men were administered CRH,
the older men remained awake longer and slept less
deeply. (People who don't get enough of this "slow-wave" sleep
may be more prone to depression.)
increased prevalence of insomnia in middle-age may,
in fact, be the result of deteriorating sleep mechanisms
associated with increased sensitivity to arousal-producing
stress hormones, such as CRH and cortisol," Vgontzas
and colleagues suggest.2
In another
study, the researchers compared patients with insomnia
to those without sleep disturbances. They found that "insomniacs
with the highest degree of sleep disturbance secreted
the highest amount of cortisol , particularly in the
evening and nighttime hours," suggesting that
chronic insomnia is a disorder of sustained hyperarousal
of the body's stress response system.3
Why do some
people lose sleep during periods of stress, while others
seem to "sleep like a baby"? Research suggests
that the difference may be explained by the ways people
At Tel Aviv
University, Dr. Avi Sadeh conducted a study of students.
He found that those "who tended to focus on their
emotions and anxiety during the high-stress period
were more likely to shorten their sleep, while those
who tended to ignore emotions and focus on tasks extended
their sleep and shut themselves off from stress."
The researchers
think that "stress may take the During a routine
week of studies, and again during a highly stressful
month, sleep patterns of 36 students
(aged 22 to 32) were
documented. Sleep quality
improved or remained the same for students who directed their focus away
from their emotions, but diminished for those who fretted and brooded as
a way to
cope with stress.
Almost titling
his paper, "If you can't cope with it, sleep on
it," Sadeh said "sometimes sleep can help
you regulate your nervousness and offer you an escape
from stress, particularly when there's nothing you
can do about it."4
A Northwestern
University study of 500 preschoolers found that those
who slept less than 10 hours in a 24-hour period (including
daytime naps) were 25% more likely to misbehave. They
were consistently at greatest risk for "acting
out" behavioral problems, such as aggression and
oppositional or noncompliant behavior.5
Research shows
that sleep disturbances in children are not only associated
with medical problems (allergies, ear infections, hearing
problems), but also with psychiatric and social issues.
Children who were aggressive, anxious, or depressed
had more trouble falling and staying asleep. Although
sleep problems usually decline as children get older,
these early patterns are the best indicator of future
sleep troubles.6
In our society,
snoring is often viewed as a comic nuisance. Couples complain
of partners keeping them awake, the kids will laugh at
grandpa snoring away during an afternoon nap, and if you
are the one who kept everyone awake during a group sleepover,
you're sure to hear about the next morning. The fact
is snoring can create serious problems for the brain and
even intellect. Curious? Check out the particulars behind
A serious
concern for the brain is obstructive sleep apnea, a
disorder of interrupted breathing when muscles relax
during sleep. It usually occurs in association with
fat buildup or loss of muscle tone with aging.
During an
episode of obstructive apnea, the person's effort to
inhale air creates suction that collapses the windpipe.
This blocks the air flow for ten seconds to a minute,
while the sleeping person struggles to breathe. When
the blood oxygen level falls, the brain responds by
awakening the person enough to tighten the upper airway
muscles and open the windpipe. The person may snort
or gasp, then resume breathing – a cycle repeated
hundreds of times a night.
awakenings due to sleep apnea may lead to personality changes such as irritability
or depression, and because it also deprives the person of oxygen,
it can lead to a decline in mental functioning and an increased risk of stroke
or heart attack.
Loud snoring
and excessive daytime sleepiness are symptoms of sleep
apnea, but not everyone who snores has this disorder.
Also, frequent morning headaches may be a sign of sleep
evaluated 1,348 adults for the association between
the risk of getting a stroke with snoring, sleep duration,
and daytime drowsiness. Even after taking classic risk
factors into consideration – age, race, gender,
cigarette smoking, high cholesterol, high blood pressure,
diabetes – the risk for stroke was independently
and significantly associated with sleep factors.
"We found
that certain sleep characteristics such as sleeping
for more than eight hours, the tendency to fall asleep
during the day, and the tendency to snore influence
the likelihood of having a stroke," says the study's
lead author Adnan I. Qureshi, M.D., assistant professor
of neurosurgery at the State University of New York
at Buffalo. "Individuals who snore severely or
have trouble staying awake during the day should see
a doctor to find out why."7
should always be considered a problem, since snoring
indicates the presence of increased upper airway resistance
during sleep," says Dr. David Gozal, a researcher
at the University of Louisville.
Gozal and
his colleague Dennis W. Pope Jr. interviewed more than
1,500 middle-school students. About 13% of those ranking
in the bottom quarter of their class reported loud
and frequent snoring in early childhood, compared to
only 5% in the top quarter. Half the loud snorers lived
with adults who smoked.
The disordered
breathing – and disrupted sleep – associated
with snoring can lead to attention-deficits and hyperactivity,
asthma and allergies, as well as aggression, the investigators
found. Because these problems can adversely affect
academic performance, snoring can be considered a serious
threat to a child's intellectual potential.
findings suggest that children who experienced sleep-disordered
breathing during a period traditionally associated
with major brain growth and substantial acquisition
of cognitive and intellectual capabilities may suffer
from a partially irreversible compromise of their.
. . potential for academic achievement," reported
the researchers.
Gozal believes "that
the presence of frequent and loud snoring in children
who also demonstrate behavioral problems, learning
problems, bedwetting, or failure to thrive, should
prompt referral to a primary care physician and strong
consideration of an evaluation by a pediatric sleep
Dr. David
Gozal, a researcher at the University of Louisville,
found a connection between snoring and attention-deficit/hyperactivity
disorder (ADHD) in some young children. After collecting
data on more than 5,000 six-year-olds, and surveying
the parents of 11,000 first-graders, he and his team
found that twice as many ADHD children experienced
frequent loud snoring, compared to the general population
of children. An even greater risk factor than parents's
snoring habits was exposure to secondhand smoke at
When he treated
kids for their snoring, their ADHD became much better
or totally disappeared, says Gozal. Even if it did
not lead to complete resolution, there was some improvement
in behavior and less need for medication.9
In an Italian
study of more than 2,200 children, the group with the
highest body mass index (BMI) was more than twice as
likely to snore, compared to the group with the lowest
BMI (a measurement of weight in relation to height).10
Because the
respiratory system is greatly influenced by the force
of gravity, the effect of weightlessness on sleep-related
breathing problems was observed in five space shuttle
astronauts. Dr. G. Kim Prisk from the University of
California at San Diego found that, without gravity,
breathing problems were reduced by 55% – and
snoring was nearly eliminated.
His report
suggests that obstructed breathing might be alleviated
by sleeping in a more upright position, instead of
on the back.11
There is nothing like a good night's sleep. You feel
refreshed and ready for the day. But did you know that
during sleep you are enhancing your learning and memory?
Did you know that you would probably do better on an exam
if you had a good night's sleep versus pulling an
all-nighter? Find out more about the surprising benefits
of sleep and how you can make the most out of those blissful
Animal studies
show that sleep dramatically enhances changes in
brain connections during a period of early development.
Researchers at the University of California, San
Francisco, examined the effect of sleep on brain
plasticity in young cats that had just experienced
an environmental challenge. The animals that were
allowed to sleep for six hours after the stimulation
developed twice the amount of brain change, compared
to cats kept awake afterward.
is the first direct evidence that sleep modifies
the effect of environmental stimuli on the development
of new brain connections," said Marcos G. Frank,
Ph.D. The finding has broader implications for plasticity
in the brains of adult animals and people.
think it's likely to be true that other areas of
the brain, higher areas of the brain, have their
critical (developmental) periods later in life," said
the study's senior author Michael P. Stryker, Ph.D., "and
some of them, in the highest areas, the critical
periods never close until senility."12
What's more,
the amount of plasticity (connections between nerve
cells) in the brain depends on the amount of deep
sleep, which is indicated by large slow brain waves.
This is the sleep that a person falls into when they
first go to sleep, and accounts for half of sleep
time in young animals and human babies, (who get
up to three times more sleep than adults). Stryker
said this is precisely the time in life when the
brain reorganizes its connections to attain the perfect
precision it needs as an adult.
Sleep could
prove to be an important part of the strategy for
preparing for challenges such as exams. "The
fact that sleep provoked slightly more plasticity
(connections between nerve cells) than double the
amount of exposure to experience – suggests
that if you reviewed your notes thoroughly until
you were tired and then slept, you'd achieve as much
plasticity, or 'learning,' in the brain as if you'd
pulled an all-nighter repeating your review of the
material," says Michael P. Stryker, Ph.D., researcher
at the University of California, San Francisco
have shown that sleep-loss affects learning and memory.
When animals and humans are deprived of sleep, they
do not perform
well on memory tasks.
Human research
supports the function of rapid eye movement (REM) sleep
in memory formation. German scientists at the University
of Bamberg Department of Physiological Psychology compared
memory retention of emotional versus neutral text material.
Participants were tested over intervals covering either
early sleep (dominated by slow wave sleep) or late
sleep when REM sleep is dominant.
Sleep not
only improved retention, compared to a wake group,
but "late sleep particularly enhanced memory for
emotional texts. This effect was highly significant
in comparison with memory for neutral texts," said
the authors. "Results are consonant with a supportive
function of REM sleep predominating late sleep for
the formation of emotional memory in humans."13
After reviewing
the existing research on sleep, dreams, learning, and
memory, Dr. Robert Stickgold and his colleagues at
Harvard Medical School concluded that REM sleep seems
to be essential for learning how to do things. Learning
to play a musical instrument is an example of such "procedural
also appears to benefit from this overnight form of
cogitation. During sleep, particularly the REM phase,
the brain integrates information it took in during
the day but couldn't process at the time. "Sleeping
on it" is not necessary, however, for simple memory
or learning tasks.
also believes that sleep may be involved in "erasing
memories from the immediate and distant past," and
that dreaming is probably a piece of this process.14
Earlier studies
with rodents, birds, and humans have suggested that
brain activity initiated while awake is later reactivated
during subsequent sleep, as part of the process that
consolidates recent experience into memory.
at Rockefeller University showed that, in rats, certain
brain cells that activate during daytime exploration
tend to reactivate during sleep. Sidarta Ribeiro, Constantine
Pavlides, and colleagues found that exposure to a "memorable" environment
causes the brain to turn on a gene called zif-268 that
is associated with strengthened communication between
nerve cells.
The researchers
exposed a group of rats to novel, enriched environments
(labyrinths with toys), and another group of rats to
their normal home cages. Then the rats went to sleep,
passing through successive stages of slow wave and
REM sleep.
During slow
wave sleep, zif-268 turned off in all rats, regardless
of which environment they had experienced. But during
REM sleep, zif-268 turned on in the cerebral cortex
and hippocampus of only rats that had explored the
labyrinths. The gene stayed off in rats that had not
experienced the enriched environments.
This retrieval
of zif-268 activity during REM sleep may couple with
other reactivated brain mechanisms to "process" memories
of novel experiences. Such processing may in turn prove
important for cementing the memories acquired while
Why do cats
nap? Because they can. But so can you. Simply taking
a nap may be one of the best things you can do to correct
poor mental performance, especially after a stressful
night of disrupted sleep, such as from sleep apnea
or snoring . Naps can help make up for nighttime loss.
In a study
of Japanese men, a mid-afternoon nap had positive effects
upon the maintenance of their daytime vigilance level.
The 20-minute nap improved performance level and their
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text:
The prototypic Toll protein of Drosophila melanogaster
is a plasma membrane receptor characterized by a single transmembrane
domain and a series of leucine-rich ectodomain repeats. It has been shown
to fulfill both developmental and immunological functions, triggering
dorsoventral patterning of the embryo [1, 2] and defending against fungal
infections in adult life [3]. Similarly, the Toll ortholog 18-wheeler
is required for defense against bacterial infections [4].
Mammals express an array of receptors with structural similarity
to Toll. The first of these to be recognized was the IL-1 receptor [5,
6]. Subsequently, the IL-1 receptor accessory protein (IL-1RAcP), and
both chains of the IL-18 receptor [7], were noted to have cytoplasmic
domains with homology to the cytoplasmic domain of Toll. However, the
ectodomain structures of these receptors (like that of the more recently
discovered orphan receptor SIGIRR [8]) are based on repeats derived from
the immunoglobulin superfamily, and are not leucine rich.
Quite apart from these cytokine receptors, a total of six
orphan receptors with leucine-rich ectodomains and cytoplasmic Toll-like
domains (i.e., displaying homology to Toll over the full length
of the protein rather than in the cytoplasmic domain alone) were identified
by analysis of expressed sequence tag (EST) libraries [9-12]. Full-length
(or nearly full-length) sequences were deduced for cDNAs encoding human
Tlr1, Tlr2, Tlr3, Tlr4 [9, 11], and Tlr6 [12]; a partial sequence was
determined for Tlr5 [11]. One of these receptors (Tlr4, or "h-Toll") was
shown to be capable of triggering nuclear translocation of NF-kappaB upon
ligation, in experiments in which chimeric receptors were expressed in
mammalian cells, using a CD4 ectodomain in place of the native Tlr4 ectodomain
The function of Tlr4 became clear with the recent positional
cloning of the Lps locus, which revealed destructive mutations
of Tlr4 in endotoxin resistant mice of the C3H/HeJ and C57BL/10ScCr
strains [13, 14]. In the former strain, a point mutation modifies the
cytoplasmic domain of the Tlr4 protein, abrogating signal transduction.
In the latter strain, the gene is deleted entirely by a mutation spanning
74,723 bp of genomic sequence [15]. Moreover, knockout of the Tlr4
locus was shown to produce a phenocopy of the natural Tlr4 mutations
[16]. Hence, Tlr4 is an essential component of the LPS signal transduction
In further genetic complementation studies [17], the species
origin of Tlr4 was shown to determine reactivity toward LPS partial structures
that are known to be species-specific in their ability to stimulate macrophages.
Hence, tetraacyl lipid A, an agonist for mouse macrophages, but an antagonist
of LPS in human monocytic cell lines, was shown to be capable of activating
mouse macrophages that expressed the mouse isoform of Tlr4, but was incapable
of activating cells that expressed the human isoform of Tlr4. It would
therefore seem certain that LPS is directly engaged by Tlr4, and does
not act through an intermediary ligand.
Other microbial ligands, such as lipoteichoic acid [18],
may also utilize the Tlr4 receptor. It would therefore appear that Tlr4
may be oligospecific in its ligand preference rather than monospecific.
The Tlr2 gene product was subsequently implicated in the transduction
of signals evoked by Gram-positive bacteria [19], and knockout work has
provided evidence that signaling initiated by peptidoglycan (muramyldipeptide)
and at least some lipopeptides are both dependent upon this receptor [18,
20]. Hence Tlr2, like Tlr4, may be oligospecific rather than monospecific.
It is plausible to think that other bacterial products signal via
other Tlrs, and that in this manner, the Tlrs may collectively be responsible
for the sensing of virtually all microbial pathogens.
For this reason, there has been a compelling motive for
identifying novel Tlrs, though prospects for finding them among ESTs have
diminished with the passage of time: at present, no strong homology may
be found between any of the six known Tlrs and novel targets in dbEST,
using the TBLASTN algorithm (unpublished observation). However, as genomic
sequencing approaches a point of completion, it may be considered that
all members of the Tlr superfamily will be identified.
As of this writing, 79.1% of the human genome has been
published in the form of draft sequence, and 18.6% has been published
as "finished" sequence. We therefore undertook to examine the human genomic
sequence database in an effort to identify novel TLRs. We now detail the
sequence, genomic structure, and expression characteristics of three novel
TLRs (designated TLRs 7, 8, and 9 in accordance with the established convention)
identified by this search. Two of these TLRs are X-linked, and lie in
close apposition to one another at Xp22. A third is located at human chromosome
3p21.3. Though they are each represented as ESTs in one species or another,
the extent of sequence overlap was insufficient to permit their recognition
as "Toll-like" through a search of dbEST. The novel TLRs are longer than
any of the existing TLRs, and comprise a new phylogenetic cluster.
Search of genomic sequence for
novel Tlrs
The Web-based NCBI BLAST program was used to examine three
databases (Human Genome BLAST: finished human genomic sequence; the high-throughput
genome sequence [htgs] database of draft sequence; and the nonredundant
[nr] division of Genbank). The queries used were a region of the human
MyD88 protein sequence corresponding to the area of homology with human
Tlr4 (MyD88 residues 181-316), and also, the full-length human Tlr4 protein
sequence. The TBLASTN algorithm (which translates the target sequence
in all six frames before comparing with a peptide query) was used for
the search. The e-value of the output was set at 10.
PCR amplification of the target
human genomic sequence
Human placental cDNA purchased from Clontech was used as
the template for amplification of Tlr7 and Tlr8 sequences. THP-1 cell
mRNA was used as a template for the reverse transcription and amplification
of Tlr9 cDNA sequences. Initial amplification of TLR7 was accomplished
using the primers:
Initial amplification of TLR8 was accomplished using the primers:
Initial amplification of TLR9 was accomplished using the primers:
cDNA cloning of three novel human
THP-1 cell RNA was reverse transcribed using an oligo dT
primer. The same primers used for initial genomic amplifications were
used to amplify the major part of the corresponding cDNAs. The 5' and
3' termini of the mRNA molecules were determined by 5' and 3' RACE. For
these reactions, the following primers were used:
DNA sequencing
Using the primers shown in Table
1, the entire cDNA of each of the novel Tlrs, and the coding region
of the genomic sequences of each of the novel TLRs, was determined using
Model 373 and 377 DNA sequencers, and amplified templates. Dye-terminator
chemistry was used, and trace files were assembled with the programs phred
and Phrap (obtained from the University of Washington Genome Center).
The alignment of genomic and cDNA sequences was performed using the fasta
program of the GCG 9.0 suite, and mismatches were examined using the program
Consed (University of Washington Genome Center).
Bioinformatic analysis
As already mentioned, proteins exhibiting Toll-like cytoplasmic
domains were identified by defining the most conserved region of the Toll-like
domain in human MyD88, a rather distant member of the family. Residues
181-316 of human MyD88 were then designated as a query sequence to be
used in finding all homologous sequences by BLAST search, carried out
against the human genome (using TBLASTN) and against the nonredundant
Genbank database (using BLASTP). The GCG program Pileup was then used
to align the polypeptide sequences of Tlrs 1 though 9 and all other proteins
or open reading frames known to have homology to the Toll-like domain
of human MyD88. A gap penalty setting of 4 and a gap extension penalty
of 2 were assigned for this purpose.
Evolutionary distance assessments were performed using
the program PAUP (Smithsonian Institution), run with the Seqlab modality
of GCG, using the setting for maximum parsimony. A bootstrapping procedure
was followed, with 100 repetitive measurements performed to determine
tree structure. Only a single tree was generated for each set of input
data. Final trees were drawn by hand, according to output data generated
by PAUP. In dating divergence, an neutral drift model was used, and all
distances were calculated relative to the average separation of human
and mouse TLR2, TLR4, TLR5, TLR6, and TLR7 genes. Measurements were confirmed
by determination of synonymous (third codon) substituiton rates for all
coding sequences. All numbers presented were calculated based on the tenable
assumption that humans and mice diverged from a common ancestor 60 million
years ago.
The program Generunner was used for analysis of reading
frames. The program SMART (http://smart.emblheidelberg.de/) was used for
comparative analysis of structural domains.
Six Tlr cDNAs were known to be present in Genbank prior
to the initiation of this study. All of these (Tlrs 1, 2, 3, 4, 5, and
6) were represented in the high-throughput genomic sequencing databases
(htgs; databases encompassing phase 1 and phase 3 sequencing efforts).
Three additional high-scoring homologies were identified on the human
X chromosome (Xp22.2 to 22.3), and one high-scoring homology was identified
on chromosome 3 (3p21.3). The triad of X-chromosome homologs are distributed
over approximately 55 kb of genomic DNA, and lie in close proximity to
a pair of PRPS2 (phosphoribosylpyrophosphate synthetase II) genes; the
single chromosome 3 homolog lies in close proximity to ALAS1 (the delta-aminolevulinate
synthase gene), and is also in the same cytogenetic interval as the MyD88
Two of the X-chromosome homologs and the chromosome 3 homolog
had long open reading frames; the remaining X-chromosome homolog, lying
in opposite orientation to the first two and placed to one side of them,
did not. Reference to the dbEST database immediately revealed that the
two X-chromosome homologs with long open reading frames were expressed
as processed mRNA, in that each had several EST representatives. The chromosome
3 homolog was not initially represented by a human transcript in dbEST,
but one such EST was added in the course of our work (accession no. AW502545).
The remaining X-chromosome homolog was not represented at all, and for
this reason as well as the fact that it lacked a long open reading frame,
it was presumed to be a pseudogene.
Each Tlr cDNA was amplified by PCR and sequenced in entirety.
The furthest 5' extent of each mRNA was determined by RACE. On this basis,
the presumed full-length sequence of the two expressed X-chromosomal Tlr
cDNAs and the chromosome 3 Tlr cDNAs were submitted to Genbank as Tlrs
7, 8, and 9, respectively (AF240467 [TLR7], AF246971 [TLR8], and AF259262
and AF259263 [TLR9]). In Figure 1,
the genomic structure of each of the novel TLRs is presented, as deduced
from the cDNA sequence. Both TLR7 and TLR8 have two introns and three
exons, much as described for Tlr2 [18] and Tlr4 [14, 21].
However, as distinct from both Tlr2 and Tlr4, only exon
2 and exon 3 have coding function in TLR7 and TLR8. Moreover, only the
initiator methionine is encoded by exon 2 in either gene. Hence, the coding
region of TLR7 and TLR8 genes is almost entirely monoexonic. Two separate
splice forms of TLR9 were cloned by RACE. One had two exons, while the
other had a single exon. The biexonic protein (designated Tlr9a) has 57
additional amino acids at the N-terminus as compared with the monoexonic
protein (Tlr9b) (Figure 2).
On the basis of these findings, the length of each new
gene can be assigned. From cap site to poly-A addition site, the TLR7
gene is 23,279 bp in length; the TLR8 gene is 15,563 bp in length; the
TLR9 gene is either 5,069 or 3,109 bp in length, depending upon definition.
TLR7 and TLR8 are separated from each other by 16,273 bp of intervening
DNA and are transcribed in the same direction, though the polarity of
transcription with respect to the centromere remains unknown.
The inferred structure of the proteins specified by these
three novel TLRs are interesting in that each is longer than any of the
Tlrs reported previously (see alignment, Figure
2). Moreover, there are more leucine-rich repeats than are present
in most of the other Tlrs (15 for TLR7; 16 for TLR8; 18 for TLR9). Only
Tlr3, which has 19 repeats, falls among the new Tlrs in this respect.
All of the novel TLRs exhibit a proline residue at the site corresponding
the mutation that renders C3H/HeJ mice unresponsive to LPS; TLR3 alone
provides the exception to the rule. Some residues are even more stringently
conserved, and are in strict consensus throughout the family. mRNA encoding
each of the novel Tlrs is expressed at a very low level in mammalian tissues.
As such, only a weak hybridization signal could be obtained using any
of the full-length cDNA molecules as probes on Northern blots (not shown).
However, a sense of the expression pattern of these novel genes was obtained
using RT-PCR (Figure 3).
The evolutionary relationship among the nine existing mammalian
Toll-like receptors was examined using the method of maximum parsimony
after performing an optimal alignment using Pileup. A single solution
was obtained, regardless of parameter variation; in particular, whether
or not bootstrapping was used. In an unrooted tree denoting the these
nine mammalian receptors alone, TLR7, TLR8, and TLR9 emerge as nearest
neighbors (Figure 4). TLR1 and
TLR6 are the most closely related TLRs of the nine examined; they, in
turn were most nearly related to TLR2, and then, to TLR4. TLR3 and TLR5
appear to have diverged from a common ancestral gene, and both were isolated
from all other mammalian Tlrs by a considerable distance. An informed
estimate of the dates of divergence is presented in Table
The relationship of the mammalian Tlrs with all other proteins
bearing a Toll-like cytoplasmic domain was then examined. This independent
approach to phylogenetic assignment (Figure
5) disclosed a relationship among the mammalian TLRs identical to
that obtained using whole protein sequences, and barely distorted at all
by exclusion of the ectodomain. As with the former method and more
obviously so cytoplasmic domain homology relegates TLR7, TLR8,
and TLR9 to a cluster of their own. TLR5 and TLR3 are still more dramatically
isolated from the other TLRs. TLR1 and TLR6 are seen to be more similar
to one another than any of the other TLRs, and next most closely related
to TLR2, and then, to TLR4.
Some surprises are evident. A Drosophila protein
(cg5528) is found to even more similar to the [TLR1, TLR6, TLR2] cluster
than is TLR4. Though one of the nine Drosophila Toll-like proteins
now known to be endowed with a leucine-rich ectodomain, cg5528 was grouped
with the mammalian proteins solely on the basis of cytoplasmic domain
homology. Another Drosophila protein (cg2078) also appears within
a mammalian cluster: this time, in close proximity to MyD88 and SIGIRR.
The IL-1 and IL-18 receptors, and the related ST2L protein lie within
a distinct cluster of their own.
The identification of three novel TLR genes (here designated
TLR7, TLR8, and TLR9) was a direct consequence of high-throughput genomic
sequencing. Though retrospectively it is possible to see that ESTs derived
from each of these genes were represented in dbEST, all of these ESTs
were either too short or improperly placed, so as to preclude significant
matches with the defining Toll-like domain of any of the existing TLRs,
using either BLASTN or TBLASTN search algorithms. Though the ESTs might
have served to identify the anonymous genomic seqences of these TLRs as
genes, the inevitable fact of EST database contamination by genomic DNA
makes EST identification a somewhat risky standalone criterion to use
in gene identification.
The total number of TLRs yet to be found in the mammalian
genome remains a matter of speculation, although by this time, it is clear
that at least the majority of them have been found, and very likely all
of them. All six of the earlier-described Toll-like receptor molecules
are among these. It is therefore reasonable to discuss the phylogenetic
relationships that unite these TLRs with each other, and with other proteins
that bear Toll-like cytoplasmic domains.
In the course of this work, a large number of genomic sequences
bearing similarity to the ectodomain-encoding region of the true Tlrs
were identified. Among these sequences, which probably bear the leucine-rich
repeat module that typifies Tlrs, it is quite likely that some authentic
genes are to be found. However, the function of proteins with leucine-rich
motifs is quite variable, and in the main, is likely to be unrelated to
the function of the Tlrs. As such, we made no immediate attempt to identify
or characterize the expression patterns of genes that were bereft of a
Toll-like domain.
The leucine-rich repeat has been utilized for many purposes
in evolution. It is rather poorly conserved, and several proteins that
lack Toll-like cytoplasmic domains indeed, some secreted proteins
as well as surface receptors are recognized by BLAST searches based
on the ectodomain sequence of Toll-like receptor ectodomains. By contrast,
Toll-like homology represented in the cytoplasmic domain of all nine mammalian
Tlrs, the adapter protein MyD88, the Drosophila Toll-like receptors,
members of the IL-1 receptor family, and certain orphan receptors (for
example, SIGIRR, and ST2L) is far more conserved; i.e., it comprises
a slower molecular clock with which to assess evolutionary relationships.
As previously noted, the Tlr4 ectodomain is far more variable among species
that the Tlr4 cytoplasmic domain [21]. Further, the common structure of
the cytoplasmic domain of the true Toll-like receptors bespeaks an overlap
of function, already apparent from what is known of some of these receptors.
For example, the IL-1, IL-18, Tlr4, and Tlr2 receptors all depend upon
MyD88 for signal transduction, and all are known to deliver pro-inflammatory
signals. From all species, 47 molecules bearing Toll-like cytoplasmic
domains may now be assembled. It is, therefore, possible to answer a number
of questions concerning functional and phylogenetic relationships.
It is to be noted that divergence implies an increase in
the number of genes of a given type. While some genes may become non-functional
(i.e., pseudogenes) and degenerate to an unrecognizable state under
the pressure of mutation, several hundred million years are required for
such "resorption" to occur [22]. At present, nine Tlr genes and one Tlr
pseudogene are known to reside in the human genome. However, as may be
deduced from Table 2, 95 million
years ago, there were but nine genes at most, and just over 150 million
years ago, there were but six genes. Our best estimate holds that the
progenitor of Drosophila and humans bequeathed at most four genes
bearing Toll-like domains to the descendant phyla. In Drosophila
and humans alike, nine true Toll-like receptors may be found today.
Where TLR4 is concerned, a related inference immediately
presents itself. Mammals and birds are known to be LPS-sensitive (the
latter most obviously so during embryonic life [23]), and while evidence
exists for a reptilian response [24-30], reptiles almost surely less sensitive.
No other class in the subphylum Vertebrata is known to respond
to LPS. Mammals, reptiles and birds are believed to have evolved from
a common ancestor no more recently than 350 million years ago. It may
be supposed that each line inherited the primordial gene that became mammalian
TLR4 from this ancestor. In each descendant line, and particularly in
mammals and birds, a mechanism for LPS sensing has evolved, whereas LPS
sensing seemingly has not evolved in other vertebrate lines [31]. The
development of LPS sensitivity seems, then, to have been an example of
convergent evolution in mammals and birds, perhaps developed as a result
of changes in microbial flora that attended the development of a warm-blooded
way of life. However, it is somewhat problematic to speak of an avian
"Tlr4," since Tlr4 did not exist as a separate entity until long after
mammals and birds diverged from one another.
Several additional facts are apparent from the phylogenetic
tree presented in Figure 5. First,
since Drosophila proteins are grouped with mammalian proteins on
the basis of cytoplasmic domain similarity, it may be inferred that some
of the signaling functions present in modern-day fruit flies and mammals
were already present in a common ancestor, some five hundred million years
ago. It may be speculated that cg5528, which bears a cytoplasmic domain
more similar to TLR1, TLR6 and TLR2 than any of the other mammalian TLRs,
transmits a pro-inflammatory signal similar to that assigned to TLR2 or
TLR4. The commonality of structure within the cytoplasmic domain of these
molecules bespeaks an ancestry more ancient than might previously have
been supposed.
Further, though no mutational evidence
has yet emerged in support of the possibility, it can reasonably be proposed
that cg2078 found in a cluster with SIGIRR and MyD88 acts
in Drosophila to transduce signals much as MyD88 does in mammals.
Further to this view, the cg2078 protein has no leucine-rich ectodomain,
and indeed, appears to be strictly cytoplasmic: a fact quite independent
of its assignment to the MyD88/SIGIRR cluster. We also suggest that, in
mammals, SIGIRR may fulfill a role in signaling quite similar to that
of MyD88, this though SIGIRR is a transmembrane protein whereas MyD88
is not.
Among Drosophila transmembrane proteins with Toll-like
cytoplasmic domains, there are no representatives with ectodomains that
display immunoglobulin-type repeats. This might be taken as evidence that
the IL-1R/IL-18R/ST2L cluster arose after invertebrates and vertebrates
diverged. Indeed, the relatively tight grouping of this cluster supports
the assertion of a recent evolutionary origin. Moreover, insofar as IL-1R
and IL-18R are linked to the adaptive immune response rather than to primary
detection of microbes by the innate immune system, a more recent phylogenetic
appearance would be expected.
The fact that two X-chromosomal TLRs lie in close approximation
to one another (alongside a presumed TLR pseudogene), and the added fact
that TLR9 lies in the same cytogenetic interval as the MyD88 (a cytoplasmic
transducer with a Toll-like domain) suggests that at least some members
of the family arose from the tandem duplication of ancestral genes. Concordant
with the hypothesis of a recent duplication event, the two X-chromosome
representatives are quite closely related to one another. However, they
are less structurally similar than TLRs 1 and 6, which reside on different
chromosomes, but likely deliver very similar signals.
The assignment of function to distinct members of the Tlr
family is of paramount importance in this rapidly developing field. We
are able to draw no substantial inferences based on the distribution of
TLR gene expression. The novel TLRs, like most TLRs, seem broadly expressed,
though differentially expressed, and expressed at very low levels compared
to most "housekeeping" genes. So far, the best understood members of the
Tlr family are certainly Tlr4 and Tlr2. The function of Tlr4 as an LPS
receptor has been demonstrated by the identification of two naturally
occurring mutations that render mice resistant to LPS [13, 14], and subsequently
was confirmed by knockout of the gene [16]. It would appear that Tlr2
serves to identify lipopeptides [20] and peptidoglycan [18]. The function
of all other members of the family remains unknown, though there is speculation
that both immunologic functions (related to microbial sensing by the innate
immune system) and developmental functions (akin to dorso-ventral patterning
of the embryo subserved by Drosophila Toll) might be ascribed to
individual Tlr proteins. It would seem that the identification or production
of mutations in TLR genes comprise the best tools presently available
for the assignment of function.
From this standpoint, it is particularly fortunate that
two of the novel TLRs (TLR7 and TLR8) reside on the X chromosome. As such,
phenotypically detectable mutations should be recoverable in males, and
in some females, depending upon the extent of X-inactivation to which
the normal allele is subject. Moreover, hemizygosity for knockout mutations
of the X-chromosomal loci is conveniently achieved. Finally, insofar as
the mammalian X chromosome is conserved in toto, it may be expected
with confidence that TLR7 and TLR8 reside on the X chromosome in other
mammalian species as in humans.
We are unaware of unexplained immunologic phenotypes associated
with Xp22. However a number of developmental phenotypes map to the region
and remain unexplained, and recently, mutations affecting a novel ortholog
of the IL-1 receptor mapping to Xp22.3 have been associated with an X-linked
form of mental retardation [32]. As to the 3p21.3 location of TLR9, we
are also unable to point to phenotypes that seem certain to be caused
by mutations of this gene, but note that several neoplastic diseases have
been mapped to this region. The possibility that this Tlr, or other Tlrs
yet to be identified, might act as tumor suppressors is a plausible one,
since there is direct continuity between the Toll-like domain and pro-apoptotic
pathways within the cell. MyD88 and IRAK, for example, both downstream
intermediates for Tlr signal transduction, have well-defined death domains.
This may account for some of the effects wrought by Tlr agonists: for
example, the pro-apoptotic effect of LPS applied to cultured macrophages
1. Anderson K V, Jurgens G, Nusslein-Volhard C. 1985. Establishment
of dorsal-ventral polarity in the Drosophila embryo: genetic studies
on the role of the Toll gene product. Cell 42: 779.
2. Anderson K V, Bokla L, Nusslein-Volhard C. 1985. Establishment
of dorsal-ventral polarity in the Drosophila embryo: the induction
of polarity by the Toll gene product. Cell 42: 791.
3. Lemaitre B, Nicolas E, Michaut L, Reichhart J M, Hoffmann
J A. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus
controls the potent antifungal response in Drosophila adults. Cell
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in Drosophila host defense. EMBO J. 16: 6120.
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6. Heguy A, Baldari C T, Macchia G, Telford J L, Melli
M. 1992. Amino acids conserved in interleukin-1 receptors (IL-1Rs) and
the Drosophila toll protein are essential for IL-1R signal transduction.
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7. Born T L, Thomassen E, Bird T A, Sims J E. 1998. Cloning
of a novel receptor subunit, AcPL, required for interleukin-18 signaling.
J. Biol. Chem. 273: 29445.
8. Thomassen E, Renshaw B R, Sims J E. 1999. Identification
and characterization of SIGIRR, a molecule representing a novel subtype
of the IL-1R superfamily. Cytokine 11: 389.
9. Medzhitov R, Preston-Hurlburt P, Janeway C A Jr. 1997.
A human homologue of the Drosophila Toll protein signals activation
of adaptive immunity. Nature 388: 394.
10. Chaudhary P M, Ferguson C, Nguyen V, Nguyen O, Massa
H F, Eby M, Jasmin A, Trask B J, Hood L, Nelson P S. 1998. Cloning and
characterization of two Toll/Interleukin-1 receptor-like genes TIL3 and
TIL4: evidence for a multi-gene receptor family in humans. Blood
91: 4020.
11. Rock F L, Hardiman G, Timans J C, Kastelein R A, Bazan
J F. 1998. A family of human receptors structurally related to Drosophila
Toll. Proc. Natl. Acad. Sci. USA 95: 588.
12. Takeuchi O, Kawai T, Sanjo H, Copeland N G, Gilbert
D J, Jenkins N A, Takeda K, Akira S. 1999. TLR6: a novel member of an
expanding Toll-like receptor family. Gene 231: 59.
13. Poltorak A, Smirnova I, He X L, Liu M Y, Van Huffel
C, McNally O, Birdwell D, Alejos E, Silva M, Du X, Thompson P, Chan E
K L, Ledesma J, Roe B, Clifton S, Vogel S N, Beutler B. 1998. Genetic
and physical mapping of the Lps locus- identification of the toll-4
receptor as a candidate gene in the critical region. Blood Cells Mol.
Dis. 24: 340.
14. Poltorak A, He X, Smirnova I, Liu M Y, Van Huffel C,
Du X, Birdwell D, Alejos E, Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli
P, Layton B, Beutler B. 1998. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr
mice: mutations in Tlr4 gene. Science 282: 2085.
15. Poltorak A, Smirnova I, Clisch R, Beutler B. 2000.
Limits of a deletion spanning Tlr4 in C57BL/10ScCr mice. Submitted.
16. Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda
Y, Takeda K, Akira S. 1999. Cutting edge: Toll-like receptor 4 (TLR4)-deficient
mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the
Lps gene product. J. Immunol 162: 3749.
17. Poltorak A, Ricciardi-Castagnoli P, Citterio A, Beutler
B. 2000. Physical contact between LPS and Tlr4 revealed by genetic complementation.
Proc. Natl. Acad. Sci. USA 97: 2163.
18. Takeuchi O, Hoshino K, Kawai T, Sanjo H, Takada H,
Ogawa T, Takeda K, Akira S. 1999. Differential roles of TLR2 and TLR4
in recognition of gram-regative and gram-positive bacterial cell wall
components. Immunity 11: 443.
19. Underhill D M, Ozinsky A, Hajjar A M, Stevens A, Wilson
C B, Bassetti M, Aderem A. 1999. The Toll-like receptor 2 is recruited
to macrophage phagosomes and discriminates between pathogens. Nature
401: 811.
20. Takeuchi O, Kaufmann A, Grote K, Kawai T, Hoshino K,
Morr M, Mühlradt P F, Akira S. 2000. Cutting edge: preferentially
the R-stereoisomer of the mycoplasmal lipopeptide macrophage-activating
lipopeptide-2 activates immune cells through a Toll-like receptor 2- and
MyD88-dependent signaling pathway. J. Immunol. 164: 554.
21. Smirnova I, Poltorak A, Chan E K, McBride C, Beutler
B. 2000. Phylogenetic variation and polymorphism at the Toll-like receptor
4 locus (TLR4). Genome Biology 1: 1.
22. Li W H. 1997. In: Molecular Evolution, 177-214.
Sinauer Associates, Inc., Sunderland, MA.
23. Finkelstein R A. 1964. Observations on mode of action
of endotoxin in chick embryos. Proc. Soc. Exp. Biol. Med. 115:
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pregnancy in the viviparous lizard, Chalcides ocellatus. Vet. Immunol.
Immunopathol. 25: 279.
25. Saad A H. 1989. Sex-associated differences in the mitogenic
responsiveness of snake blood lymphocytes. Dev. Comp. Immunol.
13: 225.
26. Clark I A. 1982. Correlation between susceptibility
to malaria and babesia parasites and to endotoxicity. Trans. R. Soc.
Trop. Med. Hyg. 76: 4.
27. Zurovsky Y, Brain T, Laburn H, Mitchell D. 1987. Pyrogens
fail to produce fever in the snakes Psammophis phillipsii and Lamprophis
fuliginosus. Comp. Biochem. Physiol. A. 87: 911.
28. Zurovsky Y, Mitchell D, Laburn H. 1987. Pyrogens fail
to produce fever in the leopard tortoise Geochelone pardalis. Comp.
Biochem. Physiol. A. 87: 467.
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immune responses of the snake, Psammophis sibilans. Immunobiology
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response of Chelonia mydas. Dev. Comp. Immunol. 9: 445.
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on the toxicity of Escherichia coli lipopolysaccharide endotoxin
in various animal species. Can. J. Microbiol. 12: 1070.
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Couvert P, Zemni R, Cardona A, Van Buggenhout G, Frints S, Hamel B, Moraine
C, Ropers H H, Strom T, Howell G R, Whittaker A, Ross M T, Kahn A, Fryns
J P, Beldjord C, Marynen P, Chelly J. 1999. A new member of the IL-1 receptor
family highly expressed in hippocampus and involved in X-linked mental
retardation. Nat. Genet. 23: 25.
33. Karahashi H, Amano F. 1999. LPS-induced signals in
activation of caspase-3-like protease, a key enzyme regulating apoptotic
cell damage into a macrophage-like cell line, J774.1, in the presence
of cycloheximide. J. Leukoc. Biol. 66: 689.


text:
County Home » Departments »
Sheriff's Office » Press Releases
Location: Humboldt County
The Humboldt County Sheriff's Office Animal Shelter would like to remind pet owners of some of the potential hazards associated with the Christmas Holiday.Christmas Trees: The water in your Christmas tree stand may contain preservatives or fertilizers, which, if ingested by your pet, cold lead to stomach upset. Stagnant water can also breed bacteria, which can cause vomiting, nausea and diarrhea if ingested.Electrical Cords: If chewed, could electrocute your pet. Cover and hide them if possible.Ribbon/Tinsel: Can become lodged in the intestines and cause obstruction.Lilies: Commonly used in holiday floral arrangements, can cause kidney failure in cats if ingested.Holly/Mistletoe: Holly can cause vomiting, nausea, diarrhea and lethargy if ingested by your pet. Mistletoe can cause gastrointestinal upset and cardiovascular problems.Poinsettias: If ingested can cause irritation to your pets mouth, and mild vomiting or nausea.Antifreeze: (used in snow globes) Can be fatal to your pets if ingested, even in small quantities. Animals are attracted to the sweet taste.Chocolate: Contains Theobromine and Caffeine that can cause stimulation of the central nervous system, increased heart rate and tremors. Symptoms include diarrhea, vomiting, seizures, hyperactivity increased thirst and urination. This can be seen with the ingestion of as little as 1/4 oz. of baking chocolate by a 10 lb. dog.Macadamia nuts: If ingested by dogs can cause muscular weakness, depression, vomiting, tremors and abdominal pain.If you suspect that your pet has ingested any of these items, contact your veterinarian immediately, or the Animal Poison Control Center's Hotline @ 1-888-426-4435.There are many wonderful animals up for adoption at the shelter. Please come in and visit us at 980 Lycoming Ave. in Mckinleyville, or visit www.petharbor.com to see all of our adoptable pets.If you would like to make a donation for the benefit of the shelter animals, we would love to have toys and treats. Cash donations can be made to the Friends for Life Emergency Medical Fund at the shelter, by mail at P.O. Box 962, Eureka Ca, 95502, or by going to www.dogrescuers.orgThe staff at the shelter would like to wish everyone a happy Holiday Season!Mike DowneySheriff
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On Tuesday, the Wisconsin Supreme Court, in Noffke v. Bakke, ruled that high school cheerleaders qualify for civil liability restriction under state law. The court's ruling, apparently a first in the United States, was handed down in a suit by a cheerleader (Noffke) alleging negligence against her spotter (Bakke), who failed to catch [...]Continue Reading →
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- Developer: Adult Swim
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- Release Date: Oct 23, 2012
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Daily Joke
A Sunday school teacher asked little Susie, "Who's your favorite person in the Bible?"
Susie said, "King Solomon."
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"What do you mean?"
"He had six hundred wives and three hundred porcupines."
- Joke shared by Beliefnet member Arkansasannie
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Cow Lift
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For cows unable to stand on their own.
Fits small to large cows.
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CRJ133 Criminology (3-0-3)
This course provides an etiology of crime and the understanding of criminal behavior. The course delves into biological, psychological and sociological theories that examine the reasons for such large numbers of arrested and convicted individuals. It also views the collection of empirical data and the statistical analysis of such information which supports each theory. The importance of such empirical data garnered from sociological research and how the research is critical to the implementation within the components of the criminal justice system are examined. Students develop an informed analysis of criminal activity through an understanding of the theories discussed. S


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Using R Markdown with RStudio
R Markdown enables easy authoring of reproducible web reports from R. It offers:
- Easy creation of web reports from R that can be automatically regenerated whenever underlying code or data changes.
- A highly accessible syntax (markdown) which lower the barriers to entry for reproducible research.
- Output of a standalone HTML file (with images embedded directly in the file) that is easy to share using email, Dropbox, or by deploying to a web server.
- Support for publishing dynamic and interactive web content.
This article includes an overview of how to use R Markdown within RStudio. For more specific details on syntax and implementation, see the R Markdown article.
Markdown Basics
Markdown is a simple markup language designed to make authoring web content easy for everyone. Rather than writing HTML and CSS code, Markdown enables the use of a syntax much more like plain-text email. For example the file on the left shows basic Markdown and the resulting output as an HTML file on the right:
R Markdown Documents
To work with R Markdown (.Rmd) files in RStudio you first need to ensure that the knitr package (version 0.5 or later) in installed.
To create a new R Markdown file, go to File | New | and select R Markdown. A new file is create with a default template to get you oriented:
Note that the toolbar provides some useful tools for working with R Markdown:
- Quick Reference — Click the MD toolbar button to open a quick reference guide for Markdown.
- Knit HTML — Click to knit the current document to HTML, see the Knitting to HTML section below for more details.
- Run — Run the current line or selection of lines in the console. This allows running R code inside a code chunk similar to a normal R source file.
- Chunks — The chunks menu provides assistance with inserting, running, and chunk navigation. See the Chunk Menu and Options section below for more details.
Embedding R Code Chunks
Within an R Markdown file, R Code Chunks can be embedded using the native Markdown syntax for fenced code regions:
```{r chunkLabel}
# R code
For example, the following code chunk computes a data summary and renders a plot as a PNG image. It then embeds the results within a standalone HTML file:
Embedding Inline R Code
You can also evaluate R expressions inline by enclosing the expression within a single back-tick qualified with 'r'. For example, the following code:
Results in this output: "I counted 2 red trucks on the highway."
Embedding Equations
You can embed LaTeX or MathML equations in R Markdown files using the following syntax:
$equation$for inline equations (note there must not be whitespace adjacent to the $ delimiters)
$$ equation $$for display equations
<math ...> </math>for MathML equations.
The article on Equations in R Markdown includes more detailed information on embedded equations.
Knitting to HTML
Click the Knit HTML toolbar button (or use the Cmd+Shift+H shortcut) to process an R Markdown file into a web page. This runs
knit on the Rmd file to create a Markdown file, evaluating all R code and results as specified. Note that for reproducibility purposes, the knit runs in a separate process and environment (rather than using the current workspace). This is to ensure the script will always produce the same result and not be effected by (or pollute) your regular R environment. Finally, the generated Markdown file is converted into HTML and shown in a separate preview window.
The HTML file which is generated by invoking Knit HTML is a standalone web page. This means that images, CSS, etc. are embedded within the HTML file so it can be shared without needing to package up any additional files. You can attach the HTML file to an email, share it using Dropbox, or deploy it to a web server as a single HTML file.
Navigating Between Chunks
A popup navigation menu is located at the bottom of the editor based on the chunk labels (optional) in your Rmd file. This makes editing and navigating between chunks easy. The following screenshot shows an example of this chunk navigation menu.
Using the Chunk Menu
The chunk Menu makes it easy to insert new chunks and execute R code from within an R Markdown document.
- Insert Chunk — Inserts the basic syntax for an embedded R code chunk.
- Jump To... — Opens the Chunk Navigation Menu to jump to a specific code chunk.
- Run Current/Next Chunk — Runs the current (or next) code chunk based on the cursor position. You can use this to iteratively step through code chunks one-by-one to test your R code. This interacts with the console and acts upon the current global environment.
Run All
Run all R code chunks in the current document. This is analogous to sourcing the file which results from the
stangleof an Rnw file.
Customizing Chunk Options
You can apply knitr options to each code chunk individually or globally. When typing chunk options, code-completion is enabled to help recall and complete option names and values. See the example document on customizing chunk options or see the knitr package for a full list of chunk options.
Gallery of Examples
Dynamic Graphics with the googleVis Package
The googleVis package makes it easy to create interactive plots and motion charts inside R Markdown.
Customizing Chunk Options
The knitr package provides various options to customize the output of your code chunks globally or on an individual basis. For example whether or not to evaluate code chunks or show the underlying R code.
Caching Code Chunks
The knitr package lets you cache code chunks to save and reuse the output from code chunks.


text:
How much media is enough? When do ads wear out? Which medium is most effective? Marketing mix modeling can provide insight.
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What do people want? See? Share? Love? Discover how our unique insights can help your business.
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text:
SCEA's Associate Product Marketing Manager Chuck Lacson has revealed the ModNation Racers release date, pre-orders and PS3 box art today.
To quote: Well it's official! ModNation Racers on both PS3 and PSP releases May 25! On top of this, we kick off our official pre-order program today with participating retailers.
That's right! http://www.ratchetandclank.com/, http://www.unchartedthegame.com/, and http://www.godofwar.com/ have officially been Mod'ed! Depending on where you pre-order your copy, you'll get to race with one of your favorite characters.
Pre-order from http://www.gamestop.com/Catalog/ProductDetails.aspx?product_id=75117 and score http://www.flickr.com/photos/playstationblog/4424302482/ and his Kart of Chaos!
Pre-order from http://www.amazon.com/ModNation-Racers-Playstation-3/dp/B002BRZ7JE and race as Ratchet or Clank!
Pre-order from http://www.bestbuy.com/site/PS3-MODNATION+RACERS+-+PS3/9807458.p?skuId=9807458&id=1218176550417 and score Nathan Drake and his Jungle Jeep!
On top of this, each pre-order gets an additional BONUS Mystery Mod and Kart package that include not just a special Mod and Kart, but additional accessories that you can use to make your own creations!
Four possibilities in total, and just like a vinyl figure you buy in stores, you won't know which one you get until you download it and see for yourself. Wondering what they could be? We will reveal them soon enough! Just look for a future post right here on the Blog. :)
So there you go! Pre-order today and you might be racing with your favorite PlayStation character! To make sure you know which box to grab on May 25, here is a sneak peek at our packfront!
More PlayStation 3 News...