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Harappan City
A selection of articles related to harappan city.
Original articles from our library related to the Harappan City. See Table of Contents for further available material (downloadable resources) on Harappan City.
- King James Bible: Revelation, Chapter 21
- Chapter 21 21:1 And I saw a new heaven and a new earth: for the first heaven and the first earth were passed away; and there was no more sea. 21:2 And I John saw the holy city, new Jerusalem, coming down from God out of heaven, prepared as a bride adorned for...
New Testament >> Revelation
- Religious Tolerance In Springfield and the Greenleaf Coven
- Religious intolerance is alive and well in Springfield Missouri. The question is, to what degree, and in the terminology of "The Burning Times", how high are the flames? In 1999, the court case of Jean Webb vs. The City of Republic was a headliner...
Paganism & Wicca >> True Stories
- King James Bible: Numbers, Chapter 35
- Chapter 35 35:1 And the LORD spake unto Moses in the plains of Moab by Jordan near Jericho, saying, 35:2 Command the children of Israel, that they give unto the Levites of the inheritance of their possession cities to dwell in; and ye shall give also unto the...
Old Testament >> Numbers
- King James Bible: Genesis, Chapter 19
- Chapter 19 19:1 And there came two angels to Sodom at even; and Lot sat in the gate of Sodom: and Lot seeing them rose up to meet them; and he bowed himself with his face toward the ground; 19:2 And he said, Behold now, my lords, turn in, I pray you, into...
Old Testament >> Genesis
- Bringing it Down to Earth: A Fractal Approach
- 'Clouds are not spheres, mountains are not cones, coastlines are not circles, and bark is not smooth, nor does lightning travel in a straight line.' B. Mandelbrot W e want to think about the future - it's our nature. Unlike other creatures, humans possess an...
Mystic Sciences >> Astrology
- King James Bible: Deuteronomy, Chapter 21
- Chapter 21 21:1 If one be found slain in the land which the LORD thy God giveth thee to possess it, lying in the field, and it be not known who hath slain him: 21:2 Then thy elders and thy judges shall come forth, and they shall measure unto the cities which...
Old Testament >> Deuteronomy
Harappan City is described in multiple online sources, as addition to our editors' articles, see section below for printable documents, Harappan City books and related discussion.
Suggested News Resources
- Novel museum to come up at Harappan site: Khattar
- Describing Rakhi Garhi as an "important place", the Chief Minister said that remains of the largest city of the Harappan civilisation were found during excavation there.
- Clicked! Hrithik Roshan Rushes To His Vanity Van, But Why?
- The film is set in the ancient city of Mohenjo-daro in the era of the Indus Valley civilization that dates back to 2600 BC. It is scheduled for a worldwide release on 12 August.
- Harappan museum at Rakhigarhi
- Chandigarh: Hisar's Rakhigarhi village, once a key place in the Indus Valley civilization, will get a museum-cum-interpretation centre to preserve the biggest Harappan site in South Asia.
- 3 places in Varanasi no traveller can afford to miss
- In fact, we are well aware of the fact that it is the oldest continually inhabited city in the world. There's a mention of the city in the Vedas as well.
- Secrets of Beings: The Pillars of Shiva
- An Egyptian obelisk, made out of red granite, stands in Saint Peter's Square in the Vatican City, the heart and soul of Roman Catholicism. Such are the ... Some ancient lingams have been found in the ruins of Indus Valley located in Pakistan.
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International Edition
October, 26, 2016
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China budget airline Spring readies for US$400 million public offering
April 26, 2014, 12:01 am TWN
SHANGHAI--Chinese budget carrier Spring Airlines said it plans to raise 2.5 billion yuan (US$400 million) in an initial public offering (IPO) in Shanghai to fund fleet expansion in the country's rapidly expanding aviation sector.
The company plans to sell up to 100 million new shares for listing on the main board of the Shanghai Stock Exchange, according to a draft prospectus released late Thursday.
Proceeds will be used to help purchase up to nine Airbus A320 aircraft and three A320 flight simulators, as well as to replenish working capital, it said in a document filed with the China Securities Regulatory Commission (CSRC).
It already had 39 A320 jets in service and operated 64 inbound and outbound routes at the end of 2013, according to the document.
Spring Airlines first announced plans for an IPO in 2009, seeking to raise more than 1 billion yuan, but delayed several times due to sluggish conditions and weakness in the domestic aviation sector, state media has reported.
China's commercial airline industry is dominated by the "Big Three" — flag carrier Air China, China Eastern Airlines and China Southern Airlines — but a move towards greater competition has seen the growth of smaller players.
The aviation industry in Asia, especially China, is booming with growing middle class keen to take to the air.
This week Shandong Airlines, one of China's smaller carriers, said it has agreed to buy 50 passenger planes from U.S. manufacturer Boeing as it looks to tap that demand.
Spring's share offer plan must still pass several rounds of review by the CSRC before approval.
Based in the commercial hub of Shanghai, Spring Airlines was set up in 2004 with registered capital of 300 million yuan. The firm recorded a net profit of 732.2 million yuan last year, up 17.2 percent from 2012, the prospectus showed.

subset: commoncrawl


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Published in Investing on 29 September 2011
The Irish economy appears to be bouncing back.
"If you put two economists in a room, you get two opinions, unless one of them is Lord Keynes, in which case you get three opinions" – Winston Churchill
John Maynard Keynes is Britain's most famous economist. He is best known for his theory that whenever a country enters a recession, the state should actively manage the economy by increasing public spending to maintain the level of aggregate demand.
Keynes' theory has been adopted by most political parties in the developed world, and whenever you hear politicians discussing the level of public spending you'll find that it almost certainly lies at the heart of at least one side's argument.
One country that seems to have contradicted Keynes' theory, having reported strong economic growth for the last two quarters despite massive cuts in public spending, is Ireland. Or has it?
After Ireland's banks imploded in 2008 its government dramatically slashed the level of public spending. Amongst other things it cut public sector workers' pay by at least 5%, something which is unheard of in most countries as this is usually done by giving pay rises which are below the rate of inflation (as is the case in Britain).
The cuts have continued apace and in the second quarter of 2011 the Irish economy defied the economists' predictions with growth of 1.6% compared to the first quarter (having grown by 1.3% in the first quarter), whilst the rest of the Eurozone grew by a mere 0.2%.
At face value these figures cast some doubt upon Keynes' theory. However, it turns out that growth was driven by exports (a 24% rise in net exports) whilst the level of domestic demand has shrunk by 2.2% during the past 12 months. So Keynes appears to be correct when it comes to the Irish economy, with public spending cuts causing domestic demand to decline.
But the figures for the lightly regulated export sector demonstrate that Keynes' main opponents, Frederick Hayek and the Austrian School of Economics, are also correct. Hayek and the Austrians argue that freeing up markets is the best way to produce economic growth and this is what has happened.
Clearly when Mark Twain said that there were "lies, damned lies and statistics" he had economics in mind! Still, quarterly growth of 1.6% is not to be sneezed at and unlike Greece, which is still in deep denial over its economic problems, Ireland was and is prepared to face up to the facts.
Economics is a far simpler subject than the economy itself, which is often a capricious and highly unpredictable beast. The debate between Keynes and Hayek will run and run.
The market liked the figures and the yields on long-dated Irish government bonds have fallen sharply since they were announced. Yesterday the rate paid on 10-year bonds dropped to below 8%, having reached 14% in July, although this is still more than three times what Britain has to pay.
I'll finish by pointing out that whilst Keynes' theory comes in two parts, most politicians who call themselves Keynesians only seem to know the bit about increasing public spending during a recession. The second part of Keynes' theory holds that the government must run a budget surplus during an economic boom, in order to build up the reserves which it can then spend during the next recession.
In nearly every country where politicians are now calling for Keynesian stimulus packages, the government did no such thing (because it would cost them votes).
More on the markets:
> Tony is an Austrian.
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Interesting. The Latvian s also had a horrible experience after the credit crunch but growth came back.
Off topic but I surely Adam Smith is Britain's most famous economist.
The best Keynes can do is to prolong the pain, turning a short sharp shock into a chronic mild ache. But I expect he's spinning in his grave at what's been done in his name in recent years.Ireland, by contrast, might just be putting the pain genuinely behind it!
its a close call between smith and keynes depending on which side of the political fence you take.
Hi Graham01,I had "John Maynard Keynes is arguably Britain's most famous economist" in my first draft, but I was probably subconsciously influenced by the fact that most of the economics blogs that I read tend to mention Keynes far more frequently than Adam Smith.Also the last economics course I took mentioned Smith once but Keynes got a look in all over the place.That said, I'm firmly in the Austrian School!Cheers,Tony L
Looking at the amount of job losses/ people emigrating and the penal tax system/ high cost of living here in Ireland I see a return to the 1980's a country composed of the very young and the old, everyone else is working abroad, there will be no growth in Ireland if they keep raising taxes without end.
The penultimate paragraph makes clear what the government should have done differently. If good old Gordon Brown had stuck to prudence, maybe we could have had an end to boom and bust after all.Unfortunately it's just too easy to spend someone else's money!
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Ultimate Mini
August 6, 2014 - Dave Hecei
We are rapidly approaching the two-year anniversary of the current Mac mini. There are no indications of a new mini coming soon, except for a quickly removed reference to a mid-2014 Mac mini on an Apple support page. It is a popular computer and is very overdue for an update or even a remake. Here's what my ultimate mini would be.
The ultimate mini would look very much the same as the current mini on the outside. The mini has all the ports and connections in the back. Apple could get rid of the Firewire port as long as they replaced it with a second Thunderbolt port. They could also remove the SD card slot, who wants one of those in the back anyways? With the SD card slot gone they could add two more USB 3.0 ports. I love the speed of USB 3.0 and six ports is almost enough for the power user. Add to that the two Thunderbolt ports and this mini could handle most anything. And to make it look really sweet, like the new Mac Pro, I'd love to see the mini available in black.
One the inside, the ultimate mini would have the very latest Haswell Core i7 processor. Just having a newer processor will be a big improvement since the current mini is still running the previous generation chips called Ivy Bridge.
The latest Intel i7 is a quad-core design with Hyper Threading, which means that the Mac OS thinks there are 8-processors. It would come with 8GB of RAM and the same PCIe-based SSD storage as the latest MacBook Pros and Airs. Using PCIe instead of the more standard SATA type interface increases the read and write speeds of the SSD significantly. This means that the computer boots faster, loads apps faster, and processes data faster.
Another benefit of the latest Core i5 and i7 processors is better graphics. The current mini uses the integrated Intel 4000 HD graphics – good, but not great. Haswell has the faster Intel Iris and Iris Pro graphics. Just like having faster storage speeds, a faster graphics engine helps improve overall speeds, not just gaming.
This is all just wishful thinking. There is no reason that Apple could and would do any of these improvements to the mini, if in fact they do any at all. The mini sits at the bottom of the Mac lineup as the smallest and least expensive Mac available. But it also means that it is unique in that it can do almost anything. They make great servers, home theatre PCs, general-purpose desktops, casual gaming consol, etc. The mini is super small and consumes much less energy than a big tower PC. Pair it with a wireless keyboard and mouse and it can be installed in a closet or other cubbyhole you can find.
Unless you have a very specific use for a Mac mini today I don't recommend buying one right now. While I don't know that one is coming within the next few months, it just seems that it is due any minute now. I know if I were to buy one today, Apple would announce the new one next week.
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In its earnings call late last week, Mr. Benioff underscored the company's continued focus on Europe, and cited growth in the market there. Part of the firm's strategy includes building data centers in areas such as the U.K., France and Germany, as companies there demand infrastructure within their borders.
"Cloud is going mainstream and these countries want to make sure that these clouds are part of their national infrastructure and are part of their national assets," Mr. Benioff said on the earnings call.
"Big companies have a newish issue – or at least one exacerbated by the Internet – to deal with: adhering to the law of the land while running a shared service infrastructure," says Ted Schadler, an analyst at Forrester Research Inc.
Read more: The Wall Street Journal Blog


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HELENA, Alabama -- A structure fire that caused heavy damage to a Helena home in the Old Cahaba subdivision on Tuesday evening also resulted in three firefighters seeking medical care due to the effects of heat and smoke.
Helena Mayor Mark Hall in an interview this morning said the three firefighters received care at Shelby Baptist Medical Center in Alabaster following the emergency response at the home on the 200 block of Rivercrest Circle North.
"Three of the guys had minor dehydration from the smoke and the heat. They were treated and released last night," Hall said, adding "smoke inhalation and heat-related issues" caused the health concerns.
The emergency response started at about 5:13 p.m. when the sole occupant of the home awoke to discover a fire in the house, Hall said.
"She was OK. She got out," he said. As far as damage to the home, "I would say it's a total loss. By the time she discovered the fire, it was much too late. All she could do was get out of the house."
A Helena Fire Department engine company at Helena High School on another matter spotted the smoke from the nearby house fire and responded to the scene.
"They were up on the hill and actually saw the smoke and headed to the truck when the alarm came in," Hall said. "They were there very quickly, but the flames were already through the roof when they arrived."


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Quinault is host for Paddle Journey 2013
Rio Jaime and Miss Ann Penn-Charles represented the Quileute Ocean Going Society at the Forks Chamber of Commerce meeting held Wednesday, Dec. 19 at JT's Sweet Stuffs.
Two camping areas will be set up, he said, one at the Quileute baseball field near the Station Quillayute River Coast Guard station and one at the smaller baseball field adjacent to the Quileute Tribal School on the coast.
Penn-Charles said the Quileute's Oceanside Resort and RV facilities will remain open to all visitors during the canoe journey stop of about two days at La Push.
The Quileute canoe society recently received a $10,000 grant from the West Olympic Peninsula Betterment Association to help fund the Quileute's participation in the Paddle Journey and hosting the event at La Push.
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Originally published at: http://www.howtogeek.com/165912/how-to-send-the-contents-of-the-clipboard-to-a-text-file-via-the-send-to-menu/
We have previously covered how to send the contents of a text file to the Windows Clipboard with a simple Sent To shortcut, but what if you want to do the opposite? That is: send the contents of the clipboard to a text file with a simple shortcut.
In the first line of the article there is an error on the link.It says,simple Sent To shortcut.
The information we get here is great. I would also like to know how to make a rightclick shortcut to send to -Move to.Thanks, needtoknow
NeedToKnow: Try SendTo Toys at gabrielponti.com or Trogladite Software SendTo 1.6 at slimwareutilities.com. I have been using both of the above for several years - presently on Win7 64-bit on a new Dell laptop - and they work perfectly.
Option is not visible in the the send to menu.
The only options I have is compressed (zipped) folder and Documents, even though I have lots of other icons in the send to menu folder such as Dropbox, Skype etc. I have disabled tweaked services @ http://www.blackviper.com/2010/12/17/black-vipers-windows-7-, might that be it? I looked through services, but didn't see any description that led me to believe it was a relevant service for this function.
edit: if I create a new folder in send to folder it shows up as option, I was also able to get Desktop (Create shortcut) to work, since it was missing, by creating file Desktop (create shortcut).desklink.
There really isn't any magic to the configuration and it's odd it wouldn't even show up on your menu.
You can try making sure the shortcut appears in your user send to configuration folder by visiting the "true" path instead of using the shortcut the article references. The path is here (paste into Start > Run):
This isn't a service based function so I disabling services shouldn't remove this function - but I don't really mess with the standard services to begin with.
The fact that you have lost the 'send to desktop' shortcut is a bit alarming as this really wouldn't go away unless it was explicitly removed - or the whole send to functionality got corrupted somehow (can't really comment on this last part though because I haven't really seen it).
thanks for betting back.
Unfortunately I already visited the folder via that path, and I can see the clipboard shortcuts along with all other ones visible when doing shell:sendto
I got this to work but would it be possible to get it to automatically add a line feed?
More importantly, could it be set up to add the contents always to one certain file so I didn't have to hunt up the file in the directory tree to add the clipboard contents to it?


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Marino Adds Furniture, Football to Home Offer
Unable to find a buyer for his Weston, Fla., home, Hall of Fame quarterback Dan Marino has a new game plan: He's throwing in $1.5 million worth of designer furniture—and a signed football, too.
The former Miami Dolphin first listed the house—about 25 miles west of Fort Lauderdale—three years ago and twice cut the price. Now, Mr. Marino, 47 years old, and his wife, Claire, are asking $13.5 million for the 15,000-square-foot Tuscan home on four acres. They built it in 1998 and among other things put in a new master suite and marble showers. The home has 10 bedrooms, 12 bathrooms and two powder rooms. The property includes two guest houses, a pool, a putting green, a 5,000-bottle wine cellar and a pond stocked with fresh bass.
With three kids in college and a fourth graduating from high school soon, "we're looking to downsize a little bit," Mr. Marino says. The former footballer, who retired in 2000, first put the home on the market in 2006 for $15.9 million. Now, the home is being offered fully furnished, says listing agent Giselle Bonetti of One Sotheby's Realty, which is marketing the property with Quintessentially Estates.
Mr. Marino adds, "I'll leave one football, how's that?"
Nicole Richie Buys House
Reality-show personality Nicole Richie and her rocker boyfriend Joel Madden have paid $1.9 million for a newly renovated home in the Hollywood Hills, slightly under the asking price.
Last month, Ms. Richie, who starred with Paris Hilton in the reality series "The Simple Life," bought the contemporary home of about 5,400 square feet on 0.4 acres. The four-bedroom home has five bathrooms and a powder room and features a large living room with vaulted ceilings and a giant skylight, according to the listing. The walled compound also features a cantina-style poolside bar and a guest house.
Ms. Richie, the adopted daughter of singer Lionel Richie, and Mr. Madden, who's the lead singer of Good Charlotte, are expecting their second child. Deedee Howard of Prudential California Realty represented the couple. Ernie Carswell and Sarah Blanchard of Teles Properties represented the seller.
Collector Rosen Cuts Price
Real-estate developer and contemporary-art collector Aby Rosen has reduced the price of a newly renovated New York City townhouse by 14% to $23.75 million.
Mr. Rosen, whose real-estate company controls New York's Seagram Building and Lever House, bought the 25-foot-wide townhouse on East 94th Street in 2005 for $8.8 million, records show, then completely renovated it. The house, now just over 11,700 square feet, has five bedrooms, seven bathrooms, a powder room, an elevator, a 1,000-bottle wine cellar and a 50-foot-long pool. Rae Gilson of Classic Marketing and Kirk Henckels at Stribling & Associates share the listing.
On East 71st Street, Mr. Rosen is also offering a townhouse for $75 million, New York's priciest listing. The agents are Serena Boardman and Meredyth Smith of Sotheby's International Realty.
Write to Sara Lin at firstname.lastname@example.com


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Offer a coupon that reduces the price of something, and I am ready to clip, sort and get to the store for the savings to begin.
My coupon-clipping has been trimmed--not for lack of coupons, but for lack of coupons for the foods I now eat.
I gained weight eating original Oreo cookies. I know I do not need to indulge in their offspring: the Double Stuf, the Cakesters, the Milk Chocolate Covered, the Pure Milk Chocolate Covered Mint. But, put it in a box, attach a catchy name, add a sale and tempt me with a $1-off coupon, and we are talking about some serious willpower for me not to run to the store--and that's for something I never tasted, and know I do not need.
Magnets must be hidden in packaged foods, because I'm still pulled to them.
Multiples of foods have gotten me into trouble for years. Had I mastered the art of eating one piece of cake instead of three, or one piece of pie instead of four, my life would have been a lot healthier, not to mention simpler. When the coupon entices me with, "Buy Two, Get One Free," I've finally begun listening to my inner voice of intelligence saying, "Three? What part of you even needs one?" I put the item back on the shelf.
In the beginning I was aggravated by the newspaper's coupon section, offering drastic savings on foods that were so high in calories. Then one day while reading food labels, I noticed how many preservatives were in those foods. How long were they going to stay preserved in me?
Slowly, I turned to foods that came from the perimeters of the grocery stores rather than the aisles, foods for which there were no coupons.
Now I wonder why the newspaper coupons can't be divided into edibles and non-edibles. I still need soap and toilet paper, but I'd rather not trouble my head with all the junk food. If I don't see coupons for it, I won't want it.
What I would like to find coupons for would be "50 cents off any head of broccoli" or "Buy One, Get One Free bag of spinach."
Bunny Dimmel, of Liverpool, is a teacher at Clary Middle School in Syracuse who has lost more than 250 pounds. She weighs in every other week. Reach her through firstname.lastname@example.com.


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MUNISING - Alger County took a major step forward in emergency response capability recently with ambulance crews now staffed with paramedics trained and licensed in advanced life support techniques.
The move came last August, after county officials worked for years in preparation for the change.
"Basically, what it allows us to do is perform a lot of care out in the field that we used to have to bring patients to the hospital for," said Alger County Undersheriff Robert Hughes.
Article Photos
Paramedic Tina Waldron prints out and checks a code summary from an ambulance run in 2008. The county received its license to provide advanced life support to emergency victims. With the license, there are nine advanced life support paramedics on the job in the county, augmenting services provided by 16 basic life support EMS personnel. (Journal file photo by John Pepin)
That capability is especially important in a geographically sprawling county like Alger, where distances between people needing emergency care and hospitals can be great.
"Time is of the essence," Hughes said. "A big thing paramedics can do is utilize drugs out on the scene."
Paramedics are skilled in administering first-line cardiac drugs, antidotes and pain medications and other care.
There are now nine advanced life support paramedics working for the Alger County Ambulance Service, augmenting the efforts of 16 emergency medical technicians trained in basic life support.
Two of the county's three ambulances were fitted with advance life support response equipment and medications.
"We bought lots of equipment," Hughes said.
From field training experience in Marquette County, Hughes expects roughly one of every 25 or 30 ambulance runs in Alger County to require the advanced life support paramedics.
Three part-time, and one full-time, staff positions were recently filled to allow at least one paramedic to be working during day and afternoon shifts at the sheriff's department, rather than being on call for ambulance runs.
"It shortened our response time dramatically," Hughes said.
More positions may be filled in the future as the number of ambulance calls is expected to increase. With paramedics now working, Munising Memorial Hospital can use local ambulances to transfer patients requiring paramedics to Marquette General Hospital, rather than waiting for an advanced life support crew to come to Munising from Marquette for transports.
Alger County will also likely have increased duties making intercept runs for outlying communities like Manistique and Newberry, with Munising as a midway point between those towns and Marquette.
"Our call volume went up tremendously," Hughes said. "I think it's working out good. We're able to do normally what we had to rush them to the emergency room for."
The advanced capabilities for the emergency crews in Alger has allowed them to turn many emergency situations into non-emergencies, Hughes said.
Funding for the ambulance service and its employees is provided by patient billing and a one-mill, four-year millage levy in place since 1980, which is up for renewal again in November.
Because of the millage, the ambulance service is able to charge reduced patient billing costs to patients, Hughes said.
Alger County's first moves toward paramedic capability began in 2003 when various required medical protocols were approved and put in place. Next came finding EMTs willing to make the serious commitment to learn and study for paramedic certification tests over a two-year period. Those individuals began classes in September 2006, finishing in February.
"They wanted to help us advance and a lot of credit has to go to them," Hughes said.
Those who passed the class in February then went on to national registry testing.
"You've got to get national certification to get your state license," Hughes said.
Alger paramedics work as mentors to each other on ambulance runs and at subsequent debriefing sessions.
The county's advanced life support plans, ambulance equipment and staff training all had to pass state inspection before the county's license was issued.
Hughes said that in 1980, when he first got into emergency medical service, there was only one advanced life support paramedic in the entire Upper Peninsula. That paramedic served the Houghton area.
Since then, towns across the region have become much better prepared to respond to emergencies requiring paramedics.
"We're one of the last communities our size to get advanced life support," Hughes said. "I'm really excited about it."


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LAMBERTVILLE — An 18-year-old Solebury, Pa., man was charged with underage possession of alcohol after he was found with a bottle of vodka during a traffic stop, police said.
Michael Manoff was the passenger in a vehicle driven by Nickolas A. Kashem, 17, of New Hope, Pa., when police stopped him for driving without his headlights on at 10:22 p.m. Feb. 25, police said. Kashem was issued a summons for the headlight offense. A third passenger, a 17-year-old boy from New Hope was not charged. All three were released.


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DAPHNE, Alabama -- With the seventh annual Gulf Coast Zydeco Music & Crawfish Festival set for this weekend, this suburban Baldwin County city will once again briefly become home to a slice of rural lower Louisiana.
Here's how the Zydeco Festival's entertainment schedule breaks down, according to information provided by the Daphne Civic Center:
Doors open at 5:30 p.m.
5:30-6:15 p.m. — dance instruction
6:15-7:45p.m. — Leroy Thomas & the Zydeco Roadrunners
7:45-8 p.m. — dance instruction
8-9:30 p.m. — Curley Taylor & Zydeco Trouble
9:30-10 p.m. — dance instruction
10-midnight — T Broussard & Zydeco Steppers
Doors open at 1 p.m.
1-1:45 p.m. — dance instruction
2-3:30 p.m. — Leon Chavis & the Zydeco Flames
3:45-5:15 p.m. — Mary Jane Broussard & Creole LaLa
5:15-6 p.m. — dance instruction
6-7:30 p.m. — Corey Ledet & His Zydeco Band
7:30-8 p.m. — dance instruction
8-9:30 p.m. — Leon Chavis & the Zydeco Flames
9:45-11:30 p.m. — Curley Taylor & Zydeco Trouble
Doors open at 12:30 p.m.
12:30-1:15 p.m. — dance instruction
1:15-2:45 p.m. — Jeffery Broussard & the Creole Cowboys
2:45-3:15 p.m. — dance instruction
3:15-4:45 p.m. — Terry & the Zydeco Bad Boys
5-6:30 p.m. — Geno Delafose & French Rockin' Boogie
"It's going to be a blast," said Margaret Thigpen, director of the Daphne Civic Center. "We had just a two-day festival last year, but we're back to three this year and we have a number of fun things planned."
In addition to world-class music, instructors will provide lessons in how to dance Louisiana-style.The event, as always, will feature a range of Louisiana-style food, dancing and music, and draws fans from throughout the region. This year, activities for children will take place Saturday from 1 to 6 p.m., including an inflatable jump room, face painting, temporary tattoos and more, she said.
Admission is $20 per day or $50 for a three-day pass.
In the past, some events taking place outside the Civic Center were free to the public while admission was only charged for performances and other activities taking place inside the facility, she said. This year, admission must be paid at the gate for the entire event, Thigpen said.
Crawfish and other Creole and Cajun food will be available for purchase throughout the event.


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Peptide synthesis
In organic chemistry, peptide synthesis is the production of peptides, which are organic compounds in which multiple amino acids are linked via amide bonds, also known as peptide bonds. The biological process of producing long peptides (proteins) is known as protein biosynthesis.
- 1 Chemistry
- 2 Liquid-phase synthesis
- 3 Solid-phase synthesis
- 4 Solid supports
- 5 Protecting groups
- 5.1 N-terminal protecting groups
- 5.2 Side chain protecting groups
- 5.3 Protection schemes
- 6 Activating groups
- 7 Regioselective disulfide formation
- 8 Synthesizing long peptides
- 9 Coupling efficiency vs. peptide length
- 10 Microwave assisted peptide synthesis
- 11 Cyclic peptides
- 12 See also
- 13 References
- 14 External links
Peptides are synthesized by coupling the carboxyl group or C-terminus of one amino acid to the amino group or N-terminus of another. Due to the possibility of unintended reactions, protecting groups are usually necessary. Chemical peptide synthesis starts at the C-terminal end of the peptide and ends at the N-terminus. This is the opposite of protein biosynthesis, which starts at the N-terminal end.
Liquid-phase synthesis[edit]
Liquid-phase peptide synthesis is a classical approach to peptide synthesis. It has been replaced in most labs by solid-phase synthesis (see below). However, it retains usefulness in large-scale production of peptides for industrial purposes.
Solid-phase synthesis[edit]
Solid-phase peptide synthesis (SPPS), pioneered by Robert Bruce Merrifield,[1] caused a paradigm shift within the peptide synthesis community, and it is now the standard method for synthesizing peptides and proteins in the lab. SPPS allows for the synthesis of natural peptides which are difficult to express in bacteria, the incorporation of unnatural amino acids, peptide/protein backbone modification, and the synthesis of D-proteins, which consist of D-amino acids.
Small porous beads are treated with functional units ('linkers') on which peptide chains can be built. The peptide will remain covalently attached to the bead until cleaved from it by a reagent such as anhydrous hydrogen fluoride or trifluoroacetic acid. The peptide is thus 'immobilized' on the solid-phase and can be retained during a filtration process while liquid-phase reagents and by-products of synthesis are flushed away.
The general principle of SPPS is one of repeated cycles of deprotection-wash-coupling-wash. The free N-terminal amine of a solid-phase attached peptide is coupled (see below) to a single N-protected amino acid unit. This unit is then deprotected, revealing a new N-terminal amine to which a further amino acid may be attached. The superiority of this technique partially lies in the ability to perform wash cycles after each reaction, removing excess reagent with all of the growing peptide of interest remaining covalently attached to the insoluble resin.[citation needed]
The overwhelmingly important consideration is to generate extremely high yield in each step. For example, if each coupling step were to have 99% yield, a 26-amino acid peptide would be synthesized in 77% final yield (assuming 100% yield in each deprotection); if each step were 95%, it would be synthesized in 25% yield. Thus each amino acid is added in major excess (2~10x) and coupling amino acids together is highly optimized by a series of well-characterized agents.[citation needed]
There are two majorly used forms of SPPS – Fmoc and Boc. Unlike ribosome protein synthesis, solid-phase peptide synthesis proceeds in a C-terminal to N-terminal fashion. The N-termini of amino acid monomers is protected by either of these two groups and added onto a deprotected amino acid chain.
Automated synthesizers are available for both techniques, though many research groups continue to perform SPPS manually.
SPPS is limited by yields, and typically peptides and proteins in the range of 70 amino acids are pushing the limits of synthetic accessibility.[citation needed] Synthetic difficulty also is sequence dependent; typically amyloid peptides and proteins are difficult to make. Longer lengths can be accessed by using native chemical ligation to couple two peptides together with quantitative yields.
Since its introduction over 40 years ago, SPPS has been significantly optimized. First, the resins themselves have been optimized.[2] Furthermore, the 'linkers' between the C-terminal amino acid and polystyrene resin have improved attachment and cleavage to the point of mostly quantitative yields.[3][4][5] The evolution of side chain protecting groups has limited the frequency of unwanted side reactions. In addition, the evolution of new activating groups on the carboxyl group of the incoming amino acid have improved coupling and decreased epimerization. Finally, the process itself has been optimized. In Merrifield's initial report, the deprotection of the α-amino group resulted in the formation of a peptide-resin salt, which required neutralization with base prior to coupling. The time between neutralization of the amino group and coupling of the next amino acid allowed for aggregation of peptides, primarily through the formation of secondary structures, and adversely affected coupling. The Kent group showed that concomitant neutralization of the α-amino group and coupling of the next amino acid led to improved coupling.[6] Each of these improvements has helped SPPS become the robust technique that it is today.
BOP SPPS[edit]
The use of BOP reagent was first described by Castro et al. in 1975.
Solid supports[edit]
The name solid support implies that reactions are carried out on the surface of the support, but this is not the case. Reactions also occur within these particles, and thus the term "solid support" better describes the insolubility of the polymer. The physical properties of the solid support, and the applications to which it can be utilized, vary with the material from which the support is constructed, the amount of cross-linking, as well as the linker and handle being used. Most scientists in the field believe that supports should have the minimum amount of cross-linking to confer stability. This should result in a well-solvated system where solid-phase peptide synthesis can be carried out. Nonetheless, the characteristics of an efficient solid support include:[7]
- It must be physically stable and permit the rapid filtration of liquids, such as excess reagents
- It must be inert to all reagents and solvents used during SPPS
- It must swell extensively in the solvents used to allow for penetration of the reagents
- It must allow for the attachment of the first amino acid
There are four primary types of solid supports:[7]
- Gel-type supports: These are highly solvated polymers with an equal distribution of functional groups. This type of support is the most common, and includes:
- Polystyrene: Styrene cross-linked with 1–2% divinylbenzene
- Polyacrylamide: A hydrophilic alternative to polystyrene
- Polyethylene glycol (PEG): PEG-Polystyrene (PEG-PS) is more stable than polystyrene and spaces the site of synthesis from the polymer backbone
- PEG-based supports: Composed of a PEG-polypropylene glycol network or PEG with polyamide or polystyrene
- Surface-type supports: Many materials have been developed for surface functionalization, including controlled pore glass, cellulose fibers, and highly cross-linked polystyrene.
- Composites: Gel-type polymers supported by rigid matrices.
Polystyrene resin[edit]
Polystyrene resin is a versatile resin and it is quite useful in multi-well, automated peptide synthesis, due to its minimal swelling in dichloromethane. The initial support used by R. Bruce Merrifield was polysytrene cross-linked with 2% divinylbenzene. This support is sometimes referred to as the 'Merrifield resin.' This resin produces a hydrophobic bead that is solvated by a nonpolar solvent such as dichloromethane or dimethylformamide. Since then, new resins have been developed with the following advantages:
- Enhanced swelling or rigidity (a property of mechanical strength)
- Chemical inertness
Highly cross-linked (50%) polystyrene has been developed that possesses the features of increased mechanical stability, better filtration of reagents and solvents, and rapid reaction kinetics.
Polyamide resin[edit]
Polyamide resin is also a useful and versatile resin. It seems to swell much more than polystyrene, in which case it may not be suitable for some automated synthesizers, if the wells are too small.
PEG hybrid polystyrene resin[edit]
An example of this type of resin is the Tentagel resin. The base resin is polystyrene onto which is attached long chains (Mw ca. 3000 Da) of polyethylene glycol (PEG; also known as polyethylene oxide). Synthesis is carried out on the distal end of the PEG spacer making it suited for long and difficult peptides. In addition it is also attractive for the synthesis of combinatorial Peptide libraries and on resin screening experiments. It does not expand much during synthesis making it a preferred resin for robotic peptide synthesis.
PEG-based resin[edit]
ChemMatrix(R) is a new type of resin which is based on PEG that is crosslinked. ChemMatrix(R) has claimed a high chemical and thermal stability (is compatible with Microwave synthesis) and has shown higher degrees of swellings in acetonitrile, dichloromethane, DMF, N-methylpyrrolidone, TFA and water compared to the polystyrene-based resins. ChemMatrix has shown significant improvements to the synthesis of hydrophobic sequences. ChemMatrix may be useful for the synthesis of difficult and long peptides.
Improvements to solid supports used for peptide synthesis enhance their ability to withstand the repeated use of TFA during the deprotection step of SPPS.[8] Furthermore, different resins allow for different functional groups at the C-terminus. The oxymethylphenylacetamidomethyl (PAM) resin results in the conventional C-terminal carboxylic acid. On the other hand, the paramethylbenzhydrylamine (pMBHA) resin yields a C-terminal amide, which is useful in mimicking the interior of a protein.
Along with the development of Fmoc SPPS, different resins have also been created to be removed by TFA. Similar to the Boc strategy, two primary resins are used, based on whether a C-terminal carboxylic acid or amide is desired. The Wang resin is the most commonly used resin for peptides with C-terminal carboxylic acids.[9] If a C-terminal amide is desired, the Rink amide resin is used.
Protecting groups[edit]
Amino acids have reactive moieties at the N- and C-termini, which facilitates amino acid coupling during synthesis. Many amino acids also have reactive side chain functional groups, which can interact with free termini or other side chain groups during synthesis and peptide elongation and negatively influence yield and purity. To facilitate proper amino acid synthesis with minimal side chain reactivity, chemical groups have been developed to bind to specific amino acid functional groups and block, or protect, the functional group from nonspecific reactions. These protecting groups, while vast in nature, can be separated into three groups, as follows:
- N-terminal protecting groups
- C-terminal protecting groups (mostly used in liquid-phase synthesis)
- Side chain protecting groups
Purified, individual amino acids are reacted with these protecting groups prior to synthesis and then selectively removed during specific steps of peptide synthesis.
N-terminal protecting groups[edit]
Amino acids are added in excess to ensure complete coupling during each synthesis step, and without N-terminal protection, polymerization of unprotected amino acids could occur, resulting in low peptide yield or synthesis failure. N-terminal protection requires an additional step of removing the protecting group, termed deprotection, prior to the coupling step, creating a repeating design flow as follows:
- Protecting group is removed from the trailing amino acids in a deprotection reaction
- Deprotection reagents are washed away to provide a clean coupling environment
- Protected amino acids dissolved in a solvent such as dimethylformamide (DMF) combined with coupling reagents are pumped through the synthesis column
- Coupling reagents are washed away to provide clean deprotection environment
Currently, two protecting groups (t-Boc, Fmoc) are commonly used in solid-phase peptide synthesis. Their lability is caused by the carbamate group which readily releases CO2 for an irreversible decoupling step.
t-Boc protecting group[edit]
The original method for the synthesis of proteins relied on tert-butyloxycarbonyl (or more simply "Boc") to temporarily protect the α-amino group. In this method, the Boc group is covalently bound to the amino group to suppress its nucleophilicity. The C-terminal amino acid is covalently linked to the resin through a linker. Next, the Boc group is removed with acid, such as trifluoroacetic acid (TFA). This forms a positively charged amino group (in the presence of excess TFA; note image on the right illustrates neutral amino group), which is neutralized (via in-situ or non-in-situ methods) and coupled to the incoming activated amino acid.[6] Reactions are driven to completion by the use of excess (two- to four-fold) activated amino acid. After each deprotection and coupling step, a wash with dimethylformamide (DMF) is performed to remove excess reagents, allowing for high yields (~99%) during each cycle.[7]
t-Boc protecting strategies retain usefulness in reducing peptide aggregation during synthesis. t-Boc groups can be added to amino acids with t-Boc anhydride and a suitable base. Some researchers prefer Boc SPPS for complex syntheses . In addition, when synthesizing nonnatural peptide analogs, which are base-sensitive (such as depsipeptides), the t-Boc protecting group is necessary, because Fmoc SPPS uses a base to deprotect the α-amino group.
Permanent side-chain protecting groups are typically benzyl or benzyl-based groups. Final removal of the peptide from the linkage occurs simultaneously with side-chain deprotection with anhydrous hydrogen fluoride via hydrolytic cleavage. The final product is a fluoride salt which is relatively easy to solubilize. Importantly, scavengers such as cresol are added to the HF in order to prevent reactive t-butyl cations from generating undesired products. In fact, the use of harsh hydrogen fluoride may degrade some peptides, which was the premise for the development of a milder, base-labile method of SPPS—namely, the Fmoc method.
Fmoc protecting group[edit]
The capacity for anhydrous hydrogen fluoride to degrade proteins during the final cleavage conditions led to a new α-amino protecting group based on 9-fluorenylmethyloxycarbonyl (Fmoc). The Fmoc method allows for a milder deprotection scheme. This method utilizes a base, usually piperidine (20–50%) in DMF in order to remove the Fmoc group to expose the α-amino group for reaction with an incoming activated amino acid.[7] Unlike the acid used to deprotect the α-amino group in Boc methods, Fmoc SPPS uses a base, and thus the exposed amine is neutral. Therefore, no neutralization of the peptide-resin is required, but the lack of electrostatic repulsions between the peptides can lead to increased aggregation. Because the liberated fluorenyl group is a chromophore, deprotection by Fmoc can be monitored by UV absorbance of the runoff, a strategy which is employed in automated synthesizers.
The advantage of Fmoc is that it is cleaved under very mild basic conditions (e.g. piperidine), but stable under acidic conditions, although this has not always held true in certain synthetic sequences. This allows mild acid-labile protecting groups that are stable under basic conditions, such as Boc and benzyl groups, to be used on the side-chains of amino acid residues of the target peptide. This orthogonal protecting group strategy is common in organic synthesis. Fmoc is preferred over BOC due to ease of cleavage; however it is less atom-economical, as the fluorenyl group is much larger than the tert-butyl group. Accordingly, prices for Fmoc amino acids were high until the large-scale piloting of one of the first synthesized peptide drugs, enfuvirtide, began in the 1990s, when market demand adjusted the relative prices of the two sets of amino acids.
Semipermanent side chain protecting groups are t-butyl-based, and final cleavage of the protein from the resin and removal of permanent protecting groups is performed with TFA in the presence of scavengers. Water and triisopropylsilane (TIPS) present in a 1:1 ratio are often used as scavengers. Thus, the Fmoc method is orthogonal in two directions: deprotection of any α-amino group, deprotection of side groups and final cleavage from the resin occur by independent mechanisms. The resulting final product is a TFA salt, which is more difficult to solubilize than the fluoride salts generated in Boc SPPS. This method is thus milder than the Boc method because the deprotection/cleavage-from-resin steps occur with different conditions rather than with different reaction rates.
Comparison of Boc and Fmoc solid-phase peptide synthesis[edit]
Both the Fmoc and Boc methods offer advantages and disadvantages. The selection of one technique over another is thus made on a case-by-case basis.[10]
|Requires special equipment
|Cost of reagents
|Solubility of peptides
|Purity of hydrophobic peptides
|May be lower
|Problems with aggregation
|Less frequently
|More frequently
|Synthesis time
|~20 min/amino acid
|~20–60 min/amino acid
|Cleavage from resin
|Potentially dangerous
|Relatively safe
Boc SPPS uses special equipment to handle the final cleavage and deprotection step, which requires anhydrous hydrogen fluoride. Because the final cleavage of the peptide with Fmoc SPPS uses TFA, this special equipment is not necessary. The solubility of peptides generated by Boc SPPS is generally higher than those generated with the Fmoc method, because fluoride salts are higher in solubility than TFA salts. Next, problems with aggregation are generally more of an issue with Fmoc SPPS. This is primarily because the removal of a Boc group with TFA yields a positively charged α-amino group, whereas the removal of an Fmoc group yields a neutral α-amino group. The steric hindrance of the positively charged α-amino group limits the formation of secondary structure on the resin. Finally, the Fmoc method is considered orthogonal, since α-amino group deprotection is with base, while final cleavage from the resin is with acid. The Boc method utilizes acid for both deprotection and cleavage from the resin. Based on this comparison, one sees that both methods possess advantages and disadvantages. Thus, several factors help to decide which method may be preferable.
DMF must be 'peptide grade' i.e. little/no impurities and must also be 'fresh'. This is due to the fact that DMF undergoes photolysis to form carbon monoxide and dimethylamine. Dimethylamine may remove the Fmoc group and, therefore, lead to impurities.
Benzyloxy-carbonyl (Z) group[edit]
Another carbamate-based group is the benzyloxy-carbonyl (Z) group. It is removed in harsher conditions: HBr/acetic acid or catalytic hydrogenation. The first use of (Z) group as protecting groups was done by Max Bergmann who synthesised oligopeptides.[11] Today it is almost exclusively used for side chain protection.
Alloc protecting group[edit]
The allyloxycarbonyl (alloc) protecting group is often used to protect a carboxylic acid, hydroxyl, or amino group when an orthogonal deprotection scheme is required. It is sometimes used when conducting on-resin cyclic peptide formation, where the peptide is linked to the resin by a side-chain functional group. The alloc group can be removed using tetrakis(triphenylphosphine)palladium(0) along with a 37:2:1 mixture of methylene chloride, acetic acid, and N-Methylmorpholine (NMM) for 2 hours. The resin must then be carefully washed 0.5% DIPEA in DMF, 3 × 10 ml of 0.5% sodium diethylthiocarbamate in DMF, and then 5 × 10 ml of 1:1 DCM:DMF.
Lithographic protecting groups[edit]
For special applications like protein microarrays lithographic protecting groups are used. Those groups can be removed through exposure to light.
Side chain protecting groups[edit]
Amino acid side chains represent a broad range of functional groups and are sites of nonspecific reactivity during peptide synthesis. Because of this, many different protecting groups are required that are usually based on the benzyl (Bzl) or tert-butyl (tBu) group.[7] The specific protecting groups used during the synthesis of a given peptide vary depending on the peptide sequence and the type of N-terminal protection used (see next paragraph). Side chain protecting groups are known as permanent or semipermanent protecting groups, because they can withstand the multiple cycles of chemical treatment during synthesis and are only removed during treatment with strong acids after peptide synthesis is completed.
Protection schemes[edit]
Because multiple protecting groups are normally used during peptide synthesis, these groups must be compatible to allow deprotection of distinct protecting groups while not affecting other protecting groups. Protecting schemes are therefore established to match protecting groups so that deprotection of one protecting group does not affect the binding of the other groups. Because N-terminal deprotection occurs continuously during peptide synthesis, protecting schemes have been established in which the different types of side chain protecting groups (Bzl or tBu) are matched to either Boc or Fmoc, respectively, for optimized deprotection. These protecting schemes also incorporate each of the steps of synthesis and cleavage, as described in the table and in later sections of this page.
Activating groups[edit]
For coupling the peptides the carboxyl group is usually activated. This is important for speeding up the reaction. There are two main types of activating groups: carbodiimides and triazolols. However the use of pentafluorophenyl esters (FDPP,[12] PFPOH[13]) and BOP-Cl[14] are useful for cyclising peptides.
These activating agents were first developed. Most common are dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide (DIC). Reaction with a carboxylic acid yields a highly reactive O-acylisourea. During artificial protein synthesis (such as Fmoc solid-state synthesizers), the C-terminus is often used as the attachment site on which the amino acid monomers are added. To enhance the electrophilicity of carboxylate group, the negatively charged oxygen must first be "activated" into a better leaving group. DCC is used for this purpose. The negatively charged oxygen will act as a nucleophile, attacking the central carbon in DCC. DCC is temporarily attached to the former carboxylate group (which is now an ester group), making nucleophilic attack by an amino group (on the attaching amino acid) to the former C-terminus (carbonyl group) more efficient. The problem with carbodiimides is that they are too reactive and that they can therefore cause racemization of the amino acid.
To solve the problem of racemization, triazoles were introduced. The most important ones are 1-hydroxy-benzotriazole (HOBt) and 1-hydroxy-7-aza-benzotriazole (HOAt). Others have been developed. These substances can react with the O-acylurea to form an active ester which is less reactive and less in danger of racemization. HOAt is especially favourable because of a neighbouring group effect.[15] Recently, HOBt has been removed from many chemical vendor catalogues; although almost always found as a hydrate, HOBt may be explosive when allowed to fully dehydrate and shipment by air or sea is heavily restricted. Alternatives to HOBt and HOAt have been introduced. One of the most promising and inexpensive[citation needed] is ethyl 2-cyano-2-(hydroxyimino)acetate (trade name Oxyma Pure), which is not explosive and has a reactivity of that in between HOBt and HOAt.
Newer developments omit the carbodiimides totally. The active ester is introduced as a uronium or phosphonium salt of a non-nucleophilic anion (tetrafluoroborate or hexafluorophosphate): HBTU, HATU, HCTU, TBTU, PyBOP. Two uronium types of the coupling additive of Oxyma Pure is also available as COMU or TOTU reagent.
Regioselective disulfide formation[edit]
The formation of multiple native disulfides remains one of the primary challenges of native peptide synthesis by solid-phase methods. Random chain combination typically results in several products with nonnative disulfide bonds.[16] Stepwise formation of disulfide bonds is typically the preferred method, and performed with thiol protecting groups (PGs).[17] Different thiol PGs provide multiple dimensions of orthogonal protection. These orthogonally protected cysteines are incorporated during the solid-phase synthesis of the peptide. Successive removal of these PGs to allow for selective exposure of free thiol groups, leads to disulfide formation in a stepwise manner. The order of removal of these PGs must be considered so that only one group is removed at a time. Using this method, Kiso et al. reported the first total synthesis of insulin by this method in 1993.[18]
The thiol PGs must possess multiple characteristics. First, the PG must be reversible with conditions that do not affect the unprotected side chains. Second, the protecting group must be able to withstand the conditions of solid-phase synthesis. Third, the configuration of the removal of the thiol protecting group must be such that it leaves intact other thiol PGs, if orthogonal protection is desired. That is, the removal of PG A should not affect PG B. Some of the thiol PGs commonly used include the acetamidomethyl (Acm), tert-butyl (But), 3-nitro-2-pyridine sulfenyl (NPYS), 2-pyridine-sulfenyl (Pyr), and triphenylmethyl (Trt) groups. Importantly, the NPYS group can replace the Acm PG to yield an activated thiol.[19]
In the stepwise formation of disulfides to synthesize insulin by Kiso et al., the authors synthesize the A-chain with following protection: CysA6(But); CysA7(Acm); CysA11(But). Thus, CysA20 is unprotected. Synthesis of the B-chain is performed with the following protection: CysB7(Acm) CysB19(Pyr). The first disulfide bond, CysA20–CysB19, was formed by mixing the two chains in 8 M urea, pH 8 (RT) for 50 min. The second disulfide bond, CysA7–CysB7, was formed by treatment with iodine in aqueous acetic acid to remove the Acm groups. The third disulfide, the intramolecular CysA6–CysA11, was formed by the removal of the But groups by methyltrichlorosilane with diphenyl sulfoxide in TFA. Importantly, formation of the first disulfide in 8 M urea, pH 8 does not affect the other PGs, namely Acm and But groups. Likewise, formation of the second disulfide bond with iodine in aqueous acetic acid does not affect the But groups.
Important to the discussion of disulfide bond formation is the order in which disulfides are formed. From a logical standpoint, the order in which the thiol groups are exposed to form disulfides should be of little consequence, since the other cysteines are protected. Practically, however, the order in which disulfides are formed can have a significant effect on yields. This may be because the formation of the CysA20–CysB19 disulfide may place the thiol group of CysB7 in close proximity with both CysA6 and CysA7, leading to multiple disulfide products. This is one manifestation of the reality that solid-phase peptide synthesis is as much art as it is science.
Synthesizing long peptides[edit]
Stepwise elongation, in which the amino acids are connected step-by-step in turn, is ideal for small peptides containing between 2 and 100 amino acid residues. Another method is fragment condensation, in which peptide fragments are coupled. Although the former can elongate the peptide chain without racemization, the yield drops if only it is used in the creation of long or highly polar peptides. Fragment condensation is better than stepwise elongation for synthesizing sophisticated long peptides, but its use must be restricted in order to protect against racemization. Fragment condensation is also undesirable since the coupled fragment must be in gross excess, which may be a limitation depending on the length of the fragment.
A new development for producing longer peptide chains is chemical ligation: unprotected peptide chains react chemoselectively in aqueous solution. A first kinetically controlled product rearranges to form the amide bond. The most common form of native chemical ligation uses a peptide thioester that reacts with a terminal cysteine residue. Other methods applicable for covalently linking polypeptides in aqueous solution include the use of split inteins,[20] spontaneous isopeptide bond formation[21] and sortase ligation.[22]
In order to optimize synthesis of long peptides, Zealand Pharma (located in Denmark in Medicon Valley) invented a method for converting a difficult peptide sequence into an easy peptide sequence. The new technology, called SIP-technology, uses "structure-inducing probes" (SIP) to facilitate the synthesis of long peptides.[23] The SIP-technology is a small pre-sequence peptide sequence (e.g. Lysine (Lysn); Glutamic Acid (Glun); (LysGlu)n) that is incorporated at the C-terminus of subsequent resin bound peptide to induce an alpha-helix-like structure in the peptide. The SIP technology constrains the parent peptide into a more ordered conformation using intramolecular hydrogen bonds. This allows the peptide structure to stabilize, and the utilized hydrogen bonds reduce the likelihood of aggregation and degradation by enzymes. In this way, the SIP technology is designed to optimize peptide synthesis, increase biological half-life, improve peptide stability and inhibit enzymatic degradation without altering pharmacological activity or profile of action.[24][25]
Coupling efficiency vs. peptide length[edit]
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|Coupling Efficiency
|Coupling Efficiency
|Coupling Efficiency
|Coupling Efficiency
|Coupling Efficiency
Microwave assisted peptide synthesis[edit]
Although microwave irradiation has been around since the late 1940s, it was not until 1986 that microwave energy was used in organic chemistry. During the end of the 1980s and 1990s, microwave energy was an obvious source for completing chemical reactions in minutes that would otherwise take several hours to days. Through several technical improvements at the end of the 1990s and beginning of the 2000s, microwave synthesizers have been designed to provide both low and high energy pockets of microwave energy so that the temperature of the reaction mixture could be controlled. The microwave energy used in peptide synthesis is of a single frequency providing maximum penetration depth of the sample which is in contrast to conventional kitchen microwaves.
In peptide synthesis, microwave irradiation has been used to complete long peptide sequences with high degrees of yield and low degrees of racemization.[26] Microwave irradiation during the coupling of amino acids to a growing polypeptide chain is catalyzed not only by the increase in temperature but also by the alternating electric field of the microwave.[27] This is because the polar N-terminal amine group and peptide backbone continuously try to align with the alternating electric field, thus helping prevent aggregation and increasing access to the solid phase reaction matrix. This increases yields of the final peptide products. There is however no clear evidence that microwave is better than simple heating and some peptide laboratories regard microwave just as a convenient method for rapid heating of the peptidyl resin. Heating to above 50–55 degrees Celsius also prevents aggregation and accelerates the coupling.
Despite the main advantages of microwave irradiation of peptide synthesis, the main disadvantage is the racemization which may occur with the coupling of cysteine and histidine. A typical coupling reaction with these amino acids are performed at lower temperatures than the other 18 natural amino acids. A number of peptides do not survive microwave synthesis or heating in general. One of the more serious side effects is dehydration (loss of water) which for certain peptides can be almost quantitative like pancreatic polypeptide (PP). This side effect is also seen by simple heating without the use of microwave.
Cyclic peptides[edit]
On resin cyclization[edit]
Peptide can be cyclized on solid support. A variety of cylization reagents can be used such as HBTU/HOBt/DIEA, PyBop/DIEA, PyClock/DIEA. Head-to-tail peptides can be made on the solid support. The deprotection of the C-terminus at some suitable point allows on-resin cyclization by amide bond formation with the deprotected N-terminus. Once cyclization has taken place, the peptide is cleaved from resin by acidolysis and purified. The strategy for the solid-phase synthesis of cyclic peptides in not limited to attachment through Asp, Glu or Lys side chains. Cysteine has a very reactive sulfhydryl group on its side chain. A disulfide bridge is created when a sulfur atom from one Cysteine forms a single covalent bond with another sulfur atom from a second cysteine in a different part of the protein. These bridges help to stabilize proteins, especially those secreted from cells. Some researchers use modified cysteines using S-acetomidomethyl (Acm) to block the formation of the disulfide bond but preserve the cysteine and the protein's original primary structure.
Solution phase cyclization[edit]
|This section is empty. You can help by adding to it. (January 2011)
See also[edit]
- ^ R. B. Merrifield (1963). "Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide". J. Am. Chem. Soc. 85 (14): 2149–2154. doi:10.1021/ja00897a025.
- ^ Mitchell, A. R. K., S.B.H.; Engelhard, M.; Merrifield, R.B. (1978). "A new synthetic route to tert-butyloxycarbonylaminoacyl-4-(oxymethyl)phenylacetamidomethyl-resin, an improved support for solid-phase peptide synthesis". J. Org. Chem. 43 (13): 2845–2852. doi:10.1021/jo00408a022.
- ^ Wang, S.-S. (1973). "p-alkoxybenzyl alcohol resin and p-alkoxybenzyloxycarbonylhydrazide resin for solid phase synthesis of protected peptide fragments.". J. Am. Chem. Soc. 95 (4): 1328–33. doi:10.1021/ja00785a052. PMID 4687686.
- ^ Matsueda, G. R. a. S., J.M. (1981). "A p-methylbenzylhydrlamine resin for improved solid-phase synthesis of peptide amides". Peptides. 2 (1): 45–50. doi:10.1016/S0196-9781(81)80010-1. PMID 7243625.
- ^ Sieber, P. (1987). "A new acid-labile anchor group for the solid-phase synthesis of C-terminal peptide amides by the Fmoc method". Tetrahedron Lett. 28: 2107–10. doi:10.1016/S0040-4039(00)96055-6.
- ^ a b Schnolzer, M. A., P.; Jones, A.; Alewood, D.; Kent, S.B.H. (2007). "In Situ Neutralization in Boc-chemistry Solid Phase Peptide Synthesis". Int. J. Peptide Res. Therap. 13 (1–2): 31–44. doi:10.1007/s10989-006-9059-7.
- ^ a b c d e Albericio, F. (2000). Solid-Phase Synthesis: A Practical Guide (1 ed.). Boca Raton: CRC Press. p. 848. ISBN 0-8247-0359-6.
- ^ Feinberg, R. S.; Merrifield, R. B. (1974). "Zinc chloride-catalyzed chloromethylation of resins for solid phase peptide synthesis". Tetrahedron. 30 (17): 3209–3212. doi:10.1016/S0040-4020(01)97575-1.
- ^ Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C. (1997). "Solid-phase organic reactions II: A review of the literature Nov 95 – Nov 96". Tetrahedron. 53 (16): 5643–5678. doi:10.1016/S0040-4020(97)00279-2.
- ^ Nilsson BL, Soellner MB, Raines RT (2005). "Chemical Synthesis of Proteins". Annu. Rev. Biophys. Biomol. Struct. 34: 91–118. doi:10.1146/annurev.biophys.34.040204.144700. PMC 2845543. PMID 15869385.
- ^ Max Bergmann; Leonidas Zervas (1932). "Über ein allgemeines Verfahren der Peptid-Synthese". Berichte der deutschen chemischen Gesellschaft. 65 (7): 1192–1201. doi:10.1002/cber.19320650722.
- ^ K. C. Nicolaou; Natarajan, Swaminathan; Li, Hui; Jain, Nareshkumar F.; Hughes, Robert; Solomon, Michael E.; Ramanjulu, Joshi M.; Boddy, Christopher N. C.; Takayanagi, Masaru (1998). "Total Synthesis of Vancomycin Aglycon – Part 1: Synthesis of Amino Acids 4–7 and Construction of the AB-COD Ring Skeleton". Angew. Chem. Int. Ed. 37 (19): 2708–2714. doi:10.1002/(SICI)1521-3773(19981016)37:19<2708::AID-ANIE2708>3.0.CO;2-E.
- ^ Schmidt; Joullié, Madeleine M. (1998). "Synthetic studies of 14-membered cyclopeptide alkaloids". Tetrahedron Lett. 39 (40): 7211–7214. doi:10.1016/S0040-4039(98)01589-5.
- ^ R. Baker; J. L. Castro (1989). "The total synthesis of (+)-macbecin I". Chem. Commun. (6): 378–381. doi:10.1039/C39890000378.
- ^ L. A. Carpino (1993). "1-Hydroxy-7-azabenzotriazole. An efficient peptide coupling additive". J. Am. Chem. Soc. 115 (10): 4397–4398. doi:10.1021/ja00063a082.
- ^ Zhang, J.-W.; Wu, Cui Rong; Liu, Wen; Zhang, Jing Wen (1991). "Disulfide bond formation in peptides by dimethyl sulfoxide. Scope and applications". J. Am. Chem. Soc. 113 (17): 6657–6662. doi:10.1021/ja00017a044.
- ^ Sieber, P.; Kamber, B.; Hartmann, A.; Jöhl, A.; Riniker, B.; Rittel, W. (1977). "Total synthesis of human insulin. IV. Description of the final steps (author's transl)". Helvetica Chimica Acta. 60 (1): 27–37. doi:10.1002/hlca.19770600105. PMID 838597.
- ^ Akaji, K.; Fujino, K.; Tatsumi, T.; Kiso, Y. (1993). "Total synthesis of human insulin by regioselective disulfide formation using the silyl chloride-sulfoxide method". Journal of the American Chemical Society. 115 (24): 11384–11392. doi:10.1021/ja00077a043.
- ^ Ottl, J.; Battistuta, R.; Pieper, M.; Tschesche, H.; Bode, W.; Kuhn, K.; Moroder, L. (1996). "Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot. Models for collagen catabolism by matrix-metalloproteases". FEBS Lett. 398 (1): 31–36. doi:10.1016/S0014-5793(96)01212-4. PMID 8946948.
- ^ Aranko AS, Wlodawer A, Iwaï H (2014). "Nature's recipe for splitting inteins". Prot Eng Des Sel. 27: 263–71. doi:10.1093/protein/gzu028. PMC 4133565. PMID 25096198.
- ^ Reddington SC, Howarth M (2015). "Secrets of a covalent interaction for biomaterials and biotechnology: SpyTag and SpyCatcher". Curr Op Chem Biol. 29: 94–9. doi:10.1016/j.cbpa.2015.10.002. PMID 26517567.
- ^ Haridas V, Sadanandan S, Dheepthi NU (2014). "Sortase-based bio-organic strategies for macromolecular synthesis". Chembiochem. 15: 1857–67. doi:10.1002/cbic.201402013. PMID 25111709.
- ^ http://www.zealandpharma.com/%7B2557DE5E-28D5-4782-A161-B8EC9836CB43%7D
- ^ Kapusta, D. R.; Thorkildsen, C; Kenigs, VA; Meier, E; Vinge, MM; Quist, C; Petersen, JS (2005). "Pharmacodynamic Characterization of ZP120 (Ac-RYYRWKKKKKKK-NH2), a Novel, Functionally Selective Nociceptin/Orphanin FQ Peptide Receptor Partial Agonist with Sodium-Potassium-Sparing Aquaretic Activity". Journal of Pharmacology and Experimental Therapeutics. 314 (2): 652–60. doi:10.1124/jpet.105.083436. PMID 15855355.
- ^ Rizzi A, Rizzi D, Marzola G, et al. (October 2002). "Pharmacological characterization of the novel nociceptin/orphanin FQ receptor ligand, ZP120: in vitro and in vivo studies in mice". Br. J. Pharmacol. 137 (3): 369–74. doi:10.1038/sj.bjp.0704894. PMC 1573505. PMID 12237257.
- ^ Stacey A. Palasek; Zachary J. Cox; Jonathan M. Collins (2007). "Limiting racemization and aspartimide formation in microwave-enhanced Fmoc solid phase peptide synthesis". Journal of Peptide Science. 13 (3): 143–148. doi:10.1002/psc.804. PMID 17121420.
- ^ Palasek, Stacey A.; Cox, Zachary J.; Collins, Jonathon M. "Limiting racemization and aspartimide formation in microwave-enhanced Fmoc solid phase peptide synthesis". Journal of Peptide Science. John Wiley & Sons, Ltd. 13 (3): 143–148. doi:10.1002/psc.804.
- Atherton, E.; Sheppard, R.C. (1989). Solid Phase peptide synthesis: a practical approach. Oxford, England: IRL Press. ISBN 0-19-963067-4.
- Stewart, J.M.; Young, J.D. (1984). Solid phase peptide synthesis (2nd ed.). Rockford: Pierce Chemical Company. p. 91. ISBN 0-935940-03-0.
External links[edit]
- Amide coupling – Synthetic protocols from organic-reaction.com
|Wikimedia Commons has media related to Peptide synthesis.


text:
Ra wouldn't stand a chance in Newfoundland.
If someone ever tried to start a congregation, more people would be claiming to see Jesus coming in the rapture than the Egyptian sun god rising over Signal Hill.
Perhaps it wouldn't be so bad as that. Perhaps the populace would only be divided 50-50, with the half who claimed to see Jesus being ignored, and the half who said they saw the sun being immediately rushed to the Waterford for observation.
I leave Labrador out of the equation because the east end of St. John's sees more fog on a good weekend than Lab City sees in a bad year.
We spent several days in the old city last week. You want to know how thick the fog was? Allow me to tell you in plain and truthful language.
One of my meetings was in The Rooms. The Rooms is a fairly large edifice, which is a bit of an understatement. It towers over St. John's harbour like the Eiffel Tower rises over Paris. That may be a bit of an overstatement. Suffice to say it is broad and high.
Number One Son is familiar with the city and knows where The Rooms is, or are or whatever. (Would someone from the cultural community please tell me whether "The Rooms" is singular or plural? Thank you.) On his way to pick me up last Thursday he actually lost his bearings in the fog and made a wrong turn.
When he finally got there and told me what had happened I was somewhat skeptical. Until, that is, we went to turn out onto the street from the parking lot and literally could not see if any vehicle was coming down the street from either direction.
Most of you know where all that fog comes from. You've got your warm, gentle Gulf Stream flowing slowly up from the Caribbean or thereabouts. Then you have your ultracold Labrador Current racing down from Cape Chidley somewhere.
When that cold air and water collide a few miles east of St. John's with all that warm air and water the result is the thickest and nastiest fog on Earth.
In the old days when the Portuguese fishing fleet, the so-called White Fleet, used to frequent St. John's, several near tragedies were recorded.
One well-documented incident was when three sailors from one of the ships went ashore for a walk, got lost in the fog and couldn't find their way back to the harbour. Several days later they turned up in Bonavista .
One of the strangest stories has to do with a man named Malachi Penneyfog (not quite sure of the spelling here), originally from the West Country in Britain. In the early days of the colonization of St. John's, Malachi was falsely accused of stealing salt fish off another man's flake in what is now called the Battery. Justice was rough and swift in those days. Within one day, he was deemed to be guilty by the crowd and immediately hanged.
They had no gallows in those early days. They simply tied a rope around his neck, threw the other end over a high branch of a tall tree and pulled with might and main until the victim was dangling and kicking some 20 feet in the air.
As they were proceeding with this process, one of those dark, black, dense fog banks rolled in over Signal Hill. As Malachi was being hoisted high in the air, the fog settled over the crowd like a great woolly black blanket and he was momentarily hidden from them. Being a man able to keep his wits, even in desperate situations, Malachi saw what was happening and took advantage of it.
A natural athlete, he was able to swing his legs up over his head and onto the branch from which he was hanging. His hands had been loosely tied — they were hanging him, after all, so why bother with being careful — so he was able to free them, and then his feet.
While the crowd's attention was on the fog phenomenon and talking to each other about it, Malachi slid down the other side of the tree and took off like a bat out of perdition.
By the time the fog had partially cleared, Malachi was in what is now known as C.B.S. and picking up speed.
The rest of the story is largely conjecture. It is known that he made his way to Upper Island Cove and shipped out on a schooner heading north. He jumped ship in a small rocky cove north of St. Anthony, changed his name to Penney and settled down. There is some confusion as to whether the site of the original Penney building was in Little Brehat or Great Brehat. Most historians are silent on the matter.
Much of the early history of Newfoundland and Labrador is shrouded in fog.
We know that little coves and harbours were settled by courageous men and women attempting to escape the tyranny of the West Country merchants who were given authority over the settlers by the king. We know that the fishing admirals who ruled the fishermen by virtue of being the first to enter a harbour in the spring were often a cruel and vicious lot and made the lives of settlers miserable and often unbearable.
But we do not know the details of the stark dramas played out against that backdrop. What happened when strong men rebelled against the abuse of their families and their livelihoods and then were harshly punished for defying the "law"?
An incredible tale of death and tragedy as well as courage and survival is in my upcoming novel "The Fishing Admiral." The story of how these first settlers survived against an unrelenting sea and a British government that tried not only to discourage but also to destroy them is so powerful that mere words can hardly convey it.
But I do my level best.
Ed Smith is an author who lives in Springdale. His email address is firstname.lastname@example.com


text:
TRENTON — Legislation that would impose a mandatory five-year jail term on anyone convicted of killing a police dog cleared an Assembly panel on Monday.
Under the bill that cleared the Assembly Law and Public Safety Committee — dubbed "Schultz's Law" — those found guilty of killing a police dog or a dog engaged in a search and rescue operation would receive a mandatory minimum five-year prison term, with no eligibility for parole, and a $15,000 fine. Killing a police or search and rescue dog currently is a third-degree crime and carries penalties of between three to five years in prison and fines of up to $15,000.
Assemblyman Paul Moriarty and state Sen. Fred Madden, both D-Washington Township, introduced the bill in December after Schultz, an on-duty Gloucester Township police dog, was killed by a robbery suspect.
Schultz, a 3 1/2 year-old German shepherd and member of Gloucester's police force was part of a 100-officer manhunt for a robbery suspect. After tracking down the suspect, Schultz latched onto the man's arm. According to police, the suspect then purposely flung the dog into oncoming traffic on Route 42 in an attempt to escape his grip, where Schultz was hit by a passing car and died shortly after.
"Schultz was more than a dog to his community," said Moriarty. "He was a friend, protector and an asset to all law-abiding citizens. This law will ensure he and his fellow K-9 officers have strong protections against those who break society's rules."


text:
Claudia Rosett in Forbes on the dangers of sanctioning a body with serious designs on free-speech rights. More: Cliff May.
"Why Not To Join The U.N. Human Rights Council"
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|Isaac Gorodetski
Project Manager,
Center for Legal Policy at the
Manhattan Institute
|Katherine Lazarski
Press Officer,
Manhattan Institute


text:
The Centers for Disease Control released a new study on March 3 reporting a significant decline in premarital sexual activity for teenagers and young adults. You might think the news would provoke universal rejoicing, but you'd be wrong.
Committed feminists, like Dana Goldstein, who blogs as "ladywonk," dismissed premarital sex as the inevitable baggage of "50-year macro social trends that have brought about unprecedented gender equality and personal fulfillment."
Why would someone like Goldstein shrug off a social issue that has a disproportionate impact on teenage girls? (Unintended pregnancy comes to mind.) New York Times columnist Ross Douthat recently ventured a guess: "Many progressives and feminists have committed themselves to an absolute defense of everything that changed during the sexual revolution, out of a fear that one concession will cost women every gain."
In Douthat's judgment, when radical feminists dump on abstinence-only sex-ed programs or tolerate pornography, their puzzling behavior is actually an attempt to shore up gender equality. From their perspective, the two radical social movements that converged in the '60s — sexual liberation and women's liberation — can never be separated without weakening women's advances in society and the workplace.
Douthat's incendiary column, "Why Monogamy Matters," and his follow-up blog post on the unexamined assumptions of diehard feminists, "After the Revolution," are worth reading, but they don't go quite far enough.
The columnist's honesty and courage must be applauded: How often are Times readers reminded that casual sex is linked to higher rates of unhappiness and depression in young women? But we need to take the discussion to the next level: actually grapple with the distinctive purpose of femininity and masculinity in a culture bent on erasing those differences.
When Douthat first reviewed the CDC data, he described it as "good news." He acknowledged that some young people, who remain virgins for now, might engage in premarital sex as they matured. Still, he suggested that any delay should be applauded.
"[T]here are different kinds of premarital sex. There's sex that's actually pre-marital, in the sense that it involves monogamous couples on a path that might lead to matrimony one day. Then there's sex that's casual and promiscuous, or just premature and ill considered." He added, "This distinction is crucial to understanding what's changed in American life since the sexual revolution."
Douthat noted that social research confirmed the negative consequences of casual sex: Women who had multiple partners reported a lower level of happiness, even as they experienced economic advancement. Perhaps the previous generations that delayed sexual initiation "may have been happier for it."
The direct assault on received feminist wisdom provoked predictable broadsides from the blogosphere. Susie Bright fretted in the Huffington Post: "Douthat's faith is based on the tenets of unapologetic misogyny, sexism, gender determinism, and an all-around 'Daddy Knows Best' approach."
Douthat refused to give an inch: "Yes, an ethic of sexual restraint can be turned to patriarchal ends, but so can an ethic of sexual permissiveness, as anyone who's hung out in a frat house for any length of time can attest."
Douthat suggests that we should be content with a slight uptick in delayed premarital sex. But can't we aspire to something greater? And how do you really know whether a non-marital sexual relationship is altar-bound without the benefit of hindsight?
If there's one thing we've learned since the onset of the sexual revolution, it's that wishful thinking fueled by sexual passion often obscures the brutal truth of human intention. How many women have viewed cohabitation as a form of "courtship," only to discover that it was just a "way station" before graduate school or a better job in another city?
Before the sexual revolution, Americans understood that marriage vows secured and celebrated fundamental truths about human dignity, true love and personal fulfillment. To thrive and grow, the love between a man and a woman required permanence, fidelity and openness to children.
The sexual revolution rested on a new way of thinking about sin and personal responsibility. It embraced a utopian vision of human nature as intrinsically virtuous and fully rational. Everyone should be free to exercise his or her freedom and responsibility in creative ways — without the stultifying and unnecessary intrusion of traditional moral taboos — we were told.
The women's movement was shaped by this utopian vision. Radical feminists embraced the need for a deep transformation in women's self-perception. Women were exhorted to discard the priority they gave to family life and embrace the working world and its rewards as the basis of their identity: to think and act like men.
Almost a half century after the publication of Betty Freidan's feminist blockbuster The Feminine Mystique, women have moved away from some of the early feminist rants. But their thinking and behavior have been skewed by a mainstream culture that has normalized selfishness, including exploitative sexual relationships.
For many women, the culture has failed to provide answers to some fundamental questions: What is their vocation? If they can do without men and family life, who or what constitutes their destiny? And what is sex for — recreation, pleasure, mutual manipulation?
These perennial questions drew the attention of Pope John Paul II, who also sought to safeguard and advance the rights of women, but he proposed a very different path for achieving this goal.
In his encyclicals and other writings, and in his teaching on the theology of the body, the Pope offered an integrated vision of the human person that began with a fundamental principle: Real human freedom must be rooted in moral and spiritual truth.
"When freedom is detached from objective truth it becomes impossible to establish personal rights on a firm rational basis; and the ground is laid for a society to be at the mercy of the unrestrained will of individuals," he wrote in The Gospel of Life (Evangelium Vitae).
In his apostolic letter Mulieris Dignitatem (On the Dignity and Vocation of Women), John Paul II meditated on Mary's fulfillment of all the riches suggested by sexual difference. He showed that the inalienable dignity of women — first established in Genesis and developed in the lives of the strong women of the Old Testament — achieves a new dimension in the life of the Virgin Mary.
"The moral and spiritual strength of a woman is joined to her awareness that God entrusts the human being to her in a special way," explained the Pope. "But this entrusting concerns women in a special way — precisely by reason of their femininity — and this in a particular way determines their vocation."
The Pope acknowledged the reality of injustice against women. But he urged them to respond with moral and spiritual strength rooted in Christian truth, rather than bitterness and resentment. Through word and deed, he said, women have been called to recapitulate Mary's self-gift in response to God's invitation. Even in the midst of real evil, they must look for opportunities to affirm and defend their own dignity and the rights of those "entrusted" to them.
An unredeemed view of human existence leads women to tolerate, rather than oppose, selfish, exploitive behavior. Pope John Paul II offers words of wisdom and of hope to women — and men — yearning for true fulfillment.
Ross Douthat shatters some feminist taboos, but that's only the beginning. The growing disconnect between feminist ideology and the actual experience of young women in 21st-century America provides fertile ground for the New Evangelization.
Register correspondent Joan Frawley Desmond writes from Chevy Chase Maryland.


text:
DETROIT -- Center fielder Curtis Granderson is in a downward spiral against left-handed pitchers, but Detroit Tigers manager Jim Leyland is trying to stick with him.
"Obviously, we need him to be a regular player now, next year and in the future," Leyland said. "And he is a regular player. I think he's going to be a factor these last three weeks. I'm going to play him against two of the three left-handers in this series."
However, Granderson was batting seventh Friday night against Toronto Blue Jays left-hander Brian Tallet, and Leyland said he is trying to get him going.
It was the first time this season that Granderson, who has been the leadoff hitter 114 times in 131 starts, batted lower than fifth.
Granderson is hitting only .182 with six extra-base hits and seven RBIs against southpaws, but he's batting .279 with 46 extra-base hits and 54 RBIs against right-handers.
It's a discrepancy Leyland has tried to allow Granderson to minimize, but he has made little progress. Dropping him in the order is an alternative to not playing him at all, which has happened seven times against lefties.
"The left-handers are better this year, and that's one thing," Leyland said. "And he hasn't made the progress we thought he would."
Granderson was up to the challenge of playing regularly against southpaws last year, hitting .259 with five homers and 14 RBIs. When asked what the difference is this season, he said it was a different approach by pitchers and his inability to adjust.
"A lot of lefties want to pitch (left-handed hitters) outside, and I can cover that," Granderson said. "But they are coming inside on me now, and I've got to make adjustments to that so I can get balls to drive the other way again."
He maintains that when he can lock in on lefties, it also helps him against righties.
"It's just a case of handling the inside pitch," Granderson said. "Sometimes, they are not strikes, and I have to lay off those."
Toronto and the Oakland A's are two clubs with plenty of young left-handers, and Granderson said he will do better against them the third or fourth time he faces them.
It's been a strange year for Granderson, who made the All-Star team for the first time and scored the winning run in that game in St. Louis after a hitting a triple.
His 26 home runs in 530 at-bats have eclipsed his career-high of 23 homers in 612 at-bats in 2007. With seven triples, he is two from the AL lead. Granderson led the league in three-baggers the past two years with 23 and 13.
But after hitting .302 in 2007 and .280 in '08, he is at .259.
"It's definitely not where I want it to be," Granderson said. "That's part of the battle. You have ups and downs and a lot gets over-looked (that doesn't show in statistics). People say, 'Well, your average is down.' But my homers are up, triples are just down a little and my runs are in the same area. And my on-base percentage is where it normally is.
"It's been an interesting year all around."
Granderson has a .333 on-base percentage and 81 runs. He finished 2008 at .365 with 112 runs.
But Granderson, who hit .158 on the recent six-game road trip, never hangs his head.
"Why be down?" he said. "We're winning."