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সোমবার, ৩ ডিসেম্বর, ২০১২
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Cuba pushes swap: its spies for jailed American
In what could be the setting for a gripping thriller, Cuba and the U.S. are reportedly locked in a standoff this weekend, with the fate of an American contractor hanging in the balance. NBC's Michael Isikoff reports.
By Michael IsikoffNBC News
HAVANA, Cuba ? It seems straight out of a Cold War spy movie. A group of Cuban undercover agents sneak into the U.S. and set up a secret pro-Castro network in south Florida ? receiving instructions in code through late night radio transmissions from handlers in Havana. But the FBI gets wind, tails the agents, intercepts their messages and busts them, sending the agents off to federal prison, their ringleader for life.
Today, the story of those spies ? called La Red Avispa, or the Wasp Network ? rolled up by the feds 14 years ago is barely known in the United States. But its members, now? known as the Cuban Five, are national heroes in Cuba ? the subjects of mass demonstrations, their pictures on billboards and? posters ? and their petitions for freedom are championed around the world by Nobel Prize winners, celebrities like Danny Glover, even former President Jimmy Carter.
And they may now prove key to the tense impasse between Havana and Washington over the fate of jailed American contractor Alan Gross, arrested three years ago Monday for distributing sophisticated satellite equipment to Cuba?s tiny Jewish community and later sentenced to 15 years in prison for "acts against the independence and/or territorial integrity of the state." (Gross says he was only bringing Internet access to Cuba.)
While the U.S. is demanding that Cuba release Gross, who visitors say is angry and frail, having lost 110 pounds in prison, Cuban officials say they are willing to do so only if President Barack Obama will? release the Cuban agents.
"I understand what Mr. Gross is going through," Gerardo Hernandez, 47, the Cuban Five ringleader, said in an exclusive interview with NBC News in October at his current home --a federal prison outside Victorville, Calif. "I understand his sufferings and that of his family. ? If an agreement can be reached, to stop the sufferings of six families, then I welcome it."
The idea of a swap ? the release of Gross for Hernandez and his confederates among the Cuban Five ? faces legal and political hurdles.
NBC News
A billboard in Cuba shows the Cuban Five -- Gerardo Hern?ndez, Antonio Guerrero, Ram?n Laba?ino, Fernando Gonz?lez, and Ren? Gonz?lez.
An Obama administration official told NBC News that the "imprisonment of Alan Gross, an international development worker, is not comparable in any way to that of the five Cuban agents," noting that the Cubans were afforded their "due process rights"?and convicted of serious crimes.
Cuban Five ringleader Gerardo Hernandez
Members of Congress have denounced Cuba for holding Gross "hostage" to the release of the Cuban Five. "The Castro regime has no regard for human rights or international law," said Democratic Sen. Robert Menendez of New Jersey, a senior member of the Senate Foreign Relations Committee and frequent critic of the Castro regime. "The Cuba Five should serve their sentences for spying."
And Hernandez, who sports a trim goatee and displays a hearty laugh despite 14 years in prison,? might not make the ideal candidate for a pardon or commutation from Obama ? a precondition for a swap to take place. Asked if he regretted any of his actions, he smiled and said, ?"I regret that I got caught." In a follow up phone interview, Hernandez readily acknowledged that "we violated some U.S. laws" ? mainly failing to register as foreign agents with the U.S. Justice Department. "We came here with fake passports. Fake identities." ?But, he added, "We act out of necessity."
As Hernandez and Cuban officials tell it, the Cuban Five was not sent to spy on the U.S. government. In fact, the members weren?t accused of stealing any U.S. secrets (although they were convicted of conducting surveillance of U.S. military bases.) Instead, the mission of the Wasp Network, they say, was to infiltrate? anti-Castro exile groups in South Florida who Havana suspected of plotting terrorist attacks inside Cuba. Among those attacks: the notorious bombing of Cubana Flight 455 over the Caribbean in 1976, killing 73 passengers (including teenage members of a Cuban? national fencing team)? as? well as a string of hotel bombings in Havana in? 1997 that killed an Italian businessman and were believed to have been aimed at disrupting Cuba?s nascent tourist industry.???
"Cuba doesn?t have drones to neutralize the terrorists abroad," said Hernandez. "They need to send people to gather information and protect the Cuban people from these terrorist actions. ? I think it?s the same feeling that Americans have that defend their country and love their country when they go to infiltrate al-Qaida and send information here to avoid the terrorist acts. And the U.S. has to understand that Cuba has been involved in the war against terrorism for 50 years.?
Alan Gross in an undated family photo, left, and in 2012, after losing 110 pounds while imprisoned in Cuba.
While admitting his role in spying on anti-Castro exiles ? "I would do it again," he said ? Hernandez adamantly denies the most serious charge against him: conspiracy to commit murder. His conviction on that count, which has earned him a life sentence, was based on his alleged complicity in the February 1996 shoot-down by a Cuban fighter jet of two Cessna planes flown by members of the Cuban exile group Brothers to the Rescue, killing four men.
The anti-Castro group had provoked Cuba by dropping anti-government leaflets over Havana. At the trial of the Cuban Five, prosecutors introduced messages between Hernandez and his controllers in Havana suggesting he had prior knowledge of the shoot-down. But Hernandez insists that prosecutors misinterpreted the messages and he knew nothing that wasn?t already public.
"No, sir, absolutely not," Hernandez replied when asked if he knew in advance about the incident. "All I knew was what everybody knew: that Brothers to the Rescue through the years has violated many times Cuban air space, that there have been 16 diplomatic notes from Cuba complaining over that situation."
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Ricardo Alarcon, president of the Cuban National Assembly
Ricardo Alarcon, president of Cuba?s National Assembly (the Parliament) and a longtime Castro confidante, said this week in Havana that "the Cuban government publicly, front page in our papers, months before that incident had warned that we are not going to allow any more intrusions into our air space. ? The order, the decision (to shoot down the planes) came from the highest level. Fidel Castro himself had said that publicly, that he was responsible for that decision."
U.S. Appeals Court Judge Phyllis Kravitch of Atlanta concluded in 2008 that prosecutors never proved their case tying Hernandez to a plot to shoot down the planes, but she was outvoted two to one and his conviction on the murder conspiracy charge was upheld. Now Hernandez and his lawyers are appealing on another ground: that hundreds of thousands of dollars in secret ?U.S. government payments to anti-Castro journalists in Miami ? newly discovered through Freedom of Information Act requests ? inflamed the Miami community against the Cuban Five and made it impossible for them for them to get a fair trial. The payments were mostly made for appearances on Radio Marti, a TV and radio operation funded by the Broadcasting Board of Governors, an independent agency that oversees international broadcasting sponsored by the U.S. government.
Slideshow: Castro through the years
In court papers, lawyers for the Cuban Five have cited articles by some of the journalists, including one that denounced the "genocidal character" of Castro?s regime and another that speculated that the real purpose of the Wasp Network was to introduce "chemical or bacteriological weapons" into south Florida. ?"his information was spread throughout the Miami area and helped inflame the community against these guys," said Martin Garbus, Hernandez? lawyer. "It was total madness. ? When the case was brought, the anti-Castro feeling in the Miami area was at a fevered pitch."
Keystone / Getty Images
Ever since U.S.-backed Cuban President Fulgencio Batista was forced from power by rebels led by Fidel Castro in 1958, the relationship between the two nations has been fraught with difficulties.
U.S. prosecutors dismiss as ?implausible? and "unfounded" the idea that the Radio Marti payments were part of a U.S. government effort to influence the jury in the Cuban Five case.
?"The jury (in the case) was carefully selected, following a searching voir dire (jury selection process) that the appellate court deemed a high model for a high-profile case, and that the trial comported with the highest standards for fairness and professionalism,? wrote Caroline Heck Miller, an assistant U.S. attorney in Miami, in a court filing in July asking a judge to reject Hernandez? motion for a hearing into the payments to the journalists. She also noted, as federal prosecutors have repeatedly done when the issue has come up, that ?no Cuban-Americans ? the audience (Hernandez) hypothesizes as the target of the government campaign he imagines ? served on the jury."
Unless Hernandez can somehow persuade a court to reopen his case ?? or barring a prisoner swap with Gross ? he would seem to have few options.
American imprisoned in Cuba may have cancer, doctor says
Rene Gonzalez, another member of the Cuban Five who was not convicted of the conspiracy-to-commit-murder charge, was released from federal prison on probation late last year, but has not yet been allowed to return home to Cuba to live.
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Adriana Perez, wife of imprisoned Cuban agent, Gerardo Hernandez
The Cubans are doing their best to ratchet up the pressure. Just as Judy Gross has launched a public relations campaign in the United States to free her husband, appearing at a National Press Club press conference on Friday, this week the Cubans made Hernandez wife, Adriana, available for an interview with NBC News. A chemist in the food industry in Havana, she wept as she described the pain of separation from her husband ? and how it has left her unable to bear children. "Every detail, every single moment reminds me of him," she said. "I believe there are many people in the U.S. and the American people as a whole, who could convey to President Obama that there is a woman here suffering."
Hernandez, too, says missing his wife is the hardest part of his life in prison. And he has few illusions about his prospects of being freed. "The only thing I know for sure with me is that I have two life sentences and live with that every day," he said. "And to keep your sanity and your mind, you have to be realistic. But I would be dishonest to say that I don?t have hope."
Michael Isikoff is NBC News' national investigative correspondent; NBC News Producer Mary Murray also contributed to this report.
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Movie Review: 'Playbook' Offbeat, Charming - Los Alamitos-Seal ...
Two years after David O. Russell?s The Fighter, the infamously controversial filmmaker is back with his latest blend of crappy people and hearts of gold.
Silver Linings Playbook is a romantic comedy, which is perfect for the holiday season and families looking for entertainment. But it also has characters with mental issues, which is perfect for Oscar season. Taking a break from Mark Wahlberg, Russell cast endearing, popular actors Bradley Cooper and Jennifer Lawrence as his protagonists.
After a stay in a mental institution for anger issues and being diagnosed as bipolar, Patrick (Cooper) moves back in with his parents (Robert De Niro and Jacki Weaver) when he discovers his wife has left him. Things at home don?t go too well, either: Pat?s dad also has a bad temper and OCD, causing conflict. Soon an old friend of Pat?s sets him up on a date with his wife?s sister Tiffany (Lawrence), who also has a bad attitude and suffered depression after her husband?s death. It?s a match made in therapy; Pat is in denial about the end of his marriage and asks Tiffany to help him win his wife back.
Chris Tucker and Julia Stiles co-star as Pat?s rehab pal and Tiffany?s sister.
Russell has experimented with his share of genres the last two decades, from the romantic comedy Flirting with Disaster (1996) to the war satire Three Kings (1999) to the quirky ensemble piece I Heart Huckabees (2004) to the boxing drama The Fighter (2010). Now he steps back to his romcom roots with his adaptation of Matthew Quick?s novel Silver Linings Playbook.
Playbook manages to be light and heartfelt while dealing with serious subjects like mental illness. Cooper, known primarily for comedies like Wedding Crashers (2004) and The Hangover (2009), disappears into Pat and delivers as the lead of a talented cast. Many already think Lawrence should receive an Oscar nomination for her portrayal of aggressive, loudmouthed Tiffany, and it?s easy to see why. She is as amusing and cute as she is frustrated and bitchy.
Silver Linings Playbook is charmingly offbeat in a way few filmmakers could succeed at.
Source: http://losalamitos.patch.com/articles/silver-linings-playbook-is-charming-irreverent
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Educational Psychology for Organic Chemistry | Backlinkarticles
Even though courses in such subjects are difficult, there is one basic popular denominator amongst them ? mathematics. Vibrant students fair nicely mainly because they?ve been mastering the language of mathematics because initially grade.
Organic Chemistry is completely different. It calls for the mastering of an ?alien? language, which I normally compare to Russian, along with rapidly-paced deductive reasoning in that language. Visualize taking Russian for the very first time, studying for an exam, and understanding in class that the midterm is a test of deductive reasoning requiring thought in Russian. Sounds like it would in no way happen, yes? Properly, this is Natural Chemistry.
This program of logic based in visual-spatial learning with the intent of such finding out to be applications to unknown complications requiring quickly-paced deductive reasoning is taken by over 1 million students in the United States each year. It really is not atypical for a class average grade to hover between 30-50%. Particularly vivid students enroll in this course, and most of them obtain an common grade of 38%. This is an immense shock to students accustomed to scoring at the higher end of just about every other class they?ve taken.
Portion of the trouble is time management expertise never ever acquiring been developed, resulting in what I refer to as the ?Drama of the Alarms.? This is the series of ?emergencies? that arise when the first 3 weeks of the quarter/semester are spent ?coasting?. When the initial midterm arises, the student becomes critical and focuses exclusively upon the first midterm, ignoring every thing else. Just ahead of the 1st midterm, a further ?alarm? goes off, and the student realizes there is one more impending exam. As soon as exam a single is out of the way, the student ?crams? for exam two. Just ahead of exam two, the student ?learns? (the syllabus under no circumstances produced it to the calendar) of one other impending exam, takes exam two, and then crams for exam 3.
As soon as the vicious cycle of the Drama of the Alarms is in movement, it is like a runaway freight train having acquired far as well a lot momentum to cease. The drama continues until the end of the term, and fees the student one or additional A-grades. Rather of learning time management expertise, the student repeats the exact same pattern of behavior more than and again till graduation.
Key etiology of the ?concern? in Organic Chemistry particularly is the comfy habit of memorization put to use successfully to plan for examinations in practically each and every other topic. This method fails in Organic Chemistry. A different factor is the deceptively straightforward nature of Organic Chemistry wherein one may well search by notes, convince himself he knows the material only to understand days ahead of a midterm that he?s unable to function any of the problems effectively. The primary challenge is mastering, and becoming expected to promptly rationalize in, this extremely rigorous scientific visual-spatial language. There are no other university level courses like it, and Natural Chemistry routinely becomes a life-altering occasion.
The top teachers of Natural Chemistry are willing to do just about anything to get students to learn the topic. On one section of the blackboard, they create every thing needed for student mastery of program objectives. They indicate memorization will be their demise, and that the only successful strategy is to create abilities in vital analysis and deductive reasoning, the really abilities needed to excel in the MCAT. Exceptional teachers also take the time with each chapter of the textbook to apply principles discovered to real-life issues of interest to the students. Ultimately, these astounding Natural Chemistry teachers make themselves attainable for overview sessions either ahead of a midterm or even on a weekly basis.
As teachers of Natural Chemistry, we can?t adjust the nature of the program and nevertheless maintain its integrity. This will never come about ? it really is a option. We can, on the other hand, seek the tips of educational psychologists to find out how to get students to want to depart from the comfy habit of memorization toward that of deductive reasoning, figuring out the latter is what is expected on the MCAT. We can tell the students they have the decision of finding out MCAT abilities now with plenty of time to hone them, or they can get a C-grade in the program and hope that mastering MCAT abilities later could get them into some medical school.
Scare techniques are undesirable, having said that sadly they seem to operate greater than any strategy of good reinforcement. There are quite a few articles offered on how to succeed in Organic Chemistry. Some are read while most are not. What tiny is read is hardly ever rendered to practice. Finally, nearly endless sources are readily available to promote student accomplishment in Natural Chemistry, nonetheless most are seldom utilized.
Educational psychology is a science, and this teacher of Organic Chemistry is attractive to educational psychologists for a viral approach on how to effect permanent transform in the outcome of undergraduate Natural Chemistry. Such alter will necessitate addressing important time-management difficulties. Also expected will be introducing worth to students so they choose to do what is harder (deductive reasoning) vs. what is comfortable (memorization). Indicating such skills will become immensely beneficial on the MCAT appears like a logical approach, nevertheless the adversary right here is the tendency toward procrastination. How a lot of of us wait until April 10th to do our taxes?
This article is open ended. I am looking for the input of western educational psychologists, and am open to any recommendations that will empower students to pursue the research of Organic Chemistry with the intent of mastery rather than just obtaining a passing grade. The time for bringing educational psychology into the university classroom with regards to this topic is long overdue.
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শনিবার, ১ ডিসেম্বর, ২০১২
Great Sex Despite Chronic Medical Conditions | Psychology Today
Your doctor solemnly announces that you have diabetes, lupus, heart disease, rheumatoid arthritis or some other chronic condition, and inquires, ?Any questions?? You ask quite a few, but can?t quite manage, ?What about sex?? Every chronic condition is different. But coping sexually doesn?t depend much on the condition. To enjoy the best sex possible despite your chronic condition, follow these six steps:
1. Be Flexible
If you define ?sex? as just vaginal intercourse, and can no longer do that, you might think that sex is over for you. But if your definition of sex is more flexible, then bidding farewell to intercourse is like passing up one dish at a huge buffet. Even if you can?t have intercourse, there are many ways to enjoy physical intimacy, fulfilling lovemaking, and orgasm. Men don?t need erections to climax. Satisfying sex is based on leisurely, playful whole-body massage. Even those with severe disabilities can often kiss, cuddle, use sex toys, receive massage and oral sex, and perhaps provide it. Focus not on your disabilities, but on your abilities. Where there?s a will, there?s always a way.
2. Find Information and Support
Ask your doctor about the sexual implications of your condition and the sexual effects of your medications. Then ask your pharmacist. Next, search the Internet: sexual effects of?then list your medications. You may get different answers. But you?ll come away with a useful overview.
Join the organization devoted to your condition. It?s a rare chronic condition that doesn?t have a national organization. To find the organization, search the Internet, or visit the American Self-Help Group Clearinghouse. Then ask the organization for information on coping sexually, and possibly, for a referral to an expert on your condition?s sexual implications.
Finally, most chronic-condition organizations sponsor support groups. Consider joining and asking group members how they cope sexually.
3. Stay As Healthy As Possible
?How can I be healthy?? you ask, ?I have this damn disease.? Yes, you do. But you'll feel better, have an easier time managing your condition, and retain more sexual interest and ability if your lifestyle is as healthy as possible:
? If you smoke, quit.
? Don?t drink more than two alcoholic drinks per day.
? Eat at least five servings of fruits and vegetables a day.
? Within your abilities, strive for regular moderate exercise, ideally, at least 30 minutes a day.
? Get at least seven hours of sleep a night.
4. Look For New Opportunities
Having a chronic condition means grieving the loss of things you can no longer do, among them, how you had sex. But if you stop there, you wind up depressed?and depression kills libido and erotic enjoyment. As time passes, look for new opportunities for fun and personal growth?including new approaches to making love.
5. Try Lubricants and Toys
Diabetes and other conditions may decrease genital sensitivity. Lubricants often help. They?re inexpensive and available over the counter. In addition, vibrators might help women and vibrating penis sleeves might help men. Depending on your situation, other sex toys might also enhance your lovemaking. Try a few.
6. Consider Sex Therapy
Sex therapists are psychotherapists with advanced training in sex problems. They never have sex with clients, and they don?t watch you have sex. They discuss your situation, suggest ways you can enjoy sex, and assign erotic ?homework.? The process typically takes a few months of weekly appointments, and studies show that two-thirds of people who consult sex therapists report significant benefit. To find a sex therapist near you, visit the American Association of Sex Educators, Counselors, and Therapists, the Society for Sex Therapy and Research, or the American Board of Sexology.
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Check Out These Great Self Improvement Tips! | iNeedInfotips.com
You may have just realized that unless you radically change your behavior, you could lose all those who matter most to you. The quality of your personal life begins through personal development, but how can you address this? This article contains the keys you need to start improving your behavior today.
If you take proper care of your physical needs, you will get the maximum benefit from your personal development approach. Exercise regularly, get adequate sleep every night and enjoy a healthy diet to help you continue your personal growth. While it may sound simple, this is sometimes one of the most difficult things to do.
Are you a heavy drinker? Are nicotine or other destructive habits something that harms you? Your body is certainly a temple, yet these types of behaviors disregard its sanctity. Sometimes, eliminating bad habits is what it takes to make your life better. Analyze your life and habits, and make a point to cut out any habits that are not good for you or your body.
There are things you can do throughout the day to accomplish more work while at your job. One trick to doing this, is to take more breaks. This may seem counterproductive, but by taking constant breaks, you have time to unwind and recharge so that when you get back to work, you can get more stuff done.
If you?re not living up to the goals that you set for yourself, take a good hard look at what may be wrong. Look for resources related to your issues and ask your friends about their struggles. The problem might be that your expectations were set too high, important steps were not taken, or inadequate resources were allocated in working toward your goals.
Be realistic and smart about everything you face in life. Try and analyze things you go through to determine what aspects of your life can change and what aspects are unavoidable. Exercise modesty to stay within your boundaries. Wisdom can help you make better decisions for your future.
Be ready to write down ideas wherever you are. Start out by carrying a small notepad whenever you go out. Just write what you think about and you can work on those ideas later.
Look for pieces of writing or prose that were created for motivation. Some people may look to a religious text, while others might look for inspiring quotes. Whatever you choose to help raise your awareness of a happier state of mind, it can be a useful anchor that you can refer to again and again.
The first step in changing is making a decision to change. If we want to grow or change, we have to accept and choose the change.
In order to be properly motivated toward self improvement goals, it is important to admit how much you do not know. You need to know that in the grand scheme of things, your problems are very insignificant. A humble attitude puts you in the right mindset to learn new things and develop as a human being.
They say that speaking and listening are equally important. This is particularly sage advice if you are working on your personal development. You should make sure you are always listening when talking to yourself. If you?re not able to hear yourself, you can?t possibly get a grasp on what is truly necessary for self improvement.
Read up on what other people have done to become successful. You can avoid a lot of trial and error by learning what other successful people have done in your situation. By reading what they have learned, it will give you a positive boost on your self improvement.
Make a list of your priorities, and plan your life around these elements. You should be happier and more peaceful if you know what matters to you, and concentrate on these things.
Whereas trying to fix your problems yourself is always a great idea, sometimes you might have to seek out professional help. Self help books are useful to an extent, but they lack the substance or personal touch that a therapist can provide to a patient. Simply talking can help motivate you to succeed. You can?t have a discussion with a book.
In many ways, your attitude is reciprocal. If you wish harm upon others, harm may come to you instead. Try to only want good things to happen to other people. Focusing on positive things will help you stay happy and motivated.
The best way to go about self improvement is to concentrate your improvement efforts on one trait at a time. There are probably many things that you are wanting to change, but focusing on one will make success more likely. Remember that the goal is to change for good, and that those changes have to come slowly from the inside out.
Learn to not worry! The habit of worrying is really imagining a situation that hasn?t really happened and will most likely not ever happen. Try not to worry about everything. Also, think about the worst that could happen, then start taking steps to overcome the worst case. That way, you will feel prepared, and you will also be able to go on with your life.
Self improvement can be a difficult and laborious process, but it?s worth every second. If you are steadfast and have a strong support system, you can do it, and be proud of the results. These suggestions should assist you on your journey.
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Chromatin remodeling: Activating ACL1 with a little help from 'friends'
ScienceDaily (Nov. 29, 2012) ? Chromatin remodeling -- the packaging and unpackaging of genomic DNA and its associated proteins -- regulates a host of fundamental cellular processes including gene transcription, DNA repair, programmed cell death as well as cell fate. In their latest study, scientists at the Stowers Institute for Medical Research are continuing to unravel the finicky details of how these architectural alterations are controlled.
Through a series of biochemical experiments, Stowers Investigators Ron Conaway, Ph.D., and Joan Conaway, Ph.D., and their team discovered that chromatin remodeling enzyme and suspected oncogene ALC1 (short for Amplified in Liver Cancer 1) is activated through an unusual mechanism: Its shape shifts in the presence of its activators. Their finding identifies a new instrument in cells' molecular repertoire of chromatin-remodeling tools and a potential cancer therapeutic target.
One of the main tasks of chromatin remodeling enzymes, Ron Conaway explains, is "to make DNA accessible so events like repair and gene transcription can occur." Postdoctoral research associate and first author Aaron Gottschalk, Ph.D., previously figured out that ALC1 required protein partners to activate its remodeling function. Publishing in an upcoming issue of the Journal of Biological Chemistry, he dissects the mechanism by which this occurs.
ALC1 and its ilk have a common protein domain, SNF2, that uses the energy of ATP hydrolysis to move nucleosomes -- the basic repeating units of chromatin -- around, in a process called nucleosome sliding.
"I was intrigued because ALC1 has a unique macrodomain not found on any other SNF2 family member," Gottschalk says. His interest was further piqued when he found that while most ATP-dependent chromatin remodelers function as large multi-protein complexes, ALC1 appeared to work by itself. At the same time, where most of its group-happy family members readily demonstrated nucleosome sliding activity in vitro, ALC1 was not only a lone ranger but also "completely dead on its own."
Gottschalk deduced that ALC1 may function independently, but it needs a boost from a couple of sidekicks: PARP1, an enzyme that responds to several kinds of DNA damage; and NAD+, the substrate by which PARP1 transfers chains of poly (ADP-ribose) onto itself and other target proteins, in a process called PARylation.
Only when PARP1 and NAD+ are on the scene does ALC1 spring into action, altering the accessibility of DNA by shifting nucleosomes around. Gottschalk's earlier findings were published in the Proceedings of the National Academy of Sciences in June 2009.
"We then extended this research," Conaway says, "and the upshot of our recent JBC paper is that ALC1 is likely activated through a series of physical interactions. ALC1's unique macrodomain can bind PAR, and protein-protein interactions also occur between ALC1 and PARP1." Gottschalk and coauthor Rushi Trivedi, a graduate student in the Biochemistry & Molecular Biology department at KU Medical Center, developed a novel footprinting assay that enabled this observation. Rather than merely activating ALC1 and moving on, the researchers found that the trio of PARP1, NAD+ and ALC1 hangs out in a stable complex.
"So PARylated PARP1 and NAD+ are allosteric effectors -- by binding to ALC1, they alter its state from dormant to active," Conaway says. "It's an interesting mechanism that's different from how most other chromatin remodelers work. It may also help explain other evidence that PARP1 has the ability to rearrange nucleosomes and reorganize chromatin; this could be one way by which PARP1 exerts its influence."
Apart from its role in modifying chromatin structure, not much is currently known about ALC1. It's regarded as a possible oncogene, being found in excess in hepatocellular carcinoma cells and because overexpression of ALC1 in mice induces spontaneous tumors.
PARP1, on the other hand, has attracted plenty of interest as a potential anticancer drug target, due to its importance in maintaining genomic integrity. For example, in breast cancer cells lacking BRCA1 or BRCA2 function, blocking PARP could effectively remove the cells' last line of defense against DNA-damaging chemotherapy agents. To date, no PARP inhibitor has made it past phase III clinical trials, but pharmaceutical companies continue to chip away at the challenges around optimizing this form of targeted cancer therapy.
"A better understanding of the in-depth biochemistry we're uncovering on ALC1 and PARP1 may, in the long term, ultimately lead to new or more refined therapeutic strategies," Gottschalk says.
Meanwhile, having observed that ALC1 comes to life upon interacting with friends, Gottschalk now wants to understand precisely how this activation happens. With a knockout ALC1 mouse model handy, plans are afoot to extend his studies to an in vivo characterization of a chromatin remodeler that boasts an illustrious family pedigree, yet stands apart in the crowd.
Funding for this study came from a National Institute of General Medical Sciences grant (GM41628), and a grant to the Stowers Institute from the Helen Nelson Medical Research Fund at the Greater Kansas City Community Foundation.
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The above story is reprinted from materials provided by Stowers Institute for Medical Research.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.
Journal Reference:
- A. J. Gottschalk, R. D. Trivedi, J. W. Conaway, R. C. Conaway. Activation of the SNF2 Family ATPase ALC1 by Poly(ADP-ribose) in a Stable Nucleosome-PARP1-ALC1 Intermediate. Journal of Biological Chemistry, 2012; DOI: 10.1074/jbc.M112.401141
Note: If no author is given, the source is cited instead.
Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.
Source: http://feeds.sciencedaily.com/~r/sciencedaily/~3/miSQ5ef0V9Y/121129151918.htm
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