четверг, 15 марта 2012 г.

Pakistan's post-Musharraf ruling coalition splits

The ruling coalition that just a week ago drove U.S. ally Pervez Musharraf from the presidency broke apart Monday, throwing Pakistan into political turmoil just as it faces an increasingly difficult fight against Islamic militants.

The collapse of the fragile alliance threw more power to Asif Ali Zardari, the widower of assassinated ex-leader Benazir Bhutto and a corruption-tainted former polo player who now becomes the front-runner to replace Musharraf.

Fulfilling a threat he made last week, former prime minister Nawaz Sharif pulled his party out of the coalition after a dispute with Zardari over whether to restore the chief justice of the Supreme Court, …

Ripley 32, Capital 20

Capital (20-2) FG FT Points

Tavia Franklin 1 0-0 3

Lasha Fortson 1 0-0 2

Milan Cary 2 0-0 4

Lisa Lee 1 0-0 2

Rae Rae Sayles 3 0-2 7

Erica Reese 1 0-0 2

Totals 9 0-2 20

Ripley (19-6) FG FT Points

Jay …

4 U.N. Peacekeepers in Sudan Sent Home

UNITED NATIONS - Four U.N. peacekeepers in southern Sudan have been sent home in the past year following investigations of alleged sexual abuse and the United Nations is looking into reports that more than 20 children were raped and abused, the U.N. spokeswoman said Wednesday.

Michele Montas said the United Nations was "deeply concerned" by a report in a British newspaper alleging that U.N. personnel in Juba, the capital of southern Sudan, were involved in sexual exploitation and abuse. The U.N. was trying to determine whether the allegations were new or involved existing cases already under investigation.

The Daily Telegraph, citing an internal report by the U.N. …

Hummel sends No. 24 Purdue past Illinois 66-56

Robbie Hummel looks healthy, and Purdue is playing like the team that was picked to win the Big Ten title.

Hummel finished with 19 points and 12 rebounds Saturday, and JaJuan Johnson had 20 points and three blocks to lead the Boilermakers past Illinois 66-56 Saturday and into the Big Ten tournament championship game.

The victory ends third-seeded Purdue's three-game losing streak to the Illini (24-9) and sets up a rematch with fifth-seeded Ohio State, an 82-70 upset winner over No. 7 Michigan State. The Boilermakers and Buckeyes split the first two games this season, each winning at home.

It's the first time since 1998 that Purdue (24-9) will play …

среда, 14 марта 2012 г.

www.give.org

Planning to make a charitable donation? This Web site of theBetter Business Bureau Wise Giving Alliance reports on charitableorganizations. Visitors to the site can view reports to determinewhether an …

NOWCAST: TECHNOLOGY

NIGHT VIEWS OF MEDITERRANEAN IMPROVE OCEAN HEAT MAP

The European Space Agency (ESA) has made significant enhancements to their Medspiration project, which uses satellites to take the daily temperature of Europe's seas. The products are designed for near-real time ingestion of numerical ocean forecasting models to keep their outputs "coupled" to reality. An ultra-high-resolution sea surface temperature (SST) map focused on the Mediterranean Sea with an accuracy of less than 0.3�C is being made available daily. The most significant change to the product is the acquisition of data at night.

Satellite instruments can only measure the "skin" SST (the top 10-20 microns) rather …

Federer-Djokovic Set for Semifinal Match

Top-ranked Roger Federer will meet No. 3 Novak Djokovic in a semifinal match Friday that will determine who faces unheralded Jo-Wilfried Tsonga in the Australian Open final.

Rafael Nadal, ranked No. 2, was dominated in stunning fashion Thursday by Tsonga, who won in straight sets 6-2, 6-3, 6-2.

Nadal played well against the 38th-ranked Tsonga, who had never gone beyond the fourth round in his four previous Grand Slams. But the Frenchman was virtually untouchable, smashing 17 aces against one of the best serve returners in the game.

Nadal finished with just 12 unforced errors _ four combined in the first two sets _ while matching the fewest games he …

CPS in line to receive $105 mil. from feds; But Daley still

Chicago's financially strapped public schools are in line for a $105 million windfall from the new federal jobs bill -- enough to restore high school class sizes, bilingual education and other program cuts -- but probably not in time for the start of school Sept. 7.

The one-time windfall -- and the Board of Education's ever-changing budget shortfall -- appears to be undermining efforts to persuade the Chicago Teachers Union to forfeit a 4 percent pay raise or agree to other concessions.

The union's House of Delegates met Wednesday evening and voted unanimously to reject the concessions proposed by CPS.

Shortly beforehand, CTU President Karen Lewis accused …

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Bookmark Business Journal stories and save them for your friends with more than 30 social-bookmarking sharing widgets on our Web site. The Business Journal's home page also features a …

New Taiwan leader reportedly cautious with China

Taiwan's ex-president said Wednesday that the island's new leader will tread cautiously in dealing with rival China, despite pressure from some in his party to engage Beijing without delay.

Ex-Taiwanese President Lee Teng-hui's comments came as Chairman Wu Poh-hsiung of Taiwan's ruling Nationalist Party was meeting in Beijing with Chinese President and Communist Party chief Hu Jintao.

The meeting heightened expectations that new Taiwanese President Ma Ying-jeou might be ready to preside over a rapid improvement in political relations between the sides, which split amid civil war in 1949.

Ma took office last week.

But in an interview with …

Brown-out conditions could linger for Bears

PITTSBURGH -- No one would pin the struggles of the Bears' defenseSunday on the loss of strong safety Mike Brown, but his absence wasfelt as they surrendered a season-high 190 rushing yards to thePittsburgh Steelers.

Brown pulled his left calf muscle in practice Thursday and did notmake the trip. He has been described as "week-to-week" and could missthe next two games or more. It has been a hush-hush situation for theteam, one sign that it's serious. Brown, the Bears' third-leadingtackler, was in a walking boot Friday at Halas Hall and was notmoving well.

Also missing was rookie free safety Chris Harris, who has asprained medial collateral ligament in his right …

African and African American film center releases new African cinema 2000 collection

California Newsreel, the oldest nonprofit documentary production and distribution center in America, established in 1968, has the largest holdings in North America of film and video by and about Africa and African Americans. The center recently published its 1999-2000 resource guide featuring 14 new releases, the largest number in its history. The 64-page African Cinema 2000 catalogue includes 55 films from 21 African countries and surveys the most …

Consider custom synthesis during pharmaceutical R&D

A new chemical with promising therapeutic effects has to be tested in animals and humans for safety and efficacy as a drug. Demand for the chemical, depending upon its potency, at the various stages of development can vary from a few kilos to a few metric tons. Usually, the chemical development group in the research and development organization of the pharmaceutical company has the responsibility for sourcing the chemical (1).

Many pharmaceutical companies rely on their pilot plants as the main suppliers of chemical to meet the demands of the various toxicological and clinical studies. The chemical development group, however, really has three potential sources for developmental supplies: the pilot plant, the manufacturing plant, or custom synthesis (that is, using an external, contract manufacturer). Assuming that safety and quality are not issues, the decision to use one or more of these alternatives usually is based on the relative speed of implementation and cost. Needless to say, at the early phases of product development, the chemical process is not as well developed - so, speed is of utmost importance.

The attractions of custom synthesis

Going to a contract manufacturer may make sense for a variety of reasons: Capacity. While a company's pilot plant may be able to produce the chemical, it may not have adequate capacity to provide all the supplies needed. Often, either due to lack of capacity in existing equipment or the time required to procure new equipment, it is not prudent to try to make the chemical internally.

Coping with change. The chemical supply business in an R&D environment has to deal constantly with unexpected changes in plans and product mix. Even with the best efforts of a proactive planning system, it still may not be possible to satisfy all needs at all times. And, occasionally, it is worthwhile to go to a toll manufacturer so that an internal facility is not taxed to the point that it cannot handle any special requests for additional product.

Speed. A custom manufacturer with special expertise in certain types of organic synthesis or with access to special equipment may be able to make an intermediate faster than one possibly could internally.

Risk reduction. Because R&D invariably involves a very high failure rate, it often is not cost effective to add new equipment and expand current facilities for the rapid production of additional chemical.

Spurring innovation. The mission of a pilot plant in drug development should be to support rapid innovation, as well as to produce chemical; trying to maximize utilization of the facility may impede such efforts. At times, it may be wise to keep the unit idle in anticipation of rapid, but very short notice, production requirements for new products. Development teams also may want to try different experimental designs. Going to a toller can free up pilotplant time for such efforts.

Need for foreign supplies. Pharmaceutical companies sometimes must make supplies in an ex-U.S. facility for early clinical trials in Europe and Japan. If the company does not have a chemical development group or a pilot plant outside of the U.S., it usually uses custom manufacturers to satisfy that need.

Differences from normal sourcing

The Rc*D environment imposes special demands on custom synthesis: Quantity. The amount of a particular chemical required can vary from one kilogram or less to several hundred kilograms, depending upon the stage of development.

Speed. Often, especially at the early stages of drug development, chemical supply is on the critical path. Therefore, the ability to use a custom manufacturer to make the proper quality and quantity of chemical quickly is of utmost importance. Pharmaceutical companies often are willing to pay a premium for speed.

Flexibility. In the early stages of a project, chemical needs keep fluctuating. Pharmaceutical companies usually have a hard time finalizing the number of animals or patients they will be dosing in a study. This can cause tremendous strain between the company and the contract manufacturer. In addition, R&D projects can be dropped or priorities can change, requiring the custom manufacturer to slow down or stop working on a production project. On the other hand, sometimes, the toller may be asked to increase production by several fold.

Duration of contracts. At the R&D stage, companies usually seek short-term contracts for tolling with no long-term commitments. Sourcing long-term supplies, in most companies, is a manufacturing decision. R&D organizations should not make commitments for long-term supply.

Complexity of chemistry. Bulk pharmaceutical processes frequently involve relatively complex chemistries. For the early stages of development, the development teams do not have time to optimize the process or to develop simpler manufacturing routes. The process, in a lot of instances, may not even be well characterized. One, therefore, has to look for contractors with the ability and experience to implement relatively complex organic chemistry.

Status of technology. Often, the level of process development is insufficient. The contractor may have to undertake some process development itself before being able to run the process in its facilities. Tollers with some capabilities in organic process development definitely will have a significant edge over those without such capabilities.

Business issues

Success, of course, depends upon selecting an appropriate, capable contract manufacturer. (For tips on finding the right toller, see the article by Worstell et al. on p. 45.) The strength of the relationship with the custom manufacturer is all important. Familiarity with each other's personnel and systems, especially analytical methods and techniques, is critical to successful technology transfer. We highly recommend that staff from the toller visit the customer's facilities so as to understand its systems and meet its key people. Technical personnel from the custom manufacturer also should be free to call the customer's technical personnel to ask questions. Building trust and good communications is crucial.

Treat the custom manufacturer as a partner rather than as just a supplier. It is in the customer's interests to ensure that the toller does not go out of business or incur undue losses trying to satisfy its requirements. Indeed, the customer should make every effort to develop a relationship based on true partnership this may require a paradigm shift. But, it is important to realize that, for the pharmaceutical company to be successful, the custom manufacturer must be successful, too.

It is better to establish long-term relationships with a few reliable custom manufacturers than shortterm relationships with numerous ones. Communications are enhanced and, thus, time is saved when parties are familiar with each other's systems and personnel. The personal nature of the relationships between the two parties can be sustaining in times of crisis. Likewise, dealing with a few, trusted tollers helps to protect confidentiality; maintaining secrecy could become quite resource-intensive if one deals with a large number of custom manufacturers.

Once a contract is awarded, a project team - consisting of 3-5 key individuals from each company, including one project champion from each - should be formed. This team normally should include an engineer, chemist, analyst, and project manager. All team members must be familiar with the technology. Additional members also may be appointed, based on project-specific needs. Such a team allows better coordination and improved communication between the two companies. To avoid confusion, make sure to define the roles and responsibilities of the project team members and its leaders, and to identify communication channels.

To maximize the success of any project, it is very important to have a decision-making process that allows for the rapid evaluation and resolution of issues as they arise. The staff assigned the responsibility for managing a project on a day-today basis must be empowered to solve technical problems and decisively resolve urgent matters that inevitably occur during a project. This group of people also must be empowered with the authority, albeit limited, to make decisions that impact on a project's budget.

Technical issues

Once a contract manufacturer is chosen, the custom synthesis process involves several steps, as listed in Table 1. Technology transfer probably is the most important step to help ensure the success of the program.

Always remember in technology transfer that every contract manufacturer is unique -- perhaps with a different system for taking a process from the laboratory to the plant, and certainly with different equipment as well as people with different levels of skills and experience than other tollers you may have used.

At the initial stages of the project, the chemical development group should try to provide as much inhouse experience and knowledge as possible so that the custom manufacturer can determine the feasibility of carrying out the project and provide accurate time and cost estimates.

After the contract is agreed upon, a Technology Information Package (TIP) should be supplied to the contract manufacturer. The effectiveness of the technology transfer greatly depends upon the quality of the TIP. Often, if the quality of the TIP is very good, the custom manufacturer is able to successfully complete the job without a lot of faceto-face communication or meetings. This significantly reduces the cost and time of the project. However, the importance of direct dialogue between the two parties should not be downplayed.

The extent to which technology is transferred to a custom manufacturer can vary widely from project to project. The quality of the TIP will reflect the process's stage of development and the internal resources the pharmaceutical company has dedicated to the project. Thus, the TIP could vary widely from a rough, laboratory process description only to a process description and small-scale (5-50 gal) processing information to a process description, small-scale and largescale (200-1,000 gal) processing information with a very detailed, stepby-step operating procedure. The quality of the hazards package also may depend upon the project and its stage of development.

A well-organized TIP that includes chemical, engineering, analytical, and safety data is mandatory for smooth and successful technology transfer. We cannot overemphasize how important it is to capture all the information and observations in this package. After all, many scale-up problems result from inadequate communication between chemists in the laboratory and the engineers in the pilot plant within the same company, let alone separate companies.

The chemists, analysts, and engineers working on the project should compile the TIP. Table 2 lists the suggested contents.

People may have difficulty in finding time to prepare a good package. However, much more time may have to be spent later if a poor package resuits in poor transfer of technology.

Other considerations

Project objectives need to be well defined at the beginning and clearly understood by both parties. These include identification of specific compounds, quantity, purity, timing, specifications, requirements for Good Manufacturing Practice (GMP) and documentation, and the like.

Conducting laboratory experimentation for process familiarization. At Searle, we encourage the custom manufacturer to carry out laboratory experiments with process knowledge we supply. This is very important for process familiarization and technology transfer. Usually, this is done at Searle's expense; we consider it a worthwhile investment to ensure success of the project and continued good relations with the custom manufacturer. Searle also benefits from the study and analysis of the process from another group's perspective. Sometimes, at this stage, new problems with the process are uncovered and the two sides jointly may decide not to proceed with the work. Alternatively, the process can be much improved based on the new information.

Transfer of prior knowledge and experience. It is important to transfer as completely as possible to the custom manufacturer all knowledge derived from past experience with the project, to avoid repeating mistakes at the toller's plant. If the customer currently is making the product in its laboratory, pilot plant, or commercial plant, it is advisable that the toller witness the runs so as to anticipate problems. Similarly, chemists and engineers from the R&D organization should witness laboratory experiments and plant runs at the custom manufacturer until both sides feel comfortable with the implementation of the technology.

Raw materials and reagents. At an early stage of the contract, it is important to define the specifications and sources of the various raw materials and reagents. Often, a preferred option is to have the contractor procure, whenever possible, all required raw materials, reagents, solvents, etc. However, the customer may be actively involved in the purchase of these raw materials if there is a need or advantage to do so. The customer should provide any proprietary intermediates that are required; the contract should specify this, so there is no chance of confusion at a later date.

Quality assurance. Before a commitment to a GMP production campaign at a contractor's facility can be made, staff from the pharmaceutical company's quality assurance department must visit the proposed manufacturing site to conduct a formal QA audit. The results of the audit may be used to determine if the contractor's equipment, manufacturing practices, and staff expertise can meet the company's standards for GMP production. For the sake of establishing long-term relationships, it sometimes is beneficial for the pharmaceutical company to assist the custom manufacturer in developing systems to meet GMP requirements.

Analytical capabilities and reference standards. For all contracts, the customer normally should supply documented analytical methods, as well as samples of all available reference standards. Much of the analytical methodology may involve chromatographic techniques. The reference standards should include raw materials, intermediates, final product, known impurities, suspected impurities, etc. If the contract requires the contractor to use specific analytical methods and conduct inprocess checks, acceptance testing, or release testing, it is important that detailed documentation and samples be made available.

An option worth considering

Custom synthesis can play an important part in supplying chemicals for pharmaceutical R&D. But, this requires pharmaceutical companies to establish good relations with a select group of custom manufacturers around the world. High-quality TIPs and effective technology transfer are essential for success, as is the custom manufacturer taking the time to familiarize itself with the customer's process in its laboratories before undertaking to make the chemical on a large scale.

[Reference]

Literature Cited

[Reference]

1. Basu, P. K., J. Quaadras, R. A. Mack, and A. R Noren, "Achieve the Right Balance in Pharmaceutical Pilot Plants," Chem. Eng. Progress, 94 (2), pp. 67-74 (Feb. 1998).

2. Basu, P. K., J. Quaadras, J. E. Holliman, R. A. Mack, and A. R. Noren, "Pharmaceutical Pilot Plants are Different!," Chem. Eng. Progress, 93 (6), pp. 66-75 (June 1997).

[Author Affiliation]

P. K. BASU is Director, Process Development and Chemical Processing, for Searle Chemical Sciences R&D, a unit of Monsanto, Skokie, IL ((847 982-7733; Fax: (847) 982-7465; E-mail: prabir.k.basu@monsanto.coml. His main responsibility is to provide the chemicals required for the development of new drugs by the company via pilot-plant or contract manufacturing. He received a PhD in chemical engineering from the Univ. of California at Berkeley, and an MBA from Webster Univ. He is a member of AIChE and ACS.

[Author Affiliation]

R. L BUCHMAN is Director, Global Sourcing, for Searle, a unit of Monsanto, Skokie, IL ((847) 581-5862; Fax.: (847 581-6044; E-mail: russell.buchmanimonsanto.com). His main responsibility is to coordinate the contracting of intermediates and active pharmaceutical ingredients for the company. He received a PhD in medicinal chemistry from Purdue Univ.

[Author Affiliation]

A. L CAMPBELL is Vice President, Chemical and Bio-process Sciences, for Searle, a unit of Monsanto, Skokie, IL ((847) 982-7411; Fax: (847) 982-4799; E-mail: arthur.l.campbell@ monsanto.comr. His main responsibility is worldwide drug-substance development to support the registration and manufacture of new drugs. He received a PhD in medicinal chemistry from the Univ. of Kansas, and completed post-doctoral work at Colorado State Univ.

вторник, 13 марта 2012 г.

Teixeira Powers Braves Past Mets 13-5

NEW YORK - Mark Teixeira hit a three-run homer and the Atlanta Braves roughed up a rusty Orlando Hernandez in a 13-5 victory over the New York Mets on Tuesday night.

Yunel Escobar also went deep for Atlanta, which played without Chipper Jones for the second straight night but still managed 13 hits. Willie Harris drove in three runs, and Jeff Francoeur was 2-for-3 with two RBIs.

The Braves, clinging to their slim playoff hopes with 17 games left, pulled within 8 1/2 of NL East-leading New York. They began the day five back of San Diego in the wild-card race.

Paul Lo Duca hit a two-run homer and speedy Jose Reyes had a career-high three doubles for the Mets, who had won four straight and nine of 10. They remained six games ahead of the Phillies, who lost to Colorado.

The teams observed a pregame moment of silence to mark the sixth anniversary of the Sept. 11 attacks. The Mets also wore hats from eight New York City departments who sustained losses that day, and a firefighter sang the national anthem.

Hernandez, sporting an FDNY hat, struggled in his first start since he gave up five runs and six hits over three innings at Philadelphia on Aug. 30. He traveled back to New York after that shaky outing and got a cortisone shot in his sore right foot.

El Duque retired the Braves in order in the first but forced home a run with a bases-loaded walk to Harris in the second and gave up Escobar's two-run homer in the third.

Atlanta chased the right-hander during a six-run fourth, batting around to take a 9-0 lead. The first five hitters reached against Hernandez (9-5), who yielded run-scoring singles to pitcher Buddy Carlyle and Kelly Johnson before he was replaced by Aaron Sele.

Hernandez was charged with six hits and a season-high eight runs over three-plus innings, his first loss since July 4 at Colorado. New York was 9-1 in his previous 10 starts.

Sele got two quick outs before Teixeira connected for his 12th homer with the Braves. The slugger, who was acquired from Texas in a trade deadline deal, went 3-for-5 and scored two runs.

Carlyle gave up six hits and three runs in 4 1-3 innings for Braves, who have won four of six. Pete Moylan (5-3) threw 1 2-3 scoreless innings to earn the win, and three other relievers combined to finish it.

Moises Alou singled in the fourth to extend his hitting streak to 16 games for New York and added his 12th homer in the eighth.

Jones was a late scratch before Monday night's 3-2 loss to the Mets after he hurt himself during batting practice. The team said he is day to day.

The Braves did get Andruw Jones back after he missed the series opener with the flu. He went 0-for-3 and scored a run.

Notes:@ Atlanta purchased the contract of catcher Clint Sammons from Double-A Mississippi. ... Reyes also tied the franchise record for doubles in a game, last accomplished by Carlos Beltran on Aug. 8, 2006, against San Diego.

GOP Hopefuls Fault Bush on Iraq, Style

MANCHESTER, N.H. - President Bush drew startling criticism Tuesday night from Republican White House hopefuls unhappy with his handling of the Iraq war, his diplomatic style and his approach to immigration.

"I would certainly not send him to the United Nations" to represent the United States, said Tommy Thompson, the former Wisconsin governor and one-time member of Bush's Cabinet, midway through a spirited campaign debate.

Arizona Sen. John McCain criticized the administration for its handling of the Iraq War, and former Massachusetts Gov. Mitt Romney said, "I think we were underprepared and underplanned for what came after we knocked down Saddam Hussein."

Rep. Duncan Hunter of California said the current administration "has the slows" when it comes to building a security fence along the border with Mexico.

Rep. Tom Tancredo of Colorado recalled that White House aide Karl Rove had once told him "never darken the door of the White House." The congressman said he'd tell George Bush the same thing.

The Republicans sprinkled the criticism of Bush throughout a two-hour debate that ranged over topics from war to immigration legislation pending in Congress to religion.

Sen. Sam Brownback of Kansas and Hunter both said they would pardon Vice President Dick Cheney's former aide Lewis I. "Scooter" Libby, sentenced to 30 months in prison earlier in the day for lying and obstructing a CIA leak investigation.

Former New York Mayor Rudy Giuliani, a former prosecutor, said the sentence was excessive, which "argues in favor of a pardon."

Much of the debate focused on Iraq.

McCain and Brownback both admitted they voted to authorize the U.S. military invasion of Iraq without reading the formal National Intelligence Estimate in advance.

The confession drew a jab from former Gov. Jim Gilmore of Virginia. Members of Congress "ought to read at least that kind of material," he said.

Hunter said he had, the only member of Congress on the debate stage to make the claim.

Both McCain and Brownback said they had received numerous briefings on the situation in Iraq before they cast their votes in 2002.

National intelligence estimates are compilations of the best thinking of U.S. intelligence agencies, meant to provide the broadest guidance to government policymakers.

But they can be wrong. A 2002 assessment, for example, concluded that Iraq had continued its development of weapons of mass destruction, held arsenals of chemical and biological weapons and "probably will have a nuclear weapon during this decade."

McCain drew loud applause from the partisan debate audience when he turned a question about the war in Iraq into criticism of the leading Democratic presidential hopeful, Sen. Hillary Rodham Clinton of New York.

"When Senator Clinton says this is Mr. Bush's war, President Bush's war," she is wrong, he said. "When President Clinton was in power, I didn't say Bosnia was President Clinton's war," the Arizona senator said.

"Presidents don't lose wars. Political parties don't lose wars. Nations lose wars," he added.

The criticism of Clinton and the Democrats was standard campaign fare for Republican candidates.

But the jabs at the Republican president - traveling overseas - was a reflection of his poor poll ratings and the need of even members of his own party to campaign on platforms of change.

McCain has long criticized Bush for fumbling the aftermath of Saddam's fall, and Romney has recently begun to make some of the same criticisms.

Former Arkansas Gov. Mike Huckabee added his voice to those criticizing the war effort. He added that the Bush administration "lost credibility" with its response to Hurricane Katrina in 2005.

Thompson's answer was the most startling, coming from a man who had once served in the president's Cabinet as secretary of the Department of Health and Human Services.

Bush's decision to invade Iraq caused hard feelings with longtime allies in Europe, and elsewhere around the world.

Bush's support for the pending immigration legislation is the source of Tancredo's criticism, and the issue figured prominently in the debate.

McCain, alone among the contenders on the St. Anselm College debate stage, supports the measure, and he sought to fend off criticism from some of his rivals.

"We cannot have 12 million people washing around America illegally, my friends," he said.

Fitting distributions using maximum likelihood: Methods and packages

The most powerful tests of response time (RT) models often involve the whole shape of the RT distribution, thus avoiding mimicking that can occur at the level of RT means and variances. Nonparametric distribution estimation is, in principle, the most appropriate approach, but such estimators are sometimes difficult to obtain. On the other hand, distribution fitting, given an algebraic function, is both easy and compact. We review the general approach to performing distribution fitting with maximum likelihood (ML) and a method based on quantiles (quantile maximum probability, QMP). We show that QMP has both small bias and good efficiency when used with common distribution functions (the ex-Gaussian, Gumbel, lognormal, Wald, and Weibull distributions). In addition, we review some software packages performing ML (PASTIS, QMPE, DISFIT, and MATHEMATICA) and compare their results. In general, the differences between packages have little influence on the optimal solution found, but the form of the distribution function has: Both the lognormal and the Wald distributions have nonlinear dependencies between the parameter estimates that tend to increase the overall bias in parameter recovery and to decrease efficiency. We conclude by laying out a few pointers on how to relate descriptive models of RT to cognitive models of RT. A program that generated the random deviates used in our studies may be downloaded from www.psychonomic.org/archive/.

Since the seminal work of Townsend and Ashby (1983), it has been known that fitting or testing a model with mean response times (RT) alone has very poor diagnostic power. Often, models can mimic each other at the level of predicted means, even when their fundamental assumptions are diametrically opposed (e.g., a parallel race model can mimic the predictions of a serial model; see Van Zandt & Ratcliff, 1995). In this respect, median RT does not fare better than mean RT (Miller, 1988; Ratcliff, 1993). One solution is to consider RT means and variances simultaneously (Cousineau & Larochelle, in press). Although this provides greater constraint, some model mimicking can still occur (Townsend & Colonius, 2001). Higher order moments (e.g., skew and kurtosis) are of little help because their sample estimates are unreliable for the sample sizes typically available in empirical research. As a result, the importance of considering the whole RT distribution for testing formal models is now generally acknowledged.

Nonparametric approaches to the description of RT distributions are possible. For example, estimating the cumulative distribution function (CDF) is easily achieved with the cumulative frequencies of observed RTs. However, estimating the probability density function (PDF) and the hazard function is more difficult (see Silverman, 1986, on the former, and Bloxom, 1984, on the latter). This is a problem because some models are most easily tested with nonparametric approaches (e.g., tests of the hazard function, Burbeck & Luce, 1982, and the crossing points of two PDFs, Ashby, Tein, & Balakrishnan, 1993).

A parametric approach to RT distribution is achieved by introducing an important piece of information: a density or cumulative density function of the distribution. As we will discuss in the next section, fitting a distribution is rather easy, and there are many software packages that can automate this procedure.1 In addition, the estimation method used, maximization of the likelihood function, is well understood and is not dependent upon the use of approximate heuristics (as opposed to nonparametric PDF and hazard function estimates; see Silverman, 1986). Also, once the distribution has been fitted, all associated functions (CDF, PDF, hazard, and log-survivor functions) are completely determined. Finally, the fitting process consists simply of finding estimated values for a few parameters (generally three for RT distributions). Thus, the whole RT distribution is summarized with a very compact representation.

All these benefits come at a cost, however. An incorrect distribution function, even one fitting the data reasonably well, may give a wrong indication of what kind of psychological model has produced the data. For this reason, many authors prefer to use distribution functions as an atheoretical tool or a descriptive model (Heathcote, Popiel, & Mewhort, 1991; Ratcliff, 1979). In addition, if the true RT distribution is in fact different from the fitted distribution in some fundamental way, the parameters may not capture the regularities that exist across different distributions (Schwarz, 2001). For that reason, it is desirable for experimenters using the parametric approach to fit more than one distribution function.

In this article, we review software that can perform distribution fitting. All the software packages reviewed can fit many distinct distribution functions. The most commonly used distributions in cognitive psychology are the ex-Gaussian (Hockley, 1984), the Gumbel (Gumbel, 1958; Yellot, 1977), the lognormal (Ulrich & Miller, 1993), the Wald (Burbeck & Luce, 1982), and the Weibull (Cousineau, Goodman, & Shiffrin, 2002) distributions (see Heathcote, Brown, & Cousineau, 2004, and Luce, 1986, Appendix A, for details).2 The software reviewed can all fit these distributions, although some can fit others, as well. They are FASTIS (Cousineau & Larochelle, 1997), QMPE (previously called QMLE; Brown & Heathcote, 2003), DISFIT (Dolan, van der Maas, & Molenaar, 2002), and MATHEMATICA (Wolfram, 1996). This review will be carried out in Section 2. Because the methods and the specific details of a fitting procedure are numerous, we provide in Section 1 some information to readers interested in programming their own fitting procedure. Although many readers will prefer to rely on existing software, these details are useful to know, because they can differ from one package to another.

1. DISTRIBUTION FITTING METHODS

Estimation Methods

On one hand, there is a data set T = {t^sub i^}, i = 1 . . . n, a sample containing n response times (RT). On the other hand, there is a distribution to fit that depends on a parameter set θ. The distribution is given by its probability density function f. The objective of the fitting procedure is to find the estimated parameters τ so that the theoretical distribution will be most similar to the distribution of the data set.

Many methods can be used to fit a distribution. Van Zandt (2000) reviewed sum of square error (SSE) methods and the maximum likelihood (ML) method (presented next). Using simulations, she found the standard ML method to be the best and SSE based on CDF almost as good. The criteria used were (1) bias-repeated over multiple samples, the average θ should be exactly the true parameter set θ of the population where the samples were taken; and (2) efficiency-when repeated over different samples of data, the estimates θ should have smaller variance than when estimated with other methods.

Occasionally, Equation 1 can be solved analytically. For example, we know that the sample mean is a maximum likelihood estimator of the population mean μ if the distribution is normal (Gaussian). Maximum likelihood estimators, whether analytic or obtained from numerical optimization, have a desirable property: They are asymptotically (n [arrow right] ∞) the most efficient; that is, they make maximum use of the information contained in the sample, resulting in the least variable estimation method (Van Zandt, 2000). Of course, it is not clear whether such asymptotic property holds for small samples as well (Heathcote, Brown, & Cousineau, 2004).

One may intuitively expect QML to be inefficient, since transforming the raw RT into quantiles involves a reduction of the information available. On the other hand, if m is close to n, the loss of information can be quite small and may also provide a benefit for finite samples. This is because there may be outliers in the data, and creating quantiles simply replaces the absolute value of an outlying observation with an additional count in n^sub l^ or n^sub m^. Also, estimates are robust to the addition of a small amount of error to a given RT, because Equation 3 will not change at all, as long as the RT does not move across a quantile bound.

Heathcote et al. (2000) showed that QML (Equation 3) is superior to CML (Equation 2) in terms of bias and efficiency when tested on simulated data generated by the exGaussian distribution; Heathcote et al. (2004) showed QML to be equal to or better than CML on other distributions. In order to do so, they extended a software package called QMPE to include the lognormal, Gumbel, WaId, and Weibull distributions with both CML and QMP estimation. Before proceeding to comparisons across software, we will discuss some issues related to the implementation of a maximum likelihood fitting technique because the software reviewed in Section 2 differ on these implementation details.

Implementing a Maximum Likelihood Fitting Procedure

In order to implement an ML procedure, three ingredients are required: (1) a distribution function to be fitted, (2) an optimization routine, and (3) starting values for θ.

To be a reasonable candidate for characterizing RT, a distribution function must be able to accommodate positively skewed data. The most commonly used distributions are briefly described in Heathcote et al. (2004), and their equations are presented in Table 1. The choice of a distribution provides the PDF equation/that is inserted into the function to be minimized (Equation 2 or 3), which in this context is usually called the objective function. Due to numerical considerations, the logarithm of the objective function is usually employed because the use of the summation avoids numerical underflows. For likelihood, for example, maximizing L(θ,T) over the range 0 to 1 is then replaced by minimizing -ln L(θ,T), the value ranging from +∞ [-ln(0), unlikely] to zero [ln(1), absolutely certain]. The same rationale applies if quantiles Q are used instead of raw data T. Most computer software packages report the minimized value of -ln L(θ,T).

The second ingredient is an optimization procedure to minimize the objective function. Various algorithms exist, the oldest of which was introduced by Newton. All these methods are iterative, starting with a tentative θ^sub 0^ and updating it through various iterations until an optimal value, θ^sub p^, is found.4

Appendix A summarizes the most commonly used minimization algorithms. They are generally distinguished (Box, Davies, & Swann, 1969) by whether they use analytic derivatives of the objective function (gradient methods) to guide search, or whether they use numerical approximations to the derivative (direct search methods). In general, gradient methods can find a minimum with a smaller number of iterations. However, it may take more time to perform the iterations if the gradients are not available in closed-form equations (as is the case for the ex-Gaussian distribution).

The last ingredient in obtaining a solution consists of finding reasonable starting values θ^sub 0^. If the surface of the objective function is quadratic, it has only one minimum, and thus, all starting points will lead the minimization routine to the same optimal solution θ^sub p^. In practice, however, there may be many local minima. The best way to avoid false convergence in a local minimum is to start the routine at various locations or to start as close as possible to the optimal solution. To achieve this, heuristic estimates can be developed, often based on the first few moments of the data in order to automate the starting point selection. These heuristics are not always accurate, due to sampling variance in the moment estimates.

2. TESTING THE SOFTWARE PACKAGES

We compare different software packages aimed at fitting distributions. These packages, briefly described in Appendix B, differ in the minimization routines used and in the heuristics used for starting values. All of these packages allow the user to alter the starting value parameters. Table 2 reviews some features of the software, and Appendix C shows examples of commands for a typical fitting session with each.

Simulation Methods

The simulations repeatedly sample random deviates from one of the five distributions, with known parameters, and then estimate those parameters with each software package. The parameter estimates are then compared against the known values for both accuracy (bias) and variability (efficiency). For each of the five source distributions (ex-Gaussian, Gumbel, lognormal, Wald, and Weibull), we sampled n = 250 random deviates. The parameter values appear in Table 3, along with the associated (theoretical) mean, standard deviation, and skew. They were chosen so that (1) the means and standard deviations are all approximately 1,000 and 100, respectively; (2) the overall distribution shapes are positively skewed (the Gumbel distribution has a constant skew). We repeated the sample-and-fit process 1,000 times, making sure that the same samples were fitted by each software package.

The random samples were generated for each of the five distributions by variously transforming random uniform deviates.5 The source code of a program that generated these random values is available on the archive site of the Psychonomic Society.

For all QMP calculations, the number of quantiles used was 32. This decision probably put the QMP method at a relative disadvantage because the small number of quantiles was unnecessarily restrictive.

Simulation Results

The programs reviewed were quite robust and never crashed; MATHEMATICA could not find a solution for only one simulated set of Wald deviates. Some analyses did not finish before they reached the maximum number of iterations allowed. However, because only QMPE and MATHEMATICA return this information, we did not remove these solutions from further analyses.

Parameter space. Before turning to the computation of bias and efficiency, we take a look at parameter space. In Figures 1-5, we plotted the estimated parameters as points in the appropriate parameter spaces (two-dimensional for the Gumbel distribution and three-dimensional for the other). Each point represents one of 100 different samples. The central cross shows the position of the true parameter set used to generate each sample. The purpose of these graphs is to see to what extent parameter dependencies are present and, most importantly, whether some software packages are less sensitive to them than others.

Figure 1 shows the parameters � and σ estimated from the Gumbel random deviates. As seen, the estimates are all spread out around the true parameters with no systematic deviations, indicating no important bias. Furthermore, all software shows the same dispersion.

Figure 2 shows the parameters �, σ, and τ estimated from ex-Gaussian distributed random deviates. One thing to note is that the cloud is not uniformly spread in all directions but tends to form an ellipse. This is easier to see with the projections on the sides of the plot box. This ellipse more or less goes through the main diagonal of the box, which illustrates that the parameter estimates are not independent. For example, a moderately small estimate for � can be compensated by a moderately large value of τ and a moderately small value of σ. QMPE and DISFIT return information about this fact in the form of estimated parameter correlations, but the other software packages do not.

The results for the Weibull distribution were similar, as seen in Figure 3, except that the ellipse is oriented along a different diagonal of the cube. This indicates that a moderately large estimate for α can be compensated by a moderately small estimate for β and γ. Except for one outlier obtained by QMPE, the efficiencies are roughly comparable (that outlier generated an error exit code and so could have been either censored or remedied by manually setting the starting points).

As can be seen from comparison across the panels of Figures 2 and 3, all software packages returned an ellipse of about the same shape and orientation. In all cases, the centers of gravity of the clouds are near the central cross, suggesting only a small bias, and the overall volume of the clouds suggest equal efficiency for all the software packages. Further investigation of biases and efficiency will be performed later.

Figure 4 shows the-more complicated-results using lognormally distributed random deviates: The points form a crescent. As a consequence, many of the estimates are close to the true parameter values. However, the center of gravity, because of the curvature, will not be on the cross, resulting in mean bias. In addition, all four software packages are subject to this pathology (although to a lesser extent for MATHEMATICA), suggesting that it is due to the distribution function, not the optimization capabilities of the software. Finally, QMPE has a few outliers near the bottom of panel a. On these occasions, a singular Hessian matrix error was also returned by QMPE.

This pathology is not unique to the lognormal distribution. Wald-distributed random deviates also produced estimates that form a crescent when the parameter space is plotted, as seen in Figure 5. It had the same volume and orientation, regardless of the software package used. Such nonlinear pathology cannot be detected by the estimated parameter correlations; only visual inspection of the parameter space shows it.

Package capabilities. In the following, we proceed to an examination of bias and efficiency across packages. However, we will not consider single-parameter biases but rather concentrate on the bias shown by the whole estimated parameter set, relative to the true parameter set. To achieve this, bias was computed as the distance between the center of gravity of all the estimated parameters θ^sub i^ i = 1 . . . 1,000, and the true θ. Thus, bias = ||E(θ) - θ|| = E(||θ^sub t^ - θ||) where E(θ) denotes the average position of all the estimates, and ||. || denotes the Euclidean distance (the norm). Efficiency was computed as the standard deviation in the distances between each point θ^sub i^ and θ, SD(||θ^sub t^ - θ||).

Figure 6 shows the results expressed as a percentage relative to ||θ||. Note that the scales for each panel differ. The two most biased distributions are the lognormal and the Wald (bottom row), reaching an average of 1% and 25% biases. These are exactly the distributions showing nonlinear dependencies between parameter estimates, as seen in Figures 4 and 5. The other three distribution functions (Weibull, Gumbel, and ex-Gaussian) have much smaller biases, less than 1% in all cases. The bias is even smaller than 0.1% for the Gumbel. In this last case, since the parameter space has only two dimensions, there is less potential for bias. DISFIT turned out to be very apt (low bias, high efficiency), fitting Weibull deviates, whereas MATHEMATICA outperformed the other packages for lognormal deviates.

Overall, the QMP estimates produced by QMPE are as good as those produced by the CML methods obtained from the other software packages (DISFIT being worst for lognormal deviates). This is surprising, considering the major information reduction imposed on the data: They were reduced from 250 raw data points to only 32 quantiles, an almost eight-fold compression. QMPE efficiency, indicated by the error bars in Figure 6, is slightly worse for the Weibull deviates, but results almost entirely from a few outliers (one is visible in Figure 3). Outliers generated by QMPE were often accompanied by an error exit code related to the singularity of the Hessian matrix. Therefore, a very strict selection of the successful fits would have increased considerably the efficiency of the QMPE method, to the detriment of having a little less than 5% of the data set either rejected or requiring refit. When manually fitting a data set, the user should consider changing the starting points or changing the criteria for ending a search.

Conclusions

Overall, the four software packages lead to very similar bias and efficiency measures, confirming that they all work properly and that the different platforms and algorithms used make little difference, at least with simulated data. This was true even though different optimization routines and different starting value heuristics underlie each package. The single most important factor on the quality of the estimates was the presence of nonlinear relationships between the parameter estimates. This has implications for comparing groups of subjects. For example, the Wald estimates are so inefficient that they are likely to differ more within group than between groups. If the purpose is to see differences, the ex-Gaussian and Weibull distributions are preferable as atheoretical summaries of shape. Strategies (such as reparameterization, Bates & Watts, 1988) can reduce such nonlinearities. However, the required transformations are difficult to find, sometimes relying on a trial-and-error process.

3. GENERAL CONCLUSIONS

From Descriptive Models of RT to RT Models

Parametric estimation of RT distribution provides a compact description of RT data. In addition, once the distribution is fitted, it is easy to calculate the PDF, CDF hazard, and more. A main point of this article was to show that there are good quality software packages to perform fits and that these packages are reliable and easy to use.

A more theoretical question is to decide which distribution function to fit. As seen in this paper, five candidates can readily be explored. Although there is no consensus at this time, two points should guide one's choice.

The first point concerns the informative utility of the parameters across samples. For example, if a single change in the experimental procedure results in changes in all the parameters of the distribution, the representation is not compact across conditions. Thus, in choosing a distribution function as a descriptive model, the researcher should be mostly interested in how concisely the parameters capture the experimental manipulation. This should be sought even if it sacrifices some quality of the fit.

Differences in L(θ,T) across distributions cannot be compared since distribution functions can have different capabilities for fitting random data. For example, a distribution with more free parameters has more liberty to fit the data and will likely have a smaller -ln L(θ,T). One solution is to penalize for extra parameters, as in the AIC test (Bozdogan, 1987). However, even with an equal number of parameters, some functions may be able to accommodate more data sets, a property often termed geometric complexity. There are methods to adjust the penalty term to compensate for complexity, but these can be computationally difficult (Myung, 2000; Gr�nwald, 2000).

The second important point in the choice of a distribution to fit is related to psychological models of cognition. Whereas a researcher might simply be interested in a descriptive model of RT for convenient communication of the results, a more ambitious approach is to have a model based on psychological mechanisms that can predict not only RT but also the shape and scale of the whole RT distribution. Two cases are then possible: First, the model can be analytically solved to yield an algebraic formula for the RT distribution (see Cousineau, in press). It can either be one of the distributions reviewed here or a yet-unknown distribution function. In this case, the researcher can fit this distribution and ensure that the parameters are acting according to a priori predictions (Schwarz, 2001). Second, in the case in which the model cannot be solved analytically, the researcher can simulate the model and ehoose a descriptive model to fit the simulated RT. By doing the same to the observed RT distribution, the researcher can check that the descriptions are convergent. This is the approach used in Ratcliff (1979), where the ex-Gaussian was the intermediary between empirical and simulated data.

The best solution is to fill the gap between a model and RT data with more than just the predicted means. However, it is possible that the observed RTs are contaminated by other factors, such as fatigue or fast guess. We thus have to keep in mind the possibility of fitting mixtures of distributions (Cousineau & Shiffrin, 2004; Dolan, van der Maas, & Molenaar, 2002) or that the parameters of the distributions are changing over time. In this context, QMP estimation is likely to be more robust to the effects of outliers and measurement noise than standard CML estimation.

ARCHIVED MATERIALS

The following materials associated with this article may be accessed through the Psychonomic Society's Norms, Stimuli, and Data archive, http://www.psychonomic.org/archive/.

To access these files or links, search the archive for this article using the journal (Behavior Research Methods, Instruments, & Computers), the first author's name (Cousineau) and the publication year (2004).

FILE: Cousineau-BRMIC-2004.zip

DESCRIPTION: The compressed archive file contains three files:

randmod.f90 and random. f90 are the two parts of a Fortran 90 program that generates sets of random numbers corresponding to samples from the following distributions: ex-Gaussian, Gumbel, lognormal, Wald, and Weibull. The code is adapted from the work of Dagpunar (1988), Marsaglia and Tsang (2000), Ahrens and Dieter (1982), and Kemp (1986).

readme.txt is a text file explaining the purpose of the program and how to compile it on most stations.

(Manuscript received April 15, 2003; revision accepted for publication May 13, 2004.)

[Reference]

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[Author Affiliation]

DENIS COUSINEAU

Universit� de Montr�al, Montr�al, Qu�bec, Canada

SCOTT BROWN

University of California, Irvine, California

and

ANDREW HEATHCOTE

University of Newcastle, Callaghan, New South Wales, Australia

[Author Affiliation]

This research was supported in part by the Fonds pour la formation de Chercheurs et l'Aide � la Recherche and the Conseil de Recherches en Sciences Naturelles et en G�nie du Canada. We thank C. Dolan, G. Francis, G. Gigu�re, and S. H�lie for their comments on an earlier version of this article. Correspondence should be addressed to D. Cousineau, D�partement de psychologie, Universit� de Montr�al, C. P. 6128, succ. Centre-ville, Montr�al, PQ H3C 3J7, Canada (e-mail: denis.cousineau@umontreal.ca).

[Author Affiliation]

AUTHOR'S E-MAIL ADDRESS: denis.cousineau@umontreal.ca.

AUTHOR'S WEB SITE: http://mapageweb.umontreal.ca/cousined.

Collier, Ron(ald William)

Collier, Ron(ald William)

Collier, Ron(ald William), Canadian composer, arranger, conductor, trombonist, and teacher; b. Coleman, near Lethridge, Alberta, July 3, 1930. He studied in Vancouver (1943–50), where he played trombone in the Kitsilano Boys' Band. Following composition training with Gordon Delamont in Toronto (1951–54), he became the first jazz composer to receive a Canada Council grant, which allowed him to pursue studies with George Russell and Hall Overton in N.Y. (1961–62). He played trombone in dance bands and orchs., and eventually led his own jazz groups and big band. In 1972 he became composer-in-residence at Humber Coll. in Toronto, where he taught composition and arranging from 1974. Collier was a principal figure in the Third Stream movement in Canada.

Works

Sonata for Piano and Jazz Quintet (c. 1955); The City for Narrator-Singer and Orch. (1960); Requiem for JFK for Big Band (1964); Hear Me Talkiri to Ya for Narrator-Singer and Octet (1964; in collaboration with Don Francks); Aurora Borealis, ballet (1966); Carneval for Narrator, Flugelhorn, and Orch. (1969); Celebration for Piano and Orch. (1972; in collaboration with Duke Ellington); Humber Suite for Big Band (1973); Jupiter for Big Band (1974); Reflections on 3 for Wind Sym. (1980); Never in Nevis for Big Band (1983); 4 Kisses for Big Band (1983); To Prussia with Love and a Little Jive for Jazz Ensemble (1988); also film and television scores; arrangements.

—Nicolas Slonimsky/Laura Kuhn/Dennis McIntire

Yet another hotel for Near North

A extended-stay hotel called Residence Inn will add 221 suitesnext year to what could be the most crowded luxury hotel scene in thecountry: the Streeterville/Gold Coast area of the Near North Side.

Marriott Corp., which bought the Residence Inn chain in 1987, isrehabbing an apartment building at 201 E. Walton, right across thestreet from the Guest Quarters hotel, which also caters to guests whostay five nights or longer.

Within a block are four other hotels: the Drake, Mayfair Regent,Knickerbocker and Westin. Only Nob Hill in San Francisco can competewith such a wealth of luxury accommodations and it has fewer unitsthan the hotels bounded by Lake Shore Drive, Delaware, Oak andMichigan.

Guest Quarters is to open in July, with the Residence Inn aimingfor the first quarter of next year. And owners of the Mayfair Regentare considering the corporate apartment route, which would competehead on with the Residence Inn concept of guest stays of a month ormore.

The residential character of Streeterville convinced Marriott toveer off its beaten track on two counts: attempting a rehab andcreating an extended-stay hotel downtown.

Usually, it chooses the look of two-story townhouses built fromscratch, such as the Residence Inn in north suburban Deerfield.

"We didn't think we could do those types of buildings downtownbecause of the land costs," said Paula Butler, spokeswoman forResidence Inn.

The Residence Inn chain now has 151 hotels.

"They're very residential in character but have full hotelservices," Butler said. "We think they will work well in cities, andare going to do two more high-rise developments, in downtown Seattleand Rochester, N.Y."

Power Contracting and Engineering Corp. is general contractorand engineer on the Walton Street job. The units, targetingmonthlong guests, will have full kitchens.

Guest Quarters wants guests who might stay a week for a trainingsession or corporate meeting.

Developers had attempted - unsuccessfully - to convert theWalton Street building into condominiums in the early 1980s.

Adam Scott Takes Lead at the Memorial

DUBLIN, Ohio - When Adam Scott was on autopilot, he was racking up the birdies. It was only when he started thinking about just how low he could go that his run at a magical 59 turned to vapor. Scott matched his career low with a 10-under 62 - he was 9 under through the first 12 holes - to grab a one-stroke lead Friday after the second round of the Memorial Tournament.

"I didn't know what it (the course record) was, but I figured 59 was probably going to be it if I got there," Scott cracked.

Scott's 62 was the lowest round of the day by five shots.

"Adam obviously played amazing today," said fellow Aussie Aaron Baddeley, who shot a 68 to tie for third place. "Eleven birdies - that's pretty impressive."

Tiger Woods, left in the dust by a full 10 shots through 36 holes, said Scott is as good as anyone.

"You know, he's won two pretty good tournaments in The Players Championship and the Tour Championship. He just hasn't seemed to have contended in majors," Woods said. "But, hey, he's still young. He's got all the talent in the world."

Scott had his chances - certainly at matching the course-record 61 set by John Huston in 1996, and possibly even the PGA Tour mark of 59 held by Al Geiberger, Chip Beck and David Duval.

Scott missed a 4-foot birdie putt at No. 13, barely missed a lengthy birdie putt at 14 and had to settle for birdie at the 15th after hitting his second shot on the par-5 hole to 8 feet.

He picked up his only bogey at 16 after hitting his approach on the par-3 hole into the gaping bunker in front of the green, but then rolled in a 16-footer for birdie at the next hole before closing with a par.

The 26-year-old Scott, with five wins on the U.S. tour and seven overseas, said that as the birdies began to pile up, he started thinking about making history.

"On 13 I kind of put two and two together, if I make this 4-footer, then I'll be 10-under and I've got five holes (to make) three birdies. The way things were going, it was realistic with a par 5 in there," he said. "I think the only times I did something wrong was on those couple of putts where I thought about the outcome. That's what you can't do."

Scott said he never should have started figuring out scores in his head for what it would take to get to 59.

"I shouldn't be so good at math," he said with a laugh.

Rod Pampling, the first-round co-leader after a 65, shot a 68 and was a shot back at 11-under 133. He said he kept looking at the leaderboards, waiting for Scott to slow down, but was stunned by what he saw.

"I couldn't believe it," said Pampling, yet another Aussie. "He kept going, didn't he? He just didn't stop. He had the one hiccup on 16, but he obviously had it dialed in."

Baddeley and Bubba Watson, a Florida native who is the only non-Australian among the top four players, each shot a 68 to get to 10-under 134.

"They're trying to take over the world, I think," Watson said.

Scott said what's remarkable about all the players from Down Under is that they all seem to be coming on the scene at the same time.

"Australian golf is very deep talent-wise right now," he said. "It's been well reported that we think it's a carry-on effect of Greg Norman's influence on the game of golf in Australia. You know, he really made the game popular down there, and there were enough of us that took it seriously to get to this level."

Ryan Moore (69) and Sean O'Hair (70) were three back at 9-under 135, with Fredrik Jacobson shooting his second 68 to get to 8 under and Nick Watney, defending U.S. Open champion Geoff Ogilvy and Ted Purdy another shot back at 7 under.

Woods, a three-time winner of the Memorial, continued to have problems with his putter and followed his opening 70 with a 72. He need 31 putts on Friday; Scott needed 25.

"These greens are perfect," Woods said. "I mean, you put a putt on line, it should be in. I'm just not putting a putt on line. My speed is decent. I'm just not rolling the ball on line consistently and I'm not hitting my lines that I'm choosing."

US-Japan discussed 'action' against anti-whalers

TOKYO (AP) — Japanese and American officials discussed taking action against a prominent anti-whaling group, with Tokyo insisting that Sea Shepherd's confrontations on the high seas actually hurt efforts to reduce whaling, U.S. diplomatic cables show.

The U.S. representative to the International Whaling Commission, Monica Medina, discussed revoking the U.S.-based conservation group's tax exempt status during a meeting with senior officials from the Fisheries Agency of Japan in November 2009, according to the documents released by WikiLeaks on Monday.

Action against the anti-whaling Sea Shepherd Conservation Society would be a "major element" in achieving success at international negotiations on the number of whales killed each year, the cables cite the director general of Japan's fisheries agency, Katsuhiro Machida, as saying.

Referring to Sea Shepherd, Medina said "she believes the USG (U.S. government) can demonstrate the group does not deserve tax exempt status based on their aggressive and harmful actions," according the cables.

Sea Shepherd vessels are currently chasing Japan's whaling fleet in the Antarctic Ocean in the hopes of interrupting its hunt, which kills up to 1,000 whales a year.

Sea Shepherd's yearly protest campaigns have drawn high-profile donors and volunteers, and spawned the popular Animal Planet series "Whale Wars."

Japan hunts whales under the research exemption to a 1986 worldwide ban on commercial hunts. Critics say there is no reason to kill the animals, and the research program amounts to commercial whaling in disguise because surplus meat from the hunt is sold domestically.

Protest ships harass the whaling fleet, and clashes between the sides often take place. Last January, a Sea Shepherd boat was sunk after its bow was sheared off in a collision with a whaling vessel.

The diplomatic cables, posted on WikiLeaks' secret-sharing website early Monday but dated Jan. 1, show Japanese officials repeatedly told U.S. counterparts the group's actions were making whaling a political issue and hurting any chance of a compromise on the numbers of whales killed each year.

An International Whaling Commission meeting last year — that ended without agreement — was seen as a major chance to end a decades long stalemate. The U.S. approached Japan in late 2009 to reach a deal on the issue, calling it an "irritant" in international relations.

"Action on the SSCS (Sea Shepherd Conservation Society) would be a major element for Japan in the success of the overall negotiations," a Japanese official said, according to one cable.

Paul Watson, founder of Sea Shepherd, said his group was against anything less than a complete stop to Japan's whaling program in Antarctica. The activists hope to block whaling activities for the Japanese fleet so it incurs deep financial losses.

"I don't think a solution is going to come through politics, it's going to come through economics," Watson told The Associated Press by telephone from his ship while pursuing the Japanese fleet.

Widow became one of world's richest women

NINA WANG

1937-2007

HONG KONG -- Nina Wang, a pigtailed Hong Kong businesswoman whoturned her slain husband's fortune into a real-estate empire thatmade her one of the world's richest women, has died. She was 69.

Ms. Wang's spokesman Ringo Wong said Ms. Wang died Tuesday. Hedid not describe the cause of death, but Hong Kong media reportedthat Ms. Wang had ovarian cancer that spread to her liver and otherorgans.

Ms. Wang's rise to become Asia's richest woman, according toForbes Asia, had the plot elements of a Hollywood movie -- sex,romance, crime and courtroom drama.

Born Kung Yu-sam in Shanghai, Ms. Wang moved to Hong Kong in the1950s with Teddy Wang, who founded the Chinachem Grouppharmaceutical company.

Teddy Wang was abducted in 1990 as he left Hong Kong's exclusiveJockey Club. The family paid a $33 million ransom but he was neverreturned.

Several of the kidnappers were caught and said that the 56-year-old Wang had been thrown into the sea from the sampan -- a smallChinese boat -- where he was held.

His body was never found and he was declared dead in 1999.

Nina Wang insisted that she believed Teddy Wang was alive andwould someday return. He had been kidnapped seven years earlier andreleased for $11 million ransom.

In her husband's absence, Nina Wang built Chinachem into amassive private property developer, with office towers and apartmentcomplexes throughout Hong Kong.

Forbes magazine ranked her this year as the world's No. 204richest person, with a fortune of $4.2 billion.

Won battle over will

Ms. Wang captivated the public with her pigtails and garish,girlish outfits. She was nicknamed "Little Sweetie," the Chinesename of a princess-like character from a Japanese fairy-talecartoon.

But Ms. Wang's standing came under threat when her father-in-law, Wang Din- shin, challenged her claim to his late son's fortune.

Wang Din-shin, who is in his 90s, said he was the solebeneficiary of Teddy Wang's estate, based on a 1968 will.

He questioned a will dated a month before his son disappeared,which left everything to Nina Wang. All four documents in the willcontained the handwritten message, "one life, one love," in Englishon papers that were otherwise in Chinese.

After a 171-day trial during which Wang Din-shin showed picturesof Nina Wang with an alleged lover, a Hong Kong judge ruled inNovember 2002 that Nina Wang's will was fake and she "probably"forged part of it.

The love messages seemed suspiciously out of place, the judgesaid.

Prosecutors charged her with forgery in January 2005 in aseparate criminal case. She was released on $7 million bail, arecord for Hong Kong at the time.

Nina Wang, however, staged a legal comeback.

Hong Kong's Court of Final Appeal reversed the ruling giving theestate to her father-in-law, saying the signatures on the willappeared authentic.

"Such naturalness and style of writing is inconsistent with thatof a person trying to commit a forgery," Judge Patrick Chan said.

Ms. Wang was also cleared of forgery charges in December 2005.

Martin Lee, a prominent lawyer and lawmaker, recalled Nina Wangas a careful spender and described Nina and Teddy Wang as agenuinely loving couple.

"They didn't just go on vacation together, work together. Ibelieve they spent every day together," Lee told reporters.

понедельник, 12 марта 2012 г.

Elementary steps of the cross-bridge cycle in Bovine myocardium with and without regulatory proteins

ABSTRACT The role of regulatory proteins in the elementary steps of the cross-bridge cycle in bovine myocardium was investigated. The thin filament was selectively removed by gelsolin and the actin filament was reconstituted without tropomyosin or troponin. Further reconstitution was achieved by adding tropomyosin and troponin. The effects of MgATP and phosphate (Pi) on the rate constants of exponential processes were studied in control, actin filament-reconstituted, and thin filament-reconstituted myocardium at pCa </=4.66, pH 7.00, 25 deg C. In control myocardium, the MgATP association constant was 9.1 +/- 1.3 mM^sup -1^, and the Pi association constant 0.14 +/- 0.04 mM^sup -1^. The equilibrium constant of the cross-bridge detachment step was 2.6 _ 0.4, and the equilibrium constant of the force generation step was 0.59 +/- 0.04. In actin filament-reconstituted myocardium without regulatory proteins, the MgATP association constant was approximately the same, and the Pi association constant increased to 2.8x. The equilibrium constant of cross-bridge detachment decreased to 0.2x, but the equilibrium constant of the force generation step increased to 4X. These kinetic constants regained control values after reconstitution of the thin filament. These results indicate that tension/cross-bridge in the presence of regulatory proteins is ~1.5-1.7x of that in the absence of regulatory proteins. These results further indicate that regulatory proteins promote detachment of cross-bridges.

The authors thank Dr. Larry S. Tobacman for critical reading of the manuscript and useful suggestions. This work was supported by grant IBN 98-14441 from the National Science Foundation, and the Grant-in-Aid 99-50437N from the American Heart Association National Center. Dr. Fujita is a recipient of a Postdoctoral Fellowship award from Japan Society for Promotion of Science.

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[Author Affiliation]

Hideaki Fujita,* Daisuke Sasaki,^ Shin'ichi Ishiwata,^^^ and Masataka Kawai*

*Department of Anatomy and Cell Biology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA; ^Department of Physics, School of Science and Engineering, Waseda University, Shinjuku-ku, Tokyo 169-8555, Japan; and ^^Core Research for Evolutional Science and Technology (CREST) Team-13, Japan.

[Author Affiliation]

Submitted December 11, 2000, and accepted for publication November 7, 2001.

Address reprint request to Dr. Masataka Kawai, Department of Anatomy, College of Medicine, The University of Iowa, Iowa City, IA 52242 USA. Tel.: 319-335-8101; Fax: 319-335-7198; E-mail: masataka-kawai@uiowa.edu.