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Rare Gene Mutations Inspire New Heart Drugs

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These experimental triglyceride-reducers are in early stages of development, however, and human trials have only just begun. At the moment, the optimism of researchers is rooted less in clinical trial data than in the fact that nature has produced strong evidence they should work.

People like Anna Feurer may be walking proof.

In 1994, Mrs. Feurer, then 40, attended a health fair held by her employer, Ralston Purina, in St. Louis. She rolled up her sleeve and let a technician take blood to measure her cholesterol.

Later, the company doctor called her in and told her that her triglyceride levels were almost inconceivably low. And so were her levels of LDL, which raises the risk of heart disease, and HDL, which is linked to a lower risk. The results were so unusual that he encouraged her to see a specialist.

“It was all an accident,” Mrs. Feurer recalled in an interview. That her single blood sample could lead to new treatments is “definitely amazing.”

She went to Dr. Gustav Schonfeld at Washington University in Saint Louis. He asked Mrs. Feurer if she and others in her family might participate in a research study. She agreed, recruiting her immediate family and even a few cousins and aunts.

Some had strikingly low triglyceride levels, some had normal levels, and some were in between, Dr. Schonfeld found. He tried for years to locate the gene responsible but failed. (Dr. Schonfeld died in 2011.)

In 2009, he sent Mrs. Feurer’s DNA to Dr. Sekar Kathiresan, a cardiologist at Massachusetts General Hospital. He discovered that she carried mutations in both copies of a gene, ANGPTL3, involved in triglyceride metabolism. (Each individual carries two copies of a given gene, one from each parent.)

As it turned out, three of her nine siblings also had no working copy of the gene and extremely low triglyceride levels. Three others had one mutated gene and one normal gene; these siblings had low triglyceride levels, but nowhere near as low as those with no functioning gene.

The other three siblings had inherited two normal ANGPTL3 genes and had normal triglyceride levels.

“The big question was, ‘Does this loss-of-function mutation reduce coronary risk?’” Dr. Daniel Rader of the University of Pennsylvania, who is an author of three of the recently published studies, said.

Dr. Nathan O. Stitziel, a cardiologist at Washington University in Saint Louis, said the evidence so far was that people with Mrs. Feurer’s mutation, at least, seemed to be protected.

Dr. Stitziel and his colleagues scanned Mrs. Feurer’s coronary arteries and those of two siblings who also had two mutated ANGPTL3 genes. Each one was free of plaque, the researchers recently reported in the Journal of the American College of Cardiology.

One sibling had been a heavy smoker, had high blood pressure and even had Type 2 diabetes, a powerful risk factor for heart disease. Yet there was no plaque in his arteries.

Dr. Stitziel went on to lead an international group of researchers who looked for mutations that destroyed the gene in 180,180 people. It was a rare event, occurring in just one in 309 people.

But Dr. Stitziel and his colleagues discovered the mutation reduced heart attack risk by a third.

The second line of evidence for these drugs originated with a study of Old Order Amish in Lancaster, Pa. About 5 percent appeared to have arteries that were clear of plaque and low levels of triglycerides.

As it turned out, these lucky people had inherited a single mutated copy of another gene related to triglyceride production, called ApoC3. Researchers wanted desperately to find people who had inherited two mutated copies to see whether short-circuiting the gene might be safe.

They began by searching genetic data collected from more than 200,000 people around the world — but to no avail. Then the scientists tried a different tack, focusing on participants in a heart disease study in Pakistan, where first cousins often marry and mutations like these are more easily handed down.

The strategy worked. After combing the world and turning up nothing, the investigators discovered more than 100 in Pakistan who had mutations in both ApoC3 genes. And these people were healthy, with low levels of triglycerides, researchers reported last month in the journal Nature.

Now, with surprising speed, companies are starting to test experimental drugs that mimic a loss of ApoC3 by blocking the ApoC3 protein.

In addition, two companies, Regeneron and Ionis Pharmaceuticals, are now testing drugs based on the mutations in the same gene that was found in the Feurer family, company scientists and academic researchers reported on Wednesday in The New England Journal of Medicine.

Both companies reported that in preliminary studies, drugs based on these mutations reduced triglycerides in people with elevated levels. Both also reported studies of the drugs in mice showing the drugs protected the animals from heart disease.

“The basic bottom line is that the reductions in triglycerides with these things is pretty unprecedented,” George Yancopoulos, president and chief scientific officer at Regeneron, said. Still, it’s not yet clear to what extent this will prevent heart attacks.

Even more significant may be the way in which these drugs were identified. Finding people who are impervious to a disease like heart disease can open a door to letting the rest of the population share their genetic luck.

“It’s a huge advance,” said Dr. Christie Mitchell Ballantyne, chief of cardiology and cardiovascular research at Baylor College of Medicine and a consultant for Regeneron (although not for the triglyceride studies). “That doesn’t mean it’s easy.”

Still, he added, “what we are seeing is a new approach toward drug development.”

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Studies on drugs blocking these pathways should be interesting, since lowering triglycerides by themselves with drugs such as fibrates doesn't actually seem to reduce mortality.
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Incentive Trap 2: Calculating Minimum Time to Arrival

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When to launch a starship, given that improvements in technology could lead to a much faster ship passing yours enroute? As we saw yesterday, the problem has been attacked anew by René Heller (Max Planck Institute for Solar System Research), who re-examined a 2006 paper from Andrew Kennedy on the matter. Heller defines what he calls ‘the incentive trap’ this way:

The time to reach interstellar targets is potentially larger than a human lifetime, and so the question arises of whether it is currently reasonable to develop the required technology and to launch the probe. Alternatively, one could effectively save time and wait for technological improvements that enable gains in the interstellar travel speed, which could ultimately result in a later launch with an earlier arrival.

All this reminds me of a conversation I had with Greg Matloff, author of the indispensable The Starflight Handbook (Wiley, 1989) about this matter. We were at Marshall Space Flight Center in 2003 and I was compiling notes for my Centauri Dreams book. I had mentioned A. E. van Vogt’s story “Far Centaurus,” originally published in 1944, in which a crew arrives at Alpha Centauri only to find its system inhabited by humans who launched from Earth centuries later. I alluded to this story yesterday.

Calling it a ‘terrific story,’ Matloff discussed it in terms of Robert Forward’s thinking:

“Bob had a couple of concepts of technological advancement. He had a famous plot of the velocity of human beings versus time. And he said if this is true, and you launch a thousand-year ship today, in a century somebody could fly the same mission in a hundred years. Theyre going to be passed and will probably have to go through customs when they get to Alpha Centauri A-2.”

Customs! Clearly, we’d rather not be on the slow starship that is superseded by new technologies. What Heller and Kennedy before him want to do is to figure out a rational way to decide when to launch. If we make assumptions about the exponential growth in speed over time, we can address the question by adding the time we spend waiting for better technology to the time of the actual journey. We can then calculate a minimum value for this figure based on the growth rates we find in our historical data.

This is how Kennedy came up with a minimum figure of 712 years (from 2006) to reach Barnard’s Star, which is about 6 light years away. The figure would include a long period of waiting for technological improvement as well as the time of the journey itself. Kennedy used a 1.4 percent annual growth in speed in arriving at this figure but, examining 211 years of data on historical speed records, Heller finds a higher annual growth, some 4.72 percent.

From the Penydarren steam locomotive of 1804 to Voyager 1, we see a speed growth of about four orders of magnitude. Growth like this maintained for another 112 years leads to 1 percent of lightspeed.


Image: A Bussard ramjet in flight, as imagined for ESA’s Innovative Technologies from Science Fiction project. Credit: ESA/Manchu.

But how consistent should we expect the growth in speed over time to be? Heller points out that the introduction of new technologies invariably leads to jumps in speed. We are now in the early stages of conceptualizing the Breakthrough Starshot project, which could create exactly this kind of disruption in the trend. Starshot aims at reaching 20 percent of lightspeed.

Working with the exponential speed doubling law we began with, we would expect that a speed of 20 percent of c would not be achieved until the year 2191. But if Starshot achieves its goal in the anticipated time frame of several decades, its success would see us reaching interstellar speeds much faster than the trends indicate. Starshot, or a project like it, would if successful exert a transformative effect as a driver for interstellar exploration.

We know that speed doubling laws cannot go on forever as we push toward relativistic speeds (we can’t double values higher than 0.5 c). But as we move toward substantial percentages of the speed of light, we see powerful gains in speed as we increase the kinetic energy beamed to a small lightsail like Starshot’s. Thus Heller also presents a model based on the growth of kinetic energy, noting that today the Three Gorges Dam in China can reach power outputs of 22.5 GW. 100 seconds exposure to a beam this powerful would take a small sail probe to speeds of 7.1 percent of c. Further kinetic energy increases could allow relativistic speeds for at least gram-to-kilogram sized probes within a matter of decades.

Usefully, Heller’s calculations also show when we can stop worrying about wait times altogether. The minimum value for the wait plus travel time disappears for targets that we can reach earlier than a critical travel time which he calls the ‘incentive travel time.’ Considered in both relativistic and non-relativistic models, this figure (assuming a doubling of speed every 15 years) works out to be 21.6 years. In Heller’s words, “…targets that we can reach within about 22 yr of travel are not worth waiting for further speed improvements if speed doubles every 15 yr.”

Thus already short travel times mean there is little point in waiting for future speed improvements. And in terms of current thinking about Alpha Centauri missions, Heller notes that there is a critical interstellar speed above which gains in kinetic energy beamed to the probe would not result in smaller wait plus travel times. His equations result in a value of 19.6 percent of c, an interesting number given that Breakthrough Starshot’s baseline is a probe moving at 20 percent of c, for a 20-year travel time. Thus:

In terms of the optimal interstellar velocity for launch, the most nearby interstellar target α Cen will be worthy of sending a space probe as soon as about 20 % c can be achieved because future technological developments will not reduce the travel time by as much as the waiting time increases. This value is in agreement with the 20 % c proposed by Starshot for a journey to α Cen.

We can push this result into an analysis of stars beyond Alpha Centauri. Heller looks at speeds beyond which further speed improvements would not result in reduced wait times for ten of the nearest bright stars. The assumption here would be that Starshot or alternative technologies would be continuously upgraded according to historical trends. Plugging in that assumption, we wind up with speeds as high as 57 percent of lightspeed for 70 Ophiuchi at 16.6 light years.

Thus the conclusion: If something like Breakthrough Starshot’s beaming capabilities become available within 45 years — and assuming that the kinetic energy transferred to the probes it pushes could be increased at the historical rates traced here — then we can reach all ten of the nearest star systems with an interstellar probe within 100 years from today.

Just for fun let me conclude with a snippet from “Far Centaurus.” Here a ship is approaching the ‘slowboat’ that has just discovered that Alpha Centauri has been reached by humans long before. The crew has just puzzled out what happened:

I was sitting in the control chair an hour later when I saw the glint in the darkness. There was a flash of bright silver, that exploded into size. The next instant, an enormous spaceship had matched our velocity less than a mile away.

Blake and I looked at each other. “Did they say,” I said shakily, “that that ship left its hangar ten minutes ago?”

Blake nodded. ‘They can make the trip from Earth to Centauri in three hours,” he said.

I hadn’t heard that before. Something happened inside my brain. “What!” I shouted. “Why, it’s taken us five hund… ” I stopped. I sat there.

“Three hours!” I whispered. “How could we have forgotten human progress?”

The René Heller paper discussed in the last two posts is “Relativistic Generalization of the Incentive Trap of Interstellar Travel with Application to Breakthrough Starshot” (preprint).


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Senate Republicans likely to change custom that allows Democrats to block judicial choices

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Senate Republicans are threatening to change a custom that allows Democratic senators to block some judicial choices from their states, in an effort to speed along a conservative transformation of the federal judiciary.

Leaders are considering a change to the Senate’s “blue slip” practice, which holds that judicial nominations will not proceed unless the nominee’s home-state senators signal their consent to the Senate Judiciary Committee. Republicans say they will make the change if Democrats throw up blanket opposition to President Trump’s nominees.

Adherence to the custom has waxed and waned, depending on the views of Senate leaders. But the rule was strictly observed during the Obama administration, and GOP opposition to President Barack Obama’s nominees partly explains why Trump entered office with more than 120 judicial vacancies to fill.

Removing the blue-slip obstacle would make it much easier for Trump’s choices to be confirmed. Although Trump and Senate Republicans have clashed early in his presidency, they agree on the importance of putting conservatives on the federal bench.

Senate Republicans changed the chamber’s filibuster rule in April to confirm Neil M. Gorsuch as a Supreme Court justice and applauded Trump’s first round of nominations for federal circuit and district courts. His choices were drawn in part from the recommendations of conservative groups such as the Federalist Society and the Heritage Foundation.

The Senate acted Thursday on Trump’s first appeals-court nomination, elevating U.S. District Judge Amul Thapar of Kentucky to the U.S. Court of Appeals for the 6th Circuit, which covers Kentucky, Michigan, Ohio and Tennessee. Thapar was confirmed 52 to 44 on a party-line vote, with four Democrats not voting. Thapar’s nomination did not raise blue-slip concerns, because both of Kentucky’s senators are Republican and Thapar is a favorite of Senate Majority Leader Mitch McConnell (R-Ky.).

Conservative groups have urged McConnell and Senate Judiciary Committee Chairman Charles E. Grassley (R-Iowa) to loosen the blue-slip rules — especially on nominees to regional appellate courts — and Republicans have warned Democrats that uncompromising opposition to Trump’s nominees could trigger a change.

“Everybody agrees that blue slips on federal district judges are appropriate where the districts are contained within a state, and that’s been the tradition,” said Sen. John Cornyn (R-Tex.), the chamber’s second-ranking Republican. “My sense is that we’re going to establish a pattern where a blue slip at the circuit-court level is an expression of advice but is not determinative as to whether that judge will be confirmed or not.”

Democrats say that would be a substantial reworking of the rules and inconsistent with Grassley’s pledge to retain the blue-slip process no matter which party captured the White House last year.

“Eliminating the blue slip is essentially a move to end cooperation between the executive and legislative branch on judicial nominees, allowing nominees to be hand-picked by right-wing groups,” Sen. Dianne Feinstein (D-Calif.), the ranking Democrat on the Judiciary Committee, wrote in a memo this week.

She pointed out that the vacancy for which Thapar is nominated exists only because McConnell refused to return a blue slip for Obama’s nominee, Kentucky Supreme Court Justice Lisabeth Tabor Hughes. The seat has been vacant since 2013, and Tabor Hughes never received a hearing, because blue slips were not returned.

Christopher Kang, who advised Obama on judicial nominations, said that was the reason 17 of the president’s picks did not receive hearings, killing the nominations.

But the impact was even greater than that, because Obama gave up on trying to find nominees in some states, such as Texas, with two Republican senators. One vacancy on the U.S. Court of Appeals for the 5th Circuit, which covers Louisiana, Mississippi and Texas, has been open for five years.

“There’s no question that the blue-slip process greatly influenced the way President Obama chose nominees and whether they received hearings,” Kang said.

Now, liberal groups that denounced Republican stalling over Obama nominees — his picks languished longer before action than did President George W. Bush’s — are urging Democratic senators to use blue slips to block Trump nominees. Conservative groups until recently defended the process as time-honored.

Because it is a custom of the Senate and not a legal requirement, the blue-slip process has been interpreted different ways over the years.

Until the 1950s, objections by home-state senators did not hang up judicial nominations, according to a Congressional Research Service report. But during the civil rights movement, Southern lawmakers demanded more say over the judges from their states and succeeded in winning more deference. This proved temporary. By the 1980s, this deference was again on the wane. Then, during Obama’s tenure, senators were yet again able to assert their power to block judicial nominees.

“The blue-slip process was always intended to ensure consultation, and Grassley fully expects senators to continue to abide by that tradition,” said Taylor Foy, a Grassley spokesman.

But Democratic aides said that they expected Grassley and the White House to adhere to the stricter interpretation followed when Obama was president and that Grassley is now reneging on vows made to Democrats that he would preserve the blue-slip system no matter who was elected president in 2016. That’s what they believed in 2015, when he wrote in the Des Moines Register that “I appreciate the value of the blue-slip process and also intend to honor it.”

Russell Wheeler, a Brookings Institution scholar who follows judicial nominations, said allegiance is situational.

“All of a sudden, Republicans are discovering the blue-slip process can be abused, when in fact they’ve been abusing them to get all of these vacancies for Trump to fill,” he said.

Senate Minority Leader Charles E. Schumer (D-N.Y.) blasted Republicans for departing from tradition, saying in a statement, “The Constitution requires the advice and consent of the Senate, not right wing interest groups, on the president’s judicial nominees.”

But there is little that Democrats can do to stop Trump from nominating conservative judges and the Republican-controlled Senate from confirming them. It was Democrats, when they controlled the Senate in 2013, who changed the rules barring filibusters on judicial nominees, which required 60 votes to move forward on a nomination.

Sen. Sheldon Whitehouse (D-R.I.), a former U.S. attorney and state attorney general who is among the most liberal members of the Judiciary Committee, said he doubts that Grassley “would want to dismantle that long-standing Senate prerogative just to cater to the extremist impulses of this particular administration.”

Given that appellate court seats are historically connected to individual states, “they should continue to be able to make recommendations,” Whitehouse said. “I think that would be a really dumb mistake to make just to appease the far right, because it would have lasting consequences that would diminish the Senate both for Republican and Democrat senators.”

Leonard Leo, who is advising the White House on judicial nominations, said the potential of changing the blue-slip process has not altered the tradition of consulting with home-state senators.

“The administration has engaged in as vigorous a consulting process as I’ve ever seen and is doing anything they can to hear out Democratic senators,” he said.



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Trump has nominated 10 judges in addition to Thapar, and two of them are from states represented in the Senate by Democrats. Minnesota Supreme Court Associate Justice David R. Stras and Michigan Supreme Court Justice Joan L. Larsen were on Trump’s list of potential U.S. Supreme Court picks. Stras is nominated to the U.S. Court of Appeals for the 8th Circuit and Larsen to the 6th Circuit.

Michigan’s Democratic senators, Debbie Stabenow and Gary Peters, said they were “informed” of Trump’s intention to nominate Larsen and have made no judgment about her. “I will continue to listen to public input and consult with Michigan’s legal community to ensure that our state is served by highly qualified, fair and impartial judges that put the people of Michigan first,” Stabenow said in a statement.

Minnesota’s Democratic senators, Amy Klobuchar and Al Franken, also have been noncommittal about Stras.

But they are insisting on maintaining the deference they now receive.

“It’s customary that the blue-slip process applies equally to both district and circuit court nominees — and Republicans certainly operated that way during the Obama administration,” Franken said, adding, “The committee should continue this custom and not change it simply because there’s a new president in the White House.”

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Statue of Woman Removed From Bangladesh’s Supreme Court


“We all have to stand against this fundamentalist movement,” he added.

The influence of Islamic hard-liners has been growing steadily in Bangladesh, which broke away from Pakistan in 1971 and, for decades, defined itself as adamantly secular and democratic.

In recent years, its authorities have struggled to contain extremist violence against religious minorities, foreigners, gay people and secular intellectuals. Attendance at madrasas, or Islamic schools, is swelling, and more women are wearing the hijab, or head scarf.

The statue became a proxy for simmering tension between proponents of secularism, which is enshrined in Bangladesh’s Constitution, and religious leaders. About 90 percent of Bangladesh’s citizens are Muslim, with a steadily shrinking Hindu minority and small groups of Christians and Buddhists.

Last month, Bangladesh’s prime minister, Sheikh Hasina, signaled that she supported the statue’s removal, describing it as a depiction of Themis, the Greek goddess, who is traditionally seen blindfolded and carrying scales and a sword.

“Why would a statue of the Greek Themis be set up in Bangladesh?” she said last month.

Mr. Haque, the sculptor, denied that the statue represented the Greek goddess.

As workmen dismantled the statue on Friday, scores of left-wing, secular activists gathered outside the court’s gates, protesting its removal.

A protest leader, Asif Noor, said he believed the government complied with Hefazat’s demand in hopes of securing votes in national elections, to be held in 2019.

As dawn approached, the protesters tried to break through the Supreme Court’s gates to prevent the statue’s removal. Police officers were deployed to repel the crowd, and the sculpture was placed in a van and driven away.

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In every religion, fundamentalists are getting nuttier. Removing the statue of justice....
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Cloudflare gets another $50,000 to fight “new breed of patent troll”


Cloudflare, the CDN and Internet security company, has gone full berserker-mode in its fight against patent-holding company Blackbird Technologies.

Blackbird sued Cloudflare in March, claiming infringement of US Patent No. 6,453,335. Two weeks ago, Cloudflare explained the strategy it would use to fight back. The company pledged to not only seek to invalidate the '335 patent, but it will spend $50,000 on a "bounty" seeking to gather prior art and knock out all Blackbird-owned patents.

Today, Cloudflare CEO Michael Prince said his company is 

doubling the amount of money it will spend

to kill off Blackbird's patents and is working with state legislators to ban Blackbird's business model.

"We're excited to report that a friend in the industry who read our blog post and shares our concerns about the corrosive impact of patent trolls has made an anonymous donation of​ $50,000 to support our efforts to invalidate the Blackbird Tech patents​," wrote Prince in today's blog post. "That means that we are now committing at least $100,000 to the effort to find prior art on and initiate actions to invalidate the Blackbird Tech patents."

The initial bounty was split up, with $20,000 going toward the particular patent used to sue Cloudflare and $30,000 dedicated to other Blackbird patents. Cloudflare and its backer have gotten so many prior-art submissions on the patent used against Cloudflare that 100 percent of the newly donated $50,000 will go toward finding prior art on the other Blackbird patents.

Blackbird Technologies, a Massachusetts firm founded by two former big-firm lawyers, has said it has a "new model" that allows for more efficient monetization of patents. Essentially, Blackbird cuts costs by acting as both lawyer and client, a move that Cloudflare lawyers believe may violate attorney ethics rules. Cloudflare has asked legal regulators in Massachusetts and Illinois to take a look at the business, which Prince says is a "dangerous new model of patent trolling."

Blackbird founder Wendy Verlander told Ars in a statement that Cloudflare's allegations "are completely without merit," and she will vigorously defend against them.

Prince noted that state lawmakers are waking up to the danger of attorneys litigating their own patents. In Illinois, state Rep. Keith Wheeler has introduced a bill that would stop attorneys from earning fees for legal services relating to patents that they themselves own. The bill provides exceptions if the attorney "is actively engaged in producing a product or service" related to the patented invention.

In Massachusetts, where Blackbird is based, another


is being considered to limit "bad faith" assertions of patent infringement. That bill is

similar to ones passed in other states

, which are targeted primarily at patent demand letters.

"We’re happy to work with interested lawmakers in other states, including Delaware, to advance new laws that limit the practices of patent trolls, including Blackbird Tech’s 'new model,'" Prince says. "We can share the information we’ve learned and pull together model legislation. If you are interested or know a legislator who may be, feel free to email us."

In the post, Prince also praised the prior art submissions they've received thus far as being "exceptionally high quality." He continued:

The Cloudflare community of users and readers of our blog are an accomplished bunch, so we have a number of searches that were done by expert engineers and programmers. In one case that stood out to us, someone wrote in about a project they personally had worked on as an engineer back in 1993, which they are convinced is conclusive prior art to a Blackbird Tech patent. We will continue to collect and review these submissions.

Prince suggests that those interested in helping should take a look at the 20 Blackbird patents for which no prior art has yet been submitted. Cloudflare will update its chart of Blackbird patents, color coding them to indicate how much prior art they have on each. The new donation cash will be used to increase the bounty paid to researchers turning up prior art, as well as fund invalidation proceedings at the US Patent and Trademark Office.

And, of course, Cloudflare will implement the most powerful tool of any good patent troll hunter: T-shirts! A T-shirt celebrating the goals of "Project Jengo" will be given to anyone who submits "a legitimate entry of prior art."

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Saturday Morning Breakfast Cereal - Damsel

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Worse, he tied her to a track that is proposed to later be part of a high speed rail line that is currently being studied.

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If I may be allowed to extend the meme:
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This is relevant to my interests.
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And then he grabbed her (and then?) He tied her up (and then?) He threw her on the railroad tracks (and then?)
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