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今天的内容比较多，只是希望把好玩的话题让大家尽量都看到O(∩_∩)O
【计时一】
Stephen Hawking, CERN Physicists Receive Millions in Prize Money
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For the second time this year, Russian billionaire Yuri Milner, who made his fortune in Silicon Valley, has showered millions of dollars on prominent physicists through his brainchild, the Fundamental Physics Prize. And whereas the first round of awards sparked controversy, this time the winners are, if anything, a bit predictable, other researchers says.
Stephen Hawking, the famed British theorist who predicted that black holes would radiate, receives one of the two $3 million prizes announced today. The second goes to seven physicists whose efforts helped unearth the long-sought Higgs boson, which was discovered in July at the world's biggest atom-smasher, the Large Hadron Collider (LHC) at the European particle physics lab, CERN, near Geneva, Switzerland.
The CERN seven include: Lyn Evans of Imperial College London, who led construction of the LHC; Fabiola Gianotti of CERN, who serves as spokesperson for the 3000 scientists working with the massive ATLAS particle detector; and Joseph Incandela of the University of California (UC), Santa Barbara, who serves as spokesperson for the 3000 scientists working with the CMS particle detector. In July, the CMS and ATLAS teams independently reported that they had seen a particle that appears to be the Higgs boson. Also sharing the award are Peter Jenni of CERN, the former ATLAS spokesperson, and Guido Tonelli of the University of Pisa in Italy, Tejinder Virdee of Imperial College London, and Michel Della Negra of Imperial College London, all former CMS spokespersons.
"It was a huge surprise," Candela says. "When I was first told about it, I was literally speechless." In honoring the spokespersons of the two detector collaborations, the prize committee has taken a stab at the thorny question of how to hand out laurels for a discovery that was made by large teams of people. And the recipients seem to have interpreted the award in that way. "For me, this prize belongs to the collaboration," Gianotti says.
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In fact, both Incandela and Gianotti say they intend to give their shares of the prize money to their collaborations in some way. For example, Incandela says that it might be possible to use it to establish an annual award to recognize an outstanding junior member of the collaboration. Gianotti suggests her winnings might serve to start an endowment that would provide a boost to economically disadvantaged young researchers hoping to work at CERN.
The choices seem less controversial than those made personally by Milner in July. Then, Milner gave nine theorists—mainly string theorists—$3 million each. Many science fans hailed the prizes as overdue recognition for deep thinkers. But some observers complained that the awards went to people who were already relatively famous and overemphasized the accomplishments of string theory, which remains experimentally untested. "There's this complete imbalance between the public perception of string theory and what's actually been accomplished in the field," says Peter Woit, a mathematician and physics blogger at Columbia University. "This just drops a huge amount of money on the wrong side of that."
This time, the nine previous winners selected the new honorees. And in some regards, their choices were obvious. "Hawking? He's one of the great physicists of this age," says Matthew Strassler, a theoretical physicist and blogger at Rutgers University in Piscataway, New Jersey.
On the other hand, both Woit and Strassler question how much giving the awards to already fairly prominent researchers benefits the field. "Does Hawking need more money and more recognition?" Woit says. Strassler says: "Sinking this kind of money into institution building and young people could be transformative. So this [pair of awards] isn't bad. It is just not as good as it could be."
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However, Milner's foundation did award more modest New Horizons in Physics Prizes of $100,000 to each of three young theorists—Niklas Beisert of the Swiss Federal Institute of Technology in Zurich; Davide Gaiotto of the Perimeter Institute for Theoretical Physics in Waterloo, Canada; and Zohar Komargodski of the Weizmann Institute of Science in Rehovot, Israel.
It also announced the nominees for the next $3 million Fundamental Physics Prize, which will be awarded in March. They include Joseph Polchinski, a string theorist at UC Santa Barbara, and Alexander Polyakov, a string theorist at Princeton University. Also nominated were Charles Kane of the University of Pennsylvania, Laurens Molenkamp of the University of Würzburg in Germany, and Shoucheng Zhang of Stanford University in Palo Alto, California, who work on solids called topological insulators.
The losers of that competition get $300,000.
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【计时三】
All Eyes on RNA
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The list of RNA-binding proteins linked to amyotrophic lateral sclerosis is growing; RNA may also explain why a common mutation causes this fatal motor neuron disease—and a dementia.
In the summer of 2011, a 3-year investigation into the genetics of amyotrophic lateral sclerosis (ALS) by research teams on two continents was coming to a head. This international consortium had narrowed the search for a mutation they knew caused ALS in families to just three genes on chromosome 9. Yet detailed and thorough gene analysis, using a variety of new sequencing technologies and massive computational power, failed to turn up any mutations that could be responsible.
Knowing that something unusual must lurk in this segment of DNA, Bryan Traynor, a geneticist at the U.S. National Institute on Aging in Bethesda, Maryland, took a closer look at one particularly suspicious stretch. When a computer algorithm clearly failed to correctly assemble the relevant DNA sequences of affected family members, Traynor arranged them manually. “I had to revert back to papyrus and pencil in order to actually work it out,” he jokes.
At that moment, Traynor became the first person to look upon the most common known cause of both ALS (sometimes called Lou Gehrig's disease in the United States) and another, slightly rarer neurodegenerative disease called frontotemporal dementia (FTD). What he saw in the DNA of the ALS patients was the nucleotide sequence GGGGCC repeating itself over and over, far more than in unaffected family members. Because this type of mutation has been implicated in some other neurodegenerative diseases—repeated DNA sequences cause Huntington's disease and fragile X syndrome, for example—Traynor was confident that the consortium's long quest was over.
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【计时四】
Indeed, a team led by Rosa Rademakers of the Mayo Clinic in Jacksonville, Florida, independently discovered the same repeat in the gene, provisionally dubbed C9ORF72, and the two groups published simultaneously in Neuron in September 2011. It quickly became apparent this was the most important ALS gene discovered to date, by far. The C9ORF72 mutation accounts for 40% of familial ALS and 21% of familial FTD. It has also been found in 7% of sporadic ALS, in which there's no family history of the condition—the vast majority of cases—and in 5% of sporadic FTD. “For the first time, really, we are showing that genetics can underlie apparently sporadic disease,” Traynor says.
The whole field is waiting to find out how the mutation causes ALS—or how, in some people, indistinguishable mutations instead paradoxically trigger FTD. ALS robs a person of muscle control but spares the mind, whereas FTD does the opposite. (Many patients show symptoms of both diseases to varying degrees.)
The leading hypothesis is that the long DNA repeat spawns a bloated gob of RNA that creates a trap inside cells for one or more RNA-binding proteins necessary for a neuron's function or survival. RNA-binding proteins have been under scrutiny in ALS since 2006, when one of them, TDP-43, was reported to make up the abnormal protein deposits, known as inclusions, found in motor neurons in almost all ALS cases (Science, 6 October 2006, p. 42). Mutations in the genes for TDP-43 and in FUS, a related RNAbinding protein, can cause ALS, and mutations in a third RNA-binding protein, ataxin-2, are a powerful risk factor for the disease.
Although ALS neurons suffer many types of dysfunction, the multiple recent discoveries have led to “a convergence of ideas” that errors in RNA processing are central to ALS and they could be linked to all the cellular problems, says biochemist Don Cleveland of the University of California (UC), San Diego. Others in the field caution that ALS might actually be several distinct diseases with different causes, RNA misprocessing being only one. Nevertheless, Cleveland says, “since last September, it's been the most exciting time of discovery in ALS in the history of the planet.”
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Inward bound
What RNA-binding proteins are doing—or not doing as the case may be—in ALS and FTD remains largely a mystery. That's partly because each protein may bind so many RNAs, thousands in some cases, that it is hard to know which RNAs are important in disease. Among other duties, RNA-binding proteins trim, cap, escort, degrade, and otherwise process messenger RNA, which carries the transcribed DNA sequence from the cell nucleus to the cytoplasm for translation into protein. “There isn't a step in the process [without] a halo of RNA-binding proteins surrounding the RNA,” says Robert Bowser, a neurobiologist at the Barrow Neurological Institute in Phoenix.
For ALS and FTD researchers, a key unknown is what triggers RNA-binding proteins to aggregate into the inclusions seen in the neurons and other nervous system cells of patients. One hypothesis is that the inclusions derive from stress granules, dense balls of RNA-binding proteins that arise normally in cells in response to cellular stress. Stress granules trap RNAs and prevent their translation into proteins, presumably to husband the cell's resources until the stress is gone. “But as a consequence of having this great function, they're more susceptible to aggregating in disease in an uncontrollable fashion,” says geneticist Aaron Gitler of Stanford University in Palo Alto, California. Normally, stress granules eventually dissolve and release the trapped RNAs, but under persistent stress—or owing to genetic risk factors—they may persist and transform into the massive cytoplasmic inclusions seen in ALS and FTD.
Genetic evidence supports this idea. In 2010, Gitler, then at the University of Pennsylvania (Penn), and colleague Nancy Bonini reported that about 5% of all ALS patients have a mutation in the gene encoding ataxin-2, an RNA-binding protein involved in stress granule assembly. More recent work suggests that mutated ataxin-2 indeed contributes to inclusion formation.
The six-nucleotide repeat sequence in the C9ORF72 gene may seed a different kind of aggregate—in the cell nucleus, not the cytoplasm. Researchers strongly suspect that this DNA sequence repeat, which is in a noncoding region of the gene, gives rise to an unnatural RNA structure that captures one or more RNA-binding proteins there. And the sheer number of repeat sequences—at least 30, and often hundreds or even thousands—could sequester enough protein to disrupt a neuron and provoke its demise. Indeed, Rademakers's group has documented aggregates dubbed RNA foci in postmortem brain and spinal cord tissue from C9ORF72 mutation carriers. “The race is really on to figure out what RNA-binding protein is being sequestered in there,” Gitler says.
There are precedents for such sequestration causing disease. The best-known case is myotonic dystrophy, an adult form of muscular dystrophy, in which an expanded three-nucleotide repeat sequesters an RNA-binding protein called muscleblind that's involved in RNA splicing, forming RNA foci.
Whether or how RNA foci harm neurons is unknown. And researchers still can't agree on whether the cytoplasmic inclusions in ALS and FTD neurons kill the cells because the captured RNA-binding proteins can't carry out their normal function or because the aggregates gained a new, toxic function. The answer may be both. “I personally think that the best data out there indicate that it's both loss and gain of function that's important,” Gitler says.
Unidentified captives
Any definitive conclusion, says Zissimos Mourelatos, a pathologist at Penn, must wait until identification of the RNAs, if any, that are captured in the inclusions seen in people with ALS and FTD. Such work is now under way in several labs using a new technique called CLIP-seq. The technique uses ultraviolet radiation to create a chemical bond between RNA-binding proteins and their RNAs, enabling purification of the latter and then their sequencing and identification. In September, a group from UC San Diego reported in Nature Neuroscience that they had used CLIP-seq to reveal RNAs common to both TDP-43 and FUS. Several of these RNAs code for proteins important in synapse formation and function, suggesting that aggregation depleted these synaptic proteins, causing neurodegeneration.
TDP-43, FUS, and ataxin-2 won't be the only RNA-binding proteins involved in ALS, Gitler and Mourelatos predict. “We think that this is going to be the tip of the iceberg,” Gitler says. Indeed, in September in Acta Neuropathologica, Bowser's group reported finding inclusions containing the RNA-binding protein RBM45 in the cytoplasm of spinal cord cells from 21 of 23 ALS patients, versus none in seven control cases. (RBM45-containing inclusions were also present in all six FTD patients tested.) No mutations in the gene for RBM45 have yet been found in ALS, but that was also true of TDP-43 when first found in ALS and FTD inclusions back in 2006.
At Penn, Gitler's group cloned the genes for almost 200 RNA-binding proteins and introduced them individually into yeast cells, checking for aggregation and toxicity. Gitler so far has found mutations in two of them, TAF15 and EWSR1, in several people with ALS or FTD, suggesting possible roles in the disease. “I'm pretty confident that there will be additional RNA-binding proteins that you'll be seeing in the literature soon,” he says.
What's special about neurons?
All this begs the question of why neurons are so sensitive to changes in RNA-binding proteins, while most other cell types appear unaffected. “It's a big unknown,” says Mourelatos, who suggests that the large amount of gene splicing required for the generation of specialized protein isoforms at synapses, the connection points between neurons, could be a factor. “There's a lot of RNA processing going on in neurons,” he says. Gitler speculates that the sheer length of motor neurons—in humans, a single motor neuron axon can extend several feet—may make them more dependent on RNA trafficking and processing.
Other researchers stress that, for ALS at least, defects in RNA processing may not be the whole story. “I think it's a much more complicated disease than that,” cautions Lucie Bruijn, chief scientist at the ALS Association, which is headquartered in Washington, D.C. Bruijn cites mitochondrial dysfunction and defects in transport along motor neuron axons as two important features of ALS disease pathology. For example, a recent paper in Nature described ALS-causing mutations in the profilin-1 gene. Profilin-1 affects axon growth and regulates actin, an abundant and critical protein not involved in RNA processing. “It's not clear to me how we would fit that discovery into an RNA-binding protein world,” Cleveland admits. “So it's just a little perplexing.”
And one camp of ALS researchers maintains that it's not RNA misprocessing but a failure of the cell's protein-disposal system that causes the disease; mutations in several genes involved in protein clearance cause a small proportion of familial ALS. Most researchers believe that a combination of RNA misprocessing and failed protein clearance is responsible for most cases. “How the two meet up in the middle, we do not know,” Traynor says.
The current intense focus on disease mechanism should be accompanied by efforts to develop therapies now, even before these controversies are resolved, Bruijn says. The ALS Association, besides funding mouse models of the C9ORF72 expansion, is also collaborating with Isis Pharmaceuticals on developing “antisense” DNA drugs to bind and neutralize the repeat sequences. Although uncovering the mutation's function is important, Bruijn says, “we might never find out exactly, or all agree. And maybe if we get rid of that large expansion there will be therapeutic benefit.”
【1219】
【计时五】
Homosexuality May Start in the Womb
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From a strictly Darwinian viewpoint, homosexuality shouldn't still be around. It isn't the best way to pass along one's genes, and to complicate the picture further, no "gay genes" have even been identified. According to a newly released hypothesis, the explanation may not lie in DNA itself. Instead, as an embryo develops, sex-related genes are turned on and off in response to fluctuating levels of hormones in the womb, produced by both mother and child. This tug of war benefits the unborn child, keeping male or female development on a steady course even amid spikes in hormones. But if these so-called epigenetic changes persist once the child is born and has children of its own, some of those offspring may be homosexual, the study proposes.
Evolutionary geneticist William Rice of the University of California, Santa Barbara, felt there had to be a reason why homosexuality didn't just fade away down the generations. Research estimates that about 8% of the population is gay, and homosexuality is known to run in families. If one of a set of identical twins is gay, there's a 20% probability that the other will be, too.
Furthermore, Rice notes, "homosexuality isn't just a human thing." Among California gulls, which he watches from his office window, about 14% of pairs are female-female. In Australian black swans, some 6% of pairs are male-male, and 8% of male sheep are attracted exclusively to male partners.
But many genetic screens have failed to turn up genes that are responsible for sexual orientation. So to find out what makes homosexuality persist, Rice and colleagues began a comprehensive survey of the literature.
According to conventional wisdom, an embryo becomes a boy when a gene on the Y chromosome triggers the development of testes, which then begin to produce male sex hormones, including testosterone, at about the 8th week of gestation. With no Y chromosome and hence no testosterone, the embryo becomes a girl.
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But testosterone doesn't explain everything, the researchers found. For one thing, female fetuses are exposed to small amounts of the hormone from their adrenal glands, the placenta, and the mother's endocrine system. At many key points of gestation, male and female fetuses are often exposed to similar amounts of testosterone. Levels of the hormone can even be higher than normal in females and lower than normal in males without any effect on genital or brain structure.
Rice and his co-workers were more intrigued by studies showing that male and female fetuses respond differently to the hormones that surround them, even when one hormone is temporarily higher. In their study, published online today in The Quarterly Review of Biology, the authors propose that differences in sensitivity to sex hormones result from "epigenetic" changes. These are changes that affect not the structure of a gene but when, if, and how much of it is activated—by chemically altering a gene's promoter region or "on" switch, for example. Epigenetic changes at key points in the pathway through which testosterone exerts its effects on the fetus could blunt or enhance the hormone's activity as needed, the authors suggest.
Although epigenetic changes are usually temporary, they involve alterations in the proteins that bind together the long strands of DNA. Thus, they can sometimes be handed down to offspring. According to the hypothesis, homosexuality may be a carry-over from one's parents' own prenatal resistance to the hormones of the opposite sex. The "epi-marks" that adjusted parental genes to resist excess testosterone, for example, may alter gene activation in areas of the child's brain involved in sexual attraction and preference. "These epigenetic changes protect mom and dad during their own early development," Rice says. The initial benefit to the parents may explain why the trait of homosexuality persists throughout evolution, he says.
"The authors have done a terrific job providing a mechanism for genetic variation, especially a variation that might not be expected to persist because it's so tightly bound to reproduction," says evolutionary biologist Marlene Zuk of the University of Minnesota, Twin Cities. But she adds that to go from changes in gene expression to why someone is attracted to a person of the same sex is a question for which science may never fill in all the blanks.
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【越障】
Mysteries of the Brain——How Are Memories Retrieved?
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New work suggests that memory is far more fluid than neuroscientists thought, and that memory retrieval plays a crucial role in shaping memory over time.
So much of memory is a puzzle. How can the experiences of a lifetime—the sights and sounds, people and places, successes and failures—be recorded in the soft tissue of the brain? How can those memories persist for decades even as the neurons that encode them undergo constant molecular remodeling? And how can we (more often than not) recall a particular bit of information almost instantaneously, and with little prompting?
This last question may be the most mysterious of all. “Retrieval is such a rich phenomenon,” says Michael Hasselmo, a neuroscientist at Boston University. “You get a reminder from somebody that's maybe just a word and you somehow turn it into a rich internal movie of events that you're moving through with a perspective and a location and a sense of time passing.” Our memories are part of what makes each of us unique (see p. 35), and they give us a sense of self-identity and continuity as we move through life. “Without our memories, we're just zombies,” says György Buzsáki, a neuroscientist at New York University in New York City.
The neuroscience of memory is a complex and contentious area, but most researchers agree on a broad-brush account that goes something like this, at least for episodic memories, or memories of events. These memories are initially encoded and stored mostly in the hippocampus, deep inside the temporal lobe of the brain. For long-term storage, memories are filed away to other areas, including the neocortex, the thin sheet of tissue on the surface of the brain. A memory of any given event, the thinking goes, is represented by a sparse and scattered network of neurons, such that the sights, sounds, and emotions associated with the experience may each reside in a different location. To recall that memory, the brain must somehow reactivate just the right subset of neurons. Many details of this process are not known (or are disputed). Even so, some researchers say it's time to revise some aspects of the standard view—such as the notion that the hippocampus is not involved in retrieving older episodic memories, and that memories become fixed and unchangeable once transferred to the neocortex. Newer work suggests a far more fluid role of memory, and one in which retrieval plays a crucial role in shaping memory over time.
So what should researchers look for if they hope to learn how the brain recalls the past? One clue comes from functional magnetic resonance imaging (fMRI) studies of the human brain suggesting that remembering reactivates some of the same neural circuitry as the original experience. Recalling a face, for example, activates a part of the fusiform gyrus thought to specialize in face recognition. Recalling a place evokes a different pattern of brain activity that includes the parahippocampal gyrus, an area that lights up when people view images of landscapes and other scenes.
“We have a pretty good idea that the brain uses the same machinery for remembering that it does for experiencing things,” says Loren Frank, a neuroscientist at the University of California, San Francisco. When it comes to episodic memories, Frank says, what's stored in the brain are little snippets of the experience that can be compiled into a kind of highlight reel. The neural signature of memory retrieval, Frank argues, should look much like the neural signature of the actual experience played in fast-forward.
There's disagreement about how fast the replay should be, but several labs, including Frank's, have found something like this in the brains of rats. One example is a 2008 study from Buzsáki and colleagues, in which the researchers trained rats to alternate taking left and right turns at a particular point in a maze. They found, as others had before, that each path evoked a specific sequence of firing by so-called place cells in the rodents' hippocampus. In a twist, the researchers then gave the rats a break between turns in the maze. They found that during this time, their place cells fired in sequences that predicted which direction they would turn on their next run in the maze. One sequence played when the rat had a left turn coming up, and a different sequence played when a right turn was next (Science, 5 September 2008, p. 1322).
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Do these hippocampal firing sequences represent the rat reminding itself what it needs to do next? Buzsáki thinks so. “Plans are based on memories,” he says. Buzsáki speculates that such sequences also play a broader role in recalling episodic memories. “The hippocampus is like a librarian,” he says: Its job is to record new experiences, help file them away to the neocortex, and later retrieve them on demand. In the case of episodic memories, the firing sequence of hippocampal cells might serve the same purpose as the identifying bar code on the spine of a book, indicating which subset of neocortical neurons represents a given memory.
Recent studies support the concept that memory retrieval involves reactivating small but specific sets of neurons. In one, published online on 22 March in Nature, researchers used genetic engineering methods to tag neurons in the hippocampus that were activated as a mouse learned to associate a flash of light with an impending shock. When the researchers then reactivated those same neurons with a pulse of laser light delivered by an optical fiber, the mice froze in fearful anticipation even though they hadn't seen a flash of light.
Bridging the gap between such rodent studies and the human brain isn't easy. In rare cases, neuroscientists have taken advantage of monitoring electrodes placed in or on the brains of epilepsy patients awaiting surgery. Such studies are done only when they don't interfere with medical care. In a 2008 study, researchers asked patients to watch several short video clips from TV shows and movies and then recall as many of them as possible a short time later. Individual neurons in the hippocampus seemed to develop a preference for a specific clip, firing strongly a second or so before a patient named a clip, say, from The Simpsons, but not when he or she recalled any of the other clips (Science, 3 October 2008, p. 96). The findings provide some of the best evidence that reactivation of specific hippocampal neurons is involved in the conscious experience of memory retrieval.
Memory researchers have also begun to use methods borrowed from machine learning to analyze patterns of brain activity from fMRI scans on a finer scale than conventional methods allow (Science, 13 June 2008, p. 1412). “We can actually now identify individual memory traces by the pattern of activity in areas of the brain such as the hippocampus,” says Eleanor Maguire, a cognitive neuroscientist at University College London. “We can predict in an experiment the memory that someone is recalling.” (But only when the choices are limited: The technology is nowhere close to being able to read out any fleeting memory that crosses someone's mind.)
Maguire says that work by her group and others is beginning to challenge the dogma that the hippocampus is not involved in recalling older episodic memories. The overarching role of the hippocampus, she hypothesizes, is to pull together the various aspects of a memory residing in different regions of neocortex and bind them into a coherent scene in the mind's eye. Recent studies suggest that the hippocampus even does this when people ponder imaginary scenarios. By stitching together pieces of the past, Maguire says, the hippocampus enables us not only to vividly remember but also to envision possible futures.
Another recent challenge to traditional views of memory retrieval comes from research suggesting that memories can be incrementally strengthened, weakened, or otherwise altered each time they're recalled. “That work has changed the way people think about the persistence of memory,” says Yadin Dudai of the Weizmann Institute of Science in Rehovot, Israel. Such findings point to a more malleable memory system in which retrieval presents an opportunity to update old memories in light of new experience. Our repository of memories may be less like a library and more like Wikipedia, where each entry is open to editing anytime it's pulled up.
This type of plasticity may be crucial for fitting new memories into the existing network of old memories, says Howard Eichenbaum, a neuroscientist at Boston University. “Everything you learn has to fit in with what you already know,” Eichenbaum says. How the brain accomplishes that never-ending task is a puzzle scientists have only begun to explore.
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发表于 2012-12-12 11:03:26
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仿佛回到了当年实验室读文献的岁月....
