Archive for: October, 2010

New NIH scoring system for 2011

Oct 23 2010 Published by under Uncategorized

The NIH has just announced that in response to complaints that their new scoring system is too hard to interpret, they have decided, yet again, to revamp the way grant applications are scored. This new system will be rolled out during the first review cycle of 2011. Reviewers will now use this simplified form to check off the reasons for rejecting a grant application. The form is reproduced here:

New NIH grant scoring system.

Actually this is a film script rejection slip from the Essanay Film Manufacturing Company which operated between 1907 - 1925. Although the reasons for rejection seem very similar to comments I have received in my grant reviews, particularly the one about removing scenes of an unpleasant nature.

Source: Old Hollywood.

8 responses so far

Can you Cajal?

Oct 22 2010 Published by under Uncategorized

In the class I'm teaching this semester on controversies in neuroscience, we had earlier talked about the conflict between Golgi and Ramón y Cajal regarding the nature of the neuron. Cajal argued that neurons are independent units while Golgi argued that they formed a continuous reticulum. One thing I wanted to emphasize to my students was that even though in hindsight we know that Cajal was mostly right and Golgi mostly wrong, based on the available technology at the time, both interpretations are highly possible since the data itself is very ambiguous. Also, much of how we interpret data is biased by what we know. So in Golgi's case, the reticular theory was what was accepted,  and he was able to find what seemed like convincing evidence for it.  As an exercise, I wanted to see if the students could replicate some of Cajal's findings. So I asked around my department for Golgi stained rat brain sections (which were hard to find, most people don't use this technique much anymore) and borrowed a microscope. I asked the students to look through the slides, find what they thought was unambiguously a single neuron, draw it to the best of their abilities and identify key features, such as dendrites, spines, soma, axon, etc. As you will see, some of the results are pretty interesting. Here's a picture of a Golgi stained portion of the cerebral cortex. This is not the section that was used, but it looked similar to this. Notice that while you can see a bunch of neurons, it is hard to tell whether they are separate or form a continuous web. One way to tease this apart is to show that at points where the processes cross, different ones are at different planes of focus:

Golgi stained section of the cerebral cortex of a rodent. Source: Neurodigitech

Now here's a drawing by Cajal of the Cortex. It is important to note that Cajal's drawings are not exact copies of his slides, but rather a synthesis of the various elements arranged in a way which would increase the clarity and logic of the way the data is represented. In fact, apparently many of his drawings were done by memory, after spending a day looking through the microscope, and done while having a drink in a local brothel. I know I have sometimes analyzed data at a coffee shop, but Cajal brings this to a new level.

Cajal's drawing of the cerebral cortex.

I think that one of the main errors committed by the students, was that if you look in many textbooks, neurons tend to look like this:

Diagram of a Neuron. Source: Wikipedia.

While this diagram helps to distinguish the different neuronal elements, the stumpy little dendrites, the gigantic cell body (soma) and the really thick axon somewhat mis-represent the actual proportions of a real neuron. For example, take a look at these two neurons drawn by students in my class (click on any of the drawings to enlarge):

Both students suggested that the longest, thickest process was the axon, while the skinny little ones were dendrites. In reality, what they probably thought was the axon was the apical dendrite, which is a very large primary dendrite which many cortical neurons have. In these cases the drawings were largely guided, I think, by a preconceived idea the students had of what a neuron should look like.

In this next drawing, the processes (axons and dendrites) are a bit more realistic, although soma seems a bit exaggerated. This student also assumes that the longest process is the axon, despite it having clear dendritic spines. Interestingly, the little smooth process near the bottom looks like the actual axon, or a stump of it, the rest was likely sliced off when the brain section was made:

This other student managed to guess that the little stump he drew near the bottom was the severed axon initial segment, althoug like the previous drawing the soma is exaggerated and there's a strange blob at the top of a dendrite, probably the out-of-focus soma of a nearby cell:

The best two I think are these next ones, they look more realistic, capturing the thickness of the dendrites relative to the soma, one correctly identified the stump of the axon, the other couldn't find an axon, but made no assumptions about it:

The truth is is that neurons are three dimensional, and often will have parts of their axons and dendrites cut off in a given brain section. That is why one needs to look at a lot of cells, and draw inferences from each one, finally putting everything together in a composite picture.

Overall, I think everyone enjoyed the exercise and it gave them a feel for what doing some of the experimental work was like. They also liked the little art school-style critique I did in class of their drawings. All of them did a great job and it was great fun. Next up: stimulus intensity coding in cockroach leg nerves...


12 responses so far

Batten down the hatches, matey!

Oct 19 2010 Published by under Uncategorized

Recently a non-science friend asked me "How is your research going?" I hate answering this question because I never know what to say. Do I say, "my new grad student has been breaking all her micropipettes and killing all the cells", or "we can't get that new reagent into solution because the company that makes it changed how its made, and the one from the other company is backordered for six months so we can't do any experiments", or "my postdoc has been stuck in China for 3 months because he can't get his visa renewed"? Or do I just say "fine" and change the topic? It's always hard to find something that someone outside of science can relate to. But this time I decided to tell him about the troubles we've been having getting a paper published.

It's the typical story. My grad student has been working on this project for several years and getting good results and when it was ready to write up we submitted it to a good top-tier journal. We were excited that the journal sent it out for review, and even more excited when we got back two very positive and constructive reviews. The reviewers wanted a butt-load of experiments but which sounded reasonable, so we decided to do all of them, which took about eight months. And all of them worked, significantly strengthening our already kick-ass study. We sent a revised version with all the new data back to the journal and sat back waiting for the good news. About eight weeks later we get an email saying that they won't publish our paper. WTF!? The original two reviewers liked our revisions and new data and both suggested the paper get published. But of course, the journal decided to open the dungeon and bring out... you guessed it... the Third Reviewer. Fucking Third Reviewer!!! Whoever it was gave our paper a cursory read, blurted out some "serious concerns" which we had already explicitly addressed, suggested some impossible experiments and shat all over our paper. The editor of the journal, based on this, rejected our paper. Which goes to show that you are at the whim of some randomly chosen sadistic dude who can dismiss four years worth of work with the wave of a keyboard, just because he can. And just like that, he and the journal wasted everybody else's time.

My friend was shocked. He had developed this idea of science working in a very objective way, where scientists sit around doing experiments and soberly publishing their results so other serious scientists could mull them over and devise new experiments. He expressed surprise that science was so full of ego and susceptible to whim and trendiness and all of the imperfections that accompany every other human endeavor. That in order for your science to gain exposure you had to fight for these few spots in superglamourous journals, otherwise nobody outside your immediate field would ever read your papers – as was suggested in a recent informal poll. He was also surprised that this was all being supported by taxpayer money. But that's the way it is. Although our experiments might be objective, and ultimately we are discovering something about the natural world, all the human activity that surrounds this process sometimes overshadows the actual science and the actual facts. Which is something that is sometimes hard for people outside of science to grasp. My friend asked, "well I'm sure your University would offer to help you in this case, which sounds so unfair, right?"  But again another big misconception, that there is some undefined entity called the "University" that somehow guides the research that occurs within its walls, protecting its faithful faculty, and stepping in when necessary. Who is this "University"? The administration? They have no idea about half of the research that individuals working there are doing. Only the stuff that gets featured in the University home page when you get a publication in a fancy journal.

So what happened to the paper? I asked a senior colleague who has a lot of fancy publications for advice, and he said "fight like hell".  So that's what we're doing. We filed an appeal (which is greatly discouraged by the journal, of course) and expressed in their lengthy appeal form why we thought the Third Reviewer was out of line, added data from the one experiment he suggested that was doable (it also worked as expected), replied to all of the his petty concerns and are ready for the big fight. We've battened down the hatches, pulled out the cannons and battering rams, sharpened our swords, dug out those weapons that have the spiky balls at the end, loaded up the horses and elephants, tightened our boxing gloves, honed our arrows, tightened our bows, loaded up the guns and laser blasters, wet our spitballs… watch out fancy pants journal, we're mad, and your ass is grass! For now.

9 responses so far

Hotsy Totsy

Oct 14 2010 Published by under Uncategorized

This year we had a bumper crop of habanero peppers in our garden, and I decided to pickle them (see recipe here). So last weekend I had the Big Pickling Event and I spent about an hour slicing and dicing habaneros and a variety of vegetables and putting them in jars. After I was done I washed all the dishes and my hands, etc. I was very careful not to touch my face or eyes during the whole process and even afterwards. Nevertheless I could still feel some pepper fumes while I was cutting them and my eyes and mouth maybe felt a bit scratchy, but nothing too bad. Later that evening I was giving my kids a bath and when the hot water hit my hands they really began to burn, which makes sense, since the capsaicin receptor in our mouths and skin is the same receptor that senses noxious heat (+43°C), and maybe there was some residual capsaicin on my hands which I felt when the receptors were co-activated by heat. But still nothing too bad.

OK, here is where it gets weird. The next morning I'm having breakfast and I ate a piece of cut-up fruit and… it tastes spicy. First I thought that I didn't wash the knife or cutting board properly after habanero fest. But both my wife and kids said that the fruit did not taste spicy to them at all.

So there were a couple of possibilities, one being that prolonged exposure to pepper fumes for a good hour or so the previous day somehow sensitized my capsaicin receptors in my tongue such that I could taste trace amounts in the cut up fruit. But it wasn't just the fruit, I had some toast with jam and the jam tasted unquestionably spicy. Interesting. So that would mean that somehow the receptors may have been altered such that they could also respond to sweet flavors. This makes no sense, since the receptors for sweet flavors and for capsaicin work in very different ways. Sweetness is detected by what is known as a G-protein coupled receptor which resides in sensory neurons in the tastebuds. Activation of this receptor sets off a biochemical reaction which ultimately culminates in activation of a sensory nerve sending the signal to the brain. In contrast, capsaicin receptors belong to a class of proteins known as ion channels. And contact with capsaicin molecules, or exposure to burning heat, causes these channels to open and directly activate pain fibers going to the brain. But the effect was definitely there, and it lasted the rest of the day.

So I did a little experiment. I looked up some papers on spice perception and found a couple of studies showing that repeated exposures, about a minute apart, to very low doses of capsaicin caused sensitization of the capsaicin receptor. Meaning that each time capsaicin was given to a subject it was spicier than before. If they then waited a longer time interval then there was desensitization – which means that capsaicin became less spicy. Maybe, the hour-long exposure to pepper fumes the previous day somehow sensitized the receptors and altered the perception of sweetness in some yet unexplained way. Sort of like those African berries that make sour things taste sweet. Could I replicate this? Since I didn't feel like making more pickles I designed a carefully controlled study. I tried to recruit my wife to take part in the study, so we could have n=2, but somehow she refused to participate in my little shenanigans. I cut up a leftover habanero into tiny squares, about 1 millimeter across. I also used a different knife to cut up some strawberries, took out a loaf of bread and poured a glass of milk (bear with me). So for 8 minutes I chewed once a minute, for a few seconds, on one little pepper square, letting the pepper juice come in contact with the left side of my tongue. Consistent with the prior study, each pepper square tasted a bit spicier than the previous one, until the end when it tasted VERY, VERY spicy. I don't know if this was sensitization or just accumulated capsaicin on my tongue. Let's go with sensitization. Then I rinsed my mouth well with water, ate half a slice of bread and drank the milk. All of these things supposedly help get rid of capsaicin and sort of work if you've eaten something too spicy, like that crazy Korean food from the other day. Then I waited 5 minutes and ate a strawberry. It tasted spicy! And only on the side of my tongue which came in contact with the pepper. On the naive side it still tasted sweet. Groovy. Then came the desensitization part. I waited another 5 minutes and tasted a slightly bigger pepper square and let it get all over my tongue. Now I felt that in the previously exposed left side the spicy taste was less spicy than on the naive right side. Meaning that the left side had become desensitized. If I tasted a strawberry, it no longer tasted spicy on the left side and, ok, not on the right side either.

So, does sensitization of capsaicin receptors make them sensitive to sweet flavors? Who the hell knows. There were a few problems with my little experiment. One is that there was no good way to control for the pepper juice only touching one side of my tongue, so the whole left vs. right thing could have been imagined. Which is the other problem, since I knew what the expected results were I could have biased the perception. In addition, I only tried fruit. So it may be something else in the fruit that may have been activating the capsaicin receptors, like acidity. Sugar would have been a better test,  but strawberries are delicious. Maybe I can recruit my kids to repeat this, but I can just picture the screaming after the eighth little habanero square. One thing is for sure – I'm glad I don't study human psychophysics for a living, there's too many variables.

So there you have it. Do try this at home and let me know the results!

3 responses so far

Just So Stories

Oct 06 2010 Published by under Uncategorized

Our house is literally strewn with books. Everywhere you look there are little piles of them, some just lying around on the floor and stairs by themselves, some on the furniture, some balanced precariously on the bannister. One of the problems is that we don't have enough bookshelves, at least not in convenient locations. The other is just that we have a lot of books – our own books, books that come home from the kids' school and from our local library, books for work, baby books that somehow never got put away, magazines, etc. Many of these books are in various stages of being read, so it wouldn't make sense to shelve them upstairs. A recent survey of the books in the bathroom revealed the following: Moby Dick, Yertle the Turtle and Other Stories, Tasha the Tap Dance Fairy, a Curious George board book, a field guide to clouds, Magic Treehouse #18: Buffalo Before Breakfast and a book about Sitting Bull. My daughter recently learned to read on her own and has become a reading machine. She'll come home with a stack of library books and knock them off in a few days, then she re-reads her old ones, and anything she can get a hold off. My son is just learning to read, but he loves books. He'll grab whatever and spend a long time looking at every page, examining every detail. He particularly likes to look at textbooks, so he'll head upstairs and bring down Principles of Neuroscience or Biochemistry and just leaf through them. Once my mom was visiting and she was wondering why we had cell biology textbooks in the kitchen and cookbooks in the upstairs hallway. He also likes to go over his own books, many of which he has memorized, and read them aloud.

Recently there have been a couple of books that my kids (and me) have been really digging. The first is called Moonshot by one of my favorite illustrators, Brian Floca. It's an incredibly illustrated book about the Apollo 11 mission to the moon. It comes complete with little mission diagrams at the beginning and then relates the story with ink and watercolor illustrations that are so well-done and so detailed that you can spend hours just looking at them and talking about them. I totally wish I had this book when I was growing up and everyone should get a copy.

 

From "Moonshot" by Brian Floca.

 

The second book is D'Aulaire's Book of Greek Myths by Ingri and Edgar d'Aulaire. This is an old book which I had when I was a kid. And it actually IS the copy I had as a kid so it's a bit fragile, but it is still in print and easy to find. This is a classic. It is a straightforward retelling of the Greek Myths, the language simplified for kids, but it still has all the gory details. It's full of these amazing, vivid pencil drawings that I still remember from when I was a younger. My daughter is particularly into this book. I think she likes the idea of someone coming up with a totally random alternative explanation for natural phenomena like echoes (a nymph who's voice was stolen by Hera and could only repeat what others say) and winter (happens because Persephone must visit Hades for three months every year, one for every pomegranate seed she ate while she was there), plus she likes the drawings. My son likes the fighting parts.

 

Aphrodite in D'Aulaire's Book of Greek Myths

 

The third book, I've been reading aloud to both kids, and its The Phantom Tollbooth by Norton Juster. I used to absolutely love this book when I was growing up. It's sort of a mix between Alice in Wonderland and The Hobbit, but different, and better. It's about a kid who gets a tollbooth in the mail, assembles it and drives through it and finds himself in an alternate land with a watch-dog named Tock, who is part dog and part watch and… well you just have to read it. But the writing is excellent and full of satire and plays on words and has these great pen and ink illustrations by Jules Feiffer and I'm having as much fun reading it to my kids as they are.

 

Dr. Dischord, from The Phantom Tollbooth, by Norton Juster

 

So that's what's going down book-wise at home. How about you, reader, any interesting books that have you and your family entertained, or that you really liked when you were younger? Happy reading!

6 responses so far

Clicker

Oct 05 2010 Published by under Uncategorized

So today there was a Big Important Faculty Meeting at my university and we were all supposed to go vote on some important issues of relevance to the faculty. To expedite the voting process, they decided to provide us all with clickers, so we could vote electronically. I was waiting in line, balancing my cookies, coffee and meeting handouts, watching people file into the auditorium, being handed a clicker as they walk in. When it's my turn to get my clicker, the woman handing them out looks at me and says, "Can I help you?".

She hadn't said a word to anyone ahead of me.

I said, "Well, I would like a clicker."

"Why?"

"For the meeting… so I can vote, on the important matter."

"No."

"No?!"

"Who are you?", she says.

I tell her my name and she repeats it slowly…

"I'm sorry, but no."

"What!?"

"What department are you in?"

I tell her the name of my department…she repeats it slowly, and starts eyeing me suspiciously.

By this point everyone in line behind me is starting to wonder what the hold-up is, I start to get all self conscious and sweaty.

"Can I get my clicker now?"

"What is your position?"

"Look, clicker lady, I know I look young, and am dressed like a grad student, but I am a faculty member here, I have a right to vote and I want my fucking clicker! And if you think, for a moment, that I am going to show you my university ID you can fucking forget it!"

OK, I didn't curse at her, but in my mind I did. She finally reluctantly gives me a clicker "I just needed to make sure". Yea right, clicker lady, screw you.

As I grumpily walk into the auditorium I hear the old professorial-looking dude who was behind me in line laughing hysterically.

7 responses so far

Zapoteca, Chichimeca or Tlaxcalteca?

Oct 05 2010 Published by under Uncategorized

So over at Lab Spaces we were asked the question: what would you be doing if you were not doing science?

This is tricky, because you can answer this in a couple of different ways. One is, if I were to quit science now, what would I do? The second is, if I had taken an alternative path what would it have been? The first is somewhat scary to answer, because honestly, I have no fucking idea. I'm sure I'd come up with something, but I'm not sure what. The second is far more fun to answer - and that's the one I'll answer here.

To me, the obvious answer would be to become… an archaeologist! Although my wife kindly pointed out that archaeology IS a science; but it's different enough from what I do, so it still counts. Growing up in Mexico City I was always fascinated by the fact that buried literally beneath my feet was a whole ancient civilization. That you could basically dig a deep enough hole and you would find evidence of this, just there, in the ground. Some subway stations even have pyramids inside them. I was obsessed with the National Anthropology Museum, one of the largest in the world, which houses artifacts from every important archaeological dig in Mexico, laying out all the different pre-columbian cultures in chronological order from the Olmecs all the way to the Aztecs. I made my mother take me there over and over again until I had the ginormous museum memorized - I knew the difference between the Toltects and the Chichimecas, the Mayans and the Zapotecs. I could tell their different artistic styles apart and had my favorite pieces. I was an archaeology geek. My favorite piece was the "Luchador Olmeca":

Luchador Olmeca - the kicking-est piece at the museum!

It was made by one of the oldest civilizations in Mexico and I liked it because it was so different from the others - it looked so modern as opposed to the highly stylized pieces around it. It also helped that it was on its own little alcove with a spotlight on it. But then again the jade Mayan mask was in its own little tunnel, and I still like the Olmec warrior more. I also dragged my mom to see every archaeological site within driving distance from Mexico City - the giant pyramids in Teotihuacán, the human-like pillars in Tula, and the pyramid of Cholula, near Puebla, which has a church built on top of it, and you can visit both the pyramid and the church. The pyramid also has these long tunnels carved into it so you can see the inside.

When I was a kid, at some point some utility workers discovered the ruins of the main Aztec temple, the templo mayor, in the center of Mexico City, just off the Zócalo. Tenochtitlán was the capital of the Aztec empire, and the present day Mexico City is built right on top. So it was quite amazing that they found these ruins after so many years, probably because the buildings in the center of the city are old colonial buildings and are historic on their own, so they don't usually knock down buildings in the ceter of the city to see what's underneath. In any case it was incredibly cool to visit the archaeological dig right in the city and finally be able to visit the site once it was mostly completed. One of the highlights was a giant stone, which they called the stone of the moon, with an engraving of Coyoxautli, who was dismembered by her brother, the god Huitzilopochtli (the baby warrior), after she tried to kill their mother. I somehow convinced my third grade teacher to have the class put on a play about Coyoxautli - it was a hit, at least with the class, not sure about the parents. This came on the heels of having a class field trip to see the Templo Mayor and having the docent describe to us how the Aztecs would sacrifice prisoners atop of the temple and throw down the bodies down these stairs (which we were standing next to) and then proceed to make pozole from their dismembered bodies for the priests to eat. That kind of stuff will make anyone want to become an archaeologist.

Human sacrifice at the ol' temple.

Another cool thing about the Templo Mayor is that you get to see what would have been inside the pyramid. Many pre-columbian cultures had a belief that the world would renew every 52 years. So they would bury all the old pyramids and temples and build new ones on top of the old ones. So if you dig inside a pyramid you will like see the foundations of all the previous cycles that preceded it. Again, a hidden civilization underneath the present one.

So there you have it - that's what I was sure I was going to study until pretty much high-school, when biology somehow became more interesting. I figured, biology is just as cool and I still get to dig holes in the ground and explore cool places, little did I know I'd end up in a field where no fieldwork is required. I really like what I currently do, and am as enthusiastic about my current work as I was into archaeology, but I have to admit that I am jealous of colleagues who get to do field work. It would be a nice break from the lab and office. For the last few summers I've spent a few weeks at a time teaching part of a course at the Marine Biological Lab at Woods Hole. And just walking through town I'm always longingly looking at the research vessels from the Oceanographic Institute getting outfitted for different trips, being loaded up with all sorts of scuba gear and little submarines and all sorts of sensors and radars mounted on top, and I think, wow... I want to do that!

This post was cross-posted at Lab Spaces.


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Lab Notebook

Oct 01 2010 Published by under Uncategorized

One of my least favorite things about my job (or rather one of my least favorite things in general) is dealing with bureaucracy. One of the worst bureaucracies at my university is the grants management office. In theory, they are the folks who are supposed to facilitate submission and management of grant proposals, by helping you navigate through the government and funding agency bureaucracies. However to do this they created their own bureaucracy, and since they are not always so knowledgeable about how many granting agencies work, you basically end up having to navigate two bureaucracies, the one from the funding agency and the one from the university grants office.

One of their supposed duties is to help manage your award once you get it, by setting up accounts, keeping track of funds, filing annual budget reports, etc. Once I got a call form a perplexed person from our grants office, asking me to justify why journal publication charges were being charged to the grant since they were not part of the proposed activities. I told him that I was sure that the granting agency was not expecting me to do the experiments, send them the results and call it a day. But he was still confused. "But why do you have to publish them, that's not a scientific activity?" He then asked me to call the program officer to see if this was an allowable charge. I told him that, no, that HE could call the program officer if he had a problem. So, he did, and of course it was fine to charge it to the grant. This just simply shows that many university grant administrators have no fucking clue about what we do and what they are supposedly administering.

I think the kicker was when the same guy called me another time asking the difference between lab notebooks and "regular" notebooks, and to justify why a purchase of lab notebooks and a stapler was being charged under lab supplies, since he thought these were office supplies and those were not allowable grant charges. I told them that they were lab supplies because they were being used in the lab. "So they are a special kind of notebook?" No, I said, they are regular notebooks in which we record our fucking science. He was still confused and wanted a written justification about the charges. So this is what I emailed him:

Lab notebooks are different from regular notebooks. They are characterized by having a protective hard cover to protect them from chemical spills, they also tend to have numbered pages and most importantly pages are bound to prevent loss of data in case a page gets ripped out. Keeping adequate documentation of experimental data and procedures is an essential part of the scientific process, and to call lab notebooks "general office supplies" reveals a deep-seated ignorance of the day-to-day process of doing science. If you had familiarity with what actually happens in the lab you might not be asking me these questions and making me waste my time rather than doing the job which I am paid for and which my funding pays for, which is actually doing science. As far as the stapler, much of our data generated is on the computer and often it is printed out and incorporated into the lab notebooks. Stapling is a good way to secure this data to the proper page. Alternative methods are taping and paperclipping, both of which are vastly inferior. Tape is non archival and might unstick over time and paper clips are unstable. Staples are a far more permanent method of doing this. Since there is no such thing as a "scientific grade" stapler, we are forced to buy this in a general office supply store. We would be very interested if you are able to find us a source of "scientific data staplers" which we can then use in the future in case our current one malfunctions.

He still wanted to see a lab notebook. So I asked one of my lab members to run across the street to the grants office and show him their notebook, complete with data and stapled bits. His response was "but it says in the cover that its a 'Composition Book' and not a 'Lab Notebook'. "  So I told him that I was not changing the grant allocation for those charges and that if he wanted to pay out of his own pocket for them the was welcome to do so. He hasn't bothered me since.

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