posted
I have a question about voltage gated ion channels. My professor hasn't been able to answer it, and neither has the internet(or at least my ability to find the answer on the internet hasn't turned anything up).
Here's the question. Why do the Na channels open and close more quickly than the K channels? Or maybe the important question is why do the K channels open more slowly than the Na channels? Regardless. It seems to me that this fact is of significant importance in the firing of an action potential, and I was somewhat baffled that the Professor didn't have an explanation for this.
The only attempt at any explanation in all my searches turns up "Sodium channels are more sensitive to voltage change than Potassium channels, and thus open more quickly", but that doesn't really answer anything for me.
Also, it seems reasonable from an evolutionary perspective that things would work this way, because these circumstances make it more likely that an action potential will fire(by allowing rapid depolarization), and then i guess because of the refractory period also keeps too many action potentials from being fired one right after that other(don't know if that's a good or bad thing). So if the channels didn't act the way they do I could imagine it'd be much more difficult to achieve action potentials.
But again, that doesn't explain the mechanism of how and why this happens.
Here's what I think is some relevant text from wikipedia:
quote:it is possible to surmise that when a potential difference is introduced over the membrane, the associated electromagnetic field induces a conformational change in the potassium channel. The conformational change distorts the shape of the channel proteins sufficiently such that the cavity, or channel, opens to admit ion influx or efflux to occur across the membrane, down its electrochemical gradient.
Voltage-gated sodium channels and calcium channels are made up of a single polypeptide with four homologous domains. Each domain contains 6 membrane spanning alpha helices. One of these helices, S4, is the voltage sensing helix. It has many positive charges such that a high positive charge outside the cell repels the helix - inducing a conformational change such that ions may flow through the channel. Potassium channels function in a similar way, with the exception that they are composed of four separate polypeptide chains, each comprising one domain
I'm assuming that the difference in time for opening and closing has to do with the different make up of each type of channel, in relation to the time it takes for the conformational change to occur. But my understanding of this subject drops of completely when talk of polypeptides, amino acids, proteins and the like start up. So I'm a bit lost.
I realize this is a really specific question. Anyone here up to it? I hate to questions to places that aren't Hatrack.
edit: also, there are different types of Potassium channels that don't open so slowly, so it's not just Potassium channels in general, but this specific type...delayed rectifier
An area reaches threshold, so voltage gated (Na+) channels open. More (Na+) channels to open (positive feedback) and causes the region depolarizes. Then voltage gated (K+) channels open. (K+) rushes out of the cell, and this causes repolarization.
quote:Here's the question. Why do the Na channels open and close more quickly than the K channels? Or maybe the important question is why do the K channels open more slowly than the Na channels?
Not sure if all this is 100% right, but it's what makes sense to me:
I think the depolarization of the membrane is what caused the K+ channels to open.
In other words, I'd assumed that there are two thresholds at work here.
1. The sodium threshold potential (around -55mV) which causes the Na+ channels to open, after which Na+ influx causes the membrane potential to become more positive; and
2. Some kind of "potassium threshold potential" which causes the K+ channels to open. This potential would be more positive than the sodium potential, so it could only be reached during depolarization due to Na+ influx.
So an initial stimulus causes the membrane to reach a threshold, which causes the Na channels to open. This pushes the membrane to a second threshold, which causes the K channels to open.
And a couple of things about channel closure: First, unlike opening, closure of the sodium and potassium channels does not depend on the membrane potential. During repolarization, the membrane will pass the "potassium threshold" before the "sodium threshold" on its way back down to the resting potential, so you'd expect the K+ channels to close first -- however, the inactivation of Na channels and closure of K channels is time dependent, not voltage dependent. I imagine this is due to the structure of each protein.
Does that make sense?
--j_k
[ January 28, 2009, 12:50 AM: Message edited by: James Tiberius Kirk ]
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I'm really speculating here, but one reason you might want to have K+ channels that open at different rates is to extend the amount of time that the membrane is permeable to K+. This graph relates the membrane potential to membrane permeabilities. The period after the "peak", where the membrane is permeable to K+ but not to Na, would cause hyperpolarization and the local refractory period (which prevents the action potential from going in the wrong direction).
posted
Strider, sounds like we're in ~the exact same class. Mine is called "neurobiology" and we're learning about the exact stuff you were talking about. I'll ask my professor/GSI and see if they have an answer other than "don't worry about it."
My inclination as to why the kinetics of the delayed rectifier voltage gated K+ channels is slower than the kinetics of Na+ is in the chemical structure of the channels. Maybe the potassium channels have more intramolecular interactions than Na+ which slows their response to voltage change. (Our professor always mentions the K+ channels as opening later due to their kinetics, and doesn't mention a difference in voltage sensitivity. But maybe he's keeping it simple for now. James, what you suggested would make an awful lot of sense...
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posted
Starsnuffer, mine is called "neurobiology of sensory systems". right now it's focusing mostly on resting potential/action potential/synaptic plasticity/etc...before moving along to specific sensory systems in humans, and apparently is going to end with specialized systems that have developed in certain animals.
James, your explanation makes sense from a general theoretical standpoint, but it doesn't specifically address my question. Take this example, there is a voltage change across the membrane. Na+ and K+ channels are activated. The Na+ channels will open more quickly than the K+ channels. My question is why the process takes longer with the K+ channels. And i'm curious as to what the mechanism is behind that. My guess, similar to Starsnuffer's(and what you say right at the end of your first post) is that it has something to do with the chemical structure of the gate and the time it takes for the conformation change to occur that opens or closes the gate. But I want to understand that in more detail.
quote:2. Some kind of "potassium threshold potential" which causes the K+ channels to open. This potential would be more positive than the sodium potential, so it could only be reached during depolarization due to Na+ influx.
I'm not sure this is how it works. From my understanding K+ channels are already being opened during depolarization, but due to the time delay of opening and the run away feedback loop of the Na+ channels, the membrane potential is being overwhelmed by Na+. The reason the depolarization stops so suddenly and shoots back down during hyperpolarization has to do with the fact that the Na+ channels become maximally open towards the peak, and the same voltage change that caused them open, causes them to close. The permeability of the membrane to Na+ is thus lowered. At the same time the K+ channels are now open and driving the membrane potential back down. And the reason we see the undershoot is because of the driving force towards Ks Nernst potential and the delay in the gate closing. This is where the Sodium-Potassium pump kicks in and bring the cell back to it's resting potential. Anyway, this is my general understanding of how things are working.
Everything is a bit fuzzy for me because I have no biology background, and am taking this course for other reasons. The professor let me in, but I'm spending most of my time catching up on basic cellular and molecular biology, and behavioral neuroscience stuff that i'm completely clueless about.
Let me know what your prof says Starsnuffer.
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posted
The short answer is that we don't know specifically why K+ opens slower than Na+. Both sodium and potassium are activated at the same 'threshold' level, but the potassium channel takes longer to open probably due to reaction kinetics of specific protein structures. It just takes longer (maybe the reaction is slightly less favorable with a lower delta G). The potassium channel activation is controlled by the alpha subunit and there are several subtypes which exist in different organisms and tissues. The type of alpha subunit affects the length of the delay between signal and opening. Sodium channels close on a time dependent manner. This is why the subthreshold stimulation prevents an action potential from occurring, because sodium channels will open (individually) then close and enter the refractory period. The potassium channel opening actually starts the decline, then the sodium channels begin to close. Also NaKATPase is active the whole time, but it is simply overwhelmed by the Na+ and K+ channels.
edited to add: I was reading through the citations of the wikipedia article on voltage gated potassium channels and I found one article that seemed to address your question. Energetics of Shaker k channels block by peptide inactivation From the abstract of this article
quote: This suggests that a rate limiting step in the inactivation process is the diffusion of the NH2-terminal domain towards the pore. The
Basically they removed the N-terminal end of the protein and replaced it with a bunch of synthetic proteins that had different number of positive charges. They found that as they altered the charge on the N-terminal end they were able to speed up the rate of the channel opening. This tells us that the difference between the time of opening of a sodium channel vs. a potassium channel is probably due to the number of positively charged amino acids in the N-terminal end of the alpha subunit of the protein.
posted
I don't know if the chemistry is such that this could matter, but potassium weighs about twice as much as sodium, atom for atom. So for the same ionisation and electric field, you expect sodium atoms to move twice as fast. But it sounds to me as though the elements are embedded in some huge and hairy protein structure, which probably renders this simplistic analysis moot. And that might mean that you'd have to do a full quantum-mechanical analysis of the exact open/close mechanism, which is very nontrivial for something the size of a biologically active molecule.
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posted
wow, thanks Audeo, I'm going to have to chew on that for a while, some of this is over my head.
One question:
quote:The potassium channel opening actually starts the decline, then the sodium channels begin to close.
Just so I have this straight in my head. Are you saying that the peak of action potential coincides with the opening of K+ channels? This starts hyperpolarization, only after which the sodium channels are closed? Wouldn't the slope of the graph of an action potential then change at some point during hyperpolarization if this was the case? Because the drop off would began with the opening of K, but then a steeper drop off would occur once Na isn't coming into to the cell anymore.
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posted
Actually I think the potassium channels open before the peak, then the sodium channels begin to close which causes the peak. Here is a diagram which shows the process as I understand it. However, there are some diagrams which show potassium channels closing after the peak. However the sodium flow simply dwarfs any affect the potassium flow might have until the sodium flow shuts down, so it again is probably not easy to prove either way, and it is only important to know what order your professor thinks it occurs in as he/she is the one writing your test.
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posted
I emailed a grad student in neuroscience that I know and here's her reply:
quote:I'm definitely no expert in electrophysiology or ion channels, but I think the person who mentioned protein structure is on the right track. K+ and Na+ channels have different fundamentally different structures - classic Na+ channels have a charged gate that opens in response to ion differences (as well as the inactivating gate). K+ channels have subunits made of entire proteins that move to open or close the channel, as I recall. So size and structural differences could easily account for the time it take a channel to open or close.
Secondly, "sensing" voltage is just accomplished by a charged part of the protein moving across an electric field. A weakly charged particle won't be as sensitive to voltage as a highly charged particle. I don't know what specific charges are found on ion channel subunits, but that undoubtedly plays a role in channel responses.
And finally - intro neurobiology textbooks are full of lies. Or maybe half-truths. There isn't really one type of Na+ or K+ channel, so if you see conflicting information about how channels behave, it might all be right. I don't know much about Na+ channels, but there are at least 70 different types of K+ subunits, and they range from low-voltage activated to high voltage-activated. It kind of makes sense - there's lots of reasons for different cells to respond differently to signals and to modulate activity. Even within one neuron, you might want to have different channel mixes in the axon or in the cell body.
If I find out anything more I'll let you know, but I'm pretty content with this/Audeo's answer as the Answer, with the chemistry to show it, is probably beyond my chemistry knowledge.
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posted
Have you done a search for K+ ion channel dynamics or K+ ion channel kinetics? Searching in google isn't likely to find anything worthwhile. Try web of science (isiknowledge.com), scifinder, or maybe pubmed.
This strikes me as something that's been looked at before. Although the papers you find are likely to be rather heavy going since this likely tied into all kinds of other things.
The simple chemistry answer to why it takes longer is that the activation barrier is larger. It's a reasonable assumption lacking any other information, that the time the actual conformation change takes is similar for both channel types and whether that is true or not that the time the actual change takes is significantly shorter than the time delay between Na+ and K+ channels opening.
Edit: Since it sounds like the K+ channel requires a series of changes to open, this could, but doesn't necessarily explain the difference. Still I think your question was what the biological reason for the delay, since presumable if it was helpful to go faster they would.
Thinking about this some more, I think your too focused on the minutia here.
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quote:Actually I think the potassium channels open before the peak, then the sodium channels begin to close which causes the peak.
gotchya, that contradicts though what you just said before, and is pretty much how I described things right?
quote:so it again is probably not easy to prove either way, and it is only important to know what order your professor thinks it occurs in as he/she is the one writing your test.
hah...so true.
quote:but I'm pretty content with this/Audeo's answer as the Answer
agreed Starsnuffer. I don't understand it perfectly, but i think i have the general idea behind the mechanism enough.
quote:Still I think your question was what the biological reason for the delay, since presumable if it was helpful to go faster they would.
Thinking about this some more, I think your too focused on the minutia here.
But it's the minutia I want to understand! I intuitively understand why it's better for the neurons that there is a delay, because otherwise the membrane potential wouldn't reach threshold because the K+ efflux would match or at least dampen the effect of the Na+ influx. this delay in essence allows the action potential to occur(if i'm thinking about all this correctly). I was just curious about what the difference was between the two types of gates that made them open at different speeds, and I think I understand the principle enough now to my satisfaction.
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posted
My background is in electrical engineering, but I'll wager of couple of hypotheses.
Sodium has a much higher electrical conductivity (and lower resistance) than Potassium. Though they both have outer electron in their outer valence level, Sodium will more readily accept and release electrons. Also, Potassium is denser, thus having a greater dielectric capacitance.
In the end, the electricity will travel a little slower through the Potassium substrate. We're talking very small fractions of a millisecond, but compared to the speed of the electrical reactions --- it's calculable . . . if not measurable.
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posted
Herblay in what form are you referring to with regards to the conductivities of sodium and potassium?
These are not pure metals, they are ions in the charged state. The channels being refered to are transmissions of positively charged particles. In nature you almost never ever, ever find either Potassium or Sodium in their solid metal forms. They never have that electron in their outer valence level unless they are forced to.
The standard electrode potentials of the two are
Na+ + e- <> Na Eo= -2.71V
K+ + e- <> K Eo= -2.931V
Calcium would also be of interest
Ca2+ + 2e- <> Ca Eo= -2.868V
Ca+ + e- <> Ca Eo= -3.80V
(Source: Corrrosion Handbook for engineers, Data taken from the CRC Handbook of Chem and Phys)
My first thought was the same as KoM. You've got a pretty significant size difference between the two ions. The bigger one is almost always going to move slower. Kinetic energy = 1/2mv^2
Regarding this:
quote: But it's the minutia I want to understand! I intuitively understand why it's better for the neurons that there is a delay, because otherwise the membrane potential wouldn't reach threshold because the K+ efflux would match or at least dampen the effect of the Na+ influx. this delay in essence allows the action potential to occur
Which came first? The membrane or the neuron? You are assuming it is "better" for the neuron. It could be that the neuron works that way because the transport membranes work that way. I realize other similar channels may be faster, but still I think you may be looking for a "why" when there is no why.
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posted
A thought on the "opening" and "closing" thing, also related to the size of the ions, but thinking about it slightly differently.
The ionic radii of Na+ is 1.16 angstroms The ionic radii of K+ is 1.52 angstroms
V= 4/3 pi*r^3
1.16 cubed is ~1.56 1.52 cubed is ~3.51
This means that the volume of a potassium ion is 225% larger than that of a sodium ion
The potassium channels have to expand more to accomodate the significantly larger volume of the potassium ion, which might give them a slower response time.
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posted
Maybe. Interestingly, if you didn't know, the specificity between sodium and potassium ion channels is at least partially dependent on their size.
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posted
Of course they don't have electrons in their outer valence level unless they are "forced to". But the difference of potential "forces them to" --- at least long enough to pass current. And whether they're charged ions or not doesn't effect their overall relative conductivity.
A doped semiconductor is not in it's pure state either. But the same argument could be made about the relation of one's conductivity to the other, especially if they are both in a relative defined state.
In the end, it's about conductivity and capacitance. The more mass, the higher capacitance and the slower discharge. The more conductive, the higher rate of electric discharge. Correct?
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Ionic current is different from regular current. It refers to whole ions as your charge carrier as opposed to holes.
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posted
Herblay, do you understand the differences between wet solution electrochemistry, and solid state electrical conductivity?
How do you feel about the Nernst equation?
Even solution electrochemistry is a vast oversimplification of what is going on here.
What is happening is a giant blob of a biochemical molecule is grabbing an actual potassium ion on one side of a membrane, and passing it through itself to spit it out on the other side of the membrane.
These potassium grabbing giant molecules swallow and spit, at a different speed then their sodium grabbing giant molecular cousins do. Strider wants to know why.
quote:Originally posted by Starsnuffer: Maybe. Interestingly, if you didn't know, the specificity between sodium and potassium ion channels is at least partially dependent on their size.
I'm not sure if I knew that or not, but it doesn't surprise me. I've actually done a bit of work in the past membrane biochemistry, although it was mostly related to photosynthesis.
Chem Es do deal with membrane separators, where osmotic pressure gradients are critical. Also have had to do quite a bit of chemical kinetics, so that is where I'm coming from most recently, plus I've had lots of experience dealing with "beasties" that like to corrode things.
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quote:Originally posted by Audeo: Both sodium and potassium are activated at the same 'threshold' level, but the potassium channel takes longer to open probably due to reaction kinetics of specific protein structures.
Despite this, I'm rather reluctant to change my mental paradigm. It's served me so well on exams...
--j_k will likely regret everything he's posted here if he goes to grad school
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posted
Bear with me, as I'm just familiarizing myself with the barest basics of neurobiology.
But according to the Hodgkin-Huxley model, capacitance stays the same regardless of the ion; and the system should function as an analogue of an electric RC circuit. But the ion channels are non-linear electric conductances, so the conductance is both voltage AND time dependant.
So, differences in the Nernst potential of the ion channels are similar to differing bias thresholds in a semiconductor. So the changes in threshold would affect the capacitive discharge of the lipid bilayer and the overall time domain dishcharge curve would be different based on the applied voltage. Even if that isn't the case, the RC circuit would be changed based on the Nernst potential, and that should change the circuit accordingly.
So, wouldn't you basically be seeing the equivalent of a shift in the discharge curve of an RC circuit? Therefore, the Nernst potential of the different channels would be changing the RC discharge time, causing slower discharge of electrical energy.
Or am I missing something basic?
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Herblay, my major problem with what you said was here
quote: Sodium has a much higher electrical conductivity (and lower resistance) than Potassium. Though they both have outer electron in their outer valence level, Sodium will more readily accept and release electrons. Also, Potassium is denser, thus having a greater dielectric capacitance.
The mathematical modelling part of Hodgkin Huxley is fine.
But what you said about potassium being denser and having a greater dilectric capacitance, has no relevance to this situation, as far as I can tell.
Or maybe this is me splitting hairs. When you said "denser" did you really mean that the potassium concentration is higher inside the cell than outside the cell?
There are the mathematical equations describing what happens, and then there is the the mechanism of what actually happens. It is the mechanism that dictates the kinetics, not the other way around, even though a lot of times the numbers are easier to comprehend.
I believe Strider is trying to get more at the mechanism than the math. Things like how wide the channel has to open, are more related to the mechanism of how the ion is transported, rather than the voltage differences themselves.
quote: These potassium grabbing giant molecules swallow and spit, at a different speed then their sodium grabbing giant molecular cousins do
This isn't quite the question posed. Rather both the sodium and potassium channel have a gate that closes them completely. The gate has a mechanism that can 'sense' a change in membrane potential. At a certain voltage level both gates start to open, but it takes the potassium channel several ms longer than sodium to open, even though they are activated at the same voltage/time. The relative flow of ions through the channels is less relevant, if only because each cell has the ability to adjust the number of channels available so that total ion permeability is not dependent on a single channel.
To strider:
quote: gotchya, that contradicts though what you just said before, and is pretty much how I described things right?
You had it right the first time, sorry about that. I was shooting from the cuff, and then I looked it up and corrected myself in the second post without reading your reply closely.
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quote:Which came first? The membrane or the neuron? You are assuming it is "better" for the neuron. It could be that the neuron works that way because the transport membranes work that way. I realize other similar channels may be faster, but still I think you may be looking for a "why" when there is no why.
I knew using the word "better" was a bad idea because it was implying something that I didn't mean. Basically, the fact that the ion channels work this way is a necessary condition for the firing of an action potential, right? What I meant by better, is that from an evolutionary perspective I can understand why things would have evolved the way they did, because neurons that could fire action potentials are transferring all sorts of important information around and more likely give the organism they exist in a survival advantage. Sure it's not a simple as all that, but the point is that I understand why potassium channels take longer to open than sodium from a philosophical point of view. I want to know the mechanisms behind it.
thanks for the link Banna, I'll take a look, but I don't know why you think I have any special ability to determine its quality. I have a very tenuous grasp on all this. My background is in computer engineering, and most of my reading over the last few years has been very laymans level cognitive science, once we start talking biochemistry my brain shuts down.
quote:Originally posted by Audeo:
quote: These potassium grabbing giant molecules swallow and spit, at a different speed then their sodium grabbing giant molecular cousins do
This isn't quite the question posed. Rather both the sodium and potassium channel have a gate that closes them completely. The gate has a mechanism that can 'sense' a change in membrane potential. At a certain voltage level both gates start to open, but it takes the potassium channel several ms longer than sodium to open, even though they are activated at the same voltage/time. The relative flow of ions through the channels is less relevant, if only because each cell has the ability to adjust the number of channels available so that total ion permeability is not dependent on a single channel.
Actually, I don't think she had it wrong at all. She's not talking specifically about the flow of ions, but about the mechanisms that are taking place to allow that flow to occur. That line is quoted somewhat out of context.
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posted
Also, just something I found interesting in relation to this conversation is that the sodium and potassium channels(as well as calcium channels) all stem from a common ancestor. Which implies even more strongly a strong selective process that led those channels to their current functional states.
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posted
Yeah, I hope my post above clarified, about "mechanism" vs. Math. In my field I understand enough of the math to know that the math expert isn't totally out to lunch and then let them crunch the differential equations. I can if I absolutely have to, but I'm not a mathemetician or computer science/computer engineering type and I will happily let them do it for me.
The most basic chemical kinetics math, start out from modelling reactions based on "fast steps" and "slow steps".
The reason why concentrations are so crucial, is because concentrations are a very real measure of how often two different chemicals will collide with each other and start to react. If they aren't concentrated enough, the chance of random collision drops exponentially. (Why all of your time decay curves are exponential.) Depending on your number of species involved in the reaction and your fast steps and your slow steps, you end up with series of first, second and even third order equations.
The math is identical to any other decay curve, but even though it is familiar math, (there's only so many PDEs) the reality of what is physically happening, isn't the same thing as what is physically happening in a circuit. The math is the same because the same mathematical concepts underpin our entire universe.
Osmotic pressure gradients actually exist across membranes whether or not the species is ionic. This principle is essential to membrane separation proceses. Membrane separators have now been refined to the point where they are small units that are now used to generate nitrogen used by some automotive shops to your tires by separating it from air.
But back to our neurons. Part of the complexity (and beauty) of this kind of biochemistry, is that you've got differential equations on top of differential equations.
You have all of the chemical kinetic equations, which are dependent on temperature and concentration, as well as all of your electricity differential equations layered in together. Activation energy and potential, somewhat ties the two together, but not completely. Fortuantely when you have differential equations on top of each other like this, they normally behave as a unified differential equation, and you don't necessarily *have* to deal with each of the underlying components. Dealing with the underlying ones, may not be necessary at all, to predict the greater system.
But in the long run, I suspect this is why I suspect Strider is getting a hand waving "kinetics" answer.
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