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Antibody affinity maturation as an engineering process (and other things)

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In Kairosfocus’ very good thread about functional complexity, I posted about antibody affinity maturation as an example of a very complex engineering process embedded in biological beings. Both Kairosfocus and Dionisio suggested that I could open a new thread to discuss the issue. When such good friends ask, I can only comply.  🙂

For lack of time, I will try to be very simple.

First of all, I paste here my original post (#6 in the original thread):

KF:

Thank you for the very good summary. Among many other certainly interesting discussions, we may tend to forget sometimes that functionally specified complex information is the central point in ID theory. You are very good at reminding that to all here.

I would like to suggest a very good example of multilevel functional complexity in biology, which is often overlooked. It is an old favourite of mine, the maturation of antibody affinity after the initial immunological response.

Dionisio has recently linked an article about a very recent paper. The paper is not free, but I invite all those interested to look at the figures and legends, which can be viewed here:

http://www.nature.com/nri/jour…..28_ft.html

The interesting point is that the whole process has been defined as “darwinian”, while it is the best known example of functional protein engineering embedded in a complex biological system.

In brief, the specific B cells which respond to the epitope (antigen) at the beginning of the process undergo a sequence of targeted mutations and specific selection, so that new cells with more efficient antibody DNA sequences can be selected and become memory cells or plasma cells.

The whole process takes place in the Germinative Center of lymph nodes, and involves (at least):

1) Specific B cells with a BCR (B cell receptor) which reacts to the external epitope.

2) Specific T helper cells

3) Antigen presenting cells (Follicular dendritic cell) which retain the original epitope (the external information) during the whole process, for specific intelligent selection of the results

4) Specific, controlled somatic hypermutation of the Variable region of the Ig genes, implemented by the following molecules (at least):

a) Activation-Induced (Cytidine) Deaminase (AID): a cytosine:guanine pair is directly mutated to a uracil:guanine mismatch.

b) DNA mismatch repair proteins: the uracil bases are removed by the repair enzyme, uracil-DNA glycosylase.

c) Error-prone DNA polymerases: they fill in the gap and create mutations.

5) The mutated clones are then “measured” by interaction with the epitope presented by the Follicular DC. The process is probably repeated in multiple steps, although it could also happen in one step.

6) New clones with reduced or lost affinity are directed to apoptosis.

7) New clones with higher affinity are selected and sustained by specific T helper cells.

In a few weeks, the process yields high affinity antibody producing B cells, in the form of plasma cells and memory cells.

You have it all here: molecular complexity, high control, multiple cellular interactions, irreducible complexity in tons, spacial and temporal organization, extremely efficient engineering. The process is so delicate that errors in it are probably the cause of many human lymphomas.

Now, that’s absolute evidence for Intelligent Design, if ever I saw it. :)

The most interesting answers came from Aurelio Smith and sparc. I have already answered AS’s comment in the original thread. Spark’s comments were more specific, so I paste them here  (#58 and 59):

You haven’t looked up evolution of AID, did you?

and

BTW, you let out the part of the B-cell development that occurs without any antigen. Lots of mutations, rearragements and selection. Where and how does ID interfere in these processes. Especially, in cases of man made synthetic artificial antigens that were not present 50 years ago?

OK, I will make just a couple of comments on these two points here, and let the rest to the discussion:

a) My point was not specifically about the evolution of the individual proteins in the system, but about the amazing complexity of the whole system. So, I have not done any detailed analysis of the individual proteins I quote. However, I will look at that aspect. As sparc seems aware of specific information about the evolution of AID, I invite him ot provide some references, and we can certainly go on from there.

b) I did not “let out” the part of the B-cell development. I simply focused on affinity maturation. However, the part sparc alludes to is extremely interesting too, so I will mention here in very general lines how it works, and why it is another wonderful example of intelligent engineering. And we can obviously discuss this second aspect too.

In brief, the adaptive immune system must solve the problem of reacting t a great number of potential antigens/epitope, which are not known in advance (I will use “epitope” from now on, because that is the immulogically active part of an antigen).

So, the two branches of the adaptive immune system (B system and T system) must be “prepared” to recognized possible epitopes coming from the outer world. They do that by a “sensor” which is the B cel receptor (BCR) in the B system, and the T cell receptor (TCR) in the T system.

Let’s focus the discussion on the B system.

To recognize the greatest number of possible epitopes (IOWs, of possible small biochemical configurations, mainly of proteins but also of other molecules), the B immune system builds what is usually known as the “basic repertoire”.Very simply, B cells underso a process of somatic genetic differentiation, essentially based on the recombination of VDJ genes, which generates a basic repertoire of different B clones with specific variable genes for the heavy and light chain, IOWs a specific BCR. In that sense, immune cells are different from other somatic cells, because they have a specific genetic recombination of the variable chains of the BCR (and therefore of the antibody that they will produce.

No one knows exactly how big that repertoire is in each individual, but new techniques are helping much in studying it quantitatively. From what I have read, I would say that the size is probably somewhere between 10^6 and 10^9 (more or less the total number of B cells in an organism).

Now, what is the purpose of this basic BCR (antibody) repertoire? We can consider it as a “network” of lower affinity antibodies covering in a loose way the space of possible epitope configurations. That repertoire is generated blindly (IOWs, without any information about specific antigens) by a process of sophisticated genetic engineering (VDJ recombination and other factors), which again uses random variation in a controlled way to generate diversity.

So, to sum up. two different complex algorithms act to ensure efficient immune responses.

1) The first one generates a “blind” repertoire of lower affinity antibodies covering as well as possible the whole space of configurations of possible epitopes.

2) The second one (affinity maturation) refines the affinity of the B cells selected in the primary response (from the basic repertoire) so that they become high affinity, specialized memory cells. This is the process I described in the beginning, in my post.

Both processes are wonderful examples of sophisticated engineering and irreducibly complex systems, and they are completely different one from the other. Both processes work together in sequence in a sophisticated and irreducibly complex meta-system.

Both use controlled random variation to generate diversity. The second process also uses intelligent selection based on existing information from the environment (the epitope conserved in the Follicular GC cell).

All that is very brief, and in no way covers the whole complexity of what is known. So, let’s open the discussion.

Comments
Dionisio @ 316
Unlike you, that young man doesn’t believe in the ‘strong’ AI hogwash that you defend so blindly.
I admire your persistence in denying that we are in agreement when it comes to 'strong' AI, but do you realize you come across as a dolt ?Me_Think
February 15, 2015
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gpuccio
I really hope that Piotr may join the discussion about the “number of valid points” I’ve “left unaddressed”.
What 'valid points'? In which thread or posts? Can't they just point to the posts and quote the text that contains those 'unaddressed valid points'? What about the questions in post #157 which no one else, except you, has dared to answer? If I were in your 'moderator' position, I would have removed the unnecessary comments posted by certain interlocutors. They don't add any value to the discussion and are only unnecessary distractions. Time is too precious to be squandered in senseless discussions. However, I respect your patience/tolerance, which I have publicly praised in more than one occasion in this blog, even though I don't agree with. I definitely lack those virtues. There are general discussions threads in this same blog where they could practice their mocking/scorning abilities if they want to. But they should stay out of serious biological discussions like this, where comments should stick to the topic of the OP (in this case the antibody affinity maturation or closely related issues). BTW, a while back someone wrote an intriguing comment raising the possibility that some of the whining interlocutors could be paid agents working for this blog, in order to entertain the onlookers/lurkers, to test our patience, to increase the traffic, or for some other unknown to me reasons. However, I don't find that intriguing suggestion easy to accept as real. But who knows? :)Dionisio
February 15, 2015
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Dionisio, Thank you for the comments. You know, I would never ban anyone from a discussion, but I still believe that any sentient person has a right to decide whom it is worthwhile to discuss with. I really hope that Piotr may join the discussion about the "number of valid points" I’ve "left unaddressed".gpuccio
February 15, 2015
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gpuccio Thank you for your insightful comments #326, 327. I'm looking into those papers you referenced.Dionisio
February 15, 2015
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gpuccio This discussion, following your insightful OP, has 337 posted comments and has been visited 954 times, so far, but still no one else, except you, has dared to answer the questions in post #157. All your 'nice' and 'polite' interlocutors have done so far is whine and bark up the wrong trees. Poor things. They appear frustrated by the recent avalanche of research reports that are shedding more light on the elaborate cellular/molecular choreographies orchestrated within biological systems. We should feel sympathy for their uncomfortable situation, which will only worsen, as dedicated scientists continue to work hard trying to figure out how the biological interwoven mechanisms function.Dionisio
February 15, 2015
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If I had actually been rude, I assure you I would have been banned already. The threshold for banning is quite low here, I would know. You being "more susceptible to what people say, rather than how they say it" hasn't proven true in our conversation.Curly Howard
February 15, 2015
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Piotr: I quote myself: "Now, I would like to ask our interlocutors: here is a selection, without any doubt. What is “natural” in it? Isn’t it obvious that the selection happens because an extremely complex, irreducibly complex system, with a very specific configuration which is in no way “natural”, is already present, ready to work as soon as a foreign antigen (the environmental information) enters the system? In this figure only, I count 4 different cell types and 7 different cell states, and about 15 different complex molecules implied in the interactions. And this is certainly a gross simplification. This is the very simple meaning of what I call “Intelligent Selection”: a selection which takes place because there is a very complex and specific system, explicitly configured for the function of effecting the selection itself." I suppose this is an argument. Right or wrong, it is an argument. You are free to comment and discuss.gpuccio
February 15, 2015
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Piotr: IMO, he has been worse than rude. I am a strange person, I am more susceptible to what people say, rather than to how they say it. Dishonest people disturb me more than insults (which, in a sense, can be fun :) ). You are an interlocutor that I respect deeply. If you have any points that you want to discuss with me, even borrowed from others, I will be happy to discuss them with you in depth, as we have done so many times. You should know that I never try to evade discussion, just to evade unpleasant people.gpuccio
February 15, 2015
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#331 Gpuccio, That looks a pretty evasive manoeuvre to an observer. Curly Howard may not mince words, but he hasn't been actually rude to you, and he has raised a number of valid points you've left unaddressed.Piotr
February 15, 2015
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I'm sorry to hear that pucci, but I guess I understand why you guys don't want to talk in-depth about biology. Same goes for you silver. You guys copy/paste some complicated biology, declare irreducible complexity, and trade high-fives. But when anybody tries to debate your claims, you are forced to demonstrate your lack of biological knowledge until ultimately you back off (if you're smart enough). Good chat guys, it's been fun.Curly Howard
February 15, 2015
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Typical mock/scorn ...
A solid indicator that the person has nothing to offer.Silver Asiatic
February 15, 2015
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Just for general knowledge: I rarely decide that I will no more discuss with someone, but if I do, I stick to it.gpuccio
February 15, 2015
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I've already made my argument. You pooped your pants and ran home after I gave you a little attitude. Have you found the irreducible core of anything yet?Curly Howard
February 15, 2015
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“Yeah guys, come look at how complex all this biology is that I’ve copy/pasted! That’s definitely irreducibly complex! Right?” -Typical IDer “doing science”
Typical mock/scorn for lack of any dignified argument.gpuccio
February 15, 2015
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"Yeah guys, come look at how complex all this biology is that I've copy/pasted! That's definitely irreducibly complex! Right?" -Typical IDer "doing science"Curly Howard
February 15, 2015
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Dionisio: From this paper: http://www.nature.com/nri/journal/vaop/ncurrent/pdf/nri3801.pdf an interesting summary:
B cell and T cell lineages are ancient Although our appreciation of the B cell and T cell pathways of lymphocyte development is fairly recent, this organizational scheme has proven to be a fundamental principle of the adaptive immune system in all vertebrates. All jawed vertebrates, including sharks and other cartilaginous fish, have genes encoding the B cell receptor (BCR), ?? and ?? T cell receptors (TCRs), MHC class I and II proteins, and recombination-activating gene 1 protein (RAG1) and RAG2 (REF. 78). An alternative adaptive immune system has been defined in the extant jawless vertebrates, lamprey and hagfish, which have none of the above cardinal elements used by jawed vertebrates to generate clonally diverse receptors for B cells and T cells79. Instead of the immunoglobulin-based components that are used by lymphocytes in jawed vertebrates to construct the BCR and the TCR, lymphocytes in the jawless vertebrates use leucine-rich repeat (LRR) sequences to construct variable lymphocyte receptors (VLRs) for antigen recognition (reviewed in REF. 80). Three lamprey VLR loci — VLRA, VLRB and VLRC — each contain an incomplete germline gene that is flanked by hundreds of different LRR-encoding sequences. During their development in a thymus-equivalent or haematopoietic region, lymphocytes use the flanking LRR sequences as templates to assemble mature VLR genes in a stepwise manner. The different VLR types are expressed in a clonally diverse manner by separate lymphocyte lineages. The lamprey VLRA+ and VLRC+ lymphocytes resemble thymus-derived ?? and ?? T cells, respectively, and VLRB+ lymphocytes closely resemble mammalian B cells and give rise to plasma cells that secrete VLRB antibodies81. The remarkable parallels between these lymphocyte lineages in jawless and jawed vertebrates suggest that the genetic programmes for the major lymphocyte differentiation pathways evolved in a common ancestor before the convergent evolution of the different types of antigen receptors in jawless and jawed vertebrates.
Emphasis added.gpuccio
February 15, 2015
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Dionisio: Wonderful links. The concept of immunological synapse is specially intriguing, reminding the strong similarities between the immune system and the nervous system. Here is a link: http://www.nature.com/nri/journal/v9/n11/fig_tab/nri2644_F3.html to a figure which very "simply" sums up the interactions (or at least, part of them) between Antigen presenting cell, T helper cell, B cell and dendritic cell in the lymph node at the time of the primary response, when the responsive B cell is selected and expanded. Now, I would like to ask our interlocutors: here is a selection, without any doubt. What is "natural" in it? Isn't it obvious that the selection happens because an extremely complex, irreducibly complex system, with a very specific configuration which is in no way "natural", is already present, ready to work as soon as a foreign antigen (the environmental information) enters the system? In this figure only, I count 4 different cell types and 7 different cell states, and about 15 different complex molecules implied in the interactions. And this is certainly a gross simplification. This is the very simple meaning of what I call "Intelligent Selection": a selection which takes place because there is a very complex and specific system, explicitly configured for the function of effecting the selection itself.gpuccio
February 15, 2015
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Integrity of the dendritic cell (DC) actin cytoskeleton is essential for T cell priming, but the underlying mechanisms are poorly understood. https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-548273Dionisio
February 15, 2015
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how the adhesion and signaling activities of active LFA-1 promote T cell priming? how mechanical forces at the IS affect T cell functions in vivo? https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-548271Dionisio
February 15, 2015
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Integrin-dependent interactions between T cells and antigen-presenting cells are vital for proper T cell activation, effector function, and memory. https://uncommondescent.com/intelligent-design/mystery-at-the-heart-of-life/#comment-548268Dionisio
February 15, 2015
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We might be missing a significant amount of information, some of the latest research conclusions may even be wrong, but it’s quite obvious that the core of evolutionary biology is correct. It is the best explanation for the diversity of life that we see today.
Evolutionary biology can't get beyond populations of prokaryotes given starting populations of prokaryotes. Not very good if you need to explain anything beyond prokaryotes.Joe
February 14, 2015
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So are you agreeing that the conclusion of the gauger paper (that they can calculate a specific "waiting time" and have also shown the impossibility of evolving protein 2 from protein 1 through probability) is completely unsupported? I mean if we're being honest here, the paper is a joke. Anyways, that we "know so little about something" is a fact of every scientific field of inquiry. Should they also make sure to tell students in every other science class about how little we actually know? I mean just learning the stuff is usually frustrating enough, nevermind telling the students that some of the details they're learning might not even be correct. Let's be realistic here. We might be missing a significant amount of information, some of the latest research conclusions may even be wrong, but it's quite obvious that the core of evolutionary biology is correct. It is the best explanation for the diversity of life that we see today. If I were to try to draw a parallel, it's like you are trying to say that our current understanding of cellular processes are all wrong because we don't know the functions of many proteins, we don't know how lipid rafts work and aren't even completely sure they exist, etc. The list goes on for miles, but we aren't questioning cell biology or claiming its teachers should make sure to tell students that there is a lot we don't know. Why is that? Have you run out of nonsensical thoughts about my hypothetical first immune system? I guess someone with little knowledge of the topic being discussed should shy away from talking about it. Better to keep your mouth shut and let people think you're a fool, then open it and remove all doubt, right? Box apparently took those words to heart a while ago.Curly Howard
February 14, 2015
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Curly
As you can see, there is an almost infinite number of factors that would go into calculating the probability of a mechanism evolving through the course of evolution.
Agreed.
I don’t think we’re even close to being able to accurately calculate the probability of something arising through evolution.
That's an honest reply. At present we can't calculate it and we're not even close. I'll just echo what Joe said above - this fact you point out here should be part of the teaching on evolutionary theory.Silver Asiatic
February 14, 2015
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What does that mean, Curly? What does "something arising through evolution" mean in a debate about whether or not evolution is telic or blind and unguided? Blind and unguided evolution can neither be modeled nor tested. And if we "simply don't know enough" then that is what needs to be told to students as opposed to stifling inquiry and baldly declaring it wasn't via intentional design.Joe
February 14, 2015
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Silver, how would an immune system that fights off all pathogens, not be better? Anyways, as I said, calculating probability of something occurring through evolution is an awful way to go about science. There are simply too many unknown factors to look at protein evolution in the way that gauged does in that paper. Sure you can look at the differences in two proteins that exist today and is the central idea of that paper. But evolution does not say that the second protein evolved from the first protein, it says that both proteins evolved from a common ancestor. So right off the bat, the core of the paper is based on falsehood. Also, the paper doesn't take into account the variety of mechanisms of mutation, instead it just assumes that mutations always occur one nucleotide at a time and that nothing effects their frequency. Returning to my example we can also look at it from the other side; there's also the possibility that the pathogen evolved to be killed by what was formerly a host species. This may seem counter-intuitive at first but you have to remember that the pathogen is evolving just as the host is. A change in the pathogen may be beneficial for its survival in another host or in the environment but allows for host recognition in the original host species. Here we have an increase in survival of both species along with the arrival of a very basic immune response that can undergo changes and refinement itself. As you can see, there is an almost infinite number of factors that would go into calculating the probability of a mechanism evolving through the course of evolution. Especially one that occurred hundreds of thousands of years ago in a species that no longer exists, but only has descendants who themselves have been evolving for hundreds of thousands of years. I don't think we're even close to being able to accurately calculate the probability of something arising through evolution. We simply don't know enough.Curly Howard
February 14, 2015
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Curly
Why do you think god created such a variety of immune systems? Was he using the good ol’ trial and error method as he put his creatures together? Why not build an immune system for us that allows us to fight off all the pathogens? That would e nice wouldn’t it? Then we wouldn’t have to give ourselves those “autism-causing vaccines” and get our flu shots every year. Food for thought.
Yes, food for thought and interesting questions. I have a lot of answers to "why would God ..." questions but that kind of discussion is theological and it requires first, a belief that God exists. After that, I'd need to know what you think about God - the nature of God, etc. In this case, you're thinking that an immune system that fights off all pathogens would be better. Or, no organisms that were ever vulnerable to any pathgens at all and would never require immune systems. Or there could be no evil or suffering in the world. Or, organisms could live on earth forever - no need for reproduction. God could populate the earth and leave it at that -- there are lots of possibilities. But you have to start with God and what you know about God to be able to discover answers. Evolution has similar problems. We have to recognize that most of it is driven by chance. That's why we look at probabilities. You'd need to estimate how many mutations it would require to achieve the new function (in your example the new protein co-opted the pre-existing regulatory system so that's not the most difficult challenge), and how long it would take to evolve that number of coordinated mutations to arise in a population. Some empirical studies have been done on this (Gauger & Axe, 2012) and they concluded that it takes a minimum of 7 or more mutations to change the function of a protein. The waiting time for that is 10^27 years (the universe is 10^10 years old). But more than that, someone could estimate how many coordinated mutations, in total, were required (factoring in the effect of negative mutations) to construct the entire immune system we saw illustrated in the OP. Each step requires X mutations. How many changes in the process have to occur simultaneously? If any, that speaks to irreducible complexity because it's unreasonable to assume that mutations will occur in a coordinated pattern. Eventually, you come up with some kind of probability that the process is the result of an unintelligent, unguided process. In the end, you can still say "it might have happened" - but some events are so incredibly improbable that it has to rely on the lucky of luckiest coincidences and it's more reasonable to conclude that "it's impossible".Silver Asiatic
February 14, 2015
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#314 Me_Think Unlike you, that young man doesn't believe in the 'strong' AI hogwash that you defend so blindly. He knows how to think by himself, hence he won't accept your senseless 'emotional robots' fairy tales.Dionisio
February 14, 2015
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Curly Howard:
By the way silver, trying to calculate the probability of something arising through the course of evolution is a pretty awful way of “doing science.”
You don't have anything else, Curly. You don't have any evidence. You don't have a model and you don't have any testable entailments. THAT is a very awful way of doing science.
Why not build an immune system for us that allows us to fight off all the pathogens? That would e nice wouldn’t it?
Not in a world designed for scientific discovery.Joe
February 14, 2015
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Dionisio @ 313
BTW, the young son of a friend of mine built an interesting Arduino-based machine, which he sells online very well, as a side hobby/business. That’s not his main business.
Please keep away from him ! Let him grow with real scientific acumen.Me_Think
February 14, 2015
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#312 Me_Think You're embarrassingly wrong again, buddy. Oh, well, what else is new? There's no need to Google anything or wait for anyone. If you would have read this thread more carefully, you should have noticed that gpuccio was the only person who dared to answer all those questions, and he did it correctly. None of your party comrades dared to even attempt to present counterarguments in response to gpuccio's insightful comments on that subject. Keep busy working on your Arduino entertainment. BTW, the young son of a friend of mine built an interesting Arduino-based machine, which he sells online very well, as a side hobby/business. That's not his main business.Dionisio
February 14, 2015
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