RNA measurements may yield less insight than assumed

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December 19, 2014

News, Origin Of Life

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The majority of RNA expression differences between individuals have no connection to the abundance of a corresponding protein, report scientists from the University of Chicago and Stanford University in Science on Dec. 18. The findings point to a yet-unidentified cellular mechanism that regulates gene expression and suggest studies that rely only on RNA measurements to characterize gene function require further analysis.

“The chief assumption for studies of RNA differences is that they ultimately reflect differences in an end product, which is protein,” said senior study author Yoav Gilad, PhD, professor of human genetics at the University of Chicago. “But it turns out in most cases this may not be true.”

Interesting, when we consider the high hopes placed in RNA world.

See also: Welcome to “RNA world,” the five-star hotel of origin-of-life theories

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Comments

I think it’s funny how certain people here rely almost entirely on scientists to “prove their point” via direct copy/paste, and yet these certain people are also so comfortable disagreeing with these scientists on evolution. Watching IDers trying to talk about science is like watching a dog chase its tail.AVS_{December 22, 2014
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Roles and post?translational regulation of cardiac class IIa histone deacetylase isoforms doi: 10.1113/jphysiol.2014.282442 Although considerable progress has been made in understanding the roles of post?translational modifications (PTMs) such as phosphorylation, oxidation and proteolytic cleavage in regulating class IIa HDAC localisation and function, more work is required to explore the contributions of other PTMs, such as ubiquitination and sumoylation, as well as potential cross?regulatory interactions between distinct PTMs and between class IIa and class I HDAC isoforms. http://jp.physoc.org/content/early/2014/11/27/jphysiol.2014.282442.abstractDionisio_{December 22, 2014
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Regulation of pannexin channels by post-translational modifications DOI: http://dx.doi.org/10.1016/j.febslet.2014.01.028 The large-pore channels formed by the pannexin family of proteins have been implicated in many physiological and pathophysiological functions, mainly through their ATP release function. However, a tight regulation of channel opening is necessary to modulate their function in vivo. Post-translational modifications have been postulated as some of the regulating mechanisms for Panx1, while Panx2 and Panx3 have not been as well characterized. Positive regulators include caspase cleavage to open Panx1 channels in apoptotic cells, and activation by Src family kinases via ionotropic receptors in neurons and macrophages. S-nitrosylation of cysteines has been shown to both inhibit and activate the Panx1 channel in different cell types. All three pannexins are N-glycosylated but to different levels of modification. Their diverse glycosylation appears to regulate cellular localization, intermixing, and may restrict their ability to function as inter-cellular channels. It is clear that our understanding of pannexin post-translational modification and their role in channel function regulation is still in its infancy even a decade after their discovery. http://www.febsletters.org/article/S0014-5793(14)00057-X/abstractDionisio_{December 22, 2014
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"I also think it’s somewhat amazing that someone could cover the “News” desk at this site for so long without picking up even the most elementary understanding of biology." Funny, people talking about biology here and yet not actually knowing or learning anything seems to be a common theme.AVS_{December 22, 2014
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Surf the Post-translational Modification Network of p53 Regulation doi:10.7150/ijbs.4283 Among the human genome, p53 is one of the first tumor suppressor genes to be discovered. It has a wide range of functions covering cell cycle control, apoptosis, genome integrity maintenance, metabolism, fertility, cellular reprogramming and autophagy. Although different possible underlying mechanisms for p53 regulation have been proposed for decades, none of them is conclusive. While much literature focuses on the importance of individual post-translational modifications, further explorations indicate a new layer of p53 coordination through the interplay of the modifications, which builds up a complex 'network'. This review focuses on the necessity, characteristics and mechanisms of the crosstalk among post-translational modifications and its effects on the precise and selective behavior of p53. Although relatively unified findings related to the functions of post-translational modifications (PTMs) were obtained in vitro, the in vivo data are somehow contradictory, indicating a variable behavior of p53. Overall, PTM exerts both general and distinctive role in regulating p53 behavior. However, the contradictions between the results of the in vitro and in vivo experiments call for more in-depth studies and raise some open problems concerning the real regulatory network of PTMs. Promising as the 'code' model of p53 PTM is, the following questions remain open such as: what is the real basis for the redundancy of the individual modifications in vivo? What is the real mechanism that regulates the context-dependent behavior of p53? How exactly is p53 involved in the regulation of one specific biological effect? How general is the mechanism for the regulation of PTM and in what way do they really cooperate? With the emergence of the novel functions regulated by p53, such as metabolism and nutrient stress responses, is there a possibility to revise the demarcations between different phenotypic outcomes to a more subtle one? In order to tackle these problems, numerous further investigations are required: (i) more precise and subtle distinction of the effects of the 'code' in molecular level instead of phenotypic level; (ii) discrimination between the direct and indirect effects of specific modifications; (iii) identification of the combinatorial behaviors of the modifications using high-throughput testing method; (iv) in situ observation of the dynamic changes of the modifications marks using more reliable and direct time-resolved method. Although there is still a long way to go, it is believed that the final decipherment of the p53 code will arrive in the near future. http://www.ijbs.com/v08p0672.htmDionisio_{December 22, 2014
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Dionisio at 73:
#61 hrun0815 So far researchers are working hard trying to figure out how all those complex mechanisms work and what they do. Not much talk about how all the required pieces of the puzzle got there, in the right place, at the right time, to begin with. We’re talking about a number of different mechanisms. Have you seen any serious documentation describing that anywhere lately?
Hah. This is utterly amusing. Let's revisit my post #32:
Ahh, Box, the silly ‘you can’t explain ultimate causes so how dare you point out that some statement is stupid’?
It looks like sooner or later 'ultimate causes' are the escape hatch for many. Rather than explaining why are are posting all those clipped research results, or rather than telling us if you agree that the OP is hopelessly mangled, or rather than telling us if you agree with WD400's explanation why these statements are stupid, or rather than clarifying which question of the many you posed you actually wanted to discuss, ... you now want to know how everything got there to begin with. This is particularly interesting in light of your post #38:
Any attempt to have a meaningful discussion between two irreconcilable worldview positions fails before it starts, unless both parties are really interested in having a serious discussion, where the ultimate goal is to find the truth about the discussed subject. Obviously that’s not what is happening in this case. Your interlocutor along with his comrades and fellow travelers don’t seem interested in any serious discussion. Their motivations are not clear, but they don’t seem to be serious. That’s why they point to obscure issues related to the OP.
hrun0815_{December 22, 2014
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Dionisio at 58:
#55 wd400 I was expecting hrun0815 to respond, but it’s nice to get a little help from a friend. Anyway, thank you for expressing your opinion on the given subject.
You are confused. This is not me getting 'help' other than that I don't have to type what WD400 typed in 55. WD400 was not expressing on opinion. He was making statements of fact. Do you dispute the facts? Or do you still maintain that you can't make a decision unless I read and respond to your questions first? By the way, I still don't know exactly which would be the key question that you are interested in.hrun0815_{December 22, 2014
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Dionisio at 67:
Read those reports carefully, paying attention to the words and their meaning. Also see post #66. It may answer some of your questions. Have a good week. Ciao amico !
I see, you can post a single post five times, but it is too difficult to use your own words to describe what you actually mean? Why are you posting all these references to investigations of post-transcriptional gene expression when the criticism is that the work does NOT suggest there is a as-of-yet unidentified mechanism? (By the way, I have no doubt that many aspects of gene regulation pre- or post-transcription have yet to be described, but this work does not suggest any such a thing.)hrun0815_{December 22, 2014
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Box at 64: I truly don't get any of the three statements you made here.hrun0815_{December 22, 2014
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WD400: So, when DNA damage is detected the cell cycle is arrested, the organism needn’t know why a given cell is damaged.
This reminds me of our short discussion, a little over a year ago, on Deinococcus radiodurans. I still hold that this is an extremely claer example of the need for a top-down explanation. Dionisio, you may be interested too. Maybe I have more time tomorrow. Have to run.Box_{December 22, 2014
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Box However it is also clear that there must also be a multitude of non-standard replies of an organism. Not really, cells/organisms can react to certain stimuli. So, when DNA damage is detected the cell cycle is arrested, the organism needn't know why a given cell is damaged. Other gene regulatory networks work in similar ways, which is why some biological responses are in fact counter-productive (inflamation response, auto-immune diesaes, so called super-normal stimuli...) Slijper's goat is very interesting, but as an example of developmental plasticity and interaction of genotype and environment, rather than evidnce for some elan vital directing an organism. If an organism could really "subject its parts to its will", then whence cancer? Couldn't the organism just tell those cells to stop dividing?wd400_{December 22, 2014
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#72 Box
WD400 #69, You are correct, I misunderstood your example.
Box, you better watch out. You just wrote that wd400 is correct and that you misunderstood his example. You were confused on a simple case of the widely known lac operon. That could happen to anyone, including me, but so far, it hasn't happen to me. I don't recall any instance where I had to backtrack when discussing anything with our 'n-D e' interlocutors. Maybe because I ask them more questions than they can answer? Dunno. But don't recall that happening yet. Your holistic approach makes sense, but perhaps it is too rigid in the way you present it. I try to use the available information, in the research reports, and go from there, asking all kinds of questions about the systems described by those reports. Soon the systemic characteristics pop up in the discussion. Basically, I take what is available, and move on from there. Soon the interrelationship with other parts appear as missing links. Remember we are not designing anything, but detecting design. In order to detect design in any system, the investigation doesn't have to be top-down. We could start from any part of the whole system, investigate how it functions in details and detect top-down design, because soon we'll notice signals coming from external sources and going to external recipients, hence we'll include that external object in the investigation and continue, till we detect another external source/recipient and so on. I believe the top-down design decisions were made a priori, when the whole system was setup. Do you see my point?Dionisio_{December 22, 2014
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#76 Box
I reject a mechanical or computerish concept of an organism. In my book an organism is a whole. And this whole is capable of downward causation – an organism can subject its parts to its will. What we see here is an organism that makes the best of what is available – IOW downward causation. I hold that this capability is inherent to life and cannot be explained bottom-up.
Where do you see any bottom-up implication in my reference to mechanisms? Did you notice that as they research the mechanisms, new issues appear all over?Dionisio_{December 22, 2014
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Box What we see in most research reports are descriptions of the current mechanisms, though still missing many details. What the interlocutors should produce is a link to any documentation containing a detailed description of hypothetical processes leading to setup the mechanisms that operate within the cells in all scenarios.Dionisio_{December 22, 2014
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Dionisio #74
Dionisio: The decision making processes are mostly embedded within the complex mechanisms, which are setup to handle many different situations, depending on the surrounding circumstances, including stochastic scenarios.
I reject a mechanical or computerish concept of an organism. In my book an organism is a whole. And this whole is capable of downward causation - an organism can subject its parts to its will. A striking example is the case of Slijper’s goat:
Slijper's two-legged goat was born with a congenital defect of the front legs so that it could not walk on all fours, and so it learned to walk and run by using its hind legs alone. Then, when it died an accidental death, Slijper dissected it and documented remarkable changes in muscle and bone, including striking changes in the bones of the hind legs; the leg muscles, including a greatly thickened and elongated gluteal tongue and an innovative arrangement of small tendons, a modified shape of the thoracic skeleton, and extensive modifications of the pelvis. [West-Eberhard]
What we see here is an organism that makes the best of what is available – IOW downward causation. I hold that this capability is inherent to life and cannot be explained bottom-up.
Dionisio: The real question is how were those complex mechanisms put into place and setup to begin with.
That is another important question, but in my opinion a less profound one.Box_{December 22, 2014
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hrun0815 Did you see post #57? I'm just curious. Thank you.Dionisio_{December 22, 2014
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Box, The decision making processes are mostly embedded within the complex mechanisms, which are setup to handle many different situations, depending on the surrounding circumstances, including stochastic scenarios. Scientists don't understand many of those mechanisms yet. That's what they're working hard on. As you can read in some reports, many things remain poorly understood. To make things worse, as they dig deeper into those mechanisms, new issues appear. The real question is how were those complex mechanisms put into place and setup to begin with. Has anyone seen that building process described in details? Can we have a link to that documentation? Do you see what I mean?Dionisio_{December 22, 2014
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#61 hrun0815 So far researchers are working hard trying to figure out how all those complex mechanisms work and what they do. Not much talk about how all the required pieces of the puzzle got there, in the right place, at the right time, to begin with. We're talking about a number of different mechanisms. Have you seen any serious documentation describing that anywhere lately?Dionisio_{December 22, 2014
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WD400 #69, You are correct, I misunderstood your example. Of course I do not wish to argue that there are no standard replies of an organism to certain environmental stimuli. It's clear that they exist. However it is also clear that there must also be a multitude of non-standard replies of an organism. Every organism will be confronted with new things and will be forced to improvise - IOW make decisions. Stephen L. Talbott put it like this:
But the same mystery plays out in the mature organism, which must continually work to maintain its normal form, as well as restore it when injured. It is difficult to bring oneself fully face to face with the enormity of this accomplishment. Scientists can damage tissues in endlessly creative ways that the organism has never confronted in its evolutionary history. Yet, so far as its resources allow, it mobilizes those resources, sets them in motion, and does what it has never done before, all in the interest of restoring a dynamic form and a functioning that the individual molecules and cells certainly cannot be said to “understand” or “have in view”. We can frame the problem of identity and context with this question: Where do we find the context and activity that, in whatever sense we choose to use the phrase, does “have in view” this restorative aim? Not an easy question. Yet the achievement is repeatedly carried through; an ever-adaptive intelligence comes into play somehow, and all those molecules and cells are quite capable of participating in and being caught up in the play.
Box_{December 22, 2014
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Dionisio: In the atheistic worldview paradigm, many times the cause-effect relationship may have nothing to do with responsibilities or decision making. They believe that many times things just happened, happen and will happen, depending on the surrounding circumstances. It’s that simple. It’s a belief system.
I'm no longer sure what their concept of life is. You seem to be perfectly right when you summarize: "things just happened, happen and will happen, depending on the surrounding circumstances". Thank you for your story.
Dionisio: English is not my first language.
I haven't noticed, but that implicit compliment doesn't hold much weight, because English is not my first language either. :)Box_{December 22, 2014
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Posttranslationally modified tubulins and other cytoskeletal proteins: their role in gametogenesis, oocyte maturation, fertilization and Pre-implantation embryo development. doi: 10.1007/978-1-4939-0817-2_4. The cytoskeleton, mainly consisting of microtubules, intermediate filaments and microfilaments, along with cytoskeleton associated and interconnecting proteins as well as the centrosome, plays enormously important roles in all stages of embryogenesis and undergoes significant changes to accommodate a diversity of cellular functions during gametogenesis, oocyte maturation, fertilization and pre-implantation embryo development. The varied functions of the cytoskeleton can be accomplished on many different levels, among which are a diversity of different posttranslational modifications (PTMs), chemical modifications that regulate activity, localization and interactions with other cellular molecules. PTMs of the cytoskeleton, including phosphorylation, glycosylation, ubiquitination, detyrosination/tyrosination, (poly)glutamylation and (poly)glycylation, acetylation, sumoylation, and palmitoylation, will be addressed in this chapter. Focus will be on (1) Microtubules, microtubule organizing centers (centrosomes), intermediate filaments, microfilaments and their PTMs; (2) Cytoskeletal functions and cytoskeletal PTMs during gametogenesis and oocyte maturation; and (3) Cytoskeletal functions and cytoskeletal PTMs during fertilization and pre-implantation embryo development. http://www.ncbi.nlm.nih.gov/pubmed/25030760Dionisio_{December 22, 2014
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I don't think you understand, the lac operon example shows how specific genes are expressed in response to the presence of lactose. If a decision is being made then the description I gave you is that decision.wd400_{December 22, 2014
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wd400, You described how gene expression can be switched from “off” to “on”. My question pertains to where the decision is made which gene to switch off or on and when. The right choice is crucial for the survival of any organism. One thing we seem to agree upon: the decision cannot be made by molecules. Why do we agree? From my part I would say: because molecules lack overview. They cannot be trusted not to make a mess of things.
wd400: what’s materialism got to do with it
Under materialism there are only molecules (fermions and bosons to be precise). So how come there isn't a mess?Box_{December 22, 2014
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#61 hrun0815 Read those reports carefully, paying attention to the words and their meaning. Also see post #66. It may answer some of your questions. Have a good week. Ciao amico !Dionisio_{December 22, 2014
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#60 Box In the atheistic worldview paradigm, many times the cause-effect relationship may have nothing to do with responsibilities or decision making. They believe that many times things just happened, happen and will happen, depending on the surrounding circumstances. It's that simple. It's a belief system. Their bottom line is that matter can be transformed into energy and vice versa, but it can't be created or destroyed. It always was and always will be. Then through some still unknown processes things got to their current state. If you ask the 'third way' folks, they would give you a different account of the hypothetical events, than the orthodox 'n-D e' folks would. There are as many variations of that fairytale story as promoters. :) I don't know which party line our interlocutors adhere to. Perhaps it's a hybrid of the 'n-D e' and the 'third way' approaches. It doesn't matter. At the end of the day it's all the same garbage. :) It's easy for me to wear an atheist hat. All I have to do is dust my old one. See, I've been there, done that, bought the shirt, wore it. Before I got my engineering degree, I had to pass a comprehensive exam on dialectic materialism and all that paraphernalia. It was a requirement. No excuses were accepted. Back then I believed all that garbage. They served it without ketchup or mustard, but it tasted good. Pathetic, but that's how it was. Now you see why these new 'baby' atheists don't impress me at all. In a way I could lecture them on their own stuff, but I really don't care much about it anymore. Now I've got much better things to do than to squander my limited time on senseless discussions with those confused folks. I just pray that some of them will see reality as is, not through the distorting lenses they wear now. :) I've taken online classes on biology, provided by some universities. Currently I'm studying some of the detailed reports coming out of research, in order to understand the detailed mechanisms associated with cell fate specification and determination. The idea is to develop educational software using the same interactive 3D technology used in computer games. Sometimes I look into other related issues, like neuroscience, regulatory networks, signaling pathways, etc. It's all very difficult and challenging, but highly fascinating. Now I'm using a combination of Mind Meister + Zotero + interconnected WordPress restricted web logs, in order to gather and organize the information, which is overwhelming. Many times I share some of the references to the resources here in this site, mostly in the 'third way' thread and a couple other threads. Sometimes I take breaks away from the intensive studying and come to this blog to see what's going on here and maybe get involve in a discussion for a short while, until I feel it's time to quit and go back to work on the real stuff. It's an interesting experience too. I've learned a few things from gpuccio and other folks here. Also got exposed to many different writing styles. English is not my first language. :) Kind regards.Dionisio_{December 22, 2014
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I described how the gene expression can be switched from "off" to "on". If you call that a "decision", then I don't see that any one molecule made it. If you don't call that a decision then the phenomenon you asked to be explained can be achieved without a decision being made. I don't think you really have trouble what a cell is, do you? And what's materialism got to do with it, unless ID is trying to back biology back further than I thought by resurrecting vitalism?wd400_{December 22, 2014
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WD400, hrun0815.
hrun0815: So of course I mean ONLY.
Does information behave in accord with rules of physical chemistry?
hrun0815: (...) the answer is the interactions of a bunch of different molecules present at a given time.
I fail to grasp why anyone would think that this constitutes an answer.
Box: (...) what is responsible for the decision to do so? The cell?

wd400: Sure, why not?
What is "the cell" under materialism? Explain why it can make decisions and its constituent molecules not.Box_{December 22, 2014
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“Suppose a unicellular organism. When certain proteins slide a spool along the DNA, exposing base pairs for gene expression, what is responsible for the decision to do so? The cell
Sure, why not? Take the classic example from Biochem101, the lac operon. You have DNA encoding a protein which (a) bind to region of DNA near som other genes, preventing RNA Pol from transcibing them and (b) can bind to an environmental chemical (a metabolic product of lactose). When it binds to lactose the shape is altered such that it no longer blocks expression of the other genes, and so the cell create mRNA from the rest of the lac genes. Nothing in that sounds like a decision molecule, but gene expression has started. (there's much more to the lac operon, but the example should serve to show how these things can work)wd400_{December 22, 2014
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Box: "If you mean “only according to rules of physical chemistry” then yours is a statement of faith. One could argue that at the moment of death molecules start acting (only) according to rules of physical chemistry and notably according to the second law, which informs us that things tend to descend into chaos." I have no idea why that would be a statement of faith? If you are alluding that there might be some 'immaterial' influence on molecules in addition to basic physical chemistry (and of course at a smaller level physics proper) then you are venturing outside to what science can investigate. So of course I mean ONLY. "Suppose a unicellular organism. When certain proteins slide a spool along the DNA, exposing base pairs for gene expression, what is responsible for the decision to do so? The cell?" It depends on what you mean by 'is responsible for the decision'. If you mean in the same way that we think of, for example humans making choices then the answer is nothing and nobody. If you mean 'how come this is happening at this time' then the answer is the interactions of a bunch of different molecules present at a given time. Remember that for example the same action can occur when just a few molecules happen to be in close proximity to each other and are present at the right concentration. "Indeed, but the vast majority of ID supporters is aware of the fact that information cannot make decisions." I'm failing completely to guess what you mean here. I think everybody agrees that information cannot make decisions. What this has to do with scientists, ID, or Systems Biology is not clear to me.hrun0815_{December 22, 2014
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Dionisio, I don't understand why exactly you are pointing to published aspects of post-transcriptional regulation? This is exactly the point: why do you think the data points to an as-of-yet undiscovered mode of regulation?hrun0815_{December 22, 2014
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