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Lifespan of connective tissue cells
This post is regarding a follow up on my initial post on "Properties and life cycle of chondrocytes and tenocytes".
I am elaborating on my question on the lifespan of tenocytes and chondrocytes.
From what I have read, tenocytes and chondrocytes form from mature stem cells, more specifically Mesenchymal stem cells. These cells can replicate through mitosis, and are present in the body in different tissues like bone marrow. These cells are the key in the regeneration of diverse tissues.
When the cells that inhabit tendons or cartilage die, do new MS cells travel to the tendon or cartilage area and diffentiate into a new tenocyte or chondrocyte? Are tenocytes and chondrocytes continuously replaced?

"This post is regarding a follow up on my initial post on "Properties and life cycle of chondrocytes and tenocytes". -> could you please add a link to this post? I couldn't find it. Thanks!

Not that I'm aware of. There isn't any blood flow to either tendons or cartilage as an adult, so the pathway for migration doesn't exist.
Tendons and cartilage are tissues composed of dead cells after their formation (the cartilage growth plates cease to exist in your teen and completely ossify, tendons I'm not sure on). Damage to tendons and cartilage is permanent, and can cause arthritis (when the cartilage is completely worn away and bone-on-bone contact occurs at joints).
Unlike living tissue, because tendon cells are dead, they are much, much easier to transplant - they do not produce any signaling molecules or have any surface proteins which would trigger an immune reaction for the vast majority of people. Shoulder surgeries often utilize this to the benefit of the patient, especially acromio-clavicular injuries.
If living cells are brought to the dead tissue, some repair is initiated, as I do recall a technique where surgeons tapped into the marrow of a patient's femur to stimulate cartilage reconstruction, but I also remember reading that the new cartilage formed wasn't the same hyaline cartilage produced by chondrocytes of the growth plate, so the repairs were temporary.
Artificially produced tendons do exist, and many are braided in order to foster interaction with host tissues (when you suffer from tendonitis, the tendon itself isn't repaired - the tissue around the tendon is repaired and strengthened). I'm not aware of any successful attempts to regrow tendons.
Attempts to grow cartilage in vitro have been successful, but re-introducing it into the body to produce a surface to articulate against has presented significant difficulties. Because we cannot (currently) reproduce biological articular surfaces, joint replacement often uses composites or surgical grade metals (both of which present problems of their own, but arthritis is not one as there's no living tissue to feel pain).

I am a bit puzzled by two of your statements, could you comment on them? 1) "There isn't any blood flow to either tendons or cartilage as an adult, so the pathway for migration doesn't exist.". Since when migration needs blood flow? Plenty of cells (neurons, for instance) migrate using the extracellular matrix as a guide. 2) "Unlike living tissue, because tendon cells are dead [...] they do not produce any signaling molecules or have any surface proteins which would trigger an immune reaction": so... you mean collagen and proteoglycanes are not allergenic?

Also, adding some references will improve the quality of the answer.

@nico
The normal route for cellular migration is the circulatory system.
Collagen almost never produces an allergic reaction. Proteoglycans vary.
As an update: I was apparently out of date with tendons. Tenocytes do perform repairs, but it might take a while (as-in, measured over months or years for significant damage). -Riley, G. (2004). "The pathogenesis of tendinopathy. A molecular perspective"
Cartilage would be repaired by chondrocytes, which inhabit the lacunae of bones. Cartilage lacks lacunae. Chondrocytes, literally, cannot reach damaged cartilage unless the damage reaches bone.

I beg to differ on the circulatory system being the normal route for cellular migration. It is one of the routes for migration, surely, if you think of the immune system but, again, there are counterexamples, neuronal migration being probably the most obvious.

Then you're free to differ. To the limit of my knowledge the normal route for cell migration throughout the body is either the circulatory or lympathic systems, as those systems span the entire body. If the majority of cells use a separate route, then I am not aware of it. Neurons - as much "migration" as occurs with them after adulthood - are special cells to begin with. I'm not saying you're wrong, but I'm unaware of other major routes.

Just to clarify, what I disagree on is the term normal. For neurons you may want to have a look at the rostral migratory stream

Then define the most common route of cellular migration in the human body as you see it.
I'm not saying you're wrong, but just repeating "Neurons do it differently" isn't the same as proving I'm wrong.

I just think there are different routes, I do not like the use of the term normal because it implies the others are "anormal". Semantics, probably. Anyway, I would say that, for instance, during development many cells do not migrate through bloodstream, but rather in the extracellular matrix of the tissue.

Anyway, my point is: you cannot say that tenocytes cannot migrate in the tendons BECAUSE there is no blood vessels. This is obviously false, as there are counterexamples of cells that migrate without needing blood vessels. New cells may as well be born from locally present stem cells, as it is the case in other tissues.

Allow me a moment to be just as pedantic as you. If you're talking specifically about tenocytes, and you are right above, then the vascular system is the ONLY common path for migration out of the bone marrow from their mesenchymal stem cell progenitors. There aren't any stem cells in the somatic muscle tissue. They just don't exist, otherwise tendons might heal much, much faster.
For the rest of your tangent about cellular migratory paths, I don't see how they relate to the original question - much less how they're anything other than your opinion when you can't back up your answers.

Come on, do not take it personally. What you are saying is exactly why I am asking for references. Your answer just says: "there is no blood stream hence cell cannot migrate". Sorry, but I consider that a bad explanation. Progenitors could get near the tendon via bloodstream and then migrate through the collagen fiber. Immune cells do that, for instance during tendinitis. I am not being pedantic, but -because I am far from being an expert in tendons- I do need references to decide how to vote on your answer. If you are willing to answer the question the burden of proof is on you, not on me.

You have the burden of proof. You do not contest my initial assessment of whether or not tendons/cartilage are capable of repair, but my use of the word 'normal'. That's a separate debate which you started. You continued by naming a single cell type (Neurons) which use an alternate method, and failed to provide any other examples while it's common knowledge that the vascular system ferries Erythrocytes, Leukocytes, and Platelets all the time. Then your example of progenitor migration (which doesn't happen anyways) still uses the vascular system to migrate to the tendon.

If that's not the definition of pedantic, I don't know what is, and I'm not debating the topic with someone I don't believe has a firm grasp on basic human anatomy and physiology.

wow, we are down to personal offense now. How poor. By the way, I have a PhD in physiology so, yes, I have a basic grasp on it. Anyway, I will be happy to remove my downvote when you will add some proper references. Have a good day.

let us continue this discussion in chat


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How do I create a probe for in situ hybridization?
I tried to make the probe several times but it failed again and again. It usually turns out that the probe after hydrolysis is very very short (maybe around 50nt). I did not check the RNA before hydrolysis except last time. However, I saw a band (though very weak) last time, but it still produce very very short probe after hydrolysis.I use Sp6 polymerase to synthesize RNA, and the original length of the DNA is 1.5kb. My expected length after hydrolysis is 500nt.
I'm guessing maybe it's the phenol contamination of the phenol:chloroform extraction step because my 260/280 value is low (around 1.6-1.7), and my 260/230 is also low, which is like 1.6-1.8. Also the peak is not at 260, it's almost at 270.

I'm not all that familiar with in situ hybridization, but I'm missing a few details here. How did you synthesize the RNA probe (PCR, I assume?), and how long should it be? And that RNA is shorter than expected even before you use it in the in situ hybridization, do I understand that correctly?

50bp does not sound that short for in situ...

I had large noise with such probe, but I can see the signal. However, I need to quantify the signal so I need better probe

I dont understand what you mean by hydrolysis in this context.
The way to go about is:

Clone the DNA, that will give rise to the probe, downstream of T7 (or any other) promoter
Linearize this plasmid by digesting at (or ahead of) the 3' of cloning site
Set up an In-vitro Transcription reaction with T7 polymerase (or whatever corresponds to the promoter you used)
Precipitate and purify the RNA (you can use DNAseI to get rid of the DNA).
To check the RNA size: mix ~2$\mu$l of RNA (less or more depending on your yield) with equal volume of 2x RNA loading dye (contains formamide 95%, EDTA, SDS, and the dyes).
Heat at 85⁰C for 5min. Let it cool and run in 1% TAE/TBE-agarose gel (no need to make MOPS-Formaldehyde gel)
dsDNA ladder wont be very accurate but may be used for size estimation (if linear, the mobility of dsDNA and ssDNA/RNA wont be very different. Formamide treatment keeps the RNA linear). Use ssDNA or RNA ladder for better accuracy.

Btw.. the absorbance ratios mentioned are okay.. you don't need an RNA of supreme quality for this application (in fact this suffices for most experiments)

Later I found out that the length of RNA read from the gel is not trustworthy. I guess it's because the RNA is in hybridyzation solution that even when it's running on the gel, it cannot reflect the actually length of the probe. The only way to test the probe quality is to do the in situ.
For the pheno contamination problem, I think it's a separate problem of myself. Once RNA can be synthesized in vitro, it means there should not be pheno contamination.

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Predictable microchimerism
I read in New Scientist recently that microchimerism occurs between previously born siblings and grandparents, not just the mother.
Do we know which parts of the genome are likely to be transferred? Is it possible, given a genetic sample of relatives, to predict which genetic traits might be transferred by microchimerism?

Microchimerism, as defined by wiki, is the presence of a small number of cells in an organism that are genetically distinct, and originated from a separate organism. The example they give is an unborn child and the mother can 'swap' immune cells, and retain these for many years.
Your question about which parts of the genome are transferred is therefore not really valid, because the cells are transferred, rather than bits of genetic information. Therefore 'traits' are not transferred either, but distinct immune cell lineages can be transferred and persist - this can confer an immune advantage, so this 'trait' could be said to have transferred, but no genetic information has been swapped by the cells.
Although it does not say it on wiki, this presumably only applies to cells of the same species, but a different organism, otherwise infections would also count.

Update 20th July 2012
The New Scientist article you have linked to in the comments can be found online here.
It says that we may be more microchimeric than we imagined, because a recent study in Blood found that half of the mothers studied were positive for male T-cells (Dierselhuis, 2012). The authors note that it is remarkable that the immune cells from neither the parent or the offspring attack the other, and that this may explain the observation that siblings make better donors.
Another finding that mothers are found positive for cells from their own mothers, and even their own grandmothers, and that the cell numbers increase during pregnancy (due to clonal expansion of the inherited immune cells) reinforces the opinion that microchimerism is commonplace (Gammill, 2011).
So to reiterate, immune cells can be inherited from your mother, and she may also end up with leukocytes from her offspring, which can in turn be passed on. This is a very fascinating way in which the immune system seems even more complex and helpful.

This seems to be counter to what the article I read said. They indicated that genetic material from siblings and a grandparent was found in children.

In a sample of the blood it is not uncommon to find fragments of DNA. These may well be from a parent or grandparent, but the DNA (as I understand it) is 'left over' from (e.g.) an apoptosis event, rather than found in the host cells. It is also possible to find fragments of bacterial DNA in circulating blood, but this does not imply that the DNA has been incorporated into the hosts, and therefore no traits have been transferred.

I remember it mentioning increased risk of transfer of diseases, so I'll dig out the article tonight and post an excerpt.

@Polynomial I'd be interested, too.  I did a fairly extensive search and only found a NS article on Marmosets from 2007.  Is that the one that you found?

@jonsca Nope, this was recent, perhaps a month or so old. I completely forgot about this last night, but I'll try to remember to dig out the article tonight.

@Polynomial my apologies if I have misinterpreted your question! A link to the article would definitely help resolve this :) thanks.

Found the article! It's in edition #2869, on page 12. Got a jpeg of it here.

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What is the proper quick freezing /snap freezing protocol for pancreatic tissue?
I would like to do a quick freeze on pancreas from mice. I want to then make sections (30 µm thick).  The idea is to preserve a fluorescent staining done in vivo.
I do not know if I should place my fresh tissue directly into liquid nitrogen, then embed the tissue in OCT, and then freeze everything in cold isopentane?
Or do I have to embed the fresh tissue in OCT first, prior to putting everything in nitrogen?
Or is there another protocol to do quick freezing in order to do sectioning?

Embed the tissue in OCT first (roughly cut to remove everything what is not needed) and the flash freeze it. Then you can cut your sections.
The first protocol describes it in detail, the second gives some additional information:

Protocol for Preparation of Frozen Tissues for Sectioning
Tissue freezing methods for cryostat sectioning

do not place it directly in the N2 unless it's clean. and high grade liquid N2 costs an arm and leg. put the tissue in the oct in a conical vial and that in the N2. don't use polycarbonate it may crack. check with the OCT manufacturers suggestions first though. I've followed this BD protocol before
http://www.bdbiosciences.com/resources/protocols/frozen_tissue.jsp


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How does Yeast-two-hybrid detect interactions between several proteins in one experiment?
I am trying to understand the Y2H screening method. I can understand how we can check if two specific proteins interact with each other. For example, if we want to check whether protein A and protein B interact, we fuse A with the Activation Domain (AD) of a transcription factor and B with the Binding Domain (BD) of another transcription factor. When the two fusion proteins are transfected into a yeast cell, the reporter gene is expressed only if the AD and the BD get together and form a complete transcription factor and that happens only if proteins A and B interact with each other.
However, I have seen claims that Y2H is a high throughput system, i.e., it can be used to detect several interactions at once. But most articles online that attempt to describe it, seem vague to me.
For example, suppose I fuse the "bait" protein to the BD and several different cDNA's to the AD and let the yeast grow. Next, I observe that the reporter gene is expressed. Doesn't this observation only imply that there exists some protein from the cDNA library that interacts with our bait protein? How do we know exactly which of the target proteins have interacted with the bait and resulted in the expression of the reporter gene?

You use a library of many yeast in which each expresses only one target, or 'prey' protein. Then you grow each yeast colony separately, for example in different wells.
It's definitely not a high-throughput method if you do it the old-fashioned way, i.e. making your own yeast library, or if you do it with only a few targets.  But these days you can buy pre-made yeast libraries with thousands of target proteins, each separated into a well on a plate, then you run the experiment for all the targets simultaneously. With a visible marker you can then easily see which wells have produced successful interactions, and thus which targets interacted with your bait.

Thanks for the answer. Is there a picture available somewhere that shows what the wells on a plate look like?

Here's an example taken from this Busch et al (2007) paper.


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Why is the human body able to repair a broken bone and not a heart muscle?
The human body can repair skin/organ laceration, fractures, even repair nerves - albeit the duration and rate of recovery differ.
Why can the heart muscles not repair themselves?

I think you may need to specify to what degree of damage... increased muscle strength is (in part) achieved by damage to the old tissue, which is then repaired by immune and stem cells. At least, that's how skeletal muscle works. This differs massively from the kind of damage that impairs the function of that muscle/bone/whatever (e.g. a break/fracture). You can rest and recover from a broken bone. You die from a 'broken' heart (excuse the expression). I will be very interested to see an in depth answer.

Erm. I don't have an answer )+: just lots of inane questions

Heart muscles aren't the only exception: think of neurons. Once they're dead, they're gone for good.

@LanceLafontaine: Wasn't there an article online that said neurons regenerate - albeit at an extremely slow rate. The magnitude of regeneration was something like 1mm , but i forget the unit of time over which this growth was determined.

Part of the answer may be(*) that in bone, you have still stem cells everywhere (blood capillaries that grow until checked and osteoblasts), i.e., also in the vicinity of the wound. The same applies to skin, by the way, where the epidermis continues to produce skin layers until eternity. This facilitates repair enormously, as new cells won't have to move far to take their place.
Contrast this with heart or spinal cord, where the placement of the cells took place in early development when distances were small and most cells were undifferentiated. Also, no tissue like epidermis was left in the vicinity that could act as a near source of new cells.
(*) I said "may be" because 1. I have no ref for this, and 2. I have no idea to what extent other factors are involved. I would be thankful for counterexamples.

+1 for the suggestion. At the same time I must beg to differ to the extent that some repair happens in the eye - an organ which develops early; why should the heart then be different?

The heart does have stem cells in it, and there is cell turnover in the heart, of about 1% per year. Which is much slower than your skin, but not nothing. This allows your heart to grow during your life, and remodel itself slightly to become stronger/more efficient when you get in shape.
The heart can repair itself, when damaged it doesn't simply stay damaged. Unfortunately, the 'repair' leaves particularly useless scar tissue. After a heart attack, the dead muscle does repair itself, but very poorly. This 'scar' barely contracts, and isn't as strong as the heart wall around it.
This is mostly a function of the very specialized heart myocytes, and the evolutionary (relative) uselessness of being able to regenerate your heart after injury. In the wild, if your heart was injured, you were probably dead.

Part of the answer is in fact extremely simple: coronary arteries (irrigating the heart muscle) are terminal vessels. This means that when a coronary artery sustains damage, the area it was irrigating becomes biologically dead with a very limited potential for recovery. The affected area turns to fibrous tissue produced by cells with much lower oxygen requirements than cardiomyocytes.
A fractured bone is not dead at all, in most cases. Put a fracture under a microscope, and you will see plenty of cells performing heavy duty. That is because the area, although damaged, still receives nutrients and at least some blood.
However, there are special cases:

bone that is terminally vascularized: such bone regions will die when fractured, since they receive no more nutrients and oxygen. The classic example is fracture of the scaphoid bone in the wrist. Some types of fracture in this bone shear the nourishing artery, and the bone dies off instead of healing.
slowly progressive ischemia due to atherosclerosis: when a coronary artery progressively gets clogged instead of this being a sudden event, the cells inside the danger territory secrete messengers that will activate new vessel growth. This phenomenon is called collateralization, and will allow a subset of the cells at risk to survive when the coronary artery gets completely clogged.

Now about the stem cell issue: I seem to remember that stem cells do exist in the heart, but this is less pertinent in this case, since even stem cells need oxygen and nutrients to survive.

Ignoring the actual physiological mechanism(s) for why, consider that from a natural selection point of view, there probably isn't as much incentive for a body to heal itself of a condition that largely affects post-reproduction age individuals. While healing a broken bone would likely allow a young person to further reproduce, healing a heart ailment would have a disproportionately lower chance of doing so.

It would be great if you add some references for your response!

In simple terms, heart injury, most likely to be myocardial infarction (heart attack) involves death of the vascular heart tissue. Thus the word infarction. Death of a tissue just simply leads to the production of a fibrous scar. Therefore the heart muscle cannot repair that area of injury to 100% as before.

It would be great if you could add references to your response! From what I can tell here (http://en.wikipedia.org/wiki/Chest_injury), cardiac injury can be caused by several events, which are not all heart attacks, such as Pericardial tamponade.


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How do the pharmacodynamics of the NSAIDs differ and are there "resistant" COX phenotypes?
I know that the non-steroidal anti-inflammatory drugs (e.g., aspirin, ibuprofen, naproxen) affect the enzymes cyclooxygenase (types I and II).
Is there any difference in the degree to which these drugs manipulate/inhibit the enzymes (I assume their affinities for COX-1 and COX-2 are at least somewhat different)?  Is there any evidence as to whether the the NSAIDs collect in certain areas of the body in a compartmental fashion?
Are there differences in fat solubility, etc., between the different drugs?
Finally, are there any known phenotypes of COX-1 and COX-2 enzymes that are present in the general population that affect the ability of these drugs to act?

What do you mean by collect in certain areas of the body in a compartmental fashion?

@Masi Thanks for your answer!  I meant whether there were differences in fat solubility, etc., between the different drugs.

Thank you for your comment! I will look for the fat metabolism thing next week. Your updated question will have completely different answer than the old one.

This is a draft.
How do the pharmacodynamics of the NSAIDs differ - -?
Merck's manual ch. 36 to start little bit at an introductory level:

The anti-inflammatory activity of the NSAIDs is mediated chiefly
  through inhibition of biosynthesis of prostaglandins (Figure 36–2).
  Various NSAIDs have additional possible mechanisms of action,
  including inhibition of chemotaxis, down-regulation of interleukin-1
  production, decreased production of free radicals and superoxide,
  and interference with calcium-mediated intracellular events.  Aspirin
  irreversibly acetylates and blocks platelet cyclooxygenase, while most
  non-COX-selective NSAIDs are reversible inhibitors.

and see the coming answer below.
These questions should be answered together.
To split them can be confusing.
Is there any difference in the degree to which these drugs manipulate/inhibit the enzymes (I assume their affinities for COX-1 and COX-2 are at least somewhat different)?
Please, see ch 1.03.3 in Comprehensive Natural Products II: Chemistry and Biology: 10 Volume Set:

and their conclusions about the structure

and please, see the whole chapter of the book, since its about the topic - and I think good one.
From Katzung et al.

Selectivity for COX-1 versus COX-2 is variable and incomplete for
  the older NSAIDs, but many selective COX-2 inhibitors have been
  synthesized. The selective COX-2 inhibitors do not affect platelet
  function at their usual doses.
On the other hand, selective COX-2 inhibitors may increase the
  incidence of edema and hypertension.
To varying degrees, all newer NSAIDs are analgesic, anti-inflammatory, and antipyretic, and all (except the COX-2- selective
  agents and the nonacetylated salicylates) inhibit platelet
  aggregation. NSAIDs are all gastric irritants and can be associated
  with gastrointestinal ulcers and bleeds as well, although as a group
  the newer agents tend to cause less gas- trointestinal irritation than
  aspirin.

In short, there must be differences to which these drugs manipulate/inhibit the enzymes.
Please, see

Selinsky BS, Gupta K, Sharkey CT, Loll PJ. Structural analysis of
NSAID binding by prostaglandin H2 synthase: time-dependent and time
independent inhibitors elicit identical enzyme conformations. Biochemistry 40, 5172–5180 (2001).

Defining the COX Inhibitor Selectivity of NSAIDs: Implications for Understanding Toxicity. Expert Rev Clin Pharmacol. 2010;3(6):769-776. And see the chapter Expert Commentary which locates at the end of the publication there:

Not withstanding the caveats on the merit of IC50 values, in vitro
  analyses of COX-1 and COX-2 selectivity of NSAIDs has driven the
  concept that inhibition of COX-1 explains the predominant reduction in
  synthesis of mucosal protective PGs and hence gastrointestinal
  toxicity of NSAIDs relative to COX-2 inhibition, which plays a role in
  ulcer healin

Merck's manual chapter 36

The discovery of two cyclooxygenase isoforms (COX-1 and COX-2) led to
  the concept that the constitutive COX-1 isoform tends to be
  homeostatic in function, while COX-2 is induced during inflammation
  and tends to facilitate the inflammatory response. On this basis,
  highly selective COX-2 inhibitors have been developed and marketed on
  the assumption that such selective inhibitors would be safer than
  nonselective COX-1 inhibitors but without loss of efficacy.

Inflammatory processes are expressed by both COX-1 and COX-2 differently.
This means that a change in the cell membrane expresses lysosomal enzymes differently:

The cell damage associated with inflammation acts on cell membranes to
  cause leukocytes to release lysosomal enzymes; arachidonic acid is
  then liberated from precursor compounds, and various eicosanoids are
  synthesized.

Also, the cyclooxygenase (COX) pathway of arachidonate metabolism produces prostaglandins, which have a variety of effects on blood vessels, on nerve endings, and on cells involved in inflammation. (See Merck, ch. 18)
I like the Figure 36.2 in Merck's manual.
To better answer your question, one could label the arrows there with relevant enzymes in each processes and compare those between COX-1 and COX-2 and relate to corresponding publications (only few existing!).
Adrenaline and other compounds activate the cyclooxygenase pathway, COX-1 pathway for instance, and the conversion of arachidonate to PGs and TXs. [2, p. 67]
The classic law of mass action allows to describe the reversible binding:
\begin{equation}
    [Protein] + [L] \rightleftharpoons^{k_{1}}_{k_{-1}} [Protein-L]
\end{equation}
where $L$ is ligand, Protein-L the protein-ligand complex, $k_1$ the rate constant of the forward reaction, while $K_{-1}$ the rate constant of the reverse reaction.
This fine regulation differs between COX-1 and COX-2 at enzymatic level regulated by cytokines.
COX-1 becomes only little activated in inflammation, in comparison to COX-2.
COX-2 is present in macrophages (chronic inflammation! - cytokines), fibroblasts, endothelial cells, synovial fluids, and chondriocytes.
[A]re there “resistant” COX phenotypes?
I have not heard about this that there would not be.
There are so many components in PGHSs which can develop resistances.
[A]re there any known phenotypes of COX-1 and COX-2 enzymes that are present in the general population that affect the ability of these drugs to act?
Please, see for the phenotypes of COX-1 here, while about COX-2 much less has been research, see here - no known phenotypes, see this.
Please, note also that COX has at least two isoforms: COX-1 (PGHS-1) and COX-2 (PGHS-2).
COX-1 phenotypes

176805, here

Is there any evidence as to whether the the NSAIDs collect in certain areas of the body in a compartmental fashion?
No.
Each disease has its own characteristics.
Gout, for instance, has swelling of syvovial joints and usage of NSAIDs with COX-2.
My professor of abdominal surgery answered to this question directly - impossible to answer generally which I agree with her. (17.10.2014)
I think the OP has in mind some antibiotics which concentrate in some parts of the body (such as 1st generation quinolones concentrating in the renal tubules and bladder, thus exerting local antibacterial effect).
There is no similar effect with NSAIDs.
Instead, NSAIDs have local and systemic effects, not because they are concentrating in some parts of the body, but because they have several mechanisms itself.
Please, see this thread about Effect of NSAIDS on stomach.
Are there differences in fat solubility, etc., between the different drugs?
Fat burner - of course, there are differences in fat solubility between different NSAIDs.
Please, see this publication Solubility of Nonsteroidal Anti-inflammatory Drugs (NSAIDs) in Aqueous Solutions of Non-ionic Surfactants.
I will update this part next week more.
Other sources

Basic and Clinical Pharmacology, 11th edition, 2009, Bertram Katzung.
My notes during Biochemistry classes in Tartu 2011-2013


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Sequence of ribosomal RNA
Is it possible to sequence rRNA directly, that is, using the ribosome rather than the DNA from the nucleus? For example, this paper, Complete nucleotide sequence of a 16s rRNA gene from E. coli,  suggests that it uses DNA to find the sequence. Would it be possible to isolate the rRNA and derive the sequence from that?

Unequivocally, YES.
Before DNA sequencing was used to deduce the sequence of cloned or reverse-transcribed RNA molecules, slower and more cumbersome direct sequencing of RNA was performed using the method of Sanger et al. (Sanger, F., Brownlee, G. G. and Barrel B. G. (1965) J. Mol. Biol. 13, pp. 373–398). This used ribonucleases in a manner somewhat similar to pre-Edmann protein sequencing.
Because of its abundance and ease of purification ribosomal RNA was a suitable species for this approach, and Carbon et al reported the complete sequence of E. coli 16S rRNA in 1978 (Carbon P., Ehresmann C., Ehresmann, B. and Ebel J.P. (1978) FEBS Letters 94, pp. 152-156).
Sigh! How little do modern molecular biologists know about the history of their subject.

In addition to that most people doing (m)RNA/transcriptome sequencing nowadays actually worry about sequencing rRNA - there is so much more rRNA in cells that it needs to be thoroughly removed before you can even sequence any other RNA species.

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Introductory books about evolution
This days I read some debates on evolution. That made me more interested to read something reliable on topic - I mean books.
I'm christian - although I think it doesn't matter on that topic - and I would like to read a book that presents all weaknesses and strengths (as much as possible) of evolution. I want that not to be presented as a debate on creationism, but to be a book on evolution theory explanation and presentation.
I also would appreciate if you know to give some details about the author that wrote the recommended book. I mean if he/she is atheist or a christian or a skeptic.

You won't find a good book that presents the 'weaknesses' of the theory of evolution, and for good reason. There has to date been no convincing challenge to the theory, whilst it has been supported by experimental and circumstantial evidence as well as clear logic over and over and over again, as well as actually being observed taking place numerous times. The closest to what looking for is a book which presents our best understanding of how evolution works, or which discusses competing ideas about how evolution works - there's no question about whether it works.
The Selfish Gene by Richard Dawkins, whilst it contains some errors, has some very clear thinking about evolution in it, and in particular explains why group selection is a misguided idea.
The Logic of Chance: The Nature and Origin of Biological Evolution by Eugene Koonin is a more up-to-date coverage of our current understanding of evolution, in particular with insights from modern genomics.
There are plenty of terrible books about the weaknesses of evolution, but they are deeply flawed. Pick one and I'll be happy to debunk it for you.

I really liked "Almost Like a Whale" by Steve Jones. He revisits the Origin of Species with 150 years of molecular biology - Darwin's logic all fits with the findings, and makes for an excellent read (far easier to get your teeth into that the original). Apparently the title refers to Darwin's observation that a bear, swimming in a lake and catching insects in its mouth, might conceivably evolve over time into a creature "almost like a whale".

Hi @Richard, I would only have a question. During my research, I found one claimed weakness of evolution theory from which it is deduced evolution more like a kind of belief, not like a scientific proved fact. This would be the fact that there are no transitional fossils. I also, in some poor research that I made, I found out that absolute dating is note quite reliable, and also it creates possibility of many more interpretations. Any suggestions on those two topics? (Especially scientific works that would treat this topic.)

N.B. I don't want to challenge you, although maybe that's an implication of my question. I'm mainly in search of some material on this issue that makes approaches from a scientific point of view as much as possible. Thanks. :).

@artaxerxe A little late, but I felt compelled in case others visit here. It's worth noting first that fossils are not the strongest evidence for evolution; rather, they provide pleasant corroboration for other fields and are easier to explain to non-scientists. That being said, the number of transitional fossils is still quite large. E.g. see [1], [2], [3].

Its not a book but the stated clearly series, http://statedclearly.com/videos/what-is-evolution/ it probably the best short clear summation of evolution I have ever seen, the berkeley understanding evolution site which is based in their book is more in-depth and also amazing. https://evolution.berkeley.edu/evolibrary/home.php

Almost anything by Richard Dawkins would be excellent value. I especially like his Climbing Mount Improbable as a short but gripping account of why evolution can achieve such astoundingly complex results.
Richard Dawkins (from my link above)

Richard Dawkins taught zoology at the University of California at Berkeley and at Oxford University and is now the Charles Simonyi Professor of the Public Understanding of Science at Oxford.

He is definitely an atheist.

Two recommendations:
1 - The Origin of Species by Charles Darwin.  This is a very accessible book, filled with clear explanations and examples, and conveys the wealth of evidence that Darwin collected as he developed his theory.  It includes a chapter on issues that people might see as "weaknesses", and convincing explanations as to why they are not.
Darwin began life as a Unitarian, and considered a career as a minister.  By the end of his life he had no belief in God.
2 - The Blind Watchmaker by Richard Dawkins, mentioned several times above.

+1 for The Blind Watchmaker. As for The Origin of Species, I haven't read it myself, but I suspect something more modern, such as the Selfish Gene, is better suited for an introduction.

I found The Origin of Species quite readable, but our understanding has developed somewhat since the 1850s.

The Voyage of the Beagle I would also add.

Another book by Dawkins which I find quite excellent is The Greatest Show on Earth. Unfortunately, you might find it a bit preachy in episodes since Dawkins gets – rightfully! – exasperated with some vocal, stupid critics.
Nevertheless, it’s a very compelling and interesting read, especially since it tackles some very complementary avenues of evidence for evolution. A similar outline is followed by Sean B. Carroll in The Making of the Fittest although he clearly focuses on the most compelling evidence for evolution: DNA – hence the subtitle: “DNA and the Ultimate Forensic Record of Evolution”.
I have no idea whether Carroll is religious or atheist – but shouldn’t that be strictly irrelevant?

+1, like your taste in books. @artaxerxe, I would also recommend Endless Forms Most Beautiful by Sean B Carroll for a great molecular introduction to evolution. http://en.wikipedia.org/wiki/Evolutionary_developmental_biology

Evolution is only fun when it is used to try to explain something. So to depart from the theme of Dawkins-books, consider:

Your Inner Fish by Neil Shubin

Shub is a Professor of Organismal Biology and Anatomy, Associate Dean of Organismal Biology and Anatomy and Professor on the Committee of Evolutionary Biology at the University of Chicago. He is famous for disocovering the Tiktaalik roseae or 'fish-with-hands'. The reason the book is fun is that it not only explains the basics of evolution, it uses it to show you something: why the human body is the way it is.

I also recommend Jerry Coyne's book, "Why Evolution is True."
As an introductory text book, I recommend "Evolution" by Douglas J. Futuyma. This is a very good introductory book covers almost everything about evolution. It aims to give you an overview not the detail.

The Ancestor's Tale .
This is an utterly, utterly fascinating book.


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Does stress physically age our body?
Going by the assumption that stress eventually triggers a flight/fight response, and the subsequent realization that flight/fight puts the body in a system of readiness to use it's available resources (mental, physical).
Does it make sense to think that stress physically ages a person? I am specifically referring to characteristics identified with aging such as  bleached hair, telomere shortening, wrinkles around the eyes, etc.

The fight/flight situation, through activation of the sympathetic part of the autonomous nerve system, leads to secretion of catechol amines, i.e. adrenaline and noradrenaline. The effects of these hormones, if excreted continously or without real resting time, are thought to be bad for your health. If you recall the possible effects of those two substances (which are both similar to amphetamine, by the way), and look at what big studies have found about the impact of high blood pressure then you know the most important negative effect of stress, IMHO.
http://en.wikipedia.org/wiki/Sympathetic_nervous_system

Not sure that I am entirely convinced by this. Some studies have shown (looking for refs...) that stress can be an important stimulant of the immune system - i.e. hormesis.

This is no contradiction. The positive effects might be greater than the negative. Surely you cannot endure stress 24-7. So there must be a limit.

I didn't say there was a contradiction, but as you have just said it a clearly more complicated than saying stress=bad.

OK, I have differentiated my answer

@Poshpaws Long during stress actually triggers auto-immune diseases.


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Why is glucose our primary source of energy?
Is there any evolutionary reason for glucose being the "main" molecule used as a source of energy, beginning with glycolysis and subsequently cellular respiration (after being converted to two pyruvate molecules)? Or did this particular biochemical pathway arise "by fluke" early on in the history of life?
A colleague of mine told me that it was because as shown below, all of beta-D-glucose's hydroxyl substituents are all equatorially positioned (when in the correct chair conformation), which lends to its general stability.

Image taken from the Wikimedia Commons.
Could this have played a factor in the beginnings of energy metabolism, and if so, why?

I don't have a direct answer for you, but you should try to get hold of a copy of Romano AH, Conway T. (1996). "Evolution of carbohydrate metabolic pathways".

I thought this was a great question.  In particular because it hints at two questions.  The first is 'why carbohydrates are used to store energy' in general. The second being 'why glucose rather than other carbohydrates?' in particular.
Glucose metabolism (and glycogen storage) is a core gene pathway - its found in bacteria archaea and eukaryotes.  So probably the most that we can readily say about question one is that as @rwst points out this pathway has proven to be useful at a critical juncture of the formulation of living things on earth.  If you look at glucose metabolism pathways, you can see that glycerate compounds and pyruvate are the actual intermediates that are used to create energy.  The first thing about these molecule worth noting is that they have a good mix of carbon and oxygen, which would make it easier to extract energy - creating CO2 from these compounds may even predates the existence of atmospheric oxygen.  So glucose and fructose (which is actually derived from glucose in the metabolic pathway) are actually storage molecules themselves, easily broken down to smaller molecules.
As to the second question: there are quite a few ways to arrange oxygen around the carbohydrate ring.  why glucose?  The advantages of glucose is probably a subtle one.  The structural properties of glycogen might be a reason that the use of glucose monomer is so important for glycogen. There is no evidence that I can find for this, so its always possible that glucose was just the first hexose carbohydrate to be biologically used.  Its sort of hard to imagine that the structure of glucose does not play some sort of role in cell structure though.

One could argue ATP is used to store energy, glucose is just the means to get this energy into ATP. Semantics, I know.

true - in this case we're trying to dissect the question in terms of which is oldest/ most primal.  from a molecular biology standpoint ATP is often a better answer.

Looking at this question again, ATP does not really store energy - its a high energy currency used throughout the cell, but its used and turned over rapidly in the mitochondria.  a human body has 250 g of ATP at any given moment but uses its own weight of ATP every day: https://en.wikipedia.org/wiki/Adenosine_triphosphate

This is only a guess but I hope somewhat educated, so refute me. The establishment of glucose as nutritional molecule is mainly linked with the availability of carbohydrates in the environment, i.e. plants as nutrition. Before plants evolved however, there were only bacteria and they use glucose as one of many oligosaccharides. But more important than glucose is trehalose because it is less toxic and can be collected in large amounts in the cell. The only reserves for glucose are glycogen and the bacterial cell wall which can be catabolized. So, in my guess, the reason for the mere existence of glycolysis/gluconeogenesis pathways is the bacterial cell wall that has to be synthesized and catabolized. Only later were these pathways differentiated when land plants came up and animals that et them.

that's an interesting argument.  if you could demonstrate somehow that glucose is what plants prefer to make for some good reason, it would really reinforce the hypothesis...

Remember that land plants stem from green algae that were bacteria earlier. Green algae had not much of a glucose preference but they developed starch as an efficient reserve, in addition to glycogen and trehalose. Only when land plants needed thick cell walls and big structures, glucose needed to be produced en masse.

It is simply not true that all living organisms or even most organisms all share some ancestral version of Glycolysis.
Various versions of Glycolysis and Fermentation were later coevolutionary after thoughts which emerged after Respiration; and why?  Glucose was not readily available when life first emerged.
As a matter of fact, many Prokaryotes use two far more ancient alternate pathways to break down Glucose:  The Pentose Phosphate Pathway or the Enter-Duodoroff Pathway.
Gluconeogenesis, now that’s different.  All species can make glucose, and the major part of what many textbooks identify the glycolysis pathway is actually Gluconeogenesis running backwards.
Problem is:  the capture of light energy to produce sucrose and other carbohydrates is a highly specialized phenomenon from an evolutionary POV that's not really part of photophosphorylation and photoreduction in Prokaryotes or even Cyanobacteria.
And how about Respiration in Prokaryotes?  Most do not rely on reserves of Glucose as a precursor.
What about Eukaryotes?  There are many points of entry into aerobic respiration and NOT ONLY Glycolysis.
So why is Glucose given so much emphasis?  Glucose is the precursor of Lignin, Cellulose and Chitin.  Lignocellulose aka plant dry matter (biomass), is the most abundantly available raw material on Earth for transfer to the second trophic level.

Welcome. Can you add sources to your post so that other users can background read on your answer?


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Why can't the brain and red blood cells use fuels other than glucose?
The question is rather straight forward: I have always been curious as to why, but cannot find an explanation online.
I can imagine that the mechanism is different for each, but why does brain tissue and red blood cells use specifically and only glucose for energy metabolism?

None of the answers below go to the core of the problem. Sure, several systems have been shut off or turned down in neurons and erythrocytes limiting their fuel types. The more important and possibly unanswered question is why these cells evolved this way. See also this related question on the brain.

In the case of red blood cells: human erythrocytes (red blood cells) have no mitochondria. Since the mitochondria are the cellular site for oxidative metabolism of fatty acids, erythrocytes cannot oxidise fatty acids to release energy. The erythrocytes also cannot fully oxidise glucose (to carbon dioxide and water) because this is also a mitochondrial process, so they have to rely upon anaerobic glycolysis. The end product of anaerobic glycolysis is pyruvate, and erythrocytes reduce this to lactate (to recycle the NADH that is produced during glycolysis) and then export this lactate into the blood for further metabolism by the liver.

The brain and heart can take advantage of ketone bodies when the amount of glucose is low.  These are byproducts of fat metabolism and can be converted to acetyl-coA via the citric acid cycle.
Overproduction of these products can cause pathological conditions:

When the rate of synthesis of ketone bodies exceeds the rate of utilization ,their concentration in blood increases , this is known as ketonemia. This is followed by ketonuria- excretion of ketone bodies in urine. The overall picture of ketonemia and ketouria is commonly referred as ketosis. Smell of acetone in breath is a common feature in ketosis.

There is quite a bit of evidence that the brain normally uses lactate produced by astrocytes as a source of energy. http://www.nature.com/jcbfm/journal/v25/n10/full/9600127a.html

@nico Sounds like that could almost be its own answer.  I wasn't aware of that.

unfortunately I know about the topic only superficially and right now I do not have time to go through the literature

Lipid catabolism provides energy mainly through fatty acid beta-oxidation. This process goes through a spiral of four mitochondrial enzymatic steps: one is catalyzed by the mitochondrial trifunctional3-ketoacyl-CoA thiolase (gene HADH). The activity of this thiolase is very low in neurons, explaining the brain need of alternative energy sources. Yang et al., JBC 1987. As previosly mentioned, developing erythrocytes eliminates mitochondria trough autophagy (mitophagy), therefore they became unable to efficiently perform lipid catabolism.

But why the activity of the thiolase you mention is low in neurons? Has it any functional purpose?


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Do the simplest bacteria have ribosomes and helicase?
I find it interesting that all life on earth use DNA. I've seen video on how helicase and ribosomes work together to copy DNA sequences (to RNA) with helicase then recreate them using ribosomes. Does this process work the same way in the simplest life forms? Bacteria and other unicellular life that reproduce through mitosis, for example?

Although the definition of life is complicated, there’s general agreement that viruses aren’t alive. Furthermore, there seems to be a misconception about the mechanism of DNA replication: no intermediate step via RNA is involved. Maybe you could clarify what you mean here? Still, I think this is a good question.

You seem to have got confused between translation (making proteins from RNA templates using ribosomes) and DNA replication (direct DNA-DNA copying)

I'm voting to close this question as off-topic because it is based on the false premise that ribosomes are involved in transcription.

I've had a direct look at Carsonella rudii, which is I believe is the bacterial genome with the smallest number of genes so far - 184 as well as being only 160 kb in length.   It has a putative DNA helicase encoded in it.  37 of those genes encode for ribosomal components as well.
If there was ever a bacterium or any living cell (non virus that is) discovered without a ribosome, you would have heard about it.  nobel prizes all around.
So I would say that your answer is yes.

First, mitosis is a eukaryotic process where not only genome replication and cell division is involved but quite a few more processes, not the least because there is a nucleus in eukaryotes. Bacteria simply divide after replication. And yes, even the simplest bacteria (and even some symbionts) use ribosomes for protein production. Example:
The smallest bacteria are from species Mycoplasma. The Mycoplasma species with the smallest annotated proteome on UniProt is Mycoplasma genitalium (strain ATCC 33530 / G-37 / NCTC 10195, with 484 genes. I have attached links to the set, as well as to its helicase. (For the 16S gene you would look that up in a gene not protein database)
http://www.uniprot.org/uniprot/?query=taxonomy:243273
http://www.uniprot.org/uniprot/P47340


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Why insects are so energy-efficient while flying?
Why are insects so energy-efficient while flying? Is it because of their light weight and aerodynamics or due to very efficient biochemical transformations (food->energy)?

Your question is very vague. Energy efficient compared to what? What makes you think they are 'so' energy efficient? You should try to explain why you're asking the question, as in its current state is has no context.

-1: please improve your question by better specifying what you are comparing insects to (birds? planes? or...?)

In my original question I was asking insect energy efficiency compared to human made battery operated flying devices but some super users closed my question claiming that it should belong in a separate topic other than biology...

@AdolfoPerez that's because the answer to the original question is about the limitations of battery technology and nanoscale aeronautical engineering, not about biology :). Unfortunately the engineering SE is still at the definition stage.

@RichardSmith Now I wonder what happens when a question like mine touches different fields of knowledge? In this case bio-engineering or biological engineering. Biology knowledge applied to engineering solutions. We can't be so black and white.

@AdolfoPerez I agree it's a shame that these sorts of questions get sidelined, but the idea is to prevent off-topic questions from diluting the question pool and discouraging expert participation. We have to draw the line somewhere - if you can phrase a question so that the biology part of it is central it's usually fine here :)

Insect flight muscle is capable of achieving the highest metabolic rate of all animal tissues, and this tissue may be considered an exquisite example of biochemical adaptation.
Locusts, for example, may (almost instantaneously) increase their oxygen consumption up to 70-fold when starting to fly.  In humans, excercise can increase O2 consumption a maximum of 20-fold, and for birds in flight the figure is about 10-fold (Wegener, 1996; Sacktor, 1976).
As Wegener (1996) has put it (in his definitive paper):

The aerobic scope (the ratio of maximal to basal rate of respiration) of insects is unrivalled in the animal kingdom

Flight is powered by ATP hydrolysis, and these impressive metabolic rates are achieved by very effective control of ATP hydrolysis and regeneration.

 Metabolism is aerobic, thus allowing for much more efficient ATP production from hexoses (as compared with, say, anaerobic metabolism).
 Flight muscle may account for up to 20% of body mass.
 In insects, haemoglobin and myoglobin are absent. Instead, gaseous O2 is transported to the tissues by a system of tubules and deposited so close to the site of consumption that (seemingly) it may reach mitochondria by diffusion.
Locusts fuel flight by burning sugars in the early stages, gradually changing to use lipids as fuel. (In bees, flight is totally fuelled by hexose consumption).

This is achieved by effective control of glycogen breakdown and glycolysis, by modifying the activity glycogen phosphorylase (glycogen breakdown) and phosphofructokinase (PFK), a key control enzyme of glycolysis.
There is an enormous literature on these topics, but suffice it to say, in the case of glycolysis, control is very efficiently achieved by allosteric regulation of PKF, where fructose 1,6-bisphosphate and fructose 2,6-bisphosphate play key roles (see Sacktor, 1976).
This allosteric control very effectively allows glycolysis to be (almost instantaneously) turned on and operate at a maximum value, and to be (almost instantaneously) turned off.

References
Wegener, G. (1996) Flying insects: model systems exercise physiology
Experientia May 15;52(5):404-12. (See here)
Sacktor B. (1976) Biochemical adaptations for flight in the insect.
Biochem Soc Symp. 1976;(41):111-31. (See here)

Your detailed answer is very enlightening @TomD. There is so much to learn from nature and it is an extremely difficult challenge trying to imitate nature's efficiency when building our own flying devices. No battery ever created is as efficient as insects natural way of powering their flight given their size

The smaller an animal is the easier it becomes for it to fly. That is because surface area increases to the second power of the diameter of the animal whereas mass increases to the third. So the larger a thing is the more mass per surface are it has.
And since insects tend to be small they tend to be good at flying.
As for any other reason, I don't think insects are any more energy efficient than say, birds.

Logical, but can you provide any references for this? It would strengthen your answer significantly.

Well it's just the square-cube law: http://en.wikipedia.org/wiki/Square-cube_law.

True, but this isn't quite a complete answer. With reduced size, one compromises other areas that may benefit flight, such as wingspan (first thing that come to mind). Thus, being smaller doesn't absolutely equate to more efficient flying.

According to the square-cube law the wingspan decreases with size but the mass decreases even more. Which means flying requires less push-up force per surface area for smaller animals.


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How did the nucleobases in the Murchison meteorite form?
The Murchison meteorite is an important piece of evidence for abiogenesis, because it contained nucleobases from extraterrestrial origin, as this Wikipedia article explains.

These results demonstrate that many organic compounds which are components of life on Earth, were already present in the early solar system and may have played a key role in life's origin.

My question is: How did these nucleobases arise? Is it possible for these nucleobases to have been synthesized naturally from simpler molecules in a specific environment, like in the Miller-Urey experiment for amino acids?

I think it's fine here.  Biochemistry is on topic to a degree on both sites, but I think this is closer to Bio's scope (I'm a mod on Chem).

The Wikipedia article about the meteorite mentions nucleobases, you're asking about nucleosides. Which one of the two are you asking about?

Just to clarify, what are you actually asking? I mean, what would be the alternative to them having been synthesised naturally? The only alternatives seem way out of scope for a biology site – namely, either spontaneous formation (e.g. supernatural creator) or aliens.

@KonradRudolph I think the alternative would be that we have no idea how they formed spontaneously.

@MadScientist Sure. But whether we have an idea or not how they formed, they still formed naturally, or not at all. Or am I overseeing something here?

I've edited the question to read nucleobases. A professor had told me nucleosides. Guess he was wrong.

See my response below. The problem with Urey-Miller is that they assumed a strongly reducing environment which probably was not the case on the early Earth thereby giving them very high yields of lovely organic stickies.

@LanceLafontaine I agree with Konrad - it is meaningless to ask if they formed naturally. The only alternative is supernatural (i.e. not real). Do you perhaps mean 'is it possible for [them] to have been synthesized abiotically' i.e. without requiring a life-form as the environment of synthesis?

Also @KonradRudolph oversee != overlook :)

@Richard Duh. I’m still slightly hung over.

@Poshpaws From what I’ve heard, that criticism of the Urey-Miller experiment has been refuted by recent findings (see the section on the Wikipedia article ff). Also, didn’t early life probably form deep under the sea in environments similar to black smokers, rather than in the atmosphere?

@KonradRudolph The argument about reducing vs non reducing atmosphere goes on, but it probably was not as reducing as Urey Miller assumed. Not to take away from their very important contribution however. Regarding black smokers, yes they are favourite candidates for early life, but their chemical environments are not much like Urey Miller either!

It is interesting to note that, in the Wikipedia article, it states that

The amino acids were racemic (that is, the chirality of their enantiomers are equally left- and right-handed), indicating that they are not present due to terrestrial contamination".

This implies that, if a 'life form' did create these proteins, they are fundamentally quite different to life on earth. (Particularly in light of the 70 unique amino acids they described!).
We cannot ever 'know' how they were made, unless a pretty revolutionary discovery is made that undisputably confirms evidence for extra-terrestrial life (although this is the best evidence yet!), so we are left to speculation.
The nucleobases either formed 'randomly' in one of the countless celestial events (although the chances of this seem pretty remote given the complexity of the molecules and the homogeneity in the sample), or they were made by extra-terrestrial 'life' (much more exciting, and indeed probably more likely, as we will see). (Or the 3rd option: intelligent design, however this is dramatically less probable than either of the other two).
The Miller-Urey experiment to which you refer has been subsequently enhanced, and evidence for the "catalytic potential of cosmic dust" is now reasonably robust (Hill, 2004). They demonstrate that simple nebular iron silicate catalysts can yield methane and water from CO₂ and H₂, and ammonia from N₂ and H₂. Allowing these to react yields nitrogen-containing organics such as methyl amine.
It is not a huge jump to suppose that with enough time, mass and energy, these reactants could combine and form a molecule (chain of amino-acid-like molecules - a protein) capable of faithfully replicating itself, and thus initiate life. There is no reason to suppose that Earth is unique in this respect; there are billions of suns in our galaxy alone, and billions of years of time for these reactions to take place.

I am not sure that I would say that we are left to speculation. The fact that these chemicals are racemic would suggest that they were formed abiotically. This being the case, we can probably get to understand the chemistry which should be pretty basic.

But certainly the importance of dust should not be underestimated!

I think it's fair to say that we don't really know how these more complex organic molecules formed abiotically, but we can say that carbonaceous chondrites - a class of carbon and organic molecule bearing meteorites to which Murchison belongs (specifically CM2) - have experienced at least three distinct chemical histories:

In the interstellar medium (ISM) in cool (10 - 30 K), dense clouds where cold gas phase chemistry can lead to the formation of species such as HCN, C₂O₂ and CO.Polycyclic aromatic hydrocarbons (PAHs) have also be identified here.
In the early solar nebula. These simple organics can stick to dust grains forming "tarballs". The ultraviolet radiation field from the young star can then create some interesting chemistry through things like radical reactions and during the evaporation of ices. Things like diethyl ether have been detected in the pre/proto stellar nebulae of young stars.
In the parent body of the meteorite, such as in a meteoroid. Here most chemistry would occur through hydrothermal alteration over long timescales as the body orbited the parent star. As these bodies will invariably describe elliptical  orbits, it will undergo many freeze-thaw cycles all in the presence of an intense radiation field.

Carbonaceous chondrites in particular undergo aqueous alteration due to the presence of water in liquid form.
Figure 2 of this article gives an basic overview of some of the chemistry involved. It actually refers to the chemistry in cold molecular clouds, but is almost equally applicable to that in things like meteroids/asteroids/comets.
Ehrenfreund, P, and Charnley, S.B., 2000, Annual Reviews of Astronomy and Astrophysics, 38, 427

I've not read of complex molecules form in clouds before - are these molecules faithfully replicated in such a way as to call them living?


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Genetic Diversity and Adaptation
I am somewhat new to evolutionary biology, having studied it on my free time as a computer science student.  There is one particular thing that has always bothered me for which I have not seen a good treatment, relating to adaptations to the environment with respect to genetic diversity.  If it is possible for a population to adapt to rapid environmental changes, and they don't have an adaptation for dealing with change directly (such as a complex brain), it seems to me that every generation must have present within them almost every possible environmental adaptation that the population is capable of expressing (including many irrelevant ones and a few relevant to the particular environmental challenge).  Otherwise, it may take too many generations to deal with a change, which may be disastrous for the population.
So my question would be: how does an evolutionary biologist explain the mechanics behind the ability for a population to adapt quickly?  Are most environmental changes slow or gradual enough that the population has a few generations to happen upon the mutations that will allow it to survive, and have generally been successful in this regard for 3.5 billion years?  Or, are a large majority of possible adaptations present in almost every generation, and just serve no purpose or advantage for most of the population if the provided "benefit" is unneeded (i.e., are effectively neutral)?  Or something in between?

Yes, yes, and yes. And a too quick environmental change can kill a whole population, it happens all the time. (we at least hope so when we're infected with bacteria and give them hell)

I like the example of moth species that turned black duing the coal powered industrial age. all the cities were black... the black pheno appeared everywhere within 100 years. simple adaptions can appear in a few generations. The species doesn't change environments suddenly, they push towards new locations and if they change is too extreme, they die, so there is a balance. The planet is full of very stable environments with gradual transition times and extents.

It is a good question. The question is hard to answer though because

The answer is not completely resolved
There are many influential parameters hidden behind this question.

Your question, as I understand it, can be formulated as

Do natural populations have enough genetic variance to directly respond to an environmental change or do they have to wait for this variance to be created through mutations?

To address this question, I will have to assume you have some intermediate level of knowledge in evolutionary biology.
How do we call these two alternatives?
Adaptation can occur through selection on:

Standing genetic variance
De novo mutations

How can we tell them apart?
This section is mainly inspired from Barrett and Schluter (2008).
Adaptation from standing genetic variance and from de novo mutations tend to yield different genetic signature.
In comparison to de novo mutations, adaptation from standing genetic variation is likely to lead to

Faster evolution

Because there the respond to the new environmental is immediate, there is no need to wait for more mutations.
Because the fitness variance associated with the trait under selection is very low even when the first mutation occurs.

Fixation of more alleles of small effects.

Because phenotypic variance is alleles of large effects are likely to be deleterious in the previous environment and would therefore be purged out of the population quite quickly
Because, if adaptation occurs from de novo mutation, it is likely that only few mutation would have occurred that would allow adaptation

Spread of more recessive alleles

Because recessive alleles can reach a relatively high frequency in the previous environment even if deleterious in the homozygote mutant.
Because recessive alleles represent little to no fitness variance at low frequency and are therefore likely and it would therefore take much time for adaptation to occur from recessive alleles if they just appeared through de novo mutations.

You will note that my explanations are non-exclusive and are overlapping. They all boil down to

Loci causing high fitness variance in the previous environment are unlikely to be source of adaptation from standing genetic variance
Loci causing high fitness variance in the new environment are likely to cause adaptation.

If you have a hard time to understand these concepts, then you might want to have a look at Fisher's fundamental theorem, Mutation-selection balance and eventually follow some intermediate level course on the mechanism of natural selection.
Which mechanism is more common?
Do most adaptation occurs through selection on de novo mutations or through selection on standing genetic variance? This question is very hard to answer. It depends on

Type of adaptation
Population of interest

1. The type of adaptation
The answer is likely to differ depending on whether we are talking about

adaptation to a changing environment over the whole species range

How fast is this environment changing is important too as you noted in your post.

A single population that detach from the rest of the metapopulation to slowly colonize a new environment
Adaptation to a universally (independent of the environment) beneficial trait
Coevolutionary process
etc...

2. The population of interest
Different populations retain different level of genetic diversity. This level of genetic diversity depends on

Demographic parameters

such as the population size and its variation through time

Evolutionary history

Such as the number of recent selective sweep

Environment

Such as the diversity of environments present over the range of the species
Such as temporal variations

Genomic architecture

Such as the presence of strong epistasis that could cause large amount of hidden genetic variation (see for example Hermisson and Wagner, 2004) and the eventual "revelation" of this previously hidden genetic variation through new mutation or a new environment (see for example La Rouzic 2008).

Example
Three-spined sticklebacks are present in salt water and fresh water. They occupy several geographically isolated bodies of fresh water (connected by salt water). All populations present in fresh water environments show similar phenotypic traits. We have first thought that sticklebacks have adapted repeatedly to this freshwater habitats (repeated evolution) through de novo mutations. However, some papers suggest that, as the marine population of sticklebacks is so big, that it is possible that there is standing genetic variation for these traits that are selected for in freshwater habitats. Below are some papers of interest

Jones et al. 2012, The genomic basis of adaptive evolution in threespine sticklebacks
Feulner et al. 2012, The genomic basis of adaptive evolution in threespine sticklebacks
Colosimo et al. 2005, Widespread Parallel Evolution in Sticklebacks by Repeated Fixation of Ectodysplasin Alleles

Great question! A lot of things affect how quickly a population or species can adapt to a new environment, including population size, mutation rate, generation time, standing genetic diversity, and selective pressure.
The diversity of life encompasses practically all combinations of those variables. A bacterial population might very well contain enough diversity to allow a portion of the population to overcome a rapid change. In fact, applying antibiotics to a bacterial population and counting the survivors is a common measure of mutation rates.
On the other hand, organisms with small populations and long generation times will be much less likely to overcome a rapid environmental change. This is why there is so much concern over anthropogenic changes to the environment, including climate change.
It's hard to provide a definitive answer, since "rapid change" is a relative term, and the difficulty of adapting isn't known. Some striking adaptations can be caused by a single base pair mutation, such as in beetles and Monarch butterflies that are insensitive to toxic plant compounds.
It's important to point out that natural selection is based on relative fitness. Therefore, an adaptive mutation will spread because it's likely that carriers will be more fit than all of their neighbors. This does not necessarily mean that individuals without the mutation will die or fail to reproduce, only that those with the mutation will do it better.
Likewise, adaptation is not necessarily caused by the environment changing and wiping out all but a few lucky mutants like in the bacteria example. Instead, the environmental change might make things more difficult, but as long as the population can persist, then mutations will continue to enter the population which could confer a selective advantage against the change. So, no, a population does not (cannot) carry all possible adaptations. A population cannot adapt to an environment it hasn't encountered.
Finally, it's worth pointing out that a species can expand its range through migration. A new, unsuitable environment can act as a migration sink (that is, migrants make it there but fail to establish) for a nearby population. If this happens for long enough, some of the migrants may have a mutation allowing them to establish in the new environment.

Selection and the process of adaptation
The genetic variation for fitness is the determinant of how rapidly adaptation can occur. This is summarised within what is known as Fisher's Fundamental Theorem:

The rate of increase of fitness of any species is equal to its genetic variance in fitness

Adaptation is process resulting from two components, selection and genetic variation. The importance of genetic variation is captured by the breeders equation, where the magnitude of the adaptive response, $\Delta \bar{z}$, is the product of selection, $\beta$, and genetic variance, $G$:
$\Delta \bar{z} = G \beta$
If there is no genetic variance in fitness, there can be no adaptation. This is because adaptive evolution relies on the ever changing genetics of a population. If there is no variance in the parental generation, then reproductive variance (different reproductive success among individuals of the parental generation) will not affect the frequency of alleles. Adaptation occurs because reproductive success is connected to an individual's genotype. Selection can produce a response by acting on standing genetic variation, or by acting on novel genetic variation such as that introduced by mutation.
If an environment changes rapidly, a rapid response can occur, so long as there is enough genetic variance to allow a response. For example, a shift in the environment acted on genetic variance in the Galapagos Finches causing rapid adaptation in to multiple niches. Otherwise, when there is insufficient genetic variance, species will struggle to adapt, as is likely to occur with ongoing rapid climate change, and in the future for species which are going through genetic bottlenecks. Any cases where selection is too strong for prolonged periods will result in extinction of the population by a failure to adapt. For example, by application of antibiotics to bacterial infections, if there are no members of the affected bacterial population which carry resistance genes then the population will be wiped out, but if there are resistant individuals then the population will adapt (only resistant individuals will continue to reproduce).
You may wish to read further on Fisher's Geometric Model of Adaptation, including this paper, and Mutation-Selection(-Drift) Balance. Here's a good paper on the quantitative genetics of adaptation.

It is clear that climate-driven evolution has molded plants in deep time and within extant populations. However, it is less certain whether adaptive evolution can proceed sufficiently rapidly to maintain the fitness and demographic stability of populations subjected to exceptionally rapid contemporary climate change.


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Are there any situations in which phenylephrine is preferred to pseudoephedrine?
In the mid 2000s in the US, due to issues of drug enforcement, pseudoephedrine containing medications were brought behind the pharmacy counter and in most cases require ID, and phenylephrine was substituted in most over-the-counter products.
Pseudoephedrine increases the amount of endogenous norepinephrine, whereas phenylephrine works on α1-adrenergic receptors directly.
There are numerous cases where experts have spoken out about the effectiveness of phenylephrine, so it likely is a less effective substitute for pseudoephedrine in its main role as a decongestant.
What I'm curious about is whether there are clinical indications for which the phenylephrine is actually preferred (so situations where the α1-agonist nature without the increase of endogenous NE is sought after)?

I suppose phenylephrine might be indicated in cases where there is an interest in maintaining levels of neurepinephrine, such as when antidepressants or other medications are being administered.

Yes, in all clinical situations where you need pure vasoconstriction without heart rate acceleration (mostly valid for iv administration route).
The classical example would be in the operative setting. If the patient is in a hypotensive state due to hypnotic drugs, opiates, etc. and has atherosclerosis, you will prefer a drug that will reverse the hypotension without an increase in heart rate, i.e phenylephrine. The reason is that an increase in heart rate will shorten the duration of diastole, which will therefore shorten the time interval where the coronary arteries are perfused. Moreover, an increase in heart rate also means an increase in heart oxygen consumption. The end result will be an imbalance between oxygen input and requirement, i.e ischemia and potential heart infarction.
Conversely, if you have a patient with aortic valve insufficiency (regurgitation), you will prefer ephedrine (or any drug with beta 1 activity), because you will be aiming at shortening the available time for regurgitation to occur.

Would phenylephrine be called "non-inotropic" or something of that nature, or is that an abuse of terminology?

@jonsca it is true that (to my knownledge) phenylephrine has no inotropic effect, and can be called as such. But since it is the only pure alpha agonist commonly used for blood pressure control, it isn't really defined as part of a "non-inotropic" class in usual medical jargon.


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How and when did a dedicated immune system evolve?
I have recently been doing a lot of research into the interplay between the innate and adaptive immune systems in humans, and mammalian laboratory models. This has led to my reading some interesting information on the immune response in insects;

Insects have a highly efficient immune system.  In response to a bacterial attack, their fat body (the equivalent of the liver in mammals) synthesizes a whole range of peptides with an antibacterial and antifungal effect.

This fascinated me, as the clear inference is that there are no ‘dedicated’ immune cells, but that adipose tissue has far more diverse functions that I had realized.
I have done a little more reading, and also looked at plant immune systems, which seems far more analogous to those in insects than mammals;

Plants, unlike mammals, lack mobile defender cells and a somatic adaptive immune system. Instead, they rely on the innate immunity of each cell and on systemic signals emanating from infection sites.
  (Jones, 2006)

My questions relates to the need of an adaptive immune response in mammals. The immune systems in insects and plants - a more 'systemic' immunity due to the lack of dedicated/mobile immune cells - seems much simpler.
Given that evolution works incrementally (there are no 'jumps' - for instance, going from a non-dedicated immune system, to a dedicated immune system), I would hypothesise that organisms less distantly related to insects and plants may have tissues with duel functions (similar to insects?), but that specialize further as immune cells until gradually (down the evolutionary tree) a complex and specific immune system emerges. (This is complicated by the fact that our immune systems do have multiple roles - e.g. tissue remodelling, but I wasn't going to go into that here. Feel free in your answers if it is necessary!).
My overall curiosity can be summarized as 2 questions;

What are the possible reasons why a dedicated and immensely complex immune system evolved in some lineages of organism?
Is there any evidence of 'half-way' organisms, and about what ecological time-frame might the dedicated immune system have developed?

Immunity has probably evolved more than once as it is completely necessary for survival.  You might even argue that defenses such as antibiotics and predatory behavior are immune defenses for single celled creatures.
As you point out, plants have a different immune system than animals do.  Insects do too.  They don't have innate immune memory which many animals have, where pools of cells embody the immune response to a specific antigen.  (i.e. encode for a specific immunoglobin or a tCell Receptor variant).
I found this reference that this appears to be the collective property of jawed vertebrates.  Even so, there are many late innovations in the immune system, where reptilian and mammalian immune responses vary substantially.
Its not clear to me whether other animals have the insect system. Animals that branched off before insect lines such as radiates probably have their own way of dealing with immune response.  That's just a guess though.

As you guessed, the immune system as we think of it in humans has evolved incrementally over hundreds of millions of years.  The components that most people think of as "immune system" (T cells, B cells, antibodies) arose in sharks, around 400 million years ago. Lampreys and hagfish, which split off from the rest of the vertebrate lineage before sharks developed their adaptive immune system, have parallel solutions to the problem that are mostly independent but that involve some evolutionarily related structures.
The "innate" immune system is much more ancient.  Humans and other vertebrates share parts of the innate immune system with insects and more evolutionarily diverse organisms, so these arose well over 500 million years ago.
The topic is reasonably well understood and far too broad to discuss in any detail here.  I've written a couple of summaries elsewhere:

Same trip, different routes: Lamprey immunity (links to 12 publications)
Sea urchin immune systems (links to 3 publications)

Here are some review articles:

Design principles of adaptive immune systems
The evolution and genetics of innate immunity
Mice, men and the relatives: cross-species studies underpin innate immunity
Pioneering immunology: insect style

Immunology is a bio-chemical and nebulous concept, however it's equally complicated as the nervous, structural and circulatory morphology and chemistry. You can compare the immune system complexity to visible complexity that evolved in animals, from simple spiral and pattern shells, to metameric (repetitive segment) shells with a small amount of articulations like crabs and experimental Archean animals, to highly articulated shrimp and scorpions, and then to thousands of complex scales with specialized points and stings, which even become an endoskeleton. The evolution of the first muscled and articulated endoskeletons is as confusing as the immune system but it also happened gradually, before there were bony fish there were cartilaginous ones like sharks. In the same way, the immune system has evolved in strange steps from simple to highly complex and made of many pieces.
Bacteria have kinds of immune systems to protect against viruses, which consist  simply of DNA tricks to randomly re-arrange it's DNA and so neutralize the dangerous virus DNA which is copied within them and inherit new genes without making virii... If you want to go a step up from that in evolution complexity, then study immunology of worms and immunity of sponges.
The battle between bacteria and bacteria-eating viruses has been going on for millions of years, with viruses attempting to replicate themselves by -- in one approach -- invading bacteria cells and integrating themselves into the chromosomes of the bacteria. When this happens a bacterium makes a copy of its chromosome, which includes the virus particle. The virus then can choose at a later time to replicate itself, killing the bacterium -- similar to a ticking time bomb, Wood says.
However, things can go radically wrong for the virus because of random but abundant mutations that occur within the chromosome of the bacterium. Having already integrated itself into the bacterium's chromosome, the virus is subject to mutation as well, and some of these mutations, Wood explains, render the virus unable to replicate and kill the bacterium.
With this new diverse blend of genetic material, Wood says, a bacterium not only overcomes the virus' lethal intentions but also flourishes at a greater rate than similar bacteria that have not incorporated viral DNA.


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If body temperature is 37°C (98.6°F), why are most people more comfortable at around 21°C (70°F)?
It may be different for other people, but for me, anything above 32°C (90°F) is very uncomfortable, and my body is inclined to seek cooler temperatures.  But I would think that at 32°C, the body would have less work to do to get itself to 37°C.  So why is it not comfortable in those temperatures?
My theory is this, but I don't know if it's right:
The body's abilities for warming itself are much more sophisticated than its abilities for cooling itself (which are non-existent, possibly?). So it likes to be in an environment 20-30 degrees below optimal because it can easily handle that.  But up in the 32's and we're dangerously close to going over the optimal, and the body doesn't know how to get it back down after that, so we are inclined to seek safer temperatures.
Is it something like that?

not all animals require this body temperature - mammals have made some good business of assuming their bodies will all be at the same temperature and then warming themselves up to the right temperature.  as the others note there are biological warmers, but no biological refrigerators, so choosing a temperature above most weather conditions was a useful part of the strategy of being warm blooded ...

I refer you to the quora answer: http://www.quora.com/Temperature/Why-do-air-temperatures-in-the-low-70s-Fahrenheits-feel-comfortable-to-humans

I added more details. Check out!

@reopen The question also asks the reason why the skin temperature is lower than the core temperature. This is not dealt with in the linked question

Human body continuously generate some waste heat; that is dissipated from the body to atmosphere. If rate of heat generation and rate of heat dissipation becomes same, the object comes into thermal steady-state (no overall change of temperature). But if you increase the atmosphere's temperature, rate of heat dissipation will be decreased, an the steady state will take place in much higher temperature until the object actively increase the rate of heat dissipation (drain-out some heat) (sweating, an way of doing that in human-body using latent heat).

The body can never stop working. If the body stops working, you die.
And while the body is working it cannot avoid generating heat.
Being in an environment somewhat colder than the body makes getting rid of this excess heat easier, and is thus more comfortable.
The body's abilities for warming itself are much more sophisticated than
its abilities for cooling itself (which are non-existent, possibly?).

The body can cool itself down by sweating.

Although in general this answer seems reasonable, I would like to see some references. What is the amount of heat generated by the body, say, when you're sleeping? Does it change during the day? Depending on the season? Is it actually that non-negligible (we are talking about a 16° difference here...)

It is quite a substantial amount of heat, and it is more when we are active so therefore more during the day. I don't have the resources available nor how to calculate those amounts.

Thermodynamically, your BMR goes nearly completely towards heat, as you do no work on the environment. I have a BMR of about 1800 kCal, so I need to lose all of that heat through my 2 square meters of skin every day. Some of that is insensible perspiration, and some of it is just conduction.

As a rule of thumb, a human produces roughly the same heat as a 100-watt light bulb.

@RussellBorogove that is, slightly less than 100 watts?

This is due to the fact that skin is the interface where heat is lost.
Our body due to constant functioning, produces heat constantly as a by-product (due to exothermic reaction of ATP break mainly). The excess heat needs to be conducted away from the body, or it will cause a decrease in the body metabolism to prevent temperature rise.
Heat is lost mainly through the skin by:

Sweating - Through evaporation
Radiation - As heat waves (IR rays - That's why IR camera captures people at night)
Conduction - Directly through objects that touch skin
Convection - Through air circulation

When the ambient temperature rises, the heat lost through radiation, conduction, and convection drastically decreases. And often when the temperature is high, there is a accompanying rise in the relative humidity which decreases the heat loss through sweating (as the amount of water vapor is high in the atmosphere, the sweat does not evaporate, so no heat is lost).
So the heat which is not lost is felt as the "hot sensation". It relieves by stopping any activity, seeking shade or a cool place, etc... all of which increases the heat lost or decreases the heat produced.

You have to note that the temperature of skin is lower than the body temperature.

The Skin temperature is lower than the core body temperature for two reasons:

The skin acts as a medium through which the external temperature is measured - as such the skin temperature is at equilibrium with the external temperature. The brain regulates the core-body temperature in response to temperature measured through skin. If a person is exposed suddenly to cold environment, skin looses much of its heat in the form of radiation (radiation is direclty proportional to the temperature difference) this will cause perception of cold and the body starts shivering even though no actual heat loss has occured from the core body thermal load (only skin looses heat, not the body core). The brain anticipates that the core will loose its heat when exposed to such low temperature for prolonged periods and starts the warming mechanism before the actual cooling occurs such that the cooling is either prevented or minimized. This is called Anticipatory control and the temperature of skin being close to the ambient temperature within physiological limits is needed for this.
Skin is the medium (almost the only medium) through which the excessive heat produced by the body core during activity is expelled. The skin temperature is lower so that a constant gradient can be created between the body core and body surface to maintain the flow of heat. (Heat losses through urine and feces is minimal)

For more details see this question. All the answers in this question are good and will increase your understanding of what actually happens.

This answer clearly explains that skin is the interface where heat is lost, and why it's that interface, but I don't see any clear conclusion on why that makes <37 degrees comfortable. john-jones's answer seems to make more sense for this reason.

This answer was merged from a different question, which was removed, hence why it does not seem to be fully cogent @user75673

Your body requires energy to function.  Just like in a powerplant, the energy comes from oxidizing fuel (food, instead of coal or gas).  The efficiency Of conversion is rather low, and results in excess heat, which must be rejected to the environment.  When it's cool, the heat is easily convected to the surrounding air.  When it's warmer, or you're producing more waste heat than can be rejected through simple convection, your body relies on evaporative cooling, i.e. sweating.
When it's very cold, the normal waste heat is not sufficient to keep you warm enough for normal bodily functions, so you shiver.  This is physical activity which your body performs solely to create waste heat, which warms you up.
There's an article about muscle efficiency on Wikipedia, indicating that the human body is about 25% efficient.  This means that about 75% of the energy consumed must be rejected as heat.

It may be different for other people, but for me, anything above 32°C
  (90°F) is very uncomfortable, and my body is inclined to seek cooler
  temperatures

I think you've rather nailed the key point here. I'm going to deduce from your question that you live in a temperate country? Every year, foreign students from India come over to my university in Leicester, UK. Even when the temperature is, to us, unpleasantly hot they will be shivering in their coats and complaining it's too cold. Similarly, were I to go over to India I'd be suffering in the heat while they're thinking it's a lovely comfortable temperature.
So, I believe, the answer is nothing to do with the ability of the body to maintain certain temperatures - you'd need to go considerably above 32°C or below 21°C to reach temperatures the body can't cope with - but rather a question of acclimatisation. You find 21°C comfortable and 32°C comfortable because that is the temperature that you've become used to. You can probably even recognise this from your own experience: I'm sure you've experienced days in spring feeling delightfully warm when days of the same actual temperature in autumn feel unpleasantly cold.