biochemistry - Conversion rate of topical Retinol to Retinoic Acid (Tretinoin)?

I'm wondering if someone out there has more information than me. Retinoids have well known metabolic pathways in vivo, and it's usually something like: Retinyl Palmitate --> Retinol --> Retinaldehyde (Retinal) --> Retinoic Acid (Tretinoin) which is the biologically active form of the Retinoids.

Retinoids are used in cosmetics all the time, and while Retinol is available OTC, Retinoic Acid (Tretinoin - a.k.a. "Retin-A" by brand) is available by prescription only since it is a 'stronger' version of Retinol. It's not difficult to find 1% Retinol creams or higher, but Retinoic Acid treatments top out at 0.1%.

However, I can't help but wonder 'why'? One study I was able to dig up was here: Retinoic Acid Biosynthesis and Metabolism PDF. The table on page 5 shows Physiological Concentrations - starting at 50 microM for Retinol and ending at "<50nM?" suggesting an ultimate conversion rate of a little less than 10% which would make the 1% Retinol treatments roughly equivalent to a 0.1% Retinoic Acid treatment (and a 2% Retinol treatment to a 0.2% Retinoic Acid treatment - double what's available by prescription).

Do other studies/other evidence support the rate of conversion of Retinol to Retinoic Acid to be roughly 10% or suggest than a 1% Retinol topical treatment is equivalent to a 0.1% Retinoic Acid topical treatment? Or are there some other interfering factors that reduce the utilization of Retinol to Retinoic Acid that I'm missing?

genetics - Drosophila reference genome

That was surprisingly buried.

I found this in a paper describing genome build 3 - See "Materials and Methods". I imagine that this is consistent through to the current build. In any case it should get you started.

"Sequencing templates were made from P1, BAC and WGS DNA libraries using the D. melanogaster strain yellow (y1); cinnabar (cn1) brown (bw1) speck (sp1)."

physiology - What are potential side effects of myostatin inhibitors?

Myostatin inhibitors, which are being developed to treat muscle wasting diseases like muscular dystrophy, are likely to be abused by athletes. What are the potential long-term side-effects of taking a myostatin inhibitor? Will it have different side-effects for patients compared to healthy athletes (especially young athletes that are still developing)? Could there be adverse drug interactions with other common performance enhancing drugs like EPO, hGH, and anabolic steroids?

Sources I've explored (StackExchange is only allowing me to insert two hyperlinks):

• New Muscle Drugs Could Be The Next Big Thing In Sports Doping - NPR story by Jon Hamilton


• Wikipedia entry on myostatin


• Wyeth found one of its drugs to be safe in a clinical trial, but it stopped development because the drug was ineffective at increasing muscle mass.


• An internet search mainly brings up dieting and body building forums, which I do not trust.


• According to a review by Breitbart et al. 2011, myostatin inhibition does not have negative effects on cardiac tissue.


• According to a review by Allen et al. 2012, the increase in muscle mass caused by myostatin inhibition leads to be metabolic health (e.g. lower glucose levels and higher insulin sensitivity).

dna - There are linear and rotary molecular motors in the cells. Do any of them have a fixed or stable frequency or speed?

These molecular motors' response maybe dynamic and nonlinear. But it entirely dependent on the external influence and also the characteristics of the motor itself including number of active motors involved in operation. As it is microscopic, it will not possible to analyse by assumptions and say they have some random frequency. They do have certain frequency of operation (I do not know whether they are controlled by biological clock or some master clock but they are controlled by nucleus of the cell) and "Modeling molecular motors" explains how motors act on the filament inside the cell. It mainly talks about the influence of external force on the operation of motor and also speed(v) of the motor. The following excerpt from that paper talks about the external force on motor.

The action of the motor is induced by generalized forces, which for
the motor/filament system may be identified as the mechanical force
fext applied to the motor, and the chemical potential difference
Dm, which measures the free-energy change per consumed ‘‘fuel’’
molecule. The force fext describes external forces, for example of
optical tweezers, microneedles, or the viscous load of an object that
is carried. fext could also include viscous friction forces between
the motor and the surrounding solvent if the latter is considered as
‘‘external.’’ The chemical potential difference Dm is for the
process of the hydrolysis of Adenosinetriphosphate (ATP) to
Adenosinediphosphate(ADP) and phosphate (P).

The frequency of molecular motor according to "Biophysics of Molecular Motor" has been classified into two categories:

1. Density controlled: In the density-controlled model, it is assumed that the depolymerization rate is proportional to the motor density at the terminal site of the microtubule. Here the frequency of motor is dependent on density of the motor.




2. Flux controlled: Filament depolymerization is determined by the flux of motors
   to the end. Here the frequency is dependent on the flux of the motor.

In both the above cases the length of the filament on which motor is acting is also important. These models have been analysed and plotted on a graph to give a clear picture of it.

The paper explains the catastrophe frequency, the frequency at which the filament shrinks. Shrinking of of a filament is due to motor. So the paper concludes saying the catastrophe frequency is 0.5 per min for a 8um length of filament.

(Catastrophe = the transition from growing to shrinking of dynamic microtubules).

To summarize, these motors do have speed and frequency of operation but they are not fixed. They vary in a non linear fashion due dynamic environment. But the motor tries to be as much stable and resistant as possible.

evolution - Extraretinal photoreception in mammals?

Its pretty well established that there are photoreceptors in cells besides the cones and rods in the retina of the eye. Humans and most animals have four light receptor genes known (so far). In addition to Rhodopsin - there are the short, med and long wavelength opsin genes.

While they are mostly expressed in the retina of the eye, they can be found in many other tissues as well. The first image from GeneAtlas below shows the relative amount of RNA found for short wavelength opsin in a variety of tissues - its expressed in immune and nerve cells ( cyan and forest green respectively) relatively well too. This might imply that neurons are light reactive. Compare that to that of medium wavelength opsin, which is primarily much more common in the retina.

This is not a psychosomatic effect. Light receptors in the skin are known to help with seasonal affective disorder - shine a bright or blue light behind your knees. These receptors are not connected to optical nerves, and so you don't get any image from them, but the information can affect your biochemistry anyway.

The idea of unconscious receptor inputs from other parts of the body probably applies to many sorts of receptors. This last year there has been a great deal of interest in taste receptors which are expressed in the gut. They can taste sweetness and other flavors a second time and register the gustatory response in the brain. Its not a conscious input, but it registers in the brain in MRI.

Why would evolution do this? It seems to me that this is a new way of looking at the individual life of a cell and makes a good deal of sense. If every cell has all the genes' DNA why wouldn't a little bit of receptor expression be found in any cell which could use the information? The conscious processes of the brain probably only take in a small fraction of the information that is sent in and there maybe hundreds of other such senses from various parts of the body to integrate, only a fraction of which we are aware of.

In addition, there are probably lots of cases where receptor signals are only used locally by cells that are sensing their local environment. It really doesn't make sense that the individual cells must blind themselves. Individual bacteria and fungi have scores of receptors. It makes sense that cells that are part of an organism would have as many or more senses as well.

molecular biology - Why does the hydrolysis of ATP increasing entropy increase the Phosphoryl-­‐transfer Potential?

The phosphoryl transfer potential is one way to think about the free energy available to do useful work when ATP is hydrolysed.

As you can see from the free energy equation below, a positive change in entropy will help to decrease (i.e. make more negative) the free energy change.

This is why an endothermic reaction can still occur spontaneously if the entropy change is big enough to create an entropy term that outweighs the enthalpy term in the Gibbs free energy equation.

ΔG=ΔH - TΔS

where:
T= temperature
G = Gibbs free energy
H = enthalpy
S = entropy

toxicology - Is nicotine toxic to humans?

Nicotine acts as a ligand for nicotinic acetycholine receptors (nAChRs), which are ligand-gated ion channels normally activated by acetylcholine. This family of receptors is expressed in every mammalian cell (Schuller, 2009). A priori, at least to me, I'd suggest that it's a bad idea to chronically introduce a foreign substance that mimics the activity of an essential signaling molecule like acetylcholine.

Directly to your question of toxicity, nicotine appears to be linked to many forms of cancer (Schuller, 2009). Cancer promoting signaling pathways are stimulated as a result of calcium entry through nAChRs. Also, interactions of nAChRs with other signalling systems, such as those based on stress hormones, GABA, and dopamine, can lead to cancer.

Nicotine also has important effects in the brain. Chronic exposure to nicotine induces a homeostatic mechanism that upregulates nAChR expression in the brain to maintain responsiveness to endogenous acetylcholine. This effect partially underlies nicotine addiction (Penton and Lester, 2009). As @Armatus notes, nicotine appears to have some neuroprotective properties against neurodegenerative diseases like Parkinson's (Quik, M., Wonnacott, S., 2011) and Alzheimer's (Mehta et al, 2012).

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Schuller, H.M., 2009. Is cancer triggered by altered signalling of nicotinic acetylcholine receptors? Nature Reviews Cancer 9, 195–205.

Penton, R.E., Lester, R.A.J., 2009. Cellular events in nicotine addiction. Seminars in Cell & Developmental Biology 20, 418–431.

Quik, M., Wonnacott, S., 2011. α6β2* and α4β2* nicotinic acetylcholine receptors as drug targets for Parkinson’s disease. Pharmacol. Rev. 63, 938–966.

Mehta, M., Adem, A., Kahlon, M.S., Sabbagh, M.N., 2012. The nicotinic acetylcholine receptor: smoking and Alzheimer’s disease revisited. Front Biosci (Elite Ed) 4, 169–180.