neurotransmitter - Do mammals develop tolerance to anticholinergics?

The tolerance to antihistamines is an ongoing debate in the community. Although there were early studies citing that tolerance to therapeutic effects of antihistamines could occur, more recent data, especially studies involving nonsedating antihistamines, indicate that tolerance to the therapeutic effects of these drugs does not occur.

Overall, it seems like the mechanism driving the sedation vs. the therapeutic effects are two separate down stream effects of regulating the inflammatory response. Neuronal tolerance and synaptic transformation is a fairly fluid and ongoing process, whereas the inflammatory response is much more robust. Meaning, the neuronal response is, theoretically, more able to adapt to chronic use of the anihistmaine while still giving the therapeutic effect. This hypothesis is supported by data, but yet to be confirmed, thus creating polarization on the topic.

Also see, Goodman and Gillman Pharmacological Principles of Therapeutics

human biology - Does mixing alcoholic drinks really make you more drunk?

There is plenty of anecdotal evidence ("beer after wine and you'll feel fine, wine after beer will make you feel queer") that mixing alcoholic drink types leads to a stronger effect, but I can't find any true studies.

In fact the only studies I found are looking at mixing energy drinks and alcohol (mixing with energy drinks increases motivation for more alcohol (in college students) [1]), and discussed mixing caffeinated beverages with alcoholic ones [2].

Are there any studies specifically looking at mixing alcoholic drinks? They would have to compare people drinking the same amount of alcohol, but some people mixing, others drinking the same thing. Maybe even a cross-over study design? Same people do both, one after the other? The only way to get an unclouded answer!

I am also interested in the follow-up why question: Why does mixing some drinks make you more drunk? Presumably it is something in wine (for example) that interacts badly with something in beer at the chemical level (the metabolites maybe)?

1. Marczinski CA, et al, (2012). Mixing an Energy Drink with an Alcoholic Beverage Increases Motivation for More Alcohol in College Students. Alcohol Clin Exp Res, epub. doi: 10.1111/j.1530-0277.2012.01868.x


2. Touyz LZ, (2011). Mixing drinks and concocting troubles. Curr Oncology, 18(6):262-3. PubMed; FullText.

structural biology - RMSD during conformational transition in proteins

When I was investigating the differences between protein structures obtained by X-ray crystallography and NMR spectroscopy, I found the paper [1] compairing structures of several proteins resolved both with X-ray and NMR. The average RMSD between NMR and Xray structures is 1.4Å (max. 3.6Å), and the average RMSD between different NMR structures for same protein is 0.4Å (max. 1.3Å). I've checked some proteins studied in this paper, and they are mostly within 100–200 residues long.

However, there are plenty of papers (e.g. [2], [3], dealing with similarly sized proteins) that base their statements about conformational transitions on structures with RMSD difference 1–2Å.

I wonder what is considered reliable RMSD between two structures to draw any solid conlusions about conformational transitions (e.g. upon ligand binding) as opposed to simple thermal fluctuations or perturbance caused by the method to obtain structure?

Of course, the best way (at least in my opinion) to distinguish actual conformational transition from thermal fluctuations is to measure its lifetime, but it is often not an option.

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1. Andrec M, Snyder DA, Zhou Z, Young J, Montelione GT, Levy RM. 2007. A large data set comparison of protein structures determined by crystallography and NMR: statistical test for structural differences and the effect of crystal packing. Proteins 69: 449–65.




2. Grant BJ, Gorfe AA, McCammon JA. 2009. Ras conformational switching: simulating nucleotide-dependent conformational transitions with accelerated molecular dynamics. PLoS Computational Biology 5(3): e1000325.




3. Kumaraswami M, Newberry KJ, Brennan RG. 2010. Conformational plasticity of the coiled-coil domain of BmrR is required for bmr operator binding: the structure of unliganded BmrR. Journal of Molecular Biology 398: 264–75.