Tuesday, November 29, 2022

More utter metabolic nonsense

When will researchers stop writing utter nonsense about metabolism? I was reading this review:

Molecular Metabolism
12 November 2022, 101635
Nitin Patil Orla Howe, Paul Cahill and Hugh J.Byrne

Monitoring and modelling the dynamics of the cellular glycolysis pathway: A review and future perspectives and spotted this sentence in the text:

"Alternately, the activity of rate-limiting glycolytic enzymes can be determined by quantifying their catalytic products in vivo [115]. "

I thought, that can't be true, it's not possible to ascertain rate limitingness just from the products. So I checked out the citation they used:

Methods in Enzymology
Volume 542, 2014, Pages 91-114
Chapter Five - Techniques to Monitor Glycolysis
Tara TeSlaa and Michael A.Teitell

Well I was in for a treat, so many illogical statements in one paper. Here is one such sentence:

"While the activity of any single glycolytic enzyme is not a proxy for carbon flux through the entire pathway, specific enzymes limit the rate of glycolysis, and therefore, their activities control the maximum possible flux. Hexokinase, phosphofructokinase, and PK are the main rate-limiting enzymes in glycolysis."
v So authors are mixing up the Vmax for rate-limitation as if enzymes are even running at their Vmax. These enzymes, using the more classical definition of rate-limitingness, are not rate-limiting other than HK, but that depends on the organism and conditions. The reason they aren't rate-limiting is that they are regulated, which means any changes to their activity results in no change to the pathway flux. Not only that, it turns out that for the mentioned enzymes, particularly HK and PK, don't even have low Vmax's so even if they were running at Vmax they wouldn't be limiting the flux anyway. PFK is also not that low, since PDC and ENO have lower Vmaxs (this is in yeast). The point is there is no necessary correlation between rate-limitingness (however they define it) and an enzyme's Vmax. There are other reasons at play for determining a Vmax.

Here is another one:

"while determining the activity of rate-limiting glycolytic enzymes can provide insights into points of metabolic regulation."

There is no reason why rate-limiting steps are regulated, quite the opposite in fact. I'm not sure how much experimental data, theory, or computational research need to be done to convince them this isn't true. I never did find any reference to my orginal quesiton in the 2014 paper. Me thinks the orginal authors didn't read the 2014 review. There is simply no way to tell if a step is rate-limiting or not just from its products. The authors also have a modeling section where they state:

"Ordinary and partial differential equation can be used for both deterministic and stochastic modelling."

what were they thinking?

And another:

Mass action kinetics, rate law (Michaelis Menten models, Hill kinetics),

MM and Hill models don't follow clasical mass-action kinetics, they show fractional kinetic orders.

The authors never mention Metabolic Control Analysis at all, which is a primary language for talking objectively about metabolic control and regualation.

We've obviously gone very wrong somewhere in our education and training of systems biology researchers.

Tuesday, September 27, 2022

Experimenting with GeoGebra

This is an example of using GeoGebra to interactively simulate a two step pathway, S1 -> S2 -> S3 using simple mass-action kinetics in each reaction.

Tuesday, August 16, 2022

Plot of 1/x using pgfplots

I noticed I couldn't find pgfplots version of the $1/x$ plot that describes $e$. I needed one, so here is the LaTeX I used.

\documentclass[margin=3mm]{standalone}
\usepackage{pgfplots}
\pgfplotsset{compat=1.18}
\usepgfplotslibrary{fillbetween}

\begin{document


\begin{tikzpicture}
\begin{axis}[
ytick = {1,2},
xtick = {0,1,2,3},
xlabel=$x$, ylabel=$y$,
ymax=2.5, xmin=0, ymin=0,
xlabel style = {anchor=north east},
ylabel style = {anchor=north east}
]
\addplot [color = blue, name path=A,domain=0:4, line width = 1.4pt, samples=200] {1/x};
\path [name path=B]
    (\pgfkeysvalueof{/pgfplots/xmin},0) --
    (\pgfkeysvalueof{/pgfplots/xmax},0);
\addplot [blue!20]
    fill between [of=A and B,
                  soft clip={(1,0) rectangle (2.71,25)},];
\node at (axis cs:1.5,1.2) {$y=1/x$};
\node at (axis cs:1.6,0.31) {Area = $1$};
\node at (axis cs:2.71, 0.82) {$e$};
\addplot[-latex] coordinates
           {(2.71,0.75) (2.71,0.45)};
\end{axis}
\end{tikzpicture}

\end{document} 



Friday, July 29, 2022

To paraphrase an old saying....

 You can lead a modeler to a technical solution, but you can't make them use it.


This rephrasing of an old saying was inspired by our reproducibility work. There exist technical solutions to publishing reproducible results, and yet most studies are still not reproducible because we choose not to use those solutions. 



Sunday, June 26, 2022

MCA Rediscovered


It looks like someone has rediscovered metabolic control analysis (MCA).

A structural approach to understanding enzymatic regulation of chemical reaction networks Biochem J (2022) 479 (11): 1265–1283. Atsushi Mochizuki

The analysis is exactly the same as MCA but uses different symbols and they focus on the unscaled sensitivities instead. eg the r symbols are the unscaled elasticities. The core equation (4) can be found in equation (1) of the appendix of the following paper, and I am sure its been published elsewhere too:


However, unlike the original MCA, the latest reincarnation doesn't include support for conserved moieties so as it stands it's somewhat limited. Note equation (1) in the above paper includes additional terms to take into account any conserved moieties. 

What is more concerning is that the reviewers of the paper never spotted this duplication of work. 





Tuesday, April 19, 2022

Lorenz Attractor

I wanted to test out Google's skia 2D library so I wrote a simple interactive Lorenz attractor app over the weekend. Source code and binaries at 

https://github.com/hsauro/Lorenz_fmx

Binaries are only for Windows at the moment but hope to have a Mac version in a couple of weeks.

I used Object Pascal to write it but it should be easily translatable to something like C# and WinForms which were modeled after Object Pascal and the VCL. Looks like skia does a better job at antialiasing lines and also it's quite fast.

I use a simple Euler integration scheme to solve the Lorenz ODEs, nothing fancy but it seems to work perfectly well. 




Tuesday, April 5, 2022

Analogmachine reborn

I decided to rebuild my blog on blogger. Originally I used my own WordPress site but discovered that maintaining it was quite time-consuming. The main problem was stopping the site from being hacked and corrupted.  This happened again recently and it prompted me to move to a more resilient and less demanding platform.

Monday, April 4, 2022

Theory of the Origin, Evolution, and Nature of Life by Andrulis

 Ars Technica has an interesting article that I can't avoid bringing up here. The title of the article is:

"How the craziest f#@!ing "theory of everything" got published and promoted"

The Ars Technica article describes a paper (Theory of the Origin, Evolution, and Nature of Life) published by an assistant professor from Case Western. The author of the paper describes a theory of everything which because of a press release from Case Western manages to get amplified out of all proportion even though the content is highly suspect. Just reading the first sentence is enough to raise a big red flag. That sentence is:

"How life abides by the second law of thermodynamics yet evolutionarily complexifies and maintains its intrinsic order is a fundamental mystery in physics, chemistry, and biology [1]."

There is no mystery here as the author suggests. If he had bothered to read up on Prigogine's and Nichols well-known work on non-equilibrium thermodynamics published decades ago he would have an explanation for this "mystery".

Testing Code Formating using hightlight.js


# Python Program to find the area of triangle

if x == True:
   pass
   
a = 5
b = 6
c = 7

# Uncomment below to take inputs from the user
# a = float(input('Enter first side: '))
# b = float(input('Enter second side: '))
# c = float(input('Enter third side: '))

# calculate the semi-perimeter
s = (a + b + c) / 2

# calculate the area
area = (s*(s-a)*(s-b)*(s-c)) ** 0.5
print('The area of the triangle is %0.2f' %area)

Sunday, April 4, 2021

A note on ex nihilo

In terms of the origin of the universe, "Out of nothing" is something we often hear from theists who argue that something, i.e the universe,  cannot come from nothing from which they conclude that it must have come from something, which they call God. 

The notion of nothing 'before' the universe however is problematic because what is 'nothing'? It is better to refer to the 'nothing' as something that isn't space-time, rather than a simple negation of space-time. What 'out of nothing' seems to imply is that space-time cannot come from space-time which seems reasonable.

All our notations of cause and effect and the logical absolutes only operate within our own space-time. It is impossible for us to contemplate anything that isn't space-time, so asking questions about creation is extremely difficult if not impossible. Jumping to God as an explanation, however, makes no sense since we can't comprehend anything outside space-time, let alone an all-powerful sentient being to which the bible attaches all sorts of very specific properties. 

Thursday, September 3, 2020

Mathpix Snip

Originally Posted on  by hsauro

I came across this amazing tool that can convert images of math equations into LaTeX format. The tool can be found at https://mathpix.com/. I’ve tried it on a number of texts including some not so clear and it does a fantastic job of converting to LaTeX. Here is a screen showing part of a page from Paul’s Online Notes:



The way it works is you select the screen icon on the mathpix tool, the entire screen goes black and white, then we draw a square around the section we want to convert and that’s it. In this case, it generates the following latex

We’ll start with finding the derivative of the sine function. To do this we will need to use the definition of the derivative. It’s been a while since we’ve had to use this, but sometimes there just isn’t anything we can do about it. Here is the definition of the derivative for the sine function.
$$
\frac{d}{d x}(\sin (x))=\lim _{h \rightarrow 0} \frac{\sin (x+h)-\sin (x)}{h}
$$
since we can’t just plug in $h=0$ to evaluate the limit we will need to use the following trig formula on the first sine in the numerator.
$$
\sin (x+h)=\sin (x) \cos (h)+\cos (x) \sin (h)
$$
Doing this gives us,
$$
\begin{aligned}
\frac{d}{d x}(\sin (x)) &=\lim _{h \rightarrow 0} \frac{\sin (x) \cos (h)+\cos (x) \sin (h)-\sin (x)}{h} \\
&=\lim _{h \rightarrow 0} \frac{\sin (x)(\cos (h)-1)+\cos (x) \sin (h)}{h} \\
&=\lim _{h \rightarrow 0} \sin (x) \frac{\cos (h)-1}{h}+\lim _{h \rightarrow 0} \cos (x) \frac{\sin (h)}{h}
\end{aligned}
$$
As you can see upon using the trig formula we can combine the first and third term and then factor a sine out of that. We can then break up the fraction into two pieces, both of which can be dealt with separately.

Which when processed by LaTeX becomes:



This is rendered inside the mathpix tool but you’ll notice there isn’t a significant difference between the original and the converted image. I’ve converted some fairly rough images and it generally succeeds. It also gives you a confidence level on how well it thinks it’s done. It took under a second to generate the LaTeX.

As a harder test, I decided to attempt to translate a page from Jim Burns’ thesis. This is a thesis from the 1970s that was typed and the equations a combination of typed characters and hand drawn. The following image shows page 93 which is part of the proof for the connectivity theorem.



And here is the image analyzed by mathpix. Remarkably the conversion is almost perfect, the equations, in particular, are translated almost without error, even getting the subscripts on the subscripts correct. It got the delta F1 wrong at the start and it interpreted a mark on the paper as an apostrophe. I tried other pages that included derivatives and these converted without incident.