Look who one of the co-authors is in this journal abstract. 🙂
You can find the abstract HERE
Please show a little class in the comment section in consideration of my co-authors who are only guilty by association with me. You can trash talk about me, but in deference to the innocent parties, please don’t demean or trivialize their work, ok? Set a good example and celebrate what other people do in contributing to the advancement of knowledge.
Anyway, the abstract:
Topoisomerase II is a critical enzyme involved in unknotting and detangling DNA during replication, transcription, and cell division. Humans have two isoforms of topoisomerase II, α (Top2A) and β (Top2B), originating from genes on separate chromosomes and displaying distinct functional roles. In addition, these enzymes are the target of several successful anticancer therapeutics. Unfortunately, these agents are nonselective and a growing body of evidence implicates Top2B as a mediator of off-target toxicities, while Top2A is likely a better target for disruption of cancer cell growth. The isoforms share about 65.2% amino acid identity primarily in the N-terminus and the core regions, which contain the catalytic domains of the enzyme and the regions targeted by all clinically-relevant anticancer agents. On the other hand, the C-termini of the human enzymes share only ~30% amino acid identity across ~400 amino acids. The carboxy terminus does not participate in catalysis, but has been hypothesized to have a role in the regulation of topoisomerase II activity, which may explain how these proteins are independently regulated. Since the C-terminal region has been largely unexplored, we undertook an analysis to identify key differences between the C-termini that may help explain the differential regulation of the topoisomerase II isoforms. The relative rates of synonymous (dS) and nonsynonymous (dN) DNA substitutions between the isoforms suggests that these sequences are under purifying selection for functional constraint (dN/dS = 0.25; P < 0.0001, Z test, 1,000 bootstrap replicates). The 434 C-terminal codons, however, had a relatively high dN/dS ratio of 0.59 (P < 0.0001), reflecting elevated amino acid diversity. In addition, bioinformatic evidence from Phosphosite (Phosphosite.org) indicates that nearly half (91/191 for Top2A) of the putative post-translational modification (PTM) sites are found in the C-terminus. Of the PTM sites found in the Top2A C-terminus, over half (~50) are distinct from those found in Top2B. Aside from sequence characteristics, protein-protein interaction data from the Biogrid database (thebiogrid.org) indicate that ~143 proteins have interaction evidence with either Top2A or TOP2B. Of these proteins, only ~34 are confirmed to interact with both isoforms and several are known to interact with the C-terminal domain of Top2A or Top2B. Taken together, these data suggest distinct sequence, PTM, and interaction profile characteristics for the C-termini of the isoforms of Top2, which may provide critical insight into the differential regulation of these enzymes. We hypothesize that these results provide the foundation for topoisomerase II isoform-specific targeting strategies for anticancer therapeutics.
The highlighted portion above was my focus along with some of the co-authors. My involvement actually originated from a discussion I started at TSZ, specifically comments like this:
Promiscuous Domains are Better Explained by Common Design, Comment 8/29/18
I mailed some of the graphs I developed and posted at TSZ to the lead author in September 2018, and he was so appreciative he listed me as co-author and used my graphs at a poster presentation.
It actually took about 4 weeks of combing through data to put something coherent since I was learning the ropes on the relevant databases, and there were several dead-ends in trying to connect the bio-grid data (mentioned above) to the PTMs I was cataloging. I was hoping to find promiscuous motifs in the proteins listed in the interactome/biogrid data with the motifs that were surrounding the PTMs in TOP2A and TOP2B, but to no avail since kinases perform the “write” operation on amino acids have degeneracy in what amino acid motifs they target.
This dead-end was so daunting, I had to simply quit and hope that work on Kirk Durston’s K-Modes algorithm could solve the problem of connecting the PTMs on TOP2A and TOP2B with the PTMs on the proteins listed in respective interactomes listed through biogrid. I mentioned Kirk’s paper HERE.
Again, if you wish to trash talk about me, I’ll accept it, but please don’t demean the hard work of my co-authors just because I’m listed with them (somewhat by accident).
Thanks again to all the participants at TSZ who help get my work showcased in the FASEB journal abstract and at the Conference of Experimental Biology this past April, 2019 connected to the publication of the abstract. The editorial review I received here at TSZ was crucial in helping prepare a compelling case for some of the ideas presented in the abstract and poster.
Congrats Sal!
I’ll check the full text when I get to the office on Monday…
Unfortunately, these agents are nonselective and a growing body of evidence implicates Top2B as a mediator of off-target toxicities, while Top2A is likely a better target for disruption of cancer cell growth. The isoforms share about 65.2% amino acid identity primarily in the N-terminus and the core regions, which contain the catalytic domains of the enzyme and the regions targeted by all clinically-relevant anticancer agents.
This sounds interesting and familiar…😊
DNA_Jock should know more about it..
Thanks J-mac.
LOL. You somehow couldn’t rest content with having possibly contributed to some research.
Of course, let’s not forget that this thread begins with a title in which you congratulate yourself. Classy.
I think this is what they mean by irony.
I mentioned in this comment on another thread, the diagram I concocted below.
I particularly like this diagram because it ties in Transposable Elements, CTCF Zinc Finger Protein, and TopoIsomerase 2B (Top2B).
Chemotherapies target both Top2B and Top2A, but the 200,000 mean base-pair “loop” in the diagram is critical to gene regulation. Malformation and misregulation associated with the loop is bad juju. Chemotherapies that end up interfering with the role of Top2B might then adversely affect unintended cells. If we can focus the chemotherapies to Top2A on specific cells, we MIGHT limit the damage done in chemotherapies to healthy cells and do more damage to cancer cells.
But there is sooo little we know of how biology works. I’m hoping work on Kirk Durston’s papers will help advance knowledge a little further on this problem, but we’ve only scratched the surface.
The “CCACNAGGTGGCAG” consensus motif is spread across 55,000-65,000 locations on the genome and is critical gene regulation. In mice, these motifs often sit on Transposable elements — a Providential coincidence, I’d say. 😉
The above diagram is the focus of the next big NIH initiative and child of the much maligned (by evolutionary biologists) ENCODE project, namely the 4D Nucleome project:
That’s alright, you can trash me, but please, not the others. Alright, they’re innocent.
The above connection of the CTCF binding sites relates to this amazing paradox discovered by the head of the NIH himself, Francis Collins, and the expelled NIH evolutionary biologist Richard Sternberg.
When Sternberg reported on the paradox, many ID proponents were (figuratively speaking) opening the Champagne bottles.
The fact Top2B in the mix is icing on the cake.
ENCODE is “maligned,” not because of the important data it collected (nobody denies that the data is of enormous importance), but because of the hype in interpreting some of their results.
It’s curious how you ended up in that abstract’s list of authors without actually understanding any of what’s being presented. Again, otherwise you’d understand why the no-PUCA is a no-brainer, and why you should stop insisting on it as if it was something that evolutionary biology somehow demanded.
Still, congrats. Hopefully, that gets you started to a productive career whereby you might, sometime in the far future, finally understand some basic biology and biochemistry and thus stop [unawarely] embarrassing yourself.
LOL!
The lead author is a much better position to judge my level of understanding than you, he’s a respected researcher in the field of Topoisomerases.
You’re just trash talking me because you can’t actually refute my arguments.
Congrats.
Thanks, Walto.
You cannot possibly know that Salvador. If you understood the methods and molecular biology related to the abstract you’d have noticed that I could even be a reviewer of the manuscript (if it gets submitted). Don’t despair, if it came to that, I’d say no. Though I would judge it fairly, I’d be vomiting at the idea of reading a manuscript containing all those words you don’t even understand, and yet they’ve put you as a coauthor.
Refute? For that there must be something to refute. This has been about getting you to understand the abysmal ignorance you display in those messed up diatribes of yours that you call “arguments.” Your understanding is so poor that you haven’t even noticed that I wasn’t trying to refute anything.
And now he altered the thread title to make it sound a bit more humble. You couldn’t make this up.
Dated April 1? Hmmmmm.
Congrats, too, Sal.
Pity this abstract was not peer-reviewed; a reviewer would probably have objected to the goofy use of the term “off-target”. The effect of doxorubicin, etoposide and anthracyclines on Top2beta might be “disadvantageous”, “problematic”, or many other things, but it is really NOT “off-target”.
The effect of top2 inhibitors on top2 is ON-target.
As to the thesis of the abstract, while it is a nice idea for avoiding the top2beta-mediated side effects, targeting less well conserved regions of Top2 runs the risk of allowing for easier ‘escape’ mutants. Problematic in oncology drugs.
Finally, I will promise not to disparage Sal’s eight co-authors, if he promises not to disparage the hundreds of thousands of scientists with whom he has NOT published a meeting abstract.
🙂
ETA: see for example Nitliss, 2009
I meant I would not review it. I’d say no to the editor’s request for my review.
(Shit didn’t notice that came out so wrong when I wrote it.)
I thought you said ID wasn’t science Sal. Make up your mind on that.
Yep. In my experience, junior students often suggest targeting less conserved regions, and it’s always this tiny little detail that they didn’t think about.
The point is to suggest formulation of chemotherapies (if possible) that can target Top2A and not Tob2B at the same time which etoposides do.
But as to the wording consider this paper:
https://www.ncbi.nlm.nih.gov/pubmed/23085982
Sal,
Are you aware of any trials targeting specific cancer types?
Thanks, that was decent of you.
Thanks, DNA_Jock.
Thanks to all the participants at TSZ who have provided critical and often hostile feedback to my ideas. It has been a valuable quality assurance check to some articles and presentations I’ve been making which might get into a pro-ID/anti-Common Descent book some day for science students.
Anyway, thanks to all for their feedback on my Zinc Finger thread, it was highly useful in helping me formulate a solid 2-part presentation.
Here are the links to my slides. Let me know if they work. I planning on redoing them into youtube videos and articles.
https://debateevolution.files.wordpress.com/2019/05/promiscuous_domains_part1.pptx
https://debateevolution.files.wordpress.com/2019/05/promiscuous_domains_part2.pptx
Thats cool. I know nothing about the subject but am glad to see people thinking/figuring out things or as they call it DOING SCIENCE.
its good also that its from a creationist, as i understand you are, and TSZ shows its attracting scientific people.
Thanks for telling us too . Its cool to see progress in science stuff.
I wish you would answer my question about the old UD forum you ran. I think it was you. as i was seeking a article there.
Congrats from Canada.
Seems to me to be a odd way of speaking about toxicokinetics/toxicodynamics of xenobiotics. I can think of many examples where the distinction would be so blended between the two concepts that any discussion would be quite muddled trying to use that terminology. Examples would include instances of parent compound toxicity and reactive metabolite formation. I personaly don’t know any toxicologist/pharmacologist that speaks using those terms and I know/knew more than a few throughout the years.
In retrospect, I think it is likely phrasing used by people with limited training in toxicology.
stcordova,
This could use clarity in my opinion. Is this the abstract? Is the paper an attempt to characterize the proteins for researchers?
Thank you for your feedback. The abstracts were for posters at the Conference for Experimental Biology in Orlando 2019. It was designed to get feedback.
The lead author IS a protein researcher. He was co-author in this article in NATURE described here:
https://www.lipscomb.edu/news/pharmacy-professors-protein-research-published-journal-nature
Sal,
At a Christian school where you made a presentation a couple of years ago.
This all makes more sense now.
Actually a system of Christians Schools. I spoke at their central scholars conference, and in fact Francis Collins, head of the NIH spoke at the same gathering as Keynote Speaker a few years before my little (non-Keynote) talks in 2017 (on developments at NIH ENCODE) and 2018 (Nylon Eating Bacteria). The colleges in this particular system are affiliated with the Church of Christ denomination, Lipscomb is only one of several in the system:
keiths,
What does the fact that it is a Christian University have to do with anything keiths? Would you make the same qualifications about a school doing work on evolution and having professors in the biology department who were atheists?
Everything. Especially when Sal is involved.
You conveniently elide over the fact that you are now talking about what are not “atheist universities” but what has become merely schools.
Why? Why did you not say atheist University?
I’ve got no problem with a self avowed creationist doing science.
As long as they do actual science. Unlike, for example, the RATE liars for Jesus.
Oh crap. The typical bullshit about “different interpretations.”
Relax, phoodoo. I’m just pointing out that it makes more sense for Sal to end up as co-author on a paper whose lead author is a fellow Christian (and fellow creationist!) that he’d met at a conference, versus a paper with a secular lead author he’d never met before.
Entropy,
Deweese is technically right. There’s a sensible and rational interpretation of the evidence, adopted by the majority of scientists, and then there’s the batshit creationist interpretation.
Right, but I am pointing out the duplicity of the materialist’s mindset, which is prevalent in academia. It never gets pointed out when an atheist writes a paper on evolution, but if its a Christian, like Behe for instance, then his religion is often sited- as if their Christian belief automatically means the conclusion is suspect.
And I am not even saying their bias isn’t relevant. It may well be. But by the same token, the atheist bias is quite often, if not always, relevant.
phoodoo,
I don’t think much of a deal is made when theists write articles about evolution. Usually nobody knows what the religion of some author of a research paper is. But if somebody writes a paper on evolution who makes a big deal about some aspect of it being wrong or faked or whatever, that’s a bit different, no?
I mean, Darwin was a Christian, wasn’t he?
walto, to phoodoo:
Right. If Behe were doing nothing but good science, no one would object. When he does bad (or even dishonest) science, that gets our attention.
I still can’t believe he doctored that table. What was he thinking?
Not according to him. Darwin said, “an Agnostic [recent neologism via Huxley, 1870] would be the more correct description of my state of mind.” Not his heart, mind you; he mainly left that out. Yet that surely ‘counts’ for something too. https://en.wikipedia.org/wiki/Religious_views_of_Charles_Darwin
“There is grandeur in this view of life, with its several powers, having been originally breathed by the Creator into a few forms or into one; “
I guess by Creator Darwin meant sheer dumb luck…
If people twist the bible to accommodate their origin views, what’s stopping them from twisting Darwin’s beliefs to do the same?
So whenever we see bad science, and there is a LOT of it, and it is done by an atheism (a lot of it) we better assume its related to their atheism?
https://www.businessinsider.com/why-most-published-scientific-research-is-wrong-2013-10
OK. Thanks.
If somebody makes a big deal about their atheism and writes a shitty science paper related to those views, he’s definitely fair game. Why not? Same as the rules for theists.
phoodoo,
As walto says, it’s symmetrical. Bad (or dishonest) science motivated by an agenda — religious, atheistic, political, economic, etc. — is fair game for criticism, and it’s certainly legitimate for the agenda to be pointed out.
You’d have to make your case, however.
J-Mac,
“[W]hat’s stopping them from twisting Darwin’s beliefs”? Darwin’s recorded words.
“In March, 1863, Darwin wrote about this inclusion [not in the 1st edition] of the three significant words ~ by the Creator ~ to his friend and scientific confidante Joseph Hooker:
‘I have long [just over 3 years] regretted that I truckled to public opinion & used Pentateuchal term of creation, by which I really meant ‘appeared’ by some wholly unknown process. It is mere rubbish thinking, at present, of origin of life; one might as well think of origin of matter’.”
Origin of life – origin of matter – by the Creator – by some still wholly unknown process?
Which do I have to make my case for, the bad science, or the relation it has to atheism. Because I am not seeing anyone making the correlation between bad science and Christianity, only that they claim something is bad science, and that the bad science came from someone who was a Christian they claim.
Finding bad science done by atheists? Why that’s easier than finding a yarmulke in Tel Aviv.
Duplicity of the materialist’s mindset? As if we dont’ hear the same total shite from religionists about how it’s all just because we hate God and want to sin or similar such nonsense?