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Posts Tagged ‘glycosaminoglycans’


Of nanoparticles, cells and polyanions

It is the end of semester 2 so it’s marking season. Since we double mark (a good thing), the final year research projects are marked by both supervisor and an assessor, a member of staff who is not involved in the project. One of the projects I marked was Gemma Carolan’s on “How do SmartFlares RNA detection probes reach the cytosol? Available are the PDF of report, and posts here and here.

I had a sense of déjà vu while reading the project – the clear endosomal location of the SmartFlares, regardless of the DNA sequences brought me back to the days when antisense was the technology of the future for medicine.

While evaluating new technology it is useful to go back and look at other high flying technology. The reality is that it takes decades before we know whether the promise (and hype) were justified; this is true for any hot topic from stem cells to nanoparticles and graphene.

Antisense effects can be mediated by RNAse H, an enzyme that specifically cleaves RNA-DNA duplexes and which protects our cells from RNA viruses. There are other mechanisms, e.g., interference with splicing or translation, but the RNAse-H mediated transcript degradation should be central to many antisense effects. There were many papers reporting specific effects (evidenced by differences between sense, antisense and scrambled oligonucleotides sequences). These certainly contributed to success of individuals and of institutions, e.g., in UK Research Assessment Exercise and grant awards.
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I am a fan of PubPeer, as it provides a forum for discussion between authors and the wider community, something I have discussed in a number of posts (two examples being here and here). Two days ago, My colleague Mike Cross came by my office, having just delivered a pile of exam scripts for second marking (it’s exam and marking season), asking if I had seen a comment on our paper on PubPeer. I had not – too many e-mails and too busy to look at incoming!
So I looked at the question, which relates to panels in two figures being identical in our paper on neuropilin-1 and vascular endothelial growth factor A (VEGFA) – indeed they are labelled as being identical.
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Congratulations to Quentin Nunes, who today successfully defended his PhD today. His first paper from his thesis work was published in late 2013 in Pancreatology. This was an analysis, using public datasets of mRNA expression data, of the putative heparin-binding protein network in the healthy pancreas and in pancreatic digestive diseases. The latter part of his thesis work will be submitted for publication soon (watch this space!) and is a proteomics analysis of heparin-binding proteins in mouse pancreas and in a mouse model of acute pancreatitis.

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Virginie’s first paper on her thesis work, “Network based meta-analysis prediction of microenvironmental relays involved in stemness of human embryonic stem cells” was published yesterday at PeerJ. She first put it up as a preprint (v1 here
revised v2 here and then submitted it – my first experience of this and something I will certainly do again.
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There are many prizes for cultural activities, of which science is one. This week has seen the announcement of the Nobel prizes, a little earlier the IgNobels were awarded. There are, of course many other prizes. I have decided to set up my own.
A question that bugs me and which loomed large while I read the excellent review by Ding Xu and Jeff Esko from UCSD on “Demystifying Heparan Sulfate–Protein Interactions” is how many extracellular proteins are there? (more…)

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Dan Nieves’ paper on an easy and accessible method to covalently conjugate proteins, sugars and indeed pretty much any biomoleucle onto nanoparticles has just come out in Chem. Commun. (more…)

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Kat’s paper on the interactions of neuropilin-1 with a heparan sulfate mimetic library of modified heparins is now published in The PeerJ
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Gradually, the structural problems in sciences are making their way to the surface. There have been articles in newspapers, The Economist and other magazines around the world on the subject. These are stimulated by the constant dripping of information and studies that sit awkwardly with the perceived notion of how science functions.

The high profile controversies tend to catch our attention, simply because of a sense of outrage amongst the wider community that nothing has been done to fix the problem, or that the fixes have been inadequate. Despite the outrage, it remains the case that only a very few are willing to put their head above the parapet and say something. There has been an interesting discussion of this on Athene Donald’s blog here.

Not surprisingly, the “reproducibility question” has gained quite a lot of traction( e.g., here and here). This leads to a simple question: what qualifies as a reproduction?

I argue that an important aspect of reproduction is that it is not necessarily actual reproduction, but a re-examination of observations made with better methods, which includes analytical tools. I have two examples of how scientists deal with the changing landscape of data and their interpretation in these circumstances. The first example is an instance of good practice and is common (or should be). The second seems to ignore the past and the clear message provided by the new data.

Example 1
This is from an excellent 2012 paper in Journal of Biological Chemistry that we discussed (again) in a recent lab meeting. It deals with the molecular basis for one member of the fibroblast growth factor family, FGF-1, being a universal ligand. That is, FGF-1 can bind all FGF receptor isoforms, whereas other FGFs show clear restriction in their specificity. These differences must lie in the structural basis of the recognition of the FGF ligand, the FGF receptor and the heparan suflate co-receptor. The first model put forward by Moosa Mohamadi was superseded in his 2012 paper, when he and his group obtained higher resolution structures of the complexes. This is a great step forward, as FGFs are not just important to basic biology, but they also impact on a wide range of diseases, as well as tissue homeostasis and regeneration. I highlight the following from the paper:
To quote (page 3073, top right column)
“Based on our new FGF1-FGFR2b and FGF1-FGFR1c structures, we can conclude that the promiscuity of FGF1 toward FGFR isoforms cannot be attributed to the fact that FGF1 does not rely on the alternatively spliced betaC’-betaE loop of FGFR for binding as we initially proposed (31).”

This paper provides a great example of how science progresses and is how we should all deal with the normal refinement of data and the implications of such refinements.

Example 2
This is from the continued discussions on whether the ligands on the surface of gold nanoparticles can phase separate into stripes. This has been the subject of a good many posts on Raphael Lévy’s blog (from here to here), following his publication a year ago of his paper entitled “Stripy nanoparticles revisited“, as well as commentary here and elsewhere.

Some more papers from Stellacci and collaborators have been published in 2013. The entire oeuvre has been examined in detail by others, with guest posts on Raphael Lévy’s blog (most recent here) and comments on PubPeer relating to a paper on ArXiv that takes apart the entire body of evidence for stripes.

What is quite clear, even to a non-specialist, is that the basics of experimental science had not been followed in the Stellacci papers on the organisation of ligands on nanoparticles published from 2004 to 2012. These basics include the importance of signal being greater than noise and ensuring that experimental data sample at sufficient depth to avoid interpolation; note that in no cases did instrumentation limitation require interpolation. This might happen to any of us, we are, after all “enthusiasts”.

To conclude, I refer to my quote from Seneca “Errare humanum est sed perseverare diabolicum

This excellent advice is clearly being followed by one FGF lab. It would be good if this advice was adopted more generally across science. When we see real data and analysis (the hard stuff) that challenges our previous data and interpretations, we should all be happy to change these. This is how science (should) move forward. If everyone did this, then there would be no discussion regarding reproducibility. When we see more of the same stuff, without a clear hypothesis testing experiment, we are veering towards metaphysics.

Metaphysics is not science. I note that when data are hidden, so that analysis is restricted, we again enter the realm of metaphysics – hence, for example, the call for open access to clinical trials data.

Links with some relevance to the Seneca’s advice, reproducibility and so on:
There is an excellent post at The Curious Wavefunction’s Sci Am blog
PubPeer: here and here
Neuroskeptic’s post at Discover
Chembark’s post in response to an ACS Nano editorial on reporting misconduct.

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The Fibroblast Growth Factor Gordon Research conference is biennial, so it almost follows a Martian calendar and next year it will be five years old. The fifth Gordon Research conference on Fibroblast Growth Factors will be held in Ventura, California, March 1-7 2014. This is THE meeting for all things FGF and assembles an eclectic mix of leaders in the field, young PIs, industry scientists and scientists in training. A Gordon Research Seminar will precede the full meeting. This was introduced at the last GRC (May 2012) and was very successful. (more…)

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Ruoyan’s paper on “Analysis of the FGFR Signalling Network with Heparin as Co-Receptor: Evidence for the expansion of the core FGFR signaling network” is out.
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