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Archive for the ‘Biochemistry’ Category


 

Today was the culmination of Zaid’s PhD journey, when he successfully defended his thesis on the use of gold nanoparticles to probe the mechanism of action of a peptide that inhibits ‘flu virus infectivity. Though he approached his viva with trepidation, his beaming face afterwards told a different story. The usual smattering of corrections, a paper already up on Bioarxiv ready to submit for peer review and another to put up on Bioarxiv, and in a few weeks he will be truly done, with a CV to match.

 

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Friday Pat Eyers pushed our two papers on new screens we have developed for sulfotransferases up onto Biorxiv. More about the history of this work later. For now the briefest of summaries.

The heparan sulfate 2-O sulfotransferase paper is here

and the tyrosine sulfotransferase paper is here.

The key messages are:

(1) Mimetics of PAPS, the universal sulfate donor, that inhibit sulfotransferases are present in kinase inhibitor libraries.

(2) We demonstrate selectivity, in that some compounds inhibitor one sulfotransferase better than they do the other.

(3) PAPS mimetics look like providing a rich vein of sulfotransferase inhibitors of varying selectivity, rather like ATP mimetics have done for kinases.

(4) We have two very effective high throughput screens, which means no sulfotransferase is now beyond our reach.

Sulfation has been frustrating due to the lack of chemical tools to selectively inhibit a particular sulfotransferase. With these two papers we can foresee such tools in the not too distant future and with these, we can unpick the role of sulfation in biology, from development, through homeostasis to disease.

Exciting times!

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While reading and correcting a PhD thesis on ‘flu virus I thought I would check what strains I have encountered.

In February 1978 after playing a match for what was then RC Hermance (now HRRC) on a Sunday. I fell ill on the Tuesday, called home and was picked up by my mother.  Unfortunately, though a very smart person, critical thinking was not part of her education, which stopped at 16, and she dabbled in homeopathy. So I got sicker, spent 4 days at 41°C or above, but happily was then under our local GP (my mum was not daft) and was receiving anti-pyrogenic injections.  That time is a bit hazy, though my mother did say she thought she would lose me, so I must have been pretty ill.  This turns out to be an H1N1 virus, which only affected those under 26 years old. As this article  argues this particular ‘flu virus seems likely to have emerged from a lab (bio warfare) accident in the USSR or from vaccination (infection?) tests with live virus in China or the USSR, since the strain was almost identical to that from 26 years earlier and had not been seen in the wild in the intervening quarter century.

Fast forward to 1999 and I get a call from Tristan Bernard, past teammate at RC Hermance (now Life President, well deserved, a true evangelist for the sport) asking for a bed for him and a mate who were watching the World Cup; Liverpool was on a commute between games. A great evening, stated off in the Vines, and finished with a meal sometime after 2 am. A few days later ‘flu – this was I think brought to the UK by an Australian supporter and was an H3N2 strain virus. Not a major health incident for me though, a few days in bed and I was fine.

So the worst that rugby has done for me is ‘flu, twice, though I do have a wobbly ankle joint too.

As a side issue the murky past of the 1978 H1N1 ‘flu virus highlights the stupidity of allowing the gain of function engineering of pathogens. Regardless of whether the 1977 ‘flu virus did re-emerge from a lab, accidents, by definition, happen and viruses such as ‘flu remain an obvious war tool. I would be far more worried by N. Korean efforts in the molecular biology of viruses than by a few missiles with nuclear warheads. The latter can be stopped in flight, whereas viruses cannot.

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Congratulations to Aiseta!

On Monday 4 December Aiseta Baradji successfully defended her thesis. A long journey and a hard one as ever with its ups and downs, surprises and a certain amount of head scratching over data that push us in new directions. In the end a great thesis that will be consulted in the labs of her supervisors for a long time. Now onto the next phase.

 

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Two postdoc positions are available in my lab.

Both are part of the larger, European Commission-funded FET-Open programme, ArrestAD, which has recently been funded.

Position 1 aims to characterise heparin-binding proteins in Alzhiemer’s disease.

Position 2 aims to develop inhibitors to Golgi sulfotransferases. (more…)

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ArrestAD

The ArrestAD team had its kick off meeting in Paris on 5 January 2017. This was held on Paris, the base of our coordinator, Dulcé Papy-Garcia and was hosted by the APHP in the Espace Scipion. Team members from outside Paris stayed at the Hotel La Demeure  situated nearby and though on the Boulevard St Marcel, nice and quiet.

The kick off meeting started with a presentation form our coordinator, which provided the backdrop for the day. Science presentations from the participants then followed. These provided an overview of the position of the field of the participant and then summarised research plans. In a multidisciplinary project, one cannot be fully up to speed with the other fields, so we all learned a lot. The more technical part of these presentations gave us an opportunity to discus the nuts and bolts of our research plans and how these fitted together. It…

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Changye Sun and Yong Li, who successfully defended their PhD theses in November have published a paper each in Open Biology on the interactions of fibroblast growth factors (FGFs) with glycosaminoglycans:

Heparin binding preference and structures in the fibroblast growth factor family parallel their evolutionary diversification

and

Selectivity in glycosaminoglycan binding dictates the distribution and diffusion of fibroblast growth factors in the pericellular matrix.

(more…)

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