News

News, actualities, happenings, conferences and everything else that is related to the NEURAM project

 

 

A cell cycle-coordinated Polymerase II transcription compartment encompasses gene expression before global genome activation

Abstract

Most metazoan embryos commence development with rapid, transcriptionally silent cell divisions, with genome activation delayed until the mid-blastula transition (MBT). However, a set of genes escapes global repression and gets activated before MBT. Here we describe the formation and the spatio-temporal dynamics of a pair of distinct transcription compartments, which encompasses the earliest gene expression in zebrafish. 4D imaging of pri-miR430 and zinc-finger-gene activities by a novel, native transcription imaging approach reveals transcriptional sharing of nuclear compartments, which are regulated by homologous chromosome organisation. These compartments carry the majority of nascent-RNAs and active Polymerase II, are chromatin-depleted and represent the main sites of detectable transcription before MBT. Transcription occurs during the S-phase of increasingly permissive cleavage cycles. It is proposed, that the transcription compartment is part of the regulatory architecture of embryonic nuclei and offers a transcriptionally competent environment to facilitate early escape from repression before global genome activation.
Publication in Nature Communications, 10 from 11 February 2019.
The full article can be seen here: https://www.nature.com/articles/s41467-019-08487-5

 

Phosphino-Triazole Ligands for Palladium-Catalyzed Cross-Coupling

 

Abstract

Twelve 1,5-disubtituted and fourteen 5-substituted 1,2,3-triazole derivatives bearing diaryl or dialkyl phosphines at the 5-position were synthesized and used as ligands for palladium-catalyzed Suzuki−Miyaura cross-coupling reactions. Bulky substrates were tested, and lead-like product formation was demonstrated. The online tool SambVca2.0 was used to assess steric parameters of ligands and preliminary buried volume determination using XRDobtained data in a small number of cases proved to be informative. Two modeling approaches were compared for the determination of the buried volume of ligands where XRD data was not available. An approach with imposed steric restrictions was found to be superior in leading to buried volume determinations that closely correlate with observed reaction conversions. The online tool LLAMA was used to determine lead-likeness of potential Suzuki−Miyaura cross-coupling products, from which 10 of the most lead-like were successfully synthesized. Thus, confirming these readily accessible triazole-containing phosphines as highly suitable ligands for reaction screening and optimization in drug discovery campaigns.

Publication in Organometallics 2018, 37 (22) from 17 October 2018.

The full article can be seen here: https://pubs.acs.org/doi/pdf/10.1021/acs.organomet.8b00539

 

Balancing Bulkiness in Gold(I) Phosphino-triazole Catalysis

Abstract

The syntheses of a series of 1-phenyl-5-phosphino 1,2,3-triazoles are disclosed, within which, the phosphorus atom (at the 5-position of a triazole) is appended by one, two or three triazole motifs, and the valency of the phosphorus(III) atom is completed by two, one or zero ancillary (phenyl or cyclohexyl) groups respectively. This series of phosphines was compared with tricyclohexylphosphine and triphenylphosphine to study the effect of increasing the number of triazoles appended to the central phosphorus atom from zero to three triazoles. Gold(I) chloride complexes of the synthesised ligands were prepared and analysed by techniques including single-crystal X-ray diffraction structure determination. Gold(I) complexes were also prepared from 1-(2,6-dimethoxy)-phenyl-5-dicyclohexyl-phosphino 1,2,3-triazole and 1-(2,6-dimethoxy)-phenyl-5-diphenylphosphino 1,2,3-triazole ligands. The crystal structures thus obtained were examined using the SambVca (2.0) web tool and percentage buried volumes determined. The effectiveness of these gold(I) chloride complexes to serve as precatalysts for alkyne hydration were assessed. Furthermore, the regioselectivity of hydration of but-1-yne-1,4-diyldibenzene was probed.
Publication in European Journal of Organic Chemistry EurJoc from 30 July 2019.
The full article can be seen here: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ejoc.201900850

 

NEURAM Review Meeting

13 November 2018 in Brussels

 

From idea through invention to innovation

First is the spark, then the creativity, then the grant writing finally the implementation. Easy!
This is the short story of the NEURAM project.

 

The beginning: idea creation

How do you start a research project that ends up receiving €4.27 million from the European Commission? It is not too dissimilar to a “normal” national research grant except that you also need to find international experts who are willing to participate. This project started at the University of Birmingham where three of the principal investigators (Fossey, Mueller, Sik) work. The latter two work in the same building and also hold a British Heart Foundation project together already. So, it is natural that they would talk about science questions, new opportunities, fascinating technologies and so on. During one of the chats Ferenc (Mueller) mentioned an article where Raman spectroscopy was used to see genetic materials in fixed (dead) cells. This is definitely his field: he knows everything about genes, transcriptions, and all the complicated processes that happen in cells. Attila knows a lot of small things in many fields, many are useless, and some are occasionally useful. His input here was some knowledge on Raman spectroscopy that he briefly used in an arts project to identify the age of Chinese cloisonné objects (ancient metalwork objects that have nothing to do with biology). On top of that he knew the funding members of the microscopy company Femtonics in Budapest, Hungary where he worked many (many, many… ) years ago. After the initial idea had bounced around for a while, it looked feasible that with stimulated Raman spectroscopy (SRS) the transcription (the first step of gene expression, in which a particular segment of DNA is copied into RNA) can be visualized in living cells. Since Attila is a neurobiologist, the obvious target of where to look at gene transcription was the brain. Because Ferenc works on zebrafish (little creatures that geneticists love due to their transparency) the project was formulated: investigate how genes are copied to RNA using SRS first in the zebrafish brain, then move to more complicated systems, such as mouse and human brains.

 

The beginning: team building

Generating the idea is the first step in a complex project, but it will not go very far if you don’t have the right network of colleagues to help get it off the ground. Fortunately Balazs Rozsa and Gergely Katona (Femtonics) knew an expert in the spectroscopy field, who already had experience in Raman spectroscopy. Conveniently Miklos Veres (Wigner Research Institute) works in the same city (Budapest, Hungary) where Femtonics is located. Brilliant, only two members were missing from the dream team: a chemist with expertise in synthetic chemistry and a neurobiologist who is an expert in social behavior and works on zebrafish. Ferenc already worked with John S. Fossey (Birmingham) and, knowing that he is an experienced synthetic chemist, managed to convince him to get involved. Coincidentally, Ferenc, Balazs and Gergely all knew Herwig Baier (a word famous neurobiologist working in Munich) and after successfully pitching the idea to Herwig, we had the team! This is the perfect illustration of the power of networks (in business language, it is called ‘social capital’). So, we had the human capital (people with knowledge to carry out the project), we used our social capital (network) to build the team, the last piece of the puzzle we needed was the financial capital: money to carry out the project.

 

The beginning: getting the money

Who would think that a project would require over €4M? Well, research is expensive, but without it there is no invention. You need money to hire people to work on the project (you need money to build the microscope, to synthetize the chemicals, to do the work on zebrafish, on mice and so on), money to buy pieces to build a revolutionary microscope, to go to conferences and meet each other, to publish findings in scientific journals (indeed, it costs money to publish!), to meet the general public, go to schools, give talks and so on. H2020 is the biggest EU research an innovation programme that provides funding to finance projects that promise breakthroughs, discoveries and world-firsts by taking great ideas from the lab to the market. We decided to apply and were unsuccessful, but not far from the funding threshold.

 

The beginning: success!

Not to be deflated, we decided to resubmit the proposal… and on the second attempt we were successful despite only 1.4% of applications being accepted with just 3 projects funded in the UK (two in the neuroscience field, and both being led by research teams in the city of Birmingham: University of Birmingham and Aston University). Here is the link to the official announcement.

 

Implementation

Pulling together all the necessary resources (funding and people) is the first step, the implementation is another business. Right now we are in the process of hiring people to work in Ferenc's and Attila's lab (Herwig, John and Femtonics have already finished their hiring). If you are interested in joining the team send us an email. And follow us on this website and via the “usual suspects” – Facebook and Twitter links are at the bottom of the page.