Cepeda D.,Karolinska Institutet |
Ng H.-F.,Karolinska Institutet |
Sharifi H.R.,Karolinska Institutet |
Mahmoudi S.,Karolinska Institutet |
And 26 more authors.
EMBO Molecular Medicine | Year: 2013
SCF (Skp1/Cul1/F-box) ubiquitin ligases act as master regulators of cellular homeostasis by targeting key proteins for ubiquitylation. Here, we identified a hitherto uncharacterized F-box protein, FBXO28 that controls MYC-dependent transcription by non-proteolytic ubiquitylation. SCFFBXO28 activity and stability are regulated during the cell cycle by CDK1/2-mediated phosphorylation of FBXO28, which is required for its efficient ubiquitylation of MYC and downsteam enhancement of the MYC pathway. Depletion of FBXO28 or overexpression of an F-box mutant unable to support MYC ubiquitylation results in an impairment of MYC-driven transcription, transformation and tumourigenesis. Finally, in human breast cancer, high FBXO28 expression and phosphorylation are strong and independent predictors of poor outcome. In conclusion, our data suggest that SCFFBXO28 plays an important role in transmitting CDK activity to MYC function during the cell cycle, emphasizing the CDK-FBXO28-MYC axis as a potential molecular drug target in MYC-driven cancers, including breast cancer. FBXO28 is identified as part of a SCF complex acting as a regulator of tumor cell proliferation and an important modifier of MYC function. FBXO28 may be a new prognostic factor in breast cancer and a new potential drug target in MYC- driven tumors. © 2013 The Authors.
Jimenez R.C.,EMBL EBI |
Albar J.P.,National Center for Biotecnology |
Bhak J.,Theragen BiO Institute |
Blatter M.-C.,Swiss Institute of Bioinformatics |
And 31 more authors.
Bioinformatics | Year: 2013
We present iAnn, an open source community-driven platform for dissemination of life science events, such as courses, conferences and workshops. iAnn allows automatic visualisation and integration of customised event reports. A central repository lies at the core of the platform: curators add submitted events, and these are subsequently accessed via web services. Thus, once an iAnn widget is incorporated into a website, it permanently shows timely relevant information as if it were native to the remote site. At the same time, announcements submitted to the repository are automatically disseminated to all portals that query the system. To facilitate the visualization of announcements, iAnn provides powerful filtering options and views, integrated in Google Maps and Google Calendar. All iAnn widgets are freely available.Availability: http://iann.pro/ iannviewerContact: © 2013 The Author 2013. Published by Oxford University Press.
News Article | December 14, 2016
Jiri Lukas' research centre was at a crossroads four years ago. Bankrolled by the Novo Nordisk Foundation, the organization was facing a mid-term evaluation, and its funding was at risk. Lukas, executive director of the Center for Protein Research at the University of Copenhagen, wanted to apply for a grant extension, but was worried that his efforts would be wasted. It was rare at the time for foundations that award grants for biomedical research to further their support beyond one-time, limited-term funding. A colleague told Lukas that the science in his application was strong, but that the application itself didn't make the best case for the societal impact and unique nature of the centre. The colleague advised Lukas to consult with scientific-communication specialists at Elevate Scientific in Malmö, Sweden. “The rest was kind of a fairy tale,” Lukas says. With help from Elevate, the centre won the extension. When it comes to seeking either government or private funding, grant writers and editors are a useful resource for scientists in both academia and industry. Scientists call on them for a variety of reasons. Some simply don't have time to do it themselves. Others know that they aren't good writers, or lack a sufficient command of English. Some are struggling to get funding. Grant writers can help with finding the right organizations to fund a project, as well as with writing the application. They can hone and focus the message, ensure consistency between sections drafted by different authors and assure adherence to strict page limits. Grant writers and editors help with everything that isn't the science, yet can still significantly affect a proposal's chance of success. Many researchers still go it alone in preparing grant applications, but the funding landscape has changed, and scientists are now less hesitant to ask for help, says Sheila Cherry, president of Fresh Eyes Editing in Dayton, Ohio. Many funders expect applicants to seek assistance. The written guidelines from the US National Institutes of Health (NIH), for example, make that clear: “If writing is not your forte, seek help!” There should be no shame in asking for guidance, says Anders Tunlid, a microbial ecologist at Lund University in Sweden who has reviewed grants for the European Research Council. “We need to accept that this is the way we all do it,” he says. “I don't think that everyone has written their proposals themselves.” Colleagues may be willing to review an application's scientific content — but they are typically too busy to spare the hours needed for fine-tuning. “Everyone needs a little bit of help, if only to find typos,” points out David O'Keefe, senior grant writer at the Salk Institute in La Jolla, California. The Salk offers the service for free to its researchers, but external help comes at a price: basic editing services can run from US$500 to thousands of dollars, depending on the application. “It's an investment, for sure,” says Stefano Goffredo, a marine ecologist at the University of Bologna in Italy. But after spending months on a proposal, he thinks it's worth opening his wallet to get a professional polish. Without that polish, it's all too easy for reviewers to quickly discount an application, says Laura Hales, principal of the Isis Group, a scientific consulting and communications service in Cambridge, Massachusetts. She has served as a reviewer herself and can attest to the fact that first impressions count for everything. “You have,” she says, “one chance.” Independent data are essentially non-existent on how professional grant-writing services affect success rates. Companies' claims for success range from more than three times the average rate for NIH grants to six times the average rate for the European Union's Horizon 2020 grants. But the companies themselves concede that they can offer no guarantees. “Just because I know the formula doesn't mean I'm going to get every one,” says Hales. Institutions might pay for support for a junior scientist's first few grants, says Susan Marriott, president of BioScience Writers in Houston, Texas, but the support can be useful for mid- to later-stage-career researchers, too. Working with Elevate Scientific was a “humbling” experience, says Lukas, even as a senior scientist. The editors identified unclear sections, improved graphics and strengthened the logic in the proposal to communicate the message more effectively. Senior researchers in a collaboration may also use a grant editor as a project manager to ensure that all the pieces come together in a neat package by the submission deadline. It was just such a multi-investigator project that led Bruce Johnson to call in Fresh Eyes Editing. Every author tends to use their own formatting for elements such as headings and references, he notes, and editors can give the document a consistent style. “It makes it look so much more professional,” says Johnson, chief clinical research officer at the Dana Farber Cancer Institute in Boston, Massachusetts. Editors also catch inconsistencies and redundancies in the content. For example, a large document on lung cancer does not need to repeat in every author's section that it's the leading cause of cancer deaths in the United States. And one scientist might cite a statistic that 15% of people with lung cancer have a certain mutation, whereas another might write 25%. That inconsistency could cause reviewers to think that the collaborators aren't talking to one another, Johnson says, which would not inspire a sense of confidence that the team could carry out the project together. Grant helpers vary in the assistance they provide, and at different stages of the proposal process. Some get involved at the very start, strategizing about where to apply for funding. “It's not only about how you write an application,” says Ram May-Ron, managing partner with the FreeMind Group in Boston. “The search starts with identifying which funding opportunity is the best one for a particular part of a research project.” Scientists may have heard of big funding initiatives, such as Horizon 2020, but there might be other opportunities they should consider, says Eran Har-Paz, vice-president for sales at Sunrise Projects in Rosh Ha'Ayin, Israel. “We try to build a strategy, a few alternatives to submit to,” he says. “Don't put all your eggs in one basket.” At this level, grant helpers may reach out to programme officers, says May-Ron. For example, they might ask whether an agency has funded similar research recently, and whether they're at all interested in doing so again. “If you go to the right place, you're already in a better position,” he points out. This full-scale service comes at a price, of course. Har-Paz estimates that the simplest proposal might cost a few thousand euros, with the cost escalating to €20,000 (US$21,414) or more for elaborate applications. That includes not only the strategizing, but also writing the majority of the application. Some scientists already hand off much of the writing to others. Cath Ennis, a project manager and grant writer in Vancouver, Canada, might contribute an abstract, literature review, impact statement or budget, depending on the scientists' needs — but never the research plan itself. “Our role is to take all the jobs that we can from the principal investigator, so they can focus more on the research,” she says. Other grant professionals stick to editing — but that's more than just dotting i's and crossing t's. Grant editors consider content, clarity, logic and flow. Grant professionals can be found in a variety of places: some work for a company and others as freelancers whereas some institutions have in-house specialists (see 'How to become a grant writer'). “Start talking early,” advises Marriott, who is also a virologist at Baylor College of Medicine in Houston. “Even if you don't have a grant ready yet, even if you don't know what you're going to write.” It's beneficial to get on an editor's calendar as early as possible, because by the time the deadline rolls around, they could have many scientists clamouring for their attention. Later on, editors may be still able to help, but in a more limited fashion, she says. Scientists tend to look for someone with a PhD and the right technical expertise. But the match doesn't have to be exact. “I've edited grants about nuclear physics,” says Ennis, whose background is in cancer biology. “I can still catch a typo when someone's put 'proton' instead of 'photon'.” Equally important, Ennis says, is to look for editors who specialize in the kind of grant one's after — say, NIH, Horizon 2020 or foundation grants. Every programme has its own requirements, and the professional should know those inside out. With candidates in mind, the next step is to get to know them. Ask a potential editor or writer about their process, and the services they do and don't provide, advises Cherry. “It's a lot more than just, 'What's your fee and how soon can you get this done?'” she says. Timing and costs are, nonetheless, key questions. It's best to get an estimate in advance to avoid a surprise charge later. One should also ask for a confidentiality clause in the contract. Then, be prepared for plenty of back-and-forth. “Remember that it's a collaborative process,” says Cherry. “Don't be afraid to bring up concerns and make sure you're really collaborating.”
Raes J.,Structural and Computational Biology Unit |
Raes J.,Vrije Universiteit Brussel |
Letunic I.,Structural and Computational Biology Unit |
Yamada T.,Structural and Computational Biology Unit |
And 4 more authors.
Molecular Systems Biology | Year: 2011
Using metagenomic;parts lists' to infer global patterns on microbial ecology remains a significant challenge. To deduce important ecological indicators such as environmental adaptation, molecular trait dispersal, diversity variation and primary production from the gene pool of an ecosystem, we integrated 25 ocean metagenomes with geographical, meteorological and geophysicochemical data. We find that climatic factors (temperature, sunlight) are the major determinants of the biomolecular repertoire of each sample and the main limiting factor on functional trait dispersal (absence of biogeographic provincialism). Molecular functional richness and diversity show a distinct latitudinal gradient peaking at 20°N and correlate with primary production. The latter can also be predicted from the molecular functional composition of an environmental sample. Together, our results show that the functional community composition derived from metagenomes is an important quantitative readout for molecular trait-based biogeography and ecology. © 2011 EMBO and Macmillan Publishers Limited.
Blicher T.,Center for Protein Research |
Blicher T.,Technical University of Denmark |
Gupta R.,Technical University of Denmark |
Wesolowska A.,Technical University of Denmark |
And 3 more authors.
Current Opinion in Structural Biology | Year: 2010
Protein annotation provides a condensed and systematic view on the function of individual proteins. It has traditionally dealt with sorting proteins into functional categories, which for example has proven to be successful for the comparison of different species. However, if we are to understand the differences between many individuals of the same species. - humans in particular. - the focus needs be on the functional impact of individual residue variation. To fulfil the promises of personal genomics, we need to start asking not only what is in a genome but also how millions of small differences between individual genomes affect protein function and in turn human health. © 2010 Elsevier Ltd.
Malik L.,Copenhagen University |
Nygaard J.,Copenhagen University |
Nygaard J.,Lund University |
Christensen N.J.,Copenhagen University |
And 4 more authors.
Journal of Peptide Science | Year: 2013
α-Helical coiled coil structures, which are noncovalently associated heptad repeat peptide sequences, are ubiquitous in nature. Similar amphipathic repeat sequences have also been found in helix-containing proteins and have played a central role in de novo design of proteins. In addition, they are promising tools for the construction of nanomaterials. Small-angle X-ray scattering (SAXS) has emerged as a new biophysical technique for elucidation of protein topology. Here, we describe a systematic study of the self-assembly of a small ensemble of coiled coil sequences using SAXS and analytical ultracentrifugation (AUC), which was correlated with molecular dynamics simulations. Our results show that even minor sequence changes have an effect on the folding topology and the self-assembly and that these differences can be observed by a combination of AUC, SAXS, and circular dichroism spectroscopy. A small difference in these methods was observed, as SAXS for one peptide and revealed the presence of a population of longer aggregates, which was not observed by AUC. © 2013 European Peptide Society and John Wiley & Sons, Ltd.
Dinkel H.,SCB Unit |
Chica C.,SCB Unit |
Chica C.,French Atomic Energy Commission |
Via A.,University of Rome La Sapienza |
And 5 more authors.
Nucleic Acids Research | Year: 2011
The Phospho.ELM resource (http://phospho.elm.eu.org) is a relational database designed to store in vivo and in vitro phosphorylation data extracted from the scientific literature and phosphoproteomicanalyses. The resource has been actively developed for more than 7 years and currently comprises 42 574 serine, threonine and tyrosine non-redundant phosphorylation sites. Several new features have been implemented, such as structural disorder/ order and accessibility information and a conservation score. Additionally, the conservation of the phosphosites can now be visualized directly on the multiple sequence alignment used for the score calculation. Finally, special emphasis has been put on linking to external resources such as interaction networks and other databases. © The Author(s) 2010.
PubMed | Center for Protein Research
Type: Journal Article | Journal: Current opinion in structural biology | Year: 2010
Protein annotation provides a condensed and systematic view on the function of individual proteins. It has traditionally dealt with sorting proteins into functional categories, which for example has proven to be successful for the comparison of different species. However, if we are to understand the differences between many individuals of the same species-humans in particular - the focus needs be on the functional impact of individual residue variation. To fulfil the promises of personal genomics, we need to start asking not only what is in a genome but also how millions of small differences between individual genomes affect protein function and in turn human health.
News Article | December 11, 2015
The logo of AstraZeneca is seen on a medication package in a pharmacy in London April 28, 2014. REUTERS/Stefan Wermuth More LONDON (Reuters) - AstraZeneca is diving into the world of proteins secreted by cells - collectively known as the secretome - in the hunt for new drugs and better "cell factories" for making biotech medicines. The so-called secretome accounts for around one third of human proteins and the idea of mapping them all follows the decoding of the human genome in 2000, since when there has been a surge in scientific buzzwords ending in "ome". The secretome is one of the newest as scientists only unraveled the full array of proteins involved at the start of this year. As a result, its potential as a resource for pharmaceutical research remains largely unexplored. AstraZeneca hopes to get in on the ground floor of this opportunity through a three-year collaboration with the newly established Wallenberg Center for Protein Research in Sweden. The new center is being funded primarily by the Wallenberg family, which also owns Investor, the third largest shareholder in AstraZeneca. The Wallenberg Foundation is providing a $37 million grant over eight years for the center, while the Anglo-Swedish drugmaker will contribute $1.2 million a year for three years. In addition to hunting new drug targets for diseases ranging from heart disease to cancer, AstraZeneca said in a statement on Friday that its experts would also be looking at protein secretion processes that could improve medicine manufacturing. Currently, the drugs industry relies on a limited number of cell types - notably Chinese hamster ovary cells - to make biotech drugs in large fermentation vats. In future, there may be the potential to tap other kinds of cells that are better suited for large-scale production.