Detection of human disease conditions by single-cell morpho-rheological phenotyping of blood
- Technische Universität Dresden, Germany
- University Clinic Carl Gustav Carus, Technische Universität Dresden, Germany
- University of Glasgow, United Kingdom
- Karolinska Institutet, Sweden
- University of Cambridge, United Kingdom
Abstract
Blood is arguably the most important bodily fluid and its analysis provides crucial health status information. A first routine measure to narrow down diagnosis in clinical practice is the differential blood count, determining the frequency of all major blood cells. What is lacking to advance initial blood diagnostics is an unbiased and quick functional assessment of blood that can narrow down the diagnosis and generate specific hypotheses. To address this need, we introduce the continuous, cell-by-cell morpho-rheological (MORE) analysis of diluted whole blood, without labeling, enrichment or separation, at rates of 1,000 cells/sec. In a drop of blood we can identify all major blood cells and characterize their pathological changes in several disease conditions in vitro and in patient samples. This approach takes previous results of mechanical studies on specifically isolated blood cells to the level of application directly in blood and adds a functional dimension to conventional blood analysis.
Data availability
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Data from: Detection of human disease conditions by single-cell morpho-rheological phenotyping of whole bloodAvailable at Dryad Digital Repository under a CC0 Public Domain Dedication.
Article and author information
Author details
Funding
Alexander von Humboldt-Stiftung (Alexander von Humboldt Professorship)
- Jochen Guck
National Institute for Health Research (Cambridge Biomedical Research Centre)
- Edwin R Chilvers
GlaxoSmithKline (noncommercial grant)
- Edwin R Chilvers
Seventh Framework Programme (ERC Starting Grant #282060)
- Jochen Guck
Deutsche Forschungsgemeinschaft (TRR83 and SFB655)
- Ünal Coskun
- Martin Bornhäuser
Seventh Framework Programme (ITN)
- Lisa Ranford-Cartwright
- Birgitta Henriques Normark
- Jochen Guck
Bundesministerium für Bildung und Forschung (German Center for Diabetes Research (DZD e.V.))
- Ünal Coskun
Sächsisches Staatsministerium für Wissenschaft und Kunst (TG70 AZ 4-7531.60/29/45)
- Oliver Otto
- Jochen Guck
Tour der Hoffnung (noncommercial grant)
- Julia Stächele
Sonnenstrahl e.V. Dresden (noncommercial grant)
- Meinolf Suttorp
Center for Regenerative Therapies Dresden (Seed grant FZ 111)
- Jochen Guck
Technische Universität Dresden (Support the Best Program)
- Reinhard Berner
- Jochen Guck
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Human subjects: The work involved measurements of human blood samples. All studies complied with the Declaration of Helsinki and involved written informed consent from all participants or their legal guardians. Ethics for experiments with human blood were approved by the ethics committee of the Technische Universität Dresden (EK89032013, EK458102015), and for human blood and LPS inhalation in healthy volunteers by the East of England, Cambridge Central ethics committee (Study No. 06/Q0108/281 and ClinicalTrialReference NCT02551614).
Copyright
© 2018, Toepfner et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Detection of human disease conditions by single-cell morpho-rheological phenotyping of blood
eLife 7:e29213.
https://doi.org/10.7554/eLife.29213
Further reading
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- Structural Biology and Molecular Biophysics
In eukaryotes, RNAs transcribed by RNA Pol II are modified at the 5′ end with a 7-methylguanosine (m7G) cap, which is recognized by the nuclear cap binding complex (CBC). The CBC plays multiple important roles in mRNA metabolism, including transcription, splicing, polyadenylation, and export. It promotes mRNA export through direct interaction with a key mRNA export factor, ALYREF, which in turn links the TRanscription and EXport (TREX) complex to the 5′ end of mRNA. However, the molecular mechanism for CBC-mediated recruitment of the mRNA export machinery is not well understood. Here, we present the first structure of the CBC in complex with an mRNA export factor, ALYREF. The cryo-EM structure of CBC-ALYREF reveals that the RRM domain of ALYREF makes direct contact with both the NCBP1 and NCBP2 subunits of the CBC. Comparing CBC-ALYREF with other cellular complexes containing CBC and/or ALYREF components provides insights into the coordinated events during mRNA transcription, splicing, and export.
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Under physiological conditions, proteins continuously undergo structural fluctuations on different timescales. Some conformations are only sparsely populated, but still play a key role in protein function. Thus, meaningful structure–function frameworks must include structural ensembles rather than only the most populated protein conformations. To detail protein plasticity, modern structural biology combines complementary experimental and computational approaches. In this review, we survey available computational approaches that integrate sparse experimental data from electron paramagnetic resonance spectroscopy with molecular modeling techniques to derive all-atom structural models of rare protein conformations. We also propose strategies to increase the reliability and improve efficiency using deep learning approaches, thus advancing the field of integrative structural biology.
