TY  - JOUR
AU  - Lobentanzer, S.*
AU  - Feng, S.*
AU  - Bruderer, N.*
AU  - Maier, A.*
AU  - The BioChatter Consortium (Lucarelli, D.)
AU  - Wang, C.*
AU  - Baumbach, J.*
AU  - Abreu-Vicente, J.*
AU  - Krehl, N.*
AU  - Ma, Q.*
AU  - Lemberger, T.*
AU  - Saez-Rodriguez, J.*
C1  - 73399
C2  - 57048
SP  - 166-169
TI  - A platform for the biomedical application of large language models.
JO  - Nat. Biotechnol.
VL  - 43
IS  - 2
PY  - 2025
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Luecken, M.
AU  - Gigante, S.*
AU  - Burkhardt, D.B.*
AU  - Cannoodt, R.*
AU  - Strobl, D.C.
AU  - Markov, N.S.*
AU  - Zappia, L.
AU  - Palla, G.
AU  - Lewis, W.*
AU  - Dimitrov, D.*
AU  - Vinyard, M.E.*
AU  - Magruder, D.S.*
AU  - Müller, M.
AU  - Andersson, A.*
AU  - Dann, E.*
AU  - Qin, Q.*
AU  - Otto, D.J.*
AU  - Klein, M.*
AU  - Botvinnik, O.B.*
AU  - Deconinck, L.*
AU  - Waldrant, K.*
AU  - Yasa, S.N.*
AU  - Szałata, A.
AU  - Benz, A.*
AU  - Li, Z.*
AU  - Bloom, J.M.*
AU  - Pisco, A.O.*
AU  - Saez-Rodriguez, J.*
AU  - Wulsin, D.*
AU  - Pinello, L.*
AU  - Saeys, Y.*
AU  - Theis, F.J.
AU  - Krishnaswamy, S.*
C1  - 75057
C2  - 57908
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1035-1040
TI  - Defining and benchmarking open problems in single-cell analysis.
JO  - Nat. Biotechnol.
VL  - 43
IS  - 7
PB  - Nature Portfolio
PY  - 2025
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Efficient and accurate nanocarrier development for targeted drug delivery is hindered by a lack of methods to analyze its cell-level biodistribution across whole organisms. Here we present Single Cell Precision Nanocarrier Identification (SCP-Nano), an integrated experimental and deep learning pipeline to comprehensively quantify the targeting of nanocarriers throughout the whole mouse body at single-cell resolution. SCP-Nano reveals the tissue distribution patterns of lipid nanoparticles (LNPs) after different injection routes at doses as low as 0.0005 mg kg-1-far below the detection limits of conventional whole body imaging techniques. We demonstrate that intramuscularly injected LNPs carrying SARS-CoV-2 spike mRNA reach heart tissue, leading to proteome changes, suggesting immune activation and blood vessel damage. SCP-Nano generalizes to various types of nanocarriers, including liposomes, polyplexes, DNA origami and adeno-associated viruses (AAVs), revealing that an AAV2 variant transduces adipocytes throughout the body. SCP-Nano enables comprehensive three-dimensional mapping of nanocarrier distribution throughout mouse bodies with high sensitivity and should accelerate the development of precise and safe nanocarrier-based therapeutics.
AU  - Luo, J.
AU  - Molbay, M.
AU  - Chen, Y.
AU  - Horvath, I.
AU  - Kadletz, K.
AU  - Kick, B.*
AU  - Zhao, S.
AU  - Al-Maskari, R.
AU  - Singh, I.
AU  - Ali, M.
AU  - Bhatia, H.S.
AU  - Minde, D.-P.
AU  - Negwer, M.
AU  - Höher, L.
AU  - Calandra, G.M.*
AU  - Groschup, B.*
AU  - Su, J.
AU  - Kimna, C.
AU  - Rong, Z.
AU  - Galensowske, N.
AU  - Todorov, M.I.
AU  - Jeridi, D.
AU  - Ohn, T.-L.
AU  - Roth, S.*
AU  - Simats, A.*
AU  - Singh, V.*
AU  - Khalin, I.*
AU  - Pan, C.
AU  - Arus, B.A.
AU  - Bruns, O.T.
AU  - Zeidler, R.
AU  - Liesz, A.*
AU  - Protzer, U.
AU  - Plesnila, N.*
AU  - Ussar, S.
AU  - Hellal, F.
AU  - Paetzold, J.C.
AU  - Elsner, M.
AU  - Dietz, H.*
AU  - Ertürk, A.
C1  - 73066
C2  - 57238
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Nanocarrier imaging at single-cell resolution across entire mouse bodies with deep learning.
JO  - Nat. Biotechnol.
PB  - Nature Portfolio
PY  - 2025
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Training and deploying large-scale protein language models typically requires deep machine learning expertise-a barrier for researchers outside this field. SaprotHub overcomes this challenge by offering an intuitive platform that facilitates training and prediction as well as storage and sharing of models. Here we provide the ColabSaprot framework built on Google Colab, which potentially powers hundreds of protein training and prediction applications, enabling researchers to collaboratively build and share customized models.
AU  - Su, J.*
AU  - Li, Z.*
AU  - Tao, T.*
AU  - Han, C.*
AU  - He, Y.*
AU  - Dai, F.*
AU  - Yuan, Q.*
AU  - Gao, Y.*
AU  - Si, T.*
AU  - Zhang, X.*
AU  - Zhou, Y.*
AU  - Shan, J.*
AU  - Zhou, X.*
AU  - Chang, X.*
AU  - Jiang, S.*
AU  - Ma, D.*
AU  - Steinegger, M.*
AU  - Ovchinnikov, S.*
AU  - Yuan, F.*
AU  - The OPMC (Heinzinger, M.)
C1  - 75857
C2  - 58170
TI  - Democratizing protein language model training, sharing and collaboration.
JO  - Nat. Biotechnol.
PY  - 2025
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - The application of multiple omics technologies in biomedical cohorts has the potential to reveal patient-level disease characteristics and individualized response to treatment. However, the scale and heterogeneous nature of multi-modal data makes integration and inference a non-trivial task. We developed a deep-learning-based framework, multi-omics variational autoencoders (MOVE), to integrate such data and applied it to a cohort of 789 people with newly diagnosed type 2 diabetes with deep multi-omics phenotyping from the DIRECT consortium. Using in silico perturbations, we identified drug-omics associations across the multi-modal datasets for the 20 most prevalent drugs given to people with type 2 diabetes with substantially higher sensitivity than univariate statistical tests. From these, we among others, identified novel associations between metformin and the gut microbiota as well as opposite molecular responses for the two statins, simvastatin and atorvastatin. We used the associations to quantify drug-drug similarities, assess the degree of polypharmacy and conclude that drug effects are distributed across the multi-omics modalities.
AU  - Allesøe, R.L.*
AU  - Lundgaard, A.T.*
AU  - Hernández Medina, R.*
AU  - Aguayo-Orozco, A.*
AU  - Johansen, J.D.*
AU  - Nissen, J.N.*
AU  - Brorsson, C.*
AU  - Mazzoni, G.*
AU  - Niu, L.*
AU  - Biel, J.H.*
AU  - Brasas, V.*
AU  - Webel, H.*
AU  - Benros, M.E.*
AU  - Pedersen, A.G.*
AU  - Chmura, P.J.*
AU  - Jacobsen, U.P.*
AU  - Mari, A.*
AU  - Koivula, R.W.*
AU  - Mahajan, A.*
AU  - Viñuela, A.*
AU  - Tajes, J.F.*
AU  - Sharma, S.
AU  - Haid, M.
AU  - Hong, M.G.*
AU  - Musholt, P.B.*
AU  - De Masi, F.*
AU  - Vogt, J.*
AU  - Pedersen, H.K.*
AU  - Gudmundsdottir, V.*
AU  - Jones, A.*
AU  - Kennedy, G.*
AU  - Bell, J.*
AU  - Thomas, E.L.*
AU  - Frost, G.*
AU  - Thomsen, H.*
AU  - Hansen, E.*
AU  - Hansen, T.H.*
AU  - Vestergaard, H.*
AU  - Muilwijk, M.*
AU  - Blom, M.T.*
AU  - 't Hart, L.M.*
AU  - Pattou, F.*
AU  - Raverdy, V.*
AU  - Brage, S.*
AU  - Kokkola, T.*
AU  - Heggie, A.*
AU  - McEvoy, D.*
AU  - Mourby, M.*
AU  - Kaye, J.*
AU  - Hattersley, A.*
AU  - McDonald, T.A.*
AU  - Ridderstråle, M.*
AU  - Walker, M.*
AU  - Forgie, I.*
AU  - Giordano, G.N.*
AU  - Pavo, I.*
AU  - Ruetten, H.*
AU  - Pedersen, O.*
AU  - Hansen, T.*
AU  - Dermitzakis, E.*
AU  - Franks, P.W.*
AU  - Schwenk, J.M.*
AU  - Adamski, J.
AU  - McCarthy, M.I.*
AU  - Pearson, E.*
AU  - Banasik, K.*
AU  - Rasmussen, S.*
AU  - Brunak, S.*
AU  - IMI DIRECT Consortium (Thorand, B.
AU  - Fritsche, A.
AU  - Artati, A.
AU  - Prehn, C.
AU  - Grallert, H.
AU  - Adam, J.)
C1  - 67119
C2  - 53486
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 399-408
TI  - Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.
JO  - Nat. Biotechnol.
VL  - 41
IS  - 3
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Correction to: Nature Biotechnology. Published online 2 January 2023. In the version of this article initially published, Cristina Leal Rodríguez (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark) was omitted from the author list. The error has been corrected in the HTML and PDF versions of the article.
AU  - Allesøe, R.L.*
AU  - Lundgaard, A.T.*
AU  - Hernández Medina, R.*
AU  - Aguayo-Orozco, A.*
AU  - Johansen, J.*
AU  - Nissen, J.N.*
AU  - Brorsson, C.*
AU  - Mazzoni, G.*
AU  - Niu, L.*
AU  - Biel, J.H.*
AU  - Leal Rodríguez, C.*
AU  - Brasas, V.*
AU  - Webel, H.*
AU  - Benros, M.E.*
AU  - Pedersen, A.G.*
AU  - Chmura, P.J.*
AU  - Jacobsen, U.P.*
AU  - Mari, A.*
AU  - Koivula, R.*
AU  - Mahajan, A.*
AU  - Viñuela, A.*
AU  - Tajes, J.F.*
AU  - Sharma, S.
AU  - Haid, M.
AU  - Hong, M.G.*
AU  - Musholt, P.B.*
AU  - De Masi, F.*
AU  - Vogt, J.*
AU  - Pedersen, H.K.*
AU  - Gudmundsdottir, V.*
AU  - Jones, A.*
AU  - Kennedy, G.*
AU  - Bell, J.*
AU  - Thomas, E.L.*
AU  - Frost, G.*
AU  - Thomsen, H.*
AU  - Hansen, E.*
AU  - Hansen, T.H.*
AU  - Vestergaard, H.*
AU  - Muilwijk, M.*
AU  - Blom, M.T.*
AU  - 't Hart, L.M.*
AU  - Pattou, F.*
AU  - Raverdy, V.*
AU  - Brage, S.*
AU  - Kokkola, T.*
AU  - Heggie, A.*
AU  - McEvoy, D.*
AU  - Mourby, M.*
AU  - Kaye, J.*
AU  - Hattersley, A.*
AU  - McDonald, T.*
AU  - Ridderstråle, M.*
AU  - Walker, M.*
AU  - Forgie, I.*
AU  - Giordano, G.N.*
AU  - Pavo, I.*
AU  - Ruetten, H.*
AU  - Pedersen, O.*
AU  - Hansen, T.*
AU  - Dermitzakis, E.*
AU  - Franks, P.W.*
AU  - Schwenk, J.M.*
AU  - Adamski, J.
AU  - McCarthy, M.I.*
AU  - Pearson, E.*
AU  - Banasik, K.*
AU  - Rasmussen, S.*
AU  - Brunak, S.*
AU  - IMI DIRECT Consortium (Thorand, B.
AU  - Fritsche, A.
AU  - Artati, A.
AU  - Prehn, C.
AU  - Adam, J.)
AU  - IMI DIRECT Consortium (Grallert, H.)
C1  - 67778
C2  - 54256
TI  - Author Correction: Discovery of drug-omics associations in type 2 diabetes with generative deep-learning models.
JO  - Nat. Biotechnol.
VL  - 41
IS  - 7
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Ertürk, A.
AU  - Elsner, M.
C1  - 69391
C2  - 53883
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Breaking boundaries in whole-body imaging and disease understanding with wildDISCO.
JO  - Nat. Biotechnol.
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Chimeric antigen receptor T cells (CAR-T cells) have emerged as a powerful treatment option for individuals with B cell malignancies but have yet to achieve success in treating acute myeloid leukemia (AML) due to a lack of safe targets. Here we leveraged an atlas of publicly available RNA-sequencing data of over 500,000 single cells from 15 individuals with AML and tissue from 9 healthy individuals for prediction of target antigens that are expressed on malignant cells but lacking on healthy cells, including T cells. Aided by this high-resolution, single-cell expression approach, we computationally identify colony-stimulating factor 1 receptor and cluster of differentiation 86 as targets for CAR-T cell therapy in AML. Functional validation of these established CAR-T cells shows robust in vitro and in vivo efficacy in cell line- and human-derived AML models with minimal off-target toxicity toward relevant healthy human tissues. This provides a strong rationale for further clinical development.
AU  - Gottschlich, A.*
AU  - Thomas, M.
AU  - Grünmeier, R.*
AU  - Lesch, S.*
AU  - Rohrbacher, L.*
AU  - Igl, V.*
AU  - Briukhovetska, D.*
AU  - Benmebarek, M.R.*
AU  - Vick, B.
AU  - Dede, S.*
AU  - Müller, K.*
AU  - Xu, T.*
AU  - Dhoqina, D.*
AU  - Märkl, F.*
AU  - Robinson, S.*
AU  - Sendelhofert, A.*
AU  - Schulz, H.*
AU  - Umut, *
AU  - Kavaka, V.*
AU  - Tsiverioti, C.A.*
AU  - Carlini, E.*
AU  - Nandi, S.*
AU  - Strzalkowski, T.*
AU  - Lorenzini, T.*
AU  - Stock, S.*
AU  - Müller, P.J.*
AU  - Dörr, J.*
AU  - Seifert, M.*
AU  - Cadilha, B.L.*
AU  - Brabenec, R.
AU  - Röder, N.*
AU  - Rataj, F.*
AU  - Nüesch, M.*
AU  - Modemann, F.*
AU  - Wellbrock, J.*
AU  - Fiedler, W.*
AU  - Kellner, C.*
AU  - Beltran, E.*
AU  - Herold, T.*
AU  - Paquet, D.*
AU  - Jeremias, I.
AU  - von Baumgarten, L.*
AU  - Endres, S.
AU  - Subklewe, M.*
AU  - Marr, C.
AU  - Kobold, S.
C1  - 67728
C2  - 54036
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1618-1632
TI  - Single-cell transcriptomic atlas-guided development of CAR-T cells for the treatment of acute myeloid leukemia.
JO  - Nat. Biotechnol.
VL  - 41
IS  - 11
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Understanding the mechanisms of coronavirus disease 2019 (COVID-19) disease severity to efficiently design therapies for emerging virus variants remains an urgent challenge of the ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules and the host proteome, and the vast majority of these virus-host contacts (the 'contactome') have not been identified. Here, we present a systematic contactome map of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with the human host encompassing more than 200 binary virus-host and intraviral protein-protein interactions. We find that host proteins genetically associated with comorbidities of severe illness and long COVID are enriched in SARS-CoV-2 targeted network communities. Evaluating contactome-derived hypotheses, we demonstrate that viral NSP14 activates nuclear factor κB (NF-κB)-dependent transcription, even in the presence of cytokine signaling. Moreover, for several tested host proteins, genetic knock-down substantially reduces viral replication. Additionally, we show for USP25 that this effect is phenocopied by the small-molecule inhibitor AZ1. Our results connect viral proteins to human genetic architecture for COVID-19 severity and offer potential therapeutic targets.
AU  - Kim, D.-K.
AU  - Weller, B.
AU  - Lin, C.-W.
AU  - Sheykhkarimli, D.*
AU  - Knapp, J.J.*
AU  - Dugied, G.*
AU  - Zanzoni, A.*
AU  - Pons, C.*
AU  - Tofaute, M.J.
AU  - Maseko, S.B.*
AU  - Spirohn, K.*
AU  - Laval, F.*
AU  - Lambourne, L.*
AU  - Kishore, N.*
AU  - Rayhan, A.*
AU  - Sauer, M.
AU  - Young, V.
AU  - Halder, H.
AU  - Marin De La Rosa, N.A.
AU  - Pogoutse, O.*
AU  - Strobel, A.
AU  - Schwehn, P.
AU  - Li, R.*
AU  - Rothballer, S.T.
AU  - Altmann, M.
AU  - Cassonnet, P.*
AU  - Coté, A.G.*
AU  - Elorduy Vergara, L.
AU  - Hazelwood, I.*
AU  - Liu, B.B.*
AU  - Nguyen, M.*
AU  - Pandiarajan, R.
AU  - Dohai, B.S.M.
AU  - Rodriguez, P.A.
AU  - Poirson, J.*
AU  - Giuliana, P.*
AU  - Willems, L.*
AU  - Taipale, M.*
AU  - Jacob, Y.*
AU  - Hao, T.*
AU  - Hill, D.E.*
AU  - Brun, C.*
AU  - Twizere, J.C.*
AU  - Krappmann, D.
AU  - Heinig, M.
AU  - Falter, C.
AU  - Aloy, P.*
AU  - Demeret, C.*
AU  - Vidal, M.*
AU  - Calderwood, M.A.*
AU  - Roth, F.B.*
AU  - Falter-Braun, P.
C1  - 66326
C2  - 52781
SP  - 140–149
TI  - A proteome-scale map of the SARS-CoV-2-human contactome.
JO  - Nat. Biotechnol.
VL  - 41
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Whole-body imaging techniques play a vital role in exploring the interplay of physiological systems in maintaining health and driving disease. We introduce wildDISCO, a new approach for whole-body immunolabeling, optical clearing and imaging in mice, circumventing the need for transgenic reporter animals or nanobody labeling and so overcoming existing technical limitations. We identified heptakis(2,6-di-O-methyl)-β-cyclodextrin as a potent enhancer of cholesterol extraction and membrane permeabilization, enabling deep, homogeneous penetration of standard antibodies without aggregation. WildDISCO facilitates imaging of peripheral nervous systems, lymphatic vessels and immune cells in whole mice at cellular resolution by labeling diverse endogenous proteins. Additionally, we examined rare proliferating cells and the effects of biological perturbations, as demonstrated in germ-free mice. We applied wildDISCO to map tertiary lymphoid structures in the context of breast cancer, considering both primary tumor and metastases throughout the mouse body. An atlas of high-resolution images showcasing mouse nervous, lymphatic and vascular systems is accessible at http://discotechnologies.org/wildDISCO/atlas/index.php .
AU  - Mai, H.
AU  - Luo
AU  - Höher, L.
AU  - Al-Maskari, R.
AU  - Horvath, I.
AU  - Chen, Y.
AU  - Kofler, F.
AU  - Piraud, M.
AU  - Paetzold, J.C.
AU  - Modamio Chamarro, J.
AU  - Todorov, M.I.
AU  - Elsner, M.
AU  - Hellal, F.
AU  - Ertürk, A.
C1  - 68124
C2  - 54602
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Whole-body cellular mapping in mouse using standard IgG antibodies.
JO  - Nat. Biotechnol.
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - The epicardium, the mesothelial envelope of the vertebrate heart, is the source of multiple cardiac cell lineages during embryonic development and provides signals that are essential to myocardial growth and repair. Here we generate self-organizing human pluripotent stem cell-derived epicardioids that display retinoic acid-dependent morphological, molecular and functional patterning of the epicardium and myocardium typical of the left ventricular wall. By combining lineage tracing, single-cell transcriptomics and chromatin accessibility profiling, we describe the specification and differentiation process of different cell lineages in epicardioids and draw comparisons to human fetal development at the transcriptional and morphological levels. We then use epicardioids to investigate the functional cross-talk between cardiac cell types, gaining new insights into the role of IGF2/IGF1R and NRP2 signaling in human cardiogenesis. Finally, we show that epicardioids mimic the multicellular pathogenesis of congenital or stress-induced hypertrophy and fibrotic remodeling. As such, epicardioids offer a unique testing ground of epicardial activity in heart development, disease and regeneration.
AU  - Meier, A.B.*
AU  - Zawada, D.*
AU  - De Angelis, M.T.*
AU  - Martens, L.D.
AU  - Santamaria, G.*
AU  - Zengerle, S.*
AU  - Nowak-Imialek, M.*
AU  - Kornherr, J.*
AU  - Zhang, F.*
AU  - Tian, Q.*
AU  - Wolf, C.M.*
AU  - Kupatt, C.*
AU  - Sahara, M.*
AU  - Lipp, P.*
AU  - Theis, F.J.
AU  - Gagneur, J.
AU  - Goedel, A.*
AU  - Laugwitz, K.L.*
AU  - Dorn, T.*
AU  - Moretti, A.*
C1  - 67632
C2  - 53939
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1787-1800
TI  - Epicardioid single-cell genomics uncovers principles of human epicardium biology in heart development and disease.
JO  - Nat. Biotechnol.
VL  - 41
IS  - 12
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - While genetically encoded reporters are common for fluorescence microscopy, equivalent multiplexable gene reporters for electron microscopy (EM) are still scarce. Here, by installing a variable number of fixation-stable metal-interacting moieties in the lumen of encapsulin nanocompartments of different sizes, we developed a suite of spherically symmetric and concentric barcodes (EMcapsulins) that are readable by standard EM techniques. Six classes of EMcapsulins could be automatically segmented and differentiated. The coding capacity was further increased by arranging several EMcapsulins into distinct patterns via a set of rigid spacers of variable length. Fluorescent EMcapsulins were expressed to monitor subcellular structures in light and EM. Neuronal expression in Drosophila and mouse brains enabled the automatic identification of genetically defined cells in EM. EMcapsulins are compatible with transmission EM, scanning EM and focused ion beam scanning EM. The expandable palette of genetically controlled EM-readable barcodes can augment anatomical EM images with multiplexed gene expression maps.
AU  - Sigmund, F.
AU  - Berezin, O.
AU  - Beliakova, S.
AU  - Magerl, B.
AU  - Drawitsch, M.*
AU  - Piovesan, A.
AU  - Gonçalves, F.
AU  - Bodea, S.V.
AU  - Winkler, S.
AU  - Bousraou, Z.
AU  - Grosshauser, M.
AU  - Samara, E.*
AU  - Pujol-Martí, J.*
AU  - Schädler, S.*
AU  - So, C.*
AU  - Irsen, S.*
AU  - Walch, A.K.
AU  - Kofler, F.
AU  - Piraud, M.
AU  - Kornfeld, J.*
AU  - Briggman, K.*
AU  - Westmeyer, G.G.
C1  - 67595
C2  - 53903
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1734–1745
TI  - Genetically encoded barcodes for correlative volume electron microscopy.
JO  - Nat. Biotechnol.
VL  - 41
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Virshup, I.
AU  - Bredikhin, D.*
AU  - Heumos, L.
AU  - Palla, G.
AU  - Sturm, G.*
AU  - Gayoso, A.*
AU  - Kats, I.*
AU  - Koutrouli, M.*
AU  - Berger, B.*
AU  - Pe'er, D.*
AU  - Regev, A.*
AU  - Teichmann, S.A.*
AU  - Finotello, F.*
AU  - Wolf, F.A.
AU  - Yosef, N.*
AU  - Stegle, O.*
AU  - Theis, F.J.
C1  - 67618
C2  - 53925
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 604-606
TI  - The scverse project provides a computational ecosystem for single-cell omics data analysis.
JO  - Nat. Biotechnol.
VL  - 41
IS  - 5
PB  - Nature Portfolio
PY  - 2023
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Models of intercellular communication in tissues are based on molecular profiles of dissociated cells, are limited to receptor–ligand signaling and ignore spatial proximity in situ. We present node-centric expression modeling, a method based on graph neural networks that estimates the effects of niche composition on gene expression in an unbiased manner from spatial molecular profiling data. We recover signatures of molecular processes known to underlie cell communication.
AU  - Fischer, D.S.
AU  - Schaar, A.
AU  - Theis, F.J.
C1  - 66584
C2  - 53197
TI  - Modeling intercellular communication in tissues using spatial graphs of cells.
JO  - Nat. Biotechnol.
PY  - 2022
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Aegilops tauschii, the diploid wild progenitor of the D subgenome of bread wheat, is a reservoir of genetic diversity for improving bread wheat performance and environmental resilience. Here we sequenced 242 Ae. tauschii accessions and compared them to the wheat D subgenome to characterize genomic diversity. We found that a rare lineage of Ae. tauschii geographically restricted to present-day Georgia contributed to the wheat D subgenome in the independent hybridizations that gave rise to modern bread wheat. Through k-mer-based association mapping, we identified discrete genomic regions with candidate genes for disease and pest resistance and demonstrated their functional transfer into wheat by transgenesis and wide crossing, including the generation of a library of hexaploids incorporating diverse Ae. tauschii genomes. Exploiting the genomic diversity of the Ae. tauschii ancestral diploid genome permits rapid trait discovery and functional genetic validation in a hexaploid background amenable to breeding.
AU  - Gaurav, K.*
AU  - Arora, S.*
AU  - Silva, P.*
AU  - Sánchez-Martín, J.*
AU  - Horsnell, R.*
AU  - Gao, L.*
AU  - Brar, G.S.*
AU  - Widrig, V.*
AU  - John Raupp, W.*
AU  - Singh, N.*
AU  - Wu, S.*
AU  - Kale, S.M.*
AU  - Chinoy, C.*
AU  - Nicholson, P.*
AU  - Quiroz-Chávez, J.*
AU  - Simmonds, J.*
AU  - Hayta, S.*
AU  - Smedley, M.A.*
AU  - Harwood, W.*
AU  - Pearce, S.*
AU  - Gilbert, D.*
AU  - Kangara, N.*
AU  - Gardener, C.*
AU  - Forner-Martínez, M.*
AU  - Liu, J.*
AU  - Yu, G.*
AU  - Boden, S.A.*
AU  - Pascucci, A.*
AU  - Ghosh, S.*
AU  - Hafeez, A.N.*
AU  - O'Hara, T.*
AU  - Waites, J.*
AU  - Cheema, J.*
AU  - Steuernagel, B.*
AU  - Patpour, M.*
AU  - Justesen, A.F.*
AU  - Liu, S.*
AU  - Rudd, J.C.*
AU  - Avni, R.*
AU  - Sharon, A.*
AU  - Steiner, B.*
AU  - Kirana, R.P.*
AU  - Buerstmayr, H.*
AU  - Mehrabi, A.A.*
AU  - Nasyrova, F.Y.*
AU  - Chayut, N.*
AU  - Matny, O.*
AU  - Steffenson, B.J.*
AU  - Sandhu, N.*
AU  - Chhuneja, P.*
AU  - Lagudah, E.*
AU  - Elkot, A.F.*
AU  - Tyrrell, S.*
AU  - Bian, X.*
AU  - Davey, R.P.*
AU  - Simonsen, M.*
AU  - Schauser, L.*
AU  - Tiwari, V.K.*
AU  - Randy Kutcher, H.*
AU  - Hucl, P.J.*
AU  - Li, A.*
AU  - Liu, D.C.*
AU  - Mao, L.*
AU  - Xu, S.*
AU  - Brown-Guedira, G.*
AU  - Faris, J.*
AU  - Dvorak, J.*
AU  - Luo, M.C.*
AU  - Krasileva, K.*
AU  - Lux, T.
AU  - Artmeier, S.
AU  - Mayer, K.F.X.
AU  - Uauy, C.*
AU  - Mascher, M.*
AU  - Bentley, A.R.*
AU  - Keller, B.*
AU  - Poland, J.*
AU  - Wulff, B.B.H.*
C1  - 63423
C2  - 51428
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 422–431
TI  - Population genomic analysis of Aegilops tauschii identifies targets for bread wheat improvement.
JO  - Nat. Biotechnol.
VL  - 40
IS  - 3
PB  - Nature Portfolio
PY  - 2022
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Gayoso, A.*
AU  - Lopez, R.*
AU  - Xing, G.*
AU  - Boyeau, P.*
AU  - Valiollah Pour Amiri, V.*
AU  - Hong, J.*
AU  - Wu, K.*
AU  - Jayasuriya, M.*
AU  - Mehlman, E.*
AU  - Langevin, M.*
AU  - Liu, Y.*
AU  - Samaran, J.*
AU  - Misrachi, G.*
AU  - Nazaret, A.*
AU  - Clivio, O.*
AU  - Xu, C.*
AU  - Ashuach, T.*
AU  - Gabitto, M.*
AU  - Lotfollahi, M.
AU  - Svensson, V.*
AU  - da Veiga Beltrame, E.*
AU  - Kleshchevnikov, V.*
AU  - Talavera-López, C.*
AU  - Pachter, L.*
AU  - Theis, F.J.
AU  - Streets, A.*
AU  - Jordan, M.I.*
AU  - Regier, J.*
AU  - Yosef, N.*
C1  - 64238
C2  - 51894
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 163-166
TI  - A Python library for probabilistic analysis of single-cell omics data.
JO  - Nat. Biotechnol.
VL  - 40
IS  - 2
PB  - Nature Portfolio
PY  - 2022
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Methods for profiling RNA and protein expression in a spatially resolved manner are rapidly evolving, making it possible to comprehensively characterize cells and tissues in health and disease. To maximize the biological insights obtained using these techniques, it is critical to both clearly articulate the key biological questions in spatial analysis of tissues and develop the requisite computational tools to address them. Developers of analytical tools need to decide on the intrinsic molecular features of each cell that need to be considered, and how cell shape and morphological features are incorporated into the analysis. Also, optimal ways to compare different tissue samples at various length scales are still being sought. Grouping these biological problems and related computational algorithms into classes across length scales, thus characterizing common issues that need to be addressed, will facilitate further progress in spatial transcriptomics and proteomics.
AU  - Palla, G.
AU  - Fischer, D.S.
AU  - Regev, A.*
AU  - Theis, F.J.
C1  - 64239
C2  - 51829
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 308–318
TI  - Spatial components of molecular tissue biology.
JO  - Nat. Biotechnol.
VL  - 40
IS  - 3
PB  - Nature Portfolio
PY  - 2022
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - The accuracy of methods for assembling transcripts from short-read RNA sequencing data is limited by the lack of long-range information. Here we introduce Ladder-seq, an approach that separates transcripts according to their lengths before sequencing and uses the additional information to improve the quantification and assembly of transcripts. Using simulated data, we show that a kallisto algorithm extended to process Ladder-seq data quantifies transcripts of complex genes with substantially higher accuracy than conventional kallisto. For reference-based assembly, a tailored scheme based on the StringTie2 algorithm reconstructs a single transcript with 30.8% higher precision than its conventional counterpart and is more than 30% more sensitive for complex genes. For de novo assembly, a similar scheme based on the Trinity algorithm correctly assembles 78% more transcripts than conventional Trinity while improving precision by 78%. In experimental data, Ladder-seq reveals 40% more genes harboring isoform switches compared to conventional RNA sequencing and unveils widespread changes in isoform usage upon m6A depletion by Mettl14 knockout.
AU  - Ringeling, F.R.*
AU  - Chakraborty, S.*
AU  - Vissers, C.*
AU  - Reiman, D.*
AU  - Patel, A.M.*
AU  - Lee, K.H.*
AU  - Hong, A.*
AU  - Park, C.W.*
AU  - Reska, T.*
AU  - Gagneur, J.
AU  - Chang, H.*
AU  - Spletter, M.L.*
AU  - Yoon, K.J.*
AU  - Ming, G.l.*
AU  - Song, H.*
AU  - Canzar, S.*
C1  - 63986
C2  - 51146
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 741–750
TI  - Partitioning RNAs by length improves transcriptome reconstruction from short-read RNA-seq data.
JO  - Nat. Biotechnol.
VL  - 40
PB  - Nature Portfolio
PY  - 2022
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Annabi, N.*
AU  - Baker, M.*
AU  - Boettiger, A.*
AU  - Chakraborty, D.*
AU  - Chen, Y.*
AU  - Corbett, K.S.*
AU  - Correia, B.*
AU  - Dahlman, J.*
AU  - de Oliveira, T.*
AU  - Ertürk, A.
AU  - Yanik, M.F.*
AU  - Henaff, E.*
AU  - Huch, M.*
AU  - Iliev, I.D.*
AU  - Jacobs, T.*
AU  - Junca, H.*
AU  - Keung, A.*
AU  - Kolodkin-Gal, I.*
AU  - Krishnaswamy, S.*
AU  - Lancaster, M.*
AU  - Macosko, E.*
AU  - Martínez-Núñez, M.A.*
AU  - Miura, K.*
AU  - Molloy, J.*
AU  - Cruz, A.O.*
AU  - Platt, R.J.*
AU  - Posey, A.D.*
AU  - Shao, H.*
AU  - Simunovic, M.*
AU  - Slavov, N.*
AU  - Takebe, T.*
AU  - Vandenberghe, L.H.*
AU  - Varshney, R.K.*
AU  - Wang, J.*
C1  - 61556
C2  - 50344
SP  - 281-286
TI  - Voices of biotech research.
JO  - Nat. Biotechnol.
VL  - 39
IS  - 3
PY  - 2021
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Untargeted metabolomics experiments rely on spectral libraries for structure annotation, but, typically, only a small fraction of spectra can be matched. Previous in silico methods search in structure databases but cannot distinguish between correct and incorrect annotations. Here we introduce the COSMIC workflow that combines in silico structure database generation and annotation with a confidence score consisting of kernel density P value estimation and a support vector machine with enforced directionality of features. On diverse datasets, COSMIC annotates a substantial number of hits at low false discovery rates and outperforms spectral library search. To demonstrate that COSMIC can annotate structures never reported before, we annotated 12 natural bile acids. The annotation of nine structures was confirmed by manual evaluation and two structures using synthetic standards. In human samples, we annotated and manually validated 315 molecular structures currently absent from the Human Metabolome Database. Application of COSMIC to data from 17,400 metabolomics experiments led to 1,715 high-confidence structural annotations that were absent from spectral libraries.
AU  - Hoffmann, M.A.*
AU  - Nothias, L.F.*
AU  - Ludwig, M.*
AU  - Fleischauer, M.*
AU  - Gentry, E.C.*
AU  - Witting, M.
AU  - Dorrestein, P.C.*
AU  - Dührkop, K.*
AU  - Böcker, S.*
C1  - 63263
C2  - 51415
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 411–421
TI  - High-confidence structural annotation of metabolites absent from spectral libraries.
JO  - Nat. Biotechnol.
VL  - 40
IS  - 3
PB  - Nature Portfolio
PY  - 2021
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Large single-cell atlases are now routinely generated to serve as references for analysis of smaller-scale studies. Yet learning from reference data is complicated by batch effects between datasets, limited availability of computational resources and sharing restrictions on raw data. Here we introduce a deep learning strategy for mapping query datasets on top of a reference called single-cell architectural surgery (scArches). scArches uses transfer learning and parameter optimization to enable efficient, decentralized, iterative reference building and contextualization of new datasets with existing references without sharing raw data. Using examples from mouse brain, pancreas, immune and whole-organism atlases, we show that scArches preserves biological state information while removing batch effects, despite using four orders of magnitude fewer parameters than de novo integration. scArches generalizes to multimodal reference mapping, allowing imputation of missing modalities. Finally, scArches retains coronavirus disease 2019 (COVID-19) disease variation when mapping to a healthy reference, enabling the discovery of disease-specific cell states. scArches will facilitate collaborative projects by enabling iterative construction, updating, sharing and efficient use of reference atlases.
AU  - Lotfollahi, M.
AU  - Naghipourfar, M.
AU  - Luecken, M.
AU  - Khajavi, M.
AU  - Büttner, M.
AU  - Wagenstetter, M.
AU  - Avsec, Z.*
AU  - Gayoso, A.*
AU  - Yosef, N.*
AU  - Interlandi, M.*
AU  - Rybakov, S.
AU  - Misharin, A.V.*
AU  - Theis, F.J.
C1  - 62860
C2  - 51114
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Mapping single-cell data to reference atlases by transfer learning.
JO  - Nat. Biotechnol.
PB  - Nature Portfolio
PY  - 2021
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Reversibly photo-switchable proteins are essential for many super-resolution fluorescence microscopic and optoacoustic imaging methods. However, they have yet to be used as sensors that measure the distribution of specific analytes at the nanoscale or in the tissues of live animals. Here we constructed the prototype of a photo-switchable Ca2+ sensor based on GCaMP5G that can be switched with 405/488-nm light and describe its molecular mechanisms at the structural level, including the importance of the interaction of the core barrel structure of the fluorescent protein with the Ca2+ receptor moiety. We demonstrate super-resolution imaging of Ca2+ concentration in cultured cells and optoacoustic Ca2+ imaging in implanted tumor cells in mice under controlled Ca2+ conditions. Finally, we show the generalizability of the concept by constructing examples of photo-switching maltose and dopamine sensors based on periplasmatic binding protein and G-protein-coupled receptor-based sensors.Calcium and other analytes can be imaged at super-resolution and in vivo with photo-switchable sensors.
AU  - Mishra, K.
AU  - Fuenzalida Werner, J.P.
AU  - Pennacchietti, F.*
AU  - Janowski, R.
AU  - Chmyrov, A.
AU  - Huang, Y.
AU  - Zakian Dominguez, C.M.
AU  - Klemm, U.
AU  - Testa, I.*
AU  - Niessing, D.
AU  - Ntziachristos, V.
AU  - Stiel, A.-C.
C1  - 63668
C2  - 51497
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Genetically encoded photo-switchable molecular sensors for optoacoustic and super-resolution imaging.
JO  - Nat. Biotechnol.
PB  - Nature Portfolio
PY  - 2021
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - scVelo reconstructs transient cell states and differentiation pathways from single-cell RNA-sequencing data.RNA velocity has opened up new ways of studying cellular differentiation in single-cell RNA-sequencing data. It describes the rate of gene expression change for an individual gene at a given time point based on the ratio of its spliced and unspliced messenger RNA (mRNA). However, errors in velocity estimates arise if the central assumptions of a common splicing rate and the observation of the full splicing dynamics with steady-state mRNA levels are violated. Here we present scVelo, a method that overcomes these limitations by solving the full transcriptional dynamics of splicing kinetics using a likelihood-based dynamical model. This generalizes RNA velocity to systems with transient cell states, which are common in development and in response to perturbations. We apply scVelo to disentangling subpopulation kinetics in neurogenesis and pancreatic endocrinogenesis. We infer gene-specific rates of transcription, splicing and degradation, recover each cell's position in the underlying differentiation processes and detect putative driver genes. scVelo will facilitate the study of lineage decisions and gene regulation.
AU  - Bergen, V.
AU  - Lange, M.
AU  - Peidli, S.*
AU  - Wolf, F.A.
AU  - Theis, F.J.
C1  - 59842
C2  - 48975
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1408–1414
TI  - Generalizing RNA velocity to transient cell states through dynamical modeling.
JO  - Nat. Biotechnol.
VL  - 38
PB  - Nature Publishing Group
PY  - 2020
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Markers that distinguish pancreatic and hepatic progenitors improve stem-cell differentiation to pancreatic beta cells.Methods for differentiating human pluripotent stem cells to pancreatic and liver lineages in vitro have been limited by the inability to identify and isolate distinct endodermal subpopulations specific to these two organs. Here we report that pancreatic and hepatic progenitors can be isolated using the surface markers CD177/NB1 glycoprotein and inducible T-cell costimulatory ligand CD275/ICOSL, respectively, from seemingly homogeneous definitive endoderm derived from human pluripotent stem cells. Anterior definitive endoderm (ADE) subpopulations identified by CD177 and CD275 show inverse activation of canonical and noncanonical WNT signaling. CD177(+) ADE expresses and synthesizes the secreted WNT, NODAL and BMP antagonist CERBERUS1 and is specified toward the pancreatic fate. CD275(+) ADE receives canonical Wnt signaling and is specified toward the liver fate. Isolated CD177(+) ADE differentiates more homogeneously into pancreatic progenitors and into more functionally mature and glucose-responsive beta-like cells in vitro compared with cells from unsorted differentiation cultures.
AU  - Mahaddalkar, P.U.
AU  - Scheibner, K.
AU  - Pfluger, S.
AU  - Ansarullah
AU  - Sterr, M.
AU  - Beckenbauer, J.
AU  - Irmler, M.
AU  - Beckers, J.
AU  - Knöbel, S.*
AU  - Lickert, H.
C1  - 58971
C2  - 48466
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 1061–1072
TI  - Generation of pancreatic β cells from CD177+ anterior definitive endoderm.
JO  - Nat. Biotechnol.
VL  - 38
PB  - Nature Publishing Group
PY  - 2020
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - We develop mid-infrared optoacoustic microscopy (MiROM) for label-free, bond-selective, live-cell metabolic imaging, enabling spatiotemporal monitoring of carbohydrates, lipids and proteins in cells and tissues. Using acoustic detection of optical absorption, MiROM converts mid-infrared sensing into a positive-contrast imaging modality with negligible photodamage and high sensitivity. We use MiROM to observe changes in intrinsic carbohydrate distribution from a diffusive spatial pattern to tight co-localization with lipid droplets during adipogenesis.Mid-infrared optoacoustic microscopy enables label-free, bond-selective imaging in living cells
AU  - Pleitez, M.A.
AU  - Ali Khan, A.
AU  - Solda, A.
AU  - Chmyrov, A.
AU  - Reber, J.
AU  - Gasparin, F.
AU  - Seeger, M.
AU  - Schätz, B.
AU  - Herzig, S.
AU  - Scheideler, M.
AU  - Ntziachristos, V.
C1  - 57714
C2  - 47878
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 293-296
TI  - Label-free metabolic imaging by mid-infrared optoacoustic microscopy in living cells.
JO  - Nat. Biotechnol.
VL  - 38
IS  - 3
PB  - Nature Publishing Group
PY  - 2020
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Recent single-cell RNA-sequencing studies have suggested that cells follow continuous transcriptomic trajectories in an asynchronous fashion during development. However, observations of cell flux along trajectories are confounded with population size effects in snapshot experiments and are therefore hard to interpret. In particular, changes in proliferation and death rates can be mistaken for cell flux. Here we present pseudodynamics, a mathematical framework that reconciles population dynamics with the concepts underlying developmental trajectories inferred from time-series single-cell data. Pseudodynamics models population distribution shifts across trajectories to quantify selection pressure, population expansion, and developmental potentials. Applying this model to time-resolved single-cell RNA-sequencing of T-cell and pancreatic beta cell maturation, we characterize proliferation and apoptosis rates and identify key developmental checkpoints, data inaccessible to existing approaches.
AU  - Fischer, D.S.
AU  - Fiedler, A.
AU  - Kernfeld, E.M.*
AU  - Genga, R.M.J.*
AU  - Bastidas-Ponce, A.
AU  - Bakhti, M.
AU  - Lickert, H.
AU  - Hasenauer, J.
AU  - Maehr, R.*
AU  - Theis, F.J.
C1  - 55830
C2  - 46592
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 461-468
TI  - Inferring population dynamics from single-cell RNA-sequencing time series data.
JO  - Nat. Biotechnol.
VL  - 37
IS  - 4
PB  - Nature Publishing Group
PY  - 2019
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Large-scale single-cell RNA sequencing (scRNA-seq) data sets that are produced in different laboratories and at different times contain batch effects that may compromise the integration and interpretation of the data. Existing scRNA-seq analysis methods incorrectly assume that the composition of cell populations is either known or identical across batches. We present a strategy for batch correction based on the detection of mutual nearest neighbors (MNNs) in the high-dimensional expression space. Our approach does not rely on predefined or equal population compositions across batches; instead, it requires only that a subset of the population be shared between batches. We demonstrate the superiority of our approach compared with existing methods by using both simulated and real scRNA-seq data sets. Using multiple droplet-based scRNA-seq data sets, we demonstrate that our MNN batch-effect-correction method can be scaled to large numbers of cells.
AU  - Haghverdi, L.
AU  - Lun, A.T.L.*
AU  - Morgan, M.D.*
AU  - Marioni, J.C.*
C1  - 53533
C2  - 44742
SP  - 421-427
TI  - Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors.
JO  - Nat. Biotechnol.
VL  - 36
IS  - 5
PY  - 2018
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Hilsenbeck, O.
AU  - Schwarzfischer, M.
AU  - Skylaki, S.*
AU  - Schauberger, B.
AU  - Hoppe, P.S.*
AU  - Loeffler, D.*
AU  - Kokkaliaris, K.D.*
AU  - Hastreiter, S.*
AU  - Skylaki, E.*
AU  - Filipczyk, A.
AU  - Strasser, M.
AU  - Buggenthin, F.
AU  - Feigelman, J.
AU  - Krumsiek, J.
AU  - van den Berg, A.J.
AU  - Endele, M.
AU  - Etzrodt, M.*
AU  - Marr, C.
AU  - Theis, F.J.
AU  - Schroeder, T.
C1  - 49058
C2  - 41582
CY  - New York
SP  - 703-706
TI  - Software tools for single-cell tracking and quantification of cellular and molecular properties.
JO  - Nat. Biotechnol.
VL  - 34
IS  - 7
PB  - Nature Publishing Group
PY  - 2016
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Recent technical developments have enabled the transcriptomes of hundreds of cells to be assayed in an unbiased manner, opening up the possibility that new subpopulations of cells can be found. However, the effects of potential confounding factors, such as the cell cycle, on the heterogeneity of gene expression and therefore on the ability to robustly identify subpopulations remain unclear. We present and validate a computational approach that uses latent variable models to account for such hidden factors. We show that our single-cell latent variable model (scLVM) allows the identification of otherwise undetectable subpopulations of cells that correspond to different stages during the differentiation of naive T cells into T helper 2 cells. Our approach can be used not only to identify cellular subpopulations but also to tease apart different sources of gene expression heterogeneity in single-cell transcriptomes.
AU  - Buettner, F.
AU  - Natarajan, K.N.*
AU  - Casale, F.P.*
AU  - Proserpio, V.*
AU  - Scialdone, A.*
AU  - Theis, F.J.
AU  - Teichmann, S.A.*
AU  - Marioni, J.C.*
AU  - Stegle, O.*
C1  - 43129
C2  - 36024
CY  - New York
SP  - 155-160
TI  - Computational analysis of cell-to-cell heterogeneity in single-cell RNA-sequencing data reveals hidden subpopulations of cells.
JO  - Nat. Biotechnol.
VL  - 33
IS  - 2
PB  - Nature Publishing Group
PY  - 2015
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - The insertion of precise genetic modifications by genome editing tools such as CRISPR-Cas9 is limited by the relatively low efficiency of homology-directed repair (HDR) compared with the higher efficiency of the nonhomologous end-joining (NHEJ) pathway. To enhance HDR, enabling the insertion of precise genetic modifications, we suppressed the NHEJ key molecules KU70, KU80 or DNA ligase IV by gene silencing, the ligase IV inhibitor SCR7 or the coexpression of adenovirus 4 E1B55K and E4orf6 proteins in a 'traffic light' and other reporter systems. Suppression of KU70 and DNA ligase IV promotes the efficiency of HDR 4-5-fold. When co-expressed with the Cas9 system, E1B55K and E4orf6 improved the efficiency of HDR up to eightfold and essentially abolished NHEJ activity in both human and mouse cell lines. Our findings provide useful tools to improve the frequency of precise gene modifications in mammalian cells.
AU  - Chu, V.T.*
AU  - Weber, T.*
AU  - Wefers, B.
AU  - Wurst, W.
AU  - Sander, S.*
AU  - Rajewsky, K.*
AU  - Kühn, R.
C1  - 43965
C2  - 36733
CY  - New York
SP  - 543-548
TI  - Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells.
JO  - Nat. Biotechnol.
VL  - 33
IS  - 5
PB  - Nature Publishing Group
PY  - 2015
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with substantial heterogeneity in its clinical presentation. This makes diagnosis and effective treatment difficult, so better tools for estimating disease progression are needed. Here, we report results from the DREAM-Phil Bowen ALS Prediction Prize4Life challenge. In this crowdsourcing competition, competitors developed algorithms for the prediction of disease progression of 1,822 ALS patients from standardized, anonymized phase 2/3 clinical trials. The two best algorithms outperformed a method designed by the challenge organizers as well as predictions by ALS clinicians. We estimate that using both winning algorithms in future trial designs could reduce the required number of patients by at least 20%. The DREAM-Phil Bowen ALS Prediction Prize4Life challenge also identified several potential nonstandard predictors of disease progression including uric acid, creatinine and surprisingly, blood pressure, shedding light on ALS pathobiology. This analysis reveals the potential of a crowdsourcing competition that uses clinical trial data for accelerating ALS research and development.
AU  - Küffner, R.
AU  - Zach, N.*
AU  - Norel, R.*
AU  - Hawe, J.*
AU  - Schoenfeld, D.*
AU  - Wang, L.*
AU  - Li, G.*
AU  - Fang, L.*
AU  - Mackey, L.*
AU  - Hardiman, O.*
AU  - Cudkowicz, M.*
AU  - Sherman, A.*
AU  - Ertaylan, G.*
AU  - Grosse-Wentrup, M.*
AU  - Hothorn, T.*
AU  - van Ligtenberg, J.*
AU  - Macke, J.H.*
AU  - Meyer, T.*
AU  - Schölkopf, B.*
AU  - Tran, L.*
AU  - Vaughan, R.*
AU  - Stolovitzky, G.*
AU  - Leitner, M.L.*
C1  - 42773
C2  - 35303
CY  - New York
SP  - 51-57
TI  - Crowdsourced analysis of clinical trial data to predict amyotrophic lateral sclerosis progression.
JO  - Nat. Biotechnol.
VL  - 33
IS  - 1
PB  - Nature Publishing Group
PY  - 2015
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Reconstruction of the molecular pathways controlling organ development has been hampered by a lack of methods to resolve embryonic progenitor cells. Here we describe a strategy to address this problem that combines gene expression profiling of large numbers of single cells with data analysis based on diffusion maps for dimensionality reduction and network synthesis from state transition graphs. Applying the approach to hematopoietic development in the mouse embryo, we map the progression of mesoderm toward blood using single-cell gene expression analysis of 3,934 cells with blood-forming potential captured at four time points between E7.0 and E8.5. Transitions between individual cellular states are then used as input to develop a single-cell network synthesis toolkit to generate a computationally executable transcriptional regulatory network model of blood development. Several model predictions concerning the roles of Sox and Hox factors are validated experimentally. Our results demonstrate that single-cell analysis of a developing organ coupled with computational approaches can reveal the transcriptional programs that underpin organogenesis.
AU  - Moignard, V.*
AU  - Woodhouse, S.*
AU  - Haghverdi, L.
AU  - Lilly, A.J.*
AU  - Tanaka, Y.*
AU  - Wilkinson, A.C.*
AU  - Buettner, F.
AU  - Macaulay, I.C.*
AU  - Jawaid, W.*
AU  - Diamanti, E.*
AU  - Nishikawa, S.I.*
AU  - Piterman, N.*
AU  - Kouskoff, V.*
AU  - Theis, F.J.
AU  - Fisher, J.*
AU  - Gottgens, B.*
C1  - 43264
C2  - 36344
CY  - New York
SP  - 269-276
TI  - Decoding the regulatory network of early blood development from single-cell gene expression measurements.
JO  - Nat. Biotechnol.
VL  - 33
IS  - 3
PB  - Nature Publishing Group
PY  - 2015
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - To identify early populations of committed progenitors derived from human embryonic stem cells (hESCs), we screened self-renewing, BMP4-treated and retinoic acid-treated cultures with >400 antibodies recognizing cell-surface antigens. Sorting of >30 subpopulations followed by transcriptional analysis of developmental genes identified four distinct candidate progenitor groups. Subsets detected in self-renewing cultures, including CXCR4(+) cells, expressed primitive endoderm genes. Expression of Cxcr4 in primitive endoderm was confirmed in visceral endoderm of mouse embryos. BMP4-induced progenitors exhibited gene signatures of mesoderm, trophoblast and vascular endothelium, suggesting correspondence to gastrulation-stage primitive streak, chorion and allantois precursors, respectively. Functional studies in vitro and in vivo confirmed that ROR2(+) cells produce mesoderm progeny, APA(+) cells generate syncytiotrophoblasts and CD87(+) cells give rise to vasculature. The same progenitor classes emerged during the differentiation of human induced pluripotent stem cells (hiPSCs). These markers and progenitors provide tools for purifying human tissue-regenerating progenitors and for studying the commitment of pluripotent stem cells to lineage progenitors.
AU  - Drukker, M.
AU  - Tang, C.*
AU  - Ardehali, R.*
AU  - Rinkevich, Y.*
AU  - Seita, J.*
AU  - Lee, A.S.*
AU  - Mosley, A.R.*
AU  - Weissman, I.L.*
AU  - Soen, Y.*
C1  - 7605
C2  - 29894
SP  - 531-542
TI  - Isolation of primitive endoderm, mesoderm, vascular endothelial and trophoblast progenitors from human pluripotent stem cells.
JO  - Nat. Biotechnol.
VL  - 30
IS  - 6
PB  - Nature Publishing Group
PY  - 2012
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - no Abstract
AU  - Wichmann, H.-E.
AU  - Kuhn, K.A.*
AU  - Waldenberger, M.
AU  - Schmelcher, D.*
AU  - Schuffenhauer, S.
AU  - Meitinger, T.
AU  - Wurst, S.H.*
AU  - Lamla, G.*
AU  - Fortier, I.*
AU  - Burton, P.R*
AU  - Peltonen, L.*
AU  - Perola, M.*
AU  - Metspalu, A.*
AU  - Riegman, P.*
AU  - Landegren, U.*
AU  - Taussig, M.J.*
AU  - Litton, J.E.*
AU  - Fransson, M.N.*
AU  - Eder, J.*
AU  - Cambon-Thomsen, A.*
AU  - Bovenberg, J.*
AU  - Dagher, G.*
AU  - van Ommen, G.J.*
AU  - Griffith, M.*
AU  - Yuille, M.*
AU  - Zatloukal, K.*
C1  - 6124
C2  - 28924
SP  - 795-797
TI  - Comprehensive catalog of European biobanks.
JO  - Nat. Biotechnol.
VL  - 29
IS  - 9
PB  - Nature Publ. Group
PY  - 2011
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Nano-size particles show promise for pulmonary drug delivery, yet their behavior after deposition in the lung remains poorly understood. In this study, a series of near-infrared (NIR) fluorescent nanoparticles were systematically varied in chemical composition, shape, size and surface charge, and their biodistribution and elimination were quantified in rat models after lung instillation. We demonstrate that nanoparticles with hydrodynamic diameter (HD) less than ≈34 nm and a noncationic surface charge translocate rapidly from the lung to mediastinal lymph nodes. Nanoparticles of HD < 6 nm can traffic rapidly from the lungs to lymph nodes and the bloodstream, and then be subsequently cleared by the kidneys. We discuss the importance of these findings for drug delivery, air pollution and carcinogenesis.
AU  - Choi, H.S.*
AU  - Ashitate, Y.*
AU  - Lee, J.H.*
AU  - Kim, S.H.*
AU  - Matsui, A.*
AU  - Insin, N.*
AU  - Bawendi, M.G.*
AU  - Semmler-Behnke, M.
AU  - Frangioni, J.V.*
AU  - Tsuda, A.*
C1  - 5991
C2  - 27759
SP  - 1300-1303
TI  - Rapid translocation of nanoparticles from the lung airspaces to the body.
JO  - Nat. Biotechnol.
VL  - 28
IS  - 12
PB  - Nature Publ. Group
PY  - 2010
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - no abstract available
AU  - Kreyling, W.G.
AU  - Hirn, S.
AU  - Schleh, C.
C1  - 5761
C2  - 27824
SP  - 1275-1276
TI  - Nanoparticles in the lung.
JO  - Nat. Biotechnol.
VL  - 28
IS  - 12
PB  - Nature Publ. Group
PY  - 2010
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - Comprehensive phenotypic screening of knockout mice highlights the pleiotropic functions of secreted and transmembrane proteins.
AU  - Wurst, W.
AU  - Hrabě de Angelis, M.
C1  - 770
C2  - 27235
SP  - 684-685
TI  - Systematic phenotyping of mouse mutants.
JO  - Nat. Biotechnol.
VL  - 28
IS  - 7
PB  - Nature Publ. Group
PY  - 2010
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - A wealth of molecular interaction data is available in the literature, ranging from large-scale datasets to a single interaction confirmed by several different techniques. These data are all too often reported either as free text or in tables of variable format, and are often missing key pieces of information essential for a full understanding of the experiment. Here we propose MIMIx, the minimum information required for reporting a molecular interaction experiment. Adherence to these reporting guidelines will result in publications of increased clarity and usefulness to the scientific community and will support the rapid, systematic capture of molecular interaction data in public databases, thereby improving access to valuable interaction data.
AU  - Orchard, S.*
AU  - Salwinski, L.*
AU  - Kerrien, S.*
AU  - Montecchi-Palazzi, L.*
AU  - Oesterheld, M.
AU  - Stuempflen, V.
AU  - Ceol, A.*
AU  - Chatr-aryamontri, A.*
AU  - Armstrong, J.*
AU  - Woollard, P.*
AU  - Salama, J.J.*
AU  - Moore, S.*
AU  - Wojcik, J.*
AU  - Bader, G.D.*
AU  - Vidal, M.*
AU  - Cusick, M.E.*
AU  - Gerstein, M.*
AU  - Gavin, A.C.*
AU  - Superti-Furga, G.*
AU  - Greenblatt, J.*
AU  - Bader, J.*
AU  - Uetz, P.*
AU  - Tyers, M.*
AU  - Legrain, P.*
AU  - Fields, S.*
AU  - Mulder, N.*
AU  - Gilson, M.*
AU  - Niepmann, M.*
AU  - Burgoon, L.*
AU  - De, Las, Rivas, J.*
AU  - Prieto, C.*
AU  - Perreau, V.M.*
AU  - Hogue, C.*
AU  - Mewes, H.-W.
AU  - Apweiler, R.*
AU  - Xenarios, I.*
AU  - Eisenberg, D.*
AU  - Cesareni, G.*
AU  - Hermjakob, H.*
C1  - 1765
C2  - 24904
SP  - 894-898
TI  - The minimum information required for reporting a molecular interaction experiment (MIMIx).
JO  - Nat. Biotechnol.
VL  - 25
IS  - 8
PB  - Nature America Inc.
PY  - 2007
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Eggan, K.*
AU  - Rode, A.*
AU  - Jentsch, I.
AU  - Samuel, C.*
AU  - Hennek, Th.*
AU  - Tintrup, H.*
AU  - Zevnik, B.*
AU  - Erwin, J.*
AU  - Loring, J.*
AU  - Jackson-Grusby, L.*
AU  - Speicher, M.R.
AU  - Kuehn, R.*
AU  - Jaenisch, R.*
C1  - 9717
C2  - 20542
SP  - 455-459
TI  - Male and female mice derived from the same embryonic stem cell clone by tetraploid embryo complementation.
JO  - Nat. Biotechnol.
VL  - 20
PY  - 2002
SN  - 1087-0156
ER  - 

TY  - JOUR
AU  - Mainguy, G.*
AU  - Montesinos, M.L.*
AU  - Lesaffre, B.*
AU  - Zevnik, B.*
AU  - Karasawa, M.
AU  - Kothary, R.*
AU  - Wurst, W.
AU  - Prochiantz, A.*
AU  - Volovitch, M.*
C1  - 2783
C2  - 22820
SP  - 746-749
TI  - An induction gene trap for identifying a homeoprotein-regulated locus.
JO  - Nat. Biotechnol.
VL  - 18
PY  - 2000
SN  - 1087-0156
ER  - 

TY  - JOUR
AB  - To evaluate the feasibility of using engineered antioxidant enzymes as an approach to improve the tolerance of plants to ambient stress, we have constructed transgenic tobacco plants that overproduce superoxide dismutase (SOD), an enzyme which converts superoxide radicals into hydrogen peroxide and oxygen, and is believed to play a crucial role in antioxidant defense. We have targeted the MnSOD from Nicotiana plumbaginifolia either to the chloroplasts or to the mitochondria, and evaluated the ozone tolerance of transgenic and control plants. Enhanced SOD activity in the mitochondria had only a minor effect on ozone tolerance. However, overproduction of SOD in the chloroplasts resulted in a 3-4 fold reduction of visible ozone injury.
AU  - van Camp, W.I.M.*
AU  - Willekens, H.*
AU  - Bowler, C.*
AU  - Van Montagu, M.C.E.*
AU  - Inze ́, D.G.*
AU  - Reupold-Popp, P.
AU  - Sandermann, H.J.
AU  - Langebartels, C.
C1  - 39986
C2  - 38940
SP  - 165-168
TI  - Elevated levels of superoxide dismutase protect transgenic plants against ozone damage.
JO  - Nat. Biotechnol.
VL  - 12
IS  - 2
PY  - 1994
SN  - 1087-0156
ER  -