| 1. |
- Abramson, Alex, et al.
(author)
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Oral delivery of systemic monoclonal antibodies, peptides and small molecules using gastric auto-injectors
- 2021
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:1, s. 103-109
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Journal article (peer-reviewed)abstract
- Oral administration provides a simple and non-invasive approach for drug delivery. However, due to poor absorption and swift enzymatic degradation in the gastrointestinal tract, a wide range of molecules must be parenterally injected to attain required doses and pharmacokinetics. Here we present an orally dosed liquid auto-injector capable of delivering up to 4-mg doses of a bioavailable drug with the rapid pharmacokinetics of an injection, reaching an absolute bioavailability of up to 80% and a maximum plasma drug concentration within 30 min after dosing. This approach improves dosing efficiencies and pharmacokinetics an order of magnitude over our previously designed injector capsules and up to two orders of magnitude over clinically available and preclinical chemical permeation enhancement technologies. We administered the capsules to swine for delivery of clinically relevant doses of four commonly injected medications, including adalimumab, a GLP-1 analog, recombinant human insulin and epinephrine. These multi-day dosing experiments and oral administration in awake animal models support the translational potential of the system.
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| 2. |
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| 3. |
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| 4. |
- Adewumi, Oluseun, et al.
(author)
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative
- 2007
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 25:7, s. 803-816
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Journal article (peer-reviewed)abstract
- The International Stem Cell Initiative characterized 59 human embryonic stem cell lines from 17 laboratories worldwide. Despite diverse genotypes and different techniques used for derivation and maintenance, all lines exhibited similar expression patterns for several markers of human embryonic stem cells. They expressed the glycolipid antigens SSEA3 and SSEA4, the keratan sulfate antigens TRA-1-60, TRA-1-81, GCTM2 and GCT343, and the protein antigens CD9, Thy1 (also known as CD90), tissue- nonspecific alkaline phosphatase and class 1 HLA, as well as the strongly developmentally regulated genes NANOG, POU5F1 (formerly known as OCT4), TDGF1, DNMT3B, GABRB3 and GDF3. Nevertheless, the lines were not identical: differences in expression of several lineage markers were evident, and several imprinted genes showed generally similar allele-specific expression patterns, but some gene-dependent variation was observed. Also, some female lines expressed readily detectable levels of XIST whereas others did not. No significant contamination of the lines with mycoplasma, bacteria or cytopathic viruses was detected.
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| 5. |
- Agarwalla, Pritha, et al.
(author)
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Bioinstructive implantable scaffolds for rapid in vivo manufacture and release of CAR-T cells
- 2022
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In: Nature Biotechnology. - : Nature Publishing Group. - 1087-0156 .- 1546-1696. ; 40:8, s. 1250-1258
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Journal article (peer-reviewed)abstract
- Despite their clinical success, chimeric antigen receptor (CAR)-T cell therapies for B cell malignancies are limited by lengthy, costly and labor-intensive ex vivo manufacturing procedures that might lead to cell products with heterogeneous composition. Here we describe an implantable Multifunctional Alginate Scaffold for T Cell Engineering and Release (MASTER) that streamlines in vivo CAR-T cell manufacturing and reduces processing time to a single day. When seeded with human peripheral blood mononuclear cells and CD19-encoding retroviral particles, MASTER provides the appropriate interface for viral vector-mediated gene transfer and, after subcutaneous implantation, mediates the release of functional CAR-T cells in mice. We further demonstrate that in vivo-generated CAR-T cells enter the bloodstream and control distal tumor growth in a mouse xenograft model of lymphoma, showing greater persistence than conventional CAR-T cells. MASTER promises to transform CAR-T cell therapy by fast-tracking manufacture and potentially reducing the complexity and resources needed for provision of this type of therapy.
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| 6. |
- Albers, Stevan C., et al.
(author)
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The rise and fall of innovation in biofuels
- 2016
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 34:8, s. 814-821
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Journal article (peer-reviewed)
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| 7. |
- Ali, M, et al.
(author)
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T cells targeted to TdT kill leukemic lymphoblasts while sparing normal lymphocytes
- 2022
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In: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 40:4, s. 488-
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Journal article (peer-reviewed)abstract
- Unlike chimeric antigen receptors, T-cell receptors (TCRs) can recognize intracellular targets presented on human leukocyte antigen (HLA) molecules. Here we demonstrate that T cells expressing TCRs specific for peptides from the intracellular lymphoid-specific enzyme terminal deoxynucleotidyl transferase (TdT), presented in the context of HLA-A*02:01, specifically eliminate primary acute lymphoblastic leukemia (ALL) cells of T- and B-cell origin in vitro and in three mouse models of disseminated B-ALL. By contrast, the treatment spares normal peripheral T- and B-cell repertoires and normal myeloid cells in vitro, and in vivo in humanized mice. TdT is an attractive cancer target as it is highly and homogeneously expressed in 80–94% of B- and T-ALLs, but only transiently expressed during normal lymphoid differentiation, limiting on-target toxicity of TdT-specific T cells. TCR-modified T cells targeting TdT may be a promising immunotherapy for B-ALL and T-ALL that preserves normal lymphocytes.
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| 8. |
- Allesøe, Rosa Lundbye, et al.
(author)
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Discovery of drug–omics associations in type 2 diabetes with generative deep-learning models
- 2023
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 41:3, s. 399-408
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Journal article (peer-reviewed)abstract
- 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.
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| 9. |
- Almagro Armenteros, José Juan, et al.
(author)
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SignalP 5.0 improves signal peptide predictions using deep neural networks
- 2019
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 37:4, s. 420-423
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Journal article (peer-reviewed)abstract
- Signal peptides (SPs) are short amino acid sequences in the amino terminus of many newly synthesized proteins that target proteins into, or across, membranes. Bioinformatic tools can predict SPs from amino acid sequences, but most cannot distinguish between various types of signal peptides. We present a deep neural network-based approach that improves SP prediction across all domains of life and distinguishes between three types of prokaryotic SPs.
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| 10. |
- Ameur, Adam
(author)
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Goodbye reference, hello genome graphs
- 2019
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In: Nature Biotechnology. - : NATURE PUBLISHING GROUP. - 1087-0156 .- 1546-1696. ; 37:8, s. 866-868
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Journal article (other academic/artistic)
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| 11. |
- Amit, Ido, et al.
(author)
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Voices of biotech
- 2016
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In: Nature Biotechnology. - : Nature Publishing Group. - 1087-0156 .- 1546-1696. ; 34:3, s. 270-275
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Journal article (peer-reviewed)
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| 12. |
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| 13. |
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| 14. |
- Arteaga, H J, et al.
(author)
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Choosing CCR5 or Rev siRNA in HIV-1
- 2003
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 21:3, s. 230-231
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Journal article (peer-reviewed)
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| 15. |
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| 16. |
- Babaei, Parizad, 1990, et al.
(author)
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Challenges in modeling the human gut microbiome
- 2018
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 36:8, s. 682-686
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Journal article (other academic/artistic)
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| 17. |
- Baeyens, Luc, et al.
(author)
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Transient cytokine treatment induces acinar cell reprogramming and regenerates functional beta cell mass in diabetic mice
- 2014
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In: Nature Biotechnology. - : Springer Science and Business Media LLC. - 1087-0156 .- 1546-1696. ; 32:1, s. 76-83
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Journal article (peer-reviewed)abstract
- Reprogramming of pancreatic exocrine cells into cells resembling beta cells may provide a strategy for treating diabetes. Here we show that transient administration of epidermal growth factor and ciliary neurotrophic factor to adult mice with chronic hyperglycemia efficiently stimulates the conversion of terminally differentiated acinar cells to beta-like cells. Newly generated beta-like cells are epigenetically reprogrammed, functional and glucose responsive, and they reinstate normal glycemic control for up to 248 d. The regenerative process depends on Stat3 signaling and requires a threshold number of Neurogenin 3 (Ngn3)-expressing acinar cells. In contrast to previous work demonstrating in vivo conversion of acinar cells to beta-like cells by viral delivery of exogenous transcription factors, our approach achieves acinar-to-beta-cell reprogramming through transient cytokine exposure rather than genetic modification.
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| 18. |
- Balboa, Diego, et al.
(author)
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Functional, metabolic and transcriptional maturation of human pancreatic islets derived from stem cells.
- 2022
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 40:7, s. 1042-1055
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Journal article (peer-reviewed)abstract
- Transplantation of pancreatic islet cells derived from human pluripotent stem cells is a promising treatment for diabetes. Despite progress in the generation of stem-cell-derived islets (SC-islets), no detailed characterization of their functional properties has been conducted. Here, we generated functionally mature SC-islets using an optimized protocol and benchmarked them comprehensively against primary adult islets. Biphasic glucose-stimulated insulin secretion developed during in vitro maturation, associated with cytoarchitectural reorganization and the increasing presence of alpha cells. Electrophysiology, signaling and exocytosis of SC-islets were similar to those of adult islets. Glucose-responsive insulin secretion was achieved despite differences in glycolytic and mitochondrial glucose metabolism. Single-cell transcriptomics of SC-islets in vitro and throughout 6 months of engraftment in mice revealed a continuous maturation trajectory culminating in a transcriptional landscape closely resembling that of primary islets. Our thorough evaluation of SC-islet maturation highlights their advanced degree of functionality and supports their use in further efforts to understand and combat diabetes.
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| 19. |
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| 20. |
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| 21. |
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| 22. |
- Bergenstråhle, Ludvig, et al.
(author)
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Super-resolved spatial transcriptomics by deep data fusion
- 2022
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In: Nature Biotechnology. - : Nature Research. - 1087-0156 .- 1546-1696. ; 40:4, s. 476-479
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Journal article (peer-reviewed)abstract
- Current methods for spatial transcriptomics are limited by low spatial resolution. Here we introduce a method that integrates spatial gene expression data with histological image data from the same tissue section to infer higher-resolution expression maps. Using a deep generative model, our method characterizes the transcriptome of micrometer-scale anatomical features and can predict spatial gene expression from histology images alone.
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| 23. |
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| 24. |
- Bill, Roslyn M., et al.
(author)
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Overcoming barriers to membrane protein structure determination.
- 2011
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In: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 29:4, s. 335-40
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Journal article (peer-reviewed)abstract
- After decades of slow progress, the pace of research on membrane protein structures is beginning to quicken thanks to various improvements in technology, including protein engineering and microfocus X-ray diffraction. Here we review these developments and, where possible, highlight generic new approaches to solving membrane protein structures based on recent technological advances. Rational approaches to overcoming the bottlenecks in the field are urgently required as membrane proteins, which typically comprise ~30% of the proteomes of organisms, are dramatically under-represented in the structural database of the Protein Data Bank.
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| 25. |
- Bodén, Andreas, et al.
(author)
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Volumetric live cell imaging with three-dimensional parallelized RESOLFT microscopy
- 2021
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In: Nature Biotechnology. - : Springer Nature. - 1087-0156 .- 1546-1696. ; 39:5, s. 609-618
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Journal article (peer-reviewed)abstract
- Elucidating the volumetric architecture of organelles and molecules inside cells requires microscopy methods with a sufficiently high spatial resolution in all three dimensions. Current methods are limited by insufficient resolving power along the optical axis, long recording times and photobleaching when applied to live cell imaging. Here, we present a 3D, parallelized, reversible, saturable/switchable optical fluorescence transition (3D pRESOLFT) microscope capable of delivering sub-80-nm 3D resolution in whole living cells. We achieved rapid (1-2 Hz) acquisition of large fields of view (similar to 40 x 40 mu m(2)) by highly parallelized image acquisition with an interference pattern that creates an array of 3D-confined and equally spaced intensity minima. This allowed us to reversibly turn switchable fluorescent proteins to dark states, leading to a targeted 3D confinement of fluorescence. We visualized the 3D organization and dynamics of organelles in living cells and volumetric structural alterations of synapses during plasticity in cultured hippocampal neurons.
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