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Nature Biotechnology

Keren Bahar Halpern, Rom Shenhav, Hassan Massalha, Beata Toth, Adi Egozi, Efi E Massasa, Chiara Medgalia, Eyal David, Amir Giladi, Andreas E Moor, Ziv Porat, Ido Amit, Shalev Itzkovitz
Spatially resolved single-cell RNA sequencing (scRNAseq) is a powerful approach for inferring connections between a cell's identity and its position in a tissue. We recently combined scRNAseq with spatially mapped landmark genes to infer the expression zonation of hepatocytes. However, determining zonation of small cells with low mRNA content, or without highly expressed landmark genes, remains challenging. Here we used paired-cell sequencing, in which mRNA from pairs of attached mouse cells were sequenced and gene expression from one cell type was used to infer the pairs' tissue coordinates...
September 17, 2018: Nature Biotechnology
Omid G Sani, Yuxiao Yang, Morgan B Lee, Heather E Dawes, Edward F Chang, Maryam M Shanechi
The ability to decode mood state over time from neural activity could enable closed-loop systems to treat neuropsychiatric disorders. However, this decoding has not been demonstrated, partly owing to the difficulty of modeling distributed mood-relevant neural dynamics while dealing with the sparsity of mood state measurements. Here we develop a modeling framework to decode mood state variations from multi-site intracranial recordings in seven human subjects with epilepsy who self-reported their mood state intermittently over multiple days...
September 10, 2018: Nature Biotechnology
Donovan H Parks, Maria Chuvochina, David W Waite, Christian Rinke, Adam Skarshewski, Pierre-Alain Chaumeil, Philip Hugenholtz
Taxonomy is an organizing principle of biology and is ideally based on evolutionary relationships among organisms. Development of a robust bacterial taxonomy has been hindered by an inability to obtain most bacteria in pure culture and, to a lesser extent, by the historical use of phenotypes to guide classification. Culture-independent sequencing technologies have matured sufficiently that a comprehensive genome-based taxonomy is now possible. We used a concatenated protein phylogeny as the basis for a bacterial taxonomy that conservatively removes polyphyletic groups and normalizes taxonomic ranks on the basis of relative evolutionary divergence...
August 27, 2018: Nature Biotechnology
Xiao Wang, Jianan Li, Ying Wang, Bei Yang, Jia Wei, Jing Wu, Ruixuan Wang, Xingxu Huang, Jia Chen, Li Yang
Base editors (BEs) enable the generation of targeted single-nucleotide mutations, but currently used rat APOBEC1-based BEs are relatively inefficient in editing cytosines in highly methylated regions or in GpC contexts. By screening a variety of APOBEC and AID deaminases, we show that human APOBEC3A-conjugated BEs and versions we engineered to have narrower editing windows can mediate efficient C-to-T base editing in regions with high methylation levels and GpC dinucleotide content.
August 20, 2018: Nature Biotechnology
Alicia C Smart, Claire A Margolis, Harold Pimentel, Meng Xiao He, Diana Miao, Dennis Adeegbe, Tim Fugmann, Kwok-Kin Wong, Eliezer M Van Allen
We present an in silico approach to identifying neoepitopes derived from intron retention events in tumor transcriptomes. Using mass spectrometry immunopeptidome analysis, we show that retained intron neoepitopes are processed and presented on MHC I on the surface of cancer cell lines. RNA-derived neoepitopes should be considered for prospective personalized cancer vaccine development.
August 16, 2018: Nature Biotechnology
Jason M Gehrke, Oliver Cervantes, M Kendell Clement, Yuxuan Wu, Jing Zeng, Daniel E Bauer, Luca Pinello, J Keith Joung
Base editor technology, which uses CRISPR-Cas9 to direct cytidine deaminase enzymatic activity to specific genomic loci, enables the highly efficient introduction of precise cytidine-to-thymidine DNA alterations. However, existing base editors create unwanted C-to-T alterations when more than one C is present in the enzyme's five-base-pair editing window. Here we describe a strategy for reducing bystander mutations using an engineered human APOBEC3A (eA3A) domain, which preferentially deaminates cytidines in specific motifs according to a TCR>TCY>VCN hierarchy...
July 30, 2018: Nature Biotechnology
Michael Wainberg, Daniele Merico, Andrew Delong, Brendan J Frey
Deep learning is beginning to impact biological research and biomedical applications as a result of its ability to integrate vast datasets, learn arbitrarily complex relationships and incorporate existing knowledge. Already, deep learning models can predict, with varying degrees of success, how genetic variation alters cellular processes involved in pathogenesis, which small molecules will modulate the activity of therapeutically relevant proteins, and whether radiographic images are indicative of disease. However, the flexibility of deep learning creates new challenges in guaranteeing the performance of deployed systems and in establishing trust with stakeholders, clinicians and regulators, who require a rationale for decision making...
October 2018: Nature Biotechnology
Tess C Branon, Justin A Bosch, Ariana D Sanchez, Namrata D Udeshi, Tanya Svinkina, Steven A Carr, Jessica L Feldman, Norbert Perrimon, Alice Y Ting
Protein interaction networks and protein compartmentalization underlie all signaling and regulatory processes in cells. Enzyme-catalyzed proximity labeling (PL) has emerged as a new approach to study the spatial and interaction characteristics of proteins in living cells. However, current PL methods require over 18 h of labeling time or utilize chemicals with limited cell permeability or high toxicity. We used yeast display-based directed evolution to engineer two promiscuous mutants of biotin ligase, TurboID and miniTurbo, which catalyze PL with much greater efficiency than BioID or BioID2, and enable 10-min PL in cells with non-toxic and easily deliverable biotin...
October 2018: Nature Biotechnology
Ben M Maoz, Anna Herland, Edward A FitzGerald, Thomas Grevesse, Charles Vidoudez, Alan R Pacheco, Sean P Sheehy, Tae-Eun Park, Stephanie Dauth, Robert Mannix, Nikita Budnik, Kevin Shores, Alexander Cho, Janna C Nawroth, Daniel Segrè, Bogdan Budnik, Donald E Ingber, Kevin Kit Parker
The neurovascular unit (NVU) regulates metabolic homeostasis as well as drug pharmacokinetics and pharmacodynamics in the central nervous system. Metabolic fluxes and conversions over the NVU rely on interactions between brain microvascular endothelium, perivascular pericytes, astrocytes and neurons, making it difficult to identify the contributions of each cell type. Here we model the human NVU using microfluidic organ chips, allowing analysis of the roles of individual cell types in NVU functions. Three coupled chips model influx across the blood-brain barrier (BBB), the brain parenchymal compartment and efflux across the BBB...
October 2018: Nature Biotechnology
Devin P Sullivan, Casper F Winsnes, Lovisa Åkesson, Martin Hjelmare, Mikaela Wiking, Rutger Schutten, Linzi Campbell, Hjalti Leifsson, Scott Rhodes, Andie Nordgren, Kevin Smith, Bernard Revaz, Bergur Finnbogason, Attila Szantner, Emma Lundberg
Pattern recognition and classification of images are key challenges throughout the life sciences. We combined two approaches for large-scale classification of fluorescence microscopy images. First, using the publicly available data set from the Cell Atlas of the Human Protein Atlas (HPA), we integrated an image-classification task into a mainstream video game (EVE Online) as a mini-game, named Project Discovery. Participation by 322,006 gamers over 1 year provided nearly 33 million classifications of subcellular localization patterns, including patterns that were not previously annotated by the HPA...
October 2018: Nature Biotechnology
Erik Garrison, Jouni Sirén, Adam M Novak, Glenn Hickey, Jordan M Eizenga, Eric T Dawson, William Jones, Shilpa Garg, Charles Markello, Michael F Lin, Benedict Paten, Richard Durbin
Reference genomes guide our interpretation of DNA sequence data. However, conventional linear references represent only one version of each locus, ignoring variation in the population. Poor representation of an individual's genome sequence impacts read mapping and introduces bias. Variation graphs are bidirected DNA sequence graphs that compactly represent genetic variation across a population, including large-scale structural variation such as inversions and duplications. Previous graph genome software implementations have been limited by scalability or topological constraints...
October 2018: Nature Biotechnology
Dan Wang, Jia Li, Chun-Qing Song, Karen Tran, Haiwei Mou, Pei-Hsuan Wu, Phillip W L Tai, Craig A Mendonca, Lingzhi Ren, Blake Y Wang, Qin Su, Dominic J Gessler, Phillip D Zamore, Wen Xue, Guangping Gao
We report a genome-editing strategy to correct compound heterozygous mutations, a common genotype in patients with recessive genetic disorders. Adeno-associated viral vector delivery of Cas9 and guide RNA induces allelic exchange and rescues the disease phenotype in mouse models of hereditary tyrosinemia type I and mucopolysaccharidosis type I. This approach recombines non-mutated genetic information present in two heterozygous alleles into one functional allele without using donor DNA templates.
October 2018: Nature Biotechnology
Sarwish Rafiq, Oladapo O Yeku, Hollie J Jackson, Terence J Purdon, Dayenne G van Leeuwen, Dylan J Drakes, Mei Song, Matthew M Miele, Zhuoning Li, Pei Wang, Su Yan, Jingyi Xiang, Xiaojing Ma, Venkatraman E Seshan, Ronald C Hendrickson, Cheng Liu, Renier J Brentjens
The efficacy of chimeric antigen receptor (CAR) T cell therapy against poorly responding tumors can be enhanced by administering the cells in combination with immune checkpoint blockade inhibitors. Alternatively, the CAR construct has been engineered to coexpress factors that boost CAR-T cell function in the tumor microenvironment. We modified CAR-T cells to secrete PD-1-blocking single-chain variable fragments (scFv). These scFv-secreting CAR-T cells acted in both a paracrine and autocrine manner to improve the anti-tumor activity of CAR-T cells and bystander tumor-specific T cells in clinically relevant syngeneic and xenogeneic mouse models of PD-L1+ hematologic and solid tumors...
October 2018: Nature Biotechnology
Vincent M Isabella, Binh N Ha, Mary Joan Castillo, David J Lubkowicz, Sarah E Rowe, Yves A Millet, Cami L Anderson, Ning Li, Adam B Fisher, Kip A West, Philippa J Reeder, Munira M Momin, Christopher G Bergeron, Sarah E Guilmain, Paul F Miller, Caroline B Kurtz, Dean Falb
Phenylketonuria (PKU) is a genetic disease that is characterized by an inability to metabolize phenylalanine (Phe), which can result in neurotoxicity. To provide a potential alternative to a protein-restricted diet, we engineered Escherichia coli Nissle to express genes encoding Phe-metabolizing enzymes in response to anoxic conditions in the mammalian gut. Administration of our synthetic strain, SYNB1618, to the Pahenu2/enu2 PKU mouse model reduced blood Phe concentration by 38% compared with the control, independent of dietary protein intake...
October 2018: Nature Biotechnology
Huawei Zhang, Xiaomin Si, Xiang Ji, Rong Fan, Jinxing Liu, Kunling Chen, Daowen Wang, Caixia Gao
Translational regulation by upstream open reading frames (uORFs) is becoming established as a general mechanism for controlling the amount of protein that is synthesized from downstream primary ORFs (pORFs). We found that genome editing of endogenous uORFs in plants enabled the modulation of translation of mRNAs from four pORFs that are involved in either development or antioxidant biosynthesis. A single-guide RNA that targeted the region harboring a uORF initiation codon can produce multiple mutations. Following uORF editing, we observed varying amounts of mRNA translation in four pORFs...
October 2018: Nature Biotechnology
Maria Paz Zafra, Emma M Schatoff, Alyna Katti, Miguel Foronda, Marco Breinig, Anabel Y Schweitzer, Amber Simon, Teng Han, Sukanya Goswami, Emma Montgomery, Jordana Thibado, Edward R Kastenhuber, Francisco J Sánchez-Rivera, Junwei Shi, Christopher R Vakoc, Scott W Lowe, Darjus F Tschaharganeh, Lukas E Dow
CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created...
October 2018: Nature Biotechnology
Luke W Koblan, Jordan L Doman, Christopher Wilson, Jonathan M Levy, Tristan Tay, Gregory A Newby, Juan Pablo Maianti, Aditya Raguram, David R Liu
Base editors enable targeted single-nucleotide conversions in genomic DNA. Here we show that expression levels are a bottleneck in base-editing efficiency. We optimize cytidine (BE4) and adenine (ABE7.10) base editors by modification of nuclear localization signals (NLS) and codon usage, and ancestral reconstruction of the deaminase component. The resulting BE4max, AncBE4max, and ABEmax editors correct pathogenic SNPs with substantially increased efficiency in a variety of mammalian cell types.
October 2018: Nature Biotechnology
Rahul Satija
No abstract text is available yet for this article.
September 6, 2018: Nature Biotechnology
Cormac Sheridan
No abstract text is available yet for this article.
September 6, 2018: Nature Biotechnology
Eric Smalley
No abstract text is available yet for this article.
September 6, 2018: Nature Biotechnology
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