journal
https://read.qxmd.com/read/38806736/enhancing-prime-editing-in-hematopoietic-stem-and-progenitor-cells-by-modulating-nucleotide-metabolism
#1
JOURNAL ARTICLE
Sébastien Levesque, Andrea Cosentino, Archana Verma, Pietro Genovese, Daniel E Bauer
Therapeutic prime editing of hematopoietic stem and progenitor cells (HSPCs) holds great potential to remedy blood disorders. Quiescent cells have low nucleotide levels and resist retroviral infection, and it is possible that nucleotide metabolism could limit reverse transcription-mediated prime editing in HSPCs. We demonstrate that deoxynucleoside supplementation and Vpx-mediated degradation of SAMHD1 improve prime editing efficiency in HSPCs, especially when coupled with editing approaches that evade mismatch repair...
May 28, 2024: Nature Biotechnology
https://read.qxmd.com/read/38802562/long-term-intravital-subcellular-imaging-with-confocal-scanning-light-field-microscopy
#2
JOURNAL ARTICLE
Zhi Lu, Siqing Zuo, Minghui Shi, Jiaqi Fan, Jingyu Xie, Guihua Xiao, Li Yu, Jiamin Wu, Qionghai Dai
Long-term observation of subcellular dynamics in living organisms is limited by background fluorescence originating from tissue scattering or dense labeling. Existing confocal approaches face an inevitable tradeoff among parallelization, resolution and phototoxicity. Here we present confocal scanning light-field microscopy (csLFM), which integrates axially elongated line-confocal illumination with the rolling shutter in scanning light-field microscopy (sLFM). csLFM enables high-fidelity, high-speed, three-dimensional (3D) imaging at near-diffraction-limit resolution with both optical sectioning and low phototoxicity...
May 27, 2024: Nature Biotechnology
https://read.qxmd.com/read/38783148/mapping-variant-effects-on-anti-tumor-hallmarks-of-primary-human-t-cells-with-base-editing-screens
#3
JOURNAL ARTICLE
Zachary H Walsh, Parin Shah, Neeharika Kothapalli, Shivem B Shah, Gergo Nikolenyi, D Zack Brodtman, Giuseppe Leuzzi, Meri Rogava, Michael Mu, Patricia Ho, Sinan Abuzaid, Neil Vasan, Mohammed AlQuraishi, Joshua D Milner, Alberto Ciccia, Johannes C Melms, Benjamin Izar
Single-nucleotide variants (SNVs) in key T cell genes can drive clinical pathologies and could be repurposed to improve cellular cancer immunotherapies. Here, we perform massively parallel base-editing screens to generate thousands of variants at gene loci annotated with known or potential clinical relevance. We discover a broad landscape of putative gain-of-function (GOF) and loss-of-function (LOF) mutations, including in PIK3CD and the gene encoding its regulatory subunit, PIK3R1, LCK, SOS1, AKT1 and RHOA...
May 23, 2024: Nature Biotechnology
https://read.qxmd.com/read/38778214/mapping-medically-relevant-rna-isoform-diversity-in-the-aged-human-frontal-cortex-with-deep-long-read-rna-seq
#4
JOURNAL ARTICLE
Bernardo Aguzzoli Heberle, J Anthony Brandon, Madeline L Page, Kayla A Nations, Ketsile I Dikobe, Brendan J White, Lacey A Gordon, Grant A Fox, Mark E Wadsworth, Patricia H Doyle, Brittney A Williams, Edward J Fox, Anantharaman Shantaraman, Mina Ryten, Sara Goodwin, Elena Ghiban, Robert Wappel, Senem Mavruk-Eskipehlivan, Justin B Miller, Nicholas T Seyfried, Peter T Nelson, John D Fryer, Mark T W Ebbert
Determining whether the RNA isoforms from medically relevant genes have distinct functions could facilitate direct targeting of RNA isoforms for disease treatment. Here, as a step toward this goal for neurological diseases, we sequenced 12 postmortem, aged human frontal cortices (6 Alzheimer disease cases and 6 controls; 50% female) using one Oxford Nanopore PromethION flow cell per sample. We identified 1,917 medically relevant genes expressing multiple isoforms in the frontal cortex where 1,018 had multiple isoforms with different protein-coding sequences...
May 22, 2024: Nature Biotechnology
https://read.qxmd.com/read/38773306/author-correction-combined-small-molecule-treatment-accelerates-maturation-of-human-pluripotent-stem-cell-derived-neurons
#5
Emiliano Hergenreder, Andrew P Minotti, Yana Zorina, Polina Oberst, Zeping Zhao, Hermany Munguba, Elizabeth L Calder, Arianna Baggiolini, Ryan M Walsh, Conor Liston, Joshua Levitz, Ralph Garippa, Shuibing Chen, Gabriele Ciceri, Lorenz Studer
No abstract text is available yet for this article.
May 21, 2024: Nature Biotechnology
https://read.qxmd.com/read/38773305/development-of-multiplexed-orthogonal-base-editor-mobe-systems
#6
JOURNAL ARTICLE
Quinn T Cowan, Sifeng Gu, Wanjun Gu, Brodie L Ranzau, Tatum S Simonson, Alexis C Komor
Base editors (BEs) enable efficient, programmable installation of point mutations while avoiding the use of double-strand breaks. Simultaneous application of two or more different BEs, such as an adenine BE (which converts A·T base pairs to G·C) and a cytosine BE (which converts C·G base pairs to T·A), is not feasible because guide RNA crosstalk results in non-orthogonal editing, with all BEs modifying all target loci. Here we engineer both adenine BEs and cytosine BEs that can be orthogonally multiplexed by using RNA aptamer-coat protein systems to recruit the DNA-modifying enzymes directly to the guide RNAs...
May 21, 2024: Nature Biotechnology
https://read.qxmd.com/read/38769426/author-correction-computational-scoring-and-experimental-evaluation-of-enzymes-generated-by-neural-networks
#7
Sean R Johnson, Xiaozhi Fu, Sandra Viknander, Clara Goldin, Sarah Monaco, Aleksej Zelezniak, Kevin K Yang
No abstract text is available yet for this article.
May 20, 2024: Nature Biotechnology
https://read.qxmd.com/read/38769425/advancing-programmable-gene-expression-in-plants-using-crispri-based-boolean-gates
#8
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
May 20, 2024: Nature Biotechnology
https://read.qxmd.com/read/38769424/crispri-based-circuits-to-control-gene-expression-in-plants
#9
JOURNAL ARTICLE
Muhammad Adil Khan, Gabrielle Herring, Jia Yuan Zhu, Marina Oliva, Elliott Fourie, Benjamin Johnston, Zhining Zhang, Jarred Potter, Luke Pineda, Jahnvi Pflueger, Tessa Swain, Christian Pflueger, James P B Lloyd, David Secco, Ian Small, Brendan N Kidd, Ryan Lister
The construction of synthetic gene circuits in plants has been limited by a lack of orthogonal and modular parts. Here, we implement a CRISPR (clustered regularly interspaced short palindromic repeats) interference (CRISPRi)-based reversible gene circuit platform in plants. We create a toolkit of engineered repressible promoters of different strengths and construct NOT and NOR gates in Arabidopsis thaliana protoplasts. We determine the optimal processing system to express single guide RNAs from RNA Pol II promoters to introduce NOR gate programmability for interfacing with host regulatory sequences...
May 20, 2024: Nature Biotechnology
https://read.qxmd.com/read/38760568/decoding-gene-regulation-with-crispr-perturbations
#10
JOURNAL ARTICLE
Stefan Oberlin, Michael T McManus
No abstract text is available yet for this article.
May 17, 2024: Nature Biotechnology
https://read.qxmd.com/read/38760567/engineered-crispr-cas12a-for-higher-order-combinatorial-chromatin-perturbations
#11
JOURNAL ARTICLE
C C-S Hsiung, C M Wilson, N A Sambold, R Dai, Q Chen, N Teyssier, S Misiukiewicz, A Arab, T O'Loughlin, J C Cofsky, J Shi, L A Gilbert
Multiplexed genetic perturbations are critical for testing functional interactions among coding or non-coding genetic elements. Compared to double-stranded DNA cutting, repressive chromatin formation using CRISPR interference (CRISPRi) avoids genotoxicity and is more effective for perturbing non-coding regulatory elements in pooled assays. However, current CRISPRi pooled screening approaches are limited to targeting one to three genomic sites per cell. We engineer an Acidaminococcus Cas12a (AsCas12a) variant, multiplexed transcriptional interference AsCas12a (multiAsCas12a), that incorporates R1226A, a mutation that stabilizes the ribonucleoprotein-DNA complex via DNA nicking...
May 17, 2024: Nature Biotechnology
https://read.qxmd.com/read/38760566/bidirectional-epigenetic-editing-reveals-hierarchies-in-gene-regulation
#12
JOURNAL ARTICLE
Naomi M Pacalin, Zachary Steinhart, Quanming Shi, Julia A Belk, Dmytro Dorovskyi, Katerina Kraft, Kevin R Parker, Brian R Shy, Alexander Marson, Howard Y Chang
CRISPR perturbation methods are limited in their ability to study non-coding elements and genetic interactions. In this study, we developed a system for bidirectional epigenetic editing, called CRISPRai, in which we apply activating (CRISPRa) and repressive (CRISPRi) perturbations to two loci simultaneously in the same cell. We developed CRISPRai Perturb-seq by coupling dual perturbation gRNA detection with single-cell RNA sequencing, enabling study of pooled perturbations in a mixed single-cell population...
May 17, 2024: Nature Biotechnology
https://read.qxmd.com/read/38744947/generation-of-allogeneic-car-nkt-cells-from-hematopoietic-stem-and-progenitor-cells-using-a-clinically-guided-culture-method
#13
JOURNAL ARTICLE
Yan-Ruide Li, Yang Zhou, Jiaji Yu, Yu Jeong Kim, Miao Li, Derek Lee, Kuangyi Zhou, Yuning Chen, Yichen Zhu, Yu-Chen Wang, Zhe Li, Yanqi Yu, Zachary Spencer Dunn, Wenbin Guo, Xinjian Cen, Tiffany Husman, Aarushi Bajpai, Adam Kramer, Matthew Wilson, Ying Fang, Jie Huang, Shuo Li, Yonggang Zhou, Yuchong Zhang, Zoe Hahn, Enbo Zhu, Feiyang Ma, Calvin Pan, Aldons J Lusis, Jin J Zhou, Christopher S Seet, Donald B Kohn, Pin Wang, Xianghong Jasmine Zhou, Matteo Pellegrini, Benjamin R Puliafito, Sarah M Larson, Lili Yang
Cancer immunotherapy with autologous chimeric antigen receptor (CAR) T cells faces challenges in manufacturing and patient selection that could be avoided by using 'off-the-shelf' products, such as allogeneic CAR natural killer T (Allo CAR-NKT) cells. Previously, we reported a system for differentiating human hematopoietic stem and progenitor cells into Allo CAR-NKT cells, but the use of three-dimensional culture and xenogeneic feeders precluded its clinical application. Here we describe a clinically guided method to differentiate and expand IL-15-enhanced Allo CAR-NKT cells with high yield and purity...
May 14, 2024: Nature Biotechnology
https://read.qxmd.com/read/38744946/protein-adaptive-differential-scanning-fluorimetry-using-conformationally-responsive-dyes
#14
JOURNAL ARTICLE
Taiasean Wu, Joshua C Yu, Arundhati Suresh, Zachary J Gale-Day, Matthew G Alteen, Amanda S Woo, Zoe Millbern, Oleta T Johnson, Emma C Carroll, Carrie L Partch, Denis Fourches, Nelson R Vinueza, David J Vocadlo, Jason E Gestwicki
Differential scanning fluorimetry (DSF) is a technique that reports protein thermal stability via the selective recognition of unfolded states by fluorogenic dyes. However, DSF applications remain limited by protein incompatibilities with existing DSF dyes. Here we overcome this obstacle with the development of a protein-adaptive DSF platform (paDSF) that combines a dye library 'Aurora' with a streamlined procedure to identify protein-dye pairs on demand. paDSF was successfully applied to 94% (66 of 70) of proteins, tripling the previous compatibility and delivering assays for 66 functionally and biochemically diverse proteins, including 10 from severe acute respiratory syndrome coronavirus 2...
May 14, 2024: Nature Biotechnology
https://read.qxmd.com/read/38744945/a-milestone-method-to-make-natural-killer-t-cells
#15
JOURNAL ARTICLE
Leonid S Metelitsa
No abstract text is available yet for this article.
May 14, 2024: Nature Biotechnology
https://read.qxmd.com/read/38740992/linking-crispr-cas9-double-strand-break-profiles-to-gene-editing-precision-with-breaktag
#16
JOURNAL ARTICLE
Gabriel M C Longo, Sergi Sayols, Andriana G Kotini, Sabine Heinen, Martin M Möckel, Petra Beli, Vassilis Roukos
Cas9 can cleave DNA in both blunt and staggered configurations, resulting in distinct editing outcomes, but what dictates the type of Cas9 incisions is largely unknown. In this study, we developed BreakTag, a versatile method for profiling Cas9-induced DNA double-strand breaks (DSBs) and identifying the determinants of Cas9 incisions. Overall, we assessed cleavage by SpCas9 at more than 150,000 endogenous on-target and off-target sites targeted by approximately 3,500 single guide RNAs. We found that approximately 35% of SpCas9 DSBs are staggered, and the type of incision is influenced by DNA:gRNA complementarity and the use of engineered Cas9 variants...
May 13, 2024: Nature Biotechnology
https://read.qxmd.com/read/38724669/decoding-cell-replicational-age-from-single-cell-atac-seq-data
#17
JOURNAL ARTICLE
(no author information available yet)
No abstract text is available yet for this article.
May 9, 2024: Nature Biotechnology
https://read.qxmd.com/read/38724668/tracking-single-cell-evolution-using-clock-like-chromatin-accessibility-loci
#18
JOURNAL ARTICLE
Yu Xiao, Wan Jin, Lingao Ju, Jie Fu, Gang Wang, Mengxue Yu, Fangjin Chen, Kaiyu Qian, Xinghuan Wang, Yi Zhang
Single-cell chromatin accessibility sequencing (scATAC-seq) reconstructs developmental trajectory by phenotypic similarity. However, inferring the exact developmental trajectory is challenging. Previous studies showed age-associated DNA methylation (DNAm) changes in specific genomic regions, termed clock-like differential methylation loci (ClockDML). Age-associated DNAm could either result from or result in chromatin accessibility changes at ClockDML. As cells undergo mitosis, the heterogeneity of chromatin accessibility on clock-like loci is reduced, providing a measure of mitotic age...
May 9, 2024: Nature Biotechnology
https://read.qxmd.com/read/38720152/an-effective-mash-drug-is-good-but-biotech-can-make-it-better
#19
EDITORIAL
(no author information available yet)
No abstract text is available yet for this article.
May 8, 2024: Nature Biotechnology
https://read.qxmd.com/read/38714897/identification-of-clinically-relevant-t-cell-receptors-for-personalized-t-cell-therapy-using-combinatorial-algorithms
#20
JOURNAL ARTICLE
Rémy Pétremand, Johanna Chiffelle, Sara Bobisse, Marta A S Perez, Julien Schmidt, Marion Arnaud, David Barras, Maria Lozano-Rabella, Raphael Genolet, Christophe Sauvage, Damien Saugy, Alexandra Michel, Anne-Laure Huguenin-Bergenat, Charlotte Capt, Jonathan S Moore, Claudio De Vito, S Intidhar Labidi-Galy, Lana E Kandalaft, Denarda Dangaj Laniti, Michal Bassani-Sternberg, Giacomo Oliveira, Catherine J Wu, George Coukos, Vincent Zoete, Alexandre Harari
A central challenge in developing personalized cancer cell immunotherapy is the identification of tumor-reactive T cell receptors (TCRs). By exploiting the distinct transcriptomic profile of tumor-reactive T cells relative to bystander cells, we build and benchmark TRTpred, an antigen-agnostic in silico predictor of tumor-reactive TCRs. We integrate TRTpred with an avidity predictor to derive a combinatorial algorithm of clinically relevant TCRs for personalized T cell therapy and benchmark it in patient-derived xenografts...
May 7, 2024: Nature Biotechnology
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