eLife最新文献_第10页

Structure transfer and consolidation in visual implicit learning. 视觉内隐学习中的结构迁移与巩固。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-16 DOI: 10.7554/eLife.100785

Dominik Garber, József Fiser

{"title":"Structure transfer and consolidation in visual implicit learning.","authors":"Dominik Garber, József Fiser","doi":"10.7554/eLife.100785","DOIUrl":"10.7554/eLife.100785","url":null,"abstract":"Transfer learning, the re-application of previously learned higher-level regularities to novel input, is a key challenge in cognition. While previous empirical studies investigated human transfer learning in supervised or reinforcement learning for explicit knowledge, it is unknown whether such transfer occurs during naturally more common implicit and unsupervised learning and, if so, how it is related to memory consolidation. We compared the transfer of newly acquired explicit and implicit abstract knowledge during unsupervised learning by extending a visual statistical learning paradigm to a transfer learning context. We found transfer during unsupervised learning, but with important differences depending on the explicitness/implicitness of the acquired knowledge. Observers acquiring explicit knowledge during initial learning could transfer the learned structures immediately. In contrast, observers with the same amount but implicit knowledge showed the opposite effect, a structural interference during transfer. However, with sleep between the learning phases, implicit observers, while still remaining implicit, switched their behavior and showed the same pattern of transfer as explicit observers did. This effect was specific to sleep and not found after non-sleep consolidation. Our results highlight similarities and differences between explicit and implicit learning while acquiring generalizable higher-level knowledge and relying on consolidation for restructuring internal representations.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440352/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Altered thymic niche synergistically drives the massive proliferation of malignant thymocytes. 改变胸腺生态位协同驱动恶性胸腺细胞的大量增殖。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-16 DOI: 10.7554/eLife.101137

Erika Tsingos, Advaita M Dick, Baubak Bajoghli

{"title":"Altered thymic niche synergistically drives the massive proliferation of malignant thymocytes.","authors":"Erika Tsingos, Advaita M Dick, Baubak Bajoghli","doi":"10.7554/eLife.101137","DOIUrl":"10.7554/eLife.101137","url":null,"abstract":"The discovery of genetic alterations in patient samples over the last decades has reinforced a cell-autonomous view of proliferative expansion during T-cell acute lymphoblastic leukemia (T-ALL) development in the thymus. However, the potential contribution of non-cell-autonomous factors, particularly the impact of thymic epithelial cells (TECs) within the thymic niche during the initiation phase, remains unexplored. In this study, we combine a cell-based computational model of the thymus with complementary in vivo experiments in medaka (Oryzias latipes) to systematically analyze the impact of 12 cell-autonomous and non-autonomous factors, individually and in combination, on the proliferation of normal and malignant thymocytes carrying interleukin-7 receptor (IL7R) gain-of-function mutations or elevated IL7R levels, as observed in T-ALL patients. By simulating over 1500 scenarios, we show that while a dense TEC network favored the proliferation of normal thymocytes, it inhibited the proliferation of malignant lineages, which achieved their maximal proliferative capacity when TECs were sparsely distributed. Our in silico model further predicts that specific mutations could accelerate proliferative expansion within a few days. This prediction was experimentally validated, revealing the rapid onset of thymic lymphoma and systemic infiltration of malignant T cells within just 8 days of embryonic development. These findings demonstrate that synergistic interaction between oncogenic alterations and modifications in the thymic niche can significantly accelerate disease progression. Our results also suggest that negative feedback from the proliferative state suppresses thymocyte differentiation. Overall, this multidisciplinary work reveals the critical role of TEC-thymocyte interactions in both the initiation and progression of T-ALL, highlighting the importance of the thymic microenvironment in early leukemogenesis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440356/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The success of artificial selection for collective composition hinges on initial and target values. 集体作文人工选择的成功与否取决于初始值和目标值。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-15 DOI: 10.7554/eLife.97461

Juhee Lee, Wenying Shou, Hye Jin Park

{"title":"The success of artificial selection for collective composition hinges on initial and target values.","authors":"Juhee Lee, Wenying Shou, Hye Jin Park","doi":"10.7554/eLife.97461","DOIUrl":"10.7554/eLife.97461","url":null,"abstract":"Microbial collectives can perform functions beyond the capability of individual members. Enhancing collective functions through artificial selection is, however, challenging. Here, we explore the 'rafting-a-waterfall' metaphor where achieving a target population composition depends on both target and initial compositions. Specifically, collectives comprising fast-growing (F) and slow-growing (S) individuals were grown for 'maturation' time, and the collective with S-frequency closest to the target value is chosen to 'reproduce' via inoculating offspring collectives. During collective maturation, intra-collective selection acts like a waterfall, relentlessly driving the S-frequency to lower values, while during collective reproduction, inter-collective selection resembles a rafter striving to reach the target frequency. Using simulations and analytical calculations, we show that intermediate target S frequencies are the most challenging, akin to a target within the vertical drop of a waterfall, rather than above or below it. This arises because intra-collective selection is the strongest at intermediate S-frequencies, which can overpower inter-collective selection. While achieving a low target S frequencies is consistently feasible, attaining high target S-frequencies requires an initially high S-frequency - much like a raft that can descend but not ascend a waterfall. As Newborn size increases, the region of achievable target frequency is reduced until no frequency is achievable. In contrast, the number of collectives under selection plays a less critical role. In scenarios involving more than two populations, the evolutionary trajectory must navigate entirely away from the metaphorical 'waterfall drop.' Our findings illustrate that the strength of intra-collective evolution is frequency-dependent, with implications in experimental planning.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435894/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

SETD2 suppresses tumorigenesis in a KRAS^G12C-driven lung cancer model, and its catalytic activity is regulated by histone acetylation. 在krasg12c驱动的肺癌模型中，SETD2抑制肿瘤发生，其催化活性受组蛋白乙酰化调节。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-15 DOI: 10.7554/eLife.107451

Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani

{"title":"SETD2 suppresses tumorigenesis in a KRASG12C-driven lung cancer model, and its catalytic activity is regulated by histone acetylation.","authors":"Ricardo J Mack, Natasha M Flores, Geoffrey C Fox, Hanyang Dong, Metehan Cebeci, Simone Hausmann, Tourkian Chasan, Jill M Dowen, Brian D Strahl, Pawel K Mazur, Or Gozani","doi":"10.7554/eLife.107451","DOIUrl":"10.7554/eLife.107451","url":null,"abstract":"Histone H3 trimethylation at lysine 36 (H3K36me3) is a key chromatin modification that regulates fundamental physiological and pathological processes. In humans, SETD2 is the only known enzyme that catalyzes H3K36me3 in somatic cells and is implicated in tumor suppression across multiple cancer types. While there is considerable crosstalk between the SETD2-H3K36me3 axis and other epigenetic modifications, much remains to be understood. Here, we show that Setd2 functions as a potent tumor suppressor in a KRASG12C-driven lung adenocarcinoma (LUAD) mouse model, and that acetylation enhances SETD2 in vitro methylation of H3K36 on nucleosome substrates. In vivo, Setd2 ablation accelerates lethality in an autochthonous KRASG12C-driven LUAD mouse tumor model. Biochemical analyses reveal that polyacetylation of histone tails in a nucleosome context promotes H3K36 methylation by SETD2. In addition, monoacetylation exerts position-specific effects to stimulate SETD2 methylation activity. In contrast, mono-ubiquitination at various histone sites, including at H2AK119 and H2BK120, does not affect SETD2 methylation of nucleosomes. Together, these findings provide insight into how SETD2 integrates histone modification signals to regulate H3K36 methylation and highlights the potential role of SETD2-associated epigenetic crosstalk in cancer pathogenesis.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435893/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145063534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Horizontally transferred cell-free chromatin particles function as autonomous 'satellite genomes' and vehicles for transposable elements within host cells. 水平转移的无细胞染色质颗粒作为自主的“卫星基因组”和宿主细胞内转座因子的载体。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-15 DOI: 10.7554/eLife.103771

Soumita Banerjee, Soniya Sanjay Shende, Laxmi Kata, Relestina Simon Lopes, Swathika Praveen, Ruchi Joshi, Naveen Kumar Khare, Gorantla V Raghuram, Snehal Shabrish, Indraneel Mittra

{"title":"Horizontally transferred cell-free chromatin particles function as autonomous 'satellite genomes' and vehicles for transposable elements within host cells.","authors":"Soumita Banerjee, Soniya Sanjay Shende, Laxmi Kata, Relestina Simon Lopes, Swathika Praveen, Ruchi Joshi, Naveen Kumar Khare, Gorantla V Raghuram, Snehal Shabrish, Indraneel Mittra","doi":"10.7554/eLife.103771","DOIUrl":"10.7554/eLife.103771","url":null,"abstract":"Horizontal gene transfer (HGT) plays an important evolutionary role in prokaryotes, but it is less frequent in mammals. We previously reported that cell-free chromatin particles (cfChPs) - chromosomal fragments released from the billions of dying cells that circulate in human blood - are horizontally transferred to healthy cells with biological effects. However, the underlying mechanism and function of these effects remained unclear. We treated NIH3T3 mouse fibroblasts cells with cfChPs isolated from human serum and serially passaged the cells. The intracellular activities of cfChPs were analysed using chromatin fibre fluorography, cytogenetic analysis, immunofluorescence, and fluorescent in situ hybridisation. We discovered that the internalised cfChPs were almost exclusively comprised of non-coding DNA, and the disparate DNA sequences contained within them had randomly combined to form complex concatemers, some of which were multi-mega base pairs in size. The concatemers autonomously performed many functions attributable to the nuclear genome such as DNA, RNA and protein synthesis. They harboured human LINE-1 and Alu elements, with the potential to rearrange themselves within the mouse genome. Our results suggest that a cell simultaneously harbours two autonomous genome forms: one that is inherited (hereditary genome) and numerous others that are acquired (satellite genomes). The satellite genomes may have evolutionary functions given their ability to serve as vehicles for transposable elements and to generate a plethora of novel proteins. Our results also suggest that 'within-self' HGT may occur in mammals on a massive scale via the medium of cfChP concatemers that have undergone extensive and complex modifications resulting in their behaviour as 'foreign' genetic elements.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435896/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Crosslinking by ZapD drives the assembly of short FtsZ filaments into toroidal structures in solution. 通过ZapD交联驱动短FtsZ细丝在溶液中组装成环形结构。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-15 DOI: 10.7554/eLife.95557

Adrián Merino-Salomón, Jonathan Scheneider, Leon Babl, Jan-Hagen Krohn, Marta Sobrinos-Sanguino, Tillman Schaefer, Juan Ramon Luque-Ortega, Carlos Alfonso, Mercedes Jiménez, Marion Jasnin, Petra Schwille, German Rivas

{"title":"Crosslinking by ZapD drives the assembly of short FtsZ filaments into toroidal structures in solution.","authors":"Adrián Merino-Salomón, Jonathan Scheneider, Leon Babl, Jan-Hagen Krohn, Marta Sobrinos-Sanguino, Tillman Schaefer, Juan Ramon Luque-Ortega, Carlos Alfonso, Mercedes Jiménez, Marion Jasnin, Petra Schwille, German Rivas","doi":"10.7554/eLife.95557","DOIUrl":"10.7554/eLife.95557","url":null,"abstract":"Cell division in Escherichia coli relies on the Z ring, a cytoskeletal structure that acts as a scaffold for the assembly of the divisome. To date, the detailed mechanisms underlying the assembly and stabilization of the Z ring remain elusive. This study highlights the role of the FtsZ-associated protein (Zap) ZapD in the assembly and stabilization of Z-ring-like structures via filament crosslinking. Using cryo-electron tomography and biochemical analysis, we show that, at equimolar concentrations of ZapD and FtsZ, ZapD induces the formation of toroidal structures composed of short, curved FtsZ filaments that are crosslinked vertically, but also laterally and diagonally. At higher concentrations of ZapD, regularly spaced ZapD dimers crosslink FtsZ filaments from above, resulting in the formation of straight bundles. Despite the simplicity of this reconstituted system, these findings provide valuable insights into the structural organization and stabilization of the Z ring by Zap proteins in bacterial cells, revealing the key role of optimal crosslinking density and geometry in enabling filament curvature and ring formation.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12435895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The general version of Hamilton's rule. 汉密尔顿法则的一般版本。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-12 DOI: 10.7554/eLife.105065

Matthijs van Veelen

{"title":"The general version of Hamilton's rule.","authors":"Matthijs van Veelen","doi":"10.7554/eLife.105065","DOIUrl":"10.7554/eLife.105065","url":null,"abstract":"The generality of Hamilton's rule is much debated. In this paper, I show that this debate can be resolved by constructing a general version of Hamilton's rule, which allows for a large variety of ways in which the fitness of an individual can depend on the social behavior of oneself and of others. For this, I first derive the Generalized Price equation, which reconnects the Price equation with the statistics it borrows its terminology from. The Generalized Price equation, moreover, shows that there is not just one Price equation, but there is a Price-like equation for every possible true model. This implies that there are also multiple, nested rules to describe selection. The simplest rule is the rule for selection of non-social traits with linear fitness effects. This rule is nested in the classical version of Hamilton's rule, for which there is consensus that it works for social traits with linear, independent fitness effects. The classical version of Hamilton's rule, in turn, is nested in more general rules that, for instance, allow for nonlinear and/or interdependent fitness effects, like Queller's rule. The general version of Hamilton's rule, therefore, is a constructive solution that allows us to accurately describe when costly cooperation evolves in a wide variety of circumstances. As a byproduct, we also find a hierarchy of nested rules for selection of non-social traits.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431776/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Ancient trans-species polymorphism at the Major Histocompatibility Complex in primates. 灵长类动物主要组织相容性复合体的古代跨物种多态性。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-12 DOI: 10.7554/eLife.103547

Alyssa Lyn Fortier, Jonathan K Pritchard

{"title":"Ancient trans-species polymorphism at the Major Histocompatibility Complex in primates.","authors":"Alyssa Lyn Fortier, Jonathan K Pritchard","doi":"10.7554/eLife.103547","DOIUrl":"10.7554/eLife.103547","url":null,"abstract":"Classical genes within the Major Histocompatibility Complex (MHC) are responsible for peptide presentation to T cells, thus playing a central role in immune defense against pathogens. These genes are subject to strong selective pressures including both balancing and directional selection, resulting in exceptional genetic diversity-thousands of alleles per gene in humans. Moreover, some allelic lineages appear to be shared between primate species, a phenomenon known as trans-species polymorphism (TSP) or incomplete lineage sorting, which is rare in the genome overall. However, despite the clinical and evolutionary importance of MHC diversity, we currently lack a full picture of primate MHC evolution. In particular, we do not know to what extent genes and allelic lineages are retained across speciation events. To start addressing this gap, we explore variation across genes and species in our companion paper (Fortier and Pritchard, 2025), and here we explore variation within individual genes. We used Bayesian phylogenetic methods to determine the extent of TSP at 17 MHC genes, including classical and non-classical Class I and Class II genes. We find strong support for ancient TSP in 7 of 10 classical genes, including-remarkably-between humans and old-world monkeys in MHC-DQB1. In addition to the long-term persistence of ancient lineages, we additionally observe rapid evolution at nucleotides encoding the proteins' peptide-binding domains. The most rapidly-evolving amino acid positions are extremely enriched for autoimmune and infectious disease associations. Together, these results suggest complex selective forces-arising from differential peptide binding-that drive short-term allelic turnover within lineages while also maintaining deeply divergent lineages for at least 31 million years in some cases.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431779/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sequence action representations contextualize during early skill learning. 在早期技能学习过程中，序列动作表征是情境化的。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-12 DOI: 10.7554/eLife.102475

Debadatta Dash, Fumiaki Iwane, William Hayward, Roberto F Salamanca-Giron, Marlene Bönstrup, Ethan R Buch, Leonardo G Cohen

{"title":"Sequence action representations contextualize during early skill learning.","authors":"Debadatta Dash, Fumiaki Iwane, William Hayward, Roberto F Salamanca-Giron, Marlene Bönstrup, Ethan R Buch, Leonardo G Cohen","doi":"10.7554/eLife.102475","DOIUrl":"10.7554/eLife.102475","url":null,"abstract":"Activities of daily living rely on our ability to acquire new motor skills composed of precise action sequences. Here, we asked in humans if the millisecond-level neural representation of an action performed at different contextual sequence locations within a skill differentiates or remains stable during early motor learning. We first optimized machine learning decoders predictive of sequence-embedded finger movements from magnetoencephalographic (MEG) activity. Using this approach, we found that the neural representation of the same action performed in different contextual sequence locations progressively differentiated-primarily during rest intervals of early learning (offline)-correlating with skill gains. In contrast, representational differentiation during practice (online) did not reflect learning. The regions contributing to this representational differentiation evolved with learning, shifting from the contralateral pre- and post-central cortex during early learning (trials 1-11) to increased involvement of the superior and middle frontal cortex once skill performance plateaued (trials 12-36). Thus, the neural substrates supporting finger movements and their representational differentiation during early skill learning differ from those supporting stable performance during the subsequent skill plateau period. Representational contextualization extended to Day 2, exhibiting specificity for the practiced skill sequence. Altogether, our findings indicate that sequence action representations in the human brain contextually differentiate during early skill learning, an issue relevant to brain-computer interface applications in neurorehabilitation.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"13 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431778/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039402","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Spatial and longitudinal tracking of enhancer-AAV vectors that target transgene expression to injured mouse myocardium. 靶向转基因表达损伤小鼠心肌的增强aav载体的空间和纵向追踪。

IF 6.4 1区生物学

eLife Pub Date : 2025-09-12 DOI: 10.7554/eLife.107148

David W Wolfson, Joshua A Hull, Yongwu Li, Trevor J Gonzalez, Mourya D Jayaram, Garth W Devlin, Valentina Cigliola, Kelsey A Oonk, Alan Rosales, Nenad Bursac, Aravind Asokan, Kenneth D Poss

{"title":"Spatial and longitudinal tracking of enhancer-AAV vectors that target transgene expression to injured mouse myocardium.","authors":"David W Wolfson, Joshua A Hull, Yongwu Li, Trevor J Gonzalez, Mourya D Jayaram, Garth W Devlin, Valentina Cigliola, Kelsey A Oonk, Alan Rosales, Nenad Bursac, Aravind Asokan, Kenneth D Poss","doi":"10.7554/eLife.107148","DOIUrl":"10.7554/eLife.107148","url":null,"abstract":"Tissue regeneration enhancer elements (TREEs) direct expression of target genes in injured and regenerating tissues. Additionally, TREEs of zebrafish origin were shown to direct expression of transgenes in border zone regions after cardiac injury when packaged into recombinant adeno-associated viral (AAV) vectors and introduced into mice. Future implementation of TREEs into AAV-based vectors as research tools and potential gene therapy modalities requires a deeper understanding of expression dynamics and potential off-target effects. Here, we applied in vivo bioluminescent imaging to mice systemically injected with AAV vectors containing different combinations of capsids, enhancers, and timing of delivery. Longitudinal tracking of expression directed by different TREEs revealed distinct amplitudes and durations of reporter gene expression in the injured heart. The liver-de-targeted AAV capsid, AAV.cc84, could deliver TREEs either pre- or post-cardiac injury to negate off-target expression in the liver while maintaining transduction in the heart. By screening AAV9-based capsid libraries dosed systemically in mice post-cardiac injury, we discovered a new capsid variant, AAV.IR41, with enhanced transduction in cardiac injuries and with elevated transduction of TREE-driven transgenes versus conventional AAV9 vectors. In vivo bioluminescence imaging offers insights into how enhancers and engineered capsids can be implemented to modulate spatiotemporal transgene expression for targeted therapies.","PeriodicalId":11640,"journal":{"name":"eLife","volume":"14 ","pages":""},"PeriodicalIF":6.4,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12431772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0