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| Open AccessDNA diamond formulates a decomposable composite letter constellation model for DNA data storage
Composite-letter DNA data storage promises higher density but suffers from readout challenges. Here, the authors present a decomposable diamond constellation and an entropy-guided two-stage detection strategy, enabling reliable recovery at low sequencing coverage for high-density DNA data storage.
- Qi Ge
- , Menghui Ren
- & Weigang Chen
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Article
| Open AccessDiscover the maze-like network for glabridin biosynthesis
The complexity of the evolved metabolic networks of flavonoids complicates pathway elucidation and design. Here, the authors identify enzymes that modify isoflavan scaffolds from the genome and transcriptome data of Glycyrrhiza glabra, and reconstruct de novo glabridin biosynthesis in yeast.
- Zhen Zhang
- , Wenqiang Li
- & Chun Li
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Article
| Open AccessBio-based oxalic acid production in Issatchenkia orientalis enables sustainable rare earth recovery
The growing demand for rare earth elements (REEs) underscores the need for sustainable recovery methods and a reliable supply. Here the authors establish a platform using a yeast to produce bio-oxalic acid for REE recovery, achieving 99% REE recovery from low-grade ore.
- Jingxia Lu
- , Wenjun Guo
- & Huimin Zhao
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Article
| Open AccessThe biological role of local and global fMRI BOLD signal variability in multiscale human brain organization
Baracchini et al. reveal that temporal variability in fMRI brain signals encodes biologically meaningful information across spatial and temporal scales, highlighting its role in healthy brain function and systems-level organization.
- Giulia Baracchini
- , Yigu Zhou
- & R. Nathan Spreng
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Article
| Open AccessSingle-cell atlas of human lung aging identifies cell type dyssynchrony and increased transcriptional entropy
The changing cellular, transcriptional, and genomic landscape of human lung aging can be characterized using single-cell RNA sequencing. Here, the authors show that lung aging is cell-type dyssynchronous, with alveolar epithelial and endothelial cells exhibiting the greatest changes in gene expression, transcriptional entropy, and a high level of somatic mutations.
- Ruben De Man
- , John E. McDonough
- & Naftali Kaminski
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Article
| Open AccessModeling tissue-specific Drosophila metabolism identifies high sugar diet-induced metabolic dysregulation in muscle at reaction and pathway levels
This study develops tissue-specific genome-scale metabolic models for Drosophila and shows how constraint-based flux analyses from the muscle model can identify high sugar diet-induced metabolic dysregulation at reaction and pathway levels.
- Sun Jin Moon
- , Yanhui Hu
- & Norbert Perrimon
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Article
| Open AccessEngineering energy-efficient Saccharomyces cerevisiae for methanol and CO2 assimilation
Synthetic methylotrophic S. cerevisiae often faces energetic constrains during one-carbon assimilation. Here, the authors address this issue by engineering of heterologous methanol-formate-formaldehyde oxidation pathways to enable CO2 assimilation via non-native Calvin cycle during methanol fermentation.
- Wei Zhong
- , Nana Liu
- & Yajie Wang
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Article
| Open AccessAn artificial cell capable of signal transduction mediated by ADRB2 for the regulation of glycogenolysis
Signal transduction from extracellular to intracellular artificial cells is essential for autonomous artificial cells. Here the authors reconstitute a G protein-coupled receptor (GPCR) signaling pathway in an artificial cell to regulate downstream glycogen metabolism.
- Yanhao Liu
- , Wan Zhao
- & Xiaojun Han
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Comment
| Open AccessAssembling unregulated DNA segments bypasses synthesis screening: regulate fragments as select agents
U.S. select agent regulations ignore easily assembled DNA fragments, making synthesis screening ineffective regardless of accuracy. We acquired unregulated DNA collectively sufficient for a skilled individual to generate 1918 influenza from dozens of providers, demonstrating that fragments must be regulated as select agents.
- Rey Edison
- , Shay Toner
- & Kevin M. Esvelt
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Article
| Open AccessVolumetric compression regulates the phase separation of AXIN and acts as an operational amplifier to bidirectionally modulate Wnt signaling in organoids
The scaffold protein AXIN can promote the formation of two opposing complexes: the Wnt signalosome and a degradation complex that inhibits Wnt. Here, the authors show that mechanical compression and the presence/absence of Wnt ligand are inputs in a circuit that acts as a logic gate to control which complex is formed.
- Jinyun Shi
- , Linze Wu
- & Yiwei Li
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Article
| Open Access
Tuning evolvability via plasmid copy number and regulatory architecture
Plasmid copy number and gene circuit design together shape how genetic mutations emerge at the phenotypic level in bacteria. Here the authors characterize how the interplay of gene dosage via plasmid copy number and regulatory architecture affect the phenotypic mutation rate.
- Ximing Li
- & Andras Gyorgy
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Article
| Open Access
The Health for Life in Singapore (HELIOS) Study: delivering precision medicine research for Asian populations
With rich, multi-layered baseline data and long-term follow-up through linkage, the HELIOS Study provides a resource to investigate the behavioural, environmental, genomic, and molecular factors impacting health in Asian populations.
- Xiaoyan Wang
- , Theresia Mina
- & John C. Chambers
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Article
| Open Access
Geometry-preserving vector field reconstruction of high-dimensional cell-state dynamics using ddHodge
Cell-state transitions arise from complex gene-expression dynamics. Here, authors develop ddHodge, a geometry-preserving method based on Hodge decomposition that reconstructs potential landscapes and all dynamic components from RNA velocity, revealing cell-state stability and lineage transitions.
- Kazumitsu Maehara
- & Yasuyuki Ohkawa
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Article
| Open Access
Leveraging genomic and transcriptomic data of diverse ancestry to uncover mechanisms of psychiatric risk in the adult and developing brain
Genetic models for psychiatric disorders often overlook ancestry diversity. Here, the authors use PsychENCODE and GWAS data to build ancestry-specific GReX models, improving TWAS and revealing novel genes and pathways linked to brain development and psychiatric risk.
- Aarti Jajoo
- , Vijetha Balakundi
- & Nikolaos P. Daskalakis
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Article
| Open Access
Toward single-cell control: noise-robust perfect adaptation in biomolecular systems
Biological systems often struggle to maintain stable outputs at the single-cell level under noise. Here, authors introduce a noise controller that, when combined with antithetic integral feedback, preserves both mean and noise after perturbations, enabling robust single-cell regulation.
- Dongju Lim
- , Seokhwan Moon
- & Jae Kyoung Kim
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Article
| Open Access
A stationary phase-specific bacterial green light sensor for enhancing metabolite production
Genetically encoded sensors are generally optimized to function during exponential growth rather than stationary phase, which limits their potential value for metabolic engineering and bioproduction. Here, authors engineer a stationary phase green light sensor and use pulsatile light to optimize production of industrially relevant small molecules.
- John T. Lazar
- , Daniel J. Haller
- & Jeffrey J. Tabor
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Article
| Open Access
Single-cell RNA sequencing reveals a quiescence-senescence continuum and distinct senotypes following chemotherapy
Quiescent and senescent cells often arise side by side after stress, yet their molecular relationship remains unclear. Here, the authors combine live-cell imaging and single-cell RNA sequencing to reveal a continuum of cell-cycle withdrawal.
- Brianna Fernandez
- , Victor J. Passanisi
- & Sabrina L. Spencer
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Article
| Open Access
Temporal gene regulation enables controlled expression of gas vesicles and preserves bacterial viability
Gas vesicle protein nanostructures can damage host bacteria when strongly expressed. Here, authors develop a dual-inducer timing circuit that pre-expresses assembly-factor proteins, limiting toxic aggregation while maintaining gas vesicle production.
- Zongru Li
- , Chia-Yu Ho
- & George J. Lu
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Article
| Open Access
Decoding necrosome assembly: harmonizing signal amplification and attenuation through optimal RIP3 stoichiometry
Signalosomes amplify cellular responses, but how they avoid uncontrolled activation is unclear. The authors use quantitative super-resolution imaging and mathematical modeling to reveal optimal RIP3:RIP1 ratios that ensure precise cell death signaling.
- Xiang Li
- , Yating Cao
- & Xin Chen
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Article
| Open Access
Intracellularly coupled oscillators for synthetic biology
Synthetic biology aims to engineer or re-engineer living systems to achieve increasingly complex functionalities. Here the authors propose oscillator-based circuit designs and use modelling to predict a wide range of distinct dynamic behaviors.
- Gábor Holló
- , Jung Hun Park
- & Yolanda Schaerli
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Article
| Open Access
Exploring single-cell biosynthetic noise and dynamics for enhanced betaxanthin production in Escherichia coli
Cell-to-cell variability limits efficient microbial production. Here, the authors track single cells to reveal enzyme noise as the main source of bioproduction variation, and by coupling growth to pathway performance, they selectively enrich high producers and substantially boost overall titres.
- Xinyue Mu
- , Alexander C. Schmitz
- & Fuzhong Zhang
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Article
| Open Access
Genetic and dietary determinants of gut microbiome-bile acid interactions in the BXD genetic reference population
The authors show that genetic and dietary factors reshape the microbiome and influence gut microbiome–bile acid crosstalk. They also identify potential modulators and offer insights into microbiome–host communication.
- Xiaoxu Li
- , Alessia Perino
- & Johan Auwerx
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Article
| Open Access
Enzymatic synthesis of key RNA therapeutic building blocks using simple phosphate donors
Nucleoside triphosphates (NTPs) are important building blocks that underpin emerging enzymatic approaches to RNA therapeutics manufacturing. Here, authors develop a biocatalytic strategy to convert nucleosides into NTPs containing clinically relevant modifications, using simple phosphate donors.
- Qinglong Meng
- , Caecilie Benckendorff
- & Sarah L. Lovelock
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Article
| Open Access
Immunological and transcriptomic profile of chimeric live-attenuated Zika vaccine linked to protection in non-human primates
The chimeric candidate Zika virus vaccine YF-ZIK has been previously shown to confer protection in mice after a single dose regimen. Here the authors further characterise the response to YF-ZIK and show induction of immunity and protection in non-human primates.
- Ji Ma
- , Bert Malengier-Devlies
- & Kai Dallmeier
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Article
| Open Access
The non-catalytic DNA polymerase ε subunit is an NPF motif recognition protein
Short linear motifs in disordered protein regions are involved numerous protein–protein interactions. Here, the authors find that the POLE2 subunit of human DNA polymerase ε acts as a motif binding protein capable to interact with a large number of protein molecules all containing NPF motifs.
- Salla Keskitalo
- , Boglarka Zambo
- & Gergo Gogl
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Article
| Open Access
Engineering the auxin-inducible degron system for tunable in vivo control of organismal physiology
Auxin-inducible degradation (AID) is a powerful tool for degrading target proteins in live organisms. Here, the authors develop the AID system to provide more precise, quantitative control over single or multiple tissue-specific target proteins.
- Jeremy Vicencio
- , Daisuke Chihara
- & Nicholas Stroustrup
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Article
| Open Access
Knowledge-guided adaptation of pathology foundation models effectively improves cross-domain generalization and demographic fairness
Pathology foundation models can still struggle with generalizability and fairness across demographic groups. Here, the authors develop FLEX, a framework to enhance cross-domain generalization and demographic fairness in pathology foundation models, improving performance and mitigating disparities in cancer datasets.
- Yanyan Huang
- , Weiqin Zhao
- & Lequan Yu
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Article
| Open Access
Engineering microbial consortia for mixed plastic upcycling
The chemical complexity of post-consumer ‘mixed’ plastic waste limits its use as a feedstock for biomanufacturing. Here the authors combine transition-metal-free plastic deconstruction with a microbial consortium platform to upcycle real-world mixed plastic waste into value-added chemicals.
- Jinjin Diao
- , Yuxin Tian
- & Tae Seok Moon
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Article
| Open Access
Efficient cellular transformation via protein delivery through the protrusion-derived extracellular vesicles
The efficiency of protein transfer by extracellular vesicles (EVs) remains unclear. Here, authors show that EVs from cell protrusions deliver functional Rac1 and genome-editing enzymes more efficiently than well-studied endosome-derived EVs, highlighting their potential as delivery tools.
- Toshifumi Fujioka
- , Tamako Nishimura
- & Shiro Suetsugu
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Article
| Open Access
Clonal cell states link gastroesophageal junction tissues with metaplasia and cancer
The cell states and lineage connections underlying the progression from Barrett’s esophagus to esophageal adenocarcinoma remain unresolved. Here, the authors use single-cell lineage tracing and transcriptomics to analyse patient samples from the gastroesophageal junction and identify cellular relationships in the progression of Barrett’s esophagus to cancer.
- Rodrigo A. Gier
- , Sydney A. Bracht
- & Sydney M. Shaffer
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Article
| Open Access
Benchmarking pre-trained genomic language models for RNA sequence-related predictive applications
Recent advances in AI have transformed RNA research by enabling powerful sequence-based predictions. Here, the authors benchmark eleven genomic language models across four RNA-related tasks, showing that biological context and model design, not just scale, drive performance and inform model selection.
- Ningyuan You
- , Chang Liu
- & Ning Shen
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Article
| Open Access
Spatial proximity dictates bacterial competition and expansion in microbial communities
Here, the authors show that immotile bacteria degrade antibiotics to alter their environment and facilitate nearby motile competitors to expand. As expansion proceeds, the immotile degrader is outcompeted, becoming a hidden driver of community spread.
- Emrah ÅžimÅŸek
- , César A. Villalobos
- & Lingchong You
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Article
| Open Access
Maternal histone methyltransferases antagonistically regulate autosomal random monoallelic expression (aRMAE) in C. elegans
Random monoallelic expression affects everything from the penetrance of genetic disease to immune cell function. Here, the authors found that epigenetic monoallelic expression is regulated in early embryos by two conserved maternal histone methyltransferases.
- Bryan Sands
- , Soo R. Yun
- & Alexander R. Mendenhall
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Article
| Open Access
Multimodal single cell analyses reveal gene networks of planarian stem cell differentiation
Single cell transcriptomics and chromatin accessibility uncover the gene networks underlying planarian cell type differentiation, revealing insights into the combinatorial logic of planarian cell fate specification.
- Alberto Pérez-Posada
- , Helena GarcÃa-Castro
- & Jordi Solana
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Article
| Open Access
Seal milk oligosaccharides rival human milk complexity and exhibit functional dynamics during lactation
Jin et al. discovered Atlantic grey seal milk contains 332 complex sugars, including 166 novel structures. Seal milk rivals human milk complexity, includes giant molecules up to 28 sugar units, changes during lactation, and shows immune-boosting effects.
- Chunsheng Jin
- , Jon Lundstrøm
- & Daniel Bojar
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Article
| Open Access
Protein Set Transformer: a protein-based genome language model to power high-diversity viromics
A genome language model, Protein Set Transformer, trained on viral datasets, uncovers evolutionary rules of protein content and organization driving precise virus identification, host prediction, and protein annotation for viral genomics and ecology.
- Cody Martin
- , Anthony Gitter
- & Karthik Anantharaman
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Article
| Open Access
Unifying regulatory motifs in endocrine circuits
Hormone systems control diverse physiological functions but consistent rules to model these circuits remain incompletely understood. Here the authors use mathematical modelling to report that 43 hormone circuits can be divided into five classes based on regulatory motifs and that the circuit structure relates to function.
- Moriya Raz
- , David S. Glass
- & Uri Alon
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Article
| Open Access
Multi-omics profiling reveals atypical sugar utilization and a key membrane composition regulator in Streptococcus pneumoniae
The pathogen Streptococcus pneumoniae can adapt to diverse microenvironments in the human body. Here, De Bakker et al. study these adaptation responses, showing unusual sugar utilization and identifying FasR as a regulator of membrane composition and heat stress resistance.
- Vincent de Bakker
- , Xue Liu
- & Jan-Willem Veening
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Article
| Open Access
Systematic benchmarking of imaging spatial transcriptomics platforms in FFPE tissues
Wang, Huang, Nelson, Gao, and colleagues perform a head-to-head comparison of multiple platforms for imaging spatial transcriptomics, determining their relative sensitivity, specificity, and ability to identify major cell types in clinical pathology samples.
- Huan Wang
- , Ruixu Huang
- & Samouil L. Farhi
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Article
| Open Access
Combinatorial protein engineering identifies potent CRISPR activators with reduced toxicity
CRISPR activators are powerful tools for controlling gene expression, but they suffer from inconsistent efficacy and high toxicity. Here, authors develop a high-throughput method to test thousands of CRISPR activators, revealing distinct principles of activator biology and delivering improved tools.
- Marla Giddins
- , Alexander F. Kratz
- & Alejandro Chavez
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Article
| Open Access
Omnireg-gpt: a high-efficiency foundation model for comprehensive genomic sequence understanding
Understanding long-range genomic regulation is a key challenge for DNA foundation models. Here, authors develop OmniReg-GPT with a hybrid local-global attention architecture, enabling efficient analysis of multi-scale regulatory features across long DNA sequences.
- Aowen Wang
- , Jiaqi Li
- & Junbo Zhao
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Article
| Open Access
Approaching single-molecule assembly-free readout from medium-length encoded DNA
Nanopore sequencing offers rapid DNA readout but suffers from severe insertion/deletion errors. Here, authors devise medium-length DNA fragments using a PNC-LDPC coding scheme, with an efficient cleavage library preparation to quickly recover original data at very low coverages without assembly.
- Weigang Chen
- , Rui Qin
- & Yingjin Yuan
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Article
| Open Access
Heterogeneity in responses to ribosome-targeting antibiotics mediated by bacterial RNA repair
RNA repair helps bacteria survive antibiotic stress. Here, authors show that Rtc-driven repair causes cell-to-cell variation in resistance levels, revealing a potential form of heteroresistance, and identify key Rtc targets to enhance antibiotic effectiveness.
- Hollie J. Hindley
- , Zechuan Gong
- & Andrea Y. Weiße
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Review Article
| Open Access
Learning from nature: phytochemical strategies to protect against UV-B damage
Land plants have developed chemical and structural strategies to cope with UV-B stress, including specialized metabolites that absorb UV-B and reduce oxidative damage. This review highlights how genetic variation and breeding strategies can boost UV resilience and nutritional value in crops.
- Mustafa Bulut
- , Takayuki Tohge
- & Alisdair R. Fernie
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Article
| Open Access
Systematic characterization of the composition and dynamics of processing body-associated mRNAs
The methods for systematically profiling RNA composition of processing bodies (PBs) are limited. Here, the authors present PB-TRIBE-STAMP and LSM14A-TRIBE-ID, two RNA editing-based methods enabling systematic characterization of dynamic PB-RNAs association.
- Zhiyuan Sun
- , Xiaozhen Wen
- & Wei Chen
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Article
| Open Access
Regulation of therapeutic protein release in response to circadian biomarkers
Circadian clocks integrate external environmental and internal physiological cues to generate oscillations of secreted endocrine signals. Here the authors build a melatonin-based circadian biomarker-driven gene switch in mammalian cells for type-2 diabetes treatment by oscillatory GLP-1 release.
- Nik Franko
- , Shichao Li
- & Martin Fussenegger
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Article
| Open Access
A cross-study transcriptional patient map of heart failure defines conserved multicellular coordination in cardiac remodeling
Cardiac tissue remodeling in heart failure is driven by interactions between multiple cell types, but existing studies have not fully captured these coordinated responses. Here, the authors show that integrating bulk and single-cell transcriptomics across 1,524 individuals reveals robust multicellular programs that link fibroblast activation to cardiomyocyte stress and recovery.
- Jan D. Lanzer
- , Ricardo O. Ramirez Flores
- & Julio Saez-Rodriguez
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Comment
| Open Access
Collective intelligence in animals and robots
This commentary explores how collective intelligence arises from local interactions in animal groups and how these principles inform the design of swarm robotic systems, addressing the challenge of achieving robust, responsive, and scalable collective behaviors without centralized control.
- Iain D. Couzin
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Article
| Open Access
scRNA-seq reveals persistent aberrant differentiation of nasal epithelium driven by TNFα and TGFβ in post-COVID syndrome
In this work, authors apply single-cell transcriptomics to nasal biopsies from post-COVID syndrome patients, revealing chronic inflammation driven by TNFα and TGFβ, alongside persistent airway epithelial remodelling in the absence of viral load.
- K. D. Reddy
- , Y. Maluje
- & A. Fähnrich
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