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<title>bioRxiv Subject Collection: Genomics Bioinformatics Genetics Molecular Biology Developmental Biology</title>
<link>https://biorxiv.org</link>
<description>
This feed contains articles for bioRxiv Subject Collection "Genomics Bioinformatics Genetics Molecular Biology Developmental Biology"
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<link>https://www.biorxiv.org</link>
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<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746620v1?rss=1">
<title>
<![CDATA[
PhageLysData: an evidence-aware and AI-ready dataset of phage lytic enzymes and depolymerases 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746620v1?rss=1
</link>
<description><![CDATA[
Bacteriophage lytic enzymes and depolymerases are relevant to phage biology, antimicrobial development, and protein engineering, but their sequence and annotation data remain dispersed across general databases, specialized resources, genome-centred collections, and prediction-oriented datasets. We present PhageLysData, an evidence-aware and AI-ready resource constructed through reproducible multisource integration, provenance tracking, and exact-sequence consolidation. The release integrates 807,366 source observations from seven primary resources into 759,105 unique exact-sequence entities, comprising an evidence-supported Core of 11,867 entities, a Prediction Extension of 745,092 prediction-only candidates, and 2,146 Context entities retained for provenance and reference. This architecture preserves broad sequence-space coverage while maintaining a clear distinction between non-predictive and prediction-derived support. Core entities are enriched with harmonized biological annotations, physicochemical properties, independent InterProScan-derived functional annotations, mapped PDB and AlphaFold DB structural assets, and reusable numerical representations. For 11,259 eligible Core sequences, PhageLysData provides embeddings from 11 protein language models together with one-hot encoding under a common representation contract. Release-facing examples demonstrate latent-space exploration, unsupervised clustering, supervised classification, and evidence-aware candidate retrieval without defining a universal predictive benchmark. PhageLysData provides a traceable, versioned, and computationally accessible foundation for protein retrieval, comparative analysis, task-specific dataset construction, and machine-learning applications involving phage lytic enzymes and depolymerases.
]]></description>
<dc:creator><![CDATA[ Medina-Ortiz, D., Olivera-Nappa, A., Lienqueo, M. E., Opazo, R., Romero, J. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746620</dc:identifier>
<dc:title><![CDATA[PhageLysData: an evidence-aware and AI-ready dataset of phage lytic enzymes and depolymerases]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.21.746139v1?rss=1">
<title>
<![CDATA[
AFP-R: An Open Resource Dedicated to Antifreeze Proteins 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.21.746139v1?rss=1
</link>
<description><![CDATA[
Antifreeze proteins (AFPs), lower the freezing point via thermal hysteresis activity and/or ice recrystallization inhibition, playing a crucial role in protecting organisms from freezing damage under sub-zero milieu. This property endows them with promising applications in biomedicine and agriculture, ranging from tissue-organ cryopreservation to the development of frost-resistant crops. However, the lack of comprehensive resources dedicated for AFPs hinders further progress in elucidating their functional mechanisms and advancing their applications. Here, we report AFP-R, an online resource comprising AFP-DB and AFP-Predictor. AFP-DB is a comprehensive database with manually curated proteins bearing experimentally validated antifreeze activity derived from published literature, whereas AFP-Predictor is a sequence-based machine-learning model to identify AFPs. AFP-DB stores diverse AFP-related information, including sequences, structures, post-translational modifications, taxonomy and annotations of antifreeze-activity experimental assays. It now holds 186 entries, 607 sub-entries, and 1444 experimental records. AFP-Predictor, an AFP-identification algorithm built on protein language model ESM2 (Evolutionary Scale Modeling2), is trained on data in AFP-DB and outperforms several existing models. This work offers a valuable resource for systematically dissecting the mechanisms underlying AFP antifreeze activity and will facilitate their broader applications.
]]></description>
<dc:creator><![CDATA[ Liu, W., Zhang, Y., Xiu, D., Liu, Y., Wang, T., Chai, X., Qu, H., Min, Y., Zhang, Z. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.21.746139</dc:identifier>
<dc:title><![CDATA[AFP-R: An Open Resource Dedicated to Antifreeze Proteins]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.21.746170v1?rss=1">
<title>
<![CDATA[
Detecting CYP2C19 deletions from genotyping array signals using neural networks 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.21.746170v1?rss=1
</link>
<description><![CDATA[
Since copy number variations (CNVs) in pharmacogenes can cause significant alterations in drug metabolism, their reliable detection is of high importance both for large-scale studies and personalized medicine. Whole-genome sequencing, and specifically long-read sequencing, is the gold standard for CNV detection. Despite increasing availability of these technologies, genotyping arrays are still widely used as cost-effective alternatives in biobank and clinical settings, yet calling CNVs based on array intensity signals is challenging due to low base pair resolution. In this work, we developed a neural network model, nnCNV, to predict deletions in the CYP2C19 pharmacogene region from array intensity signals. We compared our method to the most widely used algorithm, PennCNV, and demonstrated better performance reaching 100% accuracy in the test dataset. Furthermore, we predicted probe-by-probe CYP2C19 deletion coordinates for all Estonian Biobank samples using nnCNV and PennCNV, and validated these predictions using an identity-by-descent (IBD) sharing method, which also demonstrated superior nnCNV performance. For the deletion samples with conflicting PennCNV and nnCNV predictions, we performed PCR analysis for validation, which showed 97% precision for nnCNV compared to 23% for PennCNV. Finally, we assessed the gradient-based feature importance maps and showed that nnCNV utilizes signal intensity information not only from deletion probes, but also from probes in flanking regions. Our results demonstrate that long-range information, which cannot be utilized by hidden Markov models, can improve CNV calling.
]]></description>
<dc:creator><![CDATA[ Yelmen, B., Hofmeister, R. J., Lutsar, V. K., Finianos, M., Stone, B. C., Joeloo, M., Krebs, K., Kivistik, P. A., Smit, S., Estonian Biobank Research Team,, Metspalu, M., Hudjashov, G., Milani, L. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.21.746170</dc:identifier>
<dc:title><![CDATA[Detecting CYP2C19 deletions from genotyping array signals using neural networks]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.21.746151v1?rss=1">
<title>
<![CDATA[
Addressing technical variations in ATAC-seq data and improving motif accessibility analyses 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.21.746151v1?rss=1
</link>
<description><![CDATA[
Tagmentation-based methods such as ATAC-seq and Cut&Tag have provided easy ways to profile the epigenome in low-input samples and even single cells. In this contribution, we discuss forms of bias (i.e. technical variations) in tagmentation-based data, in particular ATAC-seq, and introduce three R/bioconductor packages to facilitate bulk and single-cell epigenomic data analysis, with a special focus on motif accessibility analysis. The weightedMotifAccess package uses weight models to enable motif accessibility analysis, including transcription factor footprint information. The betterChromVAR package provides a novel, analytical re-implementation of the popular chromVAR method that offers substantial speed improvements, eliminates stochasticity, and offers additional features. Based on this, we also propose a method, CVnorm, that outperforms alternatives in normalizing technical bias in peak count data. The computational efficiency of these tools further enables a new framework for systematically investigating synergistic and antagonistic interactions between transcription factor motifs. Finally, the epiwraps package streamlines the visualization, normalization, and summarization of epigenomic data.
]]></description>
<dc:creator><![CDATA[ Wang, J., Sonder, E., Domcke, S., Robinson, M. D., Germain, P.-L. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.21.746151</dc:identifier>
<dc:title><![CDATA[Addressing technical variations in ATAC-seq data and improving motif accessibility analyses]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746727v1?rss=1">
<title>
<![CDATA[
HuMMANet: A Harmonized Cross-Study Resource for Integrative Analysis of Human Gut Microbiome Metabolome Associations 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746727v1?rss=1
</link>
<description><![CDATA[
Deciphering gut microbiome to host metabolome interaction is critical for understanding how microbial communities generate bioactive signals that shape host physiology and disease. Progress, however, has been hindered by inconsistent metabolite annotations, poor interoperability across studies, and the absence of integrated resources placing microbiome-derived metabolites within their functional, microbial, physiological, and clinical context. Here we present HuMMANet (Human Microbiome Metabolome Annotation Network), a harmonized resource integrating 46 paired gut microbiome metabolome studies (59 study-units; 14,405 samples; 13 disease categories plus a healthy/control reference category) with a scalable metabolite-harmonization framework. HuMMANet resolves heterogeneous annotations through a multi-stage workflow spanning RefMet, HMDB, PubChem, Metabolomics Workbench, SMPDB, MiMeDB 2.0, GNPS/microbeMASST, DrugBank, and DrugCentral, yielding a reference atlas of 54,914 unique metabolites, annotated with standardized chemical identifiers, biochemical pathways, microbial producer associations, physiological distributions, disease links, and structural relationships to approved therapeutics, a unified reference framework for microbiome metabolome research. Applying HuMMANet to a multi-cohort integration of adult serum and fecal metabolomes, we identified 519 serum and 322 fecal metabolites reproducibly associated with gut microbial community composition (PERMANOVA, P < 0.05 in at least 50% of studies in which detected), enriched for specific biomolecular classes and pathways. Cross-referencing these against Health Associated Core Keystone (HACK) taxa revealed 58 serum and 25 fecal metabolites (HACK positive) whose taxon-level associations tracked positively with the taxon specific HACK indices. These reproducible metabolomic signatures of microbiome health included indole3propionic acid, a gut barrier-protective microbial tryptophan metabolite, and 3phenylpropionate. Drug similarity annotation within HuMMANet linked 16 of this serum and 13 fecal HACK positive metabolites to therapeutics used in neurological, inflammatory, and vascular disease. Conversely, 38 serum and 65 fecal metabolites, including imidazole propionate and long-chain acylcarnitines such as ACar 18:0, showed HACK negative signatures previously associated with dysbiosis-linked disease. GNPS/microbeMASST and MiMeDB 2.0 annotations further traced subsets of these metabolites to putative bacterial producers. HuMMANet thus provides a standardized framework for reproducible microbiome metabolome integration, enabling cross study discovery and translational prioritization of conserved microbiome derived metabolic signatures across human populations and disease states.
]]></description>
<dc:creator><![CDATA[ Verma, S., Arora, N., Ajay, C. P., Singh, P., Mallick, H., Ghosh, T. S. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746727</dc:identifier>
<dc:title><![CDATA[HuMMANet: A Harmonized Cross-Study Resource for Integrative Analysis of Human Gut Microbiome Metabolome Associations]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746074v1?rss=1">
<title>
<![CDATA[
ASAREE: An Analytical Sandbox for Agentic AI Research, Engineering, and Experimentation 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746074v1?rss=1
</link>
<description><![CDATA[
Summary: Agentic AI platforms enable the engineering of autonomous workflows but are not designed for experimentation and hypothesis testing. ASAREE (Analytical Sandbox for Agentic AI Research, Engineering, and Experimentation), is an open-source platform to address this gap. ASAREE creates agents, connects to MCP servers and tools, and designs factorial experiments through a visual interface or Python SDK. It records a full provenance trace for every run and routes all model calls through a provider-agnostic bridge that supports local deployments, ensuring data privacy. As a use-case, we use ASAREE to evaluate key design choices in a mutli-agent machine learning pipeline. Across a 2 x 2 x 2 factorial design, more advanced models, greater reasoning effort, and critic agent use significantly increased compute time, token use, cost, and feature count without improving predictive performance. The lowest-cost baseline, Claude Sonnet 5 with medium effort and no critic, achieved the highest mean PR AUC while Claude Opus 5 with extra high effort and a critic agent cost 15.5x more (USD) and ran 13.1x longer while performing worse on average. These findings highlight ASAREE as a robust framework for evaluating agentic system performance and resource efficiency.
]]></description>
<dc:creator><![CDATA[ Moran, J., Freda, P. J., Ghosh, A., Hernandez, M. E., Moore, J. H. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746074</dc:identifier>
<dc:title><![CDATA[ASAREE: An Analytical Sandbox for Agentic AI Research, Engineering, and Experimentation]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746095v1?rss=1">
<title>
<![CDATA[
ClustoCell reveals cell states and their markers from single-cell transcriptomes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746095v1?rss=1
</link>
<description><![CDATA[
Accurate identification of cell types and states is essential for reliable single-cell RNA-sequencing analyses, yet current methods remain sensitive to continuous biological states, data preprocessing choices, and reference selection. Here we present ClustoCell, a reference-free method that resolves cell identity using within-cell transcriptional architecture. By stratifying gene expression of each cell into high and medium tiers, ClustoCell constructs cell-cell similarity graphs that prioritize intrinsic expression structure over global variance. Across 450 datasets spanning over 24 million cells, ClustoCell recovered expert annotations with high concordance (92%). Benchmarked against state-of-the-art methods, ClustoCell identifies more stable and coherent cell types and states, avoids excessive partitioning of closely related cells, and improves the identification of cell type-specific markers. From transcriptional structure alone, ClustoCell resolves rare and transitional cell states, distinguishes malignant from non-malignant cells, and refines expert cell annotations. Applied to immunotherapy datasets, ClustoCell uncovered coordinated pre-treatment immune circuits linking T cell states to PD-1 responsiveness in a tumour-type-specific manner. ClustoCell provides an interpretable and scalable foundation for single-cell analysis and translational profiling.
]]></description>
<dc:creator><![CDATA[ Salavaty, A., Foroutan, M., Pretel, N. P., Egelberg, J., Parish, I. A., Huntington, N. D., Beltran, H., Sandhu, S., Molania, R. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746095</dc:identifier>
<dc:title><![CDATA[ClustoCell reveals cell states and their markers from single-cell transcriptomes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746112v1?rss=1">
<title>
<![CDATA[
MultiFlow: coupled flow matching for predicting single-cell multiomic perturbation responses in unseen cellular contexts 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746112v1?rss=1
</link>
<description><![CDATA[
Predicting cellular responses to perturbation requires resolving coordinated changes across molecular layers, yet most single-cell perturbation models focus on transcriptional responses alone. Here we present MultiFlow, a coupled flow-matching framework that unifies generation and perturbation prediction of paired gene expression and chromatin accessibility. By learning coupled RNA-ATAC flows conditioned on perturbation and control-derived cellular-state representation, MultiFlow enables prediction of coordinated multiomic responses in unseen cellular contexts. Across multiomic generation benchmarks, MultiFlow accurately reproduced paired RNA-ATAC states and their population distributions. In multiomic perturbation benchmarks, MultiFlow achieved the strongest overall performance in predicting both gene-expression and chromatin-accessibility responses, outperforming competing modality-specific perturbation-prediction methods. Joint multiomic modeling further preserved perturbation-induced RNA-ATAC coordination, including concordant peak-gene effects and cross-modal cellular neighborhood structure. These results establish coupled flow matching as a unified generative framework for modeling paired multiomic states and predicting coordinated perturbation responses across cellular contexts. Code and tutorial for MultiFlow are available at https://github.com/liuq-lab/MultiFlow.
]]></description>
<dc:creator><![CDATA[ Wang, H., Zhang, C., Zhang, M., Nie, X., Liu, Q. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746112</dc:identifier>
<dc:title><![CDATA[MultiFlow: coupled flow matching for predicting single-cell multiomic perturbation responses in unseen cellular contexts]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.745941v1?rss=1">
<title>
<![CDATA[
Early life stress affects the transcription and chromatin accessibility of spermatogonial cells 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.745941v1?rss=1
</link>
<description><![CDATA[
Adversity in early life has lasting effects on the physiology and behavior of exposed individuals and their descendants. In mice, early-life stress alters the RNA content of adult sperm, and this RNA is sufficient to transmit some of the effects to the offspring who were never exposed. However, sperm cells are not yet formed during the early postnatal window in which the exposure occurs. Spermatogonial cells (SPGs), which give rise to them, are present at that time, but whether they respond to the exposure and maintain a molecular signature of it into adulthood is unknown. Here we show that early-life stress alters both the transcriptome and the chromatin accessibility of mouse SPGs, and that a molecular signature of the exposure remains detectable in adulthood. One day after exposure ended, the transcriptional response was extensive, with proliferation and nucleosome-organization programs coordinately up-regulated. In adulthood, the transcriptional response was modest and dominated by coordinately down-regulated gene programs. Single-cell profiling of the whole testis localized the adult response to spermatogonial stem cells (SSCs) and to genes involved in spermatogenesis. At the chromatin level, accessibility shifted one day after exposure at binding motifs for signal-responsive transcription factor families, and in adulthood at a different set of families, in both cases at primed enhancers. These data demonstrate that SPGs respond to an early postnatal environmental exposure and identify them as a candidate origin of the molecular changes later found in adult sperm.
]]></description>
<dc:creator><![CDATA[ Arzate-Mejia, R. G., Schopp, T., Uzel, K., Lazar-Contes, I., Mansuy, I. M. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.745941</dc:identifier>
<dc:title><![CDATA[Early life stress affects the transcription and chromatin accessibility of spermatogonial cells]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.745782v1?rss=1">
<title>
<![CDATA[
An Epigenetic Signature of Vulnerable Neurons is Under Selective Pressure Associated with Longevity Across Placental Mammals. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.745782v1?rss=1
</link>
<description><![CDATA[
Age is the primary risk factor for neurodegenerative diseases, which are characterized by cell-type-specific vulnerability. Yet brain-aging mechanisms remain unclear given the complex, interacting age-associated pathways across diverse neural cell types. Here, we dissect cell type- cell state-specific aging gene regulatory programs and their contribution to cellular vulnerability by leveraging epigenomics, AI methodology, and natural lifespan diversity across placental mammals. Applying the TACIT method, we associated lifespans of 240 placental mammals to the predicted open chromatin levels of over 3 million orthologous loci across 18 cortical cell types. We identified thousands of lifespan-associated open chromatin regions, enriched near genes associated with hallmarks of aging, which stratified greatly by cell type. For example, regions near mitochondrial genes showed differential selective pressure in long-lived species in energetically-demanding layer V ET neurons, while regions near inflammatory response genes were under selective pressure in glial populations. We next asked whether regions linked to vulnerable or resilient neurons in the human brain were under differential selective pressure in longer lived species. Using an adaptive representation learning approach, we decompose intrinsic aging programs from systemic effects in the prefrontal cortex and define an aging signature predictive of cell-type-specific vulnerability. In Alzheimer's disease, this intrinsic aging signature more strongly predicts vulnerability than systemic effects. Active regions in vulnerable neurons showed lower predicted activity in species with longer lifespans, suggesting selective pressure to down-regulate the vulnerability-associated networks. Overall, our findings argue against a single master regulator of aging, instead implicating different hallmarks across different cell types.
]]></description>
<dc:creator><![CDATA[ Abdelhady, G., Su, Q., Wang, A. Z., Ganesan, R., Phan, B. N., Sestili, H. H., Cherupally, V., The Vertebrate Genomes Project Consortium Phase 1,, Pfenning, A. R. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.745782</dc:identifier>
<dc:title><![CDATA[An Epigenetic Signature of Vulnerable Neurons is Under Selective Pressure Associated with Longevity Across Placental Mammals.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746068v1?rss=1">
<title>
<![CDATA[
optix regulates abdominal melanin pigmentation in the tobacco hawkmoth Manduca sexta 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746068v1?rss=1
</link>
<description><![CDATA[
Research on butterflies has uncovered a conserved "toolkit" of genes for color pattern development and evolution. One of these genes is optix, a homeobox transcription factor that regulates ommochrome and melanin pigmentation, as well as structural coloration, in nymphalid butterflies. It remains unclear, however, whether optix plays any roles in color patterning outside of the Nymphalidae. We used CRISPR-Cas9 to disrupt optix in the tobacco hornwormmoth Manduca sexta and observed a dramatic abdominal pigmentation phenotype, where orange pigmentation was replaced by black eumelanin. Chemical assays suggest that the orange pigment is not an ommochrome, indicating that optix modulates an alternative, uncharacterized pigment pathway in M. sexta. RNA-seq and chemical analyses of orange and black abdominal scales lead us to speculate that the orange pigment may be a type of melanin, perhaps N-{beta}-alanyldopamine (NBAD) sclerotin. Our results suggest that optix plays a deeply ancestral role in pigment regulation in Lepidoptera, and demonstrates evolutionary flexibility in how it interfaces with pigment chemistry across moths and butterflies.
]]></description>
<dc:creator><![CDATA[ Chatterjee, M., Hatto, G. C., Duplais, C., Varnell, J., Raguso, R. A., Reed, R. D. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746068</dc:identifier>
<dc:title><![CDATA[optix regulates abdominal melanin pigmentation in the tobacco hawkmoth Manduca sexta]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746052v1?rss=1">
<title>
<![CDATA[
MPGEM: A harmonized and transcriptome-complete resource for large-scale reuse of legacy human microarray data 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746052v1?rss=1
</link>
<description><![CDATA[
Abstract Background: Legacy microarray datasets provide an extensive record of human transcriptomic biology, but their reuse is constrained by differences in platform design, preprocessing, measurement scale, and gene coverage. Platforms measuring only subsets of genes cannot readily be integrated with higher-coverage platforms, limiting large-scale analysis and computational modeling. Results: We developed Multi-Platform Gene Expression Matrix (MPGEM), a computational framework and resource for harmonizing and completing gene-expression profiles across heterogeneous microarray platforms. MPGEM uses a Reference Quantile Distribution (RQD) and generalized Reference Subset Quantile Distribution (RSQD) framework to transform profiles with different gene coverage onto a common quantitative scale. The MPGEM Engine, a multilayer perceptron, predicts expression of unmeasured genes from genes shared across platforms. Applied to Affymetrix GPL570, GPL571, and GPL96, MPGEM uses GPL570 as a 19,320- gene reference space comprising 12,712 predictor and 6,608 target genes. The resulting resource contains 207,135 human gene-expression profiles across 19,320 genes. Evaluation using masked GPL570 profiles yielded mean sample-wise Pearson and Spearman correlations of 0.944 and 0.939, respectively, and mean gene-wise correlations of 0.830 and 0.825. The lowest-performing 5% of target genes achieved a mean Pearson correlation of 0.683. MPGEM showed comparable or higher predictive performance than baseline mean imputation and K-nearest-neighbor approaches. Conclusions: MPGEM transforms heterogeneous, partially measured legacy microarray profiles into a harmonized, transcriptome-complete representation, facilitating their reuse for large-scale transcriptomic analysis, biomarker discovery, systems biology, and machine learning. The framework, trained models, and expression resource are provided as open-source resources.
]]></description>
<dc:creator><![CDATA[ Gupta, S., Verma, A. K., Jana, S., Ahmad, S. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746052</dc:identifier>
<dc:title><![CDATA[MPGEM: A harmonized and transcriptome-complete resource for large-scale reuse of legacy human microarray data]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746749v1?rss=1">
<title>
<![CDATA[
Expression of AAACTAC satellite repeats as a long noncoding RNA in the early oocyte of Drosophila virilis 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746749v1?rss=1
</link>
<description><![CDATA[
Satellite DNA is long arrays of tandem repetitive DNA located often near the centromeres of chromosomes, whose function, or lack of, has been debated since its discovery. Although situated in heterochromatin, satellite DNA may be expressed as long noncoding RNAs (lncRNAs). Although there are a few examples of satellite lncRNAs being characterized, and functions suggested, how widespread and functionally important they may be for developmental processes is not understood. Here, we take an evolutionary approach to investigate satellite lncRNA expression in Drosophila spp. ovaries, a tissue whose development is well-characterized but where satellite expression has only been minimally explored. Using a publicly-available total RNAseq dataset, we find that 118/156 surveyed satellite DNAs were expressed across 10 species, with 33 satellites having high expression over 20 RPM. However, all but two of these expressed satellites (AAACTAC in D. virilis and ACAGACAGACAGG in D. ananassae) had higher read counts in a sister smallRNA dataset, suggesting that most satellite transcripts primarily serve as precursors for piRNA biogenesis. The two "stand-alone" lncRNAs were highly strand-biased, with 96-97% of the total reads coming from one strand. We further investigated AAACTAC expression with RNA FISH and found the transcript is specifically present in the oocyte nucleus following a dynamic spatiotemporal pattern, with the highest expression in stage 3-5 oocytes. The transcription pattern of AAACTAC is conserved in the three other virilis clade species that contain this satellite DNA. Further, we found expression of unrelated satellites in more distantly related D. borealis and littoralis both in the oocyte and the nurse cells. Overall, our work identifies a novel lncRNA AAACUAC found in the early oocyte nucleus, which is conserved across ~5 MY of evolution, and is therefore a strong candidate for the discovery of novel functions of satellite lncRNAs in development.
]]></description>
<dc:creator><![CDATA[ Vermette, O., Mixoy, R. L., Flynn, J. M. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746749</dc:identifier>
<dc:title><![CDATA[Expression of AAACTAC satellite repeats as a long noncoding RNA in the early oocyte of Drosophila virilis]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746014v1?rss=1">
<title>
<![CDATA[
Lifecourse sex-specific molecular response to early-life exposures of toxic substances 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746014v1?rss=1
</link>
<description><![CDATA[
Toxicants in the environment can significantly impact physiology. Environmental chemical exposures during early developmental stages disturb normal embryonic development and programming, and dramatically impact long-term health as individuals age. Female and male animals show distinct phenotypes when responding to a given chemical exposure. Here, through the TaRGET II (Toxicant Exposures and Responses by Genomic and Epigenomic Regulators of Transcription) consortium, we systematically explored sex-specific transcriptomic and epigenomic alterations in response to various toxicants, including arsenic (As), lead (Pb), tributyltin (TBT), bisphenol A (BPA), di(2-ethylhexyl) phthalate (DEHP), dioxin (TCDD), and fine particulate matter (PM2.5), across three time points in mice exposed two weeks prior to conception through gestation and lactation. After being exposed to toxicants during the embryonic and early postnatal developmental stages, 1,025 omics datasets were generated from the liver and analyzed across three mouse life stages. We discovered a significant sex-biased molecular response to distinct exposures in the liver at both the transcriptomic and epigenetic levels, showing dynamic changes across mouse development and aging. The perturbed pathways and transcription factors in response to different chemical exposures in both sexes were further evaluated to measure the sex-specific impact of each toxic exposure in the liver. Overall, this study presents the most detailed investigation of sex-specific molecular signatures under the influence of developmental exposures to toxic substances.
]]></description>
<dc:creator><![CDATA[ Zhang, B. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746014</dc:identifier>
<dc:title><![CDATA[Lifecourse sex-specific molecular response to early-life exposures of toxic substances]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.745837v1?rss=1">
<title>
<![CDATA[
Single-cell roadmap of bovine oogenesis and somatic niche interactions during fetal ovarian development 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.745837v1?rss=1
</link>
<description><![CDATA[
The major events of female germline establishment, from primordial germ cell (PGC) specification to assembly of primordial follicles, occur during embryonic/fetal development. This study presents a single-cell RNA-sequencing atlas of the bovine fetal ovary at four gestational timepoints: estimated day 50, and timed pregnancies at days 70, 90, and 120, capturing the progression of PGCs through commitment, meiotic entry, and early oocyte growth. Fourteen transcriptionally distinct cell populations were identified, including stromal, epithelial, endothelial, immune, somatic support cell, and germ cell lineages. Sub-clustering of the germ cell population resolved six developmental stages (PGCs, transitioning oogonia, proliferative oogonia, committed oogonia, meiotic prophase I oogonia, and oocytes), while that of the somatic support cell compartment revealed five granulosa cell subtypes (steroidogenic, pre-granulosa 1, pre-granulosa 2, pre-granulosa 3, and epithelial cells). Trajectory analysis reconstructed the developmental path of PGCs to oocytes, with sequential activation of meiotic and oocyte-specific gene programs. Representation of all six germ cell stages at day 120 pointed to asynchronous oogenesis in the fetal ovary, which was validated and shown to be region-specific by protein immunolocalization. Intercellular signaling networks between germ cells and the somatic niche were mapped, revealing strong interactions through BMP, KIT, IGF, IGFBP, WNT, and MDK pathways with temporal specificity across gestational ages. The bovine germ cell and pre-granulosa cell subtypes demonstrate significant transcriptional parallels with similarly-staged cells from human fetal ovaries, establishing the cow as a reliable model for human germ cell and ovarian development. Collectively, these data provide a developmental roadmap for bovine oogenesis at the single-cell resolution that advances fundamental understanding of gametogenesis and informs strategies for advanced assisted reproduction.
]]></description>
<dc:creator><![CDATA[ Guiltinan, C., Botigelli, R. C., Arcanjo, R. B., Smith, J. M., Grimm, C. K., Plummer, S. K., Keough, B. P., Paulsen, M. N., Rajput, S. K., Beaton, B., Denicol, A. C. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.745837</dc:identifier>
<dc:title><![CDATA[Single-cell roadmap of bovine oogenesis and somatic niche interactions during fetal ovarian development]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.25.746927v1?rss=1">
<title>
<![CDATA[
Cholesterol transport cycle of human ABCA2 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.25.746927v1?rss=1
</link>
<description><![CDATA[
Cholesterol is a key component of cellular membranes and is critical for brain function, particularly axon myelination. Among the 48 human ATP-binding cassette (ABC) transporters, ABCA2 exhibits the highest expression in the brain and is involved in cholesterol metabolism, primarily in oligodendrocytes. Notably, ABCA2 has been associated with myelin sheath integrity and maintenance, as well as Alzheimer's disease. Here, we report cryo-EM structures of human ABCA2 that reveal critical endogenous lipid-binding sites unique to ABCA2. Our five distinct conformations include a previously uncharacterized intermediate between the closed and apo states of ABCA subfamily transporters. Most importantly, we elucidated the cholesterol transport mechanism of ABCA2, which involves novel interdependent rotations of the exocytoplasmic domains (ECDs) and regulatory domains (RDs). Our structural findings provide a new perspective on ABCA transporter function and highlight the role of ABCA2 in facilitating efficient cholesterol recycling and transport in the brain.
]]></description>
<dc:creator><![CDATA[ Tan, S. M., Schnelle, K., Voskoboynikova, N., Nowacki, M., Esch, B. M., Froehlich, F., Holtmannspoetter, M., Piehler, J., Shvarev, D., Parey, K., Januliene, D., Moeller, A. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.25.746927</dc:identifier>
<dc:title><![CDATA[Cholesterol transport cycle of human ABCA2]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746764v1?rss=1">
<title>
<![CDATA[
Vangl2 acts in distinct cell types to establish bidirectional hair-bundle polarity and maintains tissue-wide alignment in zebrafish neuromasts 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746764v1?rss=1
</link>
<description><![CDATA[
The conserved core planar cell polarity (PCP) pathway orients cells and subcellular structures within an epithelium through asymmetric protein localization and intercellular communication. In vestibular organs and lateral-line neuromasts, mechanosensory hair cells are interspersed among support cells and form opposing hair-bundle orientations along a shared axis, enabling bidirectional sensitivity to head motion and water flow, respectively. In zebrafish neuromasts, Notch-mediated lateral inhibition gives rise to two hair-cell populations, distinguished by differential Emx2 expression, that orient their cell-intrinsic polarity machinery differently relative to a PCP-dependent tissue-wide axis. However, it remains unclear how PCP proteins are organized across hair cells and support cells to achieve both opposing hair-bundle orientations and tissue-wide alignment, and whether PCP signaling remains required after hair-bundle polarity is established. Combining quantitative spatial mapping of the core PCP protein Vangl2 with cell-type-specific and temporally controlled protein degradation, we show that hair cells and support cells make distinct yet coordinated contributions to the polarized Vangl2 organization within neuromasts and to bidirectional hair-bundle polarity. Support-cell Vangl2 facilitates tissue-wide alignment of hair bundles along the anteroposterior axis, whereas hair-cell Vangl2 is required to generate opposing hair-bundle orientations along this axis. Vangl2 degradation after hair bundles have formed disrupts their tissue-wide alignment, showing that planar polarity is actively maintained rather than fixed after establishment. Together, these findings reveal how Vangl2-dependent PCP signaling is distributed across distinct cell types within a heterogeneous epithelium to generate opposing polarity outcomes and remains necessary to preserve tissue-level planar organization.
]]></description>
<dc:creator><![CDATA[ Jeewajee, S., Gianoli, F., Jussila, M., Ciruna, B., Steiner, A., Jacobo, A., Hudspeth, A. J. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746764</dc:identifier>
<dc:title><![CDATA[Vangl2 acts in distinct cell types to establish bidirectional hair-bundle polarity and maintains tissue-wide alignment in zebrafish neuromasts]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746001v1?rss=1">
<title>
<![CDATA[
Acute activation of autophagy enables growth plate regeneration following radiation-induced injury. 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746001v1?rss=1
</link>
<description><![CDATA[
Purpose Radiation injury to growth plates commonly leads to skeletal late complications including short stature, limb length-discrepancy, and scoliosis/kyphosis in pediatric oncology patients. We aimed to understand the acute responses of direct growth plate irradiation that result in skeletal late complications. Materials and methods We first established an in vivo model of focal growth plate irradiation that recapitulates the clinical development of skeletal late complications and used it to explore the responses of growth plate chondrocytes within the first 72 hours of radiation exposure. To monitor acute effects of radiation exposure on human chondrocytes, rare human growth plate biopsies were exposed to ionizing radiation ex vivo. Using these approaches, we applied clonal genetic tracing and immunofluorescence to monitor changes at the cellular and molecular levels. Functional in vivo perturbations were conducted with clinically-relevant autophagy inhibitor, hydroxychloroquine. Results Growth plate irradiation disrupted the continuous production of chondrocytes required for bone elongation and was associated with DNA damage throughout the growth plate. Indicators of growth plate activity, SOX9 and the phosphorylated form of ribosomal protein S6, decreased during a 6- and 24-hour post-irradiation window but returned to normal levels 72 hours after irradiation. We identified a surge in autophagic flux throughout the growth plate during this window, based on temporal SQSTM1 and LAMP1 protein levels. The earliest stages of these response mechanisms are conserved between species and relevant to humans. Hydroxychloroquine treatment immediately after radiation injury in mice impaired growth plate regeneration, resulting in more severe late complications. Conclusion Our findings demonstrate that autophagy is an important acute response to irradiation in growth plate chondrocytes, revealing a novel potential therapeutic target for preventing radiation-induced skeletal late complications.
]]></description>
<dc:creator><![CDATA[ Mehrbani Azar, Y., Nazaraliyev, A., Avijgan, M., Savendahl, L., Blomgren, K., Newton, P. T. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746001</dc:identifier>
<dc:title><![CDATA[Acute activation of autophagy enables growth plate regeneration following radiation-induced injury.]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746683v1?rss=1">
<title>
<![CDATA[
Irregular nucleosome positioning governs a crystalline to liquid-like phase transition and tunes chromatin accessibility 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746683v1?rss=1
</link>
<description><![CDATA[
Chromatin must fold tightly enough to protect the genome while being sufficiently accessible for DNA dependent processes such as transcription. The physical rules that balance these competing roles remain unclear, as DNA sequence encodes both biochemical information such as transcription factor binding sites, and biophysical cues that shape chromatin structure. Here, using synthetic chromatin fibres assembled from physiologically relevant DNA sequences, we show that nucleosome positioning dictates the material state of chromatin. Heterochromatin-like sequences produce compact fibres stabilised by nucleosome stacking, whereas euchromatin-like sequences generate irregular nucleosome positioning that yields disrupted, heterogeneous, and mechanically deformable fibres. Quantitative polymer modelling reveals that these irregular arrays are highly dynamic, continually sampling a broad ensemble of conformations as nucleosome stacking breaks down. We identify two previously unrecognised thresholds encoded by nucleosome positioning: minimal positional irregularity (2-3 bp) triggers a transition from an ordered paracrystalline state to a liquid-like phase, whereas an order of magnitude greater irregularity (~18 bp) is required to generate accessibility and mechanical fragility permissive for transcription factor binding. Euchromatin-like arrays reside at this accessibility threshold. These findings indicate that nucleosome positioning tunes chromatin toward or away from critical structural states that couple genome protection, chromatin dynamics, and transcriptional potential, providing a physical mechanism that helps connect DNA sequence to gene expression.
]]></description>
<dc:creator><![CDATA[ Albawardi, W., Thomas, M., Kuijntjes, G.-J., Wheeldon, H., Kaczmarczyk, A., Allan, J., Ding, J., Chiang, M., Vanderlinden, W., van Noort, J., Marenduzzo, D., Brackley, C. A., Gilbert, N. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746683</dc:identifier>
<dc:title><![CDATA[Irregular nucleosome positioning governs a crystalline to liquid-like phase transition and tunes chromatin accessibility]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746594v1?rss=1">
<title>
<![CDATA[
Position-Dependent NMD Generates Diverse Protein Outcomes 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746594v1?rss=1
</link>
<description><![CDATA[
Nonsense-mediated mRNA decay (NMD) is a translation-dependent mRNA decay pathway triggered by premature termination codons (PTCs). Although NMD is known to eliminate aberrant transcripts, how PTC position influences cell-to-cell heterogeneity in NMD and the resulting protein outputs remains unclear. Here, we used a single-cell NMD analysis system that quantifies cellular variability based on the GFP/mCherry fluorescence ratio. By combining this system with fluorescence-activated cell sorting (FACS), we show that PTC location critically determines not only NMD efficiency and its variability across cells, but also the spectrum of resulting protein products. These include truncated proteins arising from premature termination, full-length proteins generated through translational readthrough, and N-terminally truncated isoforms produced by downstream reinitiation. Our findings reveal that positional and cellular heterogeneity in NMD contribute to proteomic diversity and may underlie the variable phenotypic severity of genetic diseases caused by PTCs. This work establishes a framework for dissecting NMD regulation and its translational consequences.
]]></description>
<dc:creator><![CDATA[ Pinky, N. J., Sato, H. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746594</dc:identifier>
<dc:title><![CDATA[Position-Dependent NMD Generates Diverse Protein Outcomes]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746546v1?rss=1">
<title>
<![CDATA[
CpG islands act as topological sinks for transcription-induced DNA supercoiling 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746546v1?rss=1
</link>
<description><![CDATA[
Strong evolutionary selection has maintained CpG-dense islands (CGIs) at the promoters of constitutively expressed genes throughout the vertebrate genome, suggesting an important role in regulating DNA topology. Here, using Twist-seq, a psoralen-based approach for quantitative genome-wide profiling of DNA supercoiling, we reveal distinct topological states across human gene promoters. We show that CGI promoters accumulate elevated levels of negative supercoiling relative to non-CGI promoters and define localised topological domains at highly transcribed genes. Integrating genome-wide analyses with reaction-diffusion modelling and coarse-grained molecular dynamics simulations, we find that this behaviour is encoded by the intrinsic physical properties of CGI DNA. The GC-rich sequence context promotes nucleosome depletion and focuses torsional stress onto embedded AT-rich pockets, driving localised DNA melting and plectoneme-tip bubble formation within promoter-proximal nucleosome-free regions. This provides an energetically favourable pathway for redistributing transcription-induced torsional stress through transient strand separation and writhe, consistent with increased ssDNA formation at CGI promoters observed by ssDNA-seq. We propose that CGIs function as sequence-encoded topological sinks that buffer supercoiling while maintaining a promoter architecture permissive for transcription initiation, thereby preserving promoter integrity and genome stability.
]]></description>
<dc:creator><![CDATA[ Naughton, C., Bonato, A., Chiang, M., Corless, S., Stocks, J., Grimes, G. R., Halliday, D., Bentivoglio, A., Brackley, C. A., Marenduzzo, D., Gilbert, N. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746546</dc:identifier>
<dc:title><![CDATA[CpG islands act as topological sinks for transcription-induced DNA supercoiling]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746650v1?rss=1">
<title>
<![CDATA[
DePARylation prevents DNA replication-driven PARP1 condensation 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746650v1?rss=1
</link>
<description><![CDATA[
PARG, the primary enzyme responsible for the reversal of PARP1-mediated poly(ADP-ribosyl)ation, has attracted considerable attention as a therapeutic target in cancer. Yet, the mechanisms underlying PARG inhibitor (PARGi) efficacy remain elusive. Herein, we demonstrate that PARGi prolongs PARP1 residence at damaged chromatin in a manner mechanistically distinct from PARP-inhibitor-induced trapping. That is, PARGi triggers the formation of PAR-driven, FUS-enriched PARP1 nuclear condensates upon DNA damage. Importantly, unrestrained S-phase PARylation during Okazaki fragment maturation also elicited PARP1 condensation in a manner directly reflecting intrinsic PARGi sensitivity, with FEN1 co-inhibition enhancing both PARP1 condensate formation and cytotoxicity. Finally, we discover that dePARylation prevents the rapid nuclear extrusion of PARP1 upon S-phase entry, a phenomenon that is reversible and could undermine PARP1-dependent nuclear processes. Together, our findings reveal that dePARylation precludes the replication-driven condensation of PARP1 and identify Okazaki fragment maturation as a targetable vulnerability that exacerbates condensation and PARGi cytotoxicity.
]]></description>
<dc:creator><![CDATA[ Kanev, P.-B., Milanova, V., Berkova, P., Kutrovski, D., Tosheva, K. L., Aleksandrov, R. ]]></dc:creator>
<dc:date>2026-08-25</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746650</dc:identifier>
<dc:title><![CDATA[DePARylation prevents DNA replication-driven PARP1 condensation]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-25</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.18.745563v1?rss=1">
<title>
<![CDATA[
Genetic and Behavioral Variation Underlying an Integrated Temporal Phenotype in an Admixed South American Population 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.18.745563v1?rss=1
</link>
<description><![CDATA[
Chronotype is a complex trait reflecting individual differences in the temporal organization of rest and activity, with important health implications. The Uruguayan population, characterized by a tri-hybrid origin (African, European, and Indigenous), exhibits a bias toward eveningness. The genetic variation in clock genes underlying chronotype in this population remains unexplored. To address this gap, we analyze healthy young adults from the extremes of the chronotype distribution (early, n = 37; late, n = 38; 63% female; 23.1 {+/-} 3.4 years), integrating self-reported measures, actigraphy, and low-pass whole-genome sequencing. Global ancestry is predominantly European, with Indigenous and African components, and does not differ between chronotypes. Variant density is highest in PER2. T-allele carriers of a PER2 variant previously associated with late chronotypes (rs35333999) differ from non-carriers in activity acrophase. Multidimensional scaling of variants across 19 canonical clock genes reveal differential representation of early and late chronotypes across genetic clusters. When examined by functional groups, the signal is restricted to genes involved in degradation of the circadian clock's repressor arm, with BTRC, a mediator of PER2 degradation, showing the same pattern when assessed individually. We derive a joint behavioral component capturing the variation in food intake, moderate-to-vigorous physical activity, light exposure, and sleep timing, which correlates with dim-light melatonin onset (DLMO), the gold-standard marker of circadian phase, and show differences among genetic clusters. Our integrative multilevel approach suggests a complex interplay between behavioral and genetic factors shaping chronotype in this cohort, highlighting the PER2BTRC axis as a candidate mechanism for future investigations.
]]></description>
<dc:creator><![CDATA[ Marchesano, M., Spangenberg, L., Casaravilla, C., Castillo Stratta, J., Silva, A., Tassino, B. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.18.745563</dc:identifier>
<dc:title><![CDATA[Genetic and Behavioral Variation Underlying an Integrated Temporal Phenotype in an Admixed South American Population]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.23.746358v1?rss=1">
<title>
<![CDATA[
Fendioxypyracil Exhibits Potent Inhibition of PPO-Resistant Mutant Enzymes and Robust Activity Against PPO-Resistant Amaranthus 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.23.746358v1?rss=1
</link>
<description><![CDATA[
Background: Resistance to protoporphyrinogen oxidase (PPO) inhibiting herbicides is mainly driven by diverse target-site mutations, reducing the effectiveness of this site of action in row crop systems. Fendioxypyracil is a newly developed PPO inhibitor with high intrinsic grass and broadleaf activity, but its performance against resistant populations and target-site enzyme variants remains insufficiently characterized. Results: Enzyme assays using PPO2 from Amaranthus palmeri and Setaria viridis demonstrated that fendioxypyracil maintained low IC50 values across a broad range of resistance associated mutations, including dG210 deletion and G210, R128, and G399 substitutions, whereas oxadiazon, tiafenacil, and saflufenacil showed substantial loss of potency. Greenhouse dose response experiments confirmed strong fendioxypyracil efficacy, with susceptible and G399A populations controlled at <3 g ai/ha, while dG210 and R128G populations showed only moderate shifts in sensitivity but remained effectively controlled at the recommended rate. Transgenic Arabidopsis thaliana expressing resistant PPX2 alleles exhibited faster and more severe injury with fendioxypyracil compared to saflufenacil. Field trials conducted in a PPO resistant Amaranthus palmeri population demonstrated that fendioxypyracil provided consistent weed control and density reduction, matching the performance of trifludimoxazin and saflufenacil while exceeding that of fomesafen. Conclusion: Fendioxypyracil provides robust and broad-spectrum activity against PPO resistant Amaranthus populations and target mutant enzymes, maintaining efficacy across diverse mutation backgrounds. These results demonstrate its potential as an effective tool for managing PPO inhibitor resistance and sustaining weed control in row-crop production systems.
]]></description>
<dc:creator><![CDATA[ Porri, A., Lerchl, J., Meiners, I., Parra, L., Asher, S., Stilgenbauer, S., Norsworthy, J., Sudhaka, S. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.23.746358</dc:identifier>
<dc:title><![CDATA[Fendioxypyracil Exhibits Potent Inhibition of PPO-Resistant Mutant Enzymes and Robust Activity Against PPO-Resistant Amaranthus]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.23.745486v1?rss=1">
<title>
<![CDATA[
Predicting Protein-RNA Binding Affinity Changes via Spatial Coupling-Aware State Space Modeling 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.23.745486v1?rss=1
</link>
<description><![CDATA[
Accurately predicting the effects of mutations on protein-RNA binding is crucial for elucidating disease mechanisms. Yet, exhaustively exploring the space of all possible variants is prohibitively expensive, motivating computational methods that can quantify mutation-induced changes in binding affinity (aka {Delta}{Delta}G) accurately and efficiently. We present iSCALE, an interpretable and generalizable deep learning method that adopts an implicit Spatial Coupling-Aware Ligand Encoding strategy to predict mutation-induced binding affinity changes. By injecting this implicit multiscale encoding scheme into a bidirectional state space modeling architecture, iSCALE learns a generalizable multiscale coupling pattern that achieves superior performances on not only the protein-RNA binding {Delta}{Delta}G, but also the protein stability {Delta}{Delta}G and protein-protein binding {Delta}{Delta}G predictions. Detailed analyses demonstrate that the model attention scores align well with structural characteristics. In addition, iSCALE shows good discriminative ability when predicting close samples such as complexes of same mutation but with different ligands or the same complex but with different mutation sites. In summary, iSCALE serves as an effective in silico tool for large-scale protein-RNA binding {Delta}{Delta}G prediction, which pushes the border of understanding in mutation-induced pathological outcomes.
]]></description>
<dc:creator><![CDATA[ Chen, R., Huang, X., Jiang, H., Ma, W., Bi, X., Wei, Z., Nie, J., Zhang, S. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.23.745486</dc:identifier>
<dc:title><![CDATA[Predicting Protein-RNA Binding Affinity Changes via Spatial Coupling-Aware State Space Modeling]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746034v1?rss=1">
<title>
<![CDATA[
A chromosome-level assembly of an aquatic passerine bird, the northern white-throated dipper, Cinclus cinclus cinclus (Linnaeus, 1758) 
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</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746034v1?rss=1
</link>
<description><![CDATA[
We present a chromosome-level genome assembly of a female Norwegian white-throated dipper (Cinclus cinclus cinclus) generated using Oxford Nanopore Technologies (ONT) long reads and Hi-C scaffolding. The assembly comprises two pseudo-haplotypes, hap1 (1186 Mb) and hap2 (1115 Mb), with 96.7% and 94.4% of sequences assigned to chromosome-scale scaffolds, respectively. Both pseudo-haplotypes contain 40 autosomes, with the Z and W sex chromosomes assigned to hap1. Compared with the PacBio HiFi-based C. c. gularis reference assembly bCinCin1.1.pri, which contains 38 autosomes, sequence represented as a single dot-chromosome (chr 36) is resolved into three distinct dot-chromosomes (chr 36, 39, and 40), a configuration supported by Hi-C contact patterns. BUSCO completeness was high for hap1 (99.2%) and hap2 (95.0%), with 19,003 and 17,746 predicted protein-coding genes, respectively. Compared with the HiFi-based C. c. gularis reference and HiFi-based assemblies generated from the same individual, the ONT-derived assemblies were substantially less fragmented and recovered more sequence from the smallest chromosomes. Synteny was otherwise largely conserved between subspecies. HiFi depletion increased strongly from macrochromosomes to micro- and dot-chromosomes, and HiFi-depleted regions were enriched for repeats and predicted non-B-DNA-associated features, particularly G-quadruplexes and direct repeats, whereas ONT coverage remained comparatively stable. These results show that conventional genome-wide assembly metrics can obscure substantial differences in the recovery of repeat-rich avian dot-chromosomes and highlight the value of chromosome-aware evaluation and ONT sequencing for recovering these regions.
]]></description>
<dc:creator><![CDATA[ Strand, M. A., Toerresen, O. K., Skage, M., Ferrari, G., Tooming-Klunderud, A., Johnsen, A., Jakobsen, K. S. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746034</dc:identifier>
<dc:title><![CDATA[A chromosome-level assembly of an aquatic passerine bird, the northern white-throated dipper, Cinclus cinclus cinclus (Linnaeus, 1758)]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.746067v1?rss=1">
<title>
<![CDATA[
Genome sequencing reveals novel pathogenic deep-intronic PCDH15 variants, amenable to antisense oligonucleotide-based splice correction 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.746067v1?rss=1
</link>
<description><![CDATA[
Despite substantial advances in diagnostic testing, 10-15% of Usher syndrome patients remain without a genetic diagnosis, having significant implications for genetic counseling and potential future therapeutic interventions. In this study, genome sequencing data from probands clinically presenting with Usher syndrome were analyzed. Two novel deep-intronic variants were identified in PCDH15, c.3983+3635A>G and c.3123-1728A>G, in two independent patients. Both deep-intronic variants were classified as likely pathogenic and predicted to alter PCDH15 pre-mRNA splicing. Using a minigene splice assay and iPSC-derived photoreceptor precursor cells from patients, we confirmed that both variants lead to the inclusion of a pseudoexon in the PCDH15 transcript introducing a stop codon and subsequent premature termination of protein translation. We designed and evaluated antisense oligonucleotides (ASOs) with the purpose of redirecting aberrant pre-mRNA splicing caused by both deep-intronic variants. For both variants, designed ASOs were successful in restoring normal splicing patterns, highlighting their potential as a future therapeutic intervention strategy to halt the progression of retinitis pigmentosa caused by these novel variants. Overall, these findings contribute to the understanding of Usher syndrome caused by deep-intronic pathogenic variants in PCDH15 and describe for the first time the use of an ASO-mediated splice correction strategy for individuals diagnosed with these variants.
]]></description>
<dc:creator><![CDATA[ Rodenburg, K., Fenwick, L., Pennings, R., Haer-Wigman, L., Ben-Yosef, T., van Erp, F., Reurink, J., Gilissen, C., van den Born, L. I., Cremers, F. P. M., Cohen, Y., Yntema, H., de Vrieze, E., Kremer, H., de Bruijn, S. E., Collin, R. W. J., Roosing, S., van Wijk, E. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.746067</dc:identifier>
<dc:title><![CDATA[Genome sequencing reveals novel pathogenic deep-intronic PCDH15 variants, amenable to antisense oligonucleotide-based splice correction]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.21.746284v1?rss=1">
<title>
<![CDATA[
Microenvironment-informed inference of transcriptional progression geometry 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.21.746284v1?rss=1
</link>
<description><![CDATA[
We present BIOCURRENT, a causal inference framework that reconstructs donor-specific pseudotime geometry in transcriptomic data. By modeling gene expression as a function of baseline characteristics, microenvironmental context, and latent pseudotime, BIOCURRENT enables comparison of compressed or expanded progression intervals across transcriptional state transitions. We introduce $DeltaDelta T$, a geometry-based estimator that quantifies differences in pseudotime intervals across conditions, enabling evaluation of changes in pseudotime intervals under hypothetical modulation of microenvironmental programs. Applications to thymic T-cell developmental lineages and to COVID-19 immune dysregulation reveal condition- and donor-specific distortions of progression intervals. Counterfactual simulation links microenvironmental context to changes in specific intracellular state transition intervals. By localizing deviations in pseudotime geometry, BIOCURRENT identifies whether shifts in transcriptomic programs emerge early or later along transcriptomic coordinates and reveals upstream programs associated with these distortions. Such localization supports transcriptional stage-aware mechanistic hypotheses and suggests candidate intervention checkpoints in complex biological systems.
]]></description>
<dc:creator><![CDATA[ Kobara, S., Rahman, S. A., Ribeiro, S. P., Coopersmith, C. M., Kamaleswaran, R. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.21.746284</dc:identifier>
<dc:title><![CDATA[Microenvironment-informed inference of transcriptional progression geometry]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.24.746601v1?rss=1">
<title>
<![CDATA[
CodonMamba: a foundation model for programmable mRNA coding sequence design 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.24.746601v1?rss=1
</link>
<description><![CDATA[
Although mRNA codon language models provide a generalizable framework for biological sequence design, effective CDS design requires both a learned sequence design space that captures biological constraints and context-configurable design preferences. Here we present CodonMamba, a codon language model framework for mRNA prediction and programmable CDS design. Pretrained on large-scale coding-sequence corpora, CodonMamba achieved state-of-the-art performance across a comprehensive benchmark of 12 mRNA prediction tasks, ranking first on 10 of 12 tasks. Furthermore, CodonMamba establishes a programmable CDS design framework, transforming codon optimization from a process dependent on preferences embedded during model training into an inference-time steerable generation framework. By introducing user-specified codon usage priors during generation, CodonMamba enables inference-time steering toward host- or application-specific codon preferences without retraining. In design experiments, CodonMamba enabled coordinated optimization over multiple design-relevant sequence properties and demonstrated programmable cross-host CDS retargeting through inference-time prior switching, while preserving most model-derived codon choices. Together, these results establish CodonMamba as a programmable foundation model framework for CDS design, enabling context-specific mRNA sequence engineering and highlighting a promising direction for precise mRNA design using foundation models.
]]></description>
<dc:creator><![CDATA[ Lang, M., Fang, X., Wang, Z., Chen, M., Cheng, Z., Zhu, X., Tam, K. Y., Zhang, J., Li, X. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.24.746601</dc:identifier>
<dc:title><![CDATA[CodonMamba: a foundation model for programmable mRNA coding sequence design]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
<item rdf:about="https://www.biorxiv.org/content/10.64898/2026.08.20.745474v1?rss=1">
<title>
<![CDATA[
RADF: Reference-Anchored Dynamic Flow for Spatial Perturbation Profile Completion 
]]>
</title>
<link>
https://www.biorxiv.org/content/10.64898/2026.08.20.745474v1?rss=1
</link>
<description><![CDATA[
Spatial perturbation profiling is becoming an important tool in functional genomics because it reveals how genetic interventions reshape transcription within intact tissue contexts. However, destructive readout and limited screening capacity leave many perturbation-by-location response profiles unmeasured, motivating the task of spatial perturbation profile completion. The task is to infer the held-out response population at query locations from reported profiles of the same perturbation. Existing methods either generate responses de novo or reuse these profiles without spatial adaptation. These strategies make it difficult to preserve empirical population structure while modeling location-specific variation. Our key insight is that the reported population already defines an empirical response distribution for the target perturbation. To exploit this empirical support, we propose Reference-Anchored Dynamic Flow (RADF), which employs a Sinkhorn-balanced decoder to construct a population-valued anchor in which every reference profile has equal total contribution. Additionally, a bounded dynamic relational flow is used to recompute spatial relations from the evolving expression state and query geometry. Across diverse spatial contexts, RADF reduces macro E-distance by 70.6% compared with an existing state-of-the-art spatial method, highlighting the advantage of combining a reference-supported population anchor with bounded, location-dependent refinement. Code will be made publicly available upon acceptance.
]]></description>
<dc:creator><![CDATA[ Cai, H., Wang, H., Chen, J., Xue, Z., Sheng, X., Zhang, T. ]]></dc:creator>
<dc:date>2026-08-24</dc:date>
<dc:identifier>doi:10.64898/2026.08.20.745474</dc:identifier>
<dc:title><![CDATA[RADF: Reference-Anchored Dynamic Flow for Spatial Perturbation Profile Completion]]></dc:title>
<dc:publisher>Cold Spring Harbor Laboratory</dc:publisher>
<prism:publicationDate>2026-08-24</prism:publicationDate>
<prism:section></prism:section>
</item>
</rdf:RDF>
