bioRxiv : the preprint server for biology最新文献

{"title":"VIProDesign: Viral Protein Panel Design for Highly Variable Viruses to Evaluate Immune Responses and Identify Broadly Neutralizing Antibodies.","authors":"Tatsiana Bylund, Mohammed El Anbari, Andrew Schaub, Tongqing Zhou, Reda Rawi","doi":"10.1101/2025.05.21.654924","DOIUrl":"https://doi.org/10.1101/2025.05.21.654924","url":null,"abstract":"<p><p>Highly mutable viruses continuously evolve, with some posing major pandemic risks. However, standardized neutralization assays and up-to-date viral panels are often lacking, limiting evaluation of immunogens and identification of broadly neutralizing antibodies. Closing these gaps is essential for guiding effective countermeasure development. In this study, we present Viral Protein Panel Design (VIProDesign), a computational tool for designing viral protein panels that address the high sequence diversity of rapidly evolving viruses. VIProDesign uses the Partitioning Around Medoids (PAM) algorithm to select representative strains and applies the elbow-point method based on cumulative Shannon entropy to balance diversity and panel size. We used VIProDesign to generate optimized panels for Betacoronavirus, human immunodeficiency virus-1 (HIV-1), Influenza virus, Norovirus, and Lassa virus. The tool also supports customizable panel sizes, making it suitable for both resource-limited contexts and early-stage research. This flexible approach streamlines viral panel design across diverse pathogens. Although VIProDesign was originally developed for viral proteins, its underlying framework is broadly applicable to the selection of representative protein panels across diverse taxa, including bacterial species, toxins, and other biologically relevant protein families.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190178/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unsupervised discovery and predictive sensorimotor transformation of spider prey capture through active vibration sensing.","authors":"Hsin-Yi Hung, Abel Corver, Andrew Gordus","doi":"10.1101/2025.06.08.658484","DOIUrl":"10.1101/2025.06.08.658484","url":null,"abstract":"<p><p>Animals flexibly adjust posture and movement in response to vibrational sensory input to extract information from dynamic environments. While sensorimotor transformations have been extensively studied in visual and somatosensory systems, their structure remains poorly understood in substrate-borne vibration sensing. Here, we combine high-resolution web vibration recordings with fine-scale behavioral tracking in the orb-weaving spider <i>Uloborus diversus</i> to dissect the sensorimotor basis of prey capture. Using unsupervised modeling, we identified discrete behavioral states that structure spider capture sequences, achieving over 83% classification accuracy. We then developed a predictive framework combining a linear-filtered generalized linear model (GLM) with a hidden Markov model (HMM) that robustly forecasts behavioral transitions across diverse prey vibration contexts. Notably, spiders exhibit context-dependent motor transitions-such as crouching and shaking-following decreases in prey vibrational power, consistent with active sensing behaviors that enhance signal detection. Furthermore, spiders reliably turn toward the web radius exhibiting the highest vibration amplitude during prey localization, demonstrating that amplitude alone predicts turning direction. These findings reveal a structured, predictive sensorimotor transformation linking external vibration cues to internal behavioral states. Our results highlight general principles of active sensing and closed-loop control in non-visual invertebrate systems, with broader implications for sensorimotor integration across species.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157624/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative Analysis of Deep Learning Models for Predicting Causative Regulatory Variants.","authors":"Gaetano Manzo, Kathryn Borkowski, Ivan Ovcharenko","doi":"10.1101/2025.05.19.654920","DOIUrl":"https://doi.org/10.1101/2025.05.19.654920","url":null,"abstract":"<p><strong>Motivation: </strong>Genome-wide association studies (GWAS) have identified numerous noncoding variants associated with complex human diseases, disorders, and traits. However, resolving the uncertainty between GWAS association and causality remains a significant challenge. The small subset of noncoding GWAS variants with causative effects on gene regulatory elements can only be detected through accurate methods that assess the impact of DNA sequence variation on gene regulatory activity. Deep learning models, such as those based on Convolutional Neural Networks (CNNs) and transformers, have gained prominence in predicting the regulatory effects of genetic variants, particularly in enhancers, by learning patterns from genomic and epigenomic data. Despite their potential, selecting the most suitable model is hindered by the lack of standardized benchmarks, consistent training conditions, and performance evaluation criteria in existing reviews.</p><p><strong>Results: </strong>This study evaluates state-of-the-art deep learning models for predicting the effects of genetic variants on enhancer activity using nine datasets stemming from MPRA, raQTL, and eQTL experiments, profiling the regulatory impact of 54,859 SNPs across four human cell lines. The results reveal that CNN models, such as TREDNet and SEI, consistently outperform other architectures in predicting the regulatory impact of single-nucleotide polymorphisms (SNPs). However, hybrid CNN-transformer models, such as Borzoi, display superior performance in identifying causal SNPs within a linkage disequilibrium block. While fine-tuning enhances the performance of transformer-based models, it remains insufficient to surpass CNN and hybrid models when evaluated under optimized conditions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190767/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extending Protein Language Models to a Viral Genomic Scale Using Biologically Induced Sparse Attention.","authors":"Thibaut Dejean, Barbra D Ferrell, William Harrigan, Zachary D Schreiber, Rajan Sawhney, K Eric Wommack, Shawn W Polson, Mahdi Belcaid","doi":"10.1101/2025.05.29.656907","DOIUrl":"10.1101/2025.05.29.656907","url":null,"abstract":"<p><p>The transformer architecture in deep learning has revolutionized protein sequence analysis. Recent advancements in protein language models have paved the way for significant progress across various domains, including protein function and structure prediction, multiple sequence alignments and mutation effect prediction. A protein language model is commonly trained on individual proteins, ignoring the interdependencies between sequences within a genome. However, biological understanding reveals that protein-protein interactions span entire genomic regions, underscoring the limitations of focusing solely on individual proteins. To address these limitations, we propose a novel approach that extends the context size of transformer models across the entire viral genome. By training on large genomic fragments, our method captures long-range interprotein interactions and encodes protein sequences with integrated information from distant proteins within the same genome, offering substantial benefits in various tasks. Viruses, with their densely packed genomes, minimal intergenic regions, and protein annotation challenges, are ideal candidates for genome-wide learning. We introduce a long-context protein language model, trained on entire viral genomes, leveraging a sparse attention mechanism based on protein-protein interactions. Our semi-supervised approach supports long sequences of up to 61,000 amino acids (aa). Our evaluations demonstrate that the resulting embeddings significantly surpass those generated by single-protein models and outperform alternative large-context architectures that rely on static masking or non-transformer frameworks.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12154925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gentamicin induction of the gonococcal <i>hicAB</i> toxin-antitoxin encoding system and impact on gene expression influencing biofilm formation and in vivo fitness in a strain-specific manner.","authors":"Concerta L Holley, Vijaya Dhulipala, Adriana Le Van, Jacqueline T Balthazar, Vincent J Oliver, Ann E Jerse, William M Shafer","doi":"10.1101/2025.06.11.659166","DOIUrl":"https://doi.org/10.1101/2025.06.11.659166","url":null,"abstract":"<p><p>The continued emergence of <i>Neisseria gonorrhoeae</i> (Ng) isolates resistant to first-line antibiotics has focused efforts on understanding how alternative therapies such as expanded use of gentamicin (Gen) might counteract this global public health problem. Focusing on Gen as a viable alternative antibiotic for treatment of gonorrheal infections, we used RNA-Seq to determine if sub-lethal levels of Gen might impact gonococci on a transcriptional level. We found that sub-lethal Gen levels altered expression of 23 genes in Ng strain FA19. Many of the differentially regulated genes were associated with known stress responses elaborated by Ng under different harmful conditions. We found that the transcripts of the <i>hicAB</i> operon, which encodes a putative HicA-HicB toxin-antitoxin system that is encoded by tandem genes with the prophage Ngo φ3, were increased in response to Gen. While loss of <i>hicAB</i> did not impact gonococcal susceptibility to a variety of antimicrobial agents or harmful environmental conditions it did reduce biofilm formation in Ng strains F62, FA1090, WHO X and CDC200 but not that of strain FA19. Further, in strain F62, but not FA19, loss of <i>hicAB</i> reduced the <i>in vivo</i> fitness of Ng during experimental lower genital tract infection of female mice. Further, we found that expression of <i>hicAB</i> can influence levels of the <i>norB</i> transcript, which encodes the nitrate reductase shown previously to be upregulated in gonococcal biofilms. We propose that sub-lethal Gen has the capacity to influence gonococcal pathogenesis through the action of the HicAB toxin-antitoxin system.</p><p><strong>Importance: </strong>During antibiotic treatment bacteria can be exposed to sub-lethal levels that could serve as a stress signal resulting in changes in gene expression. The continued emergence of multi-drug resistant strains of Ng has rekindled interest in expanded use of gentamicin (Gen) for treatment of gonorrheal infections. We report that sub-lethal levels of Gen can influence levels of Ng transcripts including that of the gonococcal <i>hicAB</i> -encoded toxin-antitoxin (TA) locus, which is embedded within an integrated prophage, While loss of this TA locus did not impact Ng susceptibility to Gen it reduced the biofilm forming ability of 4/5 Ng strains. Further, in an examined strain in this group we found that Ng fitness during experimental infection was negatively impacted. We propose that that levels of the <i>hicA-hicB</i> transcripts can be increased by sub-lethal levels of an antibiotic used in treatment of gonorrhea and that this could influence pathogenicity.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGR3 Deletion Rescues Developmental and Epileptic Encephalopathy in <i>Kcna1</i> -null Mice.","authors":"Arindam Ghosh Mazumder, Saifina Karedia, Nandani Adhyapak, Catharina Schimer, John Samuel Bass, Jessica L Kamen, Miranda J Jankovic, Qinglong Miao, Amelia L Gallitano, Alexander B Saltzman, Antrix Jain, Anna Malovannaya, Edward Glasscock, Isamu Aiba, Jeffrey L Noebels, Vaishnav Krishnan","doi":"10.1101/2025.06.07.658422","DOIUrl":"10.1101/2025.06.07.658422","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;KCNA1&lt;/i&gt; encodes the α-subunit of the voltage-gated potassium channel K &lt;sub&gt;V&lt;/sub&gt; 1.1. Mutations in K &lt;sub&gt;V&lt;/sub&gt; 1.1's pore domain result in developmental and epileptic encephalopathy (DEE), where early life seizures and a culprit lesion synergistically disrupt neurodevelopmental trajectories, resulting in intellectual disability that often presents with disturbances in sleep, sociability and sensory processing. Abnormalities in the subcellular localization of Kv1.1, via mutations in/autoantibodies against LGI1 and CNTNAP2, also give rise to syndromes of epilepsy and neuropsychiatric impairment. Mice with deletions of &lt;i&gt;Kcna1&lt;/i&gt; &lt;sup&gt;(\"-/-\")&lt;/sup&gt; display spontaneous seizures at 2-3 weeks of age and premature mortality. In this study, we applied instrumented home-cage monitoring to examine how aberrations in KCNA1 expression may result in pervasive alterations in spontaneous behavior. Compared to wildtype, &lt;i&gt;Kcna1&lt;/i&gt; &lt;sup&gt;-/-&lt;/sup&gt; mice displayed a robust multifaceted behavioral syndrome featuring marked nocturnal hyperactivity, insomnia, reduced sheltering, fragmented feeding/drinking rhythms, sensory over-responsivity and diminished wheel-running. In identical recordings, &lt;i&gt;Kcna1&lt;/i&gt; &lt;sup&gt;+/-&lt;/sup&gt; mice only displayed &lt;i&gt;increased&lt;/i&gt; sheltering, &lt;i&gt;Lgi1&lt;/i&gt; &lt;sup&gt;+/-&lt;/sup&gt; mice displayed mild insomnia and &lt;i&gt;Cntnap2&lt;/i&gt; &lt;sup&gt;-/-&lt;/sup&gt; mice showed home-cage &lt;i&gt;hypoactivity&lt;/i&gt; . &lt;i&gt;Kcna1&lt;/i&gt; loss in parvalbumin-positive interneurons (Pv-Cre) resulted in a subtle phenocopy, with mild insomnia accompanied by reduced sheltering behavior, while similar deletions in forebrain pyramidal neurons (Emx1-Cre) or dopaminergic neurons (DAT-Cre) were asymptomatic. Adult-onset conditional deletions of &lt;i&gt;Kcna1&lt;/i&gt; also produced only mild insomnia 6 weeks later. To survey the molecular landscape in &lt;i&gt;Kcna1&lt;/i&gt; &lt;sup&gt;-/-&lt;/sup&gt; mice, we conducted a mass spectrometry proteomic analysis of dissected hippocampal tissue (a predominant seizure onset zone and where astrogliosis is observed). This revealed significant upregulations in BDNF (brain-derived neurotrophic factor) and the immediate early transcription factor EGR3 (early growth response-3), which is necessary for the induction of BDNF following electroconvulsive seizures. Heterozygous or homozygous deletions of &lt;i&gt;Egr3&lt;/i&gt; in &lt;i&gt;Kcna1&lt;/i&gt; &lt;sup&gt;-/-&lt;/sup&gt; mice resulted in significant survival prolongation, a partial neurobehavioral rescue, and a significant improvement in the frequency of spontaneous seizures &lt;i&gt;and&lt;/i&gt; spreading depolarization events. These clinical improvements were associated with an amelioration of BDNF induction, hippocampal astrogliosis and proteomic disturbances. Together, these data illustrate how an ion channel that governs excitability at millisecond scales also shapes the spatiotemporal structure of spontaneous behavior at meso- or macroscopic time scales. Our results provide a model and a set of precision endpoints to understand how ictal and interictal features ","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12208490/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144532577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stalled translation on transcripts cleaved by RNase L activates signaling important for innate immunity.","authors":"Agnes Karasik, Grant D Jones, Nicholas R Guydosh","doi":"10.1101/2025.06.10.658914","DOIUrl":"https://doi.org/10.1101/2025.06.10.658914","url":null,"abstract":"<p><p>RNase L is an endonuclease that responds to infections by cleaving most host- and pathogen-derived single-stranded RNAs. This widespread RNA cleavage can lead to death of the infected cell via the ribotoxic stress response (RSR). An ongoing challenge is to understand how RNase L's endonuclease activity triggers cell death to benefit the host. To address this question, we used nanopore-based long-read sequencing to show that 3' mRNA fragments in the cell were not fully degraded after RNase L activation and that these fragments were translated by ribosomes. We further asked whether ribosomes on mRNA fragments stall when they reach 3' ends created by RNase L. We used ribosome profiling to capture footprints protected by these ribosomes, which can be identified by their short length (15-18 nt). We found that RNase L activation increased the number of stalled ribosomes at RNase L cleavage sites. Loss of the ribosome rescue factor PELO increased the number of short footprints derived from stalled ribosomes and augmented the RSR. Our work therefore establishes a role for fragmented mRNA in causing ribosome stalling that promotes innate immunity via the RSR.</p><p><strong>Highlights: </strong>Activation of RNase L leads to accumulation and translation of mRNA fragmentsRibosomes stall at the 3' end of the RNase L cleaved mRNA fragmentsPELO rescues ribosomes stalled due to RNase L activation.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12190479/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500141","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-species Standardised Cortico-Subcortical Tractography.","authors":"Stephania Assimopoulos, Shaun Warrington, Davide Folloni, Katherine Bryant, Wei Tang, Saad Jbabdi, Sarah Heilbronner, Rogier B Mars, Stamatios N Sotiropoulos","doi":"10.1101/2025.04.29.651254","DOIUrl":"10.1101/2025.04.29.651254","url":null,"abstract":"<p><p>Despite their importance for brain function, cortico-subcortical white matter tracts are under-represented in diffusion MRI tractography studies. Their non-invasive mapping is more challenging and less explored compared to other major cortico-cortical bundles. We introduce a set of standardised tractography protocols for delineating tracts between the cortex and various deep subcortical structures, including the caudate, putamen, amygdala, thalamus and hippocampus. To enable comparative studies, our protocols are designed for both human and macaque brains. We demonstrate how tractography reconstructions follow topographical principles obtained from tracers in the macaque and how these translate to humans. We show that the proposed protocols are robust against data quality and preserve aspects of individual variability stemming from family structure in humans. Lastly, we demonstrate the value of these species-matched protocols in mapping homologous grey matter regions in humans and macaques, both in cortex and subcortex.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dogme: A nextflow pipeline for reprocessing nanopore RNA and DNA modifications.","authors":"Elnaz Abdollahzadeh, Ali Mortazavi","doi":"10.1101/2025.06.04.657941","DOIUrl":"10.1101/2025.06.04.657941","url":null,"abstract":"<p><strong>Motivation: </strong>The Oxford Nanopore Technologies (ONT) platform allows for the direct detection of RNA and DNA modifications from unamplified nucleic acids, which is a significant advantage over other platforms. However, the rapid updates to ONT basecalling models and the evolving landscape of computational tools for modification detection bring about challenges for reproducible and standardized analyses. To address these challenges, we developed Dogme, which is a Nextflowbased workflow that automates the processing of ONT data, including basecalling, alignment, modification detection, and transcript quantification. Dogme automates the reprocessing of ONT POD5 files by integrating basecalling using Dorado, read mapping using minimap2 and subsequent analysis steps such as running modkit. The pipeline supports three major types of ONT sequencing data - direct RNA (dRNA), complementary DNA (cDNA), and genomic DNA (gDNA) - enabling comprehensive analyses across different library preparations. Dogme facilitates detection of diverse RNA modifications supported by Dorado such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), inosine, pseudouridine, 2'-Omethylation (Nm) and DNA methylation, while concurrently quantifying full-length transcript isoforms LR-Kallisto for transcript quantification for dRNA and cDNA.</p><p><strong>Results: </strong>We applied Dogme to three separate mouse C2C12 myoblast replicates using direct RNA sequencing on MinION flow cells. We detected an average of 147,879 m6A, 86,673 m5C, 21,242 inosine, 24,540 pseudouridine, and 83,841 2'- O-methylation sites per replicate with 96,581 m6A, 43,446 m5C, 8,825 inosine, 10,048 pseudouridine, and 30,157 2'-O- methylation sites detected in all three biological replicates. The pipeline produced reproducible modification profiles and transcript expression levels across replicates, demonstrating its utility for integrative long-read transcriptomic and epigenomic analyses.</p><p><strong>Availability: </strong>Dogme is implemented in Nextflow and is freely available under the MIT license at https://github.com/mortazavilab/dogme , with documentation provided for installation and usage.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The mechanism of ribosomal recruitment during translation initiation on Type 2 IRESs.","authors":"Sayan Bhattacharjee, Irina S Abaeva, Zuben P Brown, Yani Arhab, Hengameh Fallah, Christopher U T Hellen, Joachim Frank, Tatyana V Pestova","doi":"10.1101/2025.06.11.659010","DOIUrl":"https://doi.org/10.1101/2025.06.11.659010","url":null,"abstract":"<p><p>The encephalomyocarditis virus (EMCV) IRES and other Type 2 IRESs comprise domains H-L and specifically interact with eIF4G/eIF4A through their essential JK domain. However, the JK domain is not sufficient for IRES function, which also requires the preceding domain I of unknown function. To identify interactions that drive ribosomal recruitment of eIF4G/eIF4A-bound Type 2 IRESs, we determined the cryo-EM structure of 48S initiation complexes formed on the EMCV IRES. It revealed that the apical domain I cloverleaf contacts ribosomal proteins uS13 and uS19 via its Id subdomain and that the essential GNRA tetraloop in subdomain Ic interacts directly with the TψC domain of initiator tRNA. Functional assays supported the exceptional role of these interactions for initiation on this IRES. The strong conservation of primary and secondary structures of the apex of domain I among Type 2 IRESs suggests that the reported interactions are a common essential feature of them all.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12191231/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144500193","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}