bioRxiv : the preprint server for biology最新文献

{"title":"DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.","authors":"Evelyn D Harris, Morgan McGovern, Sara Pernikoff, Ren Ikeda, Lea Kipnis, William Hannon, Elizabeth B Sobolik, Matthew Gray, Alexander L Greninger, Sijia He, Chen-Ni Chin, Tong-Ming Fu, Marie Pancera, Jim Boonyaratanakornkit","doi":"10.1101/2025.06.09.657676","DOIUrl":"10.1101/2025.06.09.657676","url":null,"abstract":"<p><p>Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144644696","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":"Variation in social feeding behavior and interactions among Caenorhabditis nematodes.","authors":"Dustin Haskell, Jhelaine Palo, Reina F H Eugene, Christopher Ryan Livingston Large, Michael P Hart","doi":"10.1101/2025.06.26.661336","DOIUrl":"10.1101/2025.06.26.661336","url":null,"abstract":"<p><p>The ability to respond to complex stimuli and environmental cues is essential for organisms to survive and reproduce. Responding to a wide range of stimuli requires a neuronal network that can integrate cues and execute behavioral responses. Evolution of behaviors occurs ubiquitously in most established ecological niches, especially among closely related species. To uncover the genetic and neuronal drivers of evolving behaviors, we have taken advantage of the large and ancient divergence in the Caenorhabditis clade of nematodes to ask how different Caenorhabditis nematodes respond to environmental stimuli and are behavioral traits shared or distinct. Here, we assayed foraging behaviors of twelve members of the Caenorhabditis clade, including members of both the elegans and japonica supergroup, and the basal taxon C. monodelphis. For each species, we analyzed social feeding and bordering behaviors, which are well characterized in C. elegans. These behaviors are the functional readout of complex sensory integration of multiple sensory cues including pheromones, touch, O2/CO2 concentration, and attractive and noxious stimuli. We hypothesized that the evolutionary divergence between species would correlate to divergence in these behaviors. We observed wide variation in aggregate social feeding and bordering behaviors of hermaphrodite and female animals, but the variation did not correlate with evolutionary relatedness of the species. Combination of both sexes of individual species increased aggregation behavior of select species that had lower levels of aggregation in single sex assays. Combination of C. elegans with a second species in the same assay altered aggregate feeding behavior of C. elegans in a species-specific manner. Intraspecies and interspecies interactions can modify behavioral paradigms. Overall, we find that foraging and social feeding behaviors vary widely across Caenorhabditis species, likely due to species-specific responses and integration of context sensory cues.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12262687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144645117","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":"SUZ12-Nucleic Acid Interactions Constrain PRC2 Activity to Maintain Targeted Gene Silencing Essential to Diffuse Midline Glioma.","authors":"Tyler J Reich, Paul A Clark, Audrey Baguette, Joanna K Lempiainen, Caterina Russo, Andrew Q Rashoff, Truman J Do, Benjamin A Garcia, Claudia L Kleinman, Nada Jabado, Zachary S Morris, Peter W Lewis","doi":"10.1101/2025.07.18.665585","DOIUrl":"https://doi.org/10.1101/2025.07.18.665585","url":null,"abstract":"<p><p>Polycomb Repressive Complex 2 (PRC2) mediates transcriptional silencing through trimethylation of histone H3 at lysine 27 (H3K27me3), an epigenetic modification critical for development and frequently altered in cancer. Pediatric diffuse midline gliomas (DMGs) bearing the histone H3 K27M mutation exhibit global loss of H3K27me3 due to dominant inhibition of PRC2 by the mutant histone. Despite widespread hypomethylation, focal retention of H3K27me3 persists, and tumor cells maintain dependency on residual PRC2 activity for proliferation. The molecular basis underlying this residual enzymatic function and its regulation remain poorly defined. To address this mechanism, we investigated the role of SUZ12, the architectural core of PRC2 that facilitates interactions with accessory subunits. We identified the SUZ12 N-terminal region as a regulatory domain that constrains PRC2 catalytic activity through transient interactions with nucleic acids, thereby limiting non-specific chromatin engagement. Expression of a truncated SUZ12 variant retaining the catalytic VEFS domain, but lacking the nucleic acid-binding regulatory elements, led to widespread H3K27 hypermethylation, displacement of canonical PRC1 complexes, disruption of chromatin architecture, and impaired H3 K27M glioma cell growth <i>in vitro</i> and <i>in vivo</i> . Biochemical analyses revealed a SUZ12 N-terminal domain that modulates PRC2 activity by promoting non-productive binding to nucleic acids, thus establishing a kinetic equilibrium essential for precise chromatin targeting. These findings redefine Polycomb specificity as a dynamic equilibrium between productive nucleosomal engagement and non-productive nucleic acid interactions, providing critical insights into PRC2 regulation and highlighting potential therapeutic vulnerabilities in PRC2-dependent cancers.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12288949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144710483","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":"Genome-wide analysis reveals pathways important for the development and maturation of excitatory synaptic connections to GABAergic neurons.","authors":"Devyn B Oliver, Shankar Ramachandran, Kasturi Biswas, Claire Benard, Maria Doitsidou, Hailey McKillop, Noelia Genao, Michele L Lemons, Michael M Francis","doi":"10.1101/2025.07.05.663213","DOIUrl":"10.1101/2025.07.05.663213","url":null,"abstract":"<p><p>A high degree of cell and circuit-specific regulation has presented challenges for efforts to precisely define molecular mechanisms controlling synapse formation and maturation. Here, we pursue an unbiased forward genetic approach to identify C. elegans genes involved in the formation and maturation of cholinergic synaptic connections with GABAergic motor neurons as indicated by the distribution of GFP-tagged postsynaptic AChRs in GABAergic dendrites. We identified mutations in 3 genes that identify key processes in synapse/circuit maturation: postsynaptic receptor assembly, cargo trafficking, and synapse structural organization. Mutation of the RUN domain (RPIP8, UNC-14, and NESCA) cargo adaptor unc-14 dramatically impacted both dendritic spines and overall GABAergic neuron morphology. In contrast, mutation of the nicotinic acetylcholine alpha subunit unc-63 caused a failure in AChR assembly in GABAergic neurons but did not significantly alter dendritic spine structure or abundance. Notably, specific expression of wild type unc-14 cDNA in either GABAergic neurons or presynaptic cholinergic neurons was not sufficient to rescue the unc-14 mutant phenotype while pan neuronal expression provided significant rescue, indicating that disruptions in GABAergic neuron morphology arise from compound effects. Finally, we obtained a mutation in the Liprin-α; synaptic scaffold syd-2 that produces a stop codon in a C-terminal SAM domain and has severe effects on dendritic spines and AChR localization. Our unbiased strategy identified key genes that implicate three distinct cellular processes important for synapse/circuit development and maturation. The identification of these genes from our screen highlights how mechanisms for receptor assembly, cargo trafficking and synapse structural organization each contribute to circuit connectivity.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593502","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":"An Enhancement of Extrachromosomal Circular DNA Enrichment and Amplification to Address the Extreme Low Overlap Between Replicates.","authors":"Charles M Burnham, Alongkorn Kurilung, Visanu Wanchai, Birgitte Regenberg, Jesus Delgado-Calle, Alexei G Basnakian, Intawat Nookaew","doi":"10.1101/2025.06.28.662146","DOIUrl":"10.1101/2025.06.28.662146","url":null,"abstract":"<p><p>Extrachromosomal circular DNA (eccDNA) of chromosomal origin is commonly present in all eukaryotic organisms and tissue tested so far. EccDNA populations exhibit immense diversity and a characteristically low degree of overlap between samples, suggesting low inherence of eccDNA between cells or a deficiency the methods by which eccDNA is detected. This study revisits the Circle-seq approach for enrichment of eccDNA to address if these limitations, hypothesizing that experimental procedures significantly contribute to the observed low eccDNA overlap. We optimized the protocol by reducing the time. Linear DNA is digested by increasing exonuclease V activity. We employed CRISPR-Cas9 for mitochondrial linearization, which proved superior to restriction enzymes. A key finding is the critical role of random hexamer primer concentration and genomic DNA input in Rolling Circle Amplification (RCA) for generating high-quality long amplicons from eccDNA (concatemeric tandem copy, CTC), essential for confident de novo eccDNA construction from long-read sequencing data. Lower primer concentrations substantially increased the percentage of CTC-derived eccDNA and improved the overlap of identified eccDNAs in technical replicates. Applying this revisited approach to human myeloma and breast cancer cell lines, as well as xenograft models, demonstrated that the optimized conditions enhanced the overlap of detected eccDNA up to over 50% overlap which substantially improved over previous studies (less than 1%). Additionally, the oncogenic signature of eccDNAs can be identified across all replicates. These findings provide guidelines for developing standardized procedures for eccDNA profiling, advancing our understanding of eccDNA biology and its potential clinical applications.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651804","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":"Targeting Siglec-10/α3β1 Integrin Interactions Enhances Macrophage-Mediated Phagocytosis of Pancreatic Cancer.","authors":"Pratima Saini, Gauri Mirji, S M Shamsul Islam, Lacy M Simons, Sajad Ahmad Bhat, Amanda P Bonfanti, Kar Muthumani, Priyesh Agrawal, Joel Cassel, Hsin-Yao Tang, Hiroaki Tateno, Rugang Zhang, Judd F Hultquist, Rahul Shinde, Mohamed Abdel-Mohsen","doi":"10.1101/2025.05.06.652455","DOIUrl":"10.1101/2025.05.06.652455","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) in the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME) exhibit immunosuppressive phenotypes and impaired phagocytic activity, facilitating tumor progression and immune evasion. Here, we identify integrin α3β1, composed of ITGA3 and ITGB1 subunits, as a sialylated glycoprotein ligand for Siglec-10, an inhibitory glyco-immune checkpoint receptor highly expressed on TAMs in PDAC. The interaction between Siglec-10 on TAMs and α3β1 on PDAC cells suppresses macrophage-mediated phagocytosis, thereby promoting immune evasion. Consistently, disrupting Siglec-10 interactions with monoclonal antibodies significantly enhances macrophage phagocytosis of PDAC cells and alleviates myeloid cell-mediated inhibition of T cell proliferation and activation in vitro. In both a PDAC xenograft mouse model engrafted with human macrophages and a human Siglec-10 transgenic mouse model, targeting Siglec-10 with monoclonal antibodies reduces PDAC tumor growth. These findings suggest that Siglec-10 interactions are key mediators of TAM-driven immune evasion in PDAC and highlight the therapeutic potential of targeting these interactions to restore anti-tumor immunity.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144629145","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":"GatorST: A Versatile Contrastive Meta-Learning Framework for Spatial Transcriptomic Data Analysis.","authors":"Song Wang, Yuxi Liu, Zhenhao Zhang, Qin Ma, Qianqian Song, Jiang Bian","doi":"10.1101/2025.07.01.662625","DOIUrl":"10.1101/2025.07.01.662625","url":null,"abstract":"<p><strong>Introduction: </strong>Recent advances in spatial transcriptomics (ST) technologies have revolutionized our understanding of cellular functions by providing gene expression profiles with rich spatial context. Effectively learning spatial representations is crucial for downstream analyses and requires robust integration of spatial information with transcriptomic data. While existing methods have shown promise, they often fail to adequately capture both local (neighbor-level) and global (tissue-wide) spatial contexts. Moreover, they tend to rely heavily on augmentation strategies, which can introduce noise and instability.</p><p><strong>Objectives: </strong>This study aims to introduce and demonstrate a novel, versatile framework called GatorST, which explicitly combines graph-based modeling with advanced learning strategies to generate spatially informed representations of ST data. GatorST is designed to improve various downstream tasks, including identification of spatial domains, gene expression imputation, batch effect removal, and trajectory inference.</p><p><strong>Methods: </strong>GatorST constructs a spot-spot graph by connecting each node to its k nearest spatial neighbors and extracts two-hop neighborhood subgraphs to capture local context. At the global level, gene expression profiles are clustered using soft K-means to generate pseudo-labels, which serve as weak supervision signals within a contrastive learning framework. This process encourages the alignment of embeddings with shared pseudo-labels while separating those with different labels. GatorST further adopts an episodic training strategy inspired by meta-learning, wherein each episode consists of a support set for contrastive optimization and a disjoint query set for embedding classification, guided by the pseudo-labeled data. This design enables the model to classify unseen samples based on learned embeddings, thereby enhancing its generalization to new spatial contexts.</p><p><strong>Results: </strong>Comprehensive comparisons with fifteen state-of-the-art methods across fourteen spatial transcriptomics datasets demonstrate that GatorST consistently achieves superior performance in identifying spatial domains, imputing gene expressions, and removing batch effects. The results showcase the versatility and strong generalization capabilities of GatorST across diverse tissue types and experimental settings.</p><p><strong>Conclusion: </strong>GatorST effectively integrates spatial topology and global gene expression through graph-based modeling, pseudo-labeling, and contrastive meta-learning. This framework generates biologically meaningful representations and significantly improves key downstream tasks, including spatial domain identification, gene expression imputation, batch effect removal, and trajectory inference.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144651857","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":"Antibiotic treatment modulates <i>Escherichia coli</i> -derived bacterial extracellular vesicle (BEV) production and their capacity to upregulate ICAM-1 in human endothelial cells.","authors":"Louis P Widom, Panteha Torabian, Abigail C Wojehowski, Sina Ghaemmaghami, Lea V Michel, Thomas R Gaborski","doi":"10.1101/2025.05.12.653517","DOIUrl":"10.1101/2025.05.12.653517","url":null,"abstract":"<p><p>Antibiotic treatment is often necessary to eliminate life-threatening bacterial infections. However, these treatments can alter production of bacterial extracellular vesicles (BEVs), which often contain pro-inflammatory biomolecules. In this study, we examined how the clinically-relevant antibiotics meropenem, tobramycin, and ciprofloxacin impacted BEV production from a urinary tract infection-associated <i>Escherichia coli</i> strain (CFT073 [WAM2267]) and a meningitis-associated strain (K1 RS218). BEVs from both strains caused a dose-dependent increase in expression of intercellular adhesion molecule-1 (ICAM-1) in human umbilical vein endothelial cells, priming the endothelium for interactions with immune cells. Blockade of toll-like receptor 4 revealed that this receptor was responsible for BEV-endothelial interactions. Treatment with meropenem, a β-lactam antibiotic, increased production of BEVs from strain K1 RS218. Furthermore, meropenem treatment caused strain CFT073 [WAM2267] to produce BEVs with heightened stimulatory capacity, possibly by amplifying the content of lipoprotein Lpp in these BEVs as measured by mass spectrometry. To our knowledge, this is the first study examining the interplay between antibiotic treatment and the effects of the resulting BEVs on endothelial ICAM-1 expression. Our results indicate treatment risks of certain antibiotics against specific strains of <i>E. coli</i> and could help identify therapeutic targets to reduce BEV-mediated endothelial stimulation during infection.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12132173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144218186","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":"Identification of antibody-drug conjugate payloads which are substrates of ATP-binding cassette drug efflux transporters.","authors":"Jacob S Roth, Hui Guo, Lu Chen, Min Shen, Omotola Gbadegesin, Robert W Robey, Michael M Gottesman, Matthew D Hall","doi":"10.1101/2025.05.22.651305","DOIUrl":"10.1101/2025.05.22.651305","url":null,"abstract":"<p><strong>Aim: </strong>Antibody-drug conjugates (ADCs) feature an antibody recognizing a specific protein joined to a potent toxic payload. Numerous antibody-drug conjugates have received FDA approval; however, clinical resistance arises. Resistance mechanisms include decreased expression or mutation of the antibody target, impaired payload release, or increased expression of ATP-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC multidrug transporters with ADC payloads.</p><p><strong>Methods: </strong>We performed a high-throughput screen with 27 common ADC payloads using cells lines expressing ABC transporters P-glycoprotein (P-gp, encoded by <i>ABCB1</i> ) or ABCG2 (encoded by <i>ABCG2</i> ). Confirmatory assays were also performed using cells transfected to express P-gp, ABCG2, or MRP1 (encoded by <i>ABCC1</i> ).</p><p><strong>Results: </strong>Several commonly used ADC payloads were substrates of P-gp, including calicheamicin gamma1, monomethyl auristatin E, DM1, and DM4. All the pyrrolobenzodiazepines tested-SJG136, SGD-1882, SG2057, and SG3199-were substrates of P-gp, ABCG2, and MRP1. The modified anthracyclines nemorubicin and its metabolite PNU-159682 were poorly transported by both ABCB1 and ABCG2 and displayed nanomolar to picomolar toxicity. Further, we found that the efficacy of the FDA-approved ADC mirvetuximab soravtansine, with DM4 as the toxic payload, was decreased in cell lines expressing P-gp. Duocarmycin DM and PNU-159682 were exquisitely toxic to a panel of 99 cancer cell lines of varying origins.</p><p><strong>Conclusion: </strong>Several commonly used ADC payloads can be transported by ABC transporters, potentially leading to transporter-mediated drug resistance in patients. Future ADCs should be developed using payloads that are not ABC transporter substrates.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12154920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277562","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":"Persistent cortical excitatory neuron dysregulation in adult <i>Chd8</i> haploinsufficient mice.","authors":"Cesar P Canales, Stephanie A Lozano, Nicholas A Frost, Karol Cichewicz, Wellington Amaral, Nicolas Seban, Ethan Fenton, Ayanna Wade, Nickolas Chu, Emily Smith, Cory Ardekani, Samuel Frank, Jeffrey Bennett, Pierre Lavenex, Aspen Kopley-Smith, Darlene Rahbarian, Melissa Corea, Daniela Perla, Liam Davis, Jiyuan Zhu, Rebecca Ortiz, Paris Beauregard, Sarah Morse, Jacob Baker, Jingqi Sun, Boxuan Ma, Ju Lu, Vikaas S Sohal, David G Amaral, Yi Zuo, Alex S Nord","doi":"10.1101/2025.06.04.657776","DOIUrl":"10.1101/2025.06.04.657776","url":null,"abstract":"<p><p><i>CHD8</i> mutations cause autism spectrum disorder, cognitive deficits, and macrocephaly. <i>Chd8 ^+/-</i> mouse models exhibit macrocephaly and transcriptional pathology, with inconsistent findings regarding neurogenesis, neuron function, and behavior. Via stereology and single nucleus transcriptomics (snRNA-seq), we found increased <i>Chd8 ^+/-</i> cortical volume was not explained by increase in neuron number. Differential expression (DE) was present across cortical cell types, with excitatory neurons exhibiting high DE burden and shared and subclass-specific DE signatures. Bulk RNA-seq DE of constitutive <i>Chd8 ^+/-</i> and conditional <i>Camk2a-Cre Chd8 ^+/-</i> mice identified shared transcriptional pathology. DE in synaptosomal versus nuclear mRNA identified overlapping DEGs, but also significant differences and exaggerated synaptosomal changes. Building on DE findings implicating glutamatergic neurons, we found <i>Chd8 ^+/-</i> mice exhibited altered excitatory neuron spine density and dynamics, decreased GCaMP activity correlation, and sleep perturbation. Thus, <i>Chd8</i> haploinsufficiency causes lasting excitatory neuron dysfunction, perturbs RNA regulation beyond transcription, and impacts neuronal properties, cortical microcircuits, and behavior.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12157415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277781","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}