bioRxiv : the preprint server for biology最新文献

{"title":"Contributions of distinct attention mechanisms to saccadic choices in a gamified, dynamic environment.","authors":"Evan A Kattner, Terrence R Stanford, Emilio Salinas","doi":"10.1101/2025.01.25.634882","DOIUrl":"10.1101/2025.01.25.634882","url":null,"abstract":"<p><p>Visuospatial attention is key for parsing visual information and selecting targets to look at. Based on regimented laboratory tasks, it is now well established that three types of mechanism determine when and where attention is deployed; these are stimulus-driven (exogenous), goal-driven (endogenous), and history-driven (reflecting recent experience). It is unclear, however, how these distinct attentional signals interact and contribute in visual environments that are more akin to natural scanning, when stimuli may change rapidly and no fixation requirements are imposed. Here, we investigate this via a gamified task in which participants (male and female) make continuous saccadic choices at a rapid pace --- and yet, perceptual performance can be accurately tracked over time as the choice process unfolds. The results reveal unequivocal markers of exogenous capture toward salient stimuli; endogenous guidance toward valuable targets and relevant locations; and history-driven effects, which produce large, involuntary modulations in processing capacity. Under dynamic conditions, success probability is dictated by temporally precise interplay between different forms of spatial attention, with recent history making a particularly prominent contribution.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785244/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143082941","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":"Neuroligin 3 highlights sexually dimorphic circuitry in Drosophila social spacing.","authors":"J W Robinson, A T Bechard, M R Evans, R Ataei, J Kurbaj, K Mosuro, J R Isaacson, S Pillay, D S Lin, A Sahota, J N de Belle, G I Robinson, A J Moehring, A F Simon","doi":"10.1101/2024.10.28.620699","DOIUrl":"10.1101/2024.10.28.620699","url":null,"abstract":"<p><p>In <i>Drosophila melanogaster</i>, the autism-related Neuroligin 3 (Nlg3) protein is a postsynaptic membrane protein important for synapse development and regulation, which plays a role in social spacing behaviour. Here, we report the localization of Nlg3 to the calyx of the mushroom bodies (MB), optic lobes (OL), and protocerebral bridge (PB). Using RNA interference, <i>nlg3</i> knockdown in each of these structures recapitulated the effect of knocking down it in all <i>nlg-3</i> neurons. Hyperactivation and silencing of these neurons in the MB, but not the PB, controls social space in males and females, while hyperactivating and silencing of all <i>nlg3</i>-expressing neurons, including within the MB, PB, and OL, regulates male and female social space. Knocking down neurotransmitter biosynthesis enzymes, which decreases the amount of neurotransmitter release, showed that reducing acetylcholine release from the MB decreased female social space, whereas knocking down any dopamine receptor in the MB increased male social space. Lastly, to investigate the sexually dimorphic effects on social spacing previously seen in <i>nlg3</i> mutants, we examined a subset of sexually dimorphic <i>fruitless</i>-expressing (<i>fru)P1</i> neurons known to regulate sexually dimorphic behaviours. Hyperactivation of those <i>fruP1</i> neurons decreased social space in both sexes, while silencing those <i>fruP1</i> neurons specifically increased male social space without affecting females. Our findings highlight a sex-specific social space neural circuitry that includes the OL, MB, and <i>fruP1</i> neurons, while uncovering the underlying basis of some of the sex differences in this behaviour.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12154865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144277694","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":"Ptbp1 is not required for retinal neurogenesis and cell fate specification.","authors":"Haley Appel, Rogger Carmen-Orozco, Clayton Santiago, Thanh Hoang, Seth Blackshaw","doi":"10.1101/2025.07.02.662808","DOIUrl":"10.1101/2025.07.02.662808","url":null,"abstract":"<p><p>The RNA-binding protein Ptbp1 has been proposed as a master regulator of neuronal fate, repressing neurogenesis through its effects on alternative splicing and miRNA maturation. While prior studies using RNA interference suggested that Ptbp1 loss promotes neurogenesis, recent genetic studies have failed to replicate glia-to-neuron conversion following Ptbp1 loss of function. To evaluate the role of Ptbp1 in developmental neurogenesis in vivo, we conditionally disrupted Ptbp1 in retinal progenitors. Ptbp1 was robustly expressed in both retinal progenitors and Muller glia but absent from postmitotic neurons, and efficient loss of function in mutant animals was confirmed using immunostaining for Ptbp1. Furthermore, bulk RNA-Seq at E16 revealed accelerated expression of late-stage progenitor and photoreceptor-specific genes and altered splicing patterns in Ptbp1 mutants, including increased inclusion of rod photoreceptor-specific exons. However, we observed no defects in retinal lamination, progenitor proliferation, or cell fate specification in mature retina. ScRNA-Seq of mature mutant retinas revealed only modest transcriptional changes which partially recapitulate alterations seen following selective deletion of Ptbp1 in mature glia. Our findings demonstrate that Ptbp1 is dispensable for retinal development and suggest that its proposed role as a central repressor of neurogenesis should be reevaluated.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12236599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144593615","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":"Independent signaling pathways provide a fail-safe mechanism to prevent tumorigenesis.","authors":"Sari Anschütz, Andrea Schubert, Jobelle M Peralta, Todd G Nystul, Katja Rust","doi":"10.1101/2025.02.28.640798","DOIUrl":"10.1101/2025.02.28.640798","url":null,"abstract":"<p><p>Controlled signaling activity is vital for normal tissue homeostasis and oncogenic signaling activation facilitates tumorigenesis. Here we use single-cell transcriptomics to investigate the effects of pro-proliferative signaling on epithelial homeostasis using the <i>Drosophila</i> follicle cell lineage. Notably, EGFR-Ras overactivation induces cell cycle defects by activating the transcription factors Pointed and E2f1 and impedes differentiation. Hh signaling simultaneously promotes an undifferentiated state and induces differentiation via activation of EMT-associated transcription factors zfh1 and Mef2. As a result, overactivation of Hh signaling generates a transcriptional hybrid state comparable to epithelial-mesenchymal-transition. Co-overactivation of Hh signaling with EGFR-Ras signaling blocks differentiation and induces key characteristics of tumor cells including a loss of tissue architecture caused by reduced expression of cell adhesion molecules, sustained proliferation and an evasion of cell cycle checkpoints. These findings provide new insight into how non-interacting signaling pathways converge at the transcriptional level to prevent malignant cell behavior.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11908167/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653154","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":"Artificial intelligence-enabled automated analysis of transmission electron micrographs to evaluate chemotherapy impact on mitochondrial morphology in triple negative breast cancer.","authors":"Argenis Arriojas, Mokryun L Baek, Mariah J Berner, Jiaqi Wang, Joseph Duraisingh, Alexander Zhurkevich, Antentor Othrell Hinton, Matthew D Meyer, Lacey E Dobrolecki, Michael T Lewis, Kourosh Zarringhalam, Gloria V Echeverria","doi":"10.1101/2025.02.19.635300","DOIUrl":"10.1101/2025.02.19.635300","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Advancements in transmission electron microscopy (TEM) have enabled in-depth studies of biological specimens, offering new avenues to large-scale imaging experiments with subcellular resolution. Mitochondrial structure is of growing interest in cancer biology due to its crucial role in regulating the multi-faceted functions of mitochondria. We and others have established the crucial role of mitochondria in triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer with limited therapeutic options. Building upon our previous work demonstrating the regulatory role of mitochondrial structure dynamics in metabolic adaptation and survival of chemotherapy-refractory TNBC cells, we sought to extend those findings to a large-scale analysis of transmission electron micrographs. Here we present a UNet artificial intelligence (AI) model for automatic annotation and assessment of mitochondrial morphology and feature quantification. Our model is trained on 11,039 manually annotated mitochondria across 125 micrographs derived from a variety of orthotopic patient-derived xenograft (PDX) mouse model tumors and adherent cell cultures. The model achieves an F1 score of 0.85 on test micrographs at the pixel level. To validate the ability of our model to detect expected mitochondrial structural features, we utilized micrographs from mouse primary skeletal muscle cells genetically modified to lack Dynamin-related protein 1 (Drp1). The algorithm successfully detected a significant increase in mitochondrial elongation, in alignment with the well-established role of Drp1 as a driver of mitochondrial fission. Further, we subjected in vitro and in vivo TNBC models to conventional chemotherapy treatments commonly used for clinical management of TNBC, including doxorubicin, carboplatin, paclitaxel, and docetaxel (DTX). We found substantial within-sample heterogeneity of mitochondrial structure in both in vitro and in vivo TNBC models and observed a consistent reduction in mitochondrial elongation in DTX-treated specimens. We went on to compare mammary tumors and matched lung metastases in a highly metastatic PDX model of TNBC, uncovering significant reduction in mitochondrial length in metastatic lesions. Our large, curated dataset provides high statistical power to detect frequent chemotherapy-induced shifts in mitochondrial shapes and sizes in residual cells left behind after treatment. The successful application of our AI model to capture mitochondrial structure marks a step forward in high-throughput analysis of mitochondrial structures, enhancing our understanding of how morphological changes may relate to chemotherapy efficacy and mechanism of action. Finally, our large, manually curated electron micrograph dataset - now publicly available - serves as a unique gold-standard resource for developing, benchmarking, and applying computational models, while further advancing investigations into mitochondrial morphology and its impact on cancer biolo","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11870520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143545553","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":"Cellular and molecular underpinnings of functional networks in the human brain.","authors":"Guozheng Feng, Jiayu Chen, Jing Sui, Vince D Calhoun","doi":"10.1101/2025.04.28.651051","DOIUrl":"10.1101/2025.04.28.651051","url":null,"abstract":"<p><p>Understanding how cellular and molecular architecture underpins the large-scale organization of human brain function is a central challenge in neuroscience. By integrating transcriptomic (microarray data and single-nucleus RNA-sequencing [sn-RNA] data), molecular imaging, and neuroimaging datasets, we observed spatial correspondences suggesting that the distributions of diverse cell types, neurotransmitter systems, and mitochondrial phenotypes are aligned with intrinsic connectivity networks (ICNs)-the macroscale scaffolding of brain function. These associations extend beyond local correspondence to reflect network-level structure: inter-ICN similarity networks derived from cellular and molecular profiles significantly recapitulate both static and dynamic patterns of functional network connectivity (FNC), mirroring the established division of ICNs into canonical functional domains. Importantly, these cellular and molecular profiles not only colocalize with ICNs and FNCs but also appear to support their role as intermediaries linking microscale biological substrates to cognitive function. Mediation analyses reveal that specific ICNs statistically mediate the relationship between microscale cell-type architecture and domain-specific cognitive and behavioral processes. Moreover, FNCs capture the mediating pathways linking cell-type and neurotransmitter similarity networks to cognitive network organization. Taken together, our findings suggest that the brain's functional architecture shows systematic associations with cellular and molecular organization, which may act as a biological constraint guiding functional network formation and contribute to the neural basis of cognition.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12440017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082910","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":"Noninvasive profiling of input-output excitability curves in human prefrontal cortex.","authors":"Nai-Feng Chen, Umair Hassan, Jessica M Ross, Lily Forman, James W Hartford, Juha Gogulski, Sara Parmigiani, Jade Truong, Corey J Keller, Christopher C Cline","doi":"10.1101/2025.09.26.678876","DOIUrl":"https://doi.org/10.1101/2025.09.26.678876","url":null,"abstract":"<p><strong>Background: </strong>The human prefrontal cortex plays a critical role in cognitive control and behavior, and its dysfunction has been linked to numerous psychiatric and neurological disorders. However, noninvasive measurement of prefrontal activity remains challenging, limiting our understanding of how to optimize prefrontal treatments. Input-output relationships reveal how neural circuits respond to different inputs and are essential for determining optimal treatment parameters and understanding individual variability in treatment response, yet systematic investigation of prefrontal input-output relationships has been lacking.</p><p><strong>Objective: </strong>To characterize human prefrontal excitability with input-output (I/O) curves.</p><p><strong>Methods: </strong>We employed transcranial magnetic stimulation (TMS) with electroencephalography in a randomized mixed-block design with 28 healthy participants receiving single-pulse TMS to left dorsolateral prefrontal cortex (dlPFC) across 12 stimulation intensities (60-140% of resting motor threshold). We quantified prefrontal excitability using early local TMS-evoked potentials (EL-TEPs), local cortical responses measured locally 20-60 ms post-stimulus.</p><p><strong>Results: </strong>We observed a strong effect of TMS intensity on prefrontal EL-TEPs. Sigmoidal EL-TEP I/O curves were observed in 57% of participants, with the sigmoidality partially explained by the signal quality of the EL-TEP. Correlations were observed between EL-TEP and motor-evoked potential curve parameters, but intensity parameterization approaches did not significantly differ in explaining inter-individual EL-TEP response variability. Reliable EL-TEPs could be obtained using fewer TMS pulses at higher intensities, and test-retest assessments revealed robust I/O curve profiles.</p><p><strong>Conclusions: </strong>These findings provide a systematic noninvasive characterization of prefrontal input-output physiology in humans, establishing a validated framework for estimating prefrontal excitability. The comparison of various intensity parameterizations motivates the need for enhanced models and individualized measurement of stimulation responses.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215302","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":"Dopamine receptor sensitivity and Pavlovian conditioned approach.","authors":"Nana K Amissah, Jordan A Tripi, Christopher P King, Paul J Meyer","doi":"10.1101/2025.09.26.678801","DOIUrl":"https://doi.org/10.1101/2025.09.26.678801","url":null,"abstract":"<p><p>Understanding the determinants of individual differences in cue-reactivity and drug sensitivity is critical to identifying neurobiological mechanisms underlying vulnerability to addiction. In this study, we examined the relationship between dopamine D1 and D2 receptor sensitivity and the attribution of incentive salience to reward cues and sensitivity to cocaine. Male Sprague Dawley rats were classified as having high or low sensitivity to the D2 receptor agonist quinpirole, and a subset was tested with the D1 receptor agonist SKF 82958. Cue-reactivity was assessed using a Pavlovian conditioned approach (PavCA) task, which distinguishes between sign-tracking (approach to a cue that predicts reward) and goal-tracking (approach to the site of reward delivery). Cocaine sensitivity was measured by locomotor activity and 50-kHz ultrasonic vocalizations (USVs), a putative measure of appetitive states. High D2 responders exhibited more sign-tracking and greater cocaine-induced USVs than low responders despite no difference in cocaine-induced locomotion. Sign-trackers also showed greater locomotor sensitivity to D1 receptor stimulation than goal-trackers and produced more cocaine-induced USVs. Rats with high sensitivity to both D1 and D2 receptor stimulation showed the strongest sign-tracking behavior and affective response to cocaine. These findings suggest that dopamine receptor sensitivity is associated with the propensity to attribute incentive salience to reward cues and potentially the appetitive effects of cocaine. This dopaminergic phenotype may reflect a mechanism contributing to both individual differences in cue-reactivity and drug responsiveness.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485688/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215322","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":"Flexible Working Memory in the Peripheral Nervous System.","authors":"Sihan Yang, Yueying Dong, Anastasia Kiyonaga","doi":"10.1101/2025.09.26.678884","DOIUrl":"https://doi.org/10.1101/2025.09.26.678884","url":null,"abstract":"<p><p>Working memory (WM) representations that are distributed across the brain can be flexibly recruited to best guide behavior. For instance, information may be represented relatively more strongly in visual cortex when a WM task requires fine visual detail, or more strongly in motor cortex when a specific response can be prepared. If WM is geared to prospectively guide actions, then we might also expect such task-oriented neural signals to propagate to the peripheral sensors and effectors that realize WM goals. Likewise, there is now evidence that oculomotor signals like saccade biases can track simple visuo-spatial WM features. However, it is unclear if such signatures are functionally meaningful, and how much information is contained in them. Here, we test the idea that WM content is adaptively distributed across the nervous system according to behavioral demands. Namely, we test whether visual WM stimulus features are expressed in patterns of both eye and hand movements during a WM delay, and whether the distribution of such peripheral motor activity shifts with the task context. In a delayed recall task, we manipulated how human participants reported their memory by having them either draw a line or adjust a wheel to match a remembered orientation. Via eye- and stylus-tracking, we found that remembered orientations were decodable from small inflections in both gaze and hand movements during the blank WM delay. Moreover, this decoding strength varied by response format: gaze patterns tracked memorized features relatively better in the wheel condition (vs. draw), while hand movements were better in the draw condition (vs. wheel). Individuals who showed greater wheel benefits in gaze-based decoding also showed greater draw benefits in hand-based decoding, suggesting a strategic processing shift to the more relevant system. Therefore, visually encoded WM contents may be adaptively allocated to the most task-relevant motor effectors, balancing WM representations across peripheral activity according to behavioral needs.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215340","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":"Furin Inhibition Protects Against Acute Lung Injury in a Mouse Model of Pseudomonas Aeruginosa Infection.","authors":"Melia Magnen, Olivier Bernard, Mark R Looney, Michelle A Yu, Michael Kwon","doi":"10.1101/2025.09.25.678606","DOIUrl":"https://doi.org/10.1101/2025.09.25.678606","url":null,"abstract":"<p><p>Pseudomonas aeruginosa (PA) is responsible for significant morbidity and mortality particularly in patients with chronic lung diseases such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF) as well as hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). The rise of antibiotic-resistant PA strains necessitates alternative treatment strategies. Among the different toxins secreted by PA, Exotoxin-A (Exo-A) becomes cytotoxic when cleaved by furin. This study investigates the therapeutic potential of furin inhibitor BOS-318 in mitigating acute lung injury induced by Exo-A and PA infection. Furin inhibition significantly improved survival rates and reduced lung injury in mouse pneumonia models using Exo-A and PA103. Additionally, BOS-318 accelerated bacterial clearance in vivo, and increased phagocytosis by alveolar macrophages. Bulk RNA-seq immune profiling revealed modulation of the natural killer (NK) cell signaling pathway possibly due to a decrease in NK recruitment, suggesting a role of furin in shaping the immune response. Overall, our findings demonstrate that furin inhibition protects against PA-induced acute lung injury and hastens bacterial clearance. These results are the first to characterize furin inhibition in animal models and supports its potential use as an adjunctive therapeutic strategy for treating PA infections.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12485732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145215352","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}