bioRxiv : the preprint server for biology最新文献

{"title":"Space- and object-based attention in patients with a single hemisphere following childhood resection.","authors":"Sophia Robert, Michael C Granovetter, Shouyu Ling, Marlene Behrmann","doi":"10.1101/2024.12.06.627251","DOIUrl":"10.1101/2024.12.06.627251","url":null,"abstract":"<p><p>The neural processes underlying attentional processing are typically lateralized in adults, with spatial attention associated with the right hemisphere (RH) and object-based attention with the left hemisphere (LH). Using a modified two-rectangle attention paradigm, we compared the lateralization profiles of individuals with childhood hemispherectomy (either LH or RH) and age-matched, typically developing controls. Although patients exhibited slower reaction times (RTs) compared to controls, both groups benefited from valid attentional cueing. However, patients experienced significantly higher costs for invalid trials-reflected by larger RT differences between validly and invalidly cued targets. This was true for invalid trials on both cued and uncued objects, probes of object- and space-based attentional processes, respectively. Notably, controls showed no significant RT cost differences between invalidly cued locations on cued versus uncued objects. By contrast, patients exhibited greater RT costs for targets on uncued versus cued objects, suggesting greater difficulty shifting attention across objects. We explore potential explanations for this group difference and the lack of difference between patients with LH or RH resection. These findings enhance our understanding of spatial and object-based attention in typical development and reveal how significant neural injury affects the development of attentional systems in the LH and RH.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661120/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879370","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":"Selective Targeting of a Defined Subpopulation of Corticospinal Neurons using a Novel Klhl14-Cre Mouse Line Enables Molecular and Anatomical Investigations through Development into Maturity.","authors":"Jake Lustig, Alexander Lammers, Julia Kaiser, Payal Patel, Aidan Raghu, James M Conner, Phong Nguyen, Eiman Azim, Vibhu Sahni","doi":"10.1101/2024.12.10.627648","DOIUrl":"10.1101/2024.12.10.627648","url":null,"abstract":"<p><p>The corticospinal tract (CST) facilitates skilled, precise movements, which necessitates that subcerebral projection neurons (SCPN) establish segmentally specific connectivity with brainstem and spinal circuits. Developmental molecular delineation enables prospective identification of corticospinal neurons (CSN) projecting to thoraco-lumbar spinal segments; however, it remains unclear whether other SCPN subpopulations in developing sensorimotor cortex can be prospectively identified in this manner. Such molecular tools could enable investigations of SCPN circuitry with precision and specificity. During development, Kelch-like 14 (<i>Klhl14</i>) is specifically expressed by a specific SCPN subpopulation, CSN_BC-lat, that reside in lateral sensorimotor cortex with axonal projections exclusively to bulbar-cervical targets. In this study, we generated Klhl14-T2A-Cre knock-in mice to investigate SCPN that are <i>Klhl14</i>+ during development into maturity. Using conditional anterograde and retrograde labeling, we find that Klhl14-Cre is specifically expressed by CSN_BC-lat only at specific developmental time points. We establish conditional viral labeling in Klhl14-T2A-Cre mice as a new approach to reliably investigate CSN_BC-lat axon targeting and confirm that this identifies known molecular regulators of CSN axon targeting. Therefore, Klhl14-T2A-Cre mice can be used as a novel tool for identifying molecular regulators of CST axon guidance in a relatively high-throughput manner <i>in vivo</i>. Finally, we demonstrate that intersectional viral labeling enables precise targeting of only Klhl14-Cre+ CSN_BC-lat in the adult central nervous system. Together, our results establish that developmental molecular delineation of SCPN subpopulations can be used to selectively and specifically investigate their development, as well as anatomical and functional organization into maturity.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661177/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879550","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":"Perivascular Macrophages Convert Physical Wound Signals Into Rapid Vascular Responses.","authors":"Zaza Gelashvili, Zhouyang Shen, Yanan Ma, Mark Jelcic, Philipp Niethammer","doi":"10.1101/2024.12.09.627538","DOIUrl":"10.1101/2024.12.09.627538","url":null,"abstract":"<p><p>Leukocytes detect distant wounds within seconds to minutes, which is essential for effective pathogen defense, tissue healing, and regeneration. Blood vessels must detect distant wounds just as rapidly to initiate local leukocyte extravasation, but the mechanism behind this immediate vascular response remains unclear. Using high-speed imaging of live zebrafish larvae, we investigated how blood vessels achieve rapid wound detection. We monitored two hallmark vascular responses: vessel dilation and serum exudation. Our experiments-including genetic, pharmacologic, and osmotic perturbations, along with chemogenetic leukocyte depletion-revealed that the cPla₂ nuclear shape sensing pathway in perivascular macrophages converts a fast (~50 μm/s) osmotic wound signal into a vessel-permeabilizing, 5-lipoxygenase (Alox5a) derived lipid within seconds of injury. These findings demonstrate that perivascular macrophages act as physicochemical relays, bridging osmotic wound signals and vascular responses. By uncovering this novel type of communication, we provide new insights into the coordination of immune and vascular responses to injury.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879502","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":"Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.","authors":"Shellaina J V Gordon, Florian Perner, Laura MacPherson, Daniela V Wenge, Wallace Bourgeois, Katie Fennell, Tabea Klaus, Jelena Petrovic, Jakub Horvath, Joan Cao, John Lapek, Sean Uryu, Jeffrey White, Enid Y N Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin Blyth, Michelle A Camerino, Ylyva E Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A Stupple, Ian P Street, Brendon J Monahan, Shikhar Sharma, Elanor N Wainwright, Dane Vassiliadis, Thomas A Paul, Scott A Armstrong, Mark A Dawson","doi":"10.1101/2024.12.11.627663","DOIUrl":"10.1101/2024.12.11.627663","url":null,"abstract":"<p><p>Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate the MLL-FP transcriptional program. Inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of MLL-FP. Consequently, combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Moreover, PF-9363 or genetic depletion of KAT7 can also overcome acquired genetic/non-genetic resistance to Menin inhibition. These data provide the molecular rationale for rapid clinical translation of combination therapy in MLL-FP leukaemia.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661155/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879406","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 AI-Cyborg System for Adaptive Intelligent Modulation of Organoid Maturation.","authors":"Ren Liu, Zhaolin Ren, Xinhe Zhang, Qiang Li, Wenbo Wang, Zuwan Lin, Richard T Lee, Jie Ding, Na Li, Jia Liu","doi":"10.1101/2024.12.07.627355","DOIUrl":"10.1101/2024.12.07.627355","url":null,"abstract":"<p><p>Recent advancements in flexible bioelectronics have enabled continuous, long-term stable interrogation and intervention of biological systems. However, effectively utilizing the interrogated data to modulate biological systems to achieve specific biomedical and biological goals remains a challenge. In this study, we introduce an AI-driven bioelectronics system that integrates tissue-like, flexible bioelectronics with cyber learning algorithms to create a long-term, real-time bidirectional b ioelectronic interface with o ptimized a daptive intelligent m odulation (BIO-AIM). When integrated with biological systems as an AI-cyborg system, BIO-AIM continuously adapts and optimizes stimulation parameters based on stable cell state mapping, allowing for real-time, closed-loop feedback through tissue-embedded flexible electrode arrays. Applied to human pluripotent stem cell-derived cardiac organoids, BIO-AIM identifies optimized stimulation conditions that accelerate functional maturation. The effectiveness of this approach is validated through enhanced extracellular spike waveforms, increased conduction velocity, and improved sarcomere organization, outperforming both fixed and no stimulation conditions.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661133/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879180","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":"Regulatory interactions between APOBEC3B N- and C-terminal domains.","authors":"Mac Kevin E Braza, Özlem Demir, Surl-Hee Ahn, Clare K Morris, Carla Calvó-Tusell, Kelly L McGuire, Bárbara de la Peña Avalos, Michael A Carpenter, Yanjun Chen, Lorenzo Casalino, Hideki Aihara, Mark A Herzik, Reuben S Harris, Rommie E Amaro","doi":"10.1101/2024.12.11.628032","DOIUrl":"10.1101/2024.12.11.628032","url":null,"abstract":"<p><p>APOBEC3B (A3B) is implicated in DNA mutations that facilitate tumor evolution. Although structures of its individual N- and C-terminal domains (NTD and CTD) have been resolved through X-ray crystallography, the full-length A3B (fl-A3B) structure remains elusive, limiting understanding of its dynamics and mechanisms. In particular, the APOBEC3B C-terminal domain (A3Bctd) active site is frequently closed in models and structures. In this study, we built several new models of fl-A3B using integrative structural biology methods and selected a top model for further dynamical investigation. We compared dynamics of the truncated (A3Bctd) to the fl-A3B via conventional and Gaussian accelerated molecular dynamics (MD) simulations. Subsequently, we employed weighted ensemble methods to explore the fl-A3B active site opening mechanism, finding that interactions at the NTD-CTD interface enhance the opening frequency of the fl-A3B active site. Our findings shed light on the structural dynamics of fl-A3B, which may offer new avenues for therapeutic intervention in cancer.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879523","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":"Deconstruction of a memory engram reveals distinct ensembles recruited at learning.","authors":"Clément Pouget, Flora Morier, Nadja Treiber, Pablo Fernández García, Nina Mazza, Run Zhang, Isaiah Reeves, Stephen Winston, Mark A Brimble, Christina K Kim, Gisella Vetere","doi":"10.1101/2024.12.11.627894","DOIUrl":"10.1101/2024.12.11.627894","url":null,"abstract":"<p><p>How are associative memories formed? Which cells represent a memory, and when are they engaged? By visualizing and tagging cells based on their calcium influx with unparalleled temporal precision, we identified non-overlapping dorsal CA1 neuronal ensembles that are differentially active during associative fear memory acquisition. We dissected the acquisition experience into periods during which salient stimuli were presented or certain mouse behaviors occurred and found that cells associated with specific acquisition periods are sufficient alone to drive memory expression and contribute to fear engram formation. This study delineated the different identities of the cell ensembles active during learning, and revealed, for the first time, which ones form the core engram and are essential for memory formation and recall.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661170/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879248","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":"Calmodulin binding is required for calcium mediated TRPA1 desensitization.","authors":"Justin H Sanders, Kehinde M Taiwo, Glory A Adekanye, Avnika Bali, Yuekang Zhang, Candice E Paulsen","doi":"10.1101/2024.12.11.627969","DOIUrl":"10.1101/2024.12.11.627969","url":null,"abstract":"<p><p>Calcium (Ca²⁺) ions affect nearly all aspects of biology. Excessive Ca²⁺ entry is cytotoxic and Ca²⁺-mobilizing receptors have evolved diverse mechanisms for tight regulation that often include Calmodulin (CaM). TRPA1, an essential Ca²⁺-permeable ion channel involved in pain signaling and inflammation, exhibits complex Ca²⁺ regulation with initial channel potentiation followed by rapid desensitization. The molecular mechanisms of TRPA1 Ca²⁺ regulation and whether CaM plays a role remain elusive. We find that TRPA1 binds CaM best at basal Ca²⁺ concentration, that they co-localize in resting cells, and that CaM suppresses TRPA1 activity. Combining biochemical, biophysical, modeling, NMR spectroscopy, and functional approaches, we identify an evolutionarily conserved, high-affinity CaM binding element in the distal TRPA1 C-terminus (DCTCaMBE). Genetic or biochemical perturbation of Ca²⁺/CaM binding to the TRPA1 DCTCaMBE yields hyperactive channels that exhibit drastic slowing of desensitization with no effect on potentiation. Ca²⁺/CaM TRPA1 regulation does not require the N-lobe, raising the possibility that CaM is not the Ca²⁺ sensor, <i>per se</i>. Higher extracellular Ca²⁺ can partially rescue slowed desensitization suggesting Ca²⁺/CaM binding to the TRPA1 DCTCaMBE primes an intrinsic TRPA1 Ca²⁺ binding site that, upon binding Ca²⁺, triggers rapid desensitization. Collectively, our results identify a critical regulatory element in an unstructured TRPA1 region highlighting the importance of these domains, they reveal Ca²⁺/CaM is an essential TRPA1 auxiliary subunit required for rapid desensitization that establishes proper channel function with implications for all future TRPA1 work, and they uncover a mechanism for receptor regulation by Ca²⁺/CaM that expands the scope of CaM biology.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879418","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":"Integrating qualitative and quantitative data across multiple labs for model calibration.","authors":"Rodolfo Blanco-Rodriguez, Tanya A Miura, Esteban Hernandez-Vargas","doi":"10.1101/2024.12.08.627398","DOIUrl":"10.1101/2024.12.08.627398","url":null,"abstract":"<p><p>The integration of computational models with experimental data is a cornerstone for gaining insight into biomedical applications. However, parameter fitting procedures often require an immense availability and frequency of data that are challenging to obtain from a single source. Here, we present a novel methodology designed to integrate qualitative data from multiple laboratories, overcoming the constraints of single-lab data collection. Our method harmonizes disparate qualitative assessments-ranging from expert annotations to categorical observations-into a unified framework for parameter estimation. These qualitative constraints are represented as dynamic \"qualitative windows\" that capture significant trends that models must adhere to. For numerical implementation, we developed a GPU-accelerated version of differential evolution to navigate in the residuals that integrated quantitative and qualitative data. We validate our approach across a series of case studies, demonstrating significant improvements in model accuracy and parameter identifiability. This work opens new avenues for collaborative science, enabling a methodology to combine and compare findings between studies to improve our understanding of biological systems.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661082/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142879436","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":"Modulation of all- <i>trans</i> retinoic acid by light and dopamine in the murine eye.","authors":"Sarah Talwar, Reece Mazade, Melissa Bentley-Ford, Jianshi Yu, Nageswara Pilli, Maureen A Kane, C Ross Ethier, Machelle T Pardue","doi":"10.1101/2024.12.06.627245","DOIUrl":"10.1101/2024.12.06.627245","url":null,"abstract":"<p><strong>Purpose: </strong>Ambient light exposure is linked to myopia development in children and affects myopia susceptibility in animal models. Currently, it is unclear which signals mediate the effects of light on myopia. All- <i>trans</i> retinoic acid (atRA) and dopamine (DA) oppositely influence experimental myopia and may be involved in the retino-scleral signaling cascade underlying myopic eye growth. However, how ocular atRA responds to different lighting and whether atRA and DA interact remains unknown.</p><p><strong>Methods: </strong>Dark-adapted C57BL/6J mice (29-31 days old) were exposed to Dim (1 lux), Mid (59 lux), or Bright (12,000 lux) ambient lighting for 5-60 minutes. Some mice were also systemically administered the DA precursor, LDOPA, or atRA prior to light exposure. After exposure, the retina and the back-of-the-eye (BOE) were collected and analyzed for levels of atRA, DA, and the DA metabolite, DOPAC.</p><p><strong>Results: </strong>DA turnover (DOPAC/DA ratio) in the retina increased in magnitude after only five minutes of exposure to higher ambient luminance but was minimal in the BOE. In contrast, atRA levels in the retina and BOE significantly decreased with higher ambient luminance and longer duration exposure. Intriguingly, LDOPA-treated mice had a transient reduction in retinal atRA compared to saline-treated mice, whereas atRA treatment had no effect on ocular DA.</p><p><strong>Conclusions: </strong>Ocular atRA was affected by the duration of exposure to different ambient lighting and retinal atRA levels decreased with increased DA. Overall, these data suggest specific interactions between ambient lighting, atRA, and DA that could have implications for the retino-scleral signaling cascade underlying myopic eye growth.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11661107/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142878651","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}