Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.606907
Jorge Martinez Armas, Kenneth Knoblauch, H. Kennedy, Zoltan Toroczkai
Structural connectivity between cortical areas, as revealed by tract-tracing is in the form of highly dense, weighted, directed, and spatially embedded complex networks. Extracting the community structure of these networks and aligning them with brain function is challenging, as most methods use local density measures, best suited for sparse graphs. Here we introduce a principled approach, based on distinguishability of connectivity profiles using the Hellinger distance, which is relatable to function. Applying it to tract-tracing data in the macaque, we show that the cortex at the interareal level is organized into a hierarchy of link-communities alongside with a node-community hierarchy. We find that the ½-Rényi divergence of connection profiles, a non-linear transform of the Hellinger metric, follows a Weibull-like distribution and scales linearly with the interareal distances, a quantitative expression between functional organization and cortical geometry. We discuss the relationship with the extensively studied SLN-based hierarchy.
{"title":"A principled approach to community detection in interareal cortical networks","authors":"Jorge Martinez Armas, Kenneth Knoblauch, H. Kennedy, Zoltan Toroczkai","doi":"10.1101/2024.08.07.606907","DOIUrl":"https://doi.org/10.1101/2024.08.07.606907","url":null,"abstract":"Structural connectivity between cortical areas, as revealed by tract-tracing is in the form of highly dense, weighted, directed, and spatially embedded complex networks. Extracting the community structure of these networks and aligning them with brain function is challenging, as most methods use local density measures, best suited for sparse graphs. Here we introduce a principled approach, based on distinguishability of connectivity profiles using the Hellinger distance, which is relatable to function. Applying it to tract-tracing data in the macaque, we show that the cortex at the interareal level is organized into a hierarchy of link-communities alongside with a node-community hierarchy. We find that the ½-Rényi divergence of connection profiles, a non-linear transform of the Hellinger metric, follows a Weibull-like distribution and scales linearly with the interareal distances, a quantitative expression between functional organization and cortical geometry. We discuss the relationship with the extensively studied SLN-based hierarchy.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"2 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.607005
Lucas P. Medeiros, Darian K. Sorenson, Bethany J. Johnson, E. Palkovacs, Stephan B. Munch
Many ecosystems can exist in alternative dynamical regimes for which small changes in an environmental driver can cause sudden jumps between regimes. However, predicting the dynamics of regimes that occur under unobserved levels of the environmental driver has remained an unsolved challenge in ecology with important implications for conservation and management. Here we show that integrating population time-series data and information on the putative driver into an empirical dynamic model allows us to predict new dynamical regimes without the need to specify a population dynamics model. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen driver levels for a range of simulated models. For a model with an abrupt population collapse, we show that our approach can anticipate the regime that follows the tipping point. We then apply our approach to data from an experimental microbial ecosystem and from a lake planktonic ecosystem. We find that we can reconstruct transitions away from chaos in the experimental ecosystem and anticipate the dynamics of the oligotrophic regime in the lake ecosystem. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems.
{"title":"Revealing unseen dynamical regimes of ecosystems from population time-series data","authors":"Lucas P. Medeiros, Darian K. Sorenson, Bethany J. Johnson, E. Palkovacs, Stephan B. Munch","doi":"10.1101/2024.08.07.607005","DOIUrl":"https://doi.org/10.1101/2024.08.07.607005","url":null,"abstract":"Many ecosystems can exist in alternative dynamical regimes for which small changes in an environmental driver can cause sudden jumps between regimes. However, predicting the dynamics of regimes that occur under unobserved levels of the environmental driver has remained an unsolved challenge in ecology with important implications for conservation and management. Here we show that integrating population time-series data and information on the putative driver into an empirical dynamic model allows us to predict new dynamical regimes without the need to specify a population dynamics model. As a proof of concept, we demonstrate that we can accurately predict fixed-point, cyclic, or chaotic dynamics under unseen driver levels for a range of simulated models. For a model with an abrupt population collapse, we show that our approach can anticipate the regime that follows the tipping point. We then apply our approach to data from an experimental microbial ecosystem and from a lake planktonic ecosystem. We find that we can reconstruct transitions away from chaos in the experimental ecosystem and anticipate the dynamics of the oligotrophic regime in the lake ecosystem. These results lay the groundwork for making rational decisions about preventing, or preparing for, regime shifts in natural ecosystems.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"23 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923391","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.606975
Yi Wang
Decades ago, colorectal cancer was rarely diagnosed. Today, it is the fourth leading cause of cancer-related deaths worldwide, with nearly 90,000 fatalities each year. By analyzing single-cell data from tumor-bearing colorectal cancer model mice with Lphn1 knockout and wild-type Lphn1, we identified five key target genes for anticancer therapy: Ulbp1, Klrk1, Ccl6, Tlr4, Cd48, Prdm5, VSTM2A, RET, OAS2, Hdac11 and Ptchd4, along with their corresponding cell types. Additionally, we discovered tumor-inhibiting cell subpopulations, including Cd244a_T_cells_subcluster_1, Cd48_Cd244a_NK_cells_subcluster_2, and C3_Macrophages_subcluster_1, which are potential candidates for therapeutic intervention. We propose that cancer-associated fibroblasts (CAFs) serve as the primary antigen presenters for MHC class I, providing antigens to macrophages, NK cells, and T cells to combat colorectal cancer. These findings could open new avenues for the treatment of colorectal cancer and contribute to the development of personalized medicine.
几十年前，人们很少诊断出结直肠癌。如今，它已成为全球癌症相关死亡的第四大原因，每年有近 90,000 人死于此病。通过分析Lphn1基因敲除和野生型Lphn1的肿瘤结直肠癌模型小鼠的单细胞数据，我们发现了抗癌治疗的五个关键靶基因：Ulbp1、Klrk1、Ccl6、Tlr4、Cd48、Prdm5、VSTM2A、RET、OAS2、Hdac11 和 Ptchd4，以及它们相应的细胞类型。此外，我们还发现了抑制肿瘤的细胞亚群，包括Cd244a_T_cells_subcluster_1、Cd48_Cd244a_NK_cells_subcluster_2和C3_Macrophages_subcluster_1，它们是治疗干预的潜在候选细胞。我们提出，癌症相关成纤维细胞（CAFs）是 MHC I 类的主要抗原呈递者，为巨噬细胞、NK 细胞和 T 细胞提供抗原，以对抗结直肠癌。这些发现将为治疗结直肠癌开辟新的途径，并促进个性化医疗的发展。
{"title":"Research on the Mechanism of Lphn1 Knockout in Inhibiting Colorectal Cancer","authors":"Yi Wang","doi":"10.1101/2024.08.07.606975","DOIUrl":"https://doi.org/10.1101/2024.08.07.606975","url":null,"abstract":"Decades ago, colorectal cancer was rarely diagnosed. Today, it is the fourth leading cause of cancer-related deaths worldwide, with nearly 90,000 fatalities each year. By analyzing single-cell data from tumor-bearing colorectal cancer model mice with Lphn1 knockout and wild-type Lphn1, we identified five key target genes for anticancer therapy: Ulbp1, Klrk1, Ccl6, Tlr4, Cd48, Prdm5, VSTM2A, RET, OAS2, Hdac11 and Ptchd4, along with their corresponding cell types. Additionally, we discovered tumor-inhibiting cell subpopulations, including Cd244a_T_cells_subcluster_1, Cd48_Cd244a_NK_cells_subcluster_2, and C3_Macrophages_subcluster_1, which are potential candidates for therapeutic intervention. We propose that cancer-associated fibroblasts (CAFs) serve as the primary antigen presenters for MHC class I, providing antigens to macrophages, NK cells, and T cells to combat colorectal cancer. These findings could open new avenues for the treatment of colorectal cancer and contribute to the development of personalized medicine.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.607026
Daniel D. Kato, Randy M. Bruno
Merging information from across sensory modalities is key to forming robust, disambiguated percepts of the world, yet how the brain achieves this feat remains unclear. Recent observations of cross-modal influences in primary sensory cortical areas have suggested that multisensory integration may occur in the earliest stages of cortical processing, but the role of these responses is still poorly understood. We address these questions by testing several hypotheses about the possible functions served by auditory influences on the barrel field of mouse primary somatosensory cortex (S1) using in vivo 2-photon calcium imaging. We observed sound-evoked spiking activity in a small fraction of cells overall, and moreover that this sparse activity was insufficient to encode auditory stimulus identity; few cells responded preferentially to one sound or another, and a linear classifier trained to decode auditory stimuli from population activity performed barely above chance. Moreover S1 did not encode information about specific audio-tactile feature conjunctions that we tested. Our ability to decode auditory audio-tactile stimuli from neural activity remained unchanged after both passive experience and reinforcement. Collectively, these results suggest that while a primary sensory cortex is highly plastic with regard to its own modality, the influence of other modalities are remarkably stable and play a largely stimulus-non-specific role.
{"title":"Stability of cross-sensory input to primary somatosensory cortex across experience","authors":"Daniel D. Kato, Randy M. Bruno","doi":"10.1101/2024.08.07.607026","DOIUrl":"https://doi.org/10.1101/2024.08.07.607026","url":null,"abstract":"Merging information from across sensory modalities is key to forming robust, disambiguated percepts of the world, yet how the brain achieves this feat remains unclear. Recent observations of cross-modal influences in primary sensory cortical areas have suggested that multisensory integration may occur in the earliest stages of cortical processing, but the role of these responses is still poorly understood. We address these questions by testing several hypotheses about the possible functions served by auditory influences on the barrel field of mouse primary somatosensory cortex (S1) using in vivo 2-photon calcium imaging. We observed sound-evoked spiking activity in a small fraction of cells overall, and moreover that this sparse activity was insufficient to encode auditory stimulus identity; few cells responded preferentially to one sound or another, and a linear classifier trained to decode auditory stimuli from population activity performed barely above chance. Moreover S1 did not encode information about specific audio-tactile feature conjunctions that we tested. Our ability to decode auditory audio-tactile stimuli from neural activity remained unchanged after both passive experience and reinforcement. Collectively, these results suggest that while a primary sensory cortex is highly plastic with regard to its own modality, the influence of other modalities are remarkably stable and play a largely stimulus-non-specific role.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"15 5","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
In most plants, the zygote divides asymmetrically to define the body axis. In Arabidopsis thaliana, the zygote undergoes polar elongation maintaining a transverse band of cortical microtubules (MTs), and divides asymmetrically forming another MT band, preprophase band (PPB). How the MT band is maintained at the actively growing cell tip and whether it contributes to PPB formation remain elusive. By combining live-cell imaging and mechanical simulation, we show that zygote elongation induces a temporal change (large material derivative) in surface tension at the growing tip to maintain the MT band, which in turn supports polar elongation. The MT band then guides PPB to determine the cell division site. Therefore, autonomous mechanical feedback between cell elongation and MT organization ensures the zygote division asymmetry.
{"title":"Temporal changes in surface tension guide the accurate asymmetric division of Arabidopsis zygotes","authors":"Zichen Kang, Sakumi Nakagawa, Hikari Matsumoto, Yukitaka Ishimoto, T. Nonoyama, Yuga Hanaki, Satoru Tsugawa, Minako Ueda","doi":"10.1101/2024.08.07.605794","DOIUrl":"https://doi.org/10.1101/2024.08.07.605794","url":null,"abstract":"In most plants, the zygote divides asymmetrically to define the body axis. In Arabidopsis thaliana, the zygote undergoes polar elongation maintaining a transverse band of cortical microtubules (MTs), and divides asymmetrically forming another MT band, preprophase band (PPB). How the MT band is maintained at the actively growing cell tip and whether it contributes to PPB formation remain elusive. By combining live-cell imaging and mechanical simulation, we show that zygote elongation induces a temporal change (large material derivative) in surface tension at the growing tip to maintain the MT band, which in turn supports polar elongation. The MT band then guides PPB to determine the cell division site. Therefore, autonomous mechanical feedback between cell elongation and MT organization ensures the zygote division asymmetry.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"46 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.08.607031
Oscar Cipolato, Matthias Fauconneau, Paige J. LeValley, Robert Nißler, Benjamin Suter, Inge K. Herrmann
Fluorescence-guided surgical techniques, including tumor resection and tissue soldering, are advancing the frontiers of surgical precision by offering enhanced control that minimizes tissue damage and improves recovery as well as outcomes. However, integrating the visualization of the fluorescent signal and temperature monitoring seamlessly into surgical workflows has not been fully realized and remains a challenge, thus limiting their effectiveness and wide-spread clinical adoption. To address this issue, we introduce an augmented reality (AR) visor designed to unite nanomaterial excitation along with fluorescence detection, and temperature monitoring during surgical procedures. The AR visor was evaluated using advanced fluorescent nanoparticles, such as indocyanine green-doped particles and singlewalled carbon nanotubes. By consolidating fluorescence visualization, excitation monitoring, and precise temperature control into a single AR platform, we equip surgeons with a comprehensive view of both the surgical field and sub-surface conditions invisible to the naked eye. This integration notably improves the safety and efficacy of fluorescence-guided surgeries, as well as emerging technologies including laser tissue soldering, by ensuring the soldering temperature stays within therapeutic thresholds and the laser is accurately guided by real-time fluorescence signals. The presented technology not only enhances existing surgical techniques but also supports the development of new strategies and sensing technologies in areas where traditional methods fall short, marking significant progress in precision surgery, which could ultimately improve patient care.
荧光引导外科技术，包括肿瘤切除和组织焊接，通过加强控制，最大限度地减少组织损伤，改善恢复和疗效，正在推动外科手术的精确性向前发展。然而，将荧光信号可视化和温度监测无缝集成到手术工作流程中尚未完全实现，仍然是一项挑战，因此限制了其有效性和临床广泛采用。为了解决这个问题，我们推出了一种增强现实（AR）面罩，旨在将纳米材料激发、荧光检测和手术过程中的温度监测结合起来。我们使用先进的荧光纳米粒子，如掺杂吲哚菁绿的粒子和单壁碳纳米管，对增强现实面罩进行了评估。通过将荧光可视化、激发监测和精确温度控制整合到一个 AR 平台中，我们为外科医生提供了一个全面的视角，既能看到手术区域，也能看到肉眼看不到的表层下情况。这种集成通过确保焊接温度保持在治疗阈值内，并通过实时荧光信号精确引导激光，显著提高了荧光引导手术以及包括激光组织焊接在内的新兴技术的安全性和有效性。所展示的技术不仅增强了现有的外科技术，还支持在传统方法不足的领域开发新的策略和传感技术，标志着精准外科的重大进展，最终可改善病人护理。
{"title":"An Augmented Reality Visor for Intraoperative Visualization, Guidance and Temperature Monitoring using Fluorescence","authors":"Oscar Cipolato, Matthias Fauconneau, Paige J. LeValley, Robert Nißler, Benjamin Suter, Inge K. Herrmann","doi":"10.1101/2024.08.08.607031","DOIUrl":"https://doi.org/10.1101/2024.08.08.607031","url":null,"abstract":"Fluorescence-guided surgical techniques, including tumor resection and tissue soldering, are advancing the frontiers of surgical precision by offering enhanced control that minimizes tissue damage and improves recovery as well as outcomes. However, integrating the visualization of the fluorescent signal and temperature monitoring seamlessly into surgical workflows has not been fully realized and remains a challenge, thus limiting their effectiveness and wide-spread clinical adoption. To address this issue, we introduce an augmented reality (AR) visor designed to unite nanomaterial excitation along with fluorescence detection, and temperature monitoring during surgical procedures. The AR visor was evaluated using advanced fluorescent nanoparticles, such as indocyanine green-doped particles and singlewalled carbon nanotubes. By consolidating fluorescence visualization, excitation monitoring, and precise temperature control into a single AR platform, we equip surgeons with a comprehensive view of both the surgical field and sub-surface conditions invisible to the naked eye. This integration notably improves the safety and efficacy of fluorescence-guided surgeries, as well as emerging technologies including laser tissue soldering, by ensuring the soldering temperature stays within therapeutic thresholds and the laser is accurately guided by real-time fluorescence signals. The presented technology not only enhances existing surgical techniques but also supports the development of new strategies and sensing technologies in areas where traditional methods fall short, marking significant progress in precision surgery, which could ultimately improve patient care.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"36 23","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141924758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.607056
B. Yorke, Helen M. Ginn
The conformational landscape of proteins and associated dynamics is an essential component of function. Diverse conformations of highly populated metastable states are well-studied, but transitions between these states are rare, fleeting events. Neither molecular dynamics simulations nor experimental methods provide information about these. To address this conundrum, we present a computationally inexpensive algorithm, “cold-inbetweening”, which generates trajectories in torsion angle space. This minimises the overall kinetic energy needed to complete a transition between experimentally determined end-states. We use this method to provide mechanistic insight into three transporter superfamilies. This method allows interrogation of structural transitions, provides unique insights into coupled motion and hypotheses of action. The alternate access model of operation [1] is ubiquitous among many superfamilies of membrane transporters [2]. The model proposes that outward and inward pore opening is mutually exclusive, allowing ligand translocation but preventing damage from free solvent flow. Here, we study DraNramp (MntH) from Deinococcus radiodurians [3], MalT (bcMalT) from Bacillus cereus [4], and MATE (PfMATE) from Pyrococcus furiosus [5]. In MalT, the trajectory demonstrates elevator transport through unwinding of a supporter arm helix, maintaining the necessary and sufficient space to transport maltose. In DraNramp, this trajectory exhibited outward-gate closure prior to inward-gate opening, suggesting that the timing of gate closure is an inherent property of the protein architecture. In the MATE transporter, switching conformation involves the rewinding of an extended N-terminal helix. We suggest that the necessary motions to avoid steric backbone clashes forces this helix to plug the cavernous ligand-binding site during the conformational change. We propose helix unwinding as a general structural mechanism in membrane transporter function due to ease of helix register slippage in the lipid bilayer.
{"title":"Adherence to the conservation of momentum to elucidate membrane transporter mechanisms","authors":"B. Yorke, Helen M. Ginn","doi":"10.1101/2024.08.07.607056","DOIUrl":"https://doi.org/10.1101/2024.08.07.607056","url":null,"abstract":"The conformational landscape of proteins and associated dynamics is an essential component of function. Diverse conformations of highly populated metastable states are well-studied, but transitions between these states are rare, fleeting events. Neither molecular dynamics simulations nor experimental methods provide information about these. To address this conundrum, we present a computationally inexpensive algorithm, “cold-inbetweening”, which generates trajectories in torsion angle space. This minimises the overall kinetic energy needed to complete a transition between experimentally determined end-states. We use this method to provide mechanistic insight into three transporter superfamilies. This method allows interrogation of structural transitions, provides unique insights into coupled motion and hypotheses of action. The alternate access model of operation [1] is ubiquitous among many superfamilies of membrane transporters [2]. The model proposes that outward and inward pore opening is mutually exclusive, allowing ligand translocation but preventing damage from free solvent flow. Here, we study DraNramp (MntH) from Deinococcus radiodurians [3], MalT (bcMalT) from Bacillus cereus [4], and MATE (PfMATE) from Pyrococcus furiosus [5]. In MalT, the trajectory demonstrates elevator transport through unwinding of a supporter arm helix, maintaining the necessary and sufficient space to transport maltose. In DraNramp, this trajectory exhibited outward-gate closure prior to inward-gate opening, suggesting that the timing of gate closure is an inherent property of the protein architecture. In the MATE transporter, switching conformation involves the rewinding of an extended N-terminal helix. We suggest that the necessary motions to avoid steric backbone clashes forces this helix to plug the cavernous ligand-binding site during the conformational change. We propose helix unwinding as a general structural mechanism in membrane transporter function due to ease of helix register slippage in the lipid bilayer.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"59 8","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922766","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.07.606980
Preethi Rajamannar, O. Raz, G. Levkowitz
The hypothalamo-neurohypophyseal system is an important neuroendocrine brain-to-blood conduit through which the neurohormones oxytocin and arginine-vasopressin are released from the brain into the general circulation to affect peripheral physiological functions such as salt balance, metabolism and reproduction. However, whether an active mechanism executes fast and efficient neurohormone release to the periphery remains unsolved. We show that a hyperosmotic physiological challenge elicits a local increase in neurohypophyseal blood flow velocities and a change in capillary diameter, which is dictated by the geometry of the hypophyseal vascular microcircuit. Genetic ablation of oxytocin neurons and inhibition of oxytocin receptor signaling attenuated capillary blood flow and diameter. Optogenetic stimulation of oxytocin neurons resulted in an oxytocin receptor-dependent increase in blood flow velocities. Lastly, both osmotic challenge and oxytocin neuronal activation elicited a local rise in neurohypophyseal capillary permeability in an oxytocin signaling-dependent manner. Our study demonstrates that physiologically elicited changes in neurohypophyseal blood flow and permeability are regulated by oxytocin. We propose that oxytocin-dependent neuro-vascular coupling facilitates its efficient uptake into the blood circulation, suggesting a self-perpetuating mechanism of peripheral hormone transfer.
{"title":"Neuropeptide oxytocin facilitates its own brain-to-periphery uptake by regulating blood flow dynamics and permeability","authors":"Preethi Rajamannar, O. Raz, G. Levkowitz","doi":"10.1101/2024.08.07.606980","DOIUrl":"https://doi.org/10.1101/2024.08.07.606980","url":null,"abstract":"The hypothalamo-neurohypophyseal system is an important neuroendocrine brain-to-blood conduit through which the neurohormones oxytocin and arginine-vasopressin are released from the brain into the general circulation to affect peripheral physiological functions such as salt balance, metabolism and reproduction. However, whether an active mechanism executes fast and efficient neurohormone release to the periphery remains unsolved. We show that a hyperosmotic physiological challenge elicits a local increase in neurohypophyseal blood flow velocities and a change in capillary diameter, which is dictated by the geometry of the hypophyseal vascular microcircuit. Genetic ablation of oxytocin neurons and inhibition of oxytocin receptor signaling attenuated capillary blood flow and diameter. Optogenetic stimulation of oxytocin neurons resulted in an oxytocin receptor-dependent increase in blood flow velocities. Lastly, both osmotic challenge and oxytocin neuronal activation elicited a local rise in neurohypophyseal capillary permeability in an oxytocin signaling-dependent manner. Our study demonstrates that physiologically elicited changes in neurohypophyseal blood flow and permeability are regulated by oxytocin. We propose that oxytocin-dependent neuro-vascular coupling facilitates its efficient uptake into the blood circulation, suggesting a self-perpetuating mechanism of peripheral hormone transfer.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"11 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141923421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery, specifically targeting PTEN. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight elevated level of PTEN neddylation is markedly associated with resistance against Palbociclib, a CDK4/6 inhibitor used in HR+/HER2-breast cancer patients. Strikingly, we identified a potent inhibitor of PTEN neddylation which could obviously re-sensitized Palbociclib-therapy-resistant breast cancer. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more importantly, it stabilizes JUND by disrupting the interplay with its E3 ubiquitin ligase, ITCH. Therefore, the enhanced stability of JUND activates the AP-1/MAPK signaling pathway, resulting in the release of cytokines and chemokines, in turn, reprograming the tumor microenvironment, contributing to drug resistance, tumor recurrence and metastasis. This novel insight underscores the potential of targeting PTEN neddylation as a promising strategy for restoring the activity of key tumor suppressor and overcoming resistance in breast cancer therapy.
{"title":"PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer","authors":"Fan Liu, Weixiao Liu, Yawen Tan, Yaxin Shang, Sihui Ling, Xiaokun Jiang, Zhen Zhang, Shiyao Sun, Ping Xie","doi":"10.1101/2024.08.06.606911","DOIUrl":"https://doi.org/10.1101/2024.08.06.606911","url":null,"abstract":"The gradual emergence of a novel therapeutic approach lies in the restoration of tumor suppressive machinery, specifically targeting PTEN. Protein neddylation modification contributes to PTEN inactivation and fuels breast cancer progression. Here, we highlight elevated level of PTEN neddylation is markedly associated with resistance against Palbociclib, a CDK4/6 inhibitor used in HR+/HER2-breast cancer patients. Strikingly, we identified a potent inhibitor of PTEN neddylation which could obviously re-sensitized Palbociclib-therapy-resistant breast cancer. Mechanistically, PTEN neddylation activates the PI3K/Akt signaling pathway, and more importantly, it stabilizes JUND by disrupting the interplay with its E3 ubiquitin ligase, ITCH. Therefore, the enhanced stability of JUND activates the AP-1/MAPK signaling pathway, resulting in the release of cytokines and chemokines, in turn, reprograming the tumor microenvironment, contributing to drug resistance, tumor recurrence and metastasis. This novel insight underscores the potential of targeting PTEN neddylation as a promising strategy for restoring the activity of key tumor suppressor and overcoming resistance in breast cancer therapy.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"9 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141921733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-09DOI: 10.1101/2024.08.08.607136
K. Labek, Roberto Viviani
The cyberball paradigm has been used in numerous neuroimaging studies to elicit activation in neural substrates of social exclusion. Using arterial spin labelling, an approach allowing quantitative estimates of blood perfusion, we replicate findings of meta-analyses of this paradigm in the inferior frontal gyrus and ventral cingular cortex, but show that these areas were also active in a watch condition (in which participants were not excluded), although less so. These findings relativize a simple interpretation of these areas as the neural substrates of social exclusion, as in previous studies. In a broader experimental context, similar activations have been reported by neuroimaging studies when semantic disambiguation and evaluation of action goals are required, an interpretation that may apply also to the cyberball effects.
{"title":"The neural correlates of social rejection in the cyberball paradigm: An arterial spin labelling study","authors":"K. Labek, Roberto Viviani","doi":"10.1101/2024.08.08.607136","DOIUrl":"https://doi.org/10.1101/2024.08.08.607136","url":null,"abstract":"The cyberball paradigm has been used in numerous neuroimaging studies to elicit activation in neural substrates of social exclusion. Using arterial spin labelling, an approach allowing quantitative estimates of blood perfusion, we replicate findings of meta-analyses of this paradigm in the inferior frontal gyrus and ventral cingular cortex, but show that these areas were also active in a watch condition (in which participants were not excluded), although less so. These findings relativize a simple interpretation of these areas as the neural substrates of social exclusion, as in previous studies. In a broader experimental context, similar activations have been reported by neuroimaging studies when semantic disambiguation and evaluation of action goals are required, an interpretation that may apply also to the cyberball effects.","PeriodicalId":505198,"journal":{"name":"bioRxiv","volume":"7 9","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141922100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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