Loop Interactions Research Articles

RNA fold prediction by Monte Carlo in graph space and the statistical mechanics of tertiary interactions.

Using a graph representation of RNA structures, we have studied the ensembles of secondary and tertiary graphs two sets of RNA with Monte Carlo simulations. The first consisted of 91 target ribozyme and riboswitch sequences of moderate lengths (< 150 nt) having a variety of secondary, H-type pseudoknots and kissing loop interactions. The second set consisted of 71 more diverse sequences across many RNA families. Using a simple empirical energy model for tertiary interactions and only sequence information for each target as input, the simulations examined how tertiary interactions impact the statistical mechanics of the fold ensembles. The results show that the graphs proliferate enormously when tertiary interactions are possible, producing an entropic driving force for the ensemble to access folds having tertiary structures even though they are overall energetically unfavorable in the energy model. For each of the targets in the two test sets, we assessed the quality of the model and the simulations by examining how well the simulated structures were able to predict the native fold and compared the results to fold predictions from ViennaRNA. Our model generated good or excellent predictions in a large majority of the targets. Overall, this method was able to produce predictions of comparable quality to Vienna, but it outperformed Vienna for structures with H-type pseudoknots. The results suggest that while tertiary interactions are predicated on real-space contacts, their impacts on the folded structure of RNA can be captured by graph space information for sequences of moderate lengths, using a simple tertiary energy model for the loops, the base pairs and base stacks.

Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists.

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.

Activation of polycystin-1 signaling by binding of stalk-derived peptide agonists

Polycystin-1 (PC1) is the protein product of the PKD1 gene whose mutation causes autosomal dominant Polycystic Kidney Disease (ADPKD). PC1 is an atypical G protein-coupled receptor (GPCR) with an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal and membrane-embedded C-terminal (CTF) fragments. Recently, activation of PC1 CTF signaling was shown to be regulated by a stalk tethered agonist (TA), resembling the mechanism observed for adhesion GPCRs. Here, synthetic peptides of the first 9- (p9), 17- (p17), and 21-residues (p21) of the PC1 stalk TA were shown to re-activate signaling by a stalkless CTF mutant in human cell culture assays. Novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) simulations elucidated binding conformations of p9, p17, and p21 and revealed multiple specific binding regions to the stalkless CTF. Peptide agonists binding to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of stalk TA-mediated PC1 CTF activation. Additional sequence coevolution analyses showed the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. These insights into the structural dynamic mechanism of PC1 activation by TA peptide agonists provide an in-depth understanding that will facilitate the development of therapeutics targeting PC1 for ADPKD treatment.

The Interaction Fidelity Model: A Taxonomy to Communicate the Different Aspects of Fidelity in Virtual Reality

Fidelity describes how closely a replication resembles the original. It can be helpful to analyze how faithful interactions in virtual reality (VR) are to a reference interaction. In prior research, fidelity has been restricted to the simulation of reality—also called realism. Our definition includes other reference interactions, such as superpowers or fiction. Interaction fidelity is a multilayered concept. Unfortunately, different aspects of fidelity have either not been distinguished in scientific discourse or referred to with inconsistent terminology. Therefore, we present the Interaction Fidelity Model (IntFi Model). Based on the human-computer interaction loop, it systematically covers all stages of VR interactions. The conceptual model establishes a clear structure and precise definitions of eight distinct components. As a communication tool, it helps teams to understand and discuss fidelity in VR. It was reviewed through workshops with fourteen VR experts. We provide guidelines, diverse examples, and educational material to apply the IntFi Model universally to any VR experience and propose foundational research opportunities.

Numerical investigation of the collision of a vortex pair upon a solid wavy wall

The vortex dynamics produced by the collision of a vortex pair with a solid wavy wall are examined numerically using a proposed high-order vortex particle method. The influences of the Reynolds number (ReΓ) of the vortex pair, the wavelength (λw), and the wave amplitude (Aw) of the wall on the induced vortex structures, interactions among vortices, and the instability and reconnection of secondary vortices are discussed. The boundary layers at the top of ripples separate first to form the secondary vortices moving around the primary tubes. Meanwhile, the boundary layers at the bottom of ripples detach late, move vertically upward, and then form incomplete vortex loops due to an unsuccessful reconnection of the secondary vortices. The ReΓ effects cause the appearance of various vortex structures, such as incomplete primary vortex loops from the bottom of ripples at ReΓ=1000, secondary vortex loops due to interactions of the first loops with the wall at ReΓ=2000, and hairpin vortices at ReΓ=4000. The wavelength of the wall induces instability in the secondary vortex tubes. This instability on the secondary tubes appears at the top of ripples at λw=2r0, while it spreads over the whole secondary vortices at λw=4r0, where r0 is the initial spacing between the primary vortex tubes. This instability results in various wavy tubes that robustly interact with the primary tubes. Due to the effects of Aw, the primary vortex tubes significantly decay with time compared to those in the flat wall case.

Synchronization Stability Analysis and Parameter Design of Grid-Following Inverters Considering the Interactions of Current Control and Phase-Locked Loop

Synchronization Stability Analysis and Parameter Design of Grid-Following Inverters Considering the Interactions of Current Control and Phase-Locked Loop

Grassroots learning through indigenous co-design for a Kvmemongen in Coastal Lake Budi, Chile

ABSTRACT Given calls to decolonise engagement with Indigenous communities, this article explores how allied researchers can participate in self-determined learning with Indigenous Peoples. Drawing on over a decade of experience within an action-research collective in a Mapuche context, the authors suggest that allied researchers can accompany Indigenous-led co-design in a manner that not only strengthens genuine Indigenous participation but also fosters mutual and collective learning from within the co-creative processes themselves. Lake Budi, a biocultural hotspot in the Pacific coast of Northern Patagonia, Chile, is a coastal wetland habitat for hundreds of endemic and migratory species and the ancestral homeland for the Mapuche-Lafkenche (∼15,000) who, through grassroots learning, are determining practical steps towards restoring their territory and its self-governance for kvmemongen. This Mapuche concept refers broadly to enacting forms of living well together, humans and non-humans. As allied participants in a Mapuche-led codesign collective since 2013, in this paper, we focus on exploring key “moments of mutual learning” within this longer-than-usual co-design process. Each of these moments involved collective learning that required interaction and feedback loops across diverse areas of expertise, made possible over longer and flexible rhythms and periods. Tools, protocols, and methods gradually take shape in such a process through mutual learning opportunities provided by relationship building, cultural immersion, community-led protocols, decision-making, and evaluation mechanisms. This work suggests a new understanding of the involvement of allied researchers in Indigenous-led co-design as an emerging and increasingly relevant form of grassroots mutual learning toward climate resilience.

Tactile and kinesthetic communication glove with fusion of triboelectric sensing and pneumatic actuation

Dexterous manipulation of hand plays a crucial role in daily life, industrial productivity, and research laboratory, etc. Evolution of humanoid robot and virtual training technique raise the demand of human machine interface with fusion of both sensing and feedback functions to realize the close loop interactions. Here, we present a modular glove which combines triboelectric sensor and pneumatic actuator for enabling multi-modal and multi-dimensional sensing and feedback. Owing to commonalities of materials and structural design, pneumatic actuator and triboelectric sensor can be seamlessly merged. The integration of fingertip module and finger module offers cutaneous and kinesthetic feedback with the corresponding sensing functions. The whole glove can perform sensing and actuation for most of the interactive activities, such as touching, twisting, grabbing, rubbing, etc. With the customized wearable signal processing and control system, the robotic hand manipulation and virtual training program were demonstrated to verify the capabilities of improving the tactile perception in different scenarios. In general, the proposed device with a minimalistic design and multi-modal sensing and feedback can improve the issue of missing or mismatch of tactile communication in robotic teleoperation, virtual training, and rehabilitation.

An Oscillation Stability Analysis of a Direct-Driven Wind Power Grid-Connected System Considering Low Voltage Ride Though from an Energy Perspective

To solve the problem of the oscillation stability of direct-driven wind-powered grid-connected systems with a low-voltage crossing control, a method of oscillation stability analysis for these systems, based on interactive energy, is proposed in this paper. Firstly, a dynamic energy model of a direct-driven wind-powered grid-connected system is established, considering a low-voltage traverse control. Secondly, the energy is divided into four parts—the line parameter energy, current inner loop energy, PLL energy, and current inner loop–PLL interaction energy—and the conduction path of the energy during a low-voltage crossing is described. On this basis, the aperiodic components of each energy path are analyzed, the stability level of the system is quantified, the influence of the different control parameters on the interactive energy dissipation is deduced, the key interactive control links affecting the stability of the system are screened, and the influence rules of the parameters are expounded. Finally, a direct-driven wind-powered grid-connected system model is built on the Rt-lab platform, and it is verified by a simulation test. The results show that the interaction energy generated by the interaction of the current inner loop and phase-locked loop is a key factor affecting the stability of the direct-driven wind-powered grid-connected system. The simulation test parameters of the control group were adjusted as the current inner loop’s proportion parameter increased from 1.32 to 5.28, the current inner loop’s integral parameter increased from 4.48 to 6.42, the PLL’s proportion parameter decreased from 9.45 to 6.3, and the PLL’s integral parameter decreased from 50.25 to 40.2. Both the theoretical and experimental results show that increasing the current inner loop’s integral and proportion parameters can improve the stability level of the direct-driven wind-powered grid-connected system; reducing the phase-locked loop’s proportion and integral parameters can also improve the stability level of the grid-connected system.

Graph Artificial Intelligence in Medicine.

In clinical artificial intelligence (AI), graph representation learning, mainly through graph neural networks and graph transformer architectures, stands out for its capability to capture intricate relationships and structures within clinical datasets. With diverse data-from patient records to imaging-graph AI models process data holistically by viewing modalities and entities within them as nodes interconnected by their relationships. Graph AI facilitates model transfer across clinical tasks, enabling models to generalize across patient populations without additional parameters and with minimal to no retraining. However, the importance of human-centered design and model interpretability in clinical decision-making cannot be overstated. Since graph AI models capture information through localized neural transformations defined on relational datasets, they offer both an opportunity and a challenge in elucidating model rationale. Knowledge graphs can enhance interpretability by aligning model-driven insights with medical knowledge. Emerging graph AI models integrate diverse data modalities through pretraining, facilitate interactive feedback loops, and foster human-AI collaboration, paving the way toward clinically meaningful predictions.

Artificially inserted strong promoter containing multiple G-quadruplexes induces long-range chromatin modification.

Although the role of G-quadruplex (G4) DNA structures has been suggested in chromosomal looping this was not tested directly. Here, to test causal function, an array of G4s, or control sequence that does not form G4s, were inserted within chromatin in cells. In vivo G4 formation of the inserted G4 sequence array, and not the control sequence, was confirmed using G4-selective antibody. Compared to the control insert, we observed a remarkable increase in the number of 3D chromatin looping interactions from the inserted G4 array. This was evident within the immediate topologically associated domain (TAD) and throughout the genome. Locally, recruitment of enhancer histone marks and the transcriptional coactivator p300/Acetylated-p300 increased in the G4-array, but not in the control insertion. Resulting promoter-enhancer interactions and gene activation were clear up to 5 Mb away from the insertion site. Together, these show the causal role of G4s in enhancer function and long-range chromatin interactions. Mechanisms of 3D topology are primarily based on DNA-bound architectural proteins that induce/stabilize long-range interactions. Involvement of the underlying intrinsic DNA sequence/structure in 3D looping shown here therefore throws new light on how long-range chromosomal interactions might be induced or maintained.

Artificially inserted strong promoter containing multiple G-quadruplexes induces long-range chromatin modification

Although the role of G-quadruplex (G4) DNA structures has been suggested in chromosomal looping this was not tested directly. Here, to test causal function, an array of G4s, or control sequence that does not form G4s, were inserted within chromatin in cells. In vivo G4 formation of the inserted G4 sequence array, and not the control sequence, was confirmed using G4-selective antibody. Compared to the control insert, we observed a remarkable increase in the number of 3D chromatin looping interactions from the inserted G4 array. This was evident within the immediate topologically associated domain (TAD) and throughout the genome. Locally, recruitment of enhancer histone marks and the transcriptional coactivator p300/Acetylated-p300 increased in the G4-array, but not in the control insertion. Resulting promoter-enhancer interactions and gene activation were clear up to 5 Mb away from the insertion site. Together, these show the causal role of G4s in enhancer function and long-range chromatin interactions. Mechanisms of 3D topology are primarily based on DNA-bound architectural proteins that induce/stabilize long-range interactions. Involvement of the underlying intrinsic DNA sequence/structure in 3D looping shown here therefore throws new light on how long-range chromosomal interactions might be induced or maintained.

Transient synchronization stability of a weak‐grid connected VSC considering the interaction of outer control loops and PLL dynamics

AbstractSince these large‐scale renewable power generation (RPGs) stations are always located far away from load centres, voltage source converters (VSCs) always operate in weak‐grid connected conditions, due to the long distance of transmission line and increasing capacity of RPGs. Large power disturbance of RPGs easily causes weak‐grid connected VSCs (WG‐VSCs) suffering from transient synchronization instability issue, which is lack of theoretical and quantitative analysis. This paper is motivated to fill this gap. By considering the dynamic interaction of outer DC voltage control, reactive power loop, and phase‐locked loop (PLL), an equivalent synchronization model of a WG‐VSC system is established first. Then, the mechanism of transient synchronization instability is revealed by the combination of equal area criterion and numerical integration method. Furthermore, the concept of feasible region of active power disturbance (FR‐APD) is introduced for the first time. With the constructed FR‐APD, the transient stability of the WG‐VSC system can be confirmed. Finally, experimental results based on the RT‐BOX hardware‐in‐the‐loop platform are presented to verify the theoretical analysis.

Members of an array of zinc finger proteins specify distinct Hox chromatin boundaries.

Partitioning of repressive from actively transcribed chromatin in mammalian cells fosters cell-type specific gene expression patterns. While this partitioning is reconstructed during differentiation, the chromatin occupancy of the key insulator, CTCF, is unchanged at the developmentally important Hox clusters. Thus, dynamic changes in chromatin boundaries must entail other activities. Given its requirement for chromatin loop formation, we examined cohesin-based chromatin occupancy without known insulators, CTCF and MAZ, and identified a family of zinc finger proteins (ZNFs), some of which exhibit tissue-specific expression. Two such ZNFs foster chromatin boundaries at the Hox clusters that are distinct from each other and from MAZ. PATZ1 was critical to the thoracolumbar boundary in differentiating motor neurons and mouse skeleton, while ZNF263 contributed to cervicothoracic boundaries. We propose that these insulating activities act with cohesin, alone or combinatorially, with or without CTCF, to implement precise positional identity and cell fate during development.

Single-cell tumor heterogeneity landscape of hepatocellular carcinoma: unraveling the pro-metastatic subtype and its interaction loop with fibroblasts

BackgroundTumor heterogeneity presents a formidable challenge in understanding the mechanisms driving tumor progression and metastasis. The heterogeneity of hepatocellular carcinoma (HCC) in cellular level is not clear.MethodsIntegration analysis of single-cell RNA sequencing data and spatial transcriptomics data was performed. Multiple methods were applied to investigate the subtype of HCC tumor cells. The functional characteristics, translation factors, clinical implications and microenvironment associations of different subtypes of tumor cells were analyzed. The interaction of subtype and fibroblasts were analyzed.ResultsWe established a heterogeneity landscape of HCC malignant cells by integrated 52 single-cell RNA sequencing data and 5 spatial transcriptomics data. We identified three subtypes in tumor cells, including ARG1+ metabolism subtype (Metab-subtype), TOP2A+ proliferation phenotype (Prol-phenotype), and S100A6+ pro-metastatic subtype (EMT-subtype). Enrichment analysis found that the three subtypes harbored different features, that is metabolism, proliferating, and epithelial-mesenchymal transition. Trajectory analysis revealed that both Metab-subtype and EMT-subtype originated from the Prol-phenotype. Translation factor analysis found that EMT-subtype showed exclusive activation of SMAD3 and TGF-β signaling pathway. HCC dominated by EMT-subtype cells harbored an unfavorable prognosis and a deserted microenvironment. We uncovered a positive loop between tumor cells and fibroblasts mediated by SPP1-CD44 and CCN2/TGF-β-TGFBR1 interaction pairs. Inhibiting CCN2 disrupted the loop, mitigated the transformation to EMT-subtype, and suppressed metastasis.ConclusionBy establishing a heterogeneity landscape of malignant cells, we identified a three-subtype classification in HCC. Among them, S100A6+ tumor cells play a crucial role in metastasis. Targeting the feedback loop between tumor cells and fibroblasts is a promising anti-metastatic strategy.

Dynamic alternations of three-dimensional chromatin architecture contribute to phenotypic characteristics of breast muscle in chicken

Breast muscle growth rate and intramuscular fat (IMF) content show apparent differences between fast-growing broilers and slow-growing indigenous chickens. However, the underlying genetic basis of these phenotypic characteristics remains elusive. In this study, we investigate the dynamic alterations of three-dimensional genome architecture and chromatin accessibility in breast muscle across four key developmental stages from embryo to starter chick in Arbor Acres (AA) broilers and Yufen (YF) indigenous chickens. The limited breed-specifically up-regulated genes (Bup-DEGs) are embedded in breed-specific A compartment, while a majority of the Bup-DEGs involving myogenesis and adipogenesis are regulated by the breed-specific TAD reprogramming. Chromatin loops allow distal accessible regions to interact with myogenic genes, and those loops share an extremely low similarity between chicken with different growth rate. Moreover, AA-specific loop interactions promote the expression of 40 Bup-DEGs, such as IGF1, which contributes to myofiber hypertrophy. YF-specific loop interactions or distal accessible regions lead to increased expression of 5 Bup-DEGs, including PIGO, PEMT, DHCR7, TMEM38B, and DHDH, which contribute to IMF deposition. These results help elucidate the regulation of breast muscle growth and IMF deposition in chickens.

Reversible acetylation of HDAC8 regulates cell cycle

HDAC8, a member of class I HDACs, plays a pivotal role in cell cycle regulation by deacetylating the cohesin subunit SMC3. While cyclins and CDKs are well-established cell cycle regulators, our knowledge of other regulators remains limited. Here we reveal the acetylation of K202 in HDAC8 as a key cell cycle regulator responsive to stress. K202 acetylation in HDAC8, primarily catalyzed by Tip60, restricts HDAC8 activity, leading to increased SMC3 acetylation and cell cycle arrest. Furthermore, cells expressing the mutant form of HDAC8 mimicking K202 acetylation display significant alterations in gene expression, potentially linked to changes in 3D genome structure, including enhanced chromatid loop interactions. K202 acetylation impairs cell cycle progression by disrupting the expression of cell cycle-related genes and sister chromatid cohesion, resulting in G2/M phase arrest. These findings indicate the reversible acetylation of HDAC8 as a cell cycle regulator, expanding our understanding of stress-responsive cell cycle dynamics.

Molecular biological role of epithelial splicing regulatory protein1 in intrahepatic cholangiocarcinoma.

Epithelial splicing regulatory protein1 (ESRP1) regulates tumor progression and metastasis through the epithelial‒mesenchymal transition by interacting with zinc finger E-box binding1 (ZEB1) and CD44 in cancers. However, the role of ESRP1 in intrahepatic cholangiocarcinoma (iCCA) remains unclear. Three iCCA cell lines (HuCCT-1, SSP-25, and KKU-100) were analyzed using small interfering RNA to investigate the molecular biological functions of ESRP1 and ZEB1. The association between clinicopathological features and the expression of ESRP1 and ZEB1 in iCCA tissues was analyzed immunohistochemically. Proteomic analysis was performed to identify molecules related to ESRP1 expression. ESRP1 expression was upregulated in HuCCT-1 and SSP-25 cells. Cell migration and invasion were enhanced, and the expression of ZEB1 and CD44s (CD44 standard) isoforms were upregulated in the ESRP1 silencing cells. Moreover, ESRP1 silencing increased the expression of N-cadherin and vimentin, indicating the presence of mesenchymal properties. Conversely, ZEB1 silencing increased the expression of ESRP1 and CD44v (CD44 variant) isoforms. Immunohistochemical analysis revealed that a lower ESRP1-to-ZEB1 expression ratio was associated with poor recurrence-free survival in patients with iCCA. Flotillin 2, a lipid raft marker related to epithelial‒mesenchymal transition, was identified as a protein related to the interactive feedback loop in proteomic analysis. ESRP1 suppresses tumor progression in iCCA by interacting with ZEB1 and CD44 to regulate epithelial‒mesenchymal transition.

A decentralized optimal PID controller with disk margin-based robust stability analysis for higher-order industrial systems

ABSTRACT Decentralized control systems are frequently employed to tackle control challenges in multi-input multi-output (MIMO) systems. Hence, this paper proposes a decentralized PID controller that relies on frequency domain specifications. This controller is designed to minimize the loop interactions and fulfill the design criteria of the MIMO system. The PID parameters are calculated based on gain and phase margin specifications. Additionally, a first-order plus dead time model is derived for each of the decoupled subsystems. Furthermore, robust stability is analysed using disc margin analysis, which overcomes the constraints of traditional margins. Moreover, the paper determines a secure range of uncertainty for various levels of gain and phase uncertainties. The findings suggest that the proposed controller achieves robust stability over a broader range of margins when compared to alternative control methods.

Activation of Polycystin-1 Signaling by Binding of Stalk-derived Peptide Agonists.

Polycystin-1 (PC1) is the membrane protein product of the PKD1 gene whose mutation is responsible for 85% of the cases of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is primarily characterized by the formation of renal cysts and potential kidney failure. PC1 is an atypical G protein-coupled receptor (GPCR) consisting of 11 transmembrane helices and an autocatalytic GAIN domain that cleaves PC1 into extracellular N-terminal (NTF) and membrane-embedded C-terminal (CTF) fragments. Recently, signaling activation of the PC1 CTF was shown to be regulated by a stalk tethered agonist (TA), a distinct mechanism observed in the adhesion GPCR family. A novel allosteric activation pathway was elucidated for the PC1 CTF through a combination of Gaussian accelerated molecular dynamics (GaMD), mutagenesis and cellular signaling experiments. Here, we show that synthetic, soluble peptides with 7 to 21 residues derived from the stalk TA, in particular, peptides including the first 9 residues (p9), 17 residues (p17) and 21 residues (p21) exhibited the ability to re-activate signaling by a stalkless PC1 CTF mutant in cellular assays. To reveal molecular mechanisms of stalk peptide-mediated signaling activation, we have applied a novel Peptide GaMD (Pep-GaMD) algorithm to elucidate binding conformations of selected stalk peptide agonists p9, p17 and p21 to the stalkless PC1 CTF. The simulations revealed multiple specific binding regions of the stalk peptide agonists to the PC1 protein including an "intermediate" bound yet inactive state. Our Pep-GaMD simulation findings were consistent with the cellular assay experimental data. Binding of peptide agonists to the TOP domain of PC1 induced close TOP-putative pore loop interactions, a characteristic feature of the PC1 CTF signaling activation mechanism. Using sequence covariation analysis of PC1 homologs, we further showed that the peptide binding regions were consistent with covarying residue pairs identified between the TOP domain and the stalk TA. Therefore, structural dynamic insights into the mechanisms of PC1 activation by stalk-derived peptide agonists have enabled an in-depth understanding of PC1 signaling. They will form a foundation for development of PC1 as a therapeutic target for the treatment of ADPKD.