Cardiac sodium channel palmitoylation regulates channel availability and myocyte excitability with implications for arrhythmia generation

Cardiac voltage-gated sodium channels (Nav1.5) play an essential role in regulating cardiac electric activity by initiating and propagating action potentials in the heart. Altered Nav1.5 function is associated with multiple cardiac diseases including long-QT3 and Brugada syndrome. Here, we show that Nav1.5 is subject to palmitoylation, a reversible post-translational lipid modification. Palmitoylation increases channel availability and late sodium current activity, leading to enhanced cardiac excitability and prolonged action potential duration. In contrast, blocking palmitoylation increases closed-state channel inactivation and reduces myocyte excitability. We identify four cysteines as possible Nav1.5 palmitoylation substrates. A mutation of one of these is associated with cardiac arrhythmia (C981F), induces a significant enhancement of channel closed-state inactivation and ablates sensitivity to depalmitoylation. Our data indicate that alterations in palmitoylation can substantially control Nav1.5 function and cardiac excitability and this form of post-translational modification is likely an important contributor to acquired and congenital arrhythmias

Optical flow-based vascular respiratory motion compensation

This paper develops a new vascular respiratory motion compensation algorithm, Motion-Related Compensation (MRC), to conduct vascular respiratory motion compensation by extrapolating the correlation between invisible vascular and visible non-vascular. Robot-assisted vascular intervention can significantly reduce the radiation exposure of surgeons. In robot-assisted image-guided intervention, blood vessels are constantly moving/deforming due to respiration, and they are invisible in the X-ray images unless contrast agents are injected. The vascular respiratory motion compensation technique predicts 2D vascular roadmaps in live X-ray images. When blood vessels are visible after contrast agents injection, vascular respiratory motion compensation is conducted based on the sparse Lucas-Kanade feature tracker. An MRC model is trained to learn the correlation between vascular and non-vascular motions. During the intervention, the invisible blood vessels are predicted with visible tissues and the trained MRC model. Moreover, a Gaussian-based outlier filter is adopted for refinement. Experiments on in-vivo data sets show that the proposed method can yield vascular respiratory motion compensation in 0.032 sec, with an average error 1.086 mm. Our real-time and accurate vascular respiratory motion compensation approach contributes to modern vascular intervention and surgical robots.Comment: This manuscript has been accepted by IEEE Robotics and Automation Letter

Iterative PnP and its application in 3D-2D vascular image registration for robot navigation

This paper reports on a new real-time robot-centered 3D-2D vascular image alignment algorithm, which is robust to outliers and can align nonrigid shapes. Few works have managed to achieve both real-time and accurate performance for vascular intervention robots. This work bridges high-accuracy 3D-2D registration techniques and computational efficiency requirements in intervention robot applications. We categorize centerline-based vascular 3D-2D image registration problems as an iterative Perspective-n-Point (PnP) problem and propose to use the Levenberg-Marquardt solver on the Lie manifold. Then, the recently developed Reproducing Kernel Hilbert Space (RKHS) algorithm is introduced to overcome the ``big-to-small'' problem in typical robotic scenarios. Finally, an iterative reweighted least squares is applied to solve RKHS-based formulation efficiently. Experiments indicate that the proposed algorithm processes registration over 50 Hz (rigid) and 20 Hz (nonrigid) and obtains competing registration accuracy similar to other works. Results indicate that our Iterative PnP is suitable for future vascular intervention robot applications.Comment: Submitted to ICRA 202

Generating Giant and Tunable Nonlinearity in a Macroscopic Mechanical Resonator from Chemical Bonding Force

Nonlinearity in macroscopic mechanical system plays a crucial role in a wide variety of applications, including signal transduction and processing, synchronization, and building logical devices. However, it is difficult to generate nonlinearity due to the fact that macroscopic mechanical systems follow the Hooke's law and response linearly to external force, unless strong drive is used. Here we propose and experimentally realize a record-high nonlinear response in macroscopic mechanical system by exploring the anharmonicity in deforming a single chemical bond. We then demonstrate the tunability of nonlinear response by precisely controlling the chemical bonding interaction, and realize a cubic elastic constant of \mathversion{bold}$2 \times 10^{18}~{\rm N}/{\rm m^3}$, many orders of magnitude larger in strength than reported previously. This enables us to observe vibrational bistate transitions of the resonator driven by the weak Brownian thermal noise at 6~K. This method can be flexibly applied to a variety of mechanical systems to improve nonlinear responses, and can be used, with further improvements, to explore macroscopic quantum mechanics

Stereoselective Regulations of P-Glycoprotein by Ginsenoside Rh2 Epimers and the Potential Mechanisms From the View of Pharmacokinetics

Chirality is an interesting topic and it is meaningful to explore the interactions between chiral small molecules and stereoselective biomacromolecules, with pre-clinical and clinical significances. We have previously demonstrated that 20(S)-ginsenoside Rh2 is an effective P-glycoprotein (P-gp) inhibitor in vitro and in vivo. Considering the stereochemistry of ginsenoside Rh2, in our present study, the regulatory effects of 20(R)-Rh2 on P-gp were assayed in vivo, and the differential regulations of P-gp by ginsenoside Rh2 epimers in vivo were compared and studied. Results showed that 20(S)-Rh2 enhanced the oral absorption of digoxin in rats in a dose-dependent manner; 20(R)-Rh2 at low dosage increased the oral absorption of digoxin, but this effect diminished with elevated dosage of 20(R)-Rh2. Further studies indicated stereoselective pharmacokinetic profiles and intestinal biotransformations of Rh2 epimers. In vitro studies showed that Rh2 epimers and their corresponding deglycosylation metabolites protopanaxadiol (Ppd) epimers all exhibited stereoselective regulations of P-gp. In conclusion, in view of the in vitro and in vivo dispositions of Rh2 and the regulations of P-gp by Rh2 and Ppd, it is suggested that the P-gp regulatory effect of Rh2 in vivo actually is a double actions of both Rh2 and Ppd, and the net effect is determined by the relative balance between Rh2 and Ppd with the same configuration. Our study provides new evidence of the chiral characteristics of P-gp, and is helpful to elucidate the stereoselective P-gp regulation mechanisms of ginsenoside Rh2 epimers in vivo from a pharmacokinetic view

Differential expression of CaMKII isoforms and overall kinase activity in rat dorsal root ganglia after injury.

Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) decodes neuronal activity by translating cytoplasmic Ca(2+) signals into kinase activity that regulates neuronal functions including excitability, gene expression, and synaptic transmission. Four genes lead to developmental and differential expression of CaMKII isoforms (α, β, γ, δ). We determined mRNA levels of these isoforms in the dorsal root ganglia (DRG) of adult rats with and without nerve injury in order to determine if differential expression of CaMKII isoforms may contribute to functional differences that follow injury. DRG neurons express mRNA for all four isoforms, and the relative abundance of CaMKII isoforms was γ>α>β=δ, based on the CT values. Following ligation of the 5th lumbar (L5) spinal nerve (SNL), the β isoform did not change, but mRNA levels of both the γ and α isoforms were reduced in the directly injured L5 neurons, and the α isoform was reduced in L4 neurons, compared to their contemporary controls. In contrast, expression of the δ isoform mRNA increased in L5 neurons. CaMKII protein decreased following nerve injury in both L4 and L5 populations. Total CaMKII activity measured under saturating Ca(2+)/CaM conditions was decreased in both L4 and L5 populations, while autonomous CaMKII activity determined in the absence of Ca(2+) was selectively reduced in axotomized L5 neurons 21days after injury. Thus, loss of CaMKII signaling in sensory neurons after peripheral nerve injury may contribute to neuronal dysfunction and pain

Flexible nets: disorder and induced fit in the associations of p53 and 14-3-3 with their partners

Background: Proteins are involved in many interactions with other proteins leading to networks that regulate and control a wide variety of physiological processes. Some of these proteins, called hub proteins or hubs, bind to many different protein partners. Protein intrinsic disorder, via diversity arising from structural plasticity or flexibility, provide a means for hubs to associate with many partners (Dunker AK, Cortese MS, Romero P, Iakoucheva LM, Uversky VN: Flexible Nets: The roles of intrinsic disorder in protein interaction networks. FEBS J 2005, 272:5129-5148). Results: Here we present a detailed examination of two divergent examples: 1) p53, which uses different disordered regions to bind to different partners and which also has several individual disordered regions that each bind to multiple partners, and 2) 14-3-3, which is a structured protein that associates with many different intrinsically disordered partners. For both examples, three-dimensional structures of multiple complexes reveal that the flexibility and plasticity of intrinsically disordered protein regions as well as induced-fit changes in the structured regions are both important for binding diversity. Conclusions: These data support the conjecture that hub proteins often utilize intrinsic disorder to bind to multiple partners and provide detailed information about induced fit in structured regions