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The blood–brain barrier (BBB) has hampered the efficiency of nanoparticle delivery into the brain via conventional strategies. The widening of BBB tight junctions via focused ultrasound (FUS) offers a promising approach for enhancing the delivery of nanoparticles into the brain. However, there is currently an insufficient understanding of how nanoparticles pass through the opened BBB gaps. Here we investigated the size-dependence of nanoparticle delivery into the brain assisted by FUS-induced BBB opening, using gold nanoparticles (AuNPs) of 3, 15, and 120 nm diameter. For 3- and 15-nm AuNPs, FUS exposure significantly increased permeation across an in vitro BBB model by up to 9.5 times, and the permeability was higher with smaller diameter. However, in vivo transcranial FUS exposure in mice demonstrated that smaller particles were not necessarily better for delivery into the brain. Medium-sized (15 nm) AuNPs showed the highest delivery efficiency (0.22% ID), compared with 3- and 120-nm particles. A computational model suggested that this optimum size was determined by the competition between their permeation through opened BBB gaps and their excretion from blood. Our results would greatly contribute to designing nanoparticles for their delivery into the brain for the treatment of central nervous system diseases.

Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death. Cardiac immune cells play various roles in the maintenance of homeostasis and diseases in the heart. Here the authors show that cardiac resident macrophages are a critical regulator of cardiac impulse conduction through amphiregulin production, contributing to the prevention of sudden death.

Robot grasping constitutes an essential capability in fulfilling the complexities of advanced industrial operations. This field has been extensively investigated to address a range of practical applications. However, the generation of a stable grasp remains challenging, principally due to the constraints imposed by object geometries and the diverse objectives of the tasks. In this work, we propose a novel learning from demonstration-based grasp-planning framework. This framework is designed to extract crucial human grasp skills, namely the contact region and approach direction, from a single demonstration. Then, it formulates an optimization problem that integrates the extracted skills to generate a stable grasp. Distinct from conventional methods that rely on learning implicit synergies through human demonstration or on mapping the dissimilar kinematics between human hands and robot grippers, our approach focuses on learning the intuitive human intent that involves the potential contact regions and the grasping approach direction. Furthermore, our optimization formulation is capable of identifying the optimal grasp by minimizing the surface fitting error between the demonstrated contact regions on the object and the gripper finger surface and imposing a penalty for any misalignment between the demonstrated and the gripper’s approach directions. A series of experiments is conducted to verify the effectiveness of the proposed algorithm through both simulations and real-world scenarios.

We propose a novel approach for robotic industrial insertion tasks using the Programming by Demonstration technique. Our method allows robots to learn a high-precision task by observing human demonstration once, without requiring any prior knowledge of the object. We introduce an Imitated-to-Finetuned approach that generates imitated approach trajectories by cloning the human hand’s movements and then fine-tunes the goal position with a visual servoing approach. To identify features on the object used in visual servoing, we model object tracking as the moving object detection problem, separating each demonstration video frame into the moving foreground that includes the object and demonstrator’s hand and the static background. Then a hand keypoints estimation function is used to remove the redundant features on the hand. The experiment shows that the proposed method can make robots learn precision industrial insertion tasks from a single human demonstration.

BackgroundLaparoscopic lateral pelvic lymph node dissection (LPLND) in rectal cancer surgery requires considerable skill because the pelvic arteries, which need to be located to guide the dissection, are covered by other tissues and cannot be observed on laparoscopic views. Therefore, surgeons need to localize the pelvic arteries accurately before dissection, to prevent injury to these arteries.MethodsThis report proposes a surgical navigation system to facilitate artery localization in laparoscopic LPLND by combining ultrasonic imaging and laparoscopy. Specifically, free-hand laparoscopic ultrasound (LUS) is employed to capture the arteries intraoperatively in this approach, and a laparoscopic vision-based tracking system is utilized to track the LUS probe. To extract the artery contours from the two-dimensional ultrasound image sequences efficiently, an artery extraction framework based on local phase-based snakes was developed. After reconstructing the three-dimensional intraoperative artery model from ultrasound images, a high-resolution artery model segmented from preoperative computed tomography (CT) images was rigidly registered to the intraoperative artery model and overlaid onto the laparoscopic view to guide laparoscopic LPLND.ResultsExperiments were conducted to evaluate the performance of the vision-based tracking system, and the average reconstruction error of the proposed tracking system was found to be 2.4 mm. Then, the proposed navigation system was quantitatively evaluated on an artery phantom. The reconstruction time and average navigation error were 8 min and 2.3 mm, respectively. A navigation system was also successfully constructed to localize the pelvic arteries in laparoscopic and open surgeries of a swine. This demonstrated the feasibility of the proposed system in vivo. The construction times in the laparoscopic and open surgeries were 14 and 12 min, respectively.ConclusionsThe experimental results showed that the proposed navigation system can guide laparoscopic LPLND and requires a significantly shorter setting time than the state-of-the-art navigation systems do.

The stress relaxation test is an effective and facile method for clarifying the nonlinear rheological behavior of soft materials. A thorough analysis of the stress relaxation behavior offers valuable insights into the molecular dynamics. However, the stress relaxation behavior and underlying molecular dynamics of polymer/particle mixtures remain poorly understood, despite their widespread industrial application. In this study, we systematically investigated the nonlinear stress relaxation behavior of a simple-structured poly(ethylene oxide) (PEO)/silica nanoparticle aqueous mixture. Time‒strain separability was observed at high polymer concentrations, with the stress relaxation attributable to the relaxation of the polymer matrix. At lower polymer concentrations, the time‒strain separability was no longer valid, and changes in absorbance over time suggested that stress relaxation originated from the relaxation of the aggregated structures. A transition from time‒strain separability to inseparability was observed when the estimated number of PEO molecules forming interparticle bridges was less than 1; this suggests that structural changes during shear loading occur only when new interparticle polymer bridges are formed, leading to the development of clustered structures. These results provide a basic understanding of the relationship between deformation and relaxation, which is crucial for systematically understanding the nonlinear rheology of polymeric materials. Normalized relaxation time as a function of the estimated number of interparticle polymer bridges ( n bridge ). Images show the molecular dynamics pertaining to n bridge  < 1 and 1 <  n bridge .

Additional reductions in low-density lipoprotein-cholesterol (LDL-C) via antidiabetic therapies should be considered in statin-using patients with sub-optimal LDL-C levels. We compared the efficacy of anagliptin and sitagliptin, two antidiabetic therapies, in reducing LDL-C in type 2 diabetic patients. A randomized, open-label, parallel-group trial was conducted at 17 centres in Japan between April 2015 and January 2018. Adults (age ≥20 years) with type 2 diabetes, any atherosclerotic vascular lesions, and statin prescriptions were included. Anagliptin or sitagliptin were administered for 52 weeks. Primary and secondary endpoints were changes in LDL-C and haemoglobin A1C (HbA1c) levels, respectively. We assessed the superiority (primary endpoint) and non-inferiority (secondary endpoint) of anagliptin over sitagliptin. This study was registered at Clinicaltrials.gov (NCT02330406). Of 380 participants, 353 were eligible and randomized. Mean participant age was 68 years, and 61% were males. Baseline median LDL-C and HbA1c were 108 mg/dL and 6.9%, respectively. Changes in LDL-C were −3.7 mg/dL with anagliptin and +2.1 mg/dL with sitagliptin at 52 weeks, and the estimated treatment difference was a significant −4.5 mg/dL (P = 0.01 for superiority). Changes in HbA1c were +0.02% with anagliptin and +0.12% with sitagliptin (P < 0.0001 for non-inferiority). Overall, anagliptin was superior to sitagliptin in lowering LDL-C without deteriorating HbA1c.

Coronary stenosis has been one of the most common heart diseases that drastically increases the risk of fatal disorders such as heart attack. Angioplasty using drug coated balloons (DCB) has been one of the most safe and promising treatments. To minimize the risk of thrombosis of such DCBs during intervention, a different approach that can secure high hemocompatibility under blood flow is necessary. Here we report a method of improving the photoresponsive platform’s hemocompatibility by conjugating polyethylene glycol (PEG), onto the functional groups located at the balloon surface. In this study, latex microbeads were used as models for balloons to enable precise observation of its surface under microscopy. These beads were decorated with PEG polymers of a variety of lengths and grafting densities, along with the Cy5-Photoclevable (PC) linker conjugate to mimic drugs to be loaded onto the platform. Results showed that PEG length and grafting density are both critical factors that alter not only its hemocompatibility, but also the drug load and release efficiency of such platform. Thus, although further investigation is necessary to optimize the tradeoff between hemocompatibility, drug load, and release efficiency, it is safe to conclude that PEGylation of DCB surface is an effective method of enhancing and maintaining high hemocompatibility to minimize the risk of thrombosis during angioplasty.

Background Aggressive lipid lowering by high-dose statin treatment has been established for the secondary prevention of coronary artery disease (CAD). Regarding the low-density lipoprotein cholesterol (LDL-C) level, however, the “The lower is the better” concept has been controversial to date. We hypothesized that there is an optimal LDL-C level, i.e., a “threshold” value, below which the incidence of cardiovascular events is no longer reduced. We undertook a subanalysis of the REAL-CAD study to explore whether such an optimal target LDL-C level exists by a novel analysis procedure to verify the existence of a monotonic relationship. Methods For a total of 11,105 patients with CAD enrolled in the REAL-CAD study, the LDL-C level at 6 months after randomization and 5-year cardiovascular outcomes were assessed. We set the “threshold” value of the LDL-C level under which the hazards were assumed to be constant, by including an artificial covariate max (0, LDL-C − threshold) in the Cox model. The analysis was repeated with different LDL-C thresholds (every 10 mg/dl from 40 to 100 mg/dl) and the model fit was assessed by log-likelihood. Results For primary outcomes such as the composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization, the model fit assessed by log-likelihood was best when a threshold LDL-C value of 70 mg/dl was assumed. And in the model with a threshold LDL-C ≥ 70 mg/dl, the hazard ratio was 1.07 (95% confidence interval 1.01–1.13) as the LDL-C increased by 10 mg/dl. Therefore, the risk of cardiovascular events decreased monotonically until the LDL-C level was lowered to 70 mg/dl, but when the level was further reduced, the risk was independent of LDL-C. Conclusions Our analysis model suggests that a “threshold” value of LDL-C might exist for the secondary prevention of cardiovascular events in Japanese patients with CAD, and this threshold might be 70 mg/dl for primary composite outcomes. Trial registration http://www.clinicaltrials.gov . Unique identifier: NCT01042730.

Skin-attachable ultrasound probes face challenges in imaging the intended cross-section due to the difficulty in precisely adjusting the position and angle of attachment. While matrix element arrays are capable of imaging any cross-section within a three-dimensional field of view, their implementation presents a challenge due to the significant number of required ultrasound elements. We propose a method for optimizing the coordinates and shapes of elements based on the focusing quality onto the imaging points under the positional and angular errors in the element array. A 128-element array was optimized through the proposed method and its imaging performance was evaluated with simulated phantoms. The optimized array demonstrated the ability to clearly visualize the simulated wires, cysts, and blood vessels even with the positional error of 3 mm and the angular error of 20°. These results indicate the feasibility of developing a skin-attachable ultrasound probe that can be easily used in daily life without requiring precise positional and angular accuracy.