Downstream signalling of the disease-associated mutations on GPR56/ADGRG1.

GPR56/ADGRG1 is an adhesion G protein-coupled receptor (GPCR) and mutations on this receptor cause cortical malformation due to the over-migration of neural progenitor cells on brain surface. At pial surface, GPR56 interacts with collagen III, induces Rho-dependent activation through Gα12/13 and inhibits the neuronal migration. In human glioma cells, GPR56 inhibits cell migration through Gαq/11 -dependent Rho pathway. GPR56-tetraspanin complex is known to couple Gαq/11 . GPR56 is an aGPCR that couples with various G proteins and signals through different downstream pathways. In this study, bilateral frontoparietal polymicrogyria (BFPP) mutants disrupting GPR56 function but remaining to be expressed on plasma membrane were used to study receptor signalling through Gα12 , Gα13 and Gα11 with BRET biosensors. GPR56 showed coupling with all three G proteins and activated heterotrimeric G protein signalling upon stimulation with Stachel peptide. However, BFPP mutants showed different signalling defects for each G protein indicative of distinct activation and signalling properties of GPR56 for Gα12 , Gα13 or Gα11 . ß-arrestin recruitment was also investigated following the activation of GPR56 with Stachel peptide using BRET biosensors. N-terminally truncated GPR56 showed enhanced ß-arrestin recruitment; however, neither wild-type receptor nor BFPP mutants gave any measurable recruitment upon Stachel stimulation, pointing different activation mechanisms for ß-arrestin involvement.

A Passively Conforming Soft Robotic Gripper with Three-Dimensional Negative Bending Stiffness Fingers.

Robot grippers that lack physical compliance have a difficult time dealing with uncertainty, such as fragile objects that may not have well-defined shapes. Existing soft robotic grippers require a large empty workspace for their actuated fingers to curl around the objects of interest, limiting their performance in clutter. This article presents a three-dimensional structure that exhibits negative stiffness in every bending direction used as fingers in a class of soft robotic grippers. Our approach exploits a compliant mechanism in a conical shape such that a transverse external contact force causes the fingers to bend toward the contact, enabling passive conformation for an adaptive grasp, even in clutter. We show analytically and experimentally that the proposed fingers have a negative bending response and that they conform to objects of various diameters. We demonstrate a soft robotic gripper with three self-conforming fingers performing the following: (1) fingertip grasping, (2) power grasping, and (3) semipassive grasping in clutter. Grasping experiments focus on picking fruits, which exemplify delicate objects with unmodeled shapes with significant variation. The experimental results reveal the ability of the self-conforming structure to smoothly envelope a broad range of objects and demonstrate a 100% grasp success rate in the experiments performed. The proposed passively conforming fingers enable picking of complex and unknown geometries without disturbing nearby objects in clutter and without the need for complex grasping algorithms. The proposed structures can be tailored to deform in desired ways, enabling a robust strategy for the engineering of physical compliance for adaptive soft structures.

Design, Analysis, and Real-Time Simulation of a 3D Soft Robotic Snake.

Snakes are a remarkable source of inspiration for mobile search-and-rescue robots. Their unique slender body structure and multiple modes of locomotion are well-suited to movement in narrow passages and other difficult terrain. The design, manufacturing, modeling, and control techniques of soft robotics make it possible to imitate the structure, mechanical properties, and locomotion gaits of snakes, opening up new possibilities in robotics research. Building on our track record of contributions in this area, this article presents a soft robotic snake made of modules that can actively deform in three-dimensional (3D) and rigorously studies its performance under a range of conditions, including gait parameters, number of modules, and differences in the environment. A soft 3D-printed wave spring sheath is developed to support the robot modules, increasing the snake's performance in climbing steps threefold. Finally, we introduce a simulator and a numerical model to provide a real-time simulation of the soft robotic snake. With the help of the real-time simulator, it is possible to develop and test new locomotion gaits for the soft robotic snake within a short period of time, compared with experimental trial and error. As a result, the soft robotic snake presented in this article is able to locomote on different surfaces, perform different bioinspired and custom gaits, and climb over steps.

Ste2p Under the Microscope: the Investigation of Oligomeric States of a Yeast G Protein-Coupled Receptor.

Oligomerization of G protein-coupled receptors (GPCRs) may play important roles in maturation, internalization, signaling, and pharmacology of these receptors. However, the nature and extent of their oligomerization is still under debate. In our study, Ste2p, a yeast mating pheromone GPCR, was tagged with enhanced green fluorescent protein (EGFP), mCherry, and with split florescent protein fragments at the receptor C-terminus. The Förster resonance energy transfer (FRET) technique was used to detect receptors' oligomerization by calculating the energy transfer from EGFP to mCherry. Stimulation of Ste2p oligomers with the receptor ligand did not result in any significant change on observed FRET values. The bimolecular fluorescence complementation (BiFC) assay was combined with FRET to further investigate the tetrameric complexes of Ste2p. Our results suggest that in its quiescent (nonligand-activated) state, Ste2p is found at least as a tetrameric complex on the plasma membrane. Intriguingly, receptor tetramers in their active form showed a significant increase in FRET. This study provides a direct in vivo visualization of Ste2p tetramers and the pheromone effect on the extent of the receptor oligomerization.

Characteristics of patients with C1 esterase inhibitor deficiency: a single center study.

Summary: Hereditary angioedema (HAE) is a primary complement factor deficiency, characterized by recurrent submucosal/subcutaneous swelling episodes. SERPING1 gene defects encoding C1 esterase inhibitor (C1INH) are responsible from the disease. Fifteen patients with HAE are retrospectively evaluated in this study. All patients (n = 15) had HAE type I, 13 were from the same family, other two from two different families. Median age at onset of symptoms was 7 years (2-20); median age on diagnosis, 12 (0,5-41) and median delay in diagnosis, 3 years (0-33). Clinical symptoms were extremity edema(92,3%), facial edema(46%), abdominal pain (46%), genital edema (46%), and laryngeal edema (23%). Some patients suffered from recurrent abdominal pain, had been empirically given colchicine with familial mediterranean fever (FMF) when they admitted. One presented with bullous skin eruption, soon after developed extremity edema. Both resolved spontaneously after C1INH concentrate therapy. Two females suffered from recurrent genital edema after sexual activity. One patient experienced compartment syndrome-like swelling of extremity after playing football. One patient diagnosed with panic attack due to fear of death by asphyxiation, and was diagnosed with HAE disease. A nonsense mutation in exon 8, a missense mutation in exon 2 in SERPING1 gene was present in Family 1 and another patient (P14) from the other family, respectively. Sporadic/autosomal dominant inheritance ratio was 2/3 in the families present in our series. Patients with HAE presents with a large spectrum of symptoms. In mediterranean countries, patients with abdominal attacks may be misdiagnosed with FMF. Thus, health-care professionals should be alert, and put HAE in the first line of differential diagnoses when the disease symptoms are present. Consequently, morbidity/mortality will decrease with effective treatment options.

An Origami Continuum Robot Capable of Precise Motion Through Torsionally Stiff Body and Smooth Inverse Kinematics.

Continuum robot arms, with their hyper-redundant continuously deformable bodies, show great promise in applications deemed impossible for traditional rigid robot arms with discrete links and joints, such as navigating tight corners without getting stuck. However, existing continuum robots suffer from excessive twisting when subjected to offset loading, even resulting from their own body weight, which reduces their dexterity and precision. In this work, we present a continuum manipulator that is capable of providing passive torsional stiffness through an origami-inspired modular design, remedying the non-controllable twist typically present in continuum robots. Our proposed origami continuum module is ∼73 times stronger in torsion compared with similar-size continuum modules made out of silicone rubber, while being 50% lighter, and capable of 125% change in length. Building on these physical capabilities, we present an optimization-based method to solve for the inverse kinematics of our multi-segment origami continuum manipulator that ensures smooth motion to follow desired end-effector paths, minimizing vibrations of the long and slender body. Further, taking advantage of the length-change capabilities of our origami manipulator, we devise and evaluate grow-to-shape algorithms to plan for full-body robot insertion motions that follow tortuous paths. Lastly, we showcase various applications of our proposed continuum robot for pick-and-place, inspection/exploration, and robotic art. Our study presents a highly capable continuum robot for safe manipulation and structure inspection applications, with potential for real-world deployment.

Primary Immunodeficiency Disorders in children with Non-Cystic Fibrosis Bronchiectasis.

Summary: Introduction. Primary immunodeficiency diseases (PID) are common in patients with non-cystic fibrosis bronchiectasis (NCFB). Our objective was to determine ratio/types of PID in NCFB. Methods. Seventy NCFB patients followed up in a two-year period were enrolled. Results. Median age was 14 years (min-max: 6-30). Male/female ratio was 39/31; parental consanguinity, 38.6%. Most patients with NCFB (84.28%) had their first pulmonary infection within the first year of their lives. Patients had their first pulmonary infection at a median age of 6 months (min-max: 0.5-84), were diagnosed with bronchiectasis at about 9 years (114 months, min-max: 2-276). PID, primary ciliary dyskinesia (PCD), bronchiolitis obliterans, rheumatic/autoimmune diseases, severe congenital heart disease and tuberculosis were evaluated as the most common causes of NCFB. About 40% of patients (n=16) had bronchial hyperreactivity (BH) and asthma. Twenty-nine patients (41.4%) had a PID, and nearly all (n=28) had primary antibody deficiency, including patients with combined T and B cell deficiency. PID and non-PID groups did not differ according to gender, parental consanguinity, age at first pneumonia, age of onset of chronic pulmonary symptoms, bronchiectasis, presence of gastroesophageal reflux disease (GERD), BH and asthma (p greater-than 0.05). Admission to immunology clinic was about 3 years later in PID compared with non-PID group (p less-than 0.001). Five patients got molecular diagnosis, X-linked agammaglobulinemia (n=2), LRBA deficiency (n=1), RASGRP1 deficiency (n=1), MHC Class II deficiency (n=1). They were given monthly IVIG and HSCT was performed for three patients. Conclusions. PID accounted for about 40% of NCFB. Early diagnosis/appropriate treatment have impact on clinical course of a PID patient. Thus, follow-up in also immunology clinics should be a routine for patients who experience pneumonia in the first year of their lives and those with NCFB.

Motion Planning and Iterative Learning Control of a Modular Soft Robotic Snake.

Snake robotics is an important research topic with a wide range of applications, including inspection in confined spaces, search-and-rescue, and disaster response. Snake robots are well-suited to these applications because of their versatility and adaptability to unstructured and constrained environments. In this paper, we introduce a soft pneumatic robotic snake that can imitate the capabilities of biological snakes, its soft body can provide flexibility and adaptability to the environment. This paper combines soft mobile robot modeling, proprioceptive feedback control, and motion planning to pave the way for functional soft robotic snake autonomy. We propose a pressure-operated soft robotic snake with a high degree of modularity that makes use of customized embedded flexible curvature sensing. On this platform, we introduce the use of iterative learning control using feedback from the on-board curvature sensors to enable the snake to automatically correct its gait for superior locomotion. We also present a motion planning and trajectory tracking algorithm using an adaptive bounding box, which allows for efficient motion planning that still takes into account the kinematic state of the soft robotic snake. We test this algorithm experimentally, and demonstrate its performance in obstacle avoidance scenarios.

Reverse pneumatic artificial muscles (rPAMs): Modeling, integration, and control.

Despite offering many advantages over traditional rigid actuators, soft pneumatic actuators suffer from a lack of comprehensive, computationally efficient models and precise embedded control schemes without bulky flow-control valves and extensive computer hardware. In this article, we consider an inexpensive and reliable soft linear actuator, called the reverse pneumatic artificial muscle (rPAM), which consists of silicone rubber that is radially constrained by symmetrical double-helix threading. We describe analytical and numerical static models of this actuator, and compare their performance against experimental results. To study the application of rPAMs to operate underlying kinematic linkage skeletons, we consider a single degree-of-freedom revolute joint that is driven antagonistically by two of these actuators. An analytical model is then derived, and its accuracy in predicting the static joint angle as a function of input pressures is presented. Using this analytical model, we perform dynamic characterization of this system. Finally, we propose a sliding-mode controller, and a sliding mode controller augmented by a feed-forward term to modulate miniature solenoid valves that control air flow to each actuator. Experiments show that both controllers function well, while the feed-forward term improves the performance of the controller following dynamic trajectories.

Clinical and genetic features of the patients with X-Linked agammaglobulinemia from Turkey: Single-centre experience.

X-linked agammaglobulinemia is a primary immunodeficiency disorder resulting from BTK gene mutations. There are many studies in the literature suggesting contradictory ideas about phenotype-genotype correlation. The aim of this study was to identify the mutations and clinical findings of patients with XLA in Turkey, to determine long-term complications related to the disease and to analyse the phenotype-genotype correlation. Thirty-two patients with XLA diagnosed between 1985 and 2016 in Pediatric Immunology Department of Hacettepe University Ihsan Dogramaci Children's Hospital were investigated. A clinical survey including clinical features of the patients was completed, and thirty-two patients from 26 different families were included in the study. Getting early diagnosis and regular assessment with imaging techniques seem to be the most important issues for improving the health status of the patients with XLA. Early molecular analysis gives chance for definitive diagnosis and genetic counselling, but not for predicting the clinical severity and prognosis.

A Soft Robotic Wearable Wrist Device for Kinesthetic Haptic Feedback.

Advances in soft robotics provide a unique approach for delivering haptic feedback to a user by a soft wearable device. Such devices can apply forces directly on the human joints, while still maintaining the safety and flexibility necessary for use in close proximity to the human body. To take advantage of these properties, we present a new haptic wrist device using pressure-driven soft actuators called reverse pneumatic artificial muscles (rPAMs) mounted on four sides of the wrist. These actuators are originally pre-strained and release compressive stress under pressure, applying a safe torque around the wrist joints while being compact and portable, representing the first soft haptic device capable of real-time feedback. To demonstrate the functional utility of this device, we created a virtual path-following task, wherein the user employs the motion of their wrist to control their embodied agent. We used the haptic wrist device to assist the user in following the path and study their performance with and without haptic feedback in multiple scenarios. Our results quantify the effect of wearable soft robotic haptic feedback on user performance. Specifically, we observed that our haptic feedback system improved the performance of users following complicated paths in a statistically significant manner, but did not show improvement for simple linear paths. Based on our findings, we anticipate broader applications of wearable soft robotic haptic devices toward intuitive user interactions with robots, computers, and other users.

Toward Modular Soft Robotics: Proprioceptive Curvature Sensing and Sliding-Mode Control of Soft Bidirectional Bending Modules.

Real-world environments are complex, unstructured, and often fragile. Soft robotics offers a solution for robots to safely interact with the environment and human coworkers, but suffers from a host of challenges in sensing and control of continuously deformable bodies. To overcome these challenges, this article considers a modular soft robotic architecture that offers proprioceptive sensing of pressure-operated bending actuation modules. We present integrated custom magnetic curvature sensors embedded in the neutral axis of bidirectional bending actuators. We describe our recent advances in the design and fabrication of these modules to improve the reliability of proprioceptive curvature feedback over our prior work. In particular, we study the effect of dimensional parameters on improving the linearity of curvature measurements. In addition, we present a sliding-mode controller formulation that drives the binary solenoid valve states directly, giving the control system the ability to hold the actuator steady without continuous pressurization and depressurization. In comparison to other methods, this control approach does not rely on pulse width modulation and hence offers superior dynamic performance (i.e., faster response rates). Our experimental results indicate that the proposed soft robotic modules offer a large range of bending angles with monotonic and more linear embedded curvature measurements, and that the direct sliding-mode control system exhibits improved bandwidth and a notable reduction in binary valve actuation operations compared to our earlier iterative sliding-mode controller.

GPCR-Gα protein precoupling: Interaction between Ste2p, a yeast GPCR, and Gpa1p, its Gα protein, is formed before ligand binding via the Ste2p C-terminal domain and the Gpa1p N-terminal domain.

G protein coupled receptors bind ligands that initiate intracellular signaling cascades via heterotrimeric G proteins. In this study, involvement of the N-terminal residues of yeast G-alpha (Gpa1p) with the C-terminal residues of a full-length or C-terminally truncated Ste2p were investigated using bioluminescence resonance energy transfer (BRET), a non-radiative energy transfer phenomenon where protein-protein interactions can be quantified between a donor bioluminescent molecule and a suitable acceptor fluorophore. Constitutive and position-dependent BRET signal was observed in the absence of agonist (α-factor). Upon the activation of the receptors with α-factor, no significant change in BRET signal was observed. The location of Ste2p-Gpa1p heterodimer was investigated using confocal fluorescence microscopy and bimolecular fluorescence complementation (BiFC) assay, a technique where two non-fluorescent fragments of a fluorescent protein reassemble in vivo to restore fluorescence property thereby directly reporting a protein-protein interaction. BiFC experiments resulted in a dimerization signal intracellularly during biosynthesis on the endoplasmic reticulum (ER) and on the plasma membrane (PM). The constitutive BRET and BiFC signals observed on ER between Ste2p and Gpa1p in their quiescent and activated states are indicative of pre-coupling between these two proteins. This study is the first to show that the extreme N-terminus of yeast G protein alpha subunit is in close proximity to its receptor. The data suggests a pre-coupled heterodimer prior to receptor activation. The images presented in this study are the first direct in vivo evidence showing the localization of receptor - G protein heterodimers during biosynthesis and before reaching the plasma membrane.

The yeast Ste2p G protein-coupled receptor dimerizes on the cell plasma membrane.

Dimerization of G protein-coupled receptors (GPCR) may play an important role in maturation, internalization, signaling and/or pharmacology of these receptors. However, the location where dimerization occurs is still under debate. In our study, variants of Ste2p, a yeast mating pheromone GPCR, were tagged with split EGFP (enhanced green fluorescent protein) fragments inserted between transmembrane domain seven and the C-terminus or appended to the C-terminus. Bimolecular Fluorescence Complementation (BiFC) assay was used to determine where receptor dimerization occurred during protein trafficking by monitoring generation of EGFP fluorescence, which occurred upon GPCR dimerization. Our results suggest that these tagged receptors traffic to the membrane as monomers, undergo dimerization or higher ordered oligomerization predominantly on the plasma membrane, and are internalized as dimers/oligomers. This study is the first to provide direct in vivo visualization of GPCR dimerization/oligomerization, during trafficking to and from the plasma membrane.

Multi-crease Self-folding by Global Heating.

This study demonstrates a new approach to autonomous folding for the body of a 3D robot from a 2D sheet, using heat. We approach this challenge by folding a 0.27-mm sheetlike material into a structure. We utilize the thermal deformation of a contractive sheet sandwiched by rigid structural layers. During this baking process, the heat applied on the entire sheet induces contraction of the contracting layer and thus forms an instructed bend in the sheet. To attain the targeted folding angles, the V-fold spans method is used. The targeted angle θout can be kinematically encoded into crease geometry. The realization of this angle in the folded structure can be approximately controlled by a contraction angle θin. The process is non-reversible, is reliable, and is relatively fast. Our method can be applied simultaneously to all the folds in multi-crease origami structures. We demonstrate the use of this method to create a lightweight mobile robot.

Slithering towards autonomy: a self-contained soft robotic snake platform with integrated curvature sensing.

Soft robotic snakes promise significant advantages in achieving traveling curvature waves with a reduced number of active segments as well as allowing for safe and adaptive interaction with the environment and human users. However, current soft robot platforms suffer from a lack of accurate theoretical dynamic models and proprioceptive measurements, which impede advancements toward full autonomy. To address this gap, this paper details our recent results on the design, fabrication, and experimental evaluation of a new-generation pressure-operated soft robotic snake platform we call the WPI SRS, which employs custom magnetic sensors embedded in a flexible backbone to continuously monitor the curvature of each of its four bidirectional bending segments. In addition, we present a complete and accurate dynamic undulatory locomotion model that accounts for the propagation of frictional moments to describe linear and rotational motions of the SRS. Experimental studies indicate that on-board sensory measurements provide accurate real-time curvature feedback, and numerical simulations offer a level of abstraction for lateral undulation under ideal conditions.

Autonomous Soft Robotic Fish Capable of Escape Maneuvers Using Fluidic Elastomer Actuators.

In this work we describe an autonomous soft-bodied robot that is both self-contained and capable of rapid, continuum-body motion. We detail the design, modeling, fabrication, and control of the soft fish, focusing on enabling the robot to perform rapid escape responses. The robot employs a compliant body with embedded actuators emulating the slender anatomical form of a fish. In addition, the robot has a novel fluidic actuation system that drives body motion and has all the subsystems of a traditional robot onboard: power, actuation, processing, and control. At the core of the fish's soft body is an array of fluidic elastomer actuators. We design the fish to emulate escape responses in addition to forward swimming because such maneuvers require rapid body accelerations and continuum-body motion. These maneuvers showcase the performance capabilities of this self-contained robot. The kinematics and controllability of the robot during simulated escape response maneuvers are analyzed and compared with studies on biological fish. We show that during escape responses, the soft-bodied robot has similar input-output relationships to those observed in biological fish. The major implication of this work is that we show soft robots can be both self-contained and capable of rapid body motion.