Nociceptor spontaneous activity is responsible for fragmenting non-rapid eye movement sleep in mouse models of neuropathic pain.

Spontaneous pain, a major complaint of patients with neuropathic pain, has eluded study because there is no reliable marker in either preclinical models or clinical studies. Here, we performed a comprehensive electroencephalogram/electromyogram analysis of sleep in several mouse models of chronic pain: neuropathic (spared nerve injury and chronic constriction injury), inflammatory (Freund's complete adjuvant and carrageenan, plantar incision) and chemical pain (capsaicin). We find that peripheral axonal injury drives fragmentation of sleep by increasing brief arousals from non-rapid eye movement sleep (NREMS) without changing total sleep amount. In contrast to neuropathic pain, inflammatory or chemical pain did not increase brief arousals. NREMS fragmentation was reduced by the analgesics gabapentin and carbamazepine, and it resolved when pain sensitivity returned to normal in a transient neuropathic pain model (sciatic nerve crush). Genetic silencing of peripheral sensory neurons or ablation of CGRP+ neurons in the parabrachial nucleus prevented sleep fragmentation, whereas pharmacological blockade of skin sensory fibers was ineffective, indicating that the neural activity driving the arousals originates ectopically in primary nociceptor neurons and is relayed through the lateral parabrachial nucleus. These findings identify NREMS fragmentation by brief arousals as an effective proxy to measure spontaneous neuropathic pain in mice.

Accelerated Selective Li+ Transports Assisted by Microcrack-Free Anionic Network Polymer Membranes for Long Cyclable Lithium Metal Batteries.

Rechargeable Li metal batteries have the potential to meet the demands of high-energy density batteries for electric vehicles and grid-energy storage system applications. Achieving this goal, however, requires resolving not only safety concerns and a shortened battery cycle life arising from a combination of undesirable lithium dendrite and solid-electrolyte interphase formations. Here, a series of microcrack-free anionic network polymer membranes formed by a facile one-step click reaction are reported, displaying a high cation conductivity of 3.1 × 10-5 S cm-1 at high temperature, a wide electrochemical stability window up to 5 V, a remarkable resistance to dendrite growth, and outstanding non-flammability. These enhanced properties are attributed to the presence of tethered borate anions in microcrack-free membranes, which benefits the acceleration of selective Li+ cations transport as well as suppression of dendrite growth. Ultimately, the microcrack-free anionic network polymer membranes render Li metal batteries a safe and long-cyclable energy storage device at high temperatures with a capacity retention of 92.7% and an average coulombic efficiency of 99.867% at 450 cycles.

Self-Mixed Biphasic Liquid Metal Composite with Ultra-High Stretchability and Strain-Insensitivity for Neuromorphic Circuits.

Neuromorphic circuits that can function under extreme deformations are important for various data-driven wearable and robotic applications. Herein, biphasic liquid metal particle (BMP) with unprecedented stretchability and strain-insensitivity (ΔR/R0 = 1.4@ 1200% strain) is developed to realize a stretchable neuromorphic circuit that mimics a spike-based biologic sensory system. The BMP consists of liquid metal particles (LMPs) and rigid liquid metal particles (RLMPs), which are homogeneously mixed via spontaneous solutal-Marangoni mixing flow during coating. This permits facile single step patterning directly on various substrates at room temperature. BMP is highly conductive (2.3 × 106 S/m) without any post activation steps. BMP interconnects are utilized for a sensory system, which is capable of distinguishing variations of biaxial strains with a spiking neural network, thus demonstrating their potential for various sensing and signal processing applications.

RNA-binding protein Nocte regulates Drosophila development by promoting translation reinitiation on mRNAs with long upstream open reading frames.

RNA-binding proteins (RBPs) with intrinsically disordered regions (IDRs) are linked to multiple human disorders, but their mechanisms of action remain unclear. Here, we report that one such protein, Nocte, is essential for Drosophila eye development by regulating a critical gene expression cascade at translational level. Knockout of nocte in flies leads to lethality, and its eye-specific depletion impairs eye size and morphology. Nocte preferentially enhances translation of mRNAs with long upstream open reading frames (uORFs). One of the key Nocte targets, glass mRNA, encodes a transcription factor critical for differentiation of photoreceptor neurons and accessory cells, and re-expression of Glass largely rescued the eye defects caused by Nocte depletion. Mechanistically, Nocte counteracts long uORF-mediated translational suppression by promoting translation reinitiation downstream of the uORF. Nocte interacts with translation factors eIF3 and Rack1 through its BAT2 domain, and a Nocte mutant lacking this domain fails to promote translation of glass mRNA. Notably, de novo mutations of human orthologs of Nocte have been detected in schizophrenia patients. Our data suggest that Nocte family of proteins can promote translation reinitiation to overcome long uORFs-mediated translational suppression, and disruption of this function can lead to developmental defects and neurological disorders.

Phosphine-Triggered Structural Defects in Au44 Homologues Boost Electrocatalytic CO2 Reduction.

The systematic induction of structural defects at the atomic level is crucial to metal nanocluster research because it endows cluster-based catalysts with highly reactive centers and allows for a comprehensive investigation of viable reaction pathways. Herein, by substituting neutral phosphine ligands for surface anionic thiolate ligands, we establish that one or two Au3 triangular units can be successfully introduced into the double-stranded helical kernel of Au44 (TBBT)28 , where TBBT=4-tert-butylbenzenethiolate, resulting in the formation of two atomically precise defective Au44 nanoclusters. Along with the regular face-centered-cubic (fcc) nanocluster, the first series of mixed-ligand cluster homologues is identified, with a unified formula of Au44 (PPh3 )n (TBBT)28-2n (n=0-2). The Au44 (PPh3 )(TBBT)26 nanocluster having major structural defects at the bottom of the fcc lattice demonstrates superior electrocatalytic performance in the CO2 reduction to CO. Density functional theory calculations indicate that the active site near the defects significantly lowers the free energy for the *COOH formation, the rate-determining step in the whole catalytic process.

Natural behaviours after guided growth for idiopathic genu valgum correction: comparison between percutaneous transphyseal screw and tension-band plate.

BACKGROUND: Percutaneous epiphysiodesis using a transphyseal screw (PETS) or tension-band plating (TBP) has shown favourable correction results; however, the physeal behaviours in terms of rebound, stable correction, or overcorrection after guided growth have not been completely understood. In patients with idiopathic genu valgum, we therefore asked: (1) How is the correction maintained after implant removal of guided growth? (2) Is there any difference in the natural behaviours after PETS or TBP removal at the femur and tibia? METHODS: We retrospectively reviewed 73 skeletally immature limbs with idiopathic genu valgum treated with PETS or TBP. PETS was performed in 23 distal femurs and 13 proximal tibias, and TBP was performed in 27 distal femurs and ten proximal tibias. Mechanical axis deviation (MAD), mechanical lateral distal femoral angle (mLDFA), and mechanical medial proximal tibial angle were measured at pre-correction, implant removal, and final follow-up. Changes of ≤ 3° in mechanical angles after implant removal were considered stable. Comparisons between the implant, anatomical site, and existence of rebound were performed. RESULTS: The mean MAD improved from - 18.8 mm to 11.3 mm at implant removal and decreased to -0.2 mm at the final follow-up. At the final follow-up, 39 limbs (53.4%) remained stable and only 12 (16.4%) were overcorrected. However, 22 limbs (30.1%) showed rebound. TBP was more common, and the correction period was longer in the rebound group (p < 0.001 and 0.013, respectively). In femurs treated with PETS, the mean mLDFA increased from 86.9° at implant removal to 88.4° at the final follow-up (p = 0.031), demonstrating overcorrection. However, a significant rebound from 89.7° to 87.1° was noted at the femur in the TBP group (p < 0.001). The correction of the proximal tibia did not change after implant removal. CONCLUSION: The rebound was more common than overcorrection after guided growth; however, approximately half the cases demonstrated stable correction. The overcorrection occurred after PETS in the distal femur, while cases with TBP had a higher probability of rebound. The proximal tibia was stable after implant removal. The subsequent physeal behaviours after each implant removal should be considered in the guided growth.

Shape memory in self-adapting colloidal crystals.

Reconfigurable, mechanically responsive crystalline materials are central components in many sensing, soft robotic, and energy conversion and storage devices1-4. Crystalline materials can readily deform under various stimuli and the extent of recoverable deformation is highly dependent upon bond type1,2,5-10. Indeed, for structures held together via simple electrostatic interactions, minimal deformations are tolerated. By contrast, structures held together by molecular bonds can, in principle, sustain much larger deformations and more easily recover their original configurations. Here we study the deformation properties of well-faceted colloidal crystals engineered with DNA. These crystals are large in size (greater than 100 µm) and have a body-centred cubic (bcc) structure with a high viscoelastic volume fraction (of more than 97%). Therefore, they can be compressed into irregular shapes with wrinkles and creases, and, notably, these deformed crystals, upon rehydration, assume their initial well-formed crystalline morphology and internal nanoscale order within seconds. For most crystals, such compression and deformation would lead to permanent, irreversible damage. The substantial structural changes to the colloidal crystals are accompanied by notable and reversible optical property changes. For example, whereas the original and structurally recovered crystals exhibit near-perfect (over 98%) broadband absorption in the ultraviolet-visible region, the deformed crystals exhibit significantly increased reflection (up to 50% of incident light at certain wavelengths), mainly because of increases in their refractive index and inhomogeneity.

Real-Time Stress Analysis Affecting Nurse during Elective Spinal Surgery Using a Wearable Device.

Successful spinal surgery demands high levels of concentration and cooperation from participating health care workers. The intraoperative stress levels and concentration levels of surgeons have been studied previously; however, those of nurses are rarely studied. Therefore, the purpose of this study is to understand the stresses affecting surgical nurses by their participating role during spinal surgery. A total of 160 surgical stress records were obtained during 40 surgeries, including electroencephalography (EEG) signals and heart rate variability (HRV) from three orthopedic spinal surgeons and six nurses; concentration, tension level and physical stress were analyzed. Levels of both concentration and tension were significantly higher in circulating nurses during all surgical stages (p < 0.05). Both beats per minute and low frequency/high frequency ratios, which reflect physical stress, were higher in scrub nurses (p < 0.05). As the surgical experience of scrub nurses increased, the key parameters related to stress tended to decrease (p < 0.01). These results will contribute to understanding the pattern of intraoperative stress of surgical nurses, and therefore help in enhancing the teamwork of the surgical team for optimal outcomes.

Geometrically engineered rigid island array for stretchable electronics capable of withstanding various deformation modes.

Integration of rigid components in soft polymer matrix is considered as the most feasible architecture to enable stretchable electronics. However, a method of suppressing cracks at the interface between soft and rigid materials due to excessive and repetitive deformations of various types remains a formidable challenge. Here, we geometrically engineered Ferris wheel-shaped islands (FWIs) capable of effectively suppressing crack propagation at the interface under various deformation modes (stretching, twisting, poking, and crumpling). The optimized FWIs have notable increased strain at failure and fatigue life compared with conventional circle- and square-shaped islands. Stretchable electronics composed of various rigid components (LED and coin cell) were demonstrated using intrinsically stretchable printed electrodes. Furthermore, electronic skin capable of differentiating various tactile stimuli without interference was demonstrated. Our method enables stretchable electronics that can be used under various geometrical forms with notable enhanced durability, enabling stretchable electronics to withstand potentially harsh conditions of everyday usage.

Sym3DNet: Symmetric 3D Prior Network for Single-View 3D Reconstruction.

The three-dimensional (3D) symmetry shape plays a critical role in the reconstruction and recognition of 3D objects under occlusion or partial viewpoint observation. Symmetry structure prior is particularly useful in recovering missing or unseen parts of an object. In this work, we propose Sym3DNet for single-view 3D reconstruction, which employs a three-dimensional reflection symmetry structure prior of an object. More specifically, Sym3DNet includes 2D-to-3D encoder-decoder networks followed by a symmetry fusion step and multi-level perceptual loss. The symmetry fusion step builds flipped and overlapped 3D shapes that are fed to a 3D shape encoder to calculate the multi-level perceptual loss. Perceptual loss calculated in different feature spaces counts on not only voxel-wise shape symmetry but also on the overall global symmetry shape of an object. Experimental evaluations are conducted on both large-scale synthetic 3D data (ShapeNet) and real-world 3D data (Pix3D). The proposed method outperforms state-of-the-art approaches in terms of efficiency and accuracy on both synthetic and real-world datasets. To demonstrate the generalization ability of our approach, we conduct an experiment with unseen category samples of ShapeNet, exhibiting promising reconstruction results as well.

Nociceptor neurons promote IgE class switch in B cells.

Nociceptors, the high-threshold primary sensory neurons that trigger pain, interact with immune cells in the periphery to modulate innate immune responses. Whether they also participate in adaptive and humoral immunity is, however, not known. In this study, we probed if nociceptors have a role in distinct airway and skin models of allergic inflammation. In both models, the genetic ablation and pharmacological silencing of nociceptors substantially reduced inflammatory cell infiltration to the affected tissue. Moreover, we also found a profound and specific deficit in IgE production in these models of allergic inflammation. Mechanistically, we discovered that the nociceptor-released neuropeptide substance P helped trigger the formation of antibody-secreting cells and their release of IgE. Our findings suggest that nociceptors, in addition to their contributions to innate immunity, play a key role in modulating the adaptive immune response, particularly B cell antibody class switching to IgE.

Effect of the Osteotomy Inclination Angle in the Sagittal Plane on the Posterior Tibial Slope of the Tibiofemoral Joint in Medial Open-Wedge High Tibial Osteotomy: Three-Dimensional Computed Tomography Analysis.

The posterior tibial slope of the tibiofemoral joint changes after medial open wedge high tibial osteotomy (MOWHTO), but little is known about the effect of the sagittal osteotomy inclination angle on the change in the posterior tibial slope of the tibiofemoral joint. The purpose of this study was to investigate the effect of the osteotomy inclination angle in the sagittal plane on changes in the posterior tibial slope after MOWHTO by comparing how anterior and posterior inclination affect the posterior tibial slope of the tibiofemoral joint. The correlation between the osteotomy inclination angle and the postoperative posterior tibial slope angle was also assessed. Between May 2011 and November 2017, 80 patients with medial compartment osteoarthritis who underwent MOWHTO were included. The patients were divided into two groups according to the sagittal osteotomy inclination angle on the 3D reconstructed model. Patients with an osteotomy line inclined anteriorly to the medial tibial plateau line were classified into group A (58 patients). Patients with posteriorly inclined osteotomy line were classified as group P (22 patients). In the 3D reconstructed model, the preoperative and postoperative posterior tibial slope, osteotomy inclination angle relative to medial tibial plateau line in sagittal plane, and gap distance and ratio of the anterior and posterior osteotomy openings were measured. The preoperative and postoperative hip-knee-ankle angle, weight-bearing line ratio, and posterior tibial slope were also measured using plain radiographs. In the 3D reconstructed model, the postoperative posterior tibial slope significantly increased in group A (preoperative value = 9.7 ± 2.9°, postoperative value = 10.7 ± 3.0°, p < 0.001) and decreased in group P (preoperative value = 8.7 ± 2.7°, postoperative value = 7.7 ± 2.7°, p < 0.001). The postoperative posterior tibial slope (group A = 10.7 ± 3.0°, group P = 7.7 ± 2.7°, p < 0.001) and posterior tibial slope change before and after surgery (group A = 1.0 ± 0.8°, group P = -0.9 ± 0.8°, p < 0.001) also differed significantly between the groups. The Pearson correlation coefficient was 0.875 (p < 0.001) for the osteotomy inclination angle, and multivariate regression analysis showed that the only significant factor among the variables was the sagittal osteotomy inclination angle (ß coefficient = 0.216, p < 0.001). The posterior tibial slope changed according to the osteotomy inclination angle in the sagittal plane after MOWHTO. The postoperative posterior tibial slope tended to increase when the osteotomy line was inclined anteriorly with respect to the medial tibial plateau line but decreased when the osteotomy line was inclined posteriorly. To avoid inadvertent change of posterior tibial slope, close attention needs to be paid to maintaining the sagittal osteotomy line parallel to the medial joint line during MOWHTO.

'Eye' of the molecule-a viewpoint.

If the twentieth century was the age of precisely designed molecules, the twenty-first century is beginning to look like the age of reticulated molecules. In the spirit of the Faraday Discussion meeting, we wish to highlight the power of harnessing the reticulated molecule and suggest that its chemistry can be furthered by viewing our reticular structures from the 'eye of the molecule'. To clarify what is meant by this term, we wish to first take stock of the current state of reticular chemistry.

Human amyotrophic lateral sclerosis excitability phenotype screen: Target discovery and validation.

Drug development is hampered by poor target selection. Phenotypic screens using neurons differentiated from patient stem cells offer the possibility to validate known and discover novel disease targets in an unbiased fashion. To identify targets for managing hyperexcitability, a pathological feature of amyotrophic lateral sclerosis (ALS), we design a multi-step screening funnel using patient-derived motor neurons. High-content live cell imaging is used to evaluate neuronal excitability, and from a screen against a chemogenomic library of 2,899 target-annotated compounds, 67 reduce the hyperexcitability of ALS motor neurons carrying the SOD1(A4V) mutation, without cytotoxicity. Bioinformatic deconvolution identifies 13 targets that modulate motor neuron excitability, including two known ALS excitability modulators, AMPA receptors and Kv7.2/3 ion channels, constituting target validation. We also identify D2 dopamine receptors as modulators of ALS motor neuron excitability. This screen demonstrates the power of human disease cell-based phenotypic screens for identifying clinically relevant targets for neurological disorders.

Neuromorphic Processing of Pressure Signal Using Integrated Sensor-Synaptic Device Capable of Selective and Reversible Short- and Long-Term Plasticity Operation.

To mimic the tactile sensing properties of the human skin, signals from tactile sensors need to be processed in an efficient manner. The integration of the tactile sensor with a neuromorphic device can potentially address this issue, as the neuromorphic device has both signal processing and memory capability through which parallel and efficient processing of information is possible. In this article, an intelligent haptic perception device (IHPD) is presented that combines pressure sensing with an organic electrochemical transistor-based synaptic device into a simple device architecture. More importantly, the IHPD is capable of rapid and reversible switching between short-term plasticity (STP) and long-term plasticity (LTP) operation through which accelerated learning, processing of new information, and distinctive operation of STP and LTP are possible. Various types of pressure information such as magnitude, rate, and duration were processed utilizing STP by which error-tolerant perception was demonstrated. Meanwhile, memorization and learning of pressure through a stepwise change in a conductive state was demonstrated using LTP. These demonstrations present unique approaches to process and learn tactile information, which can potentially be utilized in various electronic skin applications in the future.

Novel charged sodium and calcium channel inhibitor active against neurogenic inflammation.

Voltage-dependent sodium and calcium channels in pain-initiating nociceptor neurons are attractive targets for new analgesics. We made a permanently charged cationic derivative of an N-type calcium channel-inhibitor. Unlike cationic derivatives of local anesthetic sodium channel blockers like QX-314, this cationic compound inhibited N-type calcium channels more effectively with extracellular than intracellular application. Surprisingly, the compound is also a highly effective sodium channel inhibitor when applied extracellularly, producing more potent inhibition than lidocaine or bupivacaine. The charged inhibitor produced potent and long-lasting analgesia in mouse models of incisional wound and inflammatory pain, inhibited release of the neuropeptide calcitonin gene-related peptide (CGRP) from dorsal root ganglion neurons, and reduced inflammation in a mouse model of allergic asthma, which has a strong neurogenic component. The results show that some cationic molecules applied extracellularly can powerfully inhibit both sodium channels and calcium channels, thereby blocking both nociceptor excitability and pro-inflammatory peptide release.

Nanoparticle-Based Hybrid Scaffolds for Deciphering the Role of Multimodal Cues in Cardiac Tissue Engineering.

Myocardial microenvironment plays a decisive role in guiding the function and fate of cardiomyocytes, and engineering this extracellular niche holds great promise for cardiac tissue regeneration. Platforms utilizing hybrid hydrogels containing various types of conductive nanoparticles have been a critical tool for constructing engineered cardiac tissues with outstanding mechanical integrity and improved electrophysiological properties. However, there has been no attempt to directly compare the efficacy of these hybrid hydrogels and decipher the mechanisms behind how these platforms differentially regulate cardiomyocyte behavior. Here, we employed gelatin methacryloyl (GelMA) hydrogels containing three different types of carbon-based nanoparticles: carbon nanotubes (CNTs), graphene oxide (GO), and reduced GO (rGO), to investigate the influence of these hybrid scaffolds on the structural organization and functionality of cardiomyocytes. Using immunofluorescent staining for assessing cellular organization and proliferation, we showed that electrically conductive scaffolds (CNT- and rGO-GelMA compared to relatively nonconductive GO-GelMA) played a significant role in promoting desirable morphology of cardiomyocytes and elevated the expression of functional cardiac markers, while maintaining their viability. Electrophysiological analysis revealed that these engineered cardiac tissues showed distinct cardiomyocyte phenotypes and different levels of maturity based on the substrate (CNT-GelMA: ventricular-like, GO-GelMA: atrial-like, and rGO-GelMA: ventricular/atrial mixed phenotypes). Through analysis of gene-expression patterns, we uncovered that the engineered cardiac tissues matured on CNT-GelMA and native cardiac tissues showed comparable expression levels of maturation markers. Furthermore, we demonstrated that engineered cardiac tissues matured on CNT-GelMA have increased functionality through integrin-mediated mechanotransduction (via YAP/TAZ) in contrast to cardiomyocytes cultured on rGO-GelMA.

A Cross-Linking Approach to Stabilizing Stimuli-Responsive Colloidal Crystals Engineered with DNA.

Two DNA-cross-linking reagents, bis-chloroethylnitrosourea and 8-methoxypsoralen, are used to covalently cross-link interstrand base pairs in DNA bonds that, in part, define colloidal crystals engineered with DNA. The irreversible linkages formed increase the chemical and thermal stability of the crystals and do not significantly affect their long-range order, as evidenced by small-angle X-ray scattering data. The post-modified crystals are stable in environments that the pre-modified structures are not, including solvents that encompass a broad range of polarities from ethanol to hexanes, and in aqueous media at pH 0 and 14. Interestingly, the cross-linked DNA bonds within these crystals still retain their flexibility, which is reflected by a solvent-dependent reversible change in lattice parameter. Since these organic cross-linking reagents, in comparison with inorganic approaches (use of silver ions or SiO2), have marginal effects on the composition and properties of the crystals, they provide an attractive alternative for stabilizing colloidal crystals engineered with DNA and make them potentially useful in a broader range of media.

Casting Nanoporous Platinum in Metal-Organic Frameworks.

Nanocasting based on porous templates is a powerful strategy in accessing materials and structures that are difficult to form by bottom-up syntheses in a controlled fashion. A facile synthetic strategy for casting ordered, nanoporous platinum (NP-Pt) networks with a high degree of control by using metal-organic frameworks (MOFs) as templates is reported here. The Pt precursor is first infiltrated into zirconium-based MOFs and subsequently transformed to 3D metallic networks via a chemical reduction process. It is demonstrated that the dimensions and topologies of the cast NP-Pt networks can be accurately controlled by using different MOFs as templates. The Brunauer-Emmett-Teller surface areas of the NP-Pt networks are estimated to be >100 m2 g-1 and they exhibit excellent catalytic activities in the methanol electrooxidation reaction (MEOR). This new methodology presents an attractive route to prepare well-defined nanoporous materials for diverse applications ranging from energy to sensing and biotechnology.

Impact of Disordered Guest-Framework Interactions on the Crystallography of Metal-Organic Frameworks.

It is a general and common practice to carry out single-crystal X-ray diffraction experiments at cryogenic temperatures in order to obtain high-resolution data. In this report, we show that this practice is not always applicable to metal-organic frameworks (MOFs), especially when these structures are highly porous. Specifically, two new MOFs are reported here, MOF-1004 and MOF-1005, for which the collection of the diffraction data at lower temperature (100 K) did not give data of sufficient quality to allow structure solution. However, collection of data at higher temperature (290 K) gave atomic-resolution data for MOF-1004 and MOF-1005, allowing for structure solution. We find that this inverse behavior, contrary to normal practice, is also true for some well-established MOFs (MOF-177 and UiO-67). Close examination of the X-ray diffraction data obtained for all four of these MOFs at various temperatures led us to conclude that disordered guest-framework interactions play a profound role in introducing disorder at low temperature, and the diminishing strength of these interactions at high temperatures reduces the disorder and gives high-resolution diffraction data. We believe our finding here is more widely applicable to other highly porous MOFs and crystals containing highly disordered molecules.