Optogenetic activation of the ventral tegmental area-hippocampal pathway facilitates rapid adaptation to changes in spatial goals.

Animal adaptation to environmental goals to pursue rewards is modulated by dopamine. However, the role of dopamine in the hippocampus, involved in spatial navigation, remains unclear. Here, we studied dopaminergic inputs from the ventral tegmental area (VTA) to the hippocampus, focusing on spatial goal persistence and adaptation. Mice with VTA dopaminergic lesions struggled to locate and update learned reward locations in a circular maze with dynamic reward locations, emphasizing the importance of VTA dopaminergic neurons in the persistence and adaptation of spatial memory. Further, these deficits were accompanied by motor impairments or motivational loss even when dopamine receptors in the dorsal hippocampus were selectively blocked. Stimulation of VTA dopaminergic axons within the dorsal hippocampus enhanced the mice's ability to adapt to changing reward locations. These findings provide insights into the contribution of dopaminergic inputs within the hippocampus to spatial goal adaptation.

Collective motion of epithelial cells along a wrinkled 3D-buckled hydrogel.

Epithelial cells migrate autonomously by aligning and inducing a collective motion. Controlling the collective motion of epithelial cells in geometrically confined environments is important for understanding physiological processes such as wound healing and self-organized morphogenesis. However, collective migration under a three-dimensional (3D) curved surface resembling living epithelial tissue has not yet been explored. In this study, we investigated the collective motion of a 3D-buckled polyacrylamide (PAAm) gel that mimics the shape of folds and wrinkles of epithelial tissue to understand the geometric effects of collective motion. We found that the velocity correlation in the space near the hydrogel boundary showed a periodic change that correlated with the wrinkled folding of the hydrogel pattern. Furthermore, the characteristic length of the velocity correlation increased proportionally with the wavelength of wrinkled folding. These observations indicated that the hydrogel pattern could steer the collective motion of epithelial cells over long distances. Our study also suggests that the wrinkled design of the hydrogel is a versatile platform for studying the geometric effect of a curved surface on complex epithelial cell dynamics.

Neuroleptic Malignant Syndrome with Adrenal Insufficiency After BNT162b2 COVID-19 Vaccination in a Man Taking Valproate: A Case Report.

BACKGROUND Considering the ongoing coronavirus disease 2019 (COVID-19) pandemic, sufficient information about common and serious adverse events is needed to rapidly distribute COVID-19 vaccines worldwide. We report a case of neuroleptic malignant syndrome (NMS) with adrenal insufficiency after initial vaccination with Pfizer/BioNTech BNT162b2. CASE REPORT A 48-year-old man presented to the Emergency Department with fever and an altered mental status 7 days after receiving the first dose of the BNT162b2 COVID-19 vaccine. The patient had a history of end-stage renal disease and epilepsy treated with valproate. He was diagnosed with NMS based on the clinical findings of hyperthermia, muscular rigidity, and an elevated creatine kinase level. Additionally, a reduction in the response of cortisol to adrenocorticotropic hormone (ACTH) stimulation was observed in the rapid ACTH stimulation test. The patient was treated with dantrolene, bromocriptine, and hydrocortisone, and he responded well to treatment. Dantrolene and bromocriptine were tapered off over 4 weeks. Hydrocortisone was also tapered, and the patient was discharged on oral hydrocortisone (30 mg). CONCLUSIONS The present case suggests a possible link between the BNT162b2 COVID-19 vaccine and NMS with adrenal insufficiency based on the temporal relationship between vaccine administration and disease onset, although the patient was taking valproate, a potential cause of NMS. Having a high level of suspicion is important because the diagnosis of NMS with adrenal insufficiency is often challenging due to non-specific clinical manifestations. However, this case does not negate the utility of vaccination because these complications are extremely rare and can be treated with early diagnosis and proper management.

Improving the strength and toughness of macroscale double networks by exploiting Poisson's ratio mismatch.

We propose a new concept that utilizes the difference in Poisson's ratio between component materials as a strengthening mechanism that increases the effectiveness of the sacrificial bond toughening mechanism in macroscale double-network (Macro-DN) materials. These Macro-DN composites consist of a macroscopic skeleton imbedded within a soft elastic matrix. We varied the Poisson's ratio of the reinforcing skeleton by introducing auxetic or honeycomb functional structures that results in Poisson's ratio mismatch between the skeleton and matrix. During uniaxial tensile experiments, high strength and toughness were achieved due to two events: (1) multiple internal bond fractures of the skeleton (like sacrificial bonds in classic DN gels) and (2) significant, biaxial deformation of the matrix imposed by the functional skeleton. The Macro-DN composite with auxetic skeleton exhibits up to 4.2 times higher stiffness and 4.4 times higher yield force than the sum of the component materials. The significant improvement in mechanical performance is correlated to the large mismatch in Poisson's ratio between component materials, and the enhancement is especially noticeable in the low-stretch regime. The strengthening mechanism reported here based on Poisson's ratio mismatch can be widely used for soft materials regardless of chemical composition and will improve the mechanical properties of elastomer and hydrogel systems.

Tough, permeable and biocompatible microfluidic devices formed through the buckling delamination of soft hydrogel films.

Microchannels in soft materials play an important role in developing movable, deformable, and biocompatible fluidic systems for applications in various fields. Intensively investigated approaches to create microscale channel architectures use mechanical instability in soft materials, which can provide intricate yet ordered architectures with low cost and high throughput. Here, for microchannel fabrication, we demonstrate the use of swelling-driven buckle delamination of hydrogels, which is a mechanical instability pattern found in compressed film/substrate layer composites. By spatially controlling interfacial bonding between a thin polyacrylamide (PAAm) gel film and glass substrate, swelling-driven compressive stress induces buckle delamination at programmed positions, resulting in the formation of continuous hollow paths as microchannels. Connecting flow tubes with a 3D-printed connecter provides a deformable microfluidic device, enabling pressure-driven flows without leakage from the connecter and rupture of the channels. Furthermore, by stacking less-swellable bulk gels on the device, we obtained a tough, permeable, and biocompatible microfluidic device. Finally, we performed a cell culture on the device and chemical stimulation to cells through the diffusion of molecules from the microchannels. The results of this work shed light on designing pressure sensitive/resistant microfluidic systems based on diverse hydrogels with intricate 3D morphologies and will be useful for applications in the fields of bioanalysis, biomimetics, tissue engineering, and cell biology.

The Reconfigurable Maze Provides Flexible, Scalable, Reproducible, and Repeatable Tests.

Multiple mazes are routinely used to test the performance of animals because each has disadvantages inherent to its shape. However, the maze shape cannot be flexibly and rapidly reproduced in a repeatable and scalable way in a single environment. Here, to overcome the lack of flexibility, scalability, reproducibility, and repeatability, we develop a reconfigurable maze system that consists of interlocking runways and an array of accompanying parts. It allows experimenters to rapidly and flexibly configure a variety of maze structures along the grid pattern in a repeatable and scalable manner. Spatial navigational behavior and hippocampal place coding were not impaired by the interlocking mechanism. As a proof-of-principle demonstration, we demonstrate that the maze morphing induces location remapping of the spatial receptive field. The reconfigurable maze thus provides flexibility, scalability, repeatability, and reproducibility, therefore facilitating consistent investigation into the neuronal substrates for learning and memory and allowing screening for behavioral phenotypes.

Double network hydrogels based on semi-rigid polyelectrolyte physical networks.

Applying the double network principle to develop tough hydrogels with different polymer chemistries is important for the potential application of hydrogel materials. Synthesis of the two interpenetrated networks with contrasting structure and properties required for double networks usually involves a two-step polymerization process. In this work, we present a new method to synthesize tough double network hydrogels by post-physical crosslinking of linear semi-rigid polyelectrolytes entrapped in a chemically crosslinked neutral network. Owing to their semi-rigid structure, the linear polyelectrolytes form a brittle physical network above their overlap concentration in multi-valent ZrCl2O ion solutions without macroscopic phase separation within the flexible neutral network. The double network hydrogels thus prepared exhibit high modulus (∼1.7 MPa), strength (∼1.3 MPa), fracture strain (∼7.3), and strain energy density (∼5.9 MJ m-3), while containing over 80% water. These materials also exhibit modest self-healing ability (∼51% after 30 minutes), demonstrating an additional benefit of a physical sacrificial network. This method is simpler than the conventional two-step polymerization and could be applied to develop tough hydrogels from rigid polyelectrolytes, including biopolymers such as DNA, HA, and chondroitin sulfate.

Macroscale Double Networks: Design Criteria for Optimizing Strength and Toughness.

The double network concept, based on the fracture of sacrificial bonds, has been revolutionary toward the creation of robust soft materials. Based on the essence of double network hydrogels, macroscale, three-dimensional printed rigid sacrificial networks are embedded within silicone rubber stretchable matrices. Preferential fracture of the sacrificial network results in a ∼60 time increase in stiffness and a ∼50% increase in the work of extension compared with the neat matrix. Maximizing yield strength while maintaining multistep internal fracture occurs when the strength of the sacrificial network approaches the strength of the matrix. Upon determining the optimal sacrificial network strength, the sacrificial bond section density can be increased to maximize energy dissipation and toughening efficiencies up to ∼70% of the maximum theoretical toughness are achieved. High toughness and dissipation are achieved because topological interlocking enables significant force transmission to the sacrificial network at smaller length scales than interfacial adhesion, allowing much higher sacrificial bond density. This method is general and can be used with a variety of materials systems, without requiring strong interfacial adhesion, contrasting traditional composite systems. Demonstrating that the double network concept can be used at length scales far beyond the molecular scale will have important implications toward the development of future structural materials.

Dynamic Creation of 3D Hydrogel Architectures via Selective Swelling Programmed by Interfacial Bonding.

The topological features of material surfaces are crucial to the emergence of functions based on characteristic architectures. Among them, the combination of surface architectures and soft materials, which are highly deformable and flexible, has great potential as regards developing functional materials toward providing/enhancing advanced functions such as switchability and variability. Therefore, a simple yet versatile method for creating three-dimensional (3D) architectures based on soft materials is strongly required. In this study, hydrogels are selected as the soft materials and hydrogel film/rigid substrate layer composites are fabricated to obtain a 3D hydrogel architecture based on swelling instability. When a hydrogel film weakly attached to a rigid substrate is exposed to water, swelling-driven compressive stress induces buckle-delamination of the film from the substrate. Utilizing the chemical modification of a rigid substrate and a conventional photolithography technique, the delamination location is successfully controlled, resulting in a high-aspect-ratio folding architecture at an arbitrary position. In addition, we systematically designed the delamination geometry and chemically tuned the swelling ratio of the hydrogel, leading to the discovery of several new morphology transitions and relationships between the morphologies and the controllable parameters. This work provides a new approach to fabricating highly programmable 3D architectures of soft materials.

4-Hydroxypanduratin A and Isopanduratin A Inhibit Tumor Necrosis Factor α-Stimulated Gene Expression and the Nuclear Factor κB-Dependent Signaling Pathway in Human Lung Adenocarcinoma A549 Cells.

Tumor necrosis factor α (TNF-α), a pro-inflammatory cytokine, regulates inflammatory and immune responses by up-regulating gene expression in a manner that is dependent on the transcription factor nuclear factor κB (NF-κB). In the present study, we found that 4-hydroxypanduratin A and isopanduratin A, constituents of the rhizomes of Boesenbergia pandurata, inhibited the TNF-α-stimulated up-regulation of intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells. 4-Hydroxypanduratin A and isopanduratin A also reduced ICAM-1 mRNA expression and NF-κB-responsive luciferase activity in TNF-α-stimulated A549 cells. Moreover, 4-hydroxypanduratin A and isopanduratin A prevented the TNF-α-stimulated translocation of the NF-κB subunit p65 to the nucleus and the phosphorylation and proteasomal degradation of the inhibitor of the NF-κB α protein. The present results revealed that 4-hydroxypanduratin A and isopanduratin A inhibit TNF-α-stimulated gene expression and the NF-κB-dependent signaling pathway in A549 cells.

Tough Hydrogels with Fast, Strong, and Reversible Underwater Adhesion Based on a Multiscale Design.

Hydrogels have promising applications in diverse areas, especially wet environments including tissue engineering, wound dressing, biomedical devices, and underwater soft robotics. Despite strong demands in such applications and great progress in irreversible bonding of robust hydrogels to diverse synthetic and biological surfaces, tough hydrogels with fast, strong, and reversible underwater adhesion are still not available. Herein, a strategy to develop hydrogels demonstrating such characteristics by combining macroscale surface engineering and nanoscale dynamic bonds is proposed. Based on this strategy, excellent underwater adhesion performance of tough hydrogels with dynamic ionic and hydrogen bonds, on diverse substrates, including hard glasses, soft hydrogels, and biological tissues is obtained. The proposed strategy can be generalized to develop other soft materials with underwater adhesion.

Creating Stiff, Tough, and Functional Hydrogel Composites with Low-Melting-Point Alloys.

Reinforcing hydrogels with a rigid scaffold is a promising method to greatly expand the mechanical and physical properties of hydrogels. One of the challenges of creating hydrogel composites is the significant stress that occurs due to swelling mismatch between the water-swollen hydrogel matrix and the rigid skeleton in aqueous media. This stress can cause physical deformation (wrinkling, buckling, or fracture), preventing the fabrication of robust composites. Here, a simple yet versatile method is introduced to create "macroscale" hydrogel composites, by utilizing a rigid reinforcing phase that can relieve stress-induced deformation. A low-melting-point alloy that can transform from a load-bearing solid state to a free-deformable liquid state at relatively low temperature is used as a reinforcing skeleton, which enables the release of any swelling mismatch, regardless of the matrix swelling degree in liquid media. This design can generally provide hydrogels with hybridized functions, including excellent mechanical properties, shape memory, and thermal healing, which are often difficult or impossible to achieve with single-component hydrogel systems. Furthermore, this technique enables controlled electrochemical reactions and channel-structure templating in hydrogel matrices. This work may play an important role in the future design of soft robots, wearable electronics, and biocompatible functional materials.

Sensitive Photodetection with Photomultiplication Effect in an Interfacial Eu2+/3+ Complex on a Mesoporous TiO2 Film.

A simple device structure composed of an interfacial Eu2+/3+ complex on a mesoporous TiO2 film is developed by a solution process and acts as the high-performance photodetector with photomultiplication phenomena. The electron transfer from the photoexcited organic ligand, 2,2':6',2″-terpyridine (terpy), as a photosensitizer to TiO2 is accelerated by the reduction level of Eu3+/2+ ions chemically bonding among terpy and TiO2, resulting in the generation of a large photocurrent. It is worth noting that its external quantum efficiency is in excess of 105% under applied reverse bias. The corresponding responsivity of the device is also determined to be 464 A/W at an irradiation light intensity of 0.7 mW/cm2 (365 nm), which is more than 3 orders of magnitude larger than those of inorganic photodetectors. A dark current of the device can be reduced to 10-9 A/cm2 by introducing a Eu oxide thin-film layer as a carrier blocking layer at the interface between transparent conducting oxide (TCO) and the TiO2 layer, and the specific detectivity reaches 5.2 × 1015 jones at 365 nm with -3 V. The performance of our organic-inorganic hybrid photodetector surpasses those of existing ultraviolet photodetectors.

Coupled instabilities of surface crease and bulk bending during fast free swelling of hydrogels.

Most studies on hydrogel swelling instability have been focused on a constrained boundary condition. In this paper, we studied the mechanical instability of a piece of disc-shaped hydrogel during free swelling. The fast swelling of the gel induces two swelling mismatches; a surface-inner layer mismatch and an annulus-disc mismatch, which lead to the formation of a surface crease pattern and a saddle-like bulk bending, respectively. For the first time, a stripe-like surface crease that is at a right angle on the two surfaces of the gel was observed. This stripe pattern is related to the mechanical coupling of surface instability and bulk bending, which is justified by investigating the swelling-induced surface pattern on thin hydrogel sheets fixed onto a saddle-shaped substrate prior to swelling. A theoretical mechanism based on an energy model was developed to show an anisotropic stripe-like surface crease pattern on a saddle-shaped surface. These results might be helpful to develop novel strategies for controlling crease patterns on soft and wet materials by changing their three-dimensional shape.

Control superstructure of rigid polyelectrolytes in oppositely charged hydrogels via programmed internal stress.

Biomacromolecules usually form complex superstructures in natural biotissues, such as different alignments of collagen fibres in articular cartilages, for multifunctionalities. Inspired by nature, there are efforts towards developing multiscale ordered structures in hydrogels (recognized as one of the best candidates of soft biotissues). However, creating complex superstructures in gels are hardly realized because of the absence of effective approaches to control the localized molecular orientation. Here we introduce a method to create various superstructures of rigid polyanions in polycationic hydrogels. The control of localized orientation of rigid molecules, which are sensitive to the internal stress field of the gel, is achieved by tuning the swelling mismatch between masked and unmasked regions of the photolithographic patterned gel. Furthermore, we develop a double network structure to toughen the hydrogels with programmed superstructures, which deform reversibly under large strain. This work presents a promising pathway to develop superstructures in hydrogels and should shed light on designing biomimetic materials with intricate molecular alignments.