Development of an anti-tauopathy mucosal vaccine specifically targeting pathologic conformers.

Alzheimer's disease (AD) and related tauopathies are associated with pathological tau protein aggregation, which plays an important role in neurofibrillary degeneration and dementia. Targeted immunotherapy to eliminate pathological tau aggregates is known to improve cognitive deficits in AD animal models. The tau repeat domain (TauRD) plays a pivotal role in tau-microtubule interactions and is critically involved in the aggregation of hyperphosphorylated tau proteins. Because TauRD forms the structural core of tau aggregates, the development of immunotherapies that selectively target TauRD-induced pathological aggregates holds great promise for the modulation of tauopathies. In this study, we generated recombinant TauRD polypeptide that form neurofibrillary tangle-like structures and evaluated TauRD-specific immune responses following intranasal immunization in combination with the mucosal adjuvant FlaB. In BALB/C mice, repeated immunizations at one-week intervals induced robust TauRD-specific antibody responses in a TLR5-dependent manner. Notably, the resulting antiserum recognized only the aggregated form of TauRD, while ignoring monomeric TauRD. The antiserum effectively inhibited TauRD filament formation and promoted the phagocytic degradation of TauRD aggregate fragments by microglia. The antiserum also specifically recognized pathological tau conformers in the human AD brain. Based on these results, we engineered a built-in flagellin-adjuvanted TauRD (FlaB-TauRD) vaccine and tested its efficacy in a P301S transgenic mouse model. Mucosal immunization with FlaB-TauRD improved quality of life, as indicated by the amelioration of memory deficits, and alleviated tauopathy progression. Notably, the survival of the vaccinated mice was dramatically extended. In conclusion, we developed a mucosal vaccine that exclusively targets pathological tau conformers and prevents disease progression.

Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarct.

Cortical neuromodulation (CNM) is widely used to promote recovery after stroke. Despite the beneficial results of CNM, the roles played by different neuron types in the effects of current CNM techniques are unable to be differentiated. Our aim was to use selective optogenetic cortical stimulation to explore how different subpopulations of neuronal cells contribute to poststroke recovery. We transduced the sensory-parietal cortex (SPC) of rats with CamKII-ChR2 (pyramidal neurons), PV-ChR2 (parvalbumin-expressing inhibitory neurons), or hSyn-ChR2 (pan-neuronal population) before inducing photothrombotic capsular infarct lesions. We found that selective stimulation of inhibitory neurons resulted in significantly greater motor recovery than stimulation of excitatory neurons or the pan-neuronal population. Furthermore, 2-deoxy-2-[18F] fluoro-D-glucose microPET (FDG-microPET) imaging revealed a significant reduction in cortical diaschisis and activation of the corticostriatal neural circuit, which were correlated with behavioral recovery in the PV-ChR2 group. The spatial pattern of brain-derived neurotrophic factor (BDNF) expression was evident in the stimulated cortex and underlying cortico-subcortical circuit. Our results indicate that the plasticity of inhibitory neurons is crucial for functional recovery after capsular infarct. Modifying CNM parameters to potentiate the stimulation of inhibitory neurons could improve poststroke outcomes.

Avian eye-inspired perovskite artificial vision system for foveated and multispectral imaging.

Avian eyes have deep central foveae as a result of extensive evolution. Deep foveae efficiently refract incident light, creating a magnified image of the target object and making it easier to track object motion. These features are essential for detecting and tracking remote objects in dynamic environments. Furthermore, avian eyes respond to a wide spectrum of light, including visible and ultraviolet light, allowing them to efficiently distinguish the target object from complex backgrounds. Despite notable advances in artificial vision systems that mimic animal vision, the exceptional object detection and targeting capabilities of avian eyes via foveated and multispectral imaging remain underexplored. Here, we present an artificial vision system that capitalizes on these aspects of avian vision. We introduce an artificial fovea and vertically stacked perovskite photodetector arrays whose designs were optimized by theoretical simulations for the demonstration of foveated and multispectral imaging. The artificial vision system successfully identifies colored and mixed-color objects and detects remote objects through foveated imaging. The potential for use in uncrewed aerial vehicles that need to detect, track, and recognize distant targets in dynamic environments is also discussed. Our avian eye-inspired perovskite artificial vision system marks a notable advance in bioinspired artificial visions.

Outlier rejection in the process of pooling.

Ensemble perception allows our visual system to process large amounts of information efficiently by summarizing its statistical properties. A key aspect of ensemble perception is the devaluation of outlying elements, which leads to more informative summary statistics with reduced variance and a more representative mean. However, the mechanisms underlying this outlier rejection process are not well understood. One possibility is that outliers are selectively excluded before summarization. To test this, we investigated whether only weaker items were excluded from averaging. We manipulated the encoding strength of items in a display by changing the emotional intensities of faces, the spatial location of emotional outliers, and the spatial distribution of emotional faces. We found that the response to outliers varied depending on their location. Specifically, outliers were more likely to be excluded from averaging when presented in more peripheral regions, while their exclusion was partial in parafoveal regions. In other words, outlier rejection in ensemble processing is more flexible than the supposed rigid designation of weighting against outliers. Alternatively, the results fit well with hierarchically structured pooling, during which outliers are discounted more dynamically without positing any separate selective mechanism before summarization. We propose an explanation for outlier rejection in light of a recently proposed population response model of ensemble processing.

Stretchable colour-sensitive quantum dot nanocomposites for shape-tunable multiplexed phototransistor arrays.

High-performance photodetecting materials with intrinsic stretchability and colour sensitivity are key requirements for the development of shape-tunable phototransistor arrays. Another challenge is the proper compensation of optical aberrations and noises generated by mechanical deformation and fatigue accumulation in a shape-tunable phototransistor array. Here we report rational material design and device fabrication strategies for an intrinsically stretchable, multispectral and multiplexed 5 × 5 × 3 phototransistor array. Specifically, a unique spatial distribution of size-tuned quantum dots, blended in a semiconducting polymer within an elastomeric matrix, was formed owing to surface energy mismatch, leading to highly efficient charge transfer. Such intrinsically stretchable quantum-dot-based semiconducting nanocomposites enable the shape-tunable and colour-sensitive capabilities of the phototransistor array. We use a deep neural network algorithm for compensating optical aberrations and noises, which aids the precise detection of specific colour patterns (for example, red, green and blue patterns) both under its flat state and hemispherically curved state (radius of curvature of 18.4 mm).

Revealing charge carrier dynamics and transport in Te-doped GaAsSb and GaAsSbN nanowires by correlating ultrafast terahertz spectroscopy and optoelectronic characterization.

Recent advances in the growth of III-V semiconductor nanowires (NWs) hold great promise for nanoscale optoelectronic device applications. It is established that a small amount of nitrogen (N) incorporation in III-V semiconductor NWs can effectively red-shift their wavelength of operation and tailor their electronic properties for specific applications. However, understanding the impact of N incorporation on non-equilibrium charge carrier dynamics and transport in semiconducting NWs is critical in achieving efficient semiconducting NW devices. In this work, ultrafast optical pump-terahertz probe spectroscopy has been used to study non-equilibrium carrier dynamics and transport in Te-doped GaAsSb and dilute nitride GaAsSbN NWs, with the goal of correlating these results with electrical characterization of their equilibrium photo-response under bias and low-frequency noise characteristics. Nitrogen incorporation in GaAsSb NWs led to a significant increase in the carrier scattering rate, resulting in a severe reduction in carrier mobility. Carrier recombination lifetimes of 33 ± 1 picoseconds (ps) and 147 ± 3 ps in GaAsSbN and GaAsSb NWs, respectively, were measured. The reduction in the carrier lifetime and photoinduced optical conductivities are due to the presence of N-induced defects, leading to deterioration in the electrical and optical characteristics of dilute nitride NWs relative to the non-nitride NWs. Finally, we observed a very fast rise time of âˆ¼2 ps for both NW materials, directly impacting their potential use as high-speed photodetectors.

Direct Observation of Coherent Longitudinal and Shear Acoustic Phonons in TaAs Using Ultrafast X-Ray Diffraction.

Using femtosecond time-resolved x-ray diffraction, we investigated optically excited coherent acoustic phonons in the Weyl semimetal TaAs. The low symmetry of the (112) surface probed in our experiment enables the simultaneous excitation of longitudinal and shear acoustic modes, whose dispersion closely matches our simulations. We observed an asymmetry in the spectral line shape of the longitudinal mode that is notably absent from the shear mode, suggesting a time-dependent frequency chirp that is likely driven by photoinduced carrier diffusion. We argue on the basis of symmetry that these acoustic deformations can transiently alter the electronic structure near the Weyl points and support this with model calculations. Our study underscores the benefit of using off-axis crystal orientations when optically exciting acoustic deformations in topological semimetals, allowing one to transiently change their crystal and electronic structures.

Keldysh Space Control of Charge Dynamics in a Strongly Driven Mott Insulator.

The fate of a Mott insulator under strong low frequency optical driving conditions is a fundamental problem in quantum many-body dynamics. Using ultrafast broadband optical spectroscopy, we measured the transient electronic structure and charge dynamics of an off-resonantly pumped Mott insulator Ca_{2}RuO_{4}. We observe coherent bandwidth renormalization and nonlinear doublon-holon pair production occurring in rapid succession within a sub-100-fs pump pulse duration. By sweeping the electric field amplitude, we demonstrate continuous bandwidth tuning and a Keldysh crossover from a multiphoton absorption to quantum tunneling dominated pair production regime. Our results provide a procedure to control coherent and nonlinear heating processes in Mott insulators, facilitating the discovery of novel out-of-equilibrium phenomena in strongly correlated systems.

High Entropy Oxide Relaxor Ferroelectrics.

Relaxor ferroelectrics are important in technological applications due to strong electromechanical response, energy storage capacity, electrocaloric effect, and pyroelectric energy conversion properties. Current efforts to discover and design materials in this class generally rely on substitutional doping as slight changes to local compositional order can significantly affect the Curie temperature, morphotropic phase boundary, and electromechanical responses. In this work, we demonstrate that moving to the strong limit of compositional complexity in an ABO3 perovskite allows stabilization of relaxor responses that do not rely on a single narrow phase transition region. Entropy-assisted synthesis approaches are utilized to synthesize single-crystal Ba(Ti0.2Sn0.2Zr0.2Hf0.2Nb0.2)O3 [Ba(5B)O] films. The high levels of configurational disorder present in this system are found to influence dielectric relaxation, phase transitions, nanopolar domain formation, and Curie temperature. Temperature-dependent dielectric, Raman spectroscopy, and second-harmonic generation measurements reveal multiple phase transitions, a high Curie temperature of 570 K, and the relaxor ferroelectric nature of Ba(5B)O films. The first-principles theory calculations are used to predict possible combinations of cations to design relaxor ferroelectrics and quantify the relative feasibility of synthesizing these highly disordered single-phase perovskite systems. The ability to stabilize single-phase perovskites with various cations on the B-sites offers possibilities for designing high-performance relaxor ferroelectric materials for piezoelectric, pyroelectric, and electrocaloric applications.

Hot Carrier Cooling and Recombination Dynamics of Chlorine-Doped Hybrid Perovskite Single Crystals.

Controlling the photoexcited properties and behavior of hybrid perovskites by halide doping has the potential to impact a wide range of emerging technologies, including solar cells and radiation detectors. Crystalline samples of methylammonium lead bromide substituted with chlorine (MAPbBr3-xClx) were examined by transient reflectivity spectroscopy and nonadiabatic molecular dynamics simulations. At picosecond time scales, the addition of chlorine to the perovskite crystal increased the observed rate of hot carrier cooling and the calculated electron-phonon coupling constants. Chlorine-doped samples also exhibit a slower surface recombination velocity and a smaller ambipolar mobility.

Excessive Astrocytic GABA Causes Cortical Hypometabolism and Impedes Functional Recovery after Subcortical Stroke.

Glucose hypometabolism in cortical structures after functional disconnection is frequently reported in patients with white matter diseases such as subcortical stroke. However, the molecular and cellular mechanisms have been poorly elucidated. Here we show, in an animal model of internal capsular infarct, that GABA-synthesizing reactive astrocytes in distant cortical areas cause glucose hypometabolism via tonic inhibition of neighboring neurons. We find that reversal of aberrant astrocytic GABA synthesis, by pharmacological inhibition and astrocyte-specific gene silencing of MAO-B, reverses the reduction in cortical glucose metabolism. Moreover, induction of aberrant astrocytic GABA synthesis by cortical injection of putrescine or adenovirus recapitulates cortical hypometabolism. Furthermore, MAO-B inhibition causes a remarkable recovery from post-stroke motor deficits when combined with a rehabilitation regimen. Collectively, our data indicate that cortical glucose hypometabolism in subcortical stroke is caused by aberrant astrocytic GABA and MAO-B inhibition and that attenuating cortical hypometabolism can be a therapeutic approach in subcortical stroke.

Ultrastructural Dendritic Changes Underlying Diaschisis After Capsular Infarct.

Diaschisis has been described as functional depression distant to the lesion. A variety of neuroscientific approaches have been used to investigate the mechanisms underlying diaschisis. However, few studies have examined the pathological changes in diaschisis at ultrastructural level. Here, we used a rat model of capsular infarct that consistently produces diaschisis in ipsilesional and contralesional motor and sensory cortices. To verify the occurrence of diaschisis and monitor time-dependent changes in diaschisis, we performed longitudinal 2-deoxy-2-[18F]-fluoro-d-glucose microPET (FDG-microPET) study. We also used light and electron microscopy to identify the microscopic and ultrastructural changes at the diaschisis site at 7, 14, and 21 days after capsular infarct modeling (CIM). FDG-microPET showed the occurrence of diaschisis after CIM. Light microscopic examinations revealed no significant histopathological changes at the diaschisis site except a mild degree of reactive astrogliosis. However, electron microscopy revealed swollen, hydropic degeneration of axial dendrites and axodendritic synapses, although the neuronal soma (including nuclear chromatin and cytoplasmic organelles) and myelinated axons were relatively well preserved up to 21 days after injury. Furthermore, number of axodendritic synapses was significantly decreased after CIM. These data indicate that a circumscribed subcortical white-matter lesion produces ultrastructural pathological changes related to the pathogenesis of diaschisis.

Recurrent Glioma With Lineage Conversion From Oligodendroglioma to Astrocytoma in Two Cases.

Following the introduction of the molecular classification of gliomas by the WHO in 2016, molecularly-proven lineage conversion during glioma recurrence has never been reported. The reported two cases were initially diagnosed as oligodendroglioma with 1p/19q-codeletion and mutation of isocitrate dehydrogenase 1 (IDH1)-R132H. The recurrent tumors showed loss of alpha-thalassemia/mental retardation X-linked (ATRX) expression, strong P53 positivity, and 1p/19q-nondeletion. Next generation sequencing analysis performed on the first case confirmed the transition of molecular traits from oligodendroglioma to astrocytoma. An IDH mutation of R132H was preserved in the episodes of recurrence, but ATRX and TP53 mutations were newly acquired and TERT promoter mutation C228T was lost at the most recent recurrence. The issue in question for the presented cases is whether the original tumors were pure oligodendrogliomas that then transdifferentiated into astrocytomas, or whether the original tumor was an oligoastrocytoma having oligodendroglioma cells that outnumbered the astrocytoma cells and where the astrocytoma cells becoming more dominant over the episodes of recurrence. With the recognition of the possibility of lineage conversion, our study suggests that molecular examination should be performed to adjust therapeutic strategies in recurrent gliomas. Indeed, our observation of lineage conversion in glioma recurrence calls into question the current distinction drawn between oligodendroglioma, astrocytoma and oligoastrocytoma, rather than simply bidding "farewell to oligoastrocytoma."

Soft High-Resolution Neural Interfacing Probes: Materials and Design Approaches.

Neural interfacing probes are located between the nervous system and the implanted electronic device in order to acquire information on the complex neuronal activity and to reconstruct impaired neural connectivity. Despite remarkable advancement in recent years, conventional neural interfacing is still unable to completely accomplish these goals, especially in long-term brain interfacing. The major limitation arises from physical and mechanical differences between neural interfacing probes and neural tissues that cause local immune responses and production of scar cells near the interface. Therefore, neural interfaces should ideally be extremely soft and have the physical scale of cells to mitigate the boundary between biotic and abiotic systems. Soft materials for neural interfaces have been intensively investigated to improve both interfacing and long-term signal transmission. The design and fabrication of micro and nanoscale devices have drastically decreased the stiffness of probes and enabled single-neuron measurement. In this Mini Review, we discuss materials and design approaches for developing soft high-resolution neural probes intended for long-term brain interfacing and outline existent challenges for achieving next-generation neural interfacing probes.

Primary Age-Related Tauopathy: An Elderly Brain Pathology Frequently Encountered during Autopsy.

Due to the progressive aging of Korean society and the introduction of brain banks to the Korean medical system, the possibility that pathologists will have access to healthy elderly brains has increased. The histopathological analysis of an elderly brain from a subject with relatively well-preserved cognition is quite different from that of a brain from a demented subject. Additionally, the histology of elderly brains differs from that of young brains. This brief review discusses primary age-related tauopathy; this term was coined to describe elderly brains with Alzheimer's diseasetype neurofibrillary tangles mainly confined to medial temporal structures, and no ß-amyloid pathology.

Intensity-modulated radiotherapy for stage I glottic cancer: a short-term outcomes compared with three-dimensional conformal radiotherapy.

PURPOSE: To investigate the differences in treatment outcomes between two radiation techniques, intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT). MATERIALS AND METHODS: We retrospectively analyzed 160 (IMRT = 23, 3DCRT = 137) patients with stage I glottic cancer treated from January 2005 through December 2016. The IMRT was performed with TomoTherapy (16 patients), volumetric-modulated arc therapy (6 patients), and step-and-shoot technique (1 patient), respectively. The 3DCRT was performed with bilateral parallel opposing fields. The median follow-up duration was 30 months (range, 31 to 42 months) in the IMRT group and 65 months (range, 20 to 143 months) in the 3DCRT group. RESULTS: The 5-year overall survival and 3-year local control rates of the 160 patients were 95.7% and 91.4%, respectively. There was no significant difference in 3-year local control rates between the IMRT and 3DCRT groups (94.4% vs. 91.0%; p = 0.587). Thirteen of 137 patients in the 3DCRT group had recurrences. In the IMRT group, one patient had a recurrence at the true vocal cord. Patients treated with IMRT had less grade 2 skin reaction than the 3DCRT group, but this had no statistical significance (4.3% vs. 21.2%; p = 0.080). CONCLUSION: IMRT had comparable outcomes with 3DCRT, and a trend of less acute skin reaction in stage I glottic cancer patients.

Highly conductive, stretchable and biocompatible Ag-Au core-sheath nanowire composite for wearable and implantable bioelectronics.

Wearable and implantable devices require conductive, stretchable and biocompatible materials. However, obtaining composites that simultaneously fulfil these requirements is challenging due to a trade-off between conductivity and stretchability. Here, we report on Ag-Au nanocomposites composed of ultralong gold-coated silver nanowires in an elastomeric block-copolymer matrix. Owing to the high aspect ratio and percolation network of the Ag-Au nanowires, the nanocomposites exhibit an optimized conductivity of 41,850 S cm-1 (maximum of 72,600 S cm-1). Phase separation in the Ag-Au nanocomposite during the solvent-drying process generates a microstructure that yields an optimized stretchability of 266% (maximum of 840%). The thick gold sheath deposited on the silver nanowire surface prevents oxidation and silver ion leaching, making the composite biocompatible and highly conductive. Using the nanocomposite, we successfully fabricate wearable and implantable soft bioelectronic devices that can be conformally integrated with human skin and swine heart for continuous electrophysiological recording, and electrical and thermal stimulation.

Spectroscopic Studies on the Metal-Insulator Transition Mechanism in Correlated Materials.

The metal-insulator transition (MIT) in correlated materials is a novel phenomenon that accompanies a large change in resistivity, often many orders of magnitude. It is important in its own right but its switching behavior in resistivity can be useful for device applications. From the material physics point of view, the starting point of the research on the MIT should be to understand the microscopic mechanism. Here, an overview of recent efforts to unravel the microscopic mechanisms for various types of MITs in correlated materials is provided. Research has focused on transition metal oxides (TMOs), but transition metal chalcogenides have also been studied. Along the way, a new class of MIT materials is discovered, the so-called relativistic Mott insulators in 5d TMOs. Distortions in the MO6 (M = transition metal) octahedron are found to have a large and peculiar effect on the band structure in an orbital dependent way, possibly paving a way to the orbital selective Mott transition. In the final section, the character of the materials suitable for applications is summarized, followed by a brief discussion of some of the efforts to control MITs in correlated materials, including a dynamical approach using light.