Development and validation of an expanded antibody toolset that captures alpha-synuclein pathological diversity in Lewy body diseases.

The abnormal aggregation and accumulation of alpha-synuclein (aSyn) in the brain is a defining hallmark of synucleinopathies. Various aSyn conformations and post-translationally modified forms accumulate in pathological inclusions and vary in abundance among these disorders. Relying on antibodies that have not been assessed for their ability to detect the diverse forms of aSyn may lead to inaccurate estimations of aSyn pathology in human brains or disease models. To address this challenge, we developed and characterized an expanded antibody panel that targets different sequences and post-translational modifications along the length of aSyn, and that recognizes all monomeric, oligomeric, and fibrillar aSyn conformations. Next, we profiled aSyn pathology across sporadic and familial Lewy body diseases (LBDs) and reveal heterogeneous forms of aSyn pathology, rich in Serine 129 phosphorylation, Tyrosine 39 nitration and N- and C-terminal tyrosine phosphorylations, scattered both to neurons and glia. In addition, we show that aSyn can become hyperphosphorylated during processes of aggregation and inclusion maturation in neuronal and animal models of aSyn seeding and spreading. The validation pipeline we describe for these antibodies paves the way for systematic investigations into aSyn pathological diversity in the human brain, peripheral tissues, as well as in cellular and animal models of synucleinopathies.

γ-Ray-Induced Photocatalytic Activity of Bi-Doped PbS toward Organic Dye Removal under Sunlight.

Photocatalysts based on semiconducting chalcogenides due to their adaptable physio-chemical characteristics are attracting attention. In this work, Bi-doped PbS (henceforth PbS:Bi) was prepared using a straightforward chemical precipitation approach, and the influence of γ-irradiation on PbS's photocatalytic ability was investigated. Synthesized samples were confirmed structurally and chemically. Pb(1-x)BixS (x = 0, 0.005, 0.01, 0.02) samples that were exposed to gamma rays showed fine-tuning of the optical bandgap for better photocatalytic action beneath visible light. The photocatalytic degradation rate of the irradiated Pb0.995Bi0.005S sample was found to be 1.16 times above that of pure PbS. This is due to the occupancy of Bi3+ ions at surface lattice sites as a result of their lower concentration in PbS, which effectively increases interface electron transport and the annealing impact of gamma irradiation. Scavenger tests show that holes are active species responsible for deterioration of the methylene blue. The irradiated PbS:Bi demonstrated high stability after being used repeatedly for photocatalytic degradation.

Non-Fermi Liquids from Kinetic Constraints in Tilted Optical Lattices.

We study Fermi-Hubbard models with kinetically constrained dynamics that conserves both total particle number and total center of mass, a situation that arises when interacting fermions are placed in strongly tilted optical lattices. Through a combination of analytics and numerics, we show how the kinetic constraints stabilize an exotic non-Fermi liquid phase described by fermions coupled to a gapless bosonic field, which in several respects mimics a dynamical gauge field. This offers a novel route towards the study of non-Fermi liquid phases in the precision environments afforded by ultracold atom platforms.

Artificial intelligence-coupled plasmonic infrared sensor for detection of structural protein biomarkers in neurodegenerative diseases.

Diagnosis of neurodegenerative disorders (NDDs) including Parkinson's disease and Alzheimer's disease is challenging owing to the lack of tools to detect preclinical biomarkers. The misfolding of proteins into oligomeric and fibrillar aggregates plays an important role in the development and progression of NDDs, thus underscoring the need for structural biomarker-based diagnostics. We developed an immunoassay-coupled nanoplasmonic infrared metasurface sensor that detects proteins linked to NDDs, such as alpha-synuclein, with specificity and differentiates the distinct structural species using their unique absorption signatures. We augmented the sensor with an artificial neural network enabling unprecedented quantitative prediction of oligomeric and fibrillar protein aggregates in their mixture. The microfluidic integrated sensor can retrieve time-resolved absorbance fingerprints in the presence of a complex biomatrix and is capable of multiplexing for the simultaneous monitoring of multiple pathology-associated biomarkers. Thus, our sensor is a promising candidate for the clinical diagnosis of NDDs, disease monitoring, and evaluation of novel therapies.

Seeding the aggregation of TDP-43 requires post-fibrillization proteolytic cleavage.

Despite the strong evidence linking the transactive response DNA-binding protein 43 (TDP-43) aggregation to the pathogenesis of frontotemporal lobar degeneration with TDP-43, amyotrophic lateral sclerosis and several neurodegenerative diseases, our knowledge of the sequence and structural determinants of its aggregation and neurotoxicity remains incomplete. Herein, we present a new method for producing recombinant full-length TDP-43 filaments that exhibit sequence and morphological features similar to those of brain-derived TDP-43 filaments. We show that TDP-43 filaments contain a ß-sheet-rich helical amyloid core that is fully buried by the flanking structured domains of the protein. We demonstrate that the proteolytic cleavage of TDP-43 filaments and exposure of this amyloid core are necessary for propagating TDP-43 pathology and enhancing the seeding of brain-derived TDP-43 aggregates. Only TDP-43 filaments with exposed amyloid core efficiently seeded the aggregation of endogenous TDP-43 in cells. These findings suggest that inhibiting the enzymes mediating cleavage of TDP-43 aggregates represents a viable disease-modifying strategy to slow the progression of amyotrophic lateral sclerosis and other TDP-43 proteinopathies.

Gamma irradiation effect on photocatalytic properties of Cu and Sr ions codoped PbS.

Gamma-irradiation effects on photocatalytic action of PbS nanocrystallites codoped with Cu and Sr ions were performed for organic dye degradation. The physical and chemical characterizations of these nanocrystallites were examined employing X-ray diffraction, Raman, and field emission electron microscopic analysis. The optical bandgaps of gamma-irradiated PbS with co-dopants have shifted from 1.95 eV (pristine PbS) to 2.45 eV in the visible spectrum. Under direct sunlight, the photocatalytic action of these compounds against methylene blue (MB) was investigated. Observations indicated that gamma-irradiated Pb(0.98)Cu0.01Sr0.01S nanocrystallite sample exhibits a higher photocatalytic degradation activity of 74.02% in 160 min and stability of 69.4% after three cycles, suggesting that gamma irradiation could potentially influence organic MB degradation. This is due to combined action of high-energy gamma irradiation (at an optimzed dose), which causes sulphur vacancies, and defects created by dopant ions, which alter the crystal structure by inducing strain in the crystal lattice, hence altering the crystallinity of PbS.

Mechanical, microstructural and fracture studies on inconel 825-SS316L functionally graded wall fabricated by wire arc additive manufacturing.

This paper presents a novel method that uses the cold metal transfer based wire arc additive manufacturing process to fabricate functionally graded Inconel 825-SS316L walls. The optical micrograph of Inconel 825 exhibits continuous and discontinuous dendritic structures. The SS316L region comprises 5% of δ-ferrite in primary austenitic (γ) dendrites which was confirmed by the Creq/Nieq ratio of 1.305. The functionally graded interface reveals a partially mixed zone with a transition from the elongated dendrites to fine equiaxed dendrites. The tensile properties of the fabricated wall were determined at room temperature using specimens extracted from Inconel 825, SS316L, and the interface regions. The morphology of the tensile tested specimens revealed significant plastic deformation, indicating ductile failure. The fracture toughness of the wall was experimentally investigated by employing the crack tip opening displacement (CTOD) test. The fracture morphology exhibited a ductile mode of fracture with striations perpendicular to the direction of crack development. Elemental mapping revealed that there was no evidence of elemental segregation on the fractured surfaces, and the elements were uniformly dispersed. The CTOD measures 0.853 mm, 0.873 mm on the Inconel 825 side and the SS316L side respectively. The test results confirm that both the Inconel 825 and SS316L sides have good fracture toughness.

Continuous Mott Transition in Moiré Semiconductors: Role of Long-Wavelength Inhomogeneities.

Recent experiments in moiré transition metal dichalcogenide materials have reported the observation of a continuous bandwidth-tuned transition from a metal to a paramagnetic Mott insulator at a fixed filling of one electron per moiré unit cell. The electrical transport measurements reveal a number of puzzling features that are seemingly at odds with the theoretical expectations of an interaction-induced, but disorder-free, bandwidth-tuned metal-insulator transition. In this Letter, we include the effects of long-wavelength inhomogeneities, building on the results for a continuous metal-insulator transition at fixed filling in the clean limit. We examine the effects of mesoscale inhomogeneities near the critical point on transport using the framework of random resistor networks, highlighting the salient differences from a simple percolation-based picture. We place our results in the context of recent and ongoing experiments.

PbS/graphene hybrid nanostructures coated glassy carbon electrode for the electrochemical sensing of copper ions in aqueous solution.

In this research, we have studied the electrochemical sensing of Cu(II) ions in aqueous solution using PbS/Graphene composite nanostructure coated glassy carbon electrode (GCE). The SEM-EDAX analysis revealed that the lead sulphide nanocrystals are homogeneously embedded on the graphene nanosheets with an uniform particle size of 100 nm, and the elements presents 92.32% and Lead content of 5.45% and Sulfur content of 0.91%. Raman spectra exhibits G with respect to the E2g sp2 hybridized C-C and D band with respect to the A1g mode in the disordered edge region of the GNS. The composite nanostructure coated GCE (PbS/Graphene/GCE) was prepared and its performance in the existence of metal ions such us Cd(II),Pb(II), Mg(II), Cu(II) and Ni(II) was studied using the current voltage curves in double distilled water within the scan rates of 25 to 300mVs-1. The PbS/Graphene coated carbon electrode exhibited the higher anodic and cathodic peak current for copper solution than the other metal ions studied, which various linearly proportional to concentration. The electrochemical sensing characteristics PbS/GNS/GCE was found to be significant towards detecting Cu2+ ion within the concentration range of 1 × 10-4 to 1 × 10-8 M, with a lowest sensing detection limit of 1 × 10-8 M.

A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity.

The alpha-synuclein mutation E83Q, the first in the NAC domain of the protein, was recently identified in a patient with dementia with Lewy bodies. We investigated the effects of this mutation on the aggregation of aSyn monomers and the structure, morphology, dynamic, and seeding activity of the aSyn fibrils in neurons. We found that it markedly accelerates aSyn fibrillization and results in the formation of fibrils with distinct structural and dynamic properties. In cells, this mutation is associated with higher levels of aSyn, accumulation of pS129, and increased toxicity. In a neuronal seeding model of Lewy body (LB) formation, the E83Q mutation significantly enhances the internalization of fibrils into neurons, induces higher seeding activity, and results in the formation of diverse aSyn pathologies, including the formation of LB-like inclusions that recapitulate the immunohistochemical and morphological features of brainstem LBs observed in brains of patients with Parkinson's disease.

Magnetically brightened dark electron-phonon bound states in a van der Waals antiferromagnet.

In van der Waals (vdW) materials, strong coupling between different degrees of freedom can hybridize elementary excitations into bound states with mixed character1-3. Correctly identifying the nature and composition of these bound states is key to understanding their ground state properties and excitation spectra4,5. Here, we use ultrafast spectroscopy to reveal bound states of d-orbitals and phonons in 2D vdW antiferromagnet NiPS3. These bound states manifest themselves through equally spaced phonon replicas in frequency domain. These states are optically dark above the Néel temperature and become accessible with magnetic order. By launching this phonon and spectrally tracking its amplitude, we establish the electronic origin of bound states as localized d-d excitations. Our data directly yield electron-phonon coupling strength which exceeds the highest known value in 2D systems6. These results demonstrate NiPS3 as a platform to study strong interactions between spins, orbitals and lattice, and open pathways to coherent control of 2D magnets.

Strange Metals as Ersatz Fermi Liquids.

A long-standing mystery of fundamental importance in correlated electron physics is to understand strange non-Fermi liquid metals that are seen in diverse quantum materials. A striking experimental feature of these metals is a resistivity that is linear in temperature (T). In this Letter we ask what it takes to obtain such non-Fermi liquid physics down to zero temperature in a translation invariant metal. If in addition the full frequency (ω) dependent conductivity satisfies ω/T scaling, we argue that the T-linear resistivity must come from the intrinsic physics of the low energy fixed point. Combining with earlier arguments that compressible translation invariant metals are "ersatz Fermi liquids" with an infinite number of emergent conserved quantities, we obtain powerful and practical conclusions. We show that there is necessarily a diverging susceptibility for an operator that is odd under inversion and time reversal symmetries, and has zero crystal momentum. We discuss a few other experimental consequences of our arguments, as well as potential loopholes, which necessarily imply other exotic phenomena.

Exciton-driven antiferromagnetic metal in a correlated van der Waals insulator.

Collective excitations of bound electron-hole pairs-known as excitons-are ubiquitous in condensed matter, emerging in systems as diverse as band semiconductors, molecular crystals, and proteins. Recently, their existence in strongly correlated electron materials has attracted increasing interest due to the excitons' unique coupling to spin and orbital degrees of freedom. The non-equilibrium driving of such dressed quasiparticles offers a promising platform for realizing unconventional many-body phenomena and phases beyond thermodynamic equilibrium. Here, we achieve this in the van der Waals correlated insulator NiPS3 by photoexciting its newly discovered spin-orbit-entangled excitons that arise from Zhang-Rice states. By monitoring the time evolution of the terahertz conductivity, we observe the coexistence of itinerant carriers produced by exciton dissociation and a long-wavelength antiferromagnetic magnon that coherently precesses in time. These results demonstrate the emergence of a transient metallic state that preserves long-range antiferromagnetism, a phase that cannot be reached by simply tuning the temperature. More broadly, our findings open an avenue toward the exciton-mediated optical manipulation of magnetism.

Security and Privacy of Cloud- and IoT-Based Medical Image Diagnosis Using Fuzzy Convolutional Neural Network.

In recent times, security in cloud computing has become a significant part in healthcare services specifically in medical data storage and disease prediction. A large volume of data are produced in the healthcare environment day by day due to the development in the medical devices. Thus, cloud computing technology is utilised for storing, processing, and handling these large volumes of data in a highly secured manner from various attacks. This paper focuses on disease classification by utilising image processing with secured cloud computing environment using an extended zigzag image encryption scheme possessing a greater tolerance to different data attacks. Secondly, a fuzzy convolutional neural network (FCNN) algorithm is proposed for effective classification of images. The decrypted images are used for classification of cancer levels with different layers of training. After classification, the results are transferred to the concern doctors and patients for further treatment process. Here, the experimental process is carried out by utilising the standard dataset. The results from the experiment concluded that the proposed algorithm shows better performance than the other existing algorithms and can be effectively utilised for the medical image diagnosis.

How specific are the conformation-specific α-synuclein antibodies? Characterization and validation of 16 α-synuclein conformation-specific antibodies using well-characterized preparations of α-synuclein monomers, fibrils and oligomers with distinct structures and morphology.

Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson's disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand their role in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validation pipeline that allows a systematic investigation of the specificity of α-syn antibodies using well-defined and well-characterized preparations of various α-syn species, including monomers, fibrils, and different oligomer preparations that are characterized by distinct morphological, chemical and secondary structure properties. This pipeline was used to characterize 18 α-syn antibodies, 16 of which have been reported as conformation- or oligomer-specific antibodies, using an array of techniques, including immunoblot analysis (slot blot and Western blot), a digital ELISA assay using single molecule array technology and surface plasmon resonance. Our results show that i) none of the antibodies tested are specific for one particular type of α-syn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar α-syn; and iii) a few antibodies showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic tools or therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.

Electrical behavior and enhanced photocatalytic activity of (Ag, Ni) co-doped ZnO nanoparticles synthesized from co-precipitation technique.

Methylene blue (MB) dye is the most common harmful, toxic, and non-biodegradable effluent produced by the textile industries. The present study investigates the effect of zinc oxide (ZnO) nanoparticles (NPs) and Ag-Ni doped ZnO NPs on the performance of photocatalytic degradation of MB dye. Pure ZnO and Ag-Ni doped ZnO NPs are synthesized using the co-precipitation method. The crystalline nature and surface morphology of the synthesized pure ZnO and Ag-Ni doped ZnO NPs was characterized by powder X-ray diffraction, scanning electron microscopy (SEM), and high resolution transmission electron microscopy (HRTEM) analysis. The presence of spherical-like morphologies was confirmed from SEM and HRTEM analysis. The presence of Ni-O and Zn-O bands in the synthesized materials was found by Fourier transform infrared (FTIR) spectroscopy analysis. The MB dye was degraded under UV-light exposure in various pH conditions. The Ag (0.02%)-Ni doped ZnO NPs exhibits highest photocatalytic activity of 77% under pH 4.

Ferromagnetism in Narrow Bands of Moiré Superlattices.

Many graphene moiré superlattices host narrow bands with nonzero valley Chern numbers. We provide analytical and numerical evidence for a robust spin and/or valley polarized insulator at total integer band filling in nearly flat bands of several different moiré materials. In the limit of a perfectly flat band, we present analytical arguments in favor of the ferromagnetic state substantiated by numerical calculations. Further, we numerically evaluate its stability for a finite bandwidth. We provide exact diagonalization results for models appropriate for ABC trilayer graphene aligned with hBN, twisted double bilayer graphene, and twisted bilayer graphene aligned with hBN. We also provide DMRG results for a honeycomb lattice with a quasiflat band and nonzero Chern number, which extend our results to larger system sizes. We find a maximally spin and valley polarized insulator at all integer fillings when the band is sufficiently flat. We also show that interactions may induce effective dispersive terms strong enough to destabilize this state. These results still hold in the case of zero valley Chern number (for example, trivial side of TLG/hBN). We give an intuitive picture based on extended Wannier orbitals, and emphasize the role of the quantum geometry of the band, whose microscopic details may enhance or weaken ferromagnetism in moiré materials.

Publisher Correction: Tunable correlated Chern insulator and ferromagnetism in a moiré superlattice.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Unraveling the complexity of amyloid polymorphism using gold nanoparticles and cryo-EM.

Increasing evidence suggests that amyloid polymorphism gives rise to different strains of amyloids with distinct toxicities and pathology-spreading properties. Validating this hypothesis is challenging due to a lack of tools and methods that allow for the direct characterization of amyloid polymorphism in hydrated and complex biological samples. Here, we report on the development of 11-mercapto-1-undecanesulfonate-coated gold nanoparticles (NPs) that efficiently label the edges of synthetic, recombinant, and native amyloid fibrils derived from different amyloidogenic proteins. We demonstrate that these NPs represent powerful tools for assessing amyloid morphological polymorphism, using cryogenic transmission electron microscopy (cryo-EM). The NPs allowed for the visualization of morphological features that are not directly observed using standard imaging techniques, including transmission electron microscopy with use of the negative stain or cryo-EM imaging. The use of these NPs to label native paired helical filaments (PHFs) from the postmortem brain of a patient with Alzheimer's disease, as well as amyloid fibrils extracted from the heart tissue of a patient suffering from systemic amyloid light-chain amyloidosis, revealed a high degree of homogeneity across the fibrils derived from human tissue in comparison with fibrils aggregated in vitro. These findings are consistent with, and strongly support, the emerging view that the physiologic milieu is a key determinant of amyloid fibril strains. Together, these advances should not only facilitate the profiling and characterization of amyloids for structural studies by cryo-EM, but also pave the way to elucidate the structural basis of amyloid strains and toxicity, and possibly the correlation between the pathological and clinical heterogeneity of amyloid diseases.