Electrically focus-tuneable ultrathin lens for high-resolution square subpixels.

Owing to the tremendous demands for high-resolution pixel-scale thin lenses in displays, we developed a graphene-based ultrathin square subpixel lens (USSL) capable of electrically tuneable focusing (ETF) with a performance competitive with that of a typical mechanical refractive lens. The fringe field due to a voltage bias in the graphene proves that our ETF-USSL can focus light onto a single point regardless of the wavelength of the visible light-by controlling the carriers at the Dirac point using radially patterned graphene layers, the focal length of the planar structure can be adjusted without changing the curvature or position of the lens. A high focusing efficiency of over 60% at a visible wavelength of 405 nm was achieved with a lens thickness of <13 nm, and a change of 19.42% in the focal length with a 9% increase in transmission was exhibited under a driving voltage. This design is first presented as an ETF-USSL that can be controlled in pixel units of flat panel displays for visible light. It can be easily applied as an add-on to high resolution, slim displays and provides a new direction for the application of multifunctional autostereoscopic displays

DIVERSITY OF TAU PROTEOFORMS IN TAUOPATHIES: RELEVANCE TO BIOMARKER ANALYSIS AND PRECLINICAL MODELING

Tauopathies are neurodegenerative diseases defined by the accumulation of pathological tau protein in neurons and glia. Alzheimer’s disease (AD), the most common tauopathy, is characterized by the presence of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein aggregates in neurons. Emerging evidence suggests that the NFT burden correlates with neuron death and cognitive decline, contributing to disease progression. Besides AD, a similar deposition of tau inclusions is found to be associated with neurodegeneration in the brains of patients with other tauopathies including progressive supranuclear palsy, corticobasal degeneration, and Pick’s disease. These diseases display clinical, biochemical, and neuropathological heterogeneity. Little is known about how tau aggregation can lead to varied phenotypes in tauopathies, and there is no disease-modifying treatment. Thus, it is necessary to understand the role of diverse tau proteoforms in tauopathies for the development of new therapeutics to treat tauopathies, including AD. In the studies summarized in Chapter 2, we investigated how the molecular diversity of tau proteoforms could impact antibody-based assays of a phospho-tau variant serving as an AD biomarker. A tau variant phosphorylated on threonine 181 (pT181-tau) has been widely investigated as a potential AD biomarker in cerebrospinal fluid (CSF) and blood. pT181-tau is present in NFTs of AD brains, and CSF levels of pT181-tau correlate with overall NFT burden. Various immuno-based analytical methods, including Western blotting and ELISA, have been used to quantify pT181-tau in human biofluids. The reliability of these methods depends on the affinity and binding specificity of the antibodies used to measure pT181-tau levels. Although both of these properties could in principle be affected by phosphorylation within or near the antibody’s cognate antigen, such effects have not been extensively studied. Here, we developed a bio-layer interferometry (BLI)-based analytical assay to assess the degree to which the affinity of pT181-tau antibodies is altered by the phosphorylation of serine or threonine residues near the target epitope. Our results revealed that phosphorylation near T181 negatively affected the binding of pT181-tau antibodies to their cognate antigen to varying degrees. In particular, two of three antibodies tested showed a complete loss of affinity for the pT181 target when S184 or S185 was phosphorylated. In the studies outlined in Chapter 3, we examined the relative abilities of different tau proteoforms to induce seeded tau aggregation and to themselves undergo seeded aggregation in cultured cells. Accumulating evidence suggests that tau aggregates, including NFTs, spread in a stereotypical pattern across neuroanatomically connected brain regions. This spreading phenomenon is thought to occur via a prion-like mechanism involving the release of tau aggregates from a diseased neuron into the extracellular space, aggregate uptake by neighboring healthy neurons, and the formation of new aggregates in the cytosol of the recipient cells via a seeding process. Although research over the past decade has revealed key molecular events involved in the cell-to-cell transmission of tau aggregates, the impact of the protein’s domain structure and phosphorylation profile on the efficiency of prion-like propagation remains poorly defined. Here, we compared three tau variants – K18, 0N4R, and 2N4R – in terms of their aggregation and seeding efficiencies in recombinant protein solutions and in cell culture models. Our results revealed that K18 had the highest fibrillization rate and yield among the three tau variants. Recombinant preformed fibrils (PFFs) derived from all three variants had similar seeding efficiencies. Additionally, we investigated the relationship between tau phosphorylation and aggregation. We found that hyperphosphorylated tau did not undergo self-assembly in the absence of heparin, whereas it formed fibrils at low yield in the presence of the cofactor. Moreover, hyperphosphorylated tau PFFs produced under these conditions induced seeded tau aggregation in cell culture. Taken together, these results point to critical roles of tau proteoforms as both AD biomarkers and drivers of disease progression. Our results indicate that the presence of different combinations of phosphorylated residues near a target phospho-tau antigen can affect the accuracy of antibody-based biomarker assays. In addition, the domain structure and phosphorylation profiles of tau proteoforms associated with AD and other tauopathies likely have a profound influence on the evolution of tau pathology in these disorders. Our findings highlight the importance of accounting for the molecular diversity of tau proteoforms in tauopathies and provide valuable insights into molecular determinants influencing tau aggregation and propagation in the brains of patients.</p

Unobtrusive, Cuffless Blood Pressure Monitoring Using a Soft Polymer Sensor Array With Flexible Hybrid Electronics

11Nsciescopu

A Flexible Patch-Type Strain Sensor Based on Polyaniline for Continuous Monitoring of Pulse Waves

A flexible, patch-type strain sensor is described for continuous monitoring of pulse waves. The proposed sensor exploits the piezo-resistivity of the conductive polymer, polyaniline (PANI), to detect dynamic volume changes in blood vessels owing to pulse waves. The proposed PANI film was fabricated through electrodeposition, which is considered as a suitable low-cost technique for mass production in the sensor manufacturing industry. Thus, it is prospective for a disposable wearable sensing system solution in remote healthcare applications. Besides, a flexible sensor packaging can be achieved by laminating the PANI films and an ECOFLEX elastomer to the film bandage. The proposed PANI sensor has high sensitivity (gauge factor of 74.28) and linearity (R-2 = 0.99). It also showed a high correlation with commercially available photoplethysmography (PPG) sensor with the small bias and confidence interval to the PPG sensor: bias < 0.1% and confidence interval < 3% for all subjects. Moreover, the proposed PANI sensor was tested for prospective circulatory system-related applications such as measuring heart rate, stiffness index, and pulse transit time. Finally, the proposed study suggests that the proposed PANI sensor is a promising candidate for continuous, long-term, unobtrusive pulse wave monitoring, which can provide real-time insights into an individual&apos;s health status.11Ysciescopu

Discovery of 4-aminoindole carboxamide derivatives to curtail alpha-synuclein and tau isoform 2N4R oligomer formation

Alzheimer’s disease (AD) is a multifactorial, chronic neurodegenerative disease characterized by the presence of extracellular β-amyloid (Aβ) plaques, intraneuronal neurofibrillary tangles (NFTs), activated microglial cells, and an inflammatory state (involving reactive oxygen species production) in the brain. NFTs are comprised of misfolded and hyperphosphorylated forms of the microtubule-binding protein tau. Interestingly, the trimeric form of the 2N4R splice isoform of tau has been found to be more toxic than the trimeric 1N4R isoform in neuron precursor cells. Few drug discovery programs have focused on specific tau isoforms. The present drug discovery project is centered on the anti-aggregation effect of a series of seventeen 4- or 5-aminoindole carboxamides on the 2N4R isoform of tau. The selection of the best compounds was performed using α-synuclein (α-syn). The anti-oligomer and -fibril activities of newly synthesized aminoindole carboxamide derivatives were evaluated with biophysical methods, such as thioflavin T fluorescence assays, photo-induced cross-linking of unmodified proteins, and transmission electron microscopy. To evaluate the reduction of inclusions and cytoprotective effects, M17D neuroblastoma cells expressing inclusion-forming α-syn were treated with the best amide representatives. The 4-aminoindole carboxamide derivatives exhibited a better anti-fibrillar activity compared to their 5-aminoindole counterparts. The amide derivatives 2, 8, and 17 exerted anti-oligomer and anti-fibril activities on α-syn and the 2N4R isoform of tau. At a concentration of 40 µM, compound 8 reduced inclusion formation in M17D neuroblastoma cells expressing inclusion-prone αSynuclein3K::YFP. Our results demonstrate the potential of 4-aminoindole carboxamide derivatives with regard to inhibiting the oligomer formation of α-syn and tau (2N4R isoform) for further optimization prior to pre-clinical studies

Developmental Pb Exposure Increases Ad Risk via Altered Intracellular Ca2+ Homeostasis in Hipsc-derived Cortical Neurons

Exposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between developmental Pb exposure and Alzheimer\u27s disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking developmental Pb exposure and increased AD risk, however, remains elusive. In this work, we used human iPSC-derived cortical neurons as a model system to study the effects of Pb exposure on AD-like pathogenesis in human cortical neurons. We exposed neural progenitor cells derived from human iPSC to 0, 15, and 50 ppb Pb for 48 h, removed Pb-containing medium, and further differentiated them into cortical neurons. Immunofluorescence, Western blotting, RNA-sequencing, ELISA, and FRET reporter cell lines were used to determine changes in AD-like pathogenesis in differentiated cortical neurons. Exposing neural progenitor cells to low-dose Pb, mimicking a developmental exposure, can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, and epigenetic landscape along with elevated AD-like pathogenesis markers, including phosphorylated tau, tau aggregates, and Aβ42/40. Collectively, our findings provide an evidence base for Ca dysregulation caused by developmental Pb exposure as a plausible molecular mechanism accounting for increased AD risk in populations with developmental Pb exposure