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.

https://www.science.org/doi/pdf/10.1126/sciadv.adg9644?download=true

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

Role of conformational dynamics in pathogenic protein aggregation.

•Aβ-Cu complexes can be leveraged to activate cli-LYTACs in AD lesion areas •Cli-LYTACs promoted Aβ degradation through the endo-lysosomal pathway •Cli-LYTACs recognize polymorphic aggregates and facilitate their degradation •Polydopamine potentiates LYTAC-mediated Aβ degradation Selective degradation of extracellular pathogenic proteins by degrader technologies such as lysosome-targeting chimeras (LYATCs) provides promising therapeutic strategies for “undruggable” targets. However, unsatisfactory blood-brain barrier (BBB) permeability, potential off-target effects, and impaired protein degradation systems limit their therapeutic applications in neurodegenerative diseases. Here, we design, synthesize, and select Pittsburgh compound B (PiB)-derived suitable chimera molecules and then construct multifunctional polydopamine-based LYTACs (KPLYs) with BBB permeability and activatable β-amyloid (Aβ) degradation ability used for Alzheimer’s disease (AD) treatment. In AD lesion areas, Aβ degrader cli-LYTACs are synthesized in situ through Aβ-Cu-catalyzed bioorthogonal reactions. Activated cli-LYTACs induce the spatial proximity between Aβ and lysosomal shuttling receptor CD206, which results in the lysosomal trafficking and degradation of Aβ aggregates. Moreover, biocompatible polydopamine can scavenge ROS, suppress inflammation, and promote microglia M2-like polarization. Therefore, KPLYs increase cell surface CD206 expression and restore lysosomal proteolytic function, two determinants of LYTAC effectiveness. Selective degradation of extracellular pathogenic proteins by degrader technologies such as lysosome-targeting chimeras (LYATCs) provides promising therapeutic strategies for “undruggable” targets. However, unsatisfactory blood-brain barrier (BBB) permeability, potential off-target effects, and impaired protein degradation systems limit their therapeutic applications in neurodegenerative diseases. Here, we design, synthesize, and select Pittsburgh compound B (PiB)-derived suitable chimera molecules and then construct multifunctional polydopamine-based LYTACs (KPLYs) with BBB permeability and activatable β-amyloid (Aβ) degradation ability used for Alzheimer’s disease (AD) treatment. In AD lesion areas, Aβ degrader cli-LYTACs are synthesized in situ through Aβ-Cu-catalyzed bioorthogonal reactions. Activated cli-LYTACs induce the spatial proximity between Aβ and lysosomal shuttling receptor CD206, which results in the lysosomal trafficking and degradation of Aβ aggregates. Moreover, biocompatible polydopamine can scavenge ROS, suppress inflammation, and promote microglia M2-like polarization. Therefore, KPLYs increase cell surface CD206 expression and restore lysosomal proteolytic function, two determinants of LYTAC effectiveness. 

Biomarker-activated multifunctional lysosome-targeting chimeras mediated selective degradation of extracellular amyloid fibrils

Purpose of reviewEndoscopists have long awaited advances in the equipment and techniques for cholangiopancreatoscopy. Since the turn of the millennium, endoscopists have witnessed an explosion in the development and refinement of the capabilities of cholangioscopes as they move from being almost exc

Cholangioscopy: the biliary tree never looked so good!

Nitrogen dioxide (NO2) has been severely polluting the atmosphere and deteriorating human beings’ sustainable lives. Therefore, development of gas sensors for high-selectivity and high-sensitivity detection of NO2 has been attracting increasing attention. The state-of-the-art inorganic NO2 gas sensors require harsh fabrication conditions or toxic materials, making the devices intrinsically eco-unfriendly. Furthermore, in most cases the sensors work at high temperatures. These disadvantages severely impede their practical applications. Herein, we report a room-temperature and highly-integrated NO2 sensor composed of p-type self-assembled peptide fibrillar nanoforests (SPNFs) scaffolded with n-type SnO2 nanoparticles (NPs) heterojunctions. The p-n conformations provide efficient access to target gases and allow reliable electron transformations, while the SPNFs afford a large specific surface area and multiporous structures for gas adsorption and SnO2 NPs dispersion, resulting in an ultrahigh selectivity for NO2 detection. Especially, the sensing performance can be optimized by modulating the thickness and density of the SPNFs, showing a high response, short response and recovery times, along with a low detection limitation. Our strategy demonstrates the development of a bioinspired platform by utilizing peptide self-assemblies to fabricate integrated sensors for polluting gas detections. 

Bioinspired Supramolecular Arrayed Heterojunction-Based Room-Temperature Sensor for High-Performance Gas Detection

benign and malignant intraductal papillary mucinous neoplasms (IPMNs) of the pancreas and to determine their exact extent. Peroral pancreatoscopy including narrow-band imaging (NBI) is useful for the evaluation of these neoplasms [1,2], but it is technically difficult and requires two skilled endoscopists and endoscopic systems [3]. The ultraslim upper endoscope has been proposed for direct visual examination of the biliopancreatic duct by a single operator [4,5]. However, the usefulness of direct peroral pancreatoscopy (D-POP) is clinically limited by the inconsistent success rates owing to the inability to keep the position of endoscope stable. An intraductal balloon passed through the endoscope may permit ease of access and stable positioning of the endoscope within the pancreatic duct. After anchoring the intraductal balloon within the proximal pancreatic duct, the endoscope can be advanced over the balloon catheter. The feasibility of intraductal balloon-guided D-POP with NBI was evaluated in four patients with IPMNs (●\" Fig. 1). An ultraslim upper endoscope (GIF-XP260N; Olympus, Tokyo, Japan) was advanced directly through the major papilla into the pancreatic duct assisted bya 5-Fr intraductal balloon catheter (MTW Endoskopie, Wesel, Germany) (●\" Fig. 2, ●\" Video 1). NBI and forceps biopsy were carried out duringD-POP, which showed the papillary tumor with villous lesions in the pancreatic duct (●\" Fig. 3). NBI showed the surface structure and capillary vessels of the lesion with greater clarity (●\" Fig. 4,●\" Video 2). All patients successfully underwent intraductal balloon-guided D-POP with NBI without procedure-related complications. Biopsy specimens showed adenocarcinomas in two patients and adenoma with dysplasia in one patient (●\" Fig. 5), all of whom were recommended surgery. The fourth patient had chronic inflammation and is being followed up regularly. In conclusion, the high success rate in this case series illustrates the feasibility of using intraductal balloon-guided D-POP with an ultraslim endoscope in patients with IPMNs. Acknowledgment !

/pdf/direct-peroral-pancreatoscopy-with-an-ultraslim-endoscope-m9b89618b6.pdf

Direct peroral pancreatoscopy with an ultraslim endoscope for the evaluation of intraductal papillary mucinous neoplasms.

The composition of soluble toxic protein aggregates formed in vivo is currently unknown in neurodegenerative diseases, due to their ultra-low concentration in human biofluids and their high degree of heterogeneity. Here we report a method to capture amyloid-containing aggregates in human biofluids in an unbiased way, a process we name amyloid precipitation. We use a structure-specific chemical dimer, a Y-shaped, bio-inspired small molecule with two capture groups, for amyloid precipitation to increase affinity. Our capture molecule for amyloid precipitation (CAP-1) consists of a derivative of Pittsburgh Compound B (dimer) to target the cross β-sheets of amyloids and a biotin moiety for surface immobilization. By coupling CAP-1 to magnetic beads, we demonstrate that we can target the amyloid structure of all protein aggregates present in human cerebrospinal fluid, isolate them for analysis and then characterize them using single-molecule fluorescence imaging and mass spectrometry. Amyloid precipitation enables unbiased determination of the molecular composition and structural features of the in vivo aggregates formed in neurodegenerative diseases. 

/pdf/structure-specific-amyloid-precipitation-in-biofluids-146c33va.pdf

Structure-specific amyloid precipitation in biofluids

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Direct peroral pancreatoscopy with an ultraslim endoscope for the evaluation of intraductal papillary mucinous neoplasms.

Structure-specific amyloid precipitation in biofluids