Amyloid cross-seeding between Ab and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes

Amyloid cross-seeding of different amyloid proteins is considered as a highly possible mechanism for exacerbating the transmissible pathogenesis of protein misfolding disease(PMDs)and for explaining a molecular link between different PMDs,including Alzheimer disease(AD)and type 2 diabetes(T2D),AD and Parkinson disease(PD),and AD and prion disease.Among them,AD and T2D are the most prevalent PMDs,affecting millions of people globally,while Ab and hIAPP are the causative peptides responsible for AD and T2D,respectively.Increasing clinical and epidemiological evidences lead to a hypothesis that the cross-seeding of Ab and hIAPP is more biologically responsible for a pathological link between AD and T2D.In this review,we particularly focus on(i)the most recent and important findings of amyloid cross-seeding between Ab and hIAPP from in vitro,in vivo,and in silico studies,(ii)a mechanistic role of structural compatibility and sequence similarity of amyloid proteins(beyond Ab and hIAPP)in amyloid cross-seeding,and(iii)several current challenges and future research directions in this lessstudied field.Review of amyloid cross-seeding hopefully provides some mechanistic understanding of amyloidogenesis and inspires more efforts for the better design of next-generation drugs/strategies to treat different PMDs simultaneously.

Highly conductive and tough double-network hydrogels for smart electronics

Development and understanding of highly mechanically robust and electronically conducting hydrogels are extremely important for ever-increasing energy-based applications.Conventional mixing/blending of conductive additives with hydrophilic polymer network prevents both high mechanical strength and electronic conductivity to be presented in polymer hydrogels.Here,we proposed a double-network(DN)engineering strategy to fabricate PVA/PPy DN hydrogels,consisting of a conductive PPy-PA network via in-situ ultrafast gelation and a tough PVA network via a subsequent freezing/thawing process.The resultant PVA/PPy hydrogels exhibited superior mechanical and electrochemical properties,including electrical conductivity of~6.8 S/m,mechanical strength of~0.39 MPa,and elastic moduli of~0.1 MPa.Upon further transformation of PVA/PPy hydrogels into supercapacitors,they demonstrated a high capacitance of~280.7 F/g and a cycle life of 2000 galvanostatic charge/discharge cycles with over 94.3%capacity retention at the current density of 2 mA/cm2 and even subzero temperatures of−20℃.Such enhanced mechanical performance and electronic conductivity of hydrogels are mainly stemmed from a synergistic combination of continuous electrically conductive PPy-PA network and the two interpenetrating DN structure.This in-situ gelation strategy is applicable to the integration of ionic-/electrical-conductive materials into DN hydrogels for smart-soft electronics,beyond the most commonly used PEDOT:PSS-based hydrogels.

Development of a radical polymerization algorithm for molecular dynamics simulations of antifreezing hydrogels with double-network structures

The development and understanding of antifreezing hydrogels are crucial both in principle and practice for the design and delivery of new materials.The current antifreezing mechanisms in hydrogels are almost exclusively derived from their incorporation of antifreezing additives,rather than from the inherent properties of the polymers themselves.Moreover,developing a computational model for the independent yet interconnected double-network(DN)structures in hydrogels has proven to be an exceptionally difficult task.Here,we develop a multiscale simulation platform,integrating‘random walk reactive polymerization’(RWRP)with molecular dynamics(MD)simulations,to computationally construct a physically-chemically linked PVA/PHEAA DN hydrogels from monomers that mimic a radical polymerization and to investigate water structures,dynamics,and interactions confined in PVA/PHEAA hydrogels with various water contents and temperatures,aiming to uncover antifreezing mechanism at atomic levels.Collective simulation results indicate that the antifreezing property of PVA/PHEAA hydrogels arises from a combination of intrinsic,strong water-binding networks and crosslinkers and tightly crosslinked and interpenetrating double-network structures,both of which enhance polymer-water interactions for competitively inhibiting ice nucleation and growth.These computational findings provide atomic-level insights into the interplay between polymers and water molecules in hydrogels,which may determine their resistance to freezing.