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Type 2 diabetes (T2D) is a common protein misfolding disease (PMD), and its pathogenesis is considered to be tightly associated with the aggregation of the disease-causative hIAPP (or amylin). Numerous studies have shown a possible pathological link between hIAPP aggregation and β-cell death; thus, different-level strategies from basic research to clinical bench applications have been applied to discover and design different types of inhibitors for preventing hIAPP aggregation and toxicity. This review surveys recent and important advances of hIAPP aggregation inhibitors in the context of amyloid aggregation, toxicity, and inhibition. Many hIAPP inhibitors have been explored to exert different inhibitory functions on hIAPP aggregation via different pathways. A further overview of molecular simulations of inhibitor-hIAPP systems highlights some consensus binding sequences and structures of hIAPP for different inhibitors, which provide molecular insights into well-defined binding targets and binding-induced inhibition mechanisms for structural-based design of hIAPP inhibitors. In a broader view, while anti-aggregation inhibitors hold substantial promise in the prevention of PMDs, many challenges still remain and need to be addressed for advancing our fundamental understanding of amyloid aggregation and practical design of clinically relevant inhibitors to treat PMDs.

The lung is an organ that is directly exposed to the external environment. Given the large surface area and extensive ventilation of the lung, it is prone to exposure to airborne substances, such as pathogens, allergens, chemicals, and particulate matter. Highly elaborate and effective mechanisms have evolved to protect and maintain homeostasis in the lung. Despite these sophisticated defense mechanisms, the respiratory system remains highly susceptible to environmental challenges. Because of the impact of respiratory exposure on human health and disease, there has been considerable interest in developing reliable and predictive in vitro model systems for respiratory toxicology and basic research. Human air-liquid-interface (ALI) organotypic airway tissue models derived from primary tracheobronchial epithelial cells have in vivo–like structure and functions when they are fully differentiated. The presence of the air-facing surface allows conducting in vitro exposures that mimic human respiratory exposures. Exposures can be conducted using particulates, aerosols, gases, vapors generated from volatile and semi-volatile substances, and respiratory pathogens. Toxicity data have been generated using nanomaterials, cigarette smoke, e-cigarette vapors, environmental airborne chemicals, drugs given by inhalation, and respiratory viruses and bacteria. Although toxicity evaluations using human airway ALI models require further standardization and validation, this approach shows promise in supplementing or replacing in vivo animal models for conducting research on respiratory toxicants and pathogens.

Prevention and detection of misfolded amyloid proteins and their β-structure-rich aggregates are the two promising but different (pre)clinical strategies to treat and diagnose neurodegenerative diseases including Alzheimer's diseases (AD) and type II diabetes (T2D). Conventional strategies prevent the design of new pharmaceutical molecules with both amyloid inhibition and detection functions. Here, we propose a "like-interacts-like" design principle to

Hypothesis Polyzwitterions as a promising class of materials are often used to construct antifouling surfaces with optimized conformation and compositions for a wide variety of antifouling applications. While numerous zwitterionic polymers have been identified for their antifouling capacity, the exact relationship among molecular structure, surface hydration property, and antifouling performance of zwitterionic polymers at different scales still remains elusive. Experiments we first designed and synthesized a new zwitterionic monomer of 3-(4-(methacryloyloxy)-1-methylpiperidin-1-ium-1-yl)-propane-1-sulfonate (MAMPS), then used MAMPS monomers to fabricate into homogenous polymer brushes on Au substrate using SI-ATRP and heterogeneous double-network (DN) hydrogels combining with Agar network via one-pot, heating-cooling-photopolymerization method, and finally evaluated their antifouling ability to resist the adsorption of protein/cell/bacteria on the two different polymer forms at microscopic and macroscopic scales. Findings For microscopic polyMAMPS brushes, they exhibited excellent resistance to nonspecific protein adsorption from both undiluted blood serum/plasma (0.3–5 ng/cm2), cell adhesion up to 3 days, and clinically relevant bacterial attachment for 72 h at the optimal film thicknesses of 20–40 nm. For macroscopic Agar/polyMAMPS DN hydrogels, they also exhibited approximately 96% less protein adhesion than tissue culture polystyrene (TCPS). Different structured materials consisting of polyMAMPS at both micro- and macro-scales demonstrate its excellent, intrinsic antifouling property, which could be related to their highly water binding character of zwitterionic groups. PolyMAMPS materials, alternative to commonly used poly(sulfobetaine methacrylate) (polySBMA) and poly(carboxybetaine methacrylate) (polyCBMA) zwitterions, hold great promise for antifouling designs and applications.

The design and fabrication of tough and fluorescent hydrogels still remains as a challenging problem due to the poor mechanical property and water-induced luminescence quenching effect. Here, a new...

Zwitterionic materials are an important class of antifouling biomaterials for various applications. Despite such desirable antifouling properties, molecular-level understanding of the structure–property relationship associated with surface chemistry/topology/hydration and antifouling performance still remains to be elucidated. In this work, we computationally studied the packing structure, surface hydration, and antifouling property of three zwitterionic polymer brushes of poly(carboxybetaine methacrylate) (pCBMA), poly(sulfobetaine methacrylate) (pSBMA), and poly((2-(methacryloyloxy)ethyl)phosporylcoline) (pMPC) brushes and a hydrophilic PEG brush using a combination of molecular mechanics (MM), Monte Carlo (MC), molecular dynamics (MD), and steered MD (SMD) simulations. We for the first time determined the optimal packing structures of all polymer brushes from a wide variety of unit cells and chain orientations in a complex energy landscape. Under the optimal packing structures, MD simulations were further conducted to study the structure, dynamics, and orientation of water molecules and protein adsorption on the four polymer brushes, while SMD simulations to study the surface resistance of the polymer brushes to a protein. The collective results consistently revealed that the three zwitterionic brushes exhibited stronger interactions with water molecules and higher surface resistance to a protein than the PEG brush. It was concluded that both the carbon space length between zwitterionic groups and the nature of the anionic groups have a distinct effect on the antifouling performance, leading to the following antifouling ranking of pCBMA > pMPC > pSBMA. This work hopefully provides some structural insights into the design of new antifouling materials beyond traditional PEG-based antifouling materials.

Abnormal aggregation of misfolded amyloid proteins into amyloid fibrils is associated with many neurodegenerative diseases, including Alzheimer's disease (AD) and Type II diabetes (T2D). In principle, any strategy to alter the amyloid aggregation process is considered as a potential therapeutic treatment for these diseases. Significant efforts and progress have been made to develop amyloid inhibitors that can slow down and prevent the amyloid aggregation process. However, much less research has been reported to discover general amyloid promoters to accelerate amyloid progress and remodel toxic amyloids. Here, for the first time we report a repurposing of the drug of aromadendrin as a dual amyloid promoter to be effective in accelerating amyloid aggregation/fibrillization and reducing neuroblastoma/insulinoma toxicity of both Aβ42 (associated with AD) and hIAPP37 (associated with T2D). ThT, AFM, and CD results showed that addition of aromadendrin to amyloid solutions with 1 to 5 molar ratios caused significant acceleration in Aβ42 fibrillization by 86–114% and hIAPP fibrillization by 20–68% as evidenced by shortening or bypassing of the lag phase, promoting the growth phase, and rapidly converting the amyloid species towards the higher ordered β-structure-rich aggregates. Seeding experiments further revealed that aromadendrin is more effective in accelerating the aggregation and structural conversion of the amyloid species at the lag and early growth phases, but unable to escalate the fibrillization of higher order protofibrils. Moreover, MTT and LDH cell assays showed that aromadendrin-treated cell samples enabled the rescue of cells from both Aβ- and hIAPP-induced toxicity by increasing cell viability by 12–15% (Aβ) and 10–49% (hIAPP) and reducing cell apoptosis by 45–67% (Aβ) and 10–30% (hIAPP). LUV assays explained the protective role of aromadendrin in cell toxicity due to the suppression of toxic oligomer formation and thus the decrease of membrane leakage. This work offers a new strategy for repurposing aromadendrin as an amyloid promoter, not as an amyloid inhibitor, to accelerate amyloid formation and remedy the amyloid-mediated toxicity for both Aβ and hIAPP, and the sequence-independent promotion effect of aromadendrin could also be applied to other amyloid proteins.

Development of mechanically strong and adhesive hydrogels with self-recovery and self-healing properties is important for many applications but has proven to be very challenging. Here, we reported ...

Development of tough and adhesive hydrogels is critical for different applications, including wound dressing, soft robotics, and wearable devices. However, achieving strong and reversible adhesion ...

Misfolded protein aggregates formed by the same (homologous) or different (heterologous/cross) sequences are the pathological hallmarks of many protein misfolding diseases (PMDs) including Alzheimer's disease (AD) and type 2 diabetes (T2D). Different from homologous-amyloid aggregation that is solely associated with a specific PMD, cross-amyloid aggregation (i.e. cross-seeding) of different amyloid proteins is more fundamentally and biologically important for understanding and untangling not only the pathological process of each PMD, but also a potential molecular cross-talk between different PMDs. However, the cross-amyloid aggregation is still a subject poorly explored and little is known about its sequence/structure-dependent aggregation mechanisms, as compared to the widely studied homo-amyloid aggregation. Here, we review the most recent and important findings of amyloid cross-seeding behaviors from in vitro, in vivo, and in silico studies. Some typical cross-seeding phenomena between Aβ/hIAPP, Aβ/tau, Aβ/α-synuclein, and tau/α-synuclein are selected and presented, and the underlying specific or general cross-seeding mechanisms are also discussed to better reveal their sequence-structure-property relationships. The potential use of the cross-seeding concept to design amyloid inhibitors is also proposed. Finally, we offer some personal perspectives on current major challenges and future research directions in this less-studied yet important field, and hopefully this work will stimulate more research to explore all possible fundamental and practical aspects of amyloid cross-seeding.

Developing functional hybrids of globular proteins and synthetic polymers into multipurpose tough hydrogels remains challenging. Here, we propose a new strategy combining double-network and protein misfolding concepts to create diverse protein–polymer double-network (DN) hydrogels with both high bulk and interfacial toughness. The method integrates an intrinsic heat-induced protein denaturation/aggregation feature and a double-network concept, which produces different bovine serum albumin (BSA)-based DN hydrogels with hybrid physical–chemical cross-linking or fully physical cross-linking to achieve a high modulus of 252–1199 kPa, high strength of 0.24–0.48 MPa, high fracture energy of 3.56–16.88 MJ/m3, high extensibility of 7.7–79.9 mm/mm, fast self-recovery (stiffness/toughness recovery of 94/80% after heat treatment at 80 °C for 30 min), and strong surface adhesion to various nonporous solid surfaces (interfacial toughness of 1176–2827 J/m2). Such tough and adhesive protein–polymer hydrogels have great ...

Amyloid cross-seeding, as a result of direct interaction and co-aggregation between different disease-causative peptides, is considered as a main mechanism for the spread of the overlapping pathology across different cells and tissues between different protein-misfolding diseases (PMDs). Despite the biomedical significance of amyloid cross-seeding in amyloidogenesis, it remains a great challenge to discover amyloid cross-seeding systems and reveal their cross-seeding structures and mechanisms. Herein, we are the first to report that GNNQQNY - a short fragment from yeast prion protein Sup35 - can cross-seed with both amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form β-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric β-zippers, formed by the two β-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric β-zippers in a variety of GNNQQNY-Aβ and GNNQQNY-hIAPP assemblies also explains amyloid polymorphism. In addition, alteration of steric zipper formation by single-point mutations of GNNQQNY and interactions of GNNQQNY with different Aβ and hIAPP seeds leads to different amyloid cross-seeding efficiencies, further confirming the existence of cross-seeding barriers. This work offers a better structural-based understanding of amyloid cross-seeding mechanisms linked to different PMDs.

Alzheimer's disease (AD), as an age-related, progressive neurodegenerative disease, poses substantial challenges and burdens on public health and disease research. While significant research, investment, and progress have been made for the better understanding of pathological mechanisms and risk factors of AD, all clinical trials for AD treatment and diagnostics have failed so far. Since early and accurate diagnostics of AD is key to AD prevention and treatment, the development of probes for AD-related biomarkers is highly important but challenging for AD diagnosis. In this review, emerging evidence highlights the importance of the Aβ cascade hypothesis and indicates a significant role of Aβ and its aggregates as biomarkers in the pathogenesis of AD; we present an up-to-date summary on Aβ-based biosensor systems. Four typical biosensor systems for Aβ detection and representative examples from each type of biosensor are carefully selected and discussed in terms of their sensing strategies, materials, and mechanisms. Finally, we address the remaining challenges and opportunities for the development of future sensing platforms for Aβ detection and Aβ-based diagnostics of AD.

Misfolding and aggregation of amyloid peptides are the key pathological events in many neurodegenerative diseases. The development of effective inhibitors and drugs to prevent amyloid peptide aggregation is considered as an important therapeutic strategy for treating these diseases. We previously reported on tanshinones, ingredients from the Chinese herb Danshen (Salvia miltiorrhiza Bunge), as a potent inhibitor against amyloid-β1-42 (Aβ) aggregation and toxicity. Considering the common structural and aggregation features, and the correlation of type II diabetes (T2D) and Alzheimer's disease (AD), herein we examine the inhibition activity of two tanshinone I (TS1) and IIA (TS2) components on the aggregation and toxicity of hIAPP1-37 using combined experimental and computational approaches. Collective experimental data from ThT, CD, and AFM confirm that both tanshinones show comparable inhibition ability to reduce hIAPP aggregates by inhibiting the fibrillation process and changing the fibrillogenesis pathway, leading to the formation of some amorphous aggregates. More importantly, both tanshinones are capable of disassembling preformed hIAPP fibrils, but TS1 shows better potency in fibril dissembling than TS2. MTT and LDH assays also show that the tanshinones at very low concentrations of 5 μM can reduce the hIAPP-induced cell toxicity. Molecular dynamics (MD) simulations further reveal that both tanshinones preferentially bind to β-sheets to prevent lateral association of hIAPP aggregates and thus to inhibit fibril growth, explaining experimental observations. This work discovers that tanshinones act as common inhibitors to inhibit the aggregation of both hIAPP and Aβ, disaggregate preformed hIAPP and Aβ amyloid fibrils, and protect cells from hIAPP- and Aβ-induced toxicity, making them very promising agents against AD, T2D, and probably other amyloid-misfolding diseases.

Antifouling materials and coatings have broad fundamental and practical applications. Strong hydration at polymer surfaces has been proven to be responsible for their antifouling property, but molecular details of interfacial water behaviors and their functional roles in protein resistance remain elusive. Here, we computationally studied the packing structure, surface hydration, and protein resistance of four poly(N-hydroxyalkyl acrylamide) (PAMs) brushes with different carbon spacer lengths (CSLs) using a combination of molecular mechanics (MM), Monte Carlo (MC), and molecular dynamics (MD) simulations. The packing structure of different PAM brushes were first determined and served as a structural basis for further exploring the CSL-dependent dynamics and structure of water molecules on PAM brushes and their surface resistance ability to lysozyme protein. Upon determining an optimal packing structure of PAMs by MM and optimal protein orientation on PAMs by MC, MD simulations further revealed that poly(N-hydroxymethyl acrylamide) (pHMAA), poly(N-(2-hydroxyethyl)acrylamide) (pHEAA), and poly(N-(3-hydroxypropyl)acrylamide) (pHPAA) brushes with shorter CSLs = 1-3 possessed a much stronger binding ability to more water molecules than a poly(N-(5-hydroxypentyl)acrylamide) (pHPenAA) brush with CSL = 5. Consequently, CSL-induced strong surface hydration on pHMAA, pHEAA, and pHPAA brushes led to high surface resistance to lysozyme adsorption, in sharp contrast to lysozyme adsorption on the pHPenAA brush. Computational studies confirmed the experimental results of surface wettability and protein adsorption from surface plasmon resonance, contact angle, and sum frequency generation vibrational spectroscopy, highlighting that small structural variation of CSLs can greatly impact surface hydration and antifouling characteristics of antifouling surfaces, which may provide structural-based design guidelines for new and effective antifouling materials and surfaces.

Stimuli-responsive hydrogel strain sensors that synergize the advantages of both soft-wet hydrogels and smart functional materials have attracted rapidly increasing interest for exploring the opportunities from material design principles to emerging applications in electronic skins, health monitors, and human–machine interfaces. Stimuli-responsive hydrogel strain sensors possess smart and on-demand ability to specifically recognize various external stimuli and convert them into strain-induced mechanical, thermal, optical, and electrical signals. This review presents an up-to-date summary over the past five years on hydrogel strain sensors from different aspects, including material designs, gelation/fabrication methods, stimuli-responsive principles, and sensing performance. Hydrogel strain sensors are classified into five major categories based on the nature of the stimuli, and representative examples from each category are carefully selected and discussed in terms of structures, response mechanisms, and potential medical applications. Finally, current challenges and future perspectives of hydrogel strain sensors are tentatively proposed to stimulate more and better research in this emerging field.

Zwitterionic hydrogels are promising biomaterials because of their high water content, three-dimensional network structure, and antifouling property. However, it still remains unclear about how mechanical properties of zwitterionic hydrogels affect their antifouling property. In this work, we propose a simple, thermal-pretreatment method to fabricate poly(sulfobetaine methacrylate) (pSBMA) hydrogels with varied mechanical properties that can be readily tuned by thermal pretreatment time and cross-linker density, as well as to correlate their mechanical property with antifouling property. The resulting thermal-treated pSBMA hydrogels show significantly enhanced mechanical properties with tunable compressive modulus and elastic modulus as compared to the untreated hydrogels. A combination of ELISA investigations and short-term cell adhesion assays also confirm that pSBMA hydrogels exhibit superior antifouling properties to resist protein adsorption and cell adhesion. Further analysis shows a linear inversion correlation between elastic modulus and protein adsorption of pSBMA hydrogels, i.e., the hydrogel with the higher elastic modulus exhibits the lower protein adsorption (the better antifouling property). This work not only provides a simple thermal-pretreatment strategy for fabricating pSBMA hydrogels, but also demonstrates multifunctional properties of the pSBMA hydrogels, which possess a great potential to fulfill some biomedical applications.

Development of smart soft actuators is highly important for fundamental research and industrial applications but has proved to be extremely challenging. In this work, we present a facile, one-pot, one-step method to prepare dual-responsive bilayer hydrogels, consisting of a thermoresponsive poly( N-isopropylacrylamide) (polyNIPAM) layer and a salt-responsive poly(3-(1-(4-vinylbenzyl)-1 H-imidazol-3-ium-3-yl)propane-1-sulfonate) (polyVBIPS) layer. Both polyNIPAM and polyVBIPS layers exhibit a completely opposite swelling/shrinking behavior, where polyNIPAM shrinks (swells) but polyVBIPS swells (shrinks) in salt solution (water) or at high (low) temperatures. By tuning NIPAM:VBIPS ratios, the resulting polyNIPAM/polyVBIPS bilayer hydrogels enable us to achieve fast and large-amplitude bidirectional bending in response to temperatures, salt concentrations, and salt types. Such bidirectional bending, bending orientation, and degree can be reversibly, repeatedly, and precisely controlled by salt- or temperature-induced cooperative swelling-shrinking properties from both layers. Based on their fast, reversible, and bidirectional bending behavior, we further design two conceptual hybrid hydrogel actuators, serving as a six-arm gripper to capture, transport, and release an object and an electrical circuit switch to turn on-and-off a lamp. Different from the conventional two- or multistep methods for preparation of bilayer hydrogels, our simple, one-pot, one-step method and a new bilayer hydrogel system provide an innovative concept to explore new hydrogel-based actuators through combining different responsive materials that allow us to program different stimuli for soft and intelligent materials applications.

The role of electrostatic interactions in the viral capsid assembly process was studied by comparing the assembly process of a truncated hepatitis B virus capsid protein Cp149 with its mutant protein D2N/D4N, which has the same conformational structure but four fewer charges per dimer. The capsid protein self-assembly was investigated under a wide range of protein surface charge densities by changing the protein concentration, buffer pH, and solution ionic strength. Lowering the protein charge density favored the capsid formation. However, lowering charge beyond a certain point resulted in capsid aggregation and precipitation. Interestingly, both the wild-type and D2N/D4N mutant displayed identical assembly profiles when their charge densities matched each other. These results indicated that the charge density was optimized by nature to ensure an efficient and effective capsid proliferation under the physiological pH and ionic strength.

Skin wound healing is a still long-history challenging problem and impeded by the foreign-body reaction including severe inflammation response, poor neovascularization, incomplete re-epithelialization and defective ECM remodeling. Development of biocompatible polymers, in combination with specific drugs or growth factors, has been considered as a promising strategy to treat skin wounds. Significant research efforts have been made to develop poly(ethylene glycol) PEG-based polymers for wound healing, however less efforts has been paid to zwitterionic materials, some of which have demonstrated their super low-fouling property in vitro and anti-inflammatory property in vivo. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied them to full-thickness cutaneous wounds in mice. The healing effects of SBMA hydrogels on the wound closure, re-epithelialization ratio, ECM remodeling, angiogenesis, and macrophage responses during wound healing processes were histologically evaluated by in vivo experiments. Collective results indicate that SBMA hydrogels promote full-thickness excisional acute wound regeneration in mice by enhancing angiogenesis, decreasing inflammation response, and modulating macrophage polarization. Consistently, the incorporation of SBMA into PEG hydrogels also improved the overall wound healing efficiency as compared to pure PEG hydrogels. This work demonstrates zwitterionic SBMA hydrogels as promising wound dressings for treating full-thickness excisional skin wounds. Statement of Significance Development of highly effective wound regeneration system is practically important for biomedical applications. Here, we synthesized ultra-low-fouling zwitterionic sulfated poly(sulfobetaine methacrylate) (polySBMA) hydrogels and applied it to full-thickness cutaneous wounds in mice, in comparison with PEG hydrogels as a control. We are the first to examine and reveal the difference between zwitterionic SBMA hydrogels and PEG hydrogels using a full-thickness excisional mice model. Overall, a series of in vivo systematic tests demonstrated that zwitterionic SBMA hydrogels exhibited superior wound healing property in almost all aspects as compared to PEG hydrogels.

Polymer brushes have been demonstrated as versatile and effective surface modification method to achieve unparalleled control over surface properties and functionality. Here, this review mainly highlights the intriguing performance and functionalities of zwitterionic polymer brushes with anti-polyelectrolyte property for a variety of applications in protein resistance, antibacterial activity, surface wetting, and surface frication. Different from other hydrophilic polymer brushes, zwitterionic brushes exhibit the unique zwitterionic-induced anti-polyelectrolyte effect, allowing for the development of new smart polymers and polymer-coated surfaces.

Low-molecular-weight gelator (LMWG)-based supramolecular hydrogels, self-assembled by small molecules via noncovalent interactions, have recently attracted great attention due to their unique structure–property relationship and potential applications spanning from functional materials to biomedical devices. Unfortunately, many LMWG-based supramolecular hydrogels are mechanically weak and can not even be handled by conventional tensile and tearing tests. Here, we propose several design principles to fabricate new LMWG-based hydrogels with a true double-network structure (G4·K+/PDMAAm DN gels), consisting of the supramolecular self-assembly of guanosine, B(OH)3 and KOH as the first, physical G4·K+ network and the covalently cross-linked poly(N,N′-dimethyacrylamide) (PDMAAm) as the second, chemical network. Different from those LMWG-based supramolecular hydrogels, G4·K+/PDMAAm DN gels exhibit high tensile properties (elastic modulus = 0.307 MPa, tensile stress = 0.273 MPa, tensile strain = 17.62 mm/mm, and w...

Tough, mechanoresponsive hydrogels have broad and significant impacts on fundamental research and practical applications, but have proved to be extremely challenging to develop. The poor solubility of mechanophores makes them difficult to be integrated into a highly hydrophilic network of hydrogels. In this work, we synthesized dimethylacrylate-functionalized spiropyran (SP) mechanophores and used them as crosslinkers to copolymerize with hydrophobic methyl acrylate (MA) monomers and hydrophilic acrylamide (AM) monomers in the presence of surfactant polysorbate 80 (TWEEN 80) micelles, forming poly(AM-co-MA/SP) hydrogels. The mechanical properties of the as-prepared and swollen poly(AM-co-MA/SP) hydrogels strongly depend on network components (AM, MA, and SP concentrations). Thus, the optimal hydrogels can achieve excellent mechanical properties (tensile stress of 1.1 MPa, tensile strain of 6 mm mm−1, elastic modulus of 1.1 MPa, and tearing energy of 3200 J m−2). Due to multi-stimuli responses of SP crosslinkers, the hydrogels exhibited the reversible changes in color and mechanical properties between the force-, heat-, and UV light-induced deformation state and the white light-induced recovery state. Based on their fast, reversible, force-induced color change behavior, we further designed a conceptual hydrogel strain sensor to monitor color change under the stretching and relaxing processes in multiple cycles. This work demonstrates that the presence of dynamically reversible SP crosslinkers and micellar structures is the key to greatly enhance both mechanical and color recoverable properties of poly(AM-co-MA/SP) hydrogels, which could serve as promising smart materials for a variety of applications such as soft robots, electronic skins, and strain/motion/damage sensors.

The development of new antimicrobial materials and strategies is of importance for many biomedical and industrial applications. In this work, we report a new strategy to integrate distinct antimicrobial, antifouling, and stimuli-responsive properties into a single hydrogel to realize bacteria resistance, killing, and releasing functions. To achieve this design, we conjugated salt-responsive anti-polyelectrolyte polyDVBAPS (poly(3-(dimethyl(4-vinylbenzyl)ammonio)propyl sulfonate)) with antifouling polyHEAA (poly(N-hydroxyethyl acrylamide)) and antimicrobial AgNPs (silver nanoparticles) to form a hybrid hydrogel of polyDVBAPS-g-polyHEAA@AgNPs, among which polyHEAA functions as a general antifouling background to prevent bacteria adsorption on the surface, AgNPs act as antimicrobial agents to kill bacteria on the surface, and polyDVBAPS uses its unique salt-responsive, anti-polyelectrolyte property to release adherent bacteria from the surface. In this design, polyDVBAPS-g-polyHEAA@AgNPs hydrogels not only effectively resist bacteria attachment and kill the adherent bacteria, but also regenerate the antifouling surface of the hydrogel by releasing the adhered bacteria to keep the surface free from bacteria. The polyDVBAPS-g-polyHEAA@AgNPs hydrogels exhibited high surface resistance to bacteria adsorption ( 96% of adherent live or dead bacteria from the surface upon a simple treatment of 1.0 M NaCl solution for 10 min. Upon the release of AgNPs, AgNPs were reloaded into the hydrogel again to achieve multiple antifouling, bactericidal, and regenerative properties. This work demonstrates a new design for a new multifunctional hydrogel to effectively achieve antimicrobial, antifouling, and surface regeneration properties, making this hydrogel very promising for antimicrobial applications.

The rational design of biomaterials with antifouling properties still remains a challenge, although this is important for many bench-to-bedside applications for biomedical implants, drug delivery carriers, and marine coatings. Herein, we synthesized and characterized poly(N-acryloylglycinamide) (polyNAGA) and then grafted poly(NAGA) onto Au substrate to form polymer brushes with well-controlled film stability, wettability, and thickness using surface-initiated atom transfer radical polymerization (SI-ATRP). The NAGA monomer integrates two hydrophilic amides on the side chain to enhance surface hydration, which is thought as a critical contributor to its antifouling property. The antifouling performances of poly(NAGA) brushes of different film thicknesses were then rigorously assessed and compared using protein adsorption assay from undiluted blood serum and plasma, cell-adhesive assay, and bacterial assay. The resulting poly(NAGA) brushes with a film thickness of 25-35 nm exhibited excellent in vitro antifouling ability to prevent unwanted protein adsorption (0.3 ng/cm

Amyloid peptides can misfold and aggregate into amyloid oligomers and fibrils containing conformationally similar β-sheet structures, which are linked to the pathological hallmark of many neurodegenerative diseases. These β-sheet-rich amyloid aggregates provide common structural motifs to accelerate amyloid formation by acting as seeds. However, little is known about how one amyloid peptide aggregation will affect another one (namely, cross-seeding). In this work, we studied the cross-seeding possibility and efficiency between rat islet amyloid polypeptide (rIAPP) and human islet amyloid polypeptide (hIAPP) solution with preformed aggregates at different aggregation phases, using a combination of different biophysical techniques. hIAPP is a well-known peptide hormone that forms amyloid fibrils and induces cytotoxicity to β-cells in type 2 diabetes, whereas rIAPP is a nonaggregating and nontoxic peptide. Experimental results showed that all different preformed hIAPP aggregates can cross-seed rIAPP to promote the final fibril formation but exhibit different cross-seeding efficiencies. Evidently, hIAPP seeds preformed at a growth phase show the strongest cross-seeding potential to rIAPP, which accelerates the conformational transition from random structures to β-sheet and the aggregation process at the fibrillization stage. Homoseeding of hIAPP is more efficient in initiating and promoting aggregation than cross-seeding of hIAPP and rIAPP. Moreover, the cross-seeding of rIAPP with hIAPP at the lag phase also reduced cell viability, probably because of the formation of more toxic hybrid oligomers at the prolonged lag phase. The cross-seeding effects in this work may add new insights into the mechanistic understanding of the aggregation and coaggregation of amyloid peptides linked to different neurodegenerative diseases.

Cardiovascular disease (CVD) and Alzheimer’s disease (AD) have a mutual cause-and-effect relationship, and they share some common risk factors. Although numerous Food and Drug Administration (FDA)-approved drugs have been developed for CVD treatment, no drugs are clinically available for AD treatment. Given the common disease-causing factors and links between the two diseases and the well-demonstrated drugs for CVD, we propose to re-examine the new potential of the existing CVD drugs as amyloid-β (Aβ) inhibitors. 3-Morpholinosydnonimine hydrochloride (SIN-1) is an FDA-approved drug for inhibiting platelet aggregation in CVD. Herein, we examine the inhibition activity of SIN-1 on the aggregation and toxicity of Aβ1–42 using combined experimental and computational approaches. Collective experimental data from ThT, circular dichroism, and atomic force microscopy demonstrate that SIN-1 can effectively inhibit amyloid formation at every stage of Aβ aggregation by prolonging lag phase, slowing down aggregation rate, and reducing final fibril formation. The cell viability assay also shows that SIN-1 enables the protection of SH-SY5Y cells from Aβ-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of Aβ toward a β-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal β-sheet grooves of an Aβ oligomer and consequently disrupts the β-sheet structure of Aβ and Aβ–Aβ association, explaining experimental observations. This work discovers a new function of SIN-1, making it a promising compound with dual protective roles in inhibiting both platelet and Aβ aggregations against CVD and AD.

Nanocomposite hydrogels (NC gels) are considered to belong to the class of high strength hydrogels. Graphene oxide (GO), owing to its amphiphilic, mechanical, and optical properties, is widely used as a filler incorporated into different hosting materials (elastomers, plastics, and hydrogels) to improve their mechanical properties. In this work, we used in situ free radical polymerization to synthesize polyacrylamide (PAAm)/GO hybrid NC gels in the presence of GO nanosheets and a very small amount of chemical cross-linkers (N,N′-methylenebisacrylamide, MBA < 0.1 mol%). By optimizing GO and MBA concentrations, the resulting PAAm/GO gels can achieve an elastic modulus of 66 kPa, a fracture stress of 0.27 MPa, a fracture strain of 13.76 mm mm−1, deformed energy of 2.52 MJ m−3, and tearing energy of 964 J m−2. Due to the presence of physical interactions between PAAm and GO nanosheets, PAAm/GO gels demonstrate λ-dependent energy dissipation and Mullins self-recovery behaviors. The gels can rapidly recover their stiffness and toughness by 76% and 60%, respectively, after 30 min of resting at room temperature. The possible toughening mechanisms and Mullins effects of PAAm/GO gels were proposed and compared with those of filler rubbers and other high strength hydrogels. This work provides new viewpoints to develop tough hydrogels by the introduction of GO into other hydrogels with a good mechanical balance between strong chemical bonding and reversible physical bonding.

The misfolding and aggregation of proteins and peptides into amyloid fibrils are believed to be responsible for the dysfunction and death of neuron cells in many neurodegenerative diseases. Resolving the atomic structures of amyloid peptides at different aggregation stages by molecular simulations has opened new ways to probe the molecular mechanisms of amyloid aggregation, toxicity, and inhibition, as well as to validate computational data with available experimental ones. In this review article, we summarize some recent and important findings on: 1) a number of atomic structures of amyloid oligomers with typical β-sheet-rich conformations, related to amyloid aggregation; 2) different amyloid peptide-induced membrane-disruption mechanisms, related to amyloid toxicity; and 3) rational design of different amyloid inhibitors capable of preventing amyloid aggregation and toxicity, related to amyloid inhibition. All these findings will provide some mechanistic implications for molecular mechanisms of amyloid aggregation, toxicity, and inhibition, which are fundamentally and practically important for the treatment of amyloid diseases.

Surface hydration has been proposed as the key antifouling mechanism of antifouling materials. However, molecular-level details of the structure, dynamics, and interactions of interfacial water around antifouling polymers still remain elusive. In this work, using all-atom molecular dynamics (MD) simulations, we studied four different acrylamides (AMs) for their interfacial water behaviors and their interactions with a protein, with special attention to the effect of carbon spacer lengths (CSLs) on the hydration properties of AMs. Collective MD simulation data revealed that although all four AMs displayed strong hydration, N-hydroxymethyl acrylamide (HMAA) and N-(2-hydroxyethyl)acrylamide (HEAA) with shorter CSLs displayed a longer residence time, slower self-diffusion, and lower coordination number of interfacial water molecules than N-(3-hydroxypropyl)acrylamide (HPAA) and N-(5-hydroxypentyl)-acrylamide (HPenAA) with longer CSLs. The shorter CSLs allow water molecules to form bridging hydrogen bonds with different hydrophilic groups in the same AM chain, thus enhancing the hydration capacity of AMs. Consequently, different from HPenAA, which had a weak but detectable interaction with the protein, HMAA, HEAA, and HPAA had almost zero interactions with the protein. This computational work provides a better fundamental understanding of the surface hydration and protein interaction of different AMs with subtle structural changes from structural, dynamic, and energy aspects at the atomic level, which hopefully will guide the design of new and effective nonfouling materials.

DDT (1,1,1-trichloro-2.2-bis(p-chlorophenyl)ethane), one of the most abused insecticides, is a highly hazardous component for both human health and environmental applications. The biodegradation of DDT into non-toxic, environmentally benign components is strongly limited by the poor bioavailability of DDT. In this work, we combined experiments and molecular simulations to examine the effect of three cyclodextrins (α-, β-, and γ-CD) on their structure-specific interactions with DDT, specifically in relation to DDT solubility and biodegradability. It was found that all three CDs were able to bind to DDT with their inner hydrophobic cavity and different binding affinities and orientations, demonstrating their ability to improve DDT solubility. Different from the strong binding between DDT and β-/γ-CDs via a fully DDT bury mode, α-CD had a relatively weak binding with DDT via a partial DDT bury mode, which allowed DDT to be readily disassociated from α-CD at the lipid membrane interface, followed by DDT permeation into and across the cell membrane. The different binding modes between DDT and CDs explain why only α-CD can promote the bioavailability and biodegradation of DDT by simultaneously increasing its aqueous solubility and membrane interaction. This work provides structural-based binding information for the further modification and optimization of these three CDs to enhance their solubility and biodegradability of DDT.

Amyloid deposits of misfolded amyloid-β protein (Aβ) on neuronal cells are a pathological hallmark of Alzheimer's disease (AD). Prevention of the abnormal Aβ aggregation has been considered as a promising therapeutic strategy for AD treatment. To prevent reinventing the wheel, we proposed to search the existing drug database for other diseases to identify potential Aβ inhibitors. Herein, we reported the inhibitory activity of HP-β-cyclodextrin (HP-β-CD), a well-known sugar used in drug delivery, genetic vector, environmental protection and treatment of Niemann-Pick disease type C1 (NPC1), against Aβ1-42 aggregation and Aβ-induced toxicity, with the aim of adding a new function as a sugar-based Aβ inhibitor. Experimental data showed that HP-β-CD molecules were not only nontoxic to cells, but also greatly inhibited Aβ fibrillization and reduced Aβ-induced toxicity in a concentration-dependent manner. At an optimal molar ratio of Aβ : HP-β-CD = 1 : 2, HP-β-CD enabled the reduction of 60% of Aβ fibrils and increased the cell viability to 92%. Such concentration-dependent inhibitor capacity of HP-β-CD was likely attributed to several combined effects, including the enhancement of Aβ-HP-β-CD interactions, prevention of structural transition of Aβ peptides towards β-sheet structures, and reduction of self-aggregation of HP-β-CD. In parallel, molecular simulations further revealed the atomic details of HP-β-CD interacting with the Aβ oligomer, showing that HP-β-CD had a high tendency to interact with hydrophobic residues of Aβ in two β-strands and the N-terminal tail. More importantly, we identified that the inner hydrophobic cavity of HP-β-CD was a key active site for Aβ inhibition. Once the inner cavity of HP-β-CD was blocked by a small hydrophobic molecule of ferulic acid, HP-β-CD completely lost its inhibition capacity against Aβ. Given the already established pharmaceutical functions of HP-β-CD in drug delivery, our findings suggest that HP-β-CD has great potential to be designed as a sugar-based Aβ inhibitor.

Abnormal misfolding and aggregation of amyloid peptides into amyloid fibrils are common and critical pathological events in many neurodegenerative diseases. Most inhibitors or drugs have been developed to prevent amyloid aggregation of a specific peptide, showing sequence-dependent inhibition mechanisms. It is more challenging to develop or discover inhibitors capable of preventing the aggregation of two or more different amyloid peptides. Genistein, a major phytoestrogen in soybean, has been widely used as an anti-inflammation and cerebrovascular drug due to its antioxidation and antiacetylcholinesterase effects. Herein, we examine the inhibitory effects of genistein on the aggregation of amyloid-β (Aβ, associated with Alzheimer's disease) and human islet amylin (hIAPP, associated with type 2 diabetes) and Aβ- and hIAPP-induced neurotoxicity using a combination of experimental and computational approaches. Collective experimental results from thioflavin T (ThT), atomic force microscopy (AFM), and circular dichroism (CD) demonstrate that genistein shows strong inhibition ability to prevent the conformational transition of both Aβ and hIAPP monomers to β-sheet structures, thus reducing final amyloid fibrillization from Aβ and hIAPP monomer aggregation by 40-63%. Further 3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH), and large unilamellar vesicle (LUV) assays show that genistein helps to increase cell viability, decrease cell apoptosis, and reduce cell membrane leakage, where the cell protection effect of genistein is likely correlated with its reduced membrane leakage. Comparative molecular dynamics (MD) simulations reveal that genistein prefers to bind the β-sheet groove, a common structural motif of amyloid fibrils, of both Aβ and hIAPP oligomers to interfere with their self-aggregation. This work for the first time demonstrates genistein as a dual inhibitor of Aβ and hIAPP aggregation. Further structural optimization and refinement of genistein may generate a series of effective sequence-independent inhibitors against the aggregation and toxicity of different amyloid peptides.

Alzheimer’s disease (AD) and type 2 diabetes (T2D) are two common protein aggregation diseases. Compelling evidence has shown a link between AD and T2D, which may derive from interspecies cross-sequence interactions between amyloid-β peptide (Aβ), associated with AD, and human islet amyloid polypeptide (hIAPP), associated with T2D. Herein, we present experimental and computational protocols and tools to study the aggregate structures and kinetics, conformational conversion, and molecular interactions of Aβ-hIAPP mixtures. These protocols could be generally applied to other cross-seeding behaviors of amyloid peptides.

Some polyzwitterionic brushes exhibit a strong "anti-polyelectrolyte effect" and ionic specificity that make them versatile platforms to build smart surfaces for many applications. However, the structure-property relationship of zwitterionic polymer brushes still remains to be elucidated. Herein, we aim to study the structure-dependent relationship between different zwitterionic polymers and the anti-polyelectrolyte effect. To this end, a series of polyzwitterionic brushes with different cationic moieties (e.g., imidazolium, ammonium, and pyridinium) in their monomeric units and with different carbon spacer lengths (e.g., CSL = 1, 3, and 4) between the cation and anion were designed and synthesized to form polymer brushes via the surface-initiated atom transfer radical polymerization. All zwitterionic brushes were carefully characterized for their surface morphologies, compositions, wettability, and film thicknesses by atomic force microscopy, contact angle measurement, and ellipsometry, respectively. The salt-responsiveness of all zwitterionic brushes to surface hydration and friction was further examined and compared both in water and in salt solutions with different salt concentrations and counterion types. The collective data showed that zwitterionic brushes with different cationic moieties and shorter CSLs in salt solution induced higher surface friction and lower surface hydration than those in water, exhibiting strong anti-polyelectrolyte effect salt-responsive behaviors. By tuning the CSLs, cationic moieties, and salt concentrations and types, the surface wettability can be changed from a highly hydrophobic surface (∼60°) to a highly hydrophilic surface (∼9°), while interfacial friction can be changed from ultrahigh friction (μ ≈ 4.5) to superior lubrication (μ ≈ 10

The interactions of amyloid peptides with cell membranes play an important role in maintaining the integrity and functionality of cell membrane. A thorough molecular-level understanding of the structure, dynamics, and interactions between amyloid peptides and cell membranes is critical to amyloid aggregation and toxicity mechanisms for the bench-to-bedside applications. Here we review the most recent computational studies of amyloid peptides at model cell membranes. Different mechanisms of action of amyloid peptides on/in cell membranes, targeted by different computational techniques at different lengthscales and timescales, are rationally discussed. Finally, we have proposed some new insights into the remaining challenges and perspectives for future studies to improve our understanding of the activity of amyloid peptides associated with protein-misfolding diseases. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy.

Interaction of human islet amyloid polypeptide (hIAPP) peptides with cell membrane is crucial for the understanding of amyloid toxicity associated with Type II diabetes (T2D). While it is known that the hIAPP-membrane interactions are considered to promote hIAPP aggregation into fibrils and induce membrane disruption, the membrane-induced conformation, orientation, aggregation, and adsorption behaviors of hIAPP peptides have not been well understood at the atomic level. Herein, we perform all-atom explicit-water molecular dynamics (MD) simulations to study the adsorption, orientation, and surface interaction of hIAPP aggregates with different sizes (monomer to tetramer) and conformations (monomer with α-helix and tetramer with β-sheet-rich U-turn) upon adsorption on the lipid bilayers composed of both pure zwitterionic POPC (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine) and mixed anionic POPC/POPE (1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine) (3:1) lipids. MD simulation results show that hIAPP monomer with α-helical conformation and hIAPP pentamer with β-sheet conformation can adsorb on both POPC and POPC/POPE bilayers via a preferential orientation of N-terminal residues facing toward the bilayer surface. The hIAPP aggregates show stronger interactions with mixed POPC/POPE lipids than pure POPC lipids, consistent with experimental observation that hIAPP adsorption and fibrililation are enhanced on mixed lipid bilayers. While electrostatic interactions are main attractive forces to drive the hIAPP aggregates to adsorb on both bilayers, the introduction of the more hydrophilic head groups of POPE lipids further promote the formation of the interfacial hydrogen bonds. Complement to our previous studies of hIAPP aggregates in bulk solution, this computational work increases our knowledge about the mechanism of amyloid peptide-membrane interactions that is central to the understanding the progression of all amyloid diseases.

Amyloid-β (Aβ) and human islet polypeptide (hIAPP) are the causative agents responsible for Alzheimer's disease (AD) and type II diabetes (T2D), respectively. While numerous studies have reported the cross-seeding behavior of Aβ and hIAPP in solution, little effort has been made to examine the cross-seeding of Aβ and hIAPP in the presence of cell membranes, which is more biologically relevant to the pathological link between AD and T2D. In this work, we computationally study the cross-seeding and adsorption behaviors of Aβ and hIAPP on zwitterionic POPC and anionic 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylglycerol (POPG) mixed bilayers using all-atom molecular dynamics (MD) simulations, particularly aiming to the effects of the initial orientation of the Aβ-hIAPP assembly and the lipid composition of cell membranes on mutual structural and interaction changes in both Aβ-hIAPP assembly and lipid bilayers at the atomic level. Aβ-hIAPP cross-seeding assembly always preferred to adopt a specific orientation and interface to associate with both lipid bilayers strongly via the N-terminal strands of Aβ. Such membrane-bound orientation explains experimental observation that hybrid Aβ-hIAPP fibrils on cell membranes showed similar morphologies to pure hIAPP fibrils. Moreover, Aβ-hIAPP assembly, regardless of its initial orientations, interacted more strongly with POPC/POPG bilayer than POPC bilayer, indicating that electrostatic interactions are the major forces governing peptide-lipid interactions. Strong electrostatic interactions were also attributed to the formation of Ca