Evaluating the Sub-Acute Toxicity of Formaldehyde Fumes in an In Vitro Human Airway Epithelial Tissue Model.

Formaldehyde (FA) is an irritating, highly reactive aldehyde that is widely regarded as an asthmagen. In addition to its use in industrial applications and being a product of combustion reaction and endogenous metabolism, FDA-regulated products may contain FA or release FA fumes that present toxicity risks for both patients and healthcare workers. Exposure to airborne FA is associated with nasal neoplastic lesions in both animals and humans. It is classified as a Group 1 carcinogen by International Agency for Research on Cancer (IARC) based on the increased incidence of cancer in animals and a known human carcinogen in the Report on Carcinogens by National Toxicology Program (NTP). Herein, we systematically evaluated the tissue responses to FA fumes in an in vitro human air-liquid-interface (ALI) airway tissue model. Cultures were exposed at the air interface to 7.5, 15, and 30 ppm of FA fumes 4 h per day for 5 consecutive days. Exposure to 30 ppm of FA induced sustained oxidative stress, along with functional changes in ciliated and goblet cells as well as possible squamous differentiation. Furthermore, secretion of the proinflammatory cytokines, IL-1ß, IL-2, IL-8, GM-CSF, TNF-a and IFN-γ, was induced by repeated exposures to FA fumes. Expression of MMP-1, MMP-3, MMP-7, MMP-10, MMP-12, and MMP-13 was downregulated at the end of the 5-day exposure. Although DNA-damage was not detected by the comet assay, FA exposures downregulated the DNA repair enzymes MGMT and FANCD2, suggesting its possible interference in the DNA repair capacity. Overall, a general concordance was observed between our in vitro responses to FA fume exposures and the reported in vivo toxicity of FA. Our findings provide further evidence supporting the application of the ALI airway system as a potential in vitro alternative for screening and evaluating the respiratory toxicity of inhaled substances.

Subacute Pulmonary Toxicity of Glutaraldehyde Aerosols in a Human In Vitro Airway Tissue Model.

Glutaraldehyde (GA) has been cleared by the Center for Devices and Radiological Health (CDRH) of the Food and Drug Administration (FDA) as a high-level disinfectant for disinfecting heat-sensitive medical equipment in hospitals and healthcare facilities. Inhalation exposure to GA is known to cause respiratory irritation and sensitization in animals and humans. To reproduce some of the known in vivo effects elicited by GA, we used a liquid aerosol exposure system and evaluated the tissue responses in a human in vitro airway epithelial tissue model. The cultures were treated at the air interface with various concentrations of GA aerosols on five consecutive days and changes in tissue function and structure were evaluated at select timepoints during the treatment phase and after a 7-day recovery period. Exposure to GA aerosols caused oxidative stress, inhibition of ciliary beating frequency, aberrant mucin production, and disturbance of cytokine and matrix metalloproteinase secretion, as well as morphological transformation. Some effects, such as those on goblet cells and ciliated cells, persisted following the 7-day recovery period. Of note, the functional and structural disturbances observed in GA-treated cultures resemble those found in ortho-phthaldehyde (OPA)-treated cultures. Furthermore, our in vitro findings on GA toxicity partially and qualitatively mimicked those reported in the animal and human survey studies. Taken together, observations from this study demonstrate that the human air-liquid-interface (ALI) airway tissue model, integrated with an in vitro exposure system that simulates human inhalation exposure, could be used for in vitro-based human hazard identification and the risk characterization of aerosolized chemicals.

Computational Investigation of Antifouling Property of Polyacrylamide Brushes.

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.

Molecular Dynamics Simulation of the Effect of Carbon Space Lengths on the Antifouling Properties of Hydroxyalkyl Acrylamides.

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.

Simple Thermal Pretreatment Strategy to Tune Mechanical and Antifouling Properties of Zwitterionic Hydrogels.

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.

Structural Dependence of Salt-Responsive Polyzwitterionic Brushes with an Anti-Polyelectrolyte Effect.

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 ≈ 10-3). This work provides important structural insights into how subtle structural changes in zwitterionic polymers can yield great changes in the salt-responsive properties at the interface, which could be used for the development of smart surfaces for different applications.

Synthesis and Characterization of Ultralow Fouling Poly(N-acryloyl-glycinamide) Brushes.

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/cm2) and bacterial and cell attachments up to 3 days. Molecular dynamics (MD) simulations further showed that two hydrophilic amide groups can interact with water molecules strongly to form a strong hydration layer via coordinated hydrogen bonds. This confirms a positive correlation between antifouling property and surface hydration. In line with a series of polyacrylamides and polyacrylates as antifouling materials synthesized in our lab, we propose that small structural changes in the pendent groups of polymers could largely improve the antifouling capacity, which may be used as a general design rule for developing next-generation antifouling materials.

Atomic elucidation of the cyclodextrin effects on DDT solubility and biodegradation.

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-, ß-, 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 ß-/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.

HP-ß-cyclodextrin as an inhibitor of amyloid-ß aggregation and toxicity.

Amyloid deposits of misfolded amyloid-ß protein (Aß) on neuronal cells are a pathological hallmark of Alzheimer's disease (AD). Prevention of the abnormal Aß 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 Aß inhibitors. Herein, we reported the inhibitory activity of HP-ß-cyclodextrin (HP-ß-CD), a well-known sugar used in drug delivery, genetic vector, environmental protection and treatment of Niemann-Pick disease type C1 (NPC1), against Aß1-42 aggregation and Aß-induced toxicity, with the aim of adding a new function as a sugar-based Aß inhibitor. Experimental data showed that HP-ß-CD molecules were not only nontoxic to cells, but also greatly inhibited Aß fibrillization and reduced Aß-induced toxicity in a concentration-dependent manner. At an optimal molar ratio of Aß : HP-ß-CD = 1 : 2, HP-ß-CD enabled the reduction of 60% of Aß fibrils and increased the cell viability to 92%. Such concentration-dependent inhibitor capacity of HP-ß-CD was likely attributed to several combined effects, including the enhancement of Aß-HP-ß-CD interactions, prevention of structural transition of Aß peptides towards ß-sheet structures, and reduction of self-aggregation of HP-ß-CD. In parallel, molecular simulations further revealed the atomic details of HP-ß-CD interacting with the Aß oligomer, showing that HP-ß-CD had a high tendency to interact with hydrophobic residues of Aß in two ß-strands and the N-terminal tail. More importantly, we identified that the inner hydrophobic cavity of HP-ß-CD was a key active site for Aß inhibition. Once the inner cavity of HP-ß-CD was blocked by a small hydrophobic molecule of ferulic acid, HP-ß-CD completely lost its inhibition capacity against Aß. Given the already established pharmaceutical functions of HP-ß-CD in drug delivery, our findings suggest that HP-ß-CD has great potential to be designed as a sugar-based Aß inhibitor.

A TDDFT study on the excited-state intramolecular proton transfer (ESIPT): excited-state equilibrium induced by electron density swing.

One important issue of current interest is the excited-state equilibrium for some ESITP dyes. However, so far, the information about the driving forces for excited-state equilibrium is very limited. In this work, the time-dependent density functional theory (TDDFT) method was employed to investigate the nature of the excited-state intramolecular proton transfer (ESIPT). The geometric structures, vibrational frequencies, frontier molecular orbitals (MOs) and the potential-energy curves for 1-hydroxy-11H-benzo[b]fluoren-11-one (HHBF) in the ground and the first singlet excited state were calculated. Analysis of the results shows that the intramolecular hydrogen bond of HHBF is strengthened from E to E*. Moreover, it is found that electron density swing between the proton acceptor and donor provides the driving forces for the forward and backward ESIPT, enabling the excited-state equilibrium to be established. Furthermore, we proposed that the photoexcitation and the interchange of position for electron-donating and electron-withdrawing groups are the main reasons for the electron density swing. The potential-energy curves suggest that the forward ESIPT and backward ESIPT may happen on the similar timescale, which is faster than the fluorescence decay of both E* and K* forms.

Conformational-specific self-assembled peptides as dual-mode, multi-target inhibitors and detectors for different amyloid proteins.

Prevention and detection of misfolded amyloid proteins and their ß-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 de novo design a series of new self-assembling peptides (SAPs), enabling them to specifically and strongly interact with conformationally similar ß-sheet motifs of Aß (association with AD) and hIAPP (association with T2D). Collective in vitro experimental data from thioflavin (ThT), atomic force microscopy (AFM), circular dichroism (CD), and cell assay demonstrate that SAPs possess two integrated functions of (i) amyloid inhibition for preventing both Aß and hIAPP aggregation by 34-61% and reducing their induced cytotoxicity by 7.6-35.4% and (ii) amyloid sensing for early detection of toxic Aß and hIAPP aggregates using in-house SAP-based paper sensors and SPR sensors. The presence of both amyloid inhibition and detection in SAPs stems from strong molecular interactions between amyloid aggregates and SAPs, thus providing a new multi-target model for expanding the new therapeutic potentials of SAPs and other designs with built-in amyloid inhibition and detection functions.

Dual amyloid cross-seeding reveals steric zipper-facilitated fibrillization and pathological links between protein misfolding diseases.

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-ß (Aß, associated with Alzheimer's disease) and human islet amyloid polypeptide (hIAPP, associated with type II diabetes) to form ß-structure-rich assemblies and to accelerate amyloid fibrillization. Dry, steric ß-zippers, formed by the two ß-sheets of different amyloid peptides, provide generally interactive and structural motifs to facilitate amyloid cross-seeding. The presence of different steric ß-zippers in a variety of GNNQQNY-Aß 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 Aß 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.

Invited review: human air-liquid-interface organotypic airway tissue models derived from primary tracheobronchial epithelial cells-overview and perspectives.

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.

Design principles and fundamental understanding of biosensors for amyloid-ß detection.

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 Aß cascade hypothesis and indicates a significant role of Aß and its aggregates as biomarkers in the pathogenesis of AD; we present an up-to-date summary on Aß-based biosensor systems. Four typical biosensor systems for Aß 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 Aß detection and Aß-based diagnostics of AD.

Introduction and Fundamentals of Human Islet Amyloid Polypeptide Inhibitors.

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 ß-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.

Molecular simulations and understanding of antifouling zwitterionic polymer brushes.

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.

Micro- and macroscopically structured zwitterionic polymers with ultralow fouling property.

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.

From design to applications of stimuli-responsive hydrogel strain sensors.

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.

Fundamentals of cross-seeding of amyloid proteins: an introduction.

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 Aß/hIAPP, Aß/tau, Aß/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.

Tanshinones inhibit hIAPP aggregation, disaggregate preformed hIAPP fibrils, and protect cultured cells.

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-ß1-42 (Aß) 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 ß-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 Aß, disaggregate preformed hIAPP and Aß amyloid fibrils, and protect cells from hIAPP- and Aß-induced toxicity, making them very promising agents against AD, T2D, and probably other amyloid-misfolding diseases.