Evaluating the effectiveness and cost-effectiveness of free influenza vaccination policy for older adults in Yinzhou, China: Study protocol of a real-world analyses.

BACKGROUND: Influenza causes excessive morbidity and mortality among older adults. While influenza vaccine provides protection against its infection, the vaccination coverage in China among older adults has been very low. Previous evidence on the cost-effectiveness of government-sponsored free influenza vaccination programs in China was primarily based on literature data, which might not always reflect real-world patient populations. The Yinzhou Health Information System (YHIS) is a regional database that captures electronic health records, insurance claims data, etc. for all residents in Yinzhou district, Zhejiang province, China. We will use YHIS to study the effectiveness, influenza-related direct medical cost and cost-effectiveness analysis (CEA) of the free influenza vaccination program for older adults. In this paper, we describe the study design and innovations in detail. METHODS: We will establish a retrospective cohort of permanent older residents aged 65 and over, using YHIS between 2016 and 2021. We will estimate the vaccine coverage rate, influenza incidence rate and influenza-related direct medical cost from 2016 to 2021. Regression discontinuity will be used to estimate vaccine effectiveness for the 2020/2021 season. We will build a decision tree model to compare the cost-effectiveness of three influenza vaccination options (free trivalent influenza vaccine, free quadrivalent influenza vaccine, and no policy) from both societal and health system perspectives. Parameter inputs will be gathered from both YHIS and published literature. We will calculate the incremental cost-effectiveness ratio with cost and quality-adjusted life years (QALYs) discounted at 5 % annually. DISCUSSION: Our CEA solidifies multiple sources including regional real-world data and literature for a rigorous evaluation of the government-sponsored free influenza vaccination program. The results will provide real-world evidence from real-world data on the cost-effectiveness of a real-world policy. Our findings are expected to support evidence-based policy making and to promote health for older adults.

Machine learning-based prediction of infarct size in patients with ST-segment elevation myocardial infarction: A multi-center study.

BACKGROUND: Cardiac magnetic resonance imaging (CMR) is the gold standard for measuring infarct size (IS). However, this method is expensive and requires a specially trained technologist to administer. We therefore sought to quantify the IS using machine learning (ML) based analysis on clinical features, which is a convenient and cost-effective alternative to CMR. METHODS AND RESULTS: We included 315 STEMI patients with CMR examined one week after morbidity in final analysis. After feature selection by XGBoost on fifty-six clinical features, we used five ML algorithms (random forest (RF), light gradient boosting decision machine, deep forest, deep neural network, and stacking) to predict IS with 26 (selected by XGBoost with information gain greater than average level of 56 features) and the top 10 features, during which 5-fold cross-validation were used to train and optimize models. We then evaluated the value of actual and ML-IS for the prediction of adverse remodeling. Our finding indicates that MLs outperform the linear regression in predicting IS. Specifically, the RF with five predictors identified by the exhaustive method performed better than linear regression (LR) with 10 indicators (R2 of RF: 0.8; LR: 0). The finding also shows that both actual and ML-IS were independently associated with adverse remodeling. ML-IS ≥ 21% was associated with a twofold increase in the risk of LV remodeling (P < 0.01) compared with patients with reference IS (1st tertile). CONCLUSION: ML-based methods can predict IS with widely available clinical features, which provide a proof-of-concept tool to quantitatively assess acute phase IS.

Mediation analysis of leisure activities on the association between cognitive function and mortality: a longitudinal study of 42,942 Chinese adults 65 years and older.

OBJECTIVES: Previous studies have established associations of cognitive function and leisure activities with mortality. This study aimed to evaluate whether leisure activities causally mediate these associations. METHODS: This longitudinal study included 42,246 participants aged over 65 years from the Chinese Longitudinal Healthy Longevity Survey. The Mini-Mental State Examination and a self-reported scale were used to measure cognitive status and leisure activities, respectively. We examined the associations of cognitive function and leisure activities with mortality using Cox proportional hazards models. Causal mediation analysis was used to assess whether leisure activities mediated the association between cognitive function and mortality. RESULTS: Cognitive function and leisure activities were inversely associated with mortality. Leisure activities accounted for 28.3% (95% confidence interval [CI], 25.6 to 31.1) of the total effect of cognitive function and mortality. A higher mediated proportion (PM) was observed for physical leisure activities (PM, 20.1%; 95% CI, 18.0 to 22.3) than for social leisure activities (PM, 17.7%; 95% CI, 15.7 to 19.7). The mediating effect was higher among participants at younger ages (PM, 41.5%; 95% CI, 21.3 to 65.4), those with higher education levels (PM, 30.5%; 95% CI, 25.3 to 36.2), and residents of rural China (PM, 42.5%; 95% CI, 25.4 to 62.5). CONCLUSIONS: Cognitive function was associated with inverse mortality. Leisure activities significantly mediated this association. Participation in leisure activities at the early stages of mild cognitive impairment could reduce the risk of mortality, which has a major impact on interventional strategies for healthy aging.

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.

Experimental and Computational Protocols for Studies of Cross-Seeding Amyloid Assemblies.

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-ß peptide (Aß), 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 Aß-hIAPP mixtures. These protocols could be generally applied to other cross-seeding behaviors of amyloid peptides.

Role of Protein Charge Density on Hepatitis B Virus Capsid Formation.

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.

Identification of a New Function of Cardiovascular Disease Drug 3-Morpholinosydnonimine Hydrochloride as an Amyloid-ß Aggregation Inhibitor.

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-ß (Aß) 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 Aß1-42 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 Aß 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 Aß-induced cell toxicity. Such an inhibition effect is attributed to interference with the structural transition of Aß toward a ß-sheet structure by SIN-1. Furthermore, molecular dynamic simulations confirm that SIN-1 preferentially binds to the C-terminal ß-sheet grooves of an Aß oligomer and consequently disrupts the ß-sheet structure of Aß and Aß-Aß 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 Aß aggregations against CVD and AD.

Seed-Induced Heterogeneous Cross-Seeding Self-Assembly of Human and Rat Islet Polypeptides.

Amyloid peptides can misfold and aggregate into amyloid oligomers and fibrils containing conformationally similar ß-sheet structures, which are linked to the pathological hallmark of many neurodegenerative diseases. These ß-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 ß-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 ß-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.

Molecular Understanding of Aß-hIAPP Cross-Seeding Assemblies on Lipid Membranes.

Amyloid-ß (Aß) 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 Aß and hIAPP in solution, little effort has been made to examine the cross-seeding of Aß 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 Aß 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 Aß-hIAPP assembly and the lipid composition of cell membranes on mutual structural and interaction changes in both Aß-hIAPP assembly and lipid bilayers at the atomic level. Aß-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 Aß. Such membrane-bound orientation explains experimental observation that hybrid Aß-hIAPP fibrils on cell membranes showed similar morphologies to pure hIAPP fibrils. Moreover, Aß-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 Ca2+ bridges connecting both negatively charged Glu of Aß and PO4 head groups of lipids, which facilitate the association of Aß-hIAPP with the POPC/POPG bilayer. It was also found that the strong peptide-lipid binding reduced lipid fluidity. Both facts imply that Aß-hIAPP assembly may induce cell damage by altering calcium homeostasis and cell membrane phase. This work provides a better fundamental understanding of cross-seeding of Aß and hIAPP on cell membranes and a potential pathological link between AD and T2D.

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.

Salt-responsive polyzwitterionic materials for surface regeneration between switchable fouling and antifouling properties.

UNLABELLED: Development of smart regenerative surface is a highly challenging but important task for many scientific and industrial applications. Specifically, very limited research efforts were made for surface regeneration between bio-adhesion and antifouling properties, because bioadhesion and antifouling are the two highly desirable but completely opposite properties of materials. Herein, we developed salt-responsive polymer brushes of poly(3-(1-(4-vinylbenzyl)-1H-imidazol-3-ium-3-yl) propane-1-sulfonate) (polyVBIPS), which can be switched reversibly and repeatedly between protein capture/release and surface wettability in a controllable manner. PolyVBIPS brush has demonstrated its switching ability to resist both protein adsorption from 100% blood plasma/serum and bacterial attachment in multiple cycles. PolyVBIPS brush also exhibits reversible surface wettability from ∼40° to 25° between in PBS and in 1M NaCl solutions in multiple cycles. Overall, the salt-responsive behaviors of polyVBIPS brushes can be interpreted by the "anti-polyelectrolyte effect", i.e. polyVBIPS brushes adopt a collapsed chain conformation at low ionic strengths to achieve surface adhesive, but an extended chain conformation at high ionic strength to realize antifouling properties. We expect that polyVBIPS will provide a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, and regenerative properties. STATEMENT OF SIGNIFICANCE: Unlike many materials with "one-time switching" capability for surface regeneration, we developed a new regenerative surface of zwitterionic polymer brush, which exhibits a reversible salt-induced switching property between a biomolecule-adhesive state and a biomolecule repellent state in complex media for multiple cycles. PolyVBIPS is easily synthesized and can be straightforward coated on the surface, which provides a simple, robust, and promising system for the fabrication of smart surfaces with biocompatible, reliable, regenerative properties.

A comparative study of the mechanical properties of hybrid double-network hydrogels in swollen and as-prepared states.

Significant efforts have been made to develop highly tough hydrogels towards many scientific and industrial applications. However, most of the as-prepared tough hydrogels lose their mechanical strength and toughness when they swell in aqueous solution. Current knowledge about the swelling-induced mechanical property changes mainly stems from single-network (SN) hydrogels and chemically linked double-network (DN) hydrogels, but little is known about the swelling mechanical properties of hybrid physically-chemically linked DN gels. Here, we synthesized hybrid agar/PAM DN hydrogels combining a physically cross-linked first network of agar and a covalently cross-linked second network of polyacrylamide (PAM), with particular attention paid to the relationship between the swelling and mechanical properties of the hydrogels. The optimal agar/PAM DN gels achieved a tensile stress of ∼1.0 MPa and a toughness of ∼3988 J m-2 in the as-prepared state and a tensile stress of 1.4 MPa and a toughness of ∼3960 J m-2 in the swollen state. The agar/PAM DN gels can readily achieve swelling ratios in the range of ∼1.3-3.6 by adjusting the concentrations of the first network, the second network, and the crosslinker. The swelling capacity of the agar/PAM DN gels was balanced by the competition between the "non-swellable" agar network and the "highly swellable" PAM network, indicating that the first and second networks play different roles in the swelling-induced mechanical properties of the agar/PAM gels. Based on a comparison of the tearing and tensile behaviors of the hybrid DN gels between both as-prepared and swollen gels, we proposed a swelling-induced fracture mechanism that is different from those of SN and chemically-linked DN hydrogels. This work not only demonstrates a very tough swollen DN gel with a hybrid network, but also provides a better understanding of the swelling characteristics of hybrid DN gels, which hopefully helps to offer some valuable insights into the development of next-generation tough hydrogel materials in both as-prepared and swollen states.

Polymorphic cross-seeding amyloid assemblies of amyloid-ß and human islet amyloid polypeptide.

Epidemiological studies have shown that the development of Alzheimer's disease (AD) is associated with type 2 diabetes (T2D), but it still remains unclear how AD and T2D are connected. Heterologous cross-seeding between the causative peptides of Aß and hIAPP may represent a molecular link between AD and T2D. Here, we computationally modeled and simulated a series of cross-seeding double-layer assemblies formed by Aß and hIAPP peptides using all-atom and coarse-gained molecular dynamics (MD) simulations. The cross-seeding Aß-hIAPP assemblies showed a wide range of polymorphic structures via a combination of four ß-sheet-to-ß-sheet interfaces and two packing orientations, focusing on a comparison of different matches of ß-sheet layers. Two cross-seeding Aß-hIAPP assemblies with different interfacial ß-sheet packings exhibited high structural stability and favorable interfacial interactions in both oligomeric and fibrillar states. Both Aß-hIAPP assemblies displayed interfacial dehydration to different extents, which in turn promoted Aß-hIAPP association depending on interfacial polarity and geometry. Furthermore, computational mutagenesis studies revealed that disruption of interfacial salt bridges largely disfavor the ß-sheet-to-ß-sheet association, highlighting the importance of salt bridges in the formation of cross-seeding assemblies. This work provides atomic-level information on the cross-seeding interactions between Aß and hIAPP, which may be involved in the interplay between these two disorders.

Cross-Seeding Interaction between ß-Amyloid and Human Islet Amyloid Polypeptide.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are two common protein misfolding diseases. Increasing evidence suggests that these two diseases may be correlated with each other via cross-sequence interactions between ß-amyloid peptide (Aß) associated with AD and human islet amyloid polypeptide (hIAPP) associated with T2D. However, little is known about how these two peptides work and how they interact with each other to induce amyloidogenesis. In this work, we study the effect of cross-sequence interactions between Aß and hIAPP peptides on hybrid amyloid structures, conformational changes, and aggregation kinetics using combined experimental and simulation approaches. Experimental results confirm that Aß and hIAPP can interact with each other to aggregate into hybrid amyloid fibrils containing ß-sheet-rich structures morphologically similar to pure Aß and hIAPP. The cross-seeding of Aß and hIAPP leads to the coexistence of both a retarded process at the initial nucleation stage and an accelerated process at the fibrillization stage, in conjunction with a conformational transition from random structures to α-helix to ß-sheet. Further molecular dynamics simulations reveal that Aß and hIAPP oligomers can efficiently cross-seed each other via the association of two highly similar U-shaped ß-sheet structures; thus, conformational compatibility between Aß and hIAPP aggregates appears to play a key role in determining barriers to cross-seeding. The cross-seeding effects in this work may provide new insights into the molecular mechanisms of interactions between AD and T2D.

Polymorphic Associations and Structures of the Cross-Seeding of Aß1-42 and hIAPP1-37 Polypeptides.

Emerging evidence have shown that the patients with Alzheimer's disease (AD) often have a higher risk of later developing type II diabetes (T2D), and vice versa, suggesting a potential pathological link between AD and T2D. Amyloid-ß (Aß) and human islet amyloid polypeptide (hIAPP) are the principle causative components responsible for the pathologies of AD and T2D, respectively. The cross-sequence interactions between Aß and hIAPP may provide a molecular basis for better understanding the potential link between AD and T2D. Herein, we systematically modeled and simulated the cross-sequence aggregation process, molecular interactions, and polymorphic structures of full-length Aß and hIAPP peptides using a combination of coarse-grained (CG) replica-exchange molecular dynamics (REMD) and all-atom molecular dynamics (MD) simulations, with particular focus on the effect of association models between Aß and hIAPP on the structural stability and polymorphic populations of hybrid Aß-hIAPP aggregates. Four distinct association models (double-layer, elongation, tail-tail, and block models) between Aß and hIAPP oligomers were identified, and the associated polymorphic Aß-hIAPP structures were determined as well. Among them, different association models led to different Aß-hIAPP aggregates, with large differences in structural morphologies and populations, interacting interfaces, and underlying association forces. The computational models support the cross-sequence interactions between Aß and hIAPP pentamers, which would lead to the complex hybrid Aß-hIAPP assemblies. This computational work may also provide a different point of view to a better understanding of a potential link between AD and T2D.

Enhanced Thermoelectric Properties of Poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) by Binary Secondary Dopants.

To simultaneously increase the electrical conductivity and Seebeck coefficient of poly(3,4-ethylenedioxythiophene):polystyrenesulfonate ( PEDOT: PSS) was a challenge for realizing efficient organic thermoelectrics. In this study, for the first time, we report both increased electrical conductivities and Seebeck coefficients, hence, enhanced thermoelectric properties of PEDOT: PSS thin films by doped with binary secondary dopants, dimethyl sulfoxide (DMSO) and poly(ethylene oxide) (PEO). Without modifying film morphology, the molar ratios of PEDOT to PSS are tuned by PEO, resulting in increased proportions of PEDOT in the bipolaron states. Our study provides a facile route to optimizing thermoelectric properties of PEDOT: PSS thin films.

Interfacial interaction and lateral association of cross-seeding assemblies between hIAPP and rIAPP oligomers.

Cross-sequence interactions between different amyloid peptides are important not only for the fundamental understanding of amyloid aggregation and polymorphism mechanisms, but also for probing a potential molecular link between different amyloid diseases. Here, we computationally modeled and simulated a series of hybrid hIAPP (human islet amyloid polypeptide)-rIAPP (rat islet amyloid polypeptide) assemblies and probed their structural stability, lateral association, and interfacial interactions using combined peptide-packing search, molecular dynamics (MD) simulations, and the Monte Carlo sampling method. We then identified a number of stable and highly populated hIAPP-rIAPP assemblies at the lowest energy states, in which hIAPP and rIAPP oligomers were stacked laterally on top of each other to form supramolecular ß-sheet double layers in an antiparallel fashion. These hIAPP-rIAPP assemblies adopted different interfaces formed by C-terminal ß-sheets of hIAPP and rIAPP oligomers (hCCr), N-terminal ß-sheets of hIAPP and rIAPP oligomers (hNNr), and alternative N-terminal/C-terminal ß-sheets of hIAPP and rIAPP oligomers (hNCr and hCNr). Different interfaces along with distinct interfacial residue packings provided different driving interfacial forces to laterally associate two ß-sheet layers of hIAPP and rIAPP together for forming polymorphic hIAPP-rIAPP assemblies. Such lateral association between hIAPP and rIAPP not only explained the experimentally observed cross-seeding behavior of hIAPP and rIAPP, but also demonstrated the co-existence of polymorphic amyloid cross-seeding species. A cross-seeding mechanism for hIAPP and rIAPP aggregation was proposed on the basis of our simulated models and experimental data. This work provides a better understanding of cross-seeding aggregation and polymorphism mechanisms of amyloidogenesis.

Mechanically strong hybrid double network hydrogels with antifouling properties.

The development of mechanically tough and biocompatible polymer hydrogels has great potential and promise for many applications. Herein, we synthesized a new type of hybrid physically-chemically crosslinked Agar/PAM double network (DN) hydrogel using a simple, one-pot method. Agar/PAM gels are designed with desirable/balanced mechanical properties by varying the network-forming parameters. Among them, a strong Agar/PAM DN gel achieves the highest tensile stress of 3.3 MPa at failure strain of 2400%, while a tough DN gel achieves the tensile strain of 3700% at failure stress of 2.8 MPa. Besides excellent mechanical properties, Agar/PAM DN hydrogels exhibited excellent antifouling properties to highly resist protein adsorption, cell adhesion, and bacterial attachment, as well as the free shapeable property to form any complex shapes. The relationship between mechanical properties and antifouling performance was discussed. We hope that the combination of the mechanical and antifouling properties in Agar/PAM gels will make them as promising "biomimetic" materials for many bio-inert applications.

Synthesis and characterization of antifouling poly(N-acryloylaminoethoxyethanol) with ultralow protein adsorption and cell attachment.

Rational design of effective antifouling polymers is challenging but important for many fundamental and applied applications. Herein we synthesize and characterize an N-acryloylaminoethoxyethanol (AAEE) monomer, which integrates three hydrophilic groups of hydroxyl, amide, and ethylene glycol in the same material. AAEE monomers were further grafted and polymerized on gold substrates to form polyAAEE brushes with well-controlled thickness via surface-initiated atomic transfer radical polymerization (SI-ATRP), with particular attention to a better understanding of the molecular structure-antifouling property relationship of hydroxyl-acrylic-based polymers. The surface hydrophilicity and antifouling properties of polyAAEE brushes as a function of film thickness are studied by combined experimental and computational methods including surface plasmon resonance (SPR) sensors, atomic force microscopy (AFM), cell adhesion assay, and molecular dynamics (MD) simulations. With the optimal polymer film thicknesses (∼10-40 nm), polyAAEE-grafted surfaces can effectively resist protein adsorption from single-protein solutions and undiluted human blood plasma and serum to a nonfouling level (i.e., <0.3 ng/cm(2)). The polyAAEE brushes also highly resist mammalian cell attachment up to 3 days. MD simulations confirm that the integration of three hydrophilic groups induce a stronger and closer hydration layer around polyAAEE, revealing a positive relationship between surface hydration and antifouling properties. The molecular structure-antifouling properties relationship of a series of hydroxyl-acrylic-based polymers is also discussed. This work hopefully provides a promising structural motif for the design of new effective antifouling materials beyond traditional ethylene glycol-based antifouling materials.

Structural and energetic insight into the cross-seeding amyloid assemblies of human IAPP and rat IAPP.

The misfolding and aggregation of human islet amyloid polypeptide (hIAPP or amylin) into small oligomers and large amyloid fibrils is believed to be responsible for the dysfunction and death of pancreatic ß-cells in diabetes type II. However, rat IAPP (rIAPP), which differs from the hIAPP by only 6 of 37 residues, lacks the ability to form amyloid fibrils and to induce cell death. Little is known about the cross-sequence interactions and cross-seeding structures between hIAPP and rIAPP peptides. Herein using explicit-solvent molecular dynamics (MD) simulations, we modeled and simulated different heteroassemblies formed by the amyloidogenic hIAPP and the nonamyloidogenic rIAPP peptides. Simulations showed that the U-shaped hIAPP monomer and oligomers can interact with conformationally similar rIAPP to form stable complexes and to coassemble into heterogeneous structures. Stable heterointeractions between hIAPP and rIAPP were shown to arise from hydrophobic contacts and hydrogen bonds at the interface, particularly at N- and C-terminal ß-sheet regions. Because of the enhanced interpeptide interactions at the interface, upon binding to hIAPP oligomers, the ß-sheet population of rIAPP was greatly increased as compared to that of rIAPP alone. More importantly, the conformational energies of rIAPP monomers at the bound state were observed to be consistently higher than those of rIAPP monomers at the unbound state. However, rIAPP monomers enable one to adopt different conformations and follow different pathways for associating with hIAPP from the high energy of the bound state to the low energy of the unbound state, without encountering any large and abrupt energy barrier. In parallel, AFM study of cross-aggregation of hIAPP and rIAPP provided additional evidence that hIAPP can seed with rIAPP to form hybrid fibrils at all concentrations similar to pure hIAPP fibrils. This work demonstrates the existence of cross-interactions between the two different IAPP peptides, which provides an improved fundamental understanding of the cross-seeding of different amyloid sequences toward amyloid aggregation and toxicity mechanisms.