Influence of ALS-linked M337V mutation on the conformational ensembles of TDP-43321-340 peptide monomer and dimer.

The transactive response (TAR) DNA/RNA-binding protein 43 (TDP-43) can self-assemble into both functional stress granules via liquid-liquid phase separation (LLPS) and pathogenic amyloid fibrillary aggregates that are closely linked to amyotrophic lateral sclerosis. Previous experimental studies reported that the low complexity domain (LCD) of TDP-43 plays an essential role in the LLPS and aggregation of the full-length protein, and it alone can also undergo LLPS to form liquid droplets mainly via intermolecular interactions in the 321-340 region. And the ALS-associated M337V mutation impairs LCD's LLPS and facilitates liquid-solid phase transition. However, the underlying atomistic mechanism is not well understood. Herein, as a first step to understand the M337V-caused LLPS disruption of TDP-43 LCD mediated by the 321-340 region and the fibrillization enhancement, we investigated the conformational properties of monomer/dimer of TDP-43321-340 peptide and its M337V mutant by performing extensive all-atom explicit-solvent replica exchange molecular dynamic simulations. Our simulations demonstrate that M337V mutation alters the residue regions with high helix/ß-structure propensities and thus affects the conformational ensembles of both monomer and dimer. M337V mutation inhibits helix formation in the N-terminal Ala-rich region and the C-terminal mutation site region, while facilitating their long ß-sheet formation, albeit with a minor impact on the average probability of both helix structure and ß-structure. Further analysis of dimer system shows that M337V mutation disrupts inter-molecular helix-helix interactions and W334-W334 π-π stacking interactions which were reported to be important for the LLPS of TDP-43 LCD, whereas enhances the overall peptide residue-residue interactions and weakens peptide-water interactions, which is conducive to peptide fibrillization. This study provides mechanistic insights into the M337V-mutation-induced impairment of phase separation and facilitation of fibril formation of TDP-43 LCD.

Dissecting the Effect of ALS Mutation G335D on the Early Aggregation of the TDP-43 Amyloidogenic Core Peptide: Helix-to-ß-Sheet Transition and Conformational Shift.

The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is associated with amyotrophic lateral sclerosis (ALS). The 311-360 fragment of TDP-43 (TDP-43311-360), the amyloidogenic core region, can spontaneously aggregate into fibrils, and the ALS-associated mutation G335D has an enhanced effect on TDP-43311-360 fibrillization. However, the molecular mechanism underlying G335D-enhanced aggregation at atomic level remains largely unknown. By utilizing all-atom molecular dynamics (MD) and replica exchange with solute tempering 2 (REST2) simulations, we investigated influences of G335D on the dimerization (the first step of aggregation) and conformational ensemble of the TDP-43311-360 peptide. Our simulations show that G335D mutation increases inter-peptide interactions, especially inter-peptide hydrogen-bonding interactions in which the mutant site has a relatively large contribution, and enhances the dimerization of TDP-43311-360 peptides. The α-helix regions in the NMR-resolved conformation of the TDP-43311-360 monomer (321-330 and 335-343) play an essential role in the formation of the dimer. G335D mutation induces helix unfolding and promotes α-to-ß conversion. G335D mutation alters the conformational distribution of TDP-43311-360 dimers and causes population shift from helix-rich to ß-sheet-rich conformations, which facilitates the fibrillization of the TDP-43311-360 peptide. Our MD and REST2 simulation results suggest that the 321-330 region is of paramount importance to α-to-ß transition and could be the initiation site for TDP-43311-360 fibrillization. Our work reveals the mechanism underlying the enhanced aggregation propensity of the G335D TDP-43311-360 peptide, which provides atomistic insights into the G335D mutation-caused pathogenicity of TDP-43 protein.

Insights into the Atomistic Mechanisms of Phosphorylation in Disrupting Liquid-Liquid Phase Separation and Aggregation of the FUS Low-Complexity Domain.

Fused in sarcoma (FUS), a nuclear RNA binding protein, can not only undergo liquid-liquid phase separation (LLPS) to form dynamic biomolecular condensates but also aggregate into solid amyloid fibrils which are associated with the pathology of amyotrophic lateral sclerosis and frontotemporal lobar degeneration diseases. Phosphorylation in the FUS low-complexity domain (FUS-LC) inhibits FUS LLPS and aggregation. However, it remains largely elusive what are the underlying atomistic mechanisms of this inhibitory effect and whether phosphorylation can disrupt preformed FUS fibrils, reversing the FUS gel/solid phase toward the liquid phase. Herein, we systematically investigate the impacts of phosphorylation on the conformational ensemble of the FUS37-97 monomer and dimer and the structure of the FUS37-97 fibril by performing extensive all-atom molecular dynamics simulations. Our simulations reveal three key findings: (1) phosphorylation shifts the conformations of FUS37-97 from the ß-rich, fibril-competent state toward a helix-rich, fibril-incompetent state; (2) phosphorylation significantly weakens protein-protein interactions and enhances protein-water interactions, which disfavor FUS-LC LLPS as well as aggregation and facilitate the dissolution of the preformed FUS-LC fibril; and (3) the FUS37-97 peptide displays a high ß-strand probability in the region spanning residues 52-67, and phosphorylation at S54 and S61 residues located in this region is crucial for the disruption of LLPS and aggregation of FUS-LC. This study may pave the way for ameliorating phase-separation-related pathologies via site-specific phosphorylation.

Effects of the digital divide on the prevention of food risk in Taiwan.

Given the frequent occurrence of various food incidents, food safety is a significant public health concern worldwide. Health information plays an important role in risk prevention. As its reach continues to broaden, the Internet is emerging as a major source of health information for the public, although some social groups continue to have limited access. This study investigates the relation between the digital divide and practices for preventing food incidents in Taiwan. Using a nationally representative survey of 2098 adults, the results of our multinomial logistic regression and bootstrapped mediation analysis indicate the existence of second- and third-level digital divides. The association between socioeconomic status and Internet use time and digital skills results in disparities in food risk prevention behaviors and is partially mediated by online food safety information acquisition. Our findings reveal that the digital divide exacerbates health inequalities in food risk prevention. In addition to providing useful food safety information online, communication interventions should address the digital inequality by delivering food safety information through alternative networks for disadvantaged members of the public.

Molecular mechanisms of resveratrol and EGCG in the inhibition of Aß42 aggregation and disruption of Aß42 protofibril: similarities and differences.

The aggregation of amyloid-ß protein (Aß) into fibrillary deposits is implicated in Alzheimer's disease (AD), and inhibiting Aß aggregation and clearing Aß fibrils are considered as promising strategies to treat AD. It has been reported that resveratrol (RSV) and epigallocatechin-3-gallate (EGCG), two of the most extensively studied natural polyphenols, are able to inhibit Aß fibrillization and remodel the preformed fibrillary aggregates into amorphous, non-toxic species. However, the mechanisms by which RSV inhibits Aß42 aggregation and disrupts Aß42 protofibril, as well as the inhibitory/disruptive mechanistic similarities and differences between RSV and EGCG, remain mostly elusive. Herein, we performed extensive all-atom molecular dynamics (MD) simulations on Aß42 dimers (the early aggregation state of Aß42) and protofibrils (the intermediate of Aß42 fibril formation and elongation) in the absence/presence of RSV or EGCG molecules. Our simulations show that both RSV and EGCG can bind with Aß42 monomers and inhibit the dimerization of Aß42. The binding of RSV with Aß42 peptide is mostly viaπ-π stacking interactions, while the binding of EGCG with Aß42 is mainly through hydrophobic, π-π stacking, and hydrogen-bonding interactions. Moreover, both RSV and EGCG disrupt the ß-sheet structure and K28-A42 salt bridges, leading to a disruption of Aß42 protofibril structure. RSV mainly binds with residues whose side-chains point inwards from the surface of the protofibril, while EGCG mostly binds with residues whose side-chains point outwards from the surface of the protofibril. Furthermore, RSV interacts with Aß42 protofibrils mostly viaπ-π stacking interactions, while EGCG interacts with Aß42 protofibrils mainly via hydrogen-bonding and hydrophobic interactions. For comparison, we also explore the effects of RSV/EGCG molecules on the aggregation inhibition and protofibril disruption of the Iowa mutant (D23N) Aß. Our findings may pave the way for the design of more effective drug candidates as well as the utilization of cocktail therapy using RSV and EGCG for the treatment of AD.

Heparin remodels the microtubule-binding repeat R3 of Tau protein towards fibril-prone conformations.

Abnormal aggregation of proteins into pathological amyloid fibrils is implicated in a wide range of devastating human neurodegenerative diseases. Intracellular fibrillary inclusions formed by Tau protein are characterized as the hallmark of tauopathies, including Alzheimer's disease and frontotemporal dementia. Heparin has been often used to trigger Tau aggregation in in vitro studies. However, the conformational changes induced by heparin and the underlying mechanism of promotion of Tau aggregation by heparin are not well understood. Structural characterization of Tau oligomers in the early stage of fibrillation is of great importance but remains challenging due to their dynamic and heterogeneous nature. R3, the third microtubule-binding repeat of Tau, contains the fibril-nucleating core (PHF6) and is crucial for Tau aggregation. In this study, utilizing extensive all-atom replica-exchange molecular dynamic simulations, we explored the conformational ensembles of R3 monomer/dimer in the absence and presence of heparin. Our results show that without heparin, both monomeric and dimeric R3 preferentially adopt collapsed ß-sheet-containing conformations and PHF6 plays an important role in the formation of interchain ß-sheet structures, while in the presence of heparin, R3 can populate relatively extended disordered states where chain dimension is similar to that of R3 in Tau filaments. Through electrostatic, hydrogen-bonding and hydrophobic interactions, heparin has a preference for interacting with residues V306/Q307/K317/K321/H329/H330/K331 which distribute throughout the entire sequence of R3, in turn acting as a template to extend R3 conformations. More importantly, heparin alters intramolecular/intermolecular interaction patterns of R3 and increases the intermolecular contact regions. Our results suggest that heparin remodels the conformations of R3 towards fibril-prone structures by increasing chain dimension and intermolecular contact regions, which may shed light on the atomic mechanism of heparin-induced amyloid fibrillization of Tau protein.

Asparagine Availability Is a Critical Limiting Factor for Infectious Spleen and Kidney Necrosis Virus Replication.

Infectious spleen and kidney necrosis virus (ISKNV) has brought huge economic loss to the aquaculture industry. Through interfering with the viral replication and proliferation process that depends on host cells, its pathogenicity can be effectively reduced. In this study, we investigated the role of asparagine metabolites in ISKNV proliferation. The results showed that ISKNV infection up-regulated the expression of some key enzymes of the asparagine metabolic pathway in Chinese perch brain (CPB) cells. These key enzymes, including glutamic oxaloacetic transaminase 1/2 (GOT1/2) and malate dehydrogenase1/2 (MDH1/2) associated with the malate-aspartate shuttle (MAS) pathway and asparagine synthetase (ASNS) involved in the asparagine biosynthesis pathway, were up-regulated during ISKNV replication and release stages. In addition, results showed that the production of ISKNV was significantly reduced by inhibiting the MAS pathway or reducing the expression of ASNS by 1.3-fold and 0.6-fold, respectively, indicating that asparagine was a critical limiting metabolite for ISKNV protein synthesis. Furthermore, when asparagine was added to the medium without glutamine, ISKNV copy number was restored to 92% of that in the complete medium, indicating that ISKNV could be fully rescued from the absence of glutamine by supplementing asparagine. The above results indicated that asparagine was a critical factor in limiting the effective replication of ISKNV, which provided a new idea for the treatment of aquatic viral diseases.

ALS-Linked A315T and A315E Mutations Enhance ß-Barrel Formation of the TDP-43307-319 Hexamer: A REST2 Simulation Study.

Pathogenic mutations of transactivation response element DNA-binding protein 43 (TDP-43) are closely linked with amyotrophic lateral sclerosis (ALS). It was recently reported that two ALS-linked familial mutants A315T and A315E of TDP-43307-319 peptides can self-assemble into oligomers including tetramers, hexamers, and octamers, among which hexamers were suggested to form the ß-barrel structure. However, due to the transient nature of oligomers, their conformational properties and the atomic mechanisms underlying the ß-barrel formation remain largely elusive. Herein, we investigated the hexameric conformational distributions of the wild-type (WT) TDP-43307-319 fragment and its A315T and A315E mutants by performing all-atom explicit-solvent replica exchange with solute tempering 2 simulations. Our simulations reveal that each peptide can self-assemble into diverse conformations including ordered ß-barrels, bilayer ß-sheets and/or monolayer ß-sheets, and disordered complexes. A315T and A315E mutants display higher propensity to form ß-barrel structures than the WT, which provides atomic explanation for their enhanced neurotoxicity reported previously. Detailed interaction analysis shows that A315T and A315E mutations increase inter-molecular interactions. Also, the ß-barrel structures formed by the three different peptides are stabilized by distinct inter-peptide side-chain hydrogen bonding, hydrophobic, and aromatic stacking interactions. This study demonstrates the enhanced ß-barrel formation of the TDP-43307-319 hexamer by the pathogenic A315T and A315E mutations and reveals the underlying molecular determinants, which may be helpful for in-depth understanding of the ALS-mutation-induced neurotoxicity of TDP-43 protein.

Breast Density Should Play a Greater Role in MRI Screening Guidelines.

Guidelines for breast cancer screening with MRI were first proposed in 2007, only a few years after its clinical introduction. Those initial guidelines, which were generated by a committee sponsored by the American Cancer Society (ACS), have served as the template for similar recommendations by several organizations, with a singular goal regarding patient candidacy for MRI screening, a qualifying threshold based on risk stratification. Higher risk in those patients recommended for MRI screening translates to higher cancer detection rates, which in turn impacts cost-effectiveness. But there is another variable that should be as important as risk stratification in selecting patients for MRI screening: the probability that screening mammography will fail to detect developing cancer. That failure rate is a function of breast density, included in the MRI screening guidelines as a traditional risk factor but neglected when one considers its role as the primary cause of false-negative mammograms. The two implications of dense mammograms are essentially independent: (1) refining risk stratification and (2) predicting the "miss rate" of mammography. In the 2007 guidelines, indications for annual screening MRI, in addition to mammography, were based on patients having a calculated probability of "greater than 20-25% lifetime risk" for developing breast cancer. Other categorical risks, such as BRCA positivity, are listed in the ACS guidelines, but in effect, the threshold for adding MRI to the screening regimen has been a 20% lifetime risk for the development of breast cancer. While risk stratification in the original MRI screening guidelines had a number of inconsistencies, the focus herein is the questionable placement of high-density patients into the category described as "no policy for or against MRI, more research needed," a category where lifetime risks were grouped as 15-19%. Thus, mammographic density was relegated to its role as a traditional risk factor, while its potentially more significant impact, predicting the "miss rate" of mammography, had no role in patient selection for screening MRI. The 2007 ACS guideline committee was limited by the lack of available data, and since there was no evidence for mortality reduction at the time, the decision was made to follow the patient selection criteria that had been used in the six international MRI screening trials, even though there was little consistency among those trials. Since then, the number of screening MRI trials has more than doubled, and new trials are being designed and implemented with a focus on both features of density: risk and cancer camouflage. Enough evidence has accumulated during the 16 years subsequent to the original ACS high-risk screening guidelines to consider a complete revision that accounts for both numerical risk levels and density levels, much like what was used in the ACRIN 6666 trial. In establishing a new set of guidelines, our first question should be: What is the "miss rate" of mammography in this patient? If the chance of a false-negative mammogram is as high as we see with Level D density, then the decision to include MRI becomes straightforward. The traditional risk assessment would then be used to help determine the optimal interval between MRI screens while maintaining cost-effective cancer detection rates.

SnS2/MWNTs/sponge electrode combined with plasma dielectric barrier discharge catalytic system: CO2 reduction and pollutant degradation.

SnS2 nanosheets combined with multi-walled carbon nanotubes (MWNTs) were made into sponge electrodes which were used for CO2 reduction reaction (CO2RR) in dielectric barrier discharges (DBD) system. The amounts of formate and formaldehyde produced by CO2 reduction with SnS2/MWNTs/sponge electrode were 299.52 and 31.62 µmol h-1, which were higher than that of MWNTs/sponge electrodes. The addition of pollutants had different degrees of inhibitory effect on CO2 reduction, among which addition of bisphenol A (BPA) had the smallest effect that the degradation rate of BPA was 94.37% and the C1 products remained 204.43 µmol after 60 min discharge. The mechanism of CO2RR was studied by quencher experiment, and the main contribution order of the active substance in DBD system for CO2RR is: H+>e->·OH>·O2-. It was found that the degradation process of pollutants consumed H+ and e- in solution, thereby inhibiting CO2RR. Generally, the SnS2/MWNTs/sponge electrode provided a reference for the design of catalysts for CO2 reduction and pollutant degradation in plasma gas-liquid system.

Role of asparagine biosynthesis pathway in Siniperca chuatsi rhabdovirus proliferation.

Viruses are non-living organisms that rely on host cellular metabolism to complete their life cycle. Siniperca chuatsi rhabdovirus (SCRV) has caused huge economic losses to the Chinese perch (Siniperca chuatsi) industry worldwide. SCRV replication is dependent on the cellular glutamine metabolism, while aspartate metabolism plays an important role in viral proliferation in glutamine deficiency. Herein, we investigated roles of asparagine metabolism in SCRV proliferation. Results showed that SCRV infection upregulated the expression of key enzymes in the aspartate metabolic pathway in CPB cells. And the key enzymes of malate-aspartic acid shuttle pathway upregulated during the virus invasion phase, and key enzymes of the asparagine biosynthesis pathway upregulated during the viral replication and release phase. When asparagine was added to the depleted medium, the SCRV copy number restored to 90% of those in replete medium, showing that asparagine and glutamine completely rescue the replication of SCRV. Moreover, inhibition of the aspartate- malate shuttle pathway and knockdown of the expression of key enzymes in the asparagine biosynthesis pathway significantly reduced SCRV production, indicating that the aspartic acid metabolic pathway was required to the replication and proliferation of SCRV. Above results provided references for elucidating pathogenic mechanism of SCRV by regulation of aspartate metabolism.

CQDs improved the photoelectrocatalytic performance of plasma assembled WO3/TiO2-NRs for bisphenol A degradation.

Carbon quantum dots (CQDs) have been supported on WO3/TiO2-NRs using a hydrothermal method and a novel CQDs/WO3/TiO2-NRs composite formed via dielectric barrier discharge. The composite electrodes were characterized using morphology, structural, optical and electrochemical analysis. The CQDs were successfully prepared on the composite electrode with the highest photocurrent density reaching 2.51 mA·cm-2 under UV-visible light irradiation (100 mW·cm-2) and an applied voltage of 0.6 V vs. Ag/AgCl. The CQDs/WO3/TiO2-NRs electrode exhibited a good degradation effect toward bisphenol A (BPA) (75.66 %) combined with the production of hydrogen (0.89 mmol) in Na2SO4 system after 2 h of the photoelectrocatalytic (PEC) reaction and the BPA degradation rate reached 100 % after 7 min of reaction in both simulated and real seawater. The CQDs/WO3/TiO2-NRs exhibited excellent stability and efficient PEC performance in which the CQDs acted as electron reservoirs to capture and promote charge separation. Our analysis of intermediates of BPA degradation indicated the possible degradation pathways that mainly formed BPA polymers in the Na2SO4 system or chlorinated compounds in the high chloride salt system.

Social Network Influence on Syphilis Testing for Black Sexual Minority Men in Baltimore, Maryland: A Cross-sectional Social Network Analysis.

ABSTRACT: Black sexual minority men (BSMM), including those with HIV, have disproportionate rates of syphilis infection. This study examines the associations of social network characteristics on syphilis testing, given that social network approaches are well established as effective methods to establish health-promoting social norms. We analyzed baseline data from a sexual health behavioral intervention. Using multivariable logistic regression, we modeled individual and social network characteristics on syphilis testing. Of the 256 participants, 37% tested for syphilis in the past year. In the adjusted model controlling for individual factors, odds of syphilis testing increased 89% for each increase in network member participants being encouraged to get a syphilis test (95% confidence interval [1.19-3.00]). Feeling comfortable accompanying a friend for HIV/sexually transmitted infection testing was associated with 2.47 increased odds of syphilis testing. Encouraging and training individuals to discuss sexual health topics with their network members may lead to the establishment of testing in social networks of Black sexual minority men.

Atomistic Insights into A315E Mutation-Enhanced Pathogenicity of TDP-43 Core Fibrils.

The aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) into fibrillary deposits is implicated in amyotrophic lateral sclerosis (ALS), and some hereditary mutations localized in the low complexity domain (LCD) facilitate the formation of pathogenic TDP-43 fibrils. A recent cryo-EM study reported the atomic-level structures of the A315E TDP-43 LCD (residues 288-319, TDP-43288-319) core fibril in which the protofilaments have R-shaped structures and hypothesized that A315E U-shaped protofilaments can readily convert to R-shaped protofilaments compared to the wild-type (WT) ones. There are no atomic structures of WT protofilaments available yet. Herein, we performed extensive all-atom explicit-solvent molecular dynamics simulations on A315E and WT protofilaments starting from both the cryo-EM-determined R-shaped and our constructed U-shaped structures. Our simulations show that WT protofilaments also adopt the R-shaped structures but are less stable than their A315E counterparts. Except for R293-E315 salt bridges, N312-F316 hydrophobic interactions and F316-F316 π-π stacking interactions are also crucial for the stabilization of the neck region of the R-shaped A315E protofilaments. The loss of R293-E315 salt bridges and the weakened interactions of N312-F316 and F316-F316 result in the reduced stability of the R-shaped WT protofilaments. Simulations starting from U-shaped folds reveal that A315E protofilaments can spontaneously convert to the cryo-EM-derived R-shaped protofilaments, whereas WT protofilaments convert to R-shape-like structures with remodeled neck regions. The R-shape-like WT protofilaments could act as intermediate states slowing down the U-to-R transition. This study reveals that A315E mutation can not only enhance the structural stability of the R-shaped TDP-43288-319 protofilaments but also promote the U-to-R transition, which provides atomistic insights into the A315E mutation-enhanced TDP-43 pathogenicity in ALS.

Healing transgender women of color in Los Angeles: A transgender-centric delivery of Seeking Safety.

Background: Transgender women of Color experience disproportionate rates of HIV, depression, and anxiety, and high rates of substance use, attempted suicide, and interpersonal verbal, physical, and sexual violence and assault. However, there are few interventions targeting transgender women of Color that address overlapping health and mental health challenges. Aims: There are two aims/research questions: (1) what are the elements of a transgender-centric model for delivering evidence based interventions and practices?, and (2) does Seeking Safety improve substance use and mental health outcomes for transgender women of Color? Methods: We present a case study of the delivery process of Seeking Safety by Special Service for Groups/Asian Pacific AIDS Intervention Team (SSG/APAIT), and analyze baseline and three month post program participant data (n = 81). Results: The transgender-centric model of intervention delivery consisted of multiple steps, also integrating the structural disadvantages experienced by transgender women of Color. Comparing baseline and three months after completion showed significant decrease in reported alcohol use, depression, and severe anxiety. Discussion: Transgender-centric approaches may lead to programs that significantly improve co-occurring substance use and mental health for transgender women of Color. We recommend that organizations aiming to existing programs include feedback from members of the communities that the adapted programs aim to help, and in addition, train community members to deliver the programs. The statistical results indicate that Seeking Safety, a trauma-based program with a short program delivery timeline, may show longer term effects on substance use and mental health. We recommend that programs targeting substance use and mental health for transgender women of Color should be combined with services that address disadvantage (i.e., lack of access to housing, income/employment, health care).

Promoting the reduction of CO2 to formate and formaldehyde via gas-liquid interface dielectric barrier discharge using a Zn0.5Cd0.5S/CoP/multiwalled carbon nanotubes catalyst.

A Zn0.5Cd0.5S (ZCS) solid solution was prepared using a hydrothermal method, in which CoP nanowires were added as a co-catalyst and co-deposited with multiwalled carbon nanotubes (MWNTs) on sponge to prepare a series of ZCS/CoP/MWNTs/sponge electrodes. The microstructures of catalysts were analyzed to confirm ZCS and CoP were successfully loaded in MWNTs/sponge. The CO2 reduction products (formate and formaldehyde) produced via dielectric barrier discharge (DBD) using the different catalysts proved that the introduction of the CoP nanowires co-catalyst can enhance the catalytic activity of ZCS/MWNTs/sponge in the DBD system. Using 10% CoP and a ZCS/CoP concentration of 2.5 g·L-1, the resulting ZCS/CoP/MWNTs/sponge catalyst exhibited the best catalytic of CO2 reduction ability toward formate (7894.6 µmol·L-1) and formaldehyde (308.5 µmol·L-1) after 60 min of discharge, respectively. The proposed DBD catalytic mechanism for the reduction of CO2 was analyzed according to the Tafel slope, density functional theory calculations, photocurrent density and plasma reaction process. Furthermore, the application of the DBD catalytic technology for CO2 capture and reduction was shown to be efficient in a seawater system, and as such, it could be useful for marine CO2 storage and conversion.

A Comprehensive Insight into the Mechanisms of Dopamine in Disrupting Aß Protofibrils and Inhibiting Aß Aggregation.

Fibrillary aggregates of amyloid-ß (Aß) are the pathological hallmark of Alzheimer's disease (AD). Clearing Aß deposition or inhibiting Aß aggregation is a promising approach to treat AD. Experimental studies reported that dopamine (DA), an important neurotransmitter, can inhibit Aß aggregation and disrupt Aß fibrils in a dose-dependent manner. However, the underlying molecular mechanisms still remain mostly elusive. Herein, we investigated the effect of DA on Aß42 protofibrils at three different DA-to-Aß molar ratios (1:1, 2:1, and 10:1) using all-atom molecular dynamics simulations. Our simulations demonstrate that protonated DA at a DA-to-Aß ratio of 2:1 exhibits stronger Aß protofibril disruptive capacity than that at a molar-ratio of 1:1 by mostly disrupting the F4-L34-V36 hydrophobic core. When the ratio of DA-to-Aß increases to 10:1, DA has a high probability to bind to the outer surface of protofibril and has negligible effect on the protofibril structure. Interestingly, at the same DA-to-Aß ratio (10:1), a mixture of protonated (DA+) and deprotonated (DA0) DA molecules significantly disrupts Aß protofibrils by the binding of DA0 to the F4-L34-V36 hydrophobic core. Replica-exchange molecular dynamics simulations of Aß42 dimer show that DA+ inhibits the formation of ß-sheets, K28-A42/K28-D23 salt-bridges, and interpeptide hydrophobic interactions and results in disordered coil-rich Aß dimers, which would inhibit the subsequent fibrillization of Aß. Further analyses reveal that DA disrupts Aß protofibril and prevents Aß dimerization mostly through π-π stacking interactions with residues F4, H6, and H13, hydrogen bonding interactions with negatively charged residues D7, E11, E22 and D23, and cation-π interactions with residues R5. This study provides a complete picture of the molecular mechanisms of DA in disrupting Aß protofibril and inhibiting Aß aggregation, which could be helpful for the design of potent drug candidates for the treatment/intervention of AD.

Feasibility of Breast MRI as the Primary Imaging Modality in a Large Asian Cohort.

Purpose Contrast-enhanced MRI has repeatedly demonstrated significantly enhanced sensitivity compared to mammography and ultrasound in breast cancer detection. The purpose of this study was to evaluate the feasibility and outcomes of using breast MRI as the initial imaging study for screening and diagnosis.  Materials and methods In this retrospective review of a cohort of 10,374 breast MRI scans in 7967 patients in Taitung County, Taiwan, a total of 5619 participants met inclusion criteria and were included in our analysis. We reviewed all biopsies that were performed subsequent to MRI studies in women (screening vs. diagnostic). The primary outcomes were false-positive (FP) biopsy rates and positive predictive value (PPV) of MRI - parameters that have historically been associated with performance that restricts more widespread use of MRI. False-positive rate based on benign biopsies (FPR-3) and the positive predictive value (PPV-3) were calculated. Results Without complementary imaging or follow-up to identify false negatives, the study of performance characteristics was limited to false positives and PPV. There were 351 benign biopsies generated by MRI out of the cohort of 5555 participants (5619 minus the malignant biopsies), generating a false-positive rate of 6.3%. Sixty-four patients out of 415 biopsies were malignant, generating a PPV-3 of 15.4%. Conclusion In this Asian cohort, utilizing breast MRI as the initial study for screening and/or diagnosis appears to be limited more by practical considerations such as cost and patient flow efficiency than by feasibility based on performance characteristics. With well-established superior sensitivity, coupled with improved interpretive skills and techniques that allow for low false-positive rates, MRI should be further studied for its role as the primary imaging modality in breast screening and diagnosis.

Multilayer Nanofiber Composite Separator for Lithium-Ion Batteries with High Safety.

An original Von Koch curve-shaped tipped electrospinneret was used to prepare a polyimide (PI)-based nanofiber membrane. A multilayer Al2O3@polyimide/polyethylene/Al2O3@polyimide (APEAP) composite membrane was tactfully designed with an Al2O3@ polyimide (AP) membrane as outer shell, imparting high temperature to the thermal run-away separator performance and a core polyethylene (PE) layer imparts the separator with a thermal shut-down property at low temperature (123 °C). An AP electrospun nanofiber was obtained by doping Al2O3 nanoparticles in PI solution. The core polyethylene layer was prepared using polyethylene powder and polyterafluoroethylene (PTFE) miniemulsion through a coating process. The addition of PTFE not only bonds PE power, but also increases the adhesion force between the PE and AP membranes. As a result, the multilayer composite separator has high safety, outstanding electrochemical properties, and better cycling performance as a lithium-ion battery separator.

Self-Assembled Human Adipose-Derived Stem Cell-Derived Extracellular Vesicle-Functionalized Biotin-Doped Polypyrrole Titanium with Long-Term Stability and Potential Osteoinductive Ability.

Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs), containing proteins or microRNAs (miRNAs), possessing various biological activity and low immunogenicity, are considered promising for surface modification of bone grafts. However, the modification efficiency is not satisfied yet, resulting in compromised therapy effects. Here, we report a novel immobilized method by self-assembling biotinylated MSC-EVs onto the surface of biotin-doped polypyrrole titanium (Bio-Ppy-Ti) to improve its biofunctions in vitro and in vivo. Using this method, the amount of human adipose-derived stem cell-EVs (hASC-EVs) anchored onto the Bio-Ppy-Ti surface was 185-fold higher than that of pure Ti after ultrasonic concussion for 30 s and it remained stable on the Bio-Ppy-Ti surface for 14 days at 4 °C. Compared to pristine Ti, EV-Bio-Ppy-Ti exhibited enhanced cell compatibility and osteoinductivity for osteoblasts in vitro and anti-apoptosis ability in the ectopic bone formation mode. Gene chip analysis further demonstrated that several osteoinductive miRNAs were encapsulated in hASC-EVs, which may explain the high bone regeneration ability of EV-Bio-Ppy-Ti. Thus, this MSC-EV biotin-immobilized method appears to be highly efficient and long-term stable for bone graft bioactive modification, demonstrating its potential for clinical metal implants.