Pd(II)-Catalyzed Site-Selective Cross Coupling Reaction: Synthesis of Highly Fluorescent Aryl-Formyl-Chromenes and its Iminoantipyrine Analogues as Selective AChE Inhibitors.

A versatile and efficient chemo selective synthesis of 4-aryl-3-formyl-2H-chromenes (AFC) was undertaken using Pd-catalyzed cross-coupling conditions. The key oxidative transmetalation was successfully applied to a significant range of substitutions on the chromene moiety and aryl ring in Ar(BOH)3, accommodating both electron-rich and electron-deficient groups. These π-extended scaffolds exhibited green-yellow fluorescence with a large Stokes shift and high quantum yield. Measurement of photophysical properties revealed that the compound with methoxy substitution in the chromene ring, 3t, caused a significant bathochromic shift. The AFCs obtained from this method can be transformed into biologically active 4-aryl-3-iminoantipyrine-2H-chromenes (AAC) through functionalization of the formyl chromenes. The AFCs and AACs with methoxy substitutions (3t and 4e) were docked against AChE inhibition, and compound 4e had the lowest binding energy of -11.20 kcal/mol. DFT calculations performed on representative compounds revealed that compound 4e is more reactive than 3t, which is in accordance with the docking studies.

Enhanced FRER Mechanism in Time-Sensitive Networking for Reliable Edge Computing.

Time-Sensitive Networking (TSN) and edge computing are promising networking technologies for the future of the Industrial Internet. TSN provides a reliable and deterministic low-latency communication service for edge computing. The Frame Replication and Elimination for Reliability (FRER) mechanism is important for improving the network reliability of TSN. It achieves high reliability by transmitting identical frames in parallel on two disjoint paths, while eliminating duplicated frames at the destination node. However, there are two problems with the FRER mechanism. One problem is that it does not consider the path reliability, and the other one is that it is difficult to find two completely disjoint path pairs in some cases. To solve the above problems, this paper proposes a method to find edge-disjoint path pairs considering path reliability for FRER in TSN. The method includes two parts: one is building a reliability model for paths, and the other one is computing a working path and a redundant path with the Edge-Disjoint Path Pairs Selection (EDPPS) algorithm. Theoretical and simulation results show that the proposed method effectively improves path reliability while reducing the delay jitter of frames. Compared with the traditional FRER mechanism, the proposed method reduces delay jitter by 15.6% when the network load is 0.9.

Bidirectional association between major depressive disorder and dementia: Two population-based cohort studies in Taiwan.

BACKGROUND: Major depressive disorder (MDD) and dementia are both major contributors to the global burden of disease. Despite existing literature on the association between MDD and dementia, there is a lack of a nationwide longitudinal cohort study that considers the competing risk of death. Therefore, this study assessed the bidirectional associations between MDD and dementia over an 11-year period in population-based settings, accounting for death as a competing risk. METHODS: We conducted two population-based retrospective cohort studies in Taiwan. We identified 80,742 patients diagnosed with MDD in 2009-2010 and matched them with patients without MDD by sex, age, and year of diagnosis to assess the relative risk of dementia. We also identified 80,108 patients diagnosed with dementia in 2009-2010 and matched them with patients without dementia by sex, age, and year of diagnosis to assess the relative risk of MDD. All patients were followed until they received a diagnosis of new onset MDD or new onset dementia, their death, or the end of 2019. Cause-specific hazards models were used to estimate adjusted hazard ratios (aHRs). RESULTS: The incidence density (ID) of dementia was higher in patients with MDD than in patients without MDD (7.63 vs. 2.99 per 1000 person-years), with an aHR of 2.71 (95% confidence interval [CI]: 2.55-2.88). The ID of MDD was higher in patients with dementia than in patients without dementia (12.77 vs. 4.69 per 1000 person-years), with an aHR of 2.47 (95% CI: 2.35-2.59). CONCLUSIONS: This population-based study found a bidirectional association between MDD and dementia. Our findings suggest the need to identify dementia in patients with MDD and vice versa.

Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices.

The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.

Two-temperature Collisional-radiative Modeling of Partially Ionized O2-Ar Mixtures over 8000-10,000 K Behind Reflected Shock Waves.

The collisional excitation kinetics of atomic oxygen was studied behind reflected shock waves using tunable diode laser absorption spectroscopy. A test gas mixture of 1% O2/Ar was shock-heated to temperatures between 8000 and 10,000 K and pressures between 0.15 and 1 atm. The time evolution of the atomic oxygen population in the 3 s 5S0 state was monitored by laser absorption at 777.2 nm. The measured O(3 s 5S0) population revealed multistage behavior that was not observed in previous measurements over a temperature range of 5300-7200 K. To interpret the multistage behavior, a three-level collisional-radiative model for atomic oxygen excitation kinetics was developed. The model utilized two independent temperatures, that is, heavy particle translational temperature Ttr and electron translational temperature Te, to describe the fundamental rate constants of atomic oxygen excitation because of collisions with heavy particles and electrons, respectively. The heavy particle excitation rate was inferred from the early stage of the measurement to be k(3P →5S0) = 3.4 × 10-27 (T/K)0.5(1.061 × 105 + 2 (T/K)) exp(-1.061 × 105 K/T) ± 50% m3 s-1. The electron impact excitation rate constant of oxygen, electron impact, and heavy particle impact ionization rate constants of Argon were modified in the model to match the experimental population time histories. The modified rate parameters are also reported for the temperature range explored in the current study.

Polyproline Tri-Helix Macrocycles as Nanosized Scaffolds to Control Ligand Patterns for Selective Protein Oligomer Interactions.

Multivalent ligand-receptor interactions play essential roles in biological recognition and signaling. As the receptor arrangement on the cell surface can alter the outcome of cell signaling and also provide spatial specificity for ligand binding, controlling the presentation of ligands has become a promising strategy to manipulate or selectively target protein receptors. The lack of adjustable universal tools to control ligand positions at the size of a few nanometers has prompted the development of polyproline tri-helix macrocycles as scaffolds to present ligands in designated patterns. Model lectin Helix pomatia agglutinin has shown selectivity toward the matching GalNAc ligand pattern matching its binding sites arrangement. The GalNAc pattern selectivity is also observed on intact asialoglycoprotein receptor oligomer on human hepatoma cells showing the pattern-selective interaction can be achieved not only on isolated protein oligomers but also the receptors arranged on the cell surface. As the scaffold design allows convenient creation of versatile ligand patterns, it can be expected as a promising tool to probe the arrangement of receptors on the cell surface and as nanomedicine to manipulate signaling or cell recognition.

Strategy and Effects of Polyproline Peptide Stapling by Copper(I)-Catalyzed Alkyne-Azide Cycloaddition Reaction.

Polyproline is a unique type of peptide that has a stable, robust, and well-defined helical structure in an aqueous environment. These features have allowed polyproline to be used as a nanosized scaffold for applications in chemical biology and related fields. To understand its structural properties and to expand the applications, this secondary structure was tested systematically by stapling the peptide at different locations with staples of various lengths. Using the efficient copper(I)-catalyzed alkyne-azide cycloaddition (CuAAC), we successfully prepared stapled polyproline and investigated the impact of this peptide macrocyclization through circular dichroism analysis. Whereas the stapling seems to have no significant effect on polyproline helix II (PPII) conformation in water, the location and the length of the staple affect the transformation of conformation in n-propanol. These results provide valuable information for future research using peptide stapling to manipulate polyproline conformation for various applications.

A multifunctional nanocarrier for efficient TRAIL-based gene therapy against hepatocellular carcinoma with desmoplasia in mice.

The anticancer efficacy of TNF-related apoptosis-inducing ligand (TRAIL)-based therapy is limited because of systemic toxicity, poor bioavailability, and development of TRAIL resistance. We developed a tumor-targeted LCPP (lipid/calcium/phosphate/protamine) nanoparticle (NP) to deliver TRAIL plasmid DNA (pDNA) into hepatocellular carcinoma (HCC) cells in a mouse model of HCC. TRAIL pDNA was encapsulated in a pH stimuli-responsive calcium phosphate (CaP) core, and protamine was added to facilitate nuclear delivery of pDNA. In addition, intracellular release of Ca2+ from the CaP core overcame TRAIL resistance by calcium influx-dependent DR5 up-regulation. TRAIL expression also attenuated fibrosis in liver tissues surrounding HCCs by reverting activated hepatic stellate cells (HSCs) to a quiescent state or by directly inducing apoptosis in activated HSCs. CONCLUSION: TRAIL pDNA delivered by HCC-targeted LCPP NPs in combination with conventional sorafenib treatment attenuated HCC progression as well as liver fibrosis. Overall, our study presents an effective TRAIL-based cancer therapy that could be developed for clinical applications. (Hepatology 2018;67:899-913).

A left common pulmonary vein: Anatomical variant predicting good outcomes of repeat catheter ablation for atrial fibrillation.

INTRODUCTION: A left common pulmonary vein (LCPV) is a common anatomical variant in atrial fibrillation (AF) patients. Whether an LCPV influences outcomes of repeated radiofrequency catheter ablation (RFCA) for AF has not been elucidated. METHODS: From a prospectively collected database, we enrolled 154 patients who received repeated RFCA for recurrent AF after the initial RFCA (56 ± 9 years, 72% paroxysmal AF, 32 patients with an LCPV, and 122 patients with typical left-sided pulmonary veins [PVs]). Median postprocedural follow-up was 26 months. The primary outcome was an episode of AF, atrial tachyarrhythmia, or atrial flutter lasting for more than 30 seconds, after the 3 months blanking period following the repeated procedure. RESULTS: After the follow-up period, 75 patients suffered recurrence after repeated ablation. In the Kaplan-Meier analysis, an LCPV was significantly associated with less recurrence (hazard ratio [HR]: 0.39; 95% confidence interval [CI]: 0.28-0.79; P = 0.005). In subgroup analysis, the significant association persisted in paroxysmal AF patients. Regarding persistent AF patients, an LCPV tended to be associated with less recurrence with no statistical significance (HR: 0.40; 95% CI: 0.20-1.03; P = 0.067). In multivariate analyses, an LCPV still independently predicted freedom from recurrence (HR: 0.44; 95% CI: 0.22-0.88; P = 0.02). CONCLUSION: Compared with typical left-sided PVs, an LCPV was independently associated with better outcomes after repeated RFCA of AF, particularly in patients with paroxysmal AF.

Quantitative 2-D OH thermometry using spectrally resolved planar laser-induced fluorescence.

A novel method is presented for quantitative two-dimensional temperature measurement in combustion gases. This method, namely spectrally resolved planar laser-induced fluorescence thermometry, utilizes a high-power, wavelength-tunable and narrow-linewidth CW laser to access the spectral lineshapes of a key combustion intermediate, the hydroxyl radical (OH), and enables high-fidelity and calibration-free quantification of non-uniform temperature fields in complex reacting flows. Specifically, the R1(11)/R1(7) line pair of the OH A2Σ+-X2Π(0,0) rovibronic band was probed with laser radiation near 306.5 nm, and their fluorescence ratios were used to infer temperature. Preliminary demonstrations of this thermometry method were performed in a series of burner-stabilized CH4-air flames.

Reactivity of NO2 with Porous and Conductive Copper Azobispyridine Metallopolymers.

We report the reactivity of copper azobispyridine (abpy) metallopolymers with nitrogen dioxide (NO2). The porous and conductive [Cu(abpy)]n mixed-valence metallopolymers undergo a redox reaction with NO2, resulting in the disproportionation of NO2 gas. Solid- and gas-phase vibrational spectroscopy and X-ray analysis of the reaction products of the NO2-dosed metallopolymer show evidence of nitrate ions and nitric oxide gas. Exposure to NO2 results in complete loss of porosity and a decrease in the room-temperature conductivity of the metallopolymer by four orders of magnitude with the loss of mixed-valence character. Notably, the porous and conductive [Cu(abpy)]n metallopolymers can be reformed by reducing the Cu-nitrate species.

Ultra-sensitive spectroscopy of OH radical in high-temperature transient reactions.

The hydroxyl (OH) radical is arguably the most important transient radical in high-temperature gas-phase combustion reactions, yet it is very difficult to measure because of its high reactivity and, thus, short lifetime and low concentration. This work reports the development of a novel method for ultra-sensitive, quantitative, and microsecond-resolved detection of OH based on UV frequency-modulation spectroscopy (FMS). To the best of the authors' knowledge, this is the first FMS demonstration in the near-UV spectral region for detection of short-lived radical species. Shot-noise-limited detection was achieved at an optical power of 25 mW. A proof-of-concept experiment in a tabletop H2O/He microwave discharge cell has reached a 1σ minimum detectable absorbance (MDA) of less than 2×10-4 over 1 MHz measurement bandwidth. High-temperature OH measurement was demonstrated in a 15 cm diameter shock tube, where a typical MDA of 3.0×10-4 was achieved at 1330 K, 0.38 atm, and 1 MHz. These preliminary results have outperformed the previous best MDA by more than a factor of 3; further improvement by another order of magnitude is anticipated, following the strategies outlined at the end of this Letter. The current method paves the path to parts per billion (ppb) -level OH detection capability and offers prospects to significantly advance fundamental combustion research by enabling direct observation of OH formation and scavenging kinetics during key stages of fuel oxidation that were inaccessible with previous methods.

Galactose Derivative-Modified Nanoparticles for Efficient siRNA Delivery to Hepatocellular Carcinoma.

Successful siRNA therapy requires suitable delivery systems with targeting moieties such as small molecules, peptides, antibodies, or aptamers. Galactose (Gal) residues recognized by the asialoglycoprotein receptor (ASGPR) can serve as potent targeting moieties for hepatocellular carcinoma (HCC) cells. However, efficient targeting to HCC via galactose moieties rather than normal liver tissues in HCC patients remains a challenge. To achieve more efficient siRNA delivery in HCC, we synthesized various galactoside derivatives and investigated the siRNA delivery capability of nanoparticles modified with those galactoside derivatives. In this study, we assembled lipid/calcium/phosphate nanoparticles (LCP NPs) conjugated with eight types of galactoside derivatives and demonstrated that phenyl ß-d-galactoside-decorated LCP NPs (L4-LCP NPs) exhibited a superior siRNA delivery into HCC cells compared to normal hepatocytes. VEGF siRNAs delivered by L4-LCP NPs downregulated VEGF expression in HCC in vitro and in vivo and led to a potent antiangiogenic effect in the tumor microenvironment of a murine orthotopic HCC model. The efficient delivery of VEGF siRNA by L4-LCP NPs that resulted in significant tumor regression indicates that phenyl galactoside could be a promising HCC-targeting ligand for therapeutic siRNA delivery to treat liver cancer.

Efficacy and Safety of Uninterrupted Low-Intensity Warfarin for Radiofrequency Catheter Ablation of Atrial Fibrillation in the Elderly.

BACKGROUND: No previous studies exist investigating the optimal intensity of uninterrupted anticoagulation with warfarin during radiofrequency catheter ablation (RFCA) for atrial fibrillation (AF) in the elderly. OBJECTIVE: Evaluate the efficacy and safety of continuous low-intensity warfarin therapy throughout the periprocedural period of RFCA for AF in the elderly. METHODS: This is a prospective randomized study. We enrolled AF patients (age ≥ 70 years) who underwent first-time RFCA for AF. Enrolled patients were randomized to group A and group B. The international normalized ratios before ablation were maintained at 1.5 to 2.0 and 2.0 to 2.5 in group A and B, respectively. Primary end points were periprocedural thromboembolic complications and major bleeding. Secondary end points included periprocedural asymptomatic cerebral emboli (ACE) and minor bleeding. RESULTS: A total of 101 patients were enrolled in our study (group A: 52; group B: 49). Baseline characteristics were well balanced between the 2 groups. Only 1 patient suffered from stroke in group B. No major bleeding events occurred in either group. The incidence of new ACE lesions was comparable between the 2 groups (11.5% vs 8.2%, P = 0.82). Minor bleeding occurred in 1 of 52 (1.9%) patients in group A and in 5 of 49 (10.2%) patients in group B ( P = 0.10). CONCLUSIONS: Uninterrupted low-intensity warfarin for RFCA of AF might be as effective as standard-intensity warfarin in preventing periprocedural thromboembolic complications and might be associated with fewer bleeding events in the elderly.

Shock Tube and Laser Absorption Study of CH2O Oxidation via Simultaneous Measurements of OH and CO.

The oxidation of Ar-diluted stoichiometric CH2O-O2 mixtures was studied behind reflected shock waves over temperatures of 1332-1685 K, at pressures of about 1.5 atm and initial CH2O mole fractions of 500, 1500, and 5000 ppm. Quantitative and time-resolved concentration histories of OH and CO (at both v″ = 0 and v″ = 1) were measured by narrow-linewidth laser absorption at 306.7 and 4854 nm, respectively. A time delay was observed between the formation of v″ = 0 and v″ = 1 states of CO, suggesting that CO was kinetically generated primarily in the ground state and then collisionally relaxed toward vibrational equilibrium. The measured CO and OH time-histories were used to evaluate the performance of four detailed reaction mechanisms regarding the oxidation chemistry of CH2O. Further analyses of these time-history data have also led to improved determination for the rate constants of two key reactions, namely H + O2 = O + OH (R1) and OH + CO = CO2 + H (R2), as follows: k1 = 8.04 × 1013 exp(-7370 K/T) cm3 mol-1 s-1, k2 = 1.90 × 1012 exp(-2760 K/T) cm3 mol-1 s-1; both expressions are valid over 1428-1685 K and have 1σ uncertainties of approximately ±10%.

Broad neutralization coverage of HIV by multiple highly potent antibodies.

Broadly neutralizing antibodies against highly variable viral pathogens are much sought after to treat or protect against global circulating viruses. Here we probed the neutralizing antibody repertoires of four human immunodeficiency virus (HIV)-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies that neutralize broadly across clades. Many of the new monoclonal antibodies are almost tenfold more potent than the recently described PG9, PG16 and VRC01 broadly neutralizing monoclonal antibodies and 100-fold more potent than the original prototype HIV broadly neutralizing monoclonal antibodies. The monoclonal antibodies largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV broadly neutralizing monoclonal antibodies now available reveals that certain combinations of antibodies should offer markedly more favourable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV broadly neutralizing monoclonal antibodies from several donors that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

Cavity-enhanced absorption spectroscopy with a ps-pulsed UV laser for sensitive, high-speed measurements in a shock tube.

We report the first application of cavity-enhanced absorption spectroscopy (CEAS) with a ps-pulsed UV laser for sensitive and rapid gaseous species time-history measurements in a transient environment (in this study, a shock tube). The broadband nature of the ps pulses enabled instantaneous coupling of the laser beam into roughly a thousand cavity modes, which grants excellent immunity to laser-cavity coupling noise in environments with heavy vibrations, even with an on-axis alignment. In this proof-of-concept experiment, we demonstrated an absorption gain of 49, which improved the minimum detectable absorbance by ~20 compared to the conventional single-pass strategy at similar experimental conditions. For absorption measurements behind reflected shock waves, an effective time-resolution of ~2 µs was achieved, which enabled time-resolved observations of transient phenomena, such as the vibrational relaxation of O(2) demonstrated here. The substantial improvement in detection sensitivity, together with microsecond measurement resolution implies excellent potential for studies of transient physical and chemical processes in nonequilibrium situations, particularly via measurements of weak absorptions of trace species in dilute reactive systems.

Improved Shock Tube Measurement of the CH4 + Ar = CH3 + H + Ar Rate Constant using UV Cavity-Enhanced Absorption Spectroscopy of CH3.

We report an improved measurement for the rate constant of methane dissociation in argon (CH4 + Ar = CH3 + H + Ar) behind reflected shock waves. The experiment was conducted using a sub-parts per million sensitivity CH3 diagnostic recently developed in our laboratory based on ultraviolet cavity-enhanced absorption spectroscopy. The high sensitivity of this diagnostic allowed for measurements of quantitatively resolved CH3 time histories during the initial stage of CH4 pyrolysis, where the reaction system is clean and free from influences of secondary reactions and temperature change. This high sensitivity also allowed extension of our measurement range to much lower temperatures (<1500 K). The current-reflected shock measurements were performed at temperatures between 1487 and 1866 K and pressures near 1.7 atm, resulting in the following Arrhenius rate constant expression for the title reaction: k(1.7 atm) = 3.7 × 10(16) exp(-42 200 K/T) cm(3)/mol·s, with a 2σ uncertainty factor of 1.25. The current data are in good consensus with various theoretical and review studies, but at the low temperature end they suggest a slightly higher (up to 35%) rate constant compared to these previous results. A re-evaluation of previous and current experimental data in the falloff region was also performed, yielding updated expressions for both the low-pressure limit and the high-pressure limit rate constants and improved agreement with all existing data.

Shock Tube Measurement for the Dissociation Rate Constant of Acetaldehyde Using Sensitive CO Diagnostics.

The rate constant of acetaldehyde thermal dissociation, CH3CHO = CH3 + HCO, was measured behind reflected shock waves at temperatures of 1273-1618 K and pressures near 1.6 and 0.34 atm. The current measurement utilized sensitive CO diagnostics to track the dissociation of CH3CHO via oxygen atom balance and inferred the title rate constant (k1) from CO time histories obtained in pyrolysis experiments of 1000 and 50 ppm of CH3CHO/Ar mixtures. By using dilute test mixtures, the current study successfully suppressed the interferences from secondary reactions and directly determined the title rate constant as k1(1.6 atm) = 1.1 × 10(14) exp(-36 700 K/T) s(-1) over 1273-1618 K and k1(0.34 atm) = 5.5 × 10(12) exp(-32 900 K/T) s(-1) over 1377-1571 K, with 2σ uncertainties of approximately ±30% for both expressions. Example simulations of existing reaction mechanisms updated with the current values of k1 demonstrated substantial improvements with regards to the acetaldehyde pyrolysis chemistry.

Kinetics of Excited Oxygen Formation in Shock-Heated O2-Ar Mixtures.

The formation of electronically excited atomic oxygen was studied behind reflected shock waves using cavity-enhanced absorption spectroscopy. Mixtures of 1% O2-Ar were shock-heated to 5400-7500 K, and two distributed-feedback diode lasers near 777.2 and 844.6 nm were used to measure time-resolved populations of atomic oxygen's 5S° and 3S° electronic states, respectively. Measurements were compared with simulated population time histories obtained using two different kinetic models that accounted for thermal nonequilibrium effects: (1) a multitemperature model and (2) a reduced collisional-radiative model. The former assumed a Boltzmann distribution of electronic energy, whereas the latter allowed for non-Boltzmann populations by treating the probed electronic states as pseudospecies and accounting for dominant electronic excitation/de-excitation processes. The effects of heavy-particle collisions were investigated and found to play a major role in the kinetics of O atom electronic excitation at the conditions studied. For the first time, rate constants (kM) for O atom electronic excitation from the ground state (3P) due to collisions with argon atoms were directly inferred using the reduced collisional-radiative model, kM(3P → 5S°) = 7.8 × 10-17T0.5 exp(-1.061 × 105K/T) ± 25% cm3 s-1 and kM(3P → 3S°) = 2.5 × 10-17T0.5 exp(-1.105 × 105K/T) ± 25% cm3 s-1.