Synthesis of oligonucleotides containing 5'-homo-4'-selenouridine derivative and its increased resistance against nuclease.

As technologies using RNA or DNA have been developed, various chemical modifications of nucleosides have been attempted to increase the stability of oligonucleotides. Since it is known that 2'-OMe-modification greatly contributes to increasing the stability of oligonucleotides, we added 2'-OMe to our previously developed 4'-selenonucleoside and 5'-homo-4'-selenonucleoside as the modified monomers for oligonucleotide: 2'-methoxy-4'-selenouridine (2'-OMe-4'-Se-U) and 5'-homo-2'-methoxy-4'-selenouridine (5'-homo-2'-OMe-4'-Se-U). We synthesized oligonucleotides containing the chemically modified 4'-selenouridine and evaluated their thermal stability and nuclease resistance. In conclusion, the nuclease stability of the oligonucleotide containing 5'-homo-2'-OMe-4'-selenouridine increased while its thermal stability decreased.

Generative-adversarial-network-based dimensional measurement of optical waveguides.

We propose a high-throughput and precise waveguide-dimensional-measurement method consisting of a generative adversarial network (GAN) and curve-fitting-based dimensional calculator using sidewall functions. The GAN can learn the differences between low-magnification (LM) and high-magnification (HM) optical microscope images taken with different objective lenses at different magnifications over the same area. The LM and HM images of the waveguides are captured using an optical microscope at magnifications of 500× and 2000×, respectively. We obtained a standard deviation of the waveguide widths of approximately 0.8 pixels (∼ 42 nm), and confirmed precise width measurement using super-resolution images at the same imaging throughput as with an LM microscope.

Synthesis and properties of fully-modified 4'-selenoRNA, an endonuclease-resistant RNA analog.

A large number of chemically modified oligonucleotides (ONs) have been developed for RNA-based technologies. In most modified RNAs, the characteristic 2'-hydroxyl (2'-OH) groups are removed to enhance both nuclease resistance and hybridization ability. However, the importance of the 2'-OH group in RNA structure and function is well known. Here, we report the synthesis and properties of 4'-selenoRNA in which all four nucleoside units retain the 2'-OH groups but contain a selenium atom instead of an oxygen atom at the 4'-position of the furanose ring. 4'-SelenoRNA has enhanced ability to form duplexes with RNA, and high endonuclease resistance despite the presence of the 2'-OH groups. X-ray crystallography analysis showed that the 4'-selenoRNA duplex adopts an A-conformation, similar to natural RNA, although one 4'-selenocytidine residue has unusual South-type sugar puckering. Furthermore, preliminary studies using 4'-seleno-modified siRNAs suggest that 4'-selenoRNA may be applicable to RNA interference technology. Collectively, our results raise the possibility of a new class of modified RNA in which 2'-OH groups do not need to be masked.

Transcranial Doppler for stratification of high-risk morphology of patent foramen ovale in patients with cryptogenic stroke.

Microbubble testing using transcranial Doppler (TCD) is an important screening tool for diagnosing paradoxical cerebral embolism with high-risk PFO. However, little is known about the association between the microbubble test by TCD and the features of high-risk PFO evaluated by transesophageal echocardiography (TEE). We studied 101 consecutive patients at Showa University, from April 2019 to October 2020, who underwent both TCD and TEE with a sufficient Valsalva maneuver and who were strongly suspected by neurologists as cryptogenic stroke. According to the appearance of microbubbles as high-intensity transient signals (HITS), the TCD grade was stratified into three categories based on the criteria (A: none, no HITS, B: small; 1-10 HITS, and C: large; > 10 HITS, or an uncountable number of HITS). Among patients with RLS through the PFO in TEE, high-risk morphological features of PFO for cerebral embolism were evaluated as follows: (1) tunnel height, (2) tunnel length, (3) total excursion distance of the atrial septum into the right and left atrium, (4) existence of Eustachian valve or Chiari network, (5) angle of PFO from the inferior vena cava, and (6) large shunt (20 or more microbubbles). Of 101 patients (TCD grade; Group A = 49, Group B = 26, Group C = 26), RLS through PFO was detected in 37 patients (grade A = 8, grade B = 6, grade C = 23) by TEE. Among PFO-positive patients, tunnel height, length, total excursion distance into the right and left atria, angle of PFO from the inferior vena cava, and frequency of large shunt in TEE were significantly larger in grade C than in grade A and B (p < 0.05). Additionally, grade C patients had significantly more forms of high-risk PFOs than those in grades A and B when the six features of high-risk PFO were compared. A multivariate logistic regression demonstrated that the tunnel length of PFO and the presence of large shunt in TEE were independently associated with large HITS in TCD (odds ratio: 1.18 and 49.5, 95% confidence interval 1.043-1.337 and 10.05-244.3, p = 0.0086 and p < 0.0001, respectively). In conclusion, the existence of a large HITS detected by TCD may have a screening advantage in predicting the high-risk morphologies of PFO that can cause paradoxical cerebral embolism.

Right ventricular contractility affects the clinical efficacy of add-on tolvaptan following hospitalization for heart failure in patients with significant tricuspid regurgitation.

Tricuspid regurgitation (TR) is a common condition that is independently associated with high mortality rates in patients with heart failure (HF). Several studies have demonstrated the clinical efficacy of add-on tolvaptan in patients hospitalized for HF. However, the effects of add-on tolvaptan in patients with significant TR are less well understood. Among the patients with moderate-to-severe TR assessed by transthoracic echocardiography during hospitalization for congestive HF, 39 patients who could complete the clinical course after starting add-on tolvaptan were included in the study. Rehospitalization due to HF and cardiac death were defined as adverse cardiac events in this study. We investigated the presence or absence of cardiac events within 2 years following the introduction of tolvaptan and evaluated echocardiographic functional parameters associated with cardiac events. The average patient age was 75 ± 14 years, and 23 patients (59%) experienced adverse cardiac events within 2 years after add-on tolvaptan administration. Serum creatinine (mg/dL) and brain natriuretic peptide (pg/mL) concentrations at discharge were significantly higher in patients with cardiac events than in those without cardiac events {1.48 [1.02-1.58] vs. 1.07 [0.79-1.41], p = 0.03; 526 [414-1044] vs. 185 [104-476], p = 0.01, respectively}. The presence or absence of past hospitalization for HF was also significantly higher in the event-positive group compared to event-free group (78 vs. 44%, p = 0.04). Comparison of echocardiographic parameters revealed that patients with cardiac events had a significantly lower left ventricular ejection fraction (40 ± 16 vs. 49 ± 15%, p = 0.049) and lower right ventricular fractional area change (RVFAC) (35 ± 12 vs. 45 ± 10%, p = 0.008) than those without cardiac events. Multiple logistic regression analysis revealed that RVFAC and past hospitalization for HF were independently associated with cardiac events following the introduction of tolvaptan (odds ratio, 0.934 and 4.992; p = 0.048 and 0.04, respectively). Right ventricular contractility as well as past history of admission for HF, left ventricular ejection fraction, renal function, and brain natriuretic peptide level at discharge may reflect the clinical outcomes after HF hospitalization in patients with significant TR who were treated with tolvaptan.

Effect of Diastolic Flow Reversal Patterns on Clinical Outcomes Following Transcatheter Aortic Valve Implantation　- An Intraprocedural Echocardiography Study.

BACKGROUND: Although diastolic flow reversal (DFR) in the descending aorta, assessed via transesophageal echocardiography (TEE), is a simple and easy indicator for evaluating aortic regurgitation, the association between DFR pattern and clinical outcomes following transcatheter aortic valve implantation (TAVI) is unclear. The purpose of this study was to evaluate the effect of DFR patterns on clinical outcomes following TAVI.Methods and Results:Two-hundred and eleven patients (mean age, 83.6±5.7 years; 69% female) who underwent TAVI were retrospectively assessed via intraprocedural TEE. DFR was evaluated using pulsed-wave Doppler in the descending aorta before and after TAVI. The primary endpoint was major adverse cardio-cerebrovascular events (MACCEs). Although only 7 patients (3.3%) had moderate or severe paravalvular leak, as assessed by color Doppler echocardiography, holo-DFR (HDFR) was observed in 33 patients (16.0%) after TAVI. MACCEs occurred in 40 patients during the median follow up of 282 days (interquartile range: 160-478 days). The estimated cumulative MACCE-free survival at 1 year was significantly lower in patients with HDFR than in those without HDFR. A Cox proportional hazards analysis revealed that HDFR after TAVI was independently associated with MACCEs. CONCLUSIONS: HDFR was associated with an increased risk of MACCEs after TAVI. DFR evaluated by intraprocedural echocardiography could serve as a simple and easy method for predicting clinical outcomes.

Synthesis and biological evaluation of novel imidazole nucleosides as potential anti-dengue virus agents.

In this work, we developed imidazole nucleoside derivatives with anti-dengue virus (DENV) activity was examined. First, compounds in a nucleosides library were screened to find lead compounds which inhibit replication of DENV. As a result, 5-ethynyl-(1-ß-d-ribofuranosyl)imidazole-4-carboxamide (1; EICAR) and its 4-carbonitrile derivative EICNR (2) were selected as promising antiviral compounds. However, both of them also exhibited cytotoxicity. In order to develop an effective and less toxic compound, 4'-thio and 4'-seleno derivatives of EICAR and EICNR 3-6 were prepared. The resulting 4'-thioEICAR and 4'-thioEICNR showed inhibitory effect on DENV replication without cytotoxicity as potent as ribavirin, a positive control.

Highly efficient on-chip excitation of orthogonal-polarized gap plasmons for a dense polarization multiplexing circuit.

We propose an on-chip excitation structure for orthogonal-polarized gap plasmons in polarization multiplexing photonic integrated circuits. The structure consists of a Au nanostripe and tapered gap for refractive index matching to a nano-scale gap plasmonic waveguide; it was fabricated on the top surface of a dielectric-stripe-type waveguide. The excitation ratio from the dielectric-stripe-surface mode to the metallic-gap mode was estimated to be 0.79 using the finite-difference time-domain method for a 100-nm-wide, 100-nm-thick gap waveguide. We experimentally observed the gap mode plasmonic intensity distribution using scanning near-field optical microscopy and confirmed the conversion.

Plasmonic slow light device using superfocusing on a bow-tied metallic waveguide.

We demonstrate a plasmonic slow light device using super focusing on a bow-tied metallic waveguide that can be fabricated using complementary metal-oxide semiconductor compatible processes. By solving the characteristic equation of a bow-tied metallic waveguide, we confirmed that the group indices increased as the waveguide width decreased and that they could attain over 11.0 in the telecommunication wavelength band. Additionally, we experimentally confirmed using an autocorrelation measurement system in which the pulse width of the bow-tied metallic waveguide was 8.0 fs longer than that of a ridged metallic waveguide. Therefore, the proposed device will contribute to the realization of all-plasmonic memories and amplifiers.

Phase reduction and synchronization of a network of coupled dynamical elements exhibiting collective oscillations.

A general phase reduction method for a network of coupled dynamical elements exhibiting collective oscillations, which is applicable to arbitrary networks of heterogeneous dynamical elements, is developed. A set of coupled adjoint equations for phase sensitivity functions, which characterize the phase response of the collective oscillation to small perturbations applied to individual elements, is derived. Using the phase sensitivity functions, collective oscillation of the network under weak perturbation can be described approximately by a one-dimensional phase equation. As an example, mutual synchronization between a pair of collectively oscillating networks of excitable and oscillatory FitzHugh-Nagumo elements with random coupling is studied.

Synthesis of 4'-Selenoribonucleosides, the Building Blocks of 4'-SelenoRNA, Using a Hypervalent Iodine.

Herein is described a detailed protocol for the synthesis of 4'-selenoribonucleoside derivatives that involves the use of a hypervalent iodine species. These derivatives are versatile units for the preparation of 4'-selenoRNA. Large-scale synthesis of a 4-selenosugar starting from D-ribose is achieved in eight steps, including a final chromatographic purification. The resulting 4-selenosugar is then subjected to the one-pot Pummerer-like reaction using hypervalent iodine in the presence of silylated nucleobases. The reaction with silylated uracil affords the desired 4'-selenouridine derivatives with excellent ß-selectivity and in good yield. Conversely, when purine nucleobases are used in the Pummerer-like reaction, N7 4'-selenoribonucleoside isomers are obtained alongside the desired N9 isomers. However, the undesired N7 isomers can be converted to the desired N9 ones under acidic conditions. © 2017 by John Wiley & Sons, Inc.

Plasmonic-multimode-interference-based logic circuit with simple phase adjustment.

All-optical logic circuits using surface plasmon polaritons have a potential for high-speed information processing with high-density integration beyond the diffraction limit of propagating light. However, a number of logic gates that can be cascaded is limited by complicated signal phase adjustment. In this study, we demonstrate a half-adder operation with simple phase adjustment using plasmonic multimode interference (MMI) devices, composed of dielectric stripes on a metal film, which can be fabricated by a complementary metal-oxide semiconductor (MOS)-compatible process. Also, simultaneous operations of XOR and AND gates are substantiated experimentally by combining 1 × 1 MMI based phase adjusters and 2 × 2 MMI based intensity modulators. An experimental on-off ratio of at least 4.3 dB is confirmed using scanning near-field optical microscopy. The proposed structure will contribute to high-density plasmonic circuits, fabricated by complementary MOS-compatible process or printing techniques.