Pathway selectivity in time-resolved spectroscopy using two-photon coincidence counting with quantum entangled photons.

Ultrafast optical spectroscopy is a powerful technique for studying the dynamic processes of molecular systems in condensed phases. However, in molecular systems containing many dye molecules, the spectra can become crowded and difficult to interpret owing to the presence of multiple nonlinear optical contributions. In this work, we theoretically propose time-resolved spectroscopy based on the coincidence counting of two entangled photons generated via parametric down-conversion with a monochromatic laser. We demonstrate that the use of two-photon counting detection of entangled photon pairs enables the selective elimination of the excited-state absorption signal. This selective elimination cannot be realized with classical coherent light. We anticipate that the proposed spectroscopy will help simplify the spectral interpretation of complex molecular and material systems comprising multiple molecules.

Comparison of multi-mode Hong-Ou-Mandel interference and multi-slit interference.

Hong-Ou-Mandel (HOM) interference of multi-mode frequency entangled states plays a crucial role in quantum metrology. However, as the number of modes increases, the HOM interference pattern becomes increasingly complex, making it challenging to comprehend intuitively. To overcome this problem, we present the theory and simulation of multi-mode-HOM interference (MM-HOMI) and compare it to multi-slit interference (MSI). We find that these two interferences have a strong mapping relationship and are determined by two factors: the envelope factor and the details factor. The envelope factor is contributed by the single-mode HOM interference (single-slit diffraction) for MM-HOMI (MSI). The details factor is given by sin (Nx)/sin (x) ([sin (Nv)/sin (v)]2) for MM-HOMI (MSI), where N is the mode (slit) number and x (v) is the phase spacing of two adjacent spectral modes (slits). As a potential application, we demonstrate that the square root of the maximal Fisher information in MM-HOMI increases linearly with the number of modes, indicating that MM-HOMI is a powerful tool for enhancing precision in time estimation. We also discuss multi-mode Mach-Zehnder interference, multi-mode NOON-state interference, and the extended Wiener-Khinchin theorem. This work may provide an intuitive understanding of MM-HOMI patterns and promote the application of MM-HOMI in quantum metrology.

Spatial-spectral mapping to prepare frequency entangled qudits.

Entangled qudits, the high-dimensional entangled states, play an important role in the study of quantum information. How to prepare entangled qudits in an efficient and easy-to-operate manner is still a challenge in quantum technology. Here, we demonstrate a method to engineer frequency entangled qudits in a spontaneous parametric downconversion process. The proposal employs an angle-dependent phase-matching condition in a nonlinear crystal, which forms a classical-quantum mapping between the spatial (pump) and spectral (biphotons) degrees of freedom. In particular, the pump profile is separated into several bins in the spatial domain, and thus shapes the down-converted biphotons into discrete frequency modes in the joint spectral space. Our approach provides a feasible and efficient method to prepare a high-dimensional frequency entangled state. As an experimental demonstration, we generate a three-dimensional entangled state by using a homemade variable slit mask.

Efficacy and safety of zuranolone in Japanese adults with major depressive disorder: A double-blind, randomized, placebo-controlled, phase 2 clinical trial.

AIM: To evaluate the efficacy and safety of an oral, once-daily, 14-day treatment course of zuranolone in Japanese patients with major depressive disorder (MDD). METHODS: This multicenter, randomized, double-blind, placebo-controlled study randomized eligible patients (1:1:1) to receive oral zuranolone 20 mg, zuranolone 30 mg, or placebo once daily for 14 days (treatment-period), followed by two 6-week follow-up periods. The primary endpoint was change from baseline in the 17-item Hamilton Depression Rating Scale (HAMD-17) total score on Day 15. RESULTS: Overall, 250 patients (enrolled: 07/07/2020-05/26/2021) were randomized to receive placebo (n = 83), zuranolone 20 mg (n = 85), or zuranolone 30 mg (n = 82). The demographic and baseline characteristics were balanced between groups. The adjusted mean (standard error) change from baseline in the HAMD-17 total score on Day 15 was -6.22 (0.62), -8.14 (0.62), and - 8.31 (0.63) in the placebo, zuranolone 20-mg, and zuranolone 30-mg groups, respectively. Significant differences in the adjusted mean (95% confidence interval [CI]) for zuranolone 20 mg versus placebo (-1.92; [-3.65, -0.19]; P = 0.0296) and zuranolone 30 mg versus placebo (-2.09; [-3.83, -0.35]; P = 0.0190) groups were observed on Day 15, and also as early as Day 3. A nonsignificant yet distinct drug-placebo separation was observed during follow-up. Somnolence (placebo [3.7%], zuranolone 20 mg [10.6%], and zuranolone 30 mg [20.7%]) and dizziness (3.7%, 9.4%, and 9.8%, respectively) were more common with zuranolone. CONCLUSION: Oral zuranolone was safe and demonstrated significant improvements in depressive symptoms, as assessed by HAMD-17 total score change from baseline over 14 days in Japanese patients with MDD.

Electrochemical Epoxidation Catalyzed by Manganese Salen Complex and Carbonate with Boron-Doped Diamond Electrode.

Epoxides are essential precursors for epoxy resins and other chemical products. In this study, we investigated whether electrochemically oxidizing carbonate ions could produce percarbonate to promote an epoxidation reaction in the presence of appropriate metal catalysts, although Tanaka and co-workers had already completed a separate study in which the electrochemical oxidation of chloride ions was used to produce hypochlorite ions for electrochemical epoxidation. We found that epoxides could be obtained from styrene derivatives in the presence of metal complexes, including manganese(III) and oxidovanadium(IV) porphyrin complexes and manganese salen complexes, using a boron-doped diamond as the anode. After considering various complexes as potential catalysts, we found that manganese salen complexes showed better performance in terms of epoxide yield. Furthermore, the substituent effect of the manganese salen complex was also investigated, and it was found that the highest epoxide yields were obtained when Jacobsen's catalyst was used. Although there is still room for improving the yields, this study has shown that the in situ electrochemical generation of percarbonate ions is a promising method for the electrochemical epoxidation of alkenes.

Safety, Tolerability, and Pharmacokinetics of the Novel Antiviral Agent Ensitrelvir Fumaric Acid, a SARS-CoV-2 3CL Protease Inhibitor, in Healthy Adults.

Ensitrelvir is a novel selective inhibitor of the 3C-like protease of SARS-CoV-2, which is essential for viral replication. This phase 1 study of ensitrelvir assessed its safety, tolerability, and pharmacokinetics of single (part 1, n = 50) and multiple (part 2, n = 33) ascending oral doses. Effect of food on the pharmacokinetics of ensitrelvir, differences in pharmacokinetics of ensitrelvir between Japanese and white participants, and effect of ensitrelvir on the pharmacokinetics of midazolam (a cytochrome P450 3A [CYP3A] substrate) were also assessed. In part 1, Japanese participants were randomized to placebo or ensitrelvir at doses of 20, 70, 250, 500, 1,000, or 2,000 mg. In part 2, Japanese and white participants were randomized to placebo or once-daily ensitrelvir at loading/maintenance dose 375/125 mg or 750/250 mg for 5 days. Most treatment-related adverse events observed were mild in severity and were resolved without treatment. Plasma exposures showed almost dose proportionality, and geometric mean half-life of ensitrelvir following the single dose was 42.2 to 48.1 h. Food intake reduced Cmax and delayed Tmax of ensitrelvir but did not impact the area under the curve (AUC), suggesting suitability for administration without food restriction. Compared with Japanese participants, plasma exposures were slightly lower for white participants. Ensitrelvir affected the pharmacokinetics of CYP3A substrates because of increase in AUC of midazolam coadministered with ensitrelvir 750/250 mg on day 6. In conclusion, ensitrelvir was well-tolerated and demonstrated favorable pharmacokinetics, including a long half-life, supporting once-daily oral dosing. These results validate further assessments of ensitrelvir in participants with SARS-CoV-2 infection.

Ultrafast measurement of a single-photon wave packet using an optical Kerr gate.

Ultrafast quantum optics with time-frequency entangled photons is at the forefront of progress towards future quantum technologies. However, to unravel the time domain structure of entangled photons and exploit fully their rich dimensionality, a single-photon detector with sub-picosecond temporal resolution is required. Here, we present ultrafast single-photon detection using an optical Kerr gate composed of a photonic crystal fiber (PCF) placed inside a Sagnac interferometer. A near-rectangle temporal waveform of a heralded single-photon generated via spontaneous parametric down-conversion is measured with temporal resolution as high as 224 ± 9 fs. The large nonlinearity and long effective interaction length of the PCF enables maximum detection efficiency to be achieved with only 30.5 mW gating pulse average power, demonstrating an order-of-magnitude improvement compared to optical gating with sum-frequency generation. Also, we discuss the trade-off relationship between detection efficiency and temporal resolution.

Mid-infrared spectrally-uncorrelated biphotons generation from doped PPLN: a theoretical investigation.

We theoretically investigate the preparation of mid-infrared (MIR) spectrally-uncorrelated biphotons from a spontaneous parametric down-conversion process using doped LN crystals, including MgO doped LN, ZnO doped LN, and In2O3 doped ZnLN with doping ratio from 0 to 7 mol%. The tilt angle of the phase-matching function and the corresponding poling period are calculated under type-II, type-I, and type-0 phase-matching conditions. We also calculate the thermal properties of the doped LN crystals and their performance in Hong-Ou-Mandel interference. It is found that the doping ratio has a substantial impact on the group-velocity-matching (GVM) wavelengths. Especially, the GVM2 wavelength of co-doped InZnLN crystal has a tunable range of 678.7 nm, which is much broader than the tunable range of less than 100 nm achieved by the conventional method of adjusting the temperature. It can be concluded that the doping ratio can be utilized as a degree of freedom to manipulate the biphoton state. The spectrally uncorrelated biphotons can be used to prepare pure single-photon source and entangled photon source, which may have promising applications for quantum-enhanced sensing, imaging, and communications at the MIR range.

Multireference Perturbation Theory Combined with PCM and RISM Solvation Models: A Benchmark Study for Chemical Energetics.

The polarizable continuum model (PCM) has been one of the most widely used approaches to take into account the solvation effect in quantum chemical calculations. In this paper, we performed a series of benchmark calculations to assess the accuracy of the PCM scheme combined with the second-order complete-active-space perturbation theory (CASPT2) for molecular systems in polar solvents. For solute molecules with extensive conjugated π orbitals, exemplified by elongated conjugated arylcarbenes, we have incorporated the ab initio density matrix renormalization group algorithm into the PCM-CASPT2 method. In the previous work, we presented a combination of the DMRG-CASPT2 method with the reference interaction site model (RISM) theory for describing the solvation effect using the radial distribution function and compared its performance to the widely used density-functional approaches (PCM-TD-DFT). The work here allows us to further show a more thorough assessment of the RISM model compared to the PCM with an equal level of the wave function treatment, the (DMRG-)CASPT2 theory, toward a high-accuracy electronic structure calculations for solvated chemical systems. With the exception that the PCM models are not capable of properly describing the hydrogen bondings, accuracy of the PCM-CASPT2 model is in most cases quite comparable to the RISM counterpart.

Local Structure of Glassy Lithium Phosphorus Oxynitride Thin Films: A Combined Experimental and Ab†Initio Approach.

Lithium phosphorus oxynitride (LiPON) is an amorphous solid-state lithium ion conductor displaying exemplary cyclability against lithium metal anodes. There is no definitive explanation for this stability due to the limited understanding of the structure of LiPON. Herein, we provide a structural model of RF-sputtered LiPON. Information about the short-range structure results from 1D and 2D solid-state NMR experiments. These results are compared with first principles chemical shielding calculations of Li-P-O/N crystals and ab initio molecular dynamics-generated amorphous LiPON models to unequivocally identify the glassy structure as primarily isolated phosphate monomers with N incorporated in both apical and as bridging sites in phosphate dimers. Structural results suggest LiPON's stability is a result of its glassy character. Free-standing LiPON films are produced that exhibit a high degree of flexibility, highlighting the unique mechanical properties of glassy materials.

Pharmacokinetic-Pharmacodynamic Modeling of Brain Dopamine Levels Based on Dopamine Transporter Occupancy after Administration of Methylphenidate in Rats.

Dopamine exerts various effects including movement coordination and reward. It is useful to understand the quantitative relationship between drug pharmacokinetics and target engagement such as the change in occupancy and dopamine level in brain for the proper treatment of dopamine-related diseases. This study was aimed at developing a pharmacokinetic-pharmacodynamic (PK-PD) model based on dopamine transporter (DAT) occupancies that could describe changes in extracellular dopamine levels in brain after administration of methylphenidate (a DAT inhibitor) to rat. First, uptake of fluorescent substrates was studied in DAT-expressing human embryonic kidney 293 cells and concentration dependently inhibited by methylphenidate. By analyzing the uptake of fluorescent substrates in the presence or absence of methylphenidate, a mathematical model could estimate the association and dissociation rate constants of methylphenidate for DAT. Next, we measured the concentrations of methylphenidate in plasma and cerebrospinal fluid (CSF) and extracellular dopamine levels in the nucleus accumbens after single intraperitoneal administration of methylphenidate. The concentrations of methylphenidate in plasma increased almost dose proportionally and the CSF-to-plasma concentration ratio was similar among evaluated dose. The extracellular dopamine levels also increased with dose. These data were analyzed using the mechanism-based PK-PD model, which incorporates dopamine biosynthesis, release from a synapse, reuptake via DAT into a synapse, and elimination from a synapse. Methylphenidate concentrations in plasma and dopamine profiles predicted by the PK-PD model were close to in vivo observations. In conclusion, our mechanism-based PK-PD model can accurately describe dopamine levels in the brain after administration of methylphenidate to rats.

Direct generation of frequency-bin entangled photons via two-period quasi-phase-matched parametric downconversion.

We report a simple scheme for direct generation of frequency-bin entangled photon pairs via spontaneous parametric downconversion. Our fabricated nonlinear optical crystal with two different poling periods can simultaneously satisfy two different, spectrally symmetric nondegenerate quasi-phase-matching conditions, enabling the direct generation of entanglement in two discrete frequency-bin modes. Our produced photon pairs exhibited Hong-Ou-Mandel interference with high-visibility beating oscillations- a signature of two-mode frequency-bin entanglement. Moreover, we demonstrate deterministic entanglement-mode conversion from frequency-bin to polarization modes, with which our source can be more versatile for various quantum applications. Our scheme can be extended to direct generation of high-dimensional frequency-bin entanglement, and thus will be a key technology for frequency-multiplexed optical quantum information processing.

Quantum manipulation of biphoton spectral distributions in a 2D frequency space toward arbitrary shaping of a biphoton wave packet.

Arbitrary shaping of optical waveform is fundamental interest from basic science to advanced optical technologies. However, it is still challenging task for shaping a biphoton wave packet. Here we experimentally manipulate the spectrum and phase of a biphoton wave packet in a two-dimensional frequency space. The spectrum is shaped by adjusting the temperature of the crystal, and the phase is controlled by tilting the dispersive glass plate. The manipulating effects are confirmed by measuring the two-photon spectral intensity (TSI) and the Hong-Ou-Mandel (HOM) interference patterns. The technique in this work paves the way for arbitrary shaping of a multi-photon wave packet in a quantum manner.

Free space optical secret key agreement.

Free space optical (FSO) communications are enabling high-speed global wireless networks. Thanks to the highly directional nature of laser beam, they also yield a greater security advantage over radio frequency counterparts. When combined with a scheme of secret key agreement (SKA), FSO-SKA can establish at high speed a symmetric secret key which cannot be decrypted even by unbounded computer resources. Although there have been many theoretical studies on SKA, experimental investigations have been quite lacking, especially on quantifying eavesdropping risks and secret key rates in realistic environment. Here, we report the first full-field implementations of FSO-SKA in a 7.8-km terrestrial link with a probing station, enabling the estimation of eavesdropping risks. We attain the final key rates from 100 kbps to 7.77 Mbps under various atmospheric and beaming conditions even with total losses of 55dB or higher, in which known quantum key distribution schemes attain impractically low key rates.

Free-space optical wiretap channel and experimental secret key agreement in 7.8 km terrestrial link.

Secret key agreement using physical properties of a wireless channel is becoming a promising scheme to establish a secret key between two users, especially in short-distance radio frequency (RF) communications. In this scheme, the existence of codes or key distillation that can make the leaked information to an eavesdropper arbitrarily small can be derived in an information theoretical way, given a priori knowledge on the channel linking a sender (Alice), a legitimate receiver (Bob), and an eavesdropper (Eve), which is called the wiretap channel. In practice, however, it is often difficult for Alice and Bob to get sufficient knowledge on Eve. In this study, we implement a free-space optical wiretap channel in a 7.8 km-terrestrial link and study how to estimate Eve's tapping ability, demonstrating high speed secret key agreement in the optical domain under a certain restricted condition of line-of-sight.

Free-space optical channel estimation for physical layer security.

We present experimental data on message transmission in a free-space optical (FSO) link at an eye-safe wavelength, using a testbed consisting of one sender and two receiver terminals, where the latter two are a legitimate receiver and an eavesdropper. The testbed allows us to emulate a typical scenario of physical-layer (PHY) security such as satellite-to-ground laser communications. We estimate information-theoretic metrics including secrecy rate, secrecy outage probability, and expected code lengths for given secrecy criteria based on observed channel statistics. We then discuss operation principles of secure message transmission under realistic fading conditions, and provide a guideline on a multi-layer security architecture by combining PHY security and upper-layer (algorithmic) security.

Low-intensity resistance training with blood flow restriction improves vascular endothelial function and peripheral blood circulation in healthy elderly people.

PURPOSE: The present study aimed to investigate the effects of low-intensity resistance training with blood flow restriction (BFR resistance training) on vascular endothelial function and peripheral blood circulation. METHODS: Forty healthy elderly volunteers aged 71 ± 4 years were divided into two training groups. Twenty subjects performed BFR resistance training (BFR group), and the remaining 20 performed ordinary resistance training without BFR. Resistance training was performed at 20 % of each estimated one-repetition maximum for 4 weeks. We measured lactate (Lac), norepinephrine (NE), vascular endothelial growth factor (VEGF) and growth hormone (GH) before and after the initial resistance training. The reactive hyperemia index (RHI), von Willebrand factor (vWF) and transcutaneous oxygen pressure in the foot (Foot-tcPO2) were assessed before and after the 4-week resistance training period. RESULTS: Lac, NE, VEGF and GH increased significantly from 8.2 ± 3.6 mg/dL, 619.5 ± 243.7 pg/mL, 43.3 ± 15.9 pg/mL and 0.9 ± 0.7 ng/mL to 49.2 ± 16.1 mg/dL, 960.2 ± 373.7 pg/mL, 61.6 ± 19.5 pg/mL and 3.1 ± 1.3 ng/mL, respectively, in the BFR group (each P < 0.01). RHI and Foot-tcPO2 increased significantly from 1.8 ± 0.2 and 62.4 ± 5.3 mmHg to 2.1 ± 0.3 and 68.9 ± 5.8 mmHg, respectively, in the BFR group (each P < 0.01). VWF decreased significantly from 175.7 ± 20.3 to 156.3 ± 38.1 % in the BFR group (P < 0.05). CONCLUSIONS: BFR resistance training improved vascular endothelial function and peripheral blood circulation in healthy elderly people.

Spectrally resolved Hong-Ou-Mandel interference between independent photon sources.

Hong-Ou-Mandel (HOM) interference between independent photon sources (HOMI-IPS) is the fundamental block for quantum information processing. All the previous HOMI-IPS experiments were carried out in time-domain, however, the spectral information during the interference was omitted. Here, we investigate the HOMI-IPS in spectral domain using the recently developed fast fiber spectrometer, and demonstrate the spectral distribution during the HOM interference between two heralded single-photon sources, and two thermal sources. This experiment not only can deepen our understanding of HOMI-IPS from the viewpoint of spectral domain, but also presents a tool to test the theoretical predictions of HOMI-IPS using spectrally engineered sources.

Pharmacokinetic-pharmacodynamic modeling for reduction of hepatic apolipoprotein B mRNA and plasma total cholesterol after administration of antisense oligonucleotide in mice.

Second-generation antisense oligonucleotides (ASOs) demonstrate excellent biological stability and in vitro/in vivo potency, and thus are considered to be attractive candidates for drugs to treat various diseases. A pharmacokinetic-pharmacodynamic (PK-PD) model of ASOs is desired for the design of appropriate PK and pharmacological studies. The objective of this study was to develop a PK-PD model to accurately simulate hepatic ASO concentration and its efficacy from plasma ASO concentration. After single subcutaneous administration of an ASO targeting hepatic apolipoprotein B (Apo-B) mRNA to mice, the ASO was absorbed rapidly and showed biphasic decline with time from the plasma and liver (t1/2: 1-3 and 81-183 h, Tmax: 0.25-0.50 and 4-8 h). After administration, hepatic Apo-B mRNA and plasma total cholesterol began decreasing at 4-8 and 8-24 h, and their Tmax values were observed at 24-72 and 72 h. To develop the PK-PD model based on the mechanisms of ASOs, we described the plasma and hepatic ASO concentration with linear two-compartment models. In addition, we inserted two indirect response models for mRNA and plasma total cholesterol. Model predictions from plasma ASO concentration gave excellent fits to the observed values of hepatic ASO concentration, Apo-B mRNA and plasma total cholesterol after single or multiple subcutaneous administrations. Our PK-PD model could accurately predict hepatic ASO concentrations and their efficacies from plasma ASO concentrations. This PK-PD model could be a useful tool for suggesting PK and pharmacological study protocols for various liver-targeted second-generation ASOs.

Pulsed Sagnac polarization-entangled photon source with a PPKTP crystal at telecom wavelength.

We demonstrate pulsed polarization-entangled photons generated from a periodically poled KTiOPO(4) (PPKTP) crystal in a Sagnac interferometer configuration at telecom wavelength. Since the group-velocity-matching (GVM) condition is satisfied, the intrinsic spectral purity of the photons is much higher than in the previous scheme at around 800 nm wavelength. The combination of a Sagnac interferometer and the GVM-PPKTP crystal makes our entangled source compact, stable, highly entangled, spectrally pure and ultra-bright. The photons were detected by two superconducting nanowire single photon detectors (SNSPDs) with detection efficiencies of 70% and 68% at dark counts of less than 1 kcps. We achieved fidelities of 0.981 ± 0.0002 for |ψ(-)〉 and 0.980 ± 0.001 for |ψ(+)〉 respectively. This GVM-PPKTP-Sagnac scheme is directly applicable to quantum communication experiments at telecom wavelength, especially in free space.