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Pendulums have long been used as force sensors due to their ultimately low dissipation (high-quality factor) characteristic. They are widely used in the measurement of the gravitational constant, detection of gravitational waves, and determination of ultralight dark matter. Furthermore, it is expected that the quantum nature of gravity will be demonstrated by performing quantum control for macroscopic pendulums. Recently, we have demonstrated that quantum entanglement between two pendulums can be generated using an optical spring [D. Miki, N. Matsumoto, A. Matsumura, T. Shichijo, Y. Sugiyama, K. Yamamoto, and N. Yamamoto, arXiv:2210.13169 (2022)]; however, we have ignored that an optical spring can reduce the quality factor (Q-factor) by applying normal-mode splitting between the pendulum and rotational modes possessing relatively high dissipation. Herein, we analyze a system composed of a cylinder suspended using a beam (a suspended mirror, i.e., a pendulum) and an optical spring to consider normal-mode splitting. The reduction in Q-factor is determined only by the beam parameters: the ratio of the radius of the mirror to the length of the beam, and the ratio of the frequency of the rotational mode to the pendulum mode in the absence of cavity photons. In our analysis, we find that the reduction factor $4.38$ is reproduced, which is consistent with the experimental result in Matsumoto \textit{et al.} [N. Matsumoto, S. B. Catan$\tilde{\text{o}}$-Lopez, M. Sugawara, S. Suzuki, N. Abe, K. Komori, Y. Michimura, Y. Aso, and K. Edamatsu, Phys. Rev. Lett. 122, 071101 (2019)]. Our analysis shows that low dissipation (high quality) can be reached using an optical spring for the realistic pendulum system considering the rotational degree of freedom., Comment: 13pages, 5 figures

This study is aimed at investigating the feasibility of generating quantum entanglement between macroscopic mechanical mirrors in optomechanical systems while under continuous measurement and feedback control. We carefully derive a covariance matrix for mechanical mirrors in a steady state, employing the Kalman filtering problem with an assumed dominant cavity photon dissipation, such that the common and differential modes of the mirrors are squeezed by the action of measuring the output light beams. We demonstrate that entanglement between the mechanical mirrors is generated when the states of the common and differential modes are squeezed with high purity in an asymmetric manner. Our results also show that quantum entanglement between $7$ mg mirrors is achievable in the short term., Comment: 20 pages, 10 figures

We consider how the energy can be stored in the boundary of spacetime, in particular in a spherical bubble that can be made by a quantum gravitational process. Our calculation is performed within the framework of classical Einstein gravity by identifying the Gibbons–Hawking–York term as the membrane action. We show that the energy of the bubble can be given consistently with the Schwarzschild metric. The solution of the consistency condition suggests positive membrane tension, which explains why we do not observe such topological defects in ordinary experiences and also gives a mechanism for suppressing the spacetime with the boundary in a dynamical way.

Background Oxaliplatin is a key drug for the chemotherapy of colorectal cancer; however, it is also known to cause non‐cirrhotic portal hypertension. We aimed to identify the characteristics of patients who developed esophagogastric varices (EGVs) after treatment with oxaliplatin. Methods This study retrospectively analyzed patients with colorectal cancer who were treated with chemotherapy including oxaliplatin between 2010 and 2016. All patients were evaluated by contrast‐enhanced computed tomography (CE‐CT) every 3 months both during and after treatment; and endoscopy was performed when appearance of portal hypertension was suspected. Results A total of 106 patients were divided into two groups: EGV formation (n = 6) and EGV non‐formation (n = 100). In the EGV group, platelet counts decreased and the size of the spleen calculated by CT (CT spleen index; CT‐SI) increased markedly. The highest area under the receiver operating characteristic curve (AUC) for the change in platelet counts was 0.81 (80% sensitivity and 83% specificity) at 3 months post treatment, and the maximum AUC for CT‐SI was 0.89 (79% sensitivity and 83% specificity) at 6 months post treatment. Conclusions EGV formation could be predicted by the assessment of platelet counts and spleen size. If progressive splenomegaly and thrombocytopenia are observed not only during but also after completion of the oxaliplatin‐containing chemotherapy, EGVs should be confirmed by endoscopy for avoiding subsequent rupture., We aimed to identify the characteristics of patients who developed esophagogastric varices (EGV) after treatment with oxaliplatin. If progressive splenomegaly and thrombocytopenia are observed not only during but also after completion of the oxaliplatin‐containing chemotherapy, EGV should be confirmed by endoscopy for avoiding subsequent rupture.

The numerical sign problem has long been a major obstacle to first-principles calculations in various important fields of physics. We report that the recently proposed algorithm, tempered Lefschetz thimble method (TLTM), and its worldvolume extension (WV-TLTM) can be a promising solution in its trustability and versatility., Comment: 9 pages, 5 figures, talk presented at The 38th International Symposium on Lattice Field Theory, LATTICE2021 26th-30th July, 2021, Zoom/Gather@Massachusetts Institute of Technology

Aggregation-induced emission (AIE) probes that can be triggered by enzymatic activity are sought for applications across the life sciences. The compound 2-(2-hydroxyphenyl)benzothiazole (HBT) is non-fluorescent in solution but exhibits AIE. To adapt HBT for potential clinical applications, two phosphoester derivatives (1 and 2) were prepared. For extension to molecular brachytherapy (delivery of a radionuclide), one phosphoester derivative (3) was prepared wherein a bromine atom is incorporated as a site for subsequent radioiodide substitution. Each probe 1–3 requires phosphatase action to engender AIE. For specificity in diagnostic and therapeutic applications, a heterologous (i.e., foreign to humans) enzyme was sought for conversion of 1–3 from aqueous-soluble to aqueous-insoluble form. Here, an archaeal phosphodiesterase PDE-MJ0936 (wild-type) was systematically engineered for activity toward 1–3. PDE-MJ0936 is a hyperthermal enzyme (activity at 70 °C and pH 9.8) and exists as a dimer, which together limit life science applications. Ten PDE mutants were engineered by site-directed mutagenesis to achieve a monomeric structure, wider substrate scope, and elastic substrate docking under physiological conditions. Among the mutants, PDE-C141D exhibited efficient activity towards bis(4-nitrophenyl)phosphate (Km = 0.28 mM, kcat = 3.0 s−1 and kcat/Km = 1.1 × 104 M−1 s−1) and efficiently hydrolyzed 3 at 37 °C and pH 7.0, conditions under which PDE-MJ0936 is silent. The substrates 1–3 are relatively resistant to alkaline phosphatase, PDE-MJ0936 and fetal bovine serum. The development of enzymatically triggered substrates and the complementary heterologous enzymes may support diverse applications in the life sciences.

The ability to cross-link molecules upon enzymatic action under physiological conditions holds considerable promise for use in diverse life sciences applications. Here, an enzymatically triggered “click reaction” has been developed by exploiting the longstanding indigo-forming reaction from indoxyl β-glucoside. The covalent cross-linking proceeds in aqueous solution, requires the presence only of an oxidant (e.g., O2), and is readily detectable owing to the blue color of the resulting indigoid dye. To achieve facile indigoid formation in the presence of a bioconjugatable tether, diverse indoxyl β-glucosides were synthesized and studied in enzyme assays with four glucosidases including from tritosomes (derived from hepatic lysosomes) and rat liver homogenates. Altogether 36 new compounds (including 15 target indoxyl-glucosides for enzymatic studies) were prepared and fully characterized in pursuit of four essential requirements: enzyme triggering, facile subsequent indigoid dye formation, bioconjugatability, and synthetic accessibility. The 4,6-dibromo motif in a 5-alkoxy-substituted indoxyl-glucoside was a key design feature for fast and high-yielding indigoid dye formation. Two attractive molecular designs include (1) an indoxyl-glucoside linked to a bicyclo[6.1.0]nonyl (BCN) group for Cu-free click chemistry, and (2) a bis(indoxyl-glucoside). In both cases the linker between the reactive moieties is composed of two short PEG groups and a central triazine derivatized with a sulfobetaine moiety for water solubilization. Glucosidase treatment of the bis(indoxyl-glucoside) in aqueous solution gave oligomers that were characterized by absorption, dynamic light-scattering, and 1H NMR spectroscopy; optical microscopy; mass spectrometry; and HPLC. Key attractions of in situ indigoid dye formation, beyond enzymatic triggering under physiological conditions without exogenous catalysts or reagents, are the chromogenic readout and compatibility with attachment to diverse molecules.

Chlorins provide many ideal features for use as red-region fluorophores but require molecular tailoring for solubilization in aqueous solution. A chlorin building-block bearing 18,18-dimethyl, 15-bromo and 10-[2,4,6-tris(propargyloxy)phenyl] substituents has been transformed via click chemistry with CH3(OCH2CH[Formula: see text]-N3 followed by Suzuki coupling with 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid, thereby installing a water-solubilization motif and a bioconjugatable handle, respectively. In toluene, [Formula: see text]-dimethylformamide (DMF) or water, the resulting facially encumbered free base chlorin exhibits characteristic chlorin absorption ([Formula: see text] [Formula: see text]412, 643 nm) and fluorescence ([Formula: see text] [Formula: see text]645 nm) spectra with only modest variation in fluorescence quantum yield ([Formula: see text] values (0.24, 0.25 and 0.19, respectively). The zinc chlorin derived therefrom exhibits similar spectral constancy ([Formula: see text] [Formula: see text]414 and 613 nm, [Formula: see text] [Formula: see text]616 nm) and [Formula: see text] 0.094, 0.10 and 0.086 in the three solvents. The results together indicate the viability of the molecular design and synthetic methodology to create red-region fluorophores for use in diverse applications.

Highlight Cannulation of the portal vein during endoscopic retrograde cholangiopancreatography is a rare complication. Nakahara and colleagues present a case of successful biliary stenting with a guidewire left in the portal vein after recognizing that the portal vein had been cannulated, without subsequent complications such as bleeding or air embolism.

BACKGROUND Common variable immunodeficiency (CVID) is a rare disease. Infectious mononucleosis-like symptoms due to Epstein-Barr virus reactivation in adulthood are also rare. Here, we aimed to report a case of Epstein-Barr virus reactivation presenting with relapsing infectious mononucleosis-like symptoms with liver failure in common variable immunodeficiency with chronic hepatitis B virus infection. CASE REPORT A 36-year-old Japanese woman with chronic hepatitis B virus infection developed relapsing fever, lymphadenopathy with marked splenomegaly, and ascites 6 months after treatment with propagermanium, a nonspecific immune modulator, and subsequent treatment with entecavir and pegylated interferon sequential therapy. Although the hepatitis B virus load was controlled, Epstein-Barr virus deoxyribose nucleic acid was detected in her serum. Seven months later, her symptoms improved following corticosteroid treatment. Prior to sequential therapy, she developed pneumonia 4 times in 2 months and exhibited consistent hypoimmunoglobulinemia before corticosteroid treatment. Further examinations showed low amounts of switched memory B cells, and absence or barely detectable levels of isohemagglutinins. Subsequently, she was diagnosed with common variable immunodeficiency. CONCLUSIONS Epstein-Barr virus reactivation with relapsing infectious mononucleosis-like symptoms can occur following immune modulation therapy in patients with common variable immunodeficiency, and this can affect the patient's primary disease. Therefore, immunoglobulin screening along with the consideration of CVID in all patients is required before immune modulation therapy is planned.

We construct an approximate trivializing map by using a Schwinger-Dyson equation. The advantage of this method is that: (1) The basis for the flow kernel can be chosen arbitrarily by hand. (2) It can be applied to the general action of interest. (3) The coefficients in the kernel are determined by lattice estimates of the observables, which does not require analytic calculations beforehand. We perform the HMC with the effective action obtained by the Schwinger-Dyson method, and show that we can have better control of the effective action than the known $t$-expansion construction. However, the algorithmic overhead is still large and overwhelming the gain though faster decorrelation is observed for long-range observables in some cases. This contribution reports the preliminary results of this attempt., Comment: 19 pages, 12 figures, talk presented at the 39th International Symposium on Lattice Field Theory (Lattice 2022)

Objectives To identify patients suitable for endoscopic injection sclerotherapy (EIS) by evaluating their portal hemodynamics and liver function. Methods We selected 58 patients with esophagogastric varices (EGV) and liver cirrhosis (LC) related to either hepatitis C virus (C) (n = 19), hepatitis B virus (n = 2), alcohol (AL) (n = 20), C + AL (n = 6), non-alcoholic steatohepatitis (n = 6), others (n = 3), or non-LC (n = 2). All patients underwent EIS. We measured their portal venous tissue blood flow (PVTBF) and hepatic arterial tissue blood flow (HATBF) using xenon computed tomography before and after EIS. We classified them into increased group and decreased group according to the PVTBF to identify the predictors that contribute to PVTBF increase post-EIS. Results Low value of indocyanine green retention at 15 min (ICG-R15), the absence of paraesophageal veins, and low baseline PVTBF/HATBF (P/A) ratio predicted increased PVTBF in the multivariate logistic analysis (odds ratio (OR) 10.46, p = 0.0391; OR 12.45, p = 0.0088; OR 13.57, p = 0.0073). The protein synthetic ability improved 1 year post-EIS in increased group. Cox proportional hazards regression identified alcohol drinking (hazard ratio; 3.67, p = 0.0261) as an independent predictor of EGV recurrence. Conclusions Patients with low ICG-R15, low P/A ratio, and the absence of paraesophageal veins were probable predictors of PVTBF improvement post-EIS. In addition, the improvement of hepatic hemodynamics likely enhanced liver function following EIS.

We propose a novel tensor network representation for two-dimensional Yang–Mills theories with arbitrary compact gauge groups. In this method, tensor indices are given directly by group elements with no direct use of the character expansion. We apply the tensor renormalization group method to this tensor network for SU(2) and SU(3), and find that the free energy density and the energy density are accurately evaluated. We also show that the singular value decomposition of a tensor has a group-theoretic structure and can be associated with the character expansion.

We discuss the statistical analysis method for the worldvolume hybrid Monte Carlo (WV-HMC) algorithm [arXiv:2012.08468], which was recently introduced to substantially reduce the computational cost of the tempered Lefschetz thimble method. In the WV-HMC algorithm, the configuration space is a continuous accumulation (worldvolume) of deformed integration surfaces, and sample averages are considered for various subregions in the worldvolume. We prove that, if a sample in the worldvolume is generated as a Markov chain, then the subsample in the subregion can also be regarded as a Markov chain. This ensures the application of the standard statistical techniques to the WV-HMC algorithm. We particularly investigate the autocorrelation times for the Markov chains in various subregions, and find that there is a linear relation between the probability to be in a subregion and the autocorrelation time for the corresponding subsample. We numerically confirm this scaling law for a chiral random matrix model., Comment: 16 pages, 6 figures

Varicella-zoster virus (VZV) can cause visceral disseminated VZV infection in immunocompromised patients. We experienced visceral disseminated VZV infection in an immunocompetent host. A 78-year-old woman visited our hospital complaining of abdominal pain that had persisted for 7 days. On day 3 after admission, a skin rash with blisters appeared mainly on her head and trunk that was diagnosed as generalized zoster via rapid skin VZV diagnostic kit. Esophagogastroduodenoscopy showed gastric erosions, and VZV was detected by real-time polymerase chain reaction testing of the gastric mucosal biopsy specimen. Computed tomography imaging also revealed pancreatitis and colitis, and she was diagnosed as having visceral disseminated VZV infection involving multiple organs. She was treated with acyclovir intravenously, after which her skin rash and abdominal pain disappeared. Because visceral disseminated VZV infection can occur in immunocompetent patients, this disease should be considered in patients with unexplained inflammatory lesions of the gastrointestinal tract or pancreas.

Based on high efficacy and safety demonstrated in clinical trials, treatment with glecaprevir/pibrentasvir (G/P) for 8 weeks is recommended for hepatitis C virus (HCV)-infected patients who are direct-acting antiviral (DAA) naïve, genotype 1 or 2, and noncirrhotic. The aim of this study was to validate real-world experience with 8-week G/P treatment in Japan. We conducted a prospective observational cohort study in 554 patients who underwent 8-week treatment from among 1,022 patients who initiated G/P therapy. The majority (54.5%) were male, with a median age of 66 years, and HCV genotype distribution was genotype 1, 43.8%; genotype 2, 55.3%; and mixed subtype, 0.9%. Overall, the sustained virologic response rate at 12 weeks (SVR12) was 92.8% (530/571) in the intention-to-treat population and 99.3% (526/530) in the per-protocol population. The SVR12 rates by subgroups were as follows: subtype 1a, 100% (6/6); 1b, 100% (189/189); 2a, 99.3% (150/151); 2b, 99.0% (103/104); and mixed subtype, 50% (2/4). Among four patients with virologic failure following 8-week treatment with G/P, none had baseline polymorphisms or treatment-emergent amino acid substitutions in NS3. However, 2 of 4 patients with virologic failure had treatment-emergent amino acid substitutions in NS5A. Adverse events (AEs) were reported in 21.5% of patients and 1.2% of patients discontinued due to drug-related AEs. In conclusion, G/P treatment for 8 weeks was safe and effective for DAA-naïve noncirrhotic genotype 1 or 2 patients in a real-world clinical setting in Japan.

Objective The efficacy and safety of concomitant use of antithrombin (AT) with recombinant human soluble thrombomodulin (rTM) for acute cholangitis-induced disseminated intravascular coagulation (AC-induced DIC) remains unclear. This study was conducted to investigate the efficacy of AT combined with rTM as anticoagulant therapy for AC-induced DIC. Methods One hundred patients with AC-induced DIC received anticoagulant therapy using rTM from April 2010 to December 2017. Of the 83 patients treated with rTM immediately after the diagnosis of DIC, excluding those who had not undergone biliary drainage or who had malignancies or a serum AT III level >70%, 56 patients were studied. Outcomes and adverse events (AEs) were retrospectively compared between the 16 patients treated with rTM alone (rTM group) and the 40 patients treated with rTM and AT (rTM+AT group). Results Patients' background characteristics did not differ markedly, except for a significantly higher serum D-dimer level in the rTM group than in the rTM+AT group (p=0.038). The DIC resolution rates on day 9 were 100% and 95.1% in the rTM and rTM+AT groups, respectively (p=0.909). The mean DIC scores were significantly lower in the rTM group than in the rTM+AT group on days 3 (p=0.012), 5 (p

As a solution towards the numerical sign problem, we propose a novel Hybrid Monte Carlo algorithm, in which molecular dynamics is performed on a continuum set of integration surfaces foliated by the antiholomorphic gradient flow ("the worldvolume of an integration surface"). This is an extension of the tempered Lefschetz thimble method (TLTM), and solves the sign and multimodal problems simultaneously as the original TLTM does. Furthermore, in this new algorithm, one no longer needs to compute the Jacobian of the gradient flow in generating a configuration, and only needs to evaluate its phase upon measurement. To demonstrate that this algorithm works correctly, we apply the algorithm to a chiral random matrix model, for which the complex Langevin method is known not to work., Comment: 41 pages, 13 figures

The worldvolume tempered Lefschetz thimble method (WV-TLTM) is an algorithm towards solving the sign problem, where hybrid Monte Carlo updates are performed on a continuous accumulation of flowed surfaces foliated by the anti-holomorphic gradient flow (the worldvolume of integration surface). Sharing the advantage with the original tempered Lefschetz thimble method (TLTM) that the sign problem is resolved without introducing the ergodicity problem, the new algorithm is expected to significantly reduce the computational cost, because it eliminates the need to compute the Jacobian of the flow in generating a configuration. We demonstrate the effectiveness of the WV-TLTM with its successful application to the Stephanov model (a chiral random matrix model), for which the complex Langevin method is known to suffer from a serious wrong convergence problem. We also discuss the statistical analysis method for the WV-TLTM., Comment: 9 pages, 3 figures, talk presented at The 38th International Symposium on Lattice Field Theory, LATTICE2021 26th-30th July, 2021, Zoom/Gather@Massachusetts Institute of Technology

We review the tempered Lefschetz thimble method and its extension, which was recently proposed as a versatile solution to the numerical sign problem. We exemplify the effectiveness of the method by its successful application to a chiral random matrix model.

Labile zinc plays various roles in cells at low concentrations which most fluorescent probes are not able to detect. Here we report a cephem-based probe which coordinates to zinc and zinc-bound water cleaves the scaffold and releases the fluorophore. In addition, the zinc is recycled and reacts with multiple probes, amplifying the signal. This signal amplification system is useful for the detection of intracellular zinc at low concentrations and has potential for further development of probes with a similar molecular design.

We present the development of a high $Q$ monolithic silica pendulum weighing 7 mg. The measured $Q$ value for the pendulum mode at 2.2 Hz was $2.0\times10^6$. To the best of our knowledge this is the lowest dissipative mg-scale mechanical oscillator to date. By employing this suspension system, the optomechanical displacement sensor for gravity measurements we recently reported in Phys. Rev. Lett. 122, 071101 (2019) can be improved to realize quantum-noise-limited sensing at several hundred Hz. In combination with the optical spring effect, the amount of intrinsic dissipation measured in the pendulum mode is enough to satisfy requirements for measurement-based quantum control of a massive pendulum confined in an optical potential. This paves the way for not only testing dark matter via quantum-limited force sensors, but also Newtonian interaction in quantum regimes, namely, between two mg-scale oscillators in quantum states, as well as improving the sensitivity of gravitational-wave detectors., 5 pages, 3 figures

Precise measurements of the displacement of, and force acting on, a mechanical oscillator can be performed by coupling the oscillator to an optical cavity. Brownian thermal forces represent a fundamental limit to measurement sensitivity which impedes the ability to use precise force measurements as a tool of fundamental enquiry, particularly in the context of macroscopic quantum measurements and tabletop gravitational experiments. A torsion pendulum with a low mechanical resonant frequency can be limited by very small thermal forces---from its suspensions---at frequencies above resonance. Here, we report torque sensing of a 10-mg torsion pendulum formed by a bar mirror, using two optical cavities on either edge. The rotational mode was measured by subtracting the two signals from the cavities, while intracavity radiation pressure forces were used to trap the torsional mode with a 1 kHz optical spring. The resulting torque sensitivity of 20 aN m/$\sqrt{\mathrm{Hz}}$ is a record for a milligram-scale torsional oscillator. This allows us to test spontaneous wave-function collapse in a parameter regime that falls in between that tested by space-based experiments, and high-frequency cryogenic cantilevers.

The tempered Lefschetz thimble method (TLTM) is a parallel-tempering algorithm towards solving the numerical sign problem. It tames both the sign and ergodicity problems simultaneously by tempering the system with the flow time of continuous deformations of the integration region. In this article, after reviewing the basics of the TLTM, we explain a new algorithm within the TLTM that enables us to estimate the expectation values precisely with a criterion ensuring global equilibrium and the sufficiency of the sample size. To demonstrate the effectiveness of the algorithm, we apply the TLTM to the quantum Monte Carlo simulation of the Hubbard model away from half filling on a two-dimensional lattice of small size, and show that the obtained numerical results agree nicely with exact values., Comment: 7 pages, 4 figures, talk presented at the 37th International Symposium on Lattice Field Theory (Lattice 2019), 16-22 June 2019, Wuhan, China

Towards formulating quantum gravity, we present a novel mechanism for the emergence of spacetime geometry from randomness. In [arXiv:1705.06097], we defined for a given Markov stochastic process "the distance between configurations," which enumerates the difficulty of transition between configurations. In this article, we consider stochastic processes of large-$N$ matrix models, where we regard the eigenvalues as spacetime coordinates. We investigate the distance for the effective stochastic process of one-eigenvalue, and argue that this distance can be interpreted in noncritical string theory as probing a classical geometry with a D-instanton. We further give an evidence that, when we apply our formalism to a tempered stochastic process of $U(N)$ matrix, where the 't Hooft coupling is treated as another dynamical variable, a Euclidean AdS$_2$ geometry emerges in the extended configuration space in the large-$N$ limit, and the horizon corresponds to the Gross-Witten-Wadia phase transition point., Comment: 10 pages, 3 figures, talk presented at Corfu Summer Institute 2019 "School and Workshops on Elementary Particle Physics and Gravity" (CORFU2019), 31 August - 25 September 2019, Corfu, Greece

Numerous astrophysical and cosmological observations are best explained by the existence of dark matter, a mass density which interacts only very weakly with visible, baryonic matter. Searching for the extremely weak signals produced by this dark matter strongly motivate the development of new, ultra-sensitive detector technologies. Paradigmatic advances in the control and readout of massive mechanical systems, in both the classical and quantum regimes, have enabled unprecedented levels of sensitivity. In this white paper, we outline recent ideas in the potential use of a range of solid-state mechanical sensing technologies to aid in the search for dark matter in a number of energy scales and with a variety of coupling mechanisms., Comment: White paper/overview based on a workshop held at the Joint Quantum Institute, Maryland. 12 pages, 4 figures, table summarizing many experimental systems, 118 references

Aims Interferon-free direct-acting antiviral agent (DAA) regimens for chronic hepatitis C virus (HCV) patients have improved their health-related quality of life (HRQOL). Currently, there are no published data assessing the impact of DAAs regimens without sofosbuvir on HRQOL. The aim of this study was to investigate the improvement of HRQOL in Japanese HCV patients treated with a protease inhibitor and a nonstructural protein 5A inhibitor. Methods and Results A total of 123 Japanese genotype 1b HCV patients receiving daclatasvir (DCV) and asunaprevir (ASV) for 24 weeks were enrolled. HRQOL was assessed using the Japanese version of the Chronic Liver Disease Questionnaire (CLDQ) at baseline; weeks 4, 12, and 24; and post-24 weeks. Changes in CLDQ scores were calculated by subtracting the CLDQ score at each time point from the baseline value. Improvement in the mean change of the Japanese version of the CLDQ score became statistically significant as early as week 4 after the initiation of treatment (+9.3%; P

AIM The therapeutic benefit of adding ribavirin (RBV) to 12 weeks of ledipasvir/sofosbuvir (LDV/SOF) for patients who experienced failure of a previous nonstructural protein (NS) 5A inhibitor-containing regimen is unclear. METHODS A total of 29 genotype 1b HCV patients who had failed prior daclatasvir (DCV) plus asunaprevir (ASV) treatment were retreated for 12 weeks of LDV/SOF, with or without RBV. Antiviral efficacy and predictive factors associating with a sustained virological response at 24 weeks (SVR24) were evaluated retrospectively. RESULTS SVR24 was achieved in 67% (10/15) of patients who received LDV/SOF with, and 64% (9/14) without, RBV. The SVR24 rates were 80% in patients with, and 58% without, mild fibrosis (FIB-4

Pactamycin, a potent antitumor and antimicrobial antibiotic, possesses a densely functionalized cyclopentane core structure. This paper describes the concise synthesis of an advanced intermediate for synthesizing the enantiomer of pactamycin that contains the cyclopentane skeleton bearing all the necessary amino functions with correct stereochemistries.