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Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge1–5. Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2associated with the risk allele in these younger patients. DOCK2expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n= 61 individuals) identified cell-type-specific downregulation of DOCK2and a COVID-19-specific decreasing effect of the risk allele on DOCK2expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.

Repeated injection of gadolinium-based contrast agents did not cause any motor or behavioral changes, whether the agents were linear or macrocyclic.

Traditional molecular conductors are composed of more than two chemical species. Two prerequisites for the design of molecular metals have long been considered to be 1) forming of the electronic band and 2) existence of charge carriers created by the intermolecular charge transfer between the molecules constructing the band and other chemical species. On the other hand, a single-component molecular metal, [Ni(tmdt)2] (tmdt = trimethylenetetrathiafulvalenedithiolate), was developed in 2001; it is a planar nickel complex coordinated by the extended-TTF dithiolate ligands, tmdt from both sides. Since then, various types of single-component molecular conductors with a variety of extended-TTF dithiolate ligands have been developed. In this account, we briefly describe the recent progress in research on single-component molecular conductors. First, single-component molecular conductors in isostructural systems, [M(tmdt)2] (M = Ni, Pd, Pt, Au, and Cu) are described. Recent orbital-selective 13C and 1H NMR experiments have genealogically elucidated the differences in the electronic states and physical properties of these systems, that is, their various unusual phenomena are produced from their multi-orbital correlated π or π-d electron systems. Next, we describe [Ni(hfdt)2] (hfdt = bis(trifluoromethyl)tetrathiafulvalenedithiolate), the first single-component molecular superconductor, which was revealed by high-pressure resistivity measurements with a diamond anvil cell (DAC). The superconducting transition occurred around 7.5–8.7 GPa with a maximum Tc(onset temperature) of 5.5 K. Recent theoretical calculation has revealed that [Ni(hfdt)2] will be a new molecular Dirac electron system. In the final section, we briefly introduce molecular Dirac electron systems. Recently, a new series of semimetals, [M(dmdt)2] (M = Pt and Ni; dmdt = dimethyltetrathiafulvalenedithiolate) was synthesized. They belong to a three-dimensional ambient-pressure molecular massless Dirac electron system. The first-principles band structure calculations of [M(dmdt)2] (M = Pt and Ni) revealed that Dirac cones emerge along the a*direction and form Dirac nodal lines.In this account, we briefly introduce our recent studies on novel single-component molecular conductors based on multi-orbital correlated π-d electron system [M(tmdt)2] (M = Ni, Pd, Pt, Cu and Au), the first single-component molecular superconductor [Ni(hfdt)2], and the nodal-line Dirac electron system [M(dmdt)2] (M = Pt and Ni).

Preclinical evidence implicates neutrophil elastase (NE) in pulmonary arterial hypertension (PAH) pathogenesis, and the NE inhibitor elafin is under early therapeutic investigation.

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Chronic stress is widely recognized as a risk factor for the development of major depression and anxiety disorders. Recently, we reported that yokukansan (YKS), a traditional Japanese herbal medicine, alleviated emotional abnormality in stress-maladaptive mice. The aim of the present study was to examine the effect of YKS on the expression of excitatory amino acid transporter (EAAT) 1–4 in the prefrontal cortex and hippocampus in stress-maladaptive mice. Mice were chronically exposed to inadaptable stress, i.e. repeated restraint stress for 240 min/day for 14 days. After the final exposure to stress, brains of mice were rapidly removed and the hippocampus and prefrontal cortex were dissected. Expressions of EAAT1-4 and glial fibrillary acidic protein (GFAP), a marker of astrocytes, in the brain tissues were analyzed by western blotting. Western blot analysis revealed that the expression level of EAAT2 was specifically decreased in the hippocampus of stress-maladaptive mice while there were no changes in the level of GFAP, and this change was inhibited by chronic treatment with YKS. In contrast, no changes were observed in the levels of EAAT1, EAAT3 or EAAT4 in stress-maladaptive mice. These results suggest that YKS may protect against the decrease in hippocampal EAAT2 expression induced by stress maladaptation, and this may contribute, at least in part, to the improvement of emotional abnormality.

Crystals of [Pd(tmdt)2] (tmdt = trimethylenetetrathiafulvalenedithiolate) were prepared in order to investigate their physical properties. The electrical resistivity of [Pd(tmdt)2] was measured on single crystals using two-probe methods and showed that the room-temperature conductivity was 100 S·cm–1. The resistivity behaviors implied that [Pd(tmdt)2] was a semimetal at approximately room temperature and became narrow-gap semiconducting as the temperature was decreased to the lowest temperature. X-ray structural studies on small single crystals of [Pd(tmdt)2] at temperatures of 20–300 K performed using synchrotron radiation at SPring-8 showed no distinct structural change over this temperature region. However, small anomalies were observed at approximately 100 K. Electron spin resonance (ESR) spectra were measured over the temperature range of 2.7–301 K. The ESR intensity increased as the temperature decreased to 100 K and then decreased linearly as the temperature was further decreased to 50 K, where an abrupt decrease in the intensity was observed. To investigate the magnetic state, 1H nuclear magnetic resonance (NMR) measurements were performed in the temperature range of 2.5–271 K, revealing broadening below 100 K. The NMR relaxation rate gradually increased below 100 K and formed a broad peak at approximately 50 K, followed by a gradual decrease down to the lowest temperature. These results suggest that most of the sample undergoes the antiferromagnetic transition at approximately 50 K with the magnetic ordering temperatures distributed over a wide range up to 100 K. These electric and magnetic properties of [Pd(tmdt)2] are quite different from those of the single-component molecular (semi)metals [Ni(tmdt)2] and [Pt(tmdt)2], which retain their stable metallic states down to extremely low temperatures. The experimental results and the band structure calculations at the density functional theory level showed that [Pd(tmdt)2] may be an antiferromagnetic Mott insulator with a strong electron correlation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread rapidly since 2019, and the number of reports regarding long COVID has increased. Although the distribution of long COVID depends on patient characteristics, epidemiological data on Japanese patients are limited. Hence, this study aimed to investigate the distribution of long COVID in Japanese patients. This study is the first nationwide Japanese prospective cohort study on long COVID.

Background:Accurate prediction of COVID-19 deterioration could enable clinicians to make optimal decisions on medical interventions or hospitalization. A machine learning-based approach using vital data is recognized as a useful tool to predict the exacerbation of infectious disease. However, in COVID-19, effective prediction models are still emerging. Here we developed an algorithm to predict clinical deterioration in non-severe COVID-19 patients using machine learning techniques with continuous core temperature (CT), SpO2and pulse rate (PR)data obtained via wearable sensors.Methods:Fifty mild to moderate COVID-19 patients admitted to Nishi-Kobe Medical Center between December 2020 and August 2021 were enrolled. Disease severity was judged by WHO criteria. All patients wore a Moni-Patch®️, a wireless CT monitoring patch and a ring-type SpO2monitoring device. CT, SpO2and PR were continuously collected to a smartphone via Bluetooth®️. Data from 41 patients were of sufficient duration and quality to be analyzed and preprocessed to adjust sampling windows before fed into the framework. Additional features were derived by modifying the sensor data using patients’ characteristics. To develop classifiers to distinguish a disease deteriorating into severe one, XGBoost, a gradient-boosted tree algorithm, with 3-fold cross-validation was used. Based on the algorithm, deterioration into severe disease within 24 hour was inferred every single hour using 12-hour time frame data. The area under the curve (AUC) of receiver operating characteristics was analyzed based on the classifier’s prediction threshold.Results:After the enrollment, 13 out of 41 patients developed severe diseases. At the enrollment, baseline characteristics were comparable between mild to moderate and severe disease, except for body temperature that was significantly higher in severe disease. The algorithm developed using the sensor data was able to achieve an AUC of 0.92.Conclusions:Our algorithm could well distinguished COVID-19 deteriorating into severe disease. The results indicates that machine learning approach with continuous CT, SpO2and PRmeasurement using wearable sensors is beneficial to predict the exacerbation of COVID-19.

A ~ - d hybrid electronic system, (DMe-DCNQI) 2 Cu, where the ~ orbital of the organic molecule, DMe-DCNQI, is strongly hybridized with the d xy orbital of Cu, has been studied by 15 N and 13 C NMR at three sites. The analysis of Knight shift, K , local spin susceptibilities in the ~ and d orbitals were determined separately. The ~ and d spin susceptibilities were found to be quite different in magnitude and temperature dependence. Moreover, the Knight shift was separated into those of two constituent bands; a one-dimensional ~ band and a three-dimensional ~ - d band. The relative weight of the band susceptibilities is strongly temperature-dependent. DCNQI: d - ~ Interaction antiferromagnetic and ferromagnetic fluctuations 13 C and 15 N-NMR

Background:Endothelial cell (EC) dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) by mediating structural changes in vasculatures. Various stress that promotes EC dysfunction also induces premature senescence in EC; however, the role of EC senescence in the development of PAH remains unknown.Hypothesis:We hypothesized that senescent ECs play a significant role in the development of PAH.Methods:We generated EC-specific progeroid mice that overexpress the dominant-negative form of telomere repeat binding factor 2 under the control of the VE-cadherin promoter. Following chronic hypoxia exposure, PH phenotypes were assessed by RVSP and lung histology. Gene expression was assessed by RT-qPCR. The interaction of pulmonary artery ECs (PAECs) and pulmonary artery smooth muscle cells (PASMCs) was analyzed using indirect and direct co-culture systems. In addition, gamma-secretase inhibitor (DAPT) was used to inhibit Notch signaling both in the in-vitro and in-vivo studies.Results:The transgene expression was specifically expressed and fairly distributed in various pulmonary blood vessels in EC-specific progeroid mice. After three weeks of hypoxia exposure, EC-specific progeroid mice exhibited exacerbated pulmonary hypertension (PH) phenotype, accompanied by the prominent medial thickening and enhanced proliferation capacity of SMCs in the distal pulmonary arteries. Interestingly, contact-mediated interaction with senescent ECs increased proliferation and migration capacities in SMCs, while the absence of EC-SMC contact abolished those effects. Mechanistically, senescent ECs expressed higher Notch ligands than in young ECs, leading to the enhanced Notch signaling in PASMCs. Consistently, pharmacological inhibition of Notch signaling attenuated senescent ECs’ effects on SMCs in vitro and the PH phenotype in EC-specific progeroid mice in vivo.Conclusions:These findings established the critical roles of senescent ECs in the PAH pathogenesis, suggesting a novel pathological-targeted therapeutic approach for PAH.

Introduction:The severity of Coronavirus disease 2019 (COVID-19) depends on the host immune cell response and dysregulation. Most COVID-19 patients had mild disease, however, 15-30 % of patients developed severe disease which could result in severe acute respiratory failure and death. Risk factors associated with severe disease such as age, smoking and comorbidities are well known, while molecular signatures to predict the disease progression are still emerging.Hypothesis:Severe COVID-19 have a unique gene expression profile in peripheral blood mononuclear cells (PBMCs) at early stage of disease compared to mild disease.Methods:We used RNA sequencing analysis and pathway analysis in PBMCs collected from COVID-19 patients at a median 4 days after the onset. Subsequent clinical course was evaluated by WHO definition (meet any of oxygen saturation < 90 %, respiratory rate > 30 breaths / min and signs of severe respiratory distress or not), and based on the severity, PBMCs obtained from mild (n=6) and severe (n=6) groups were analyzed.Results:At the sample collection, there was no significant difference in clinical characteristics between groups, but laboratory tests exhibited higher C-reactive protein and lactate dehydrogenase levels in severe group compared to mild group (Table). We identified 148 differentially expressed genes (DEGs, FDR < 0.05) that are enriched for a pathway, HDACs deacetylate histone, as the top pathway using Metascape. This includes 15 genes in HIST1cluster that has not only antimicrobial but also cytotoxic and blood coagulation effect once the proteins are released into circulation, which could result in acute lung injury.Conclusions:Our results suggest that the upregulation of HIST1cluster genes expression in PBMCs at early stage of COVID-19 could predict the subsequent disease exacerbation. These findings may also link to the pathophysiology of COVID-19 in the context of histone protein mediated lung injury and respiratory failure.

Magnetism of interacting localized spins on triangular lattice has been of keen interest. We found a quantum spin liquid state in an organic Mott insulator with nearly triangular lattice by means of nuclear-magnetic-resonance experiments. The absence of long-range magnetic ordering was evidenced at low temperatures down to 30 mK in spite of an antiferromagnetic exchange interaction of 250 K between the neighboring spins. Realization of the spin liquid is attributable to the proximity of the present system to the Mott transition, consistent with the theoretical study of the triangular-lattice Hubbard model. Field-induced inhomogeneous spin state is argued in terms of the effect of disorder on the spin liquid.

The quark-model baryon-baryon interaction fss2, proposed by the Kyoto-Niigata group, is a unified model for the complete baryon octet (B8=N, Λ, Σ and Ξ), which is formulated in a framework of the (3q)-(3q) resonating-group method (RGM) using the spin-flavor SU6 quark-model wave functions and effective meson-exchange potentials at the quark level. Model parameters are determined to reproduce properties of the nucleon-nucleon system and the low-energy cross section data for the hyperon-nucleon scattering. Due to the several improvements including the introduction of vector-meson exchange potentials, fss2 has achieved very accurate description of the NN and YN interactions, comparable to various one-boson exchange potentials. We review the essential features of fss2 and our previous model FSS, and their predictions to few-body systems in confrontation with the available experimental data. Some characteristic features of the B8 B8 interactions with the higher strangeness, S=-2, -3, -4, predicted by fss2 are discussed. These quark-model interactions are now applied to realistic calculations of few-body systems in a new three-cluster Faddeev formalism which uses two-cluster RGM kernels. As for the few-body systems, we discuss the three-nucleon bound states, the ΛNN-ΣNN system for the hypertriton, the ααΛ system for 9ΛBe, and the ΛΛα system for 6ΛΛHe.

We present the results of our 13C NMR study of the quasi-two-dimensional organic conductor $\theta$-(BEDT-TTF)2I3under pressure, which is suggested to be a zero-gap conductor by transport measurements. We found that NMR spin shift is proportional to $T$ and that spin--lattice relaxation rate follows the power law $T^{\alpha}$ ($\alpha=3{\mbox{--}}4$), where $T$ is the temperature. This behavior is consistent with the cone-like band dispersion and provides microscopic evidence for the realization of the zero-gap state in the present material under pressure.

79Br NQR measurement is performed to determine the low-energy charge-transfer/dimerization fluctuations in the organic charge-transfer complex DMTTF--2,6-QBr2Cl2. With decreasing temperature, NQR line width gradually increases and the spin--lattice relaxation rate $1/T_{1}$ shows a large enhancement from the two-phonon relaxation law ($T^{7}$). This behavior is consistent with the picture that the present material is situated in the critical region of the charge-lattice-coupled quantum transition.

For Abstract see ChemInform Abstract in Full Text.

The 3α Faddeev equation using the 2α RGM kernel involves redundant components whose contribution to the total wave function cancels out completely. We propose a practical method to solve this Faddeev equation, by eliminating the admixture of such redundant components. The equivalence of the present Faddeev approach and a variational approach using the translationally invariant harmonic-oscillator basis was numerically demonstrated with respect to the 3α bound state corresponding to the ground state of 12C.

We propose a new type of three-cluster equation which uses two-cluster resonating-group-method (RGM) kernels. In this equation, the orthogonality of the total wave function to two-cluster Pauli-forbidden states is essential to eliminate redundant components admixed in the three-cluster systems. The explicit energy dependence inherent in the exchange RGM kernel is self-consistently determined. For bound-state problems, this equation is straightforwardly transformed into the Faddeev equation, which uses a modified singularity-free T-matrix constructed from the two-cluster RGM kernel. The approximation of the present three-cluster formalism can be examined with a more complete calculation using the three-cluster RGM. As a simple example, we discuss three di-neutron (3d′) and 3α systems in the harmonic-oscillator variational calculation. The result of the Faddeev calculation is also presented for the 3d′ system.

The equivalence problem between the Faddeev equation and the usual triad of three-body Lippmann-Schwinger (LS) equations (LS triad) is re-investigated. We maintain that the LS triad does not qualify as an integral equation since its integral kernel is not uniquely defined. We give a derivation of the LS triad that is truely equivalent to the Faddeev equation (FE-LS triad) in a manner in which the correspondence to the Faddeev equation is apparent. The relation between the Faddeev components and the solution of the FE-LS triad is clarified. By probing this relation, we derive an identity that is satisfied by the solution of the LS triad, and which corresponds to the projection property of adjoint Møller operators as formulated by Sandhas. We find that this identity is a consequence of more fundamental identities satisfied by the Faddeev components. We conclude that although the usual LS triad is a valid relation satisfied by the solution of the FE-LS triad, it is not truly equivalent to the Faddeev equation. In particular, even in the absence of rearrangement channels, we find it necessary to retain the FE-LS triad.

The question of whether or not a single 3-body Lippmann-Schwinger (LS) equation can yield a unique solution in the absence of rearrangement channels (RC) is re-investigated. For a Hermitian Hamiltonian, the non-compactness of the integral kernel is shown by demonstrating the existence of continuous spectrum in a manner of Weinberg. This implies that its cause is the disconnected diagrams present with or without RC. Therefore, even in the absence of RC, either the Faddeev equation or the Faddeev-equivalent LS triad is necessary for a rigorous treatment of a 3-body scattering problem. The case with energy-independent absorbing potentials (EIAP) for 2-body interactions in RC is also discussed. The above non-compactness proof is seen to be applicable for this case as well, provided that at least one of the RC potentials is chosen to be a real potential multiplied by a complex constant. Thus, the apparent uniqueness of the CDCC solutions cannot ab initio be attributed to the use of EIAP in RC.

First, we point out that the often quoted non-uniqueness argument on a single three-body Lippmann-Schwinger equation (the LS equation) is either not valid because the manipulation leading to it is justifiable, or inconsequential because the non-uniqueness can easily be discerned and eliminated. Next, we discuss the property of the kernel with energy independent absorbing potentials (EIAP) of general forms. We find that the use of EIAP as in the CDCC approach does not make the kernel compact. it remains non-compact no matter what we use for two-body potentials. Finally, we investigate in what sense the LS equation is solvable in terms of the CDCC approach. When the wave function inside the right-hand side (RHS) of the LS equation is restricted to a small CDCC model space, the difference between the RHS and the ordinary asymptotic form assumed in the approach is found to diverge asymptotically due to contributions from higher partial waves. We conclude that the CDCC solution cannot be claimed to be the solution to the LS equation, not unless it is restricted to a small model space.

The results of Faddeev calculations of the d-α elastic scattering at Ed(Lab)=21 and 56 MeV are reported. Absorption effects in the N-α subsystem are included by using the elastic component of the t-matrix obtained by coupling to reaction channels. The N-α separable interactions up to f-waves are constructed by fitting the phase shifts and absorption coefficients for EN(Lab)≤55 MeV. A Pauli forbidden N-α bound S state is excluded by the orthogonal projection method of Kukulin. For the two-nucleon sector, the 3S1+3D1 separable interactions of Phillips and of Doleschall are utilized. No Coulomb interaction is considered. The results at 21 MeV for the cross sections and vector and tensor analyzing powers are in excellent agreement with the Tsukuba data, however, the RCNP data at 56 MeV are not reproduced well.

NN-OBEP due to Ueda, Riewe and Green is extended to ΛN and ΛΛ systems in the framework of the nonet mesons and SU(3) invariance. The data for Λp cross sections, hypertriton and the ΛΛ separation energies of ΛΛ6 He, ΛΛ10 Be and ΛΛ13 B are reasonably reproduced. No bound state exists for the ΛΛ system. The ΛΛ total cross section is predicted.

This paper proposes an N-12C optical potential. At positive energies, it has an absorption effect through couplings to reaction channels, while at negative energies it supports bound states with appropriate probability strengths of the N-12C configuration. Because of this energy dependence, it can be used for rigorous three-body analyses of nuclear reactions. Some features in a multi-channel problem are also discussed.

A family of three-body equations are investigated in relation with the Møller operator approach (MOA) of Sandhas. The family consists of a single three-body Lippmann-Schwinger (LS) equation (the LS equation), the LS triad of Glöckle, the Faddeev equation, and the Faddeev-equivalent LS triad (the FE-LS triad). We show that all of these equations can be derived from the MOA. However, of these, the LS equation and the LS triad that are derived without introducing the Faddeev decomposition of the total Green function (the FDG) have integral kernels that are either non-compact (the LS equation) or not defined uniquely (the LS triad). We show that, to derive the Faddeev equation and the FE-LS triad from the MOA, it is necessary to incorporate the FDG. This implies that the consideration of the projection properties of the Møller operators (PPMO) among three-body Hilbert spaces alone is not sufficient to assure the equivalence of the MOA to the Faddeev theory. However, we also confirm that, with or without the FDG, all the relations among scattering states obtained from the PPMO are consistent with the three-body equations that are pertinent to the treatment.