National Institutes for Quantum Science and Technology

IL-6 is involved both in immune responses and in inflammation, hematopoiesis, bone metabolism and embryonic development. IL-6 plays roles in chronic inflammation (closely related to chronic inflammatory diseases, autoimmune diseases and cancer) and even in the cytokine storm of corona virus disease 2019 (COVID-19). Acute inflammation during the immune response and wound healing is a well-controlled response, whereas chronic inflammation and the cytokine storm are uncontrolled inflammatory responses. Non-immune and immune cells, cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) and transcription factors nuclear factor-kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3) play central roles in inflammation. Synergistic interactions between NF-κB and STAT3 induce the hyper-activation of NF-κB followed by the production of various inflammatory cytokines. Because IL-6 is an NF-κB target, simultaneous activation of NF-κB and STAT3 in non-immune cells triggers a positive feedback loop of NF-κB activation by the IL-6-STAT3 axis. This positive feedback loop is called the IL-6 amplifier (IL-6 Amp) and is a key player in the local initiation model, which states that local initiators, such as senescence, obesity, stressors, infection, injury and smoking, trigger diseases by promoting interactions between non-immune cells and immune cells. This model counters dogma that holds that autoimmunity and oncogenesis are triggered by the breakdown of tissue-specific immune tolerance and oncogenic mutations, respectively. The IL-6 Amp is activated by a variety of local initiators, demonstrating that the IL-6-STAT3 axis is a critical target for treating diseases.

The newly emerging coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in Wuhan, China, but has rapidly spread all over the world. Some COVID-19 patients encounter a severe symptom of acute respiratory distress syndrome (ARDS) with high mortality. This high severity is dependent on a cytokine storm, most likely induced by the interleukin-6 (IL-6) amplifier, which is hyper-activation machinery that regulates the nuclear factor kappa B (NF-κB) pathway and stimulated by the simultaneous activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. We hypothesize that IL-6-STAT3 signaling is a promising therapeutic target for the cytokine storm in COVID-19, because IL-6 is a major STAT3 stimulator, particularly during inflammation. We herein review the pathogenic mechanism and potential therapeutic targets of ARDS in COVID-19 patients.

Among the various disorders that manifest with gait disturbance, cognitive impairment, and urinary incontinence in the elderly population, idiopathic normal pressure hydrocephalus (iNPH) is becoming of great importance. The first edition of these guidelines for management of iNPH was published in 2004, and the second edition in 2012, to provide a series of timely, evidence-based recommendations related to iNPH. Since the last edition, clinical awareness of iNPH has risen dramatically, and clinical and basic research efforts on iNPH have increased significantly. This third edition of the guidelines was made to share these ideas with the international community and to promote international research on iNPH. The revision of the guidelines was undertaken by a multidisciplinary expert working group of the Japanese Society of Normal Pressure Hydrocephalus in conjunction with the Japanese Ministry of Health, Labour and Welfare research project. This revision proposes a new classification for NPH. The category of iNPH is clearly distinguished from NPH with congenital/developmental and acquired etiologies. Additionally, the essential role of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) in the imaging diagnosis and decision for further management of iNPH is discussed in this edition. We created an algorithm for diagnosis and decision for shunt management. Diagnosis by biomarkers that distinguish prognosis has been also initiated. Therefore, diagnosis and treatment of iNPH have entered a new phase. We hope that this third edition of the guidelines will help patients, their families, and healthcare professionals involved in treating iNPH.

A benchmark experiment on (208)Pb shows that polarized proton inelastic scattering at very forward angles including 0° is a powerful tool for high-resolution studies of electric dipole (E1) and spin magnetic dipole (M1) modes in nuclei over a broad excitation energy range to test up-to-date nuclear models. The extracted E1 polarizability leads to a neutron skin thickness r(skin) = 0.156(-0.021)(+0.025) fm in (208)Pb derived within a mean-field model [Phys. Rev. C 81, 051303 (2010)], thereby constraining the symmetry energy and its density dependence relevant to the description of neutron stars.

Recently, the use of gold nanoparticles as potential tumor selective radiosensitizers has been proposed as a breakthrough in radiotherapy. Experiments in living cells and in vivo have demonstrated the efficiency of the metal nanoparticles when combined with low energy x-ray radiations (below conventional 1 MeV Linac radiation). Further studies on DNA have been performed in order to better understand the fundamental processes of sensitization and to further improve the method. In this work, we propose a new strategy based on the combination of platinum nanoparticles with irradiation by fast ions effectively used in hadron therapy. It is observed in particular that nanoparticles enhance strongly lethal damage in DNA, with an efficiency factor close to 2 for double strand breaks. In order to disentangle the effect of the nano-design architecture, a comparison with the effects of dispersed metal atoms at the same concentration has been performed. It is thus shown that the sensitization in nanoparticles is enhanced due to auto-amplified electronic cascades inside the nanoparticles, which reinforces the energy deposition in the close vicinity of the metal. Finally, the combination of fast ion radiation (hadron therapy) with platinum nanoparticles should strongly improve cancer therapy protocols.

The Telescope Array (TA) experiment, located in the western desert of Utah, USA, is designed for the observation of extensive air showers from extremely high energy cosmic rays. The experiment has a surface detector array surrounded by three fluorescence detectors to enable simultaneous detection of shower particles at ground level and fluorescence photons along the shower track. The TA surface detectors and fluorescence detectors started full hybrid observation in March, 2008. In this article we describe the design and technical features of the TA surface detector.

The fifth version of Japanese Evaluated Nuclear Data Library, JENDL-5, was developed. JENDL-5 aimed to meet a variety of needs not only from nuclear reactors but also from other applications such as accelerators. Most of the JENDL special purpose files published so far were integrated into JENDL-5 with revisions. JENDL-5 consists of 11 sublibraries: (1) Neutron, (2) Thermal scattering law, (3) Fission product yield, (4) Decay data, (5) Proton, (6) Deuteron, (7) Alpha-particle, (8) Photonuclear, (9) Photo-atomic, (10) Electro-atomic, and (11) Atomic relaxation. The neutron reaction data for a large number of nuclei in JENDL-4.0 were updated ranging from light to heavy ones, including major and minor actinides which affect nuclear reactor calculations. In addition, the number of nuclei of neutron reaction data stored in JENDL-5 was largely increased; the neutron data covered not only all of naturally existing nuclei but also their neighbor ones with half-lives longer than 1 day. JENDL-5 included the originally evaluated data of thermal scattering law and fission product yield for the first time. Light charged-particle and photon-induced reaction data were also included for the first time as the JENDL general purpose file.

After publication of the guidelines, the Committee on Guidelines for Diagnosis and Treatment of Esophageal Cancer of the Japan Esophageal Society has taken the initiative to continue to review the contents of the guidelines and conduct public relations and dissemination/utilization activities.A revision of the guidelines is planned for approximately 5 years after publication of this guideline.In addition, a prompt report will be made when the results of a clinical study(ies) are published or in accordance with changes in the medical circumstances, such as revision of the health insurance coverage.

NMR on diamonds gets down to chemistry Nuclear magnetic resonance (NMR) spectroscopy is immensely useful for chemical characterization, but it requires relatively large amounts of sample. Recent studies have leveraged nitrogen vacancy centers in diamond to detect NMR signals from samples of just a few cubic nanometers, but with low resolution. Aslam et al. optimized this technique to achieve a resolution of 1 part per million—sufficient to distinguish among alkyl, vinyl, and aryl protons in solution (see the Perspective by Bar-Gill and Retzker). They also demonstrated solid-state implementation and fluorine detection. Science , this issue p. 67 ; see also p. 38

Abstract The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu 2+ -capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu 2+ into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing 64 Cu 2+ , positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an “ideal” PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy.

Peptide-based materials that have diverse structures and functionalities are an important type of biomaterials. In former times, peptide-based nanomaterials with excellent stability were constructed through self-assembly. Compared with individual peptides, peptide-based self-assembly nanomaterials that form well-ordered superstructures possess many advantages such as good thermo- and mechanical stability, semiconductivity, piezoelectricity and optical properties. Moreover, due to their excellent biocompatibility and biological activity, peptide-based self-assembly nanomaterials have been vastly used in different fields. In this review, we provide the advances of peptide-based self-assembly nanostructures, focusing on the driving forces that dominate peptide self-assembly and assembly mechanisms of peptides. After that, we outline the synthesis and properties of peptide-based nanomaterials, followed by the applications of functional peptide nanomaterials. Finally, we provide perspectives on the challenges and future of peptide-based nanomaterials.

The Fukushima Daiichi nuclear power plant (DNPP) accident caused massive releases of radioactivity into the environment. The released highly volatile fission products, such as (129m)Te, (131)I, (134)Cs, (136)Cs and (137)Cs were found to be widely distributed in Fukushima and its adjacent prefectures in eastern Japan. However, the release of non-volatile actinides, in particular, Pu isotopes remains uncertain almost one year after the accident. Here we report the isotopic evidence for the release of Pu into the atmosphere and deposition on the ground in northwest and south of the Fukushima DNPP in the 20-30 km zones. The high activity ratio of (241)Pu/(239+240)Pu (> 100) from the Fukushima DNPP accident highlights the need for long-term (241)Pu dose assessment, and the ingrowth of (241)Am. The results are important for the estimation of reactor damage and have significant implication in the strategy of decontamination.

We describe a method to calculate the relative biological effectiveness in mixed radiation fields of therapeutic ion beams based on the modified microdosimetric kinetic model (modified MKM). In addition, we show the procedure for integrating the modified MKM into a treatment planning system for a scanned carbon beam. With this procedure, the model is fully integrated into our research version of the treatment planning system. To account for the change in radiosensitivity of a cell line, we measured one of the three MKM parameters from a single survival curve of the current cells and used the parameter in biological optimization. Irradiation of human salivary gland tumor cells was performed with a scanned carbon beam in the Heavy Ion Medical Accelerator in Chiba (HIMAC), and we then compared the measured depth-survival curve with the modified MKM predicted survival curve. Good agreement between the two curves proves that the proposed method is a candidate for calculating the biological effects in treatment planning for ion irradiation.

Abstract Scalable quantum networking requires quantum systems with quantum processing capabilities. Solid state spin systems with reliable spin–optical interfaces are a leading hardware in this regard. However, available systems suffer from large electron–phonon interaction or fast spin dephasing. Here, we demonstrate that the negatively charged silicon-vacancy centre in silicon carbide is immune to both drawbacks. Thanks to its 4 A 2 symmetry in ground and excited states, optical resonances are stable with near-Fourier-transform-limited linewidths, allowing exploitation of the spin selectivity of the optical transitions. In combination with millisecond-long spin coherence times originating from the high-purity crystal, we demonstrate high-fidelity optical initialization and coherent spin control, which we exploit to show coherent coupling to single nuclear spins with ∼1 kHz resolution. The summary of our findings makes this defect a prime candidate for realising memory-assisted quantum network applications using semiconductor-based spin-to-photon interfaces and coherently coupled nuclear spins.

Melanocytes characterized by the activities of tyrosinase, tyrosinase-related protein (TRP)-1 and TRP-2 as well as by melanosomes and dendrites are located mainly in the epidermis, dermis and hair bulb of the mammalian skin. Melanocytes differentiate from melanoblasts, undifferentiated precursors, derived from embryonic neural crest cells. Because hair bulb melanocytes are derived from epidermal melanoblasts and melanocytes, the mechanism of the regulation of the proliferation and differentiation of epidermal melanocytes should be clarified. The regulation by the tissue environment, especially by keratinocytes is indispensable in addition to the regulation by genetic factors in melanocytes. Recent advances in the techniques of tissue culture and biochemistry have enabled us to clarify factors derived from keratinocytes. Alpha-melanocyte-stimulating hormone, adrenocorticotrophic hormone, basic fibroblast growth factor, nerve growth factor, endothelins, granulocyte-macrophage colony-stimulating factor, steel factor, leukemia inhibitory factor and hepatocyte growth factor have been suggested to be the keratinocyte-derived factors and to regulate the proliferation and/or differentiation of mammalian epidermal melanocytes. Numerous factors may be produced in and released from keratinocytes and be involved in regulating the proliferation and differentiation of mammalian epidermal melanocytes through receptor-mediated signaling pathways.

Abstract Microglia-mediated neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD). Although microglia in aging and neurodegenerative disease model mice show a loss of homeostatic phenotype and activation of disease-associated microglia (DAM), a correlation between those phenotypes and the degree of neuronal cell loss has not been clarified. In this study, we performed RNA sequencing of microglia isolated from three representative neurodegenerative mouse models, App NL - G - F/NL - G - F with amyloid pathology, rTg4510 with tauopathy, and SOD1 G93A with motor neuron disease by magnetic activated cell sorting. In parallel, gene expression patterns of the human precuneus with early Alzheimer’s change (n = 11) and control brain (n = 14) were also analyzed by RNA sequencing. We found that a substantial reduction of homeostatic microglial genes in rTg4510 and SOD1 G93A microglia, whereas DAM genes were uniformly upregulated in all mouse models. The reduction of homeostatic microglial genes was correlated with the degree of neuronal cell loss. In human precuneus with early AD pathology, reduced expression of genes related to microglia- and oligodendrocyte-specific markers was observed, although the expression of DAM genes was not upregulated. Our results implicate a loss of homeostatic microglial function in the progression of AD and other neurodegenerative diseases. Moreover, analyses of human precuneus also suggest loss of microglia and oligodendrocyte functions induced by early amyloid pathology in human.

At the National Institute of Radiological Sciences (NIRS), more than 8,000 patients have been treated for various tumors with carbon-ion (C-ion) radiotherapy in the past 20 years based on a radiobiologically defined clinical-dose system. Through clinical experience, including extensive dose escalation studies, optimum dose-fractionation protocols have been established for respective tumors, which may be considered as the standards in C-ion radiotherapy. Although the therapeutic appropriateness of the clinical-dose system has been widely demonstrated by clinical results, the system incorporates several oversimplifications such as dose-independent relative biological effectiveness (RBE), empirical nuclear fragmentation model, and use of dose-averaged linear energy transfer to represent the spectrum of particles. We took the opportunity to update the clinical-dose system at the time we started clinical treatment with pencil beam scanning, a new beam delivery method, in 2011. The requirements for the updated system were to correct the oversimplifications made in the original system, while harmonizing with the original system to maintain the established dose-fractionation protocols. In the updated system, the radiation quality of the therapeutic C-ion beam was derived with Monte Carlo simulations, and its biological effectiveness was predicted with a theoretical model. We selected the most used C-ion beam with αr = 0.764 Gy(-1) and β = 0.0615 Gy(-2) as reference radiation for RBE. The C-equivalent biological dose distribution is designed to allow the prescribed survival of tumor cells of the human salivary gland (HSG) in entire spread-out Bragg peak (SOBP) region, with consideration to the dose dependence of the RBE. This C-equivalent biological dose distribution is scaled to a clinical dose distribution to harmonize with our clinical experiences with C-ion radiotherapy. Treatment plans were made with the original and the updated clinical-dose systems, and both physical and clinical dose distributions were compared with regard to the prescribed dose level, beam energy, and SOBP width. Both systems provided uniform clinical dose distributions within the targets consistent with the prescriptions. The mean physical doses delivered to targets by the updated system agreed with the doses by the original system within ± 1.5% for all tested conditions. The updated system reflects the physical and biological characteristics of the therapeutic C-ion beam more accurately than the original system, while at the same time allowing the continued use of the dose-fractionation protocols established with the original system at NIRS.

Most popular vegetables and fruits and their corresponding soil from the sub-urban industrial area of Bangladesh were collected and the concentration of carcinogenic (Pb, As, and Cd) and non-carcinogenic (Fe, Co, V, Cu, Cr, Zn, Mn, and Ni) heavy metals was determined. Health risk was evaluated by estimating daily heavy metal intake and computing cancer and non-cancer risks (ILCR and THQ) using probabilistic risk assessment model of US-EPA. Heavy metals in vegetables varied with vegetable species as well as metal types. Higher daily intake of As, Fe, Mn, and Pb was observed from the consumption of root and leafy vegetables. Moreover, the probability of an adult for developing cancer from the consumption of studied vegetables was greater than US-EPA threshold risk limit (>10−4) for As and Cd. In addition, cumulative cancer risk (∑ILCR) of all the studied vegetables and fruits exceeded the limit for fruit, root, leafy vegetables, and fruits (22, 15, 59, and 4%) with As, Cd, and Pb as 17, 81, and 2%, respectively. Non-cancer risk index also presented Pb, As, Mn, and Fe as the dominant contaminants of root and leafy vegetables that contributed 80–90% of HI. It suggests that the study area is unsuitable for growing leafy and root vegetables due to the risk of higher intakes of heavy metals which affect food safety. Mn, Pb, Fe, and As are the most predominant heavy metals posing non-cancer risk while Cd caused the highest cancer risk.

In cortical regions of brains from individuals with preclinical or clinical Alzheimer's disease (AD), extracellular β-amyloid (Aβ) deposition precedes the aggregation of pathological intracellular tau (the product of the gene microtubule-associated protein tau (MAPT)). To our knowledge, current mouse models of tauopathy reconstitute tau pathology by overexpressing mutant human tau protein. Here, through a homologous recombination approach that replaced the entire murine Mapt gene with the human ortholog, we developed knock-in mice with humanized Mapt to create an in vivo platform for studying human tauopathy. Of note, the humanized Mapt expressed all six tau isoforms present in humans. We next cross-bred the MAPT knock-in mice with single amyloid precursor protein (App) knock-in mice to investigate the Aβ–tau axis in AD etiology. The double-knock-in mice exhibited higher tau phosphorylation than did single MAPT knock-in mice but initially lacked apparent tauopathy and neurodegeneration, as observed in the single App knock-in mice. We further observed that tau humanization significantly accelerates cell-to-cell propagation of AD brain-derived pathological tau both in the absence and presence of Aβ-amyloidosis. In the presence of Aβ-amyloidosis, tau accumulation was intensified and closely associated with dystrophic neurites, consistently showing that Aβ-amyloidosis affects tau pathology. Our results also indicated that the pathological human tau interacts better with human tau than with murine tau, suggesting species-specific differences between these orthologous pathogenic proteins. We propose that the MAPT knock-in mice will make it feasible to investigate the behaviors and characteristics of human tau in an animal model.

Estimation of cosmic-ray spectra in the atmosphere has been essential for the evaluation of aviation doses. We therefore calculated these spectra by performing Monte Carlo simulation of cosmic-ray propagation in the atmosphere using the PHITS code. The accuracy of the simulation was well verified by experimental data taken under various conditions, even near sea level. Based on a comprehensive analysis of the simulation results, we proposed an analytical model for estimating the cosmic-ray spectra of neutrons, protons, helium ions, muons, electrons, positrons and photons applicable to any location in the atmosphere at altitudes below 20 km. Our model, named PARMA, enables us to calculate the cosmic radiation doses rapidly with a precision equivalent to that of the Monte Carlo simulation, which requires much more computational time. With these properties, PARMA is capable of improving the accuracy and efficiency of the cosmic-ray exposure dose estimations not only for aircrews but also for the public on the ground.