Evidence of a Hardening in the Cosmic Ray Proton Spectrum at around 166 TeV Observed by the GRAPES-3 Experiment.

We present the measurement of the cosmic ray proton spectrum from 50 TeV to 1.3 PeV using 7.81×10^{6} extensive air shower events recorded by the ground-based GRAPES-3 experiment between 1 January 2014 and 26 October 2015 with a live time of 460 day. Our measurements provide an overlap with direct observations by satellite and balloon-based experiments. The electromagnetic and muon components in the shower were measured by a dense array of plastic scintillator detectors and a tracking muon telescope, respectively. The relative composition of the proton primary from the air shower data containing all primary particles was extracted using the multiplicity distribution of muons which is a sensitive observable for mass composition. The observed proton spectrum suggests a spectral hardening at ∼166 TeV and disfavors a single power law description of the spectrum up to the Knee energy (∼3 PeV).

Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients.

Next generation risk assessment (NGRA) is an exposure-led, hypothesis-driven approach that has the potential to support animal-free safety decision-making. However, significant effort is needed to develop and test the in vitro and in silico (computational) approaches that underpin NGRA to enable confident application in a regulatory context. A workshop was held in Montreal in 2019 to discuss where effort needs to be focussed and to agree on the steps needed to ensure safety decisions made on cosmetic ingredients are robust and protective. Workshop participants explored whether NGRA for cosmetic ingredients can be protective of human health, and reviewed examples of NGRA for cosmetic ingredients. From the limited examples available, it is clear that NGRA is still in its infancy, and further case studies are needed to determine whether safety decisions are sufficiently protective and not overly conservative. Seven areas were identified to help progress application of NGRA, including further investments in case studies that elaborate on scenarios frequently encountered by industry and regulators, including those where a 'high risk' conclusion would be expected. These will provide confidence that the tools and approaches can reliably discern differing levels of risk. Furthermore, frameworks to guide performance and reporting should be developed.

Preemptive analgesia for endoscopic sinus surgery: a retrospective study.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common disease, and endoscopic sinus surgery (ESS) is widely performed. However, there is no consensus regarding postoperative pain control after ESS, and postoperative opioid abuse is a problem in many countries. Acetaminophen is reportedly effective for postoperative pain control. Preemptive analgesia has received more attention lately, wherein pain is prevented before it occurs. In this study, we assessed the use of acetaminophen for preemptive analgesia during the perioperative period in ESS. METHODOLOGY: This is a retrospective study of 175 patients who underwent ESS, septoplasty, and bilateral inferior turbinate mucosal resection at our hospital from April 2016 to February 2018. In total, 82 patients received 1,000 mg of acetaminophen during surgery and 4 hours after the first dose, while 93 patients did not receive it routinely. We compared these two groups. The primary outcome was the need to use additional analgesics prescribed by the ward physician and the secondary outcomes included postoperative pain, postoperative bleeding, reoperation, blood pressure, and body temperature. RESULTS: The use of additional oral and intravenous analgesics was significantly reduced in the patients who received acetaminophen perioperatively. CONCLUSION: Preemptive analgesia during the perioperative period of ESS could lead to satisfactory postoperative pain control.

Maturation of odour identification ability and related factors in children.

BACKGROUND: Olfaction plays an important role in our daily and social lives, both as adults and as children. This study assessed whether the ability to identify odours increases with age, as well as the ability in various age groups and the factors involved. METHODS: The survey was performed in 2017 on 697 Japanese children (366 girls and 331 boys) aged 6â€"18 years who lived in Tsunan, Niigata Prefecture, Japan by using the 'Open Essence', a card-type odour identification test. We collected information regarding age, sex, and physical characteristic. We also inquired whether participants had siblings or if members of the family smoked, and whether they had conversations about odour at home. Statistical analysis was performed to evaluate the factors affecting odour identification abilities. RESULTS: The results showed that the odour identification abilities of children increase with age, and children who have daily conversations about odours at home have better odour identification abilities. CONCLUSIONS: Odour identification ability increases with age. In addition, our findings suggest that conversation may positively affect odour identification. Hence, it is important for children to be exposed to an environment where they develop an interest in smells for better growth of their olfactory identification ability.

Heparin affects the induction of regulatory T cells independent of anti-coagulant activity and suppresses allogeneic immune responses.

Heparin is a widely used anti-coagulant that enhances anti-thrombin (AT) activity. However, heparin also suppresses immune and inflammatory responses in various rodent models and clinical trials, respectively. The mechanism by which heparin suppresses immune responses is unclear. The effect of heparin on regulatory T cells (Tregs ) in allogeneic immune responses was analysed using an acute graft-versus-host disease (aGVHD) mouse model and mixed lymphocyte reactions (MLRs). In-vitro culture systems were utilized to study the effects of heparin on Tregs . Heparin administration reduced mortality rates and increased the proportion of Tregs in the early post-transplantation period of aGVHD mice. In both murine and human MLRs, heparin increased Tregs and inhibited responder T cell proliferation. Heparin promoted functional CD4+ CD25+ forkhead box protein 3 (FoxP3)+ Treg generation from naive CD4+ T cells, increased interleukin (IL)-2 production and enhanced the activation of pre-existing Tregs with IL-2. Heparin-induced Treg increases were not associated with anti-coagulant activity through AT, but required negatively charged sulphation of heparin. Importantly, N-acetyl heparin, a chemically modified heparin without anti-coagulant activity, induced Tregs and decreased mortality in aGVHD mice. Our results indicate that heparin contributes to Treg -mediated immunosuppression through IL-2 production and suggest that heparin derivatives may be useful for immunopathological control by efficient Treg induction.

Measurement of the Electrical Properties of a Thundercloud Through Muon Imaging by the GRAPES-3 Experiment.

The GRAPES-3 muon telescope located in Ooty, India records rapid (∼10 min) variations in the muon intensity during major thunderstorms. Out of a total of 184 thunderstorms recorded during the interval of April 2011-December 2014, the one on December 1, 2014 produced a massive potential of 1.3 GV. The electric field measured by four well-separated (up to 6 km) monitors on the ground was used to help estimate some of the properties of this thundercloud, including its altitude and area that were found to be 11.4 km above mean sea level and ≥380 km^{2}, respectively. A charging time of 6 min to reach 1.3 GV implied the delivery of a power of ≥2 GW by this thundercloud that was moving at a speed of ∼60 km h^{-1}. This work possibly provides the first direct evidence for the generation of gigavolt potentials in thunderclouds that could also possibly explain the production of highest-energy (100 MeV) gamma rays in the terrestrial gamma-ray flashes.

Standardisation of defined approaches for skin sensitisation testing to support regulatory use and international adoption: position of the International Cooperation on Alternative Test Methods.

Skin sensitisation is the regulatory endpoint that has been at the centre of concerted efforts to replace animal testing in recent years, as demonstrated by the Organisation for Economic Co-operation and Development (OECD) adoption of five non-animal methods addressing mechanisms under the first three key events of the skin sensitisation adverse outcome pathway. Nevertheless, the currently adopted methods, when used in isolation, are not sufficient to fulfil regulatory requirements on the skin sensitisation potential and potency of chemicals comparable to that provided by the regulatory animal tests. For this reason, a number of defined approaches integrating data from these methods with other relevant information have been proposed and documented by the OECD. With the aim to further enhance regulatory consideration and adoption of defined approaches, the European Union Reference Laboratory for Alternatives to Animal testing in collaboration with the International Cooperation on Alternative Test Methods hosted, on 4-5 October 2016, a workshop on the international regulatory applicability and acceptance of alternative non-animal approaches, i.e., defined approaches, to skin sensitisation assessment of chemicals used in a variety of sectors. The workshop convened representatives from more than 20 regulatory authorities from the European Union, United States, Canada, Japan, South Korea, Brazil and China. There was a general consensus among the workshop participants that to maximise global regulatory acceptance of data generated with defined approaches, international harmonisation and standardisation are needed. Potential assessment criteria were defined for a systematic evaluation of existing defined approaches that would facilitate their translation into international standards, e.g., into a performance-based Test Guideline. Informed by the discussions at the workshop, the ICATM members propose practical ways to further promote the regulatory use and facilitate adoption of defined approaches for skin sensitisation assessments.

Telomere length determined by the fluorescence in situ hybridisation distinguishes malignant and benign cells in cytological specimens.

BACKGROUND: Telomeres are tandem repeats of TTAGGG at the end of eukaryotic chromosomes that play a key role in preventing chromosomal instability. The aim of the present study is to determine telomere length using fluorescence in situ hybridisation (FISH) on cytological specimens. METHODS: Aspiration samples (n = 41) were smeared on glass slides and used for FISH. RESULTS: Telomere signal intensity was significantly lower in positive cases (cases with malignancy, n = 25) as compared to negative cases (cases without malignancy, n = 16), and the same was observed for centromere intensity. The difference in DAPI intensity was not statistically significant. The ratio of telomere to centromere intensity did not show a significant difference between positive and negative cases. There was no statistical difference in the signal intensities of aspiration samples from ascites or pleural effusion (n = 23) and endoscopic ultrasound-guided FNA samples from the pancreas (n = 18). CONCLUSIONS: The present study revealed that telomere length can be used as an indicator to distinguish malignant and benign cells in cytological specimens. This novel approach may help improve diagnosis for cancer patients.

Lip b 1 is a novel allergenic protein isolated from the booklouse, Liposcelis bostrychophila.

BACKGROUND: Booklice, belonging to the order Psocoptera, are small household insect pests that are distributed worldwide. Liposcelis bostrychophila, a common home-inhabiting species of booklouse, infests old books, sheets of paper, and stored food. Recent entomological and serological studies demonstrated that L. bostrychophila accounted for the majority of detectable insects in house dust and could be a potent inducer of respiratory allergy. Our recent proteomic analysis identified a potent allergenic protein from L. bostrychophila, designated Lip b 1, and determined its partial amino acid sequences. METHODS: Cloning of cDNAs for Lip b 1 was performed by large-scale transcriptome analysis (RNA-seq) and subsequent reverse transcription polymerase chain reaction. The full-length amino acid sequences deduced from Lip b 1 cDNAs were bioinformatically analyzed. The recombinant proteins of glutathione S-transferase (GST)-fused Lip b 1 were analyzed by Western blot and enzyme-linked immunosorbent assay. RESULTS: Lip b 1 cDNAs encoding two types of 254-amino acid proteins were cloned. The clones shared 87% identity, and the deduced molecular weights and isoelectric points were consistent with those determined in our previous study. The two types of Lip b 1 proteins in the GST-fused form were similarly reactive with sera from allergic patients sensitized with L. bostrychophila. CONCLUSIONS: Lip b 1 is a novel protein possibly causing booklouse allergy.

Efficacy and safety of rebamipide liquid for chemoradiotherapy-induced oral mucositis in patients with head and neck cancer: a multicenter, randomized, double-blind, placebo-controlled, parallel-group phase II study.

BACKGROUND: Recent preclinical and phase I studies have reported that rebamipide decreased the severity of chemoradiotherapy-induced oral mucositis in patients with oral cancer. This placebo-controlled randomized phase II study assessed the clinical benefit of rebamipide in reducing the incidence of severe chemoradiotherapy-induced oral mucositis in patients with head and neck cancer (HNC). METHODS: Patients aged 20-75 years with HNC who were scheduled to receive chemoradiotherapy were enrolled. Patients were randomized to receive rebamipide 2% liquid, rebamipide 4% liquid, or placebo. The primary endpoint was the incidence of grade ≥ 3 oral mucositis determined by clinical examination and assessed by central review according to the Common Terminology Criteria of Adverse Events version 3.0. Secondary endpoints were the time to onset of grade ≥ 3 oral mucositis and the incidence of functional impairment (grade ≥ 3) based on the evaluation by the Oral Mucositis Evaluation Committee. RESULTS: From April 2014 to August 2015, 97 patients with HNC were enrolled, of whom 94 received treatment. The incidence of grade ≥ 3 oral mucositis was 29% and 25% in the rebamipide 2% and 4% groups, respectively, compared with 39% in the placebo group. The proportion of patients who did not develop grade ≥ 3 oral mucositis by day 50 of treatment was 57.9% in the placebo group, whereas the proportion was 68.0% in the rebamipide 2% group and 71.3% in the rebamipide 4% group. The incidences of adverse events potentially related to the study drug were 16%, 26%, and 13% in the placebo, rebamipide 2%, and rebamipide 4% groups, respectively. There was no significant difference in treatment compliance among the groups. CONCLUSIONS: The present phase II study suggests that mouth washing with rebamipide may be effective and safe for patients with HNC receiving chemoradiotherapy, and 4% liquid is the optimal dose of rebamipide. TRIAL REGISTRATION: ClinicalTrials.gov under the identifier NCT02085460 (the date of trial registration: March 11, 2014).

Transient Weakening of Earth's Magnetic Shield Probed by a Cosmic Ray Burst.

The GRAPES-3 tracking muon telescope in Ooty, India measures muon intensity at high cutoff rigidities (15-24 GV) along nine independent directions covering 2.3 sr. The arrival of a coronal mass ejection on 22 June 2015 18:40 UT had triggered a severe G4-class geomagnetic storm (storm). Starting 19:00 UT, the GRAPES-3 muon telescope recorded a 2 h high-energy (∼20 GeV) burst of galactic cosmic rays (GCRs) that was strongly correlated with a 40 nT surge in the interplanetary magnetic field (IMF). Simulations have shown that a large (17×) compression of the IMF to 680 nT, followed by reconnection with the geomagnetic field (GMF) leading to lower cutoff rigidities could generate this burst. Here, 680 nT represents a short-term change in GMF around Earth, averaged over 7 times its volume. The GCRs, due to lowering of cutoff rigidities, were deflected from Earth's day side by ∼210° in longitude, offering a natural explanation of its night-time detection by the GRAPES-3. The simultaneous occurrence of the burst in all nine directions suggests its origin close to Earth. It also indicates a transient weakening of Earth's magnetic shield, and may hold clues for a better understanding of future superstorms that could cripple modern technological infrastructure on Earth, and endanger the lives of the astronauts in space.

Airway intervention in cases of acute epiglottitis.

Airway intervention in cases of acute epiglottitis.Problem/objectives: In cases of acute epiglottitis, indications for airway intervention have not been established. In the present study, we reviewed patients with acute epiglottitis to identify clinical factors, which suggest airway intervention should be performed. METHODOLOGY: Patients with acute epiglottitis admitted to The Jikei University Daisan Hospital (Tokyo) from 2004 to 2013 were identified. Patients' characteristics, histories, laryngoscopic findings and laboratory findings were reviewed and analysed. RESULTS: Of the 83 patients (82 adults and one adolescent) in the sample, 16 (19%) underwent airway intervention and conservative treatment. The factors that were significantly more likely to have been present in patients who received airway intervention were odynophagia, drooling, hoarseness, muffled voice, dyspnoea, swelling of the posterior side of the epiglottis, less than 50% of the glottis area being visible with laryngoscopy, and a high white blood cell (WBC) count. The only factor that was shown by multiple logistic regression analysis to be distinctively predictive of airway intervention was "less than 50% of the glottis area being visible" (P = .000, odds ratio = 23.630, sensitivity = 86.6%, specificity = 78.6%, predictive accuracy = 85.2%). CONCLUSIONS: When considering whether airway intervention should be performed in cases of acute epiglottitis, the most important clinical factor is the laryngoscopic finding that "less than 50% of the glottis area being visible." Other important clinical factors to consider are odynophagia, drooling, hoarseness, muffled voice, dyspnoea, swelling of the posterior side of the epiglottis and a high WBC count.

Determination of HLA-A, -C, -B, -DRB1 allele and haplotype frequency in Japanese population based on family study.

The present study investigates the human leucocyte antigen (HLA) allele and haplotype frequencies in Japanese population. We carried out the frequency analysis in 5824 families living across Japanese archipelago. The studied population has mainly been typed for the purpose of transplant, especially the hematopoietic stem cell transplantation (HSCT). We determined HLA class I (A, B, and C) and HLA class II (DRB1) using Luminex technology. The haplotypes were directly counted by segregation. A total of 44 HLA-A, 29 HLA-C, 75 HLA-B, and 42 HLA-DRB1 alleles were identified. In the HLA haplotypes of A-C-B-DRB1 and C-B, the pattern of linkage disequilibrium peculiar to Japanese population has been confirmed. Moreover, the haplotype frequencies based on family study was compared with the frequencies estimated by maximum likelihood estimation (MLE), and the equivalent results were obtained. The allele and haplotype frequencies obtained in this study could be useful for anthropology, transplantation therapy, and disease association studies.

A molecular dynamics study of intramolecular proton transfer reaction of malonaldehyde in solution based upon a mixed quantum-classical approximation. II. Proton transfer reaction in non-polar solvent.

The intramolecular proton transfer reaction of malonaldehyde in neon solvent has been investigated by mixed quantum-classical molecular dynamics (QCMD) calculations and fully classical molecular dynamics (FCMD) calculations. Comparing these calculated results with those for malonaldehyde in water reported in Part I [A. Yamada, H. Kojima, and S. Okazaki, J. Chem. Phys. 141, 084509 (2014)], the solvent dependence of the reaction rate, the reaction mechanism involved, and the quantum effect therein have been investigated. With FCMD, the reaction rate in weakly interacting neon is lower than that in strongly interacting water. However, with QCMD, the order of the reaction rates is reversed. To investigate the mechanisms in detail, the reactions were categorized into three mechanisms: tunneling, thermal activation, and barrier vanishing. Then, the quantum and solvent effects were analyzed from the viewpoint of the reaction mechanism focusing on the shape of potential energy curve and its fluctuations. The higher reaction rate that was found for neon in QCMD compared with that found for water solvent arises from the tunneling reactions because of the nearly symmetric double-well shape of the potential curve in neon. The thermal activation and barrier vanishing reactions were also accelerated by the zero-point energy. The number of reactions based on these two mechanisms in water was greater than that in neon in both QCMD and FCMD because these reactions are dominated by the strength of solute-solvent interactions.

Plasma CD147 reflects histological features in patients with lupus nephritis.

OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN.

All-atom molecular dynamics calculation study of entire poliovirus empty capsids in solution.

Small viruses that belong, for example, to the Picornaviridae, such as poliovirus and foot-and-mouth disease virus, consist simply of capsid proteins and a single-stranded RNA (ssRNA) genome. The capsids are quite stable in solution to protect the genome from the environment. Here, based on long-time and large-scale 6.5 × 10(6) all-atom molecular dynamics calculations for the Mahoney strain of poliovirus, we show microscopic properties of the viral capsids at a molecular level. First, we found equilibrium rapid exchange of water molecules across the capsid. The exchange rate is so high that all water molecules inside the capsid (about 200,000) can leave the capsid and be replaced by water molecules from the outside in about 25 µs. This explains the capsid's tolerance to high pressures and deactivation by exsiccation. In contrast, the capsid did not exchange ions, at least within the present simulation time of 200 ns. This implies that the capsid can function, in principle, as a semipermeable membrane. We also found that, similar to the xylem of trees, the pressure of the solution inside the capsid without the genome was negative. This is caused by coulombic interaction of the solution inside the capsid with the capsid excess charges. The negative pressure may be compensated by positive osmotic pressure by the solution-soluble ssRNA and the counter ions introduced into it.

Irsogladine maleate reduces the incidence of fluorouracil-based chemotherapy-induced oral mucositis.

BACKGROUND: Oral mucositis is one of the most common side-effects of 5-fluorouracil (5-FU)-based chemotherapy. The objective of this study was to evaluate the effects of irsogladine maleate (IM) on fluorouracil-induced oral mucositis through a double-blind, placebo controlled trial. PATIENTS AND METHODS: Patients (N = 66) were randomly assigned to receive either placebo or IM (4 mg/day for 14 consecutive days). The incidence and maximum severity of fluorouracil-induced oral mucositis and safety of the irsogladine dosing regimen were evaluated. RESULTS: A cohort of 33 patients received placebo and 33 patients received IM. The incidence of oral mucositis was significantly lower for IM than for placebo (27% versus 73%; P < 0.001 by chi-square test). Specific adverse events considered related to IM were not found. CONCLUSION: IM significantly reduced the incidence and maximum severity of oral mucositis in patients treated with 5-FU-chemotherapy.

Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption.

The molecular mechanisms regulating the amount of dietary cholesterol retained in the body, as well as the body's ability to exclude selectively other dietary sterols, are poorly understood. An average western diet will contain about 250-500 mg of dietary cholesterol and about 200-400 mg of non-cholesterol sterols. About 50-60% of the dietary cholesterol is absorbed and retained by the normal human body, but less than 1% of the non-cholesterol sterols are retained. Thus, there exists a subtle mechanism that allows the body to distinguish between cholesterol and non-cholesterol sterols. In sitosterolemia, a rare autosomal recessive disorder, affected individuals hyperabsorb not only cholesterol but also all other sterols, including plant and shellfish sterols from the intestine. The major plant sterol species is sitosterol; hence the name of the disorder. Consequently, patients with this disease have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease. We previously mapped the STSL locus to human chromosome 2p21 and further localized it to a region of less than 2 cM bounded by markers D2S2294 and D2S2291 (M.-H.L. et al., manuscript submitted). We now report that a new member of the ABC transporter family, ABCG5, is mutant in nine unrelated sitosterolemia patients.

Granular flow experiment using artificial gravity generator at International Space Station.

Studying the gravity-dependent characteristics of regolith, fine-grained granular media covering extra-terrestrial bodies is essential for the reliable design and analysis of landers and rovers for space exploration. In this study, we propose an experimental approach to examine a granular flow under stable artificial gravity conditions for a long duration generated by a centrifuge at the International Space Station. We also perform a discrete element simulation of the granular flow in both artificial and natural gravity environments. The simulation results verify that the granular flows in artificial and natural gravity are consistent. Further, regression analysis of the experimental results reveals that the mass flow rate of granular flow quantitatively follows a well-known physics-based law with some deviations under low-gravity conditions, implying that the bulk density of the granular media decreases with gravity. This insight also indicates that the bulk density considered in simulation studies of space probes under low-gravity conditions needs to be tuned for their reliable design and analysis.

Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis.

Human noggin (NOG) is a responsible gene for multiple synostosis syndrome (SYNS1) and proximal symphalangism (SYM1), two conditions that are recently known to be within a wider range of clinical manifestations of stapes ankylosis with symphalangism. This study was performed to determine the range of phenotype caused by NOG mutations, using Japanese patients with various phenotypes including sporadic inherited SYM1, dominantly inherited SYM1, stapes ankylosis with broad thumb and toes (Teunissen and Cremer syndrome). In addition, 33 patients with typical otosclerosis (without symphalangism) were studied. Direct sequencing analysis disclosed three novel mutations of the NOG gene in three SYM1 families. None of the otosclerosis patients without symphalangism had NOG mutations, indicating that NOG mutations may be restrictively found within patients with various skeletal abnormalities. These results together with the literature review indicated that there are no clear genotype-phenotype correlations for NOG mutations. With regard to surgical outcome, most of the patients in these three families with NOG mutations showed remarkable air-bone gap recovery after stapes surgery. Molecular genetic testing is useful to differentiate syndromic stapes ankylosis from otosclerosis, and even mild skeletal anomalies can be a diagnostic indicator of NOG-associated disease.