Search for the Pair Production of Dark Particles X with K_{L}

We present the first search for the pair production of dark particles X via K_{L}^{0}→XX with X decaying into two photons using the data collected by the KOTO experiment. No signal was observed in the mass range of 40-110 MeV/c^{2} and 210-240 MeV/c^{2}. This sets upper limits on the branching fractions as B(K_{L}^{0}→XX)<(1-4)×10^{-7} and B(K_{L}^{0}→XX)<(1-2)×10^{-6} at the 90% confidence level for the two mass regions, respectively.

Gamma-Ray Observation of the Cygnus Region in the 100-TeV Energy Region.

We report observations of gamma-ray emissions with energies in the 100-TeV energy region from the Cygnus region in our Galaxy. Two sources are significantly detected in the directions of the Cygnus OB1 and OB2 associations. Based on their positional coincidences, we associate one with a pulsar PSR J2032+4127 and the other mainly with a pulsar wind nebula PWN G75.2+0.1, with the pulsar moving away from its original birthplace situated around the centroid of the observed gamma-ray emission. This work would stimulate further studies of particle acceleration mechanisms at these gamma-ray sources.

First Detection of sub-PeV Diffuse Gamma Rays from the Galactic Disk: Evidence for Ubiquitous Galactic Cosmic Rays beyond PeV Energies.

We report, for the first time, the long-awaited detection of diffuse gamma rays with energies between 100 TeV and 1 PeV in the Galactic disk. Particularly, all gamma rays above 398 TeV are observed apart from known TeV gamma-ray sources and compatible with expectations from the hadronic emission scenario in which gamma rays originate from the decay of π^{0}'s produced through the interaction of protons with the interstellar medium in the Galaxy. This is strong evidence that cosmic rays are accelerated beyond PeV energies in our Galaxy and spread over the Galactic disk.

First Detection of Photons with Energy beyond 100 TeV from an Astrophysical Source.

We report on the highest energy photons from the Crab Nebula observed by the Tibet air shower array with the underground water-Cherenkov-type muon detector array. Based on the criterion of a muon number measured in an air shower, we successfully suppress 99.92% of the cosmic-ray background events with energies E>100 TeV. As a result, we observed 24 photonlike events with E>100 TeV against 5.5 background events, which corresponds to a 5.6σ statistical significance. This is the first detection of photons with E>100 TeV from an astrophysical source.

Discovery of

The discovery of the important neutron-rich nucleus _{20}^{60}Ca_{40} and seven others near the limits of nuclear stability is reported from the fragmentation of a 345 MeV/u ^{70}Zn projectile beam on ^{9}Be targets at the radioactive ion-beam factory of the RIKEN Nishina Center. The produced fragments were analyzed and unambiguously identified using the BigRIPS two-stage in-flight separator. The eight new neutron-rich nuclei discovered, ^{47}P, ^{49}S, ^{52}Cl, ^{54}Ar, ^{57}K, ^{59,60}Ca, and ^{62}Sc, are the most neutron-rich isotopes of the respective elements. In addition, one event consistent with ^{59}K was registered. The results are compared with the drip lines predicted by a variety of mass models and it is found that the models in best agreement with the observed limits of existence in the explored region tend to predict the even-mass Ca isotopes to be bound out to at least ^{70}Ca.

Evaluation of the Interplanetary Magnetic Field Strength Using the Cosmic-Ray Shadow of the Sun.

We analyze the Sun's shadow observed with the Tibet-III air shower array and find that the shadow's center deviates northward (southward) from the optical solar disk center in the "away" ("toward") interplanetary magnetic field (IMF) sector. By comparing with numerical simulations based on the solar magnetic field model, we find that the average IMF strength in the away (toward) sector is 1.54±0.21_{stat}±0.20_{syst} (1.62±0.15_{stat}±0.22_{syst}) times larger than the model prediction. These demonstrate that the observed Sun's shadow is a useful tool for the quantitative evaluation of the average solar magnetic field.

Effect of Repetitive Sub-concussive Head Impacts on Ocular Near Point of Convergence.

This study intended to examine effects of repetitive sub-concussive head impacts on ocular near point of convergence (NPC). 20 healthy young adult soccer players were assigned to either a heading or control group. Heading subjects completed 10 headers of soccer balls projected at a speed of 11.2 m/s. Control subjects did not perform heading. Linear head acceleration was measured with a triaxial accelerometer. The NPC assessment was performed at pre-, 0 h post-, and 24 h post-heading. During the NPC assessment participants were seated and a visual target was moved towards the eyes at 1cm/sec. The participant signaled when he/she experienced diplopia or deviation of the eye was observed, and the distance was recorded. The assessment was repeated twice and average NPC scores were used for further analysis. Soccer heading induced mean group head accelerations of 14.49±5.4 g. Mild head impacts led to an increased NPC distance, which was supported by a significant Group x Time interaction. In the heading group, 0 h post- and 24 h post-heading NPC scores were significantly receded compared to baseline. Conversely, NPC scores for the control group showed no difference over time. Our findings indicate that mild frontal head impacts affekt NPC for a minimum of 24 h-post heading, suggesting that oculomotor processes are disrupted, at least transiently, by repetitive mild head impact.

Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis.

While there have been significant advances in our understanding of the autoimmune responses and the molecular nature of the target autoantigens in primary biliary cirrhosis (PBC), unfortunately these data have yet to be translated into new therapeutic agents. We have taken advantage of a unique murine model of autoimmune cholangitis in which mice expressing a dominant negative form of transforming growth factor ß receptor II (dnTGFßRII), under the control of the CD4 promoter, develop an intense autoimmune cholangitis associated with serological features similar to human PBC. CD40-CD40 ligand (CD40L) is a major receptor-ligand pair that provides key signals between cells of the adaptive immune system, prompting us to determine the therapeutic potential of treating autoimmune cholangitis with anti-CD40L antibody (anti-CD40L; MR-1). Four-week-old dnTGFßRII mice were injected intraperitoneally with either anti-CD40L or control immunoglobulin (Ig)G at days 0, 2, 4 and 7 and then weekly until 12 or 24 weeks of age and monitored for the progress of serological and histological features of PBC, including rigorous definition of liver cellular infiltrates and cytokine production. Administration of anti-CD40L reduced liver inflammation significantly to 12 weeks of age. In addition, anti-CD40L initially lowered the levels of anti-mitochondrial autoantibodies (AMA), but these reductions were not sustained. These data indicate that anti-CD40L delays autoimmune cholangitis, but the effect wanes over time. Further dissection of the mechanisms involved, and defining the events that lead to the reduction in therapeutic effectiveness will be critical to determining whether such efforts can be applied to PBC.

Probe of the solar magnetic field using the "cosmic-ray shadow" of the sun.

We report on a clear solar-cycle variation of the Sun's shadow in the 10 TeV cosmic-ray flux observed by the Tibet air shower array during a full solar cycle from 1996 to 2009. In order to clarify the physical implications of the observed solar cycle variation, we develop numerical simulations of the Sun's shadow, using the potential field source surface model and the current sheet source surface (CSSS) model for the coronal magnetic field. We find that the intensity deficit in the simulated Sun's shadow is very sensitive to the coronal magnetic field structure, and the observed variation of the Sun's shadow is better reproduced by the CSSS model. This is the first successful attempt to evaluate the coronal magnetic field models by using the Sun's shadow observed in the TeV cosmic-ray flux.

An extremely energetic cosmic ray observed by a surface detector array.

Cosmic rays are energetic charged particles from extraterrestrial sources, with the highest-energy events thought to come from extragalactic sources. Their arrival is infrequent, so detection requires instruments with large collecting areas. In this work, we report the detection of an extremely energetic particle recorded by the surface detector array of the Telescope Array experiment. We calculate the particle's energy as [Formula: see text] (~40 joules). Its arrival direction points back to a void in the large-scale structure of the Universe. Possible explanations include a large deflection by the foreground magnetic field, an unidentified source in the local extragalactic neighborhood, or an incomplete knowledge of particle physics.

Identification of lenvatinib prognostic index via recursive partitioning analysis in advanced hepatocellular carcinoma.

BACKGROUND: After the advent of new treatment options for advanced hepatocellular carcinoma (HCC), the identification of prognostic factors is crucial for the selection of the most appropriate therapy for each patient. PATIENTS AND METHODS: With the aim to fill this gap, we applied recursive partitioning analysis (RPA) to a cohort of 404 patients treated with lenvatinib. RESULTS: The application of RPA resulted in a classification based on five variables that originated a new prognostic score, the lenvatinib prognostic index (LEP) index, identifying three groups: low risk [patients with prognostic nutritional index (PNI) >43.3 and previous trans-arterial chemoembolization (TACE)]; medium risk [patients with PNI >43.3 but without previous TACE and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage B (BCLC-B)]; high risk [patients with PNI <43.3 and ALBI grade 2 and patients with PNI <43.3, albumin-bilirubin (ALBI) grade 1 and Barcelona Clinic Liver Cancer stage C (BCLC-C)]. Median overall survival was 29.8 months [95% confidence interval (CI) 22.8-29.8 months] in low risk patients (n = 128), 17.0 months (95% CI 15.0-24.0 months) in medium risk (n = 162) and 8.9 months (95% CI 8.0-10.7 months) in high risk (n = 114); low risk hazard ratio (HR) 1 (reference group), medium risk HR 1.95 (95% CI 1.38-2.74), high risk HR 4.84 (95% CI 3.16-7.43); P < 0.0001. The LEP index was validated in a cohort of 127 Italian patients treated with lenvatinib. While the same classification did not show a prognostic value in a cohort of 311 patients treated with sorafenib, we also show a possible predictive role in favor of lenvatinib in the low risk group. CONCLUSIONS: LEP index is a promising, easy-to-use tool that may be used to stratify patients undergoing systemic treatment of advanced HCC.

Nonalcoholic steatohepatitis in hepatocarcinoma: new insights about its prognostic role in patients treated with lenvatinib.

BACKGROUND: Hepatocellular carcinoma (HCC) treatment remains a big challenge in the field of oncology. The liver disease (viral or not viral) underlying HCC turned out to be crucial in determining the biologic behavior of the tumor, including its response to treatment. The aim of this analysis was to investigate the role of the etiology of the underlying liver disease in survival outcomes. PATIENTS AND METHODS: We conducted a multicenter retrospective study on a large cohort of patients treated with lenvatinib as first-line therapy for advanced HCC from both Eastern and Western institutions. Univariate and multivariate analyses were performed. RESULTS: Among the 1232 lenvatinib-treated HCC patients, 453 (36.8%) were hepatitis C virus positive, 268 hepatitis B virus positive (21.8%), 236 nonalcoholic steatohepatitis (NASH) correlate (19.2%) and 275 had other etiologies (22.3%). The median progression-free survival (mPFS) was 6.2 months [95% confidence interval (CI) 5.9-6.7 months] and the median overall survival (mOS) was 15.8 months (95% CI 14.9-17.2 months). In the univariate analysis for OS NASH-HCC was associated with longer mOS [22.2 versus 15.1 months; hazard ratio (HR) 0.69; 95% CI 0.56-0.85; P = 0.0006]. In the univariate analysis for PFS NASH-HCC was associated with longer mPFS (7.5 versus 6.5 months; HR 0.84; 95% CI 0.71-0.99; P = 0.0436). The multivariate analysis confirmed NASH-HCC (HR 0.64; 95% CI 0.48-0.86; P = 0.0028) as an independent prognostic factor for OS, along with albumin-bilirubin (ALBI) grade, extrahepatic spread, neutrophil-to-lymphocyte ratio, portal vein thrombosis, Eastern Cooperative Oncology Group (ECOG) performance status and alpha-fetoprotein. An interaction test was performed between sorafenib and lenvatinib cohorts and the results highlighted the positive predictive role of NASH in favor of the lenvatinib arm (P = 0.0047). CONCLUSION: NASH has been identified as an independent prognostic factor in a large cohort of patients with advanced HCC treated with lenvatinib, thereby suggesting the role of the etiology in the selection of patients for tyrosine kinase treatment. If validated, this result could provide new insights useful to improve the management of these patients.

Association between serotonin transporter gene polymorphism and smoking among Japanese males.

The serotoninergic system may be involved in smoking behavior because nicotine increases brain serotonin secretion, nicotine withdrawal decreases serotonin levels, and a selective serotonin reuptake inhibitor antagonizes the response to nicotine. Compared with the L allele, the S allele of the polymorphism in the upstream regulatory region of the serotonin transporter gene is associated with decreased transcription efficiency of the 5-HTT gene promoter. We examined this polymorphism in a Japanese population consisting of 387 males from two different areas in Japan. The L allele was observed significantly more often in smokers (21%) than in nonsmokers (lifetime nonsmokers + ex-smokers, 14%; P = 0.005). The presence of the L allele (the L/L + L/S genotypes) was also significantly increased in smokers (37%) compared with that in nonsmokers (24%; P = 0.003). The present study suggests that individuals with the S/S genotype are less inclined to smoke and/or can more easily stop smoking than others, supporting a role of the serotoninergic system in smoking behavior.

Methylenetetrahydrofolate reductase and apolipoprotein E polymorphisms are independent risk factors for coronary heart disease in Japanese: a case-control study.

A missense variant of the C677T (Ala --> Val) polymorphism in the methylenetetrahydrofolate reductase gene (MTHFR) (the T allele) may increase levels of plasma homocysteine. Apolipoprotein E4 increases plasma LDL-cholesterol levels. Increased levels of homocysteine and LDL-cholesterol have been recognized as risk factors for coronary heart disease (CHD). To examine whether the polymorphisms in the MTHFR gene and the APOE gene are associated with CHD in the Japanese, we analyzed 214 CHD patients with an onset age before 65 and 310 apparently healthy persons. In the controls, significantly higher plasma concentrations of homocysteine were observed in the MTHFR TT genotype (15.1+/-6.0 mmol/l) compared with the CT genotype (11.2+/-1.9 mmol/l) and the CC genotype (10.5+/-3.3 mmol/l). The MTHFR TT genotype was significantly more frequent in the CHD patients (28.5%) compared with the control subjects (13.5%); the odds ratio was 2.54 (P < 0.00003). Subjects with the apo E4 allele were significantly more frequent in the CHD group (22.9%) than in the control group (10.0%); the odds ratio was 2.74 (P < 0.00004). Multivariate analysis showed that the TT genotype of MTHFR and the apoE4 allele are independent risk factors for CHD in the Japanese.

Synthesis and evaluation of novel fluorinated methotrexate derivatives for application to rheumatoid arthritis treatment.

An ongoing search for new antifolate drugs useful against rheumatoid arthritis (RA) led us to prepare new methotrexate (MTX) derivatives containing enantiomerically pure L-erythro- or L-threo-gamma-fluoroglutamic acid. The derivatives in which the phenyl ring was replaced by a 3'-substituted phenyl or methylthiophene ring showed potent immunosuppressive activities, including in vitro inhibition of mitogen responses to both T and B cells and in vivo inhibition of antibody production in mice. These compounds also exhibited inhibitory activity in adjuvant arthritis in rats. Their toxicity was lower than that of MTX, which was probably due to the strong electronegativity of fluorine, which increases the acidity of the gamma-carboxyl group and thereby decreases polyglutamylation in normal cells. These results revealed the potential of the fluorinated MTX derivatives as candidate drugs for the treatment of RA.

A synergistic effect of serotonin transporter gene polymorphism and smoking in association with CHD.

Serotonin induces vasoconstriction in the presence of atherosclerotic lesions. Platelets acquire serotonin from the extracellular space by serotonin transporter and release it following aggregation. There is a functional polymorphism in the serotonin transporter (5-HTT) gene promoter associated with transcriptional efficacy and plasma serotonin levels. To examine whether the polymorphism is associated with coronary heart disease (CHD) in the Japanese, we analyzed 144 male CHD patients with an onset age before 65 and 222 apparently healthy men. The L allele was observed significantly more frequently in the CHD patients (26%) than in the control subjects (19%); the odds ratio was 1.48 (p <0.03). A significant interaction between the polymorphism and smoking was observed for CHD (p = 0.03), suggesting that the two have a synergistic effect on CHD. Odds ratio of the combination of the L allele and smoking was 1.95 (p <0.003). The 5-HTT gene promoter polymorphism may play a role in susceptibility to CHD, particularly when it is combined with smoking.

Effects of cyclopiazonic acid on contraction and intracellular Ca2+ in oesophageal striated muscle of normotensive and spontaneously hypertensive rats.

1. The effects of cyclopiazonic acid (CPA), a selective inhibitor of sarcoplasmic reticulum (SR) Ca2+-ATPase, on twitch contraction and on the resting state of tension and intracellular Ca2+ level ([Ca2+]i) of the oesophageal striated muscle of stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar Kyoto rats (WKY) were compared. 2. CPA (10 micronM) augmented the twitch contraction of oesophageal striated muscle preparations from both SHRSP and WKY, reducing the rate of relaxation (-dT/dt), and thus resulting in the prolongation of the time to 80% relaxation. The effect was significantly smaller in the SHRSP preparations. 3. In the resting state, CPA caused a sustained elevation of [Ca2+]i. The elevation was greater in the WKY preparations. Tension development accompanied by the elevation was observed in WKY preparations, but not in SHRSP preparations. 4. The sustained elevation of [Ca2+]i induced by CPA was eliminated by the removal of extracellular Ca2+. Both the elevated [Ca2+]i and tension in the preparations from WKY were reduced by flufenamic acid (100 micronM), mefenamic acid (100 micronM), lanthanum (La3+, 100 micronM), gadolinium (Gd3+, 100 micronM) and SK&F 96365 (100 micronM) but not by verapamil (10 micronM). 5. Thapsigargin (3 micronM), another SR Ca2+-ATPase inhibitor, produced similar effects on basal tension to those of CPA, although it reduced the amplitude of twitch contraction. 6. These results suggest that in the rat oesophageal striated muscle, (1) CPA extends the sequestrating time of Ca2+ into the SR, (2) CPA induces a Ca2+ influx mediated through verapamil-insensitive pathways, possibly nonselective cation channels, and (3) the mechanism of [Ca2+](i) modulation due to CPA-sensitive SR Ca2+-ATPase is deteriorated in the oesophageal striated muscle from SHRSP as compared with WKY preparations.

Stability and effectiveness of chlorine disinfectants in water distribution systems.

A test system for water distribution was used to evaluate the stability and effectiveness of three residual disinfectants--free chlorine, combined chlorine, and chlorine dioxide--when challenged with a sewage contaminant. The test distribution system consisted of the street main and internal plumbing for two barracks at Fort George G. Meade, MD. To the existing pipe network, 152 m (500 ft) of 13-mm (0.5 in.) copper pipe were added for sampling, and 60 m (200 ft) of 2.54-cm (1.0 in.) plastic pipe were added for circulation. The levels of residual disinfectants tested were 0.2 mg/L and 1.0 mg/L as available chlorine. In the absence of a disinfectant residual, microorganisms in the sewage contaminant were consistently recovered at high levels. The presence of any disinfectant residual reduced the microorganism level and frequency of occurrence at the consumer's tap. Free chlorine was the most effective residual disinfectant and may serve as a marker or flag in the distribution network. Free chlorine and chlorine dioxide were the least stable in the pipe network. The loss of disinfectant in the pipe network followed first-order kinetics. The half-life determined in static tests for free chlorine, chlorine dioxide, and combined chlorine was 140, 93, and 1680 min.

High prevalence rate of Helicobacter pylori resistance to clarithromycin during long-term multiple antibiotic therapy for chronic respiratory disease caused by non-tuberculous mycobacteria.

BACKGROUND: Helicobacter pylori resistance to clarithromycin, probably due to the frequent use of this antibiotic for the treatment of other diseases, is the greatest obstacle against its eradication. AIM: To clarify the prevalence of clarithromycin-resistant H. pylori in patients with non-tuberculous mycobacterial lung disease receiving multiple antibiotic treatment, including clarithromycin. METHODS: We enrolled 88 patients with non-tuberculous mycobacterial lung disease; 29 underwent upper gastrointestinal endoscopy for the diagnosis of H. pylori infection prior to treatment, and 60 underwent it during treatment. The diagnosis of H. pylori infection was confirmed by histological examination, urease test and microaerobic bacterial culture. The minimum inhibitory concentration of clarithromycin was determined and the DNA was analysed for each of the isolated H. pylori strains. RESULTS: Patients during the treatment had a high prevalence rate of clarithromycin-resistant H. pylori (100%). Analysis of DNA of the clarithromycin-resistant H. pylori isolates revealed point mutations at A2142G or A2143G. Moreover, a linear correlation was found between the total cumulative dose of clarithromycin and the minimum inhibitory concentration. CONCLUSION: All patients with non-tuberculous mycobacterial lung disease being treated long-term with multiple antibiotics, including clarithromycin, harboured clarithromycin-resistant H. pylori in the stomach. Therefore, eradication of H. pylori before commencement of long-term therapy including clarithromycin should be recommended.

Mizoroki-Heck type reaction of organoboron reagents with alkenes and alkynes. A Pd(II)-catalyzed pathway with Cu(OAc)2 as an oxidant.

[reaction: see text]. In contrast to the Pd(0)-catalyzed mechanism by Uemura, Mizoroki-Heck type reaction of boronic acids is found to proceed under a Pd(II)-mediated pathway using a catalytic amount of Pd(OAc)2 in the presence of Cu(OAc)2 as an oxidant. Treatment of a variety of alkenes with boronic acids, boronates, and sodium tetraphenylborate furnishes beta-arylated and alkenylated products in good to excellent yields. The reactions with norbornene, norbornadiene, and diphenylacetylene are also performed to give 1:2 or 2:1 coupling products.