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).

Test of the negative feedback hypothesis of colony size sensing in social insects.

Social insects can sense colony size-even without visual information in a dark environment. How they achieve this is yet largely unknown. We empirically tested a hypothesis on the proximate mechanism using ant colonies. In Diacamma colonies, the monogynous queen is known to increase the effort devoted to queen pheromone transmission behaviour (patrolling) as the colony grows, as if she perceives colony size. The negative feedback hypothesis assumes that, through repeated physical contact with workers, the queen monitors the physiological state (fertility) of workers and increases her patrolling effort when she encounters more fertile workers. Supporting this hypothesis, we found that the queen increased her patrolling effort in response to a higher ratio of fertile workers under the experimental condition of constant colony size. Furthermore, chemical analyses and bioassays suggested that cuticular hydrocarbons have queen pheromone activity and can mediate the observed queen-worker communication of fertility state. Such a self-organizing mechanism of sensing colony size may also operate in other social insects living in small colonies.

Turbulence Spreading into an Edge Stochastic Magnetic Layer Induced by Magnetic Fluctuation and Its Impact on Divertor Heat Load.

Turbulence spreading into the edge stochastic magnetic layer induced by magnetic fluctuation is observed at the sharp boundary region in the large helical device. The density fluctuation excited at the sharp boundary region with a large pressure gradient does not propagate into the boundary region due to the blocking of turbulence spreading by the large second derivative of the pressure gradient. Once the magnetic fluctuation appears at the boundary, the density fluctuation begins to penetrate the edge stochastic layer and the second derivative of the pressure gradient also decreases. The increase of density fluctuation in this layer results in the broadening and reduction of the peak divertor heat load. It is demonstrated that magnetic fluctuation plays a key role in controlling the turbulence spreading at the boundary of plasma which contributes to the reduction of divertor heat load.

Self-Sustained Divertor Oscillation Driven by Magnetic Island Dynamics in Torus Plasma.

A new type of self-sustained divertor oscillation is discovered in the Large Helical Device stellarator, where the peripheral plasma is detached from material diverters by means of externally applied perturbation fields. The divertor oscillation is found to be a self-regulation of an isolated magnetic field structure (the magnetic island) width induced by a drastic change in a poloidal inhomogeneity of the plasma radiation across the detachment-attachment transitions. A predator-prey model between the magnetic island width and a self-generated local plasma current (the bootstrap current) is introduced to describe the divertor oscillation, which successfully reproduces the experimental observations.

Effect of therapeutic plasma exchange on phenytoin plasma concentration in patients receiving intravenous fosphenytoin therapy.

We report for patients with encephalitis treated with plasma exchange (PE) and fosphenytoin. In patient 1, phenytoin levels decreased on the maintenance dose, and the phenytoin concentration was <10 µg/mL on day 12 of administration. In patient 2, the phenytoin levels was <10 µg/mL on day 4. Increasing the fosphenytoin dose pushed the phenytoin level into therapeutic range. There were no differences between the areas under the concentration-time curve of phenytoin with and without PE. We previously reported a decline in phenytoin levels after prolonged use of fosphenytoin. Therefore, dose adjustment of fosphenytoin in patients undergoing PE may be unnecessary.

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.

Altered TDP-43-dependent splicing in HSPB8-related distal hereditary motor neuropathy and myofibrillar myopathy.

BACKGROUND AND PURPOSE: Mutations in the small heat-shock protein 22 gene (HSPB8) have been associated with Charcot-Marie-Tooth disease type 2L, distal hereditary motor neuropathy (dHMN) type IIa and, more recently, distal myopathy/myofibrillar myopathy (MFM) with protein aggregates and TDP-43 inclusions. The aim was to report a novel family with HSPB8K141E -related dHMN/MFM and to investigate, in a patient muscle biopsy, whether the presence of protein aggregates was paralleled by altered TDP-43 function. METHODS: We reviewed clinical and genetic data. We assessed TDP-43 expression by qPCR and alternative splicing of four previously validated direct TDP-43 target exons in four genes by reverse transcriptase-polymerase chain reaction. RESULTS: The triplets and their mother presented in the second to third decade of life with progressive weakness affecting distal and proximal lower limb and truncal muscles. Nerve conduction study showed a motor axonal neuropathy. The clinical features, moderately raised creatin kinase levels, selective pattern of muscle involvement on magnetic resonance imaging and pathological changes on muscle biopsy, including the presence of protein aggregates, supported the diagnosis of a contemporary primary muscle involvement. In affected muscle tissue we observed a consistent alteration of TDP-43-dependent splicing in three out of four TDP-43-target transcripts (POLDIP3, FNIP1 and BRD8), as well as a significant decrease of TDP-43 mRNA levels. CONCLUSIONS: Our study confirmed the role of mutated HSPB8 as a cause of a combined neuromuscular disorder encompassing dHMN and MFM with protein aggregates. We identified impaired RNA metabolism, secondary to TDP-43 loss of function, as a possible pathological mechanism of HSPB8K141E toxicity, leading to muscle and nerve degeneration.

In vitro models of cranial neural crest development toward toxicity tests: frog, mouse, and human.

During craniofacial development, cranial neural crest (NC)-derived mesenchymal cells migrate to pharyngeal arches and contribute extensively to neurons, Schwann cells, smooth muscle cells, osteoblasts, chondrocytes, and odontoblasts, forming maxillofacial structures. In vitro models using model organism cells, such as African clawed frog (Xenopus Laevis) and mouse (Mus Musculus), were developed to understand cellular and molecular mechanisms of cranial NC development. Recent studies using human embryonic stem cells (hESCs) and human-induced pluripotent stem cells (hiPSCs) have enabled the generation of human NC cells (NCCs) in vitro to provide insight into human NC development. Understanding molecular mechanisms underlying craniofacial development will contribute to develop novel embryotoxicity tests and to decrease the incidence of drug-induced congenital anomalies in the craniofacial region, such as cleft lip or cleft palate. Here, we review culture methods to derive NCCs in vitro from Xenopus presumptive ectoderm (animal caps), mouse embryonic stem cells (mESCs), and human pluripotent stem cells (hPSCs) and discuss how these in vitro models can be used to help clarify the mechanisms underlying craniofacial development and for developing embryotoxicity tests predicting drug-induced congenital anomalies in the craniofacial region.

Enhanced regeneration potential of mobilized dental pulp stem cells from immature teeth.

OBJECTIVES: We have previously demonstrated that dental pulp stem cells (DPSCs) isolated from mature teeth by granulocyte colony-stimulating factor (G-CSF)-induced mobilization method can enhance angiogenesis/vasculogenesis and improve pulp regeneration when compared with colony-derived DPSCs. However, the efficacy of this method in immature teeth with root-formative stage has never been investigated. Therefore, the aim of this study was to examine the stemness, biological characteristics, and regeneration potential in mobilized DPSCs compared with colony-derived DPSCs from immature teeth. MATERIALS AND METHODS: Mobilized DPSCs isolated from immature teeth were compared to colony-derived DPSCs using methods including flow cytometry, migration assays, mRNA expression of angiogenic/neurotrophic factor, and induced differentiation assays. They were also compared in trophic effects of the secretome. Regeneration potential was further compared in an ectopic tooth transplantation model. RESULTS: Mobilized DPSCs had higher migration ability and expressed more angiogenic/neurotrophic factors than DPSCs. The mobilized DPSC secretome produced a higher stimulatory effect on migration, immunomodulation, anti-apoptosis, endothelial differentiation, and neurite extension. In addition, vascularization and pulp regeneration potential were higher in mobilized DPSCs than in DPSCs. CONCLUSIONS: G-CSF-induced mobilization method enhances regeneration potential of colony-derived DPSCs from immature teeth.

Spectrum of clinical and genetic features of patients with inherited platelet disorder with suspected predisposition to hematological malignancies: a nationwide survey in Japan.

BACKGROUND: Inherited thrombocytopenia (IT) contains several forms of familial thrombocytopenia and some of them have propensity to hematological malignancies. The etiological and genetic features of this heterogeneous syndrome have not yet been elucidated. PATIENTS AND METHODS: We conducted a nationwide survey to collect clinical information and samples from patients with familial thrombocytopenia and/or hematological malignancies in order to obtain a comprehensive understanding of IT. RESULTS: Among the 43 pedigrees with clinical samples, RUNX1 mutations were identified in 8 pedigrees (18.6%). While MYH9 and ANKRD26 mutations were identified in 2 and 1 pedigrees, respectively, no gene mutations were detected in the remaining 32 pedigrees from a panel of previously reported pathogenetic mutations. Clinical data were comparable between FPD/AML and non-FPD/AML probands. CONCLUSIONS: Our study clarified that it is unexpectedly difficult to diagnose FPD/AML based on clinical information alone, and thus, genetic testing is strongly recommended. Our survey also identified some pedigrees with a strong family history of myelodysplastic syndromes of unknown origin. Additionally, there were 14 pedigrees in which three or more members were affected by immune thrombocytopenia (ITP), and a computer-aided simulation suggested that such a distribution almost never happens by coincidence, which implicates a genetic predisposition to ITP.

Prognostic value of tumor-infiltrating lymphocytes differs depending on histological type and smoking habit in completely resected non-small-cell lung cancer.

BACKGROUND: T-cell infiltration in tumors has been used as a prognostic tool in non-small-cell lung cancer (NSCLC). However, the influence of smoking habit and histological type on tumor-infiltrating lymphocytes (TILs) in NSCLC remains unclear. PATIENTS AND METHODS: We evaluated the prognostic significance of TILs (CD4+, CD8+, CD20+, and FOXP3+) according to histological type and smoking habit using automatic immunohistochemical staining and cell counting in 218 patients with NSCLC. RESULTS: In multivariate survival analyses of clinical, pathological, and immunological factors, a high ratio of FOXP3+ to CD4+ T cells (FOXP3/CD4) [hazard ratio (HR): 4.46, P < 0.01 for overall survival (OS); HR: 1.96, P < 0.05 for recurrence-free survival (RFS)] and a low accumulation of CD20+ B cells (HR: 2.45, P = 0.09 for OS; HR: 2.86, P < 0.01 for RFS) were identified as worse prognostic factors in patients with adenocarcinoma (AD). In non-AD, a low number of CD8+ T cells were correlated with an unfavorable outcome (HR: 7.69, P < 0.01 for OS; HR: 3.57, P < 0.02 for RFS). Regarding smoking habit in AD, a high FOXP3/CD4 ratio was poorly prognostic with a smoking history (HR: 5.21, P < 0.01 for OS; HR: 2.38, P < 0.03 for RFS), whereas a low accumulation of CD20+ B cells (HR: 4.54, P = 0.03 for OS; HR: 2.94, P < 0.01 for RFS) was confirmed as an unfavorable factor in non-smokers with AD. CONCLUSIONS: A low number of CD8+ T cells in non-AD, a high FOXP3/CD4 ratio in smokers with AD, and a low number of CD20+ B cells in non-smokers with AD were identified as independent unfavorable prognostic factors in resected NSCLC. Evaluating the influence of histological type and smoking habit on the immunological environment may lead to the establishment of immunological diagnosis and appropriate individualized immunotherapy for NSCLC.

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.

Two cases of atretic cephalocele, and histological evaluation of skin appendages in the surrounding skin.

Atretic cephalocele is a small skin-covered lesion, usually located at or near the mid-line of the scalp. Histologically, it is composed of syncytial cells expressing neurone-specific enolase and epithelial membrane antigen. The syncytial cells form capillary-like structures *(pseudovascular areas) and collagenic fibrosis with densely packed collagen bundles (fibrous areas). Such findings suggest that the atretic cephalocele is a mild form of cephalocele, with its pathogenesis lying in the spectrum of neural tube closure abnormalities. However, few descriptions of abnormalities of the skin overlying and surrounding atretic cephalocele are available. We report two cases of atretic cephalocele that showed hamartomatous change in the surrounding cutaneous appendages. These findings suggest that atretic cephalocele is associated with abnormalities not only of the neural tube, but also of the surrounding skin.

Usefulness of immunocytochemistry using a Breast Marker antibody cocktail targeting P63/cytokeratin7/18/cytokeratin5/14 for fine needle aspiration of the breast: a retrospective cohort study of 139 cases.

OBJECTIVE: The Breast Marker Cocktail from Biocare Medical comprises five antibodies recognising p63, and cytokeratins (CKs) 7, 18, 5 and 14. Immunohistochemistry using this cocktail is useful for diagnosing proliferative intraductal breast lesions. However, cytology using the cocktail has not been reported. METHODS: We report 139 cases of mammary samples collected by fine needle aspiration (FNA) for which histological diagnoses were available. After cell transfer, immunocytochemistry was performed using the cocktail, and clusters of cells were classified. A cluster with no or limited CK5/14 expression (<20% of cells) was classified as a monotonous cluster. One with more than 20% of cells showing CK5/14 expression was defined as a mosaic cluster. When at least one p63-positive cell was present, we defined it as a cluster with p63. We also evaluated background p63-positive myoepithelial cell densities. RESULTS: The diagnostic sensitivity and specificity for carcinomas were 97.8% (89/91) and 91.7% (11/12), respectively, using the criterion of two or more monotonous clusters lacking p63. Two false-negative cases were triple-negative cancers; one false-positive was an apocrine papilloma. The numbers of monotonous clusters with p63 differed significantly between benign lesions, ductal carcinoma in situ (DCIS)/lobular carcinoma in situ (LCIS) and invasive carcinomas (P < 0.001). The background myoepithelial cell density was significantly higher in fibroepithelial tumours than in other lesions (P < 0.001). CONCLUSIONS: Immunocytochemistry using this antibody cocktail showed good sensitivity and specificity for diagnosing breast cancers. Thus, this method is useful for mammary cytology using FNA.

MRI as a promising tool for evaluation of the stability of cosmetic emulsions.

OBJECTIVE: We have recently established a novel method to evaluate the emulsion stability of pharmaceutical skin cream. The key technology of the method is magnetic resonance imaging (MRI). The purpose of this study was to verify the usefulness of the method in the cosmetic industry. METHODS: Milky lotion-type emulsions were employed as test samples. We note that the test samples were prepared by taking account of commercial milky lotions. After the sample preparation, a centrifugation treatment (5000 g for up to 120 min) was implemented to accelerate their destabilization processes. The centrifuged samples were monitored by using T2 relaxation time (T2 ) maps. Furthermore, the histograms generated from the T2 maps were analysed to investigate the destabilization process in more detail. In addition, small fractions of the upper and lower phases were collected from the centrifuged samples, and microscopic observations were conducted. RESULTS: T2 maps successfully visualized the destabilization process accompanying the centrifugation protocol. From the microscopic observations, it was clarified that the main mechanism of the destabilization process was creaming. The sensitivity of the T2 map to creaming was much superior to that of visible observation; the T2 map can detect a slight creaming that is not visible to the naked eye. In addition, the T2 map also enables the detection of slight reversible creaming-dispersion changes accompanied by a repeated centrifugation-vortexing treatment. By using the parameters derived from the histogram analysis, the creaming behaviour can be evaluated more precisely and more objectively. This study prepared emulsions containing different thickener contents and then compared their creaming behaviours. As a consequence of the analysis, we could fully evaluate the effect of thickener on the emulsion stability by the evaluation method. CONCLUSION: MRI is a promising tool for evaluation of the stability of cosmetic emulsions.

Monolithic device for modelocking and stabilization of frequency combs.

We demonstrate a device that integrates a III-V semiconductor saturable absorber mirror with a graphene electro-optic modulator, which provides a monolithic solution to modelocking and noise suppression in a frequency comb. The device offers a pure loss modulation bandwidth exceeding 5 MHz and only requires a low voltage driver. This hybrid device provides not only compactness and simplicity in laser cavity design, but also small insertion loss, compared to the previous metallic-mirror-based modulators. We believe this work paves the way to portable and fieldable phase-coherent frequency combs.

Effectiveness of antibacterial prophylaxis with non-absorbable polymyxin B compared to levofloxacin after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Fluoroquinolones are widely used for antibacterial prophylaxis during neutropenia following hematopoietic stem cell transplantation (HSCT). Nevertheless, data are inadequate as to whether fluoroquinolones decrease mortality rate compared with other antibiotics. METHODS: We retrospectively compared the efficacy of antibacterial prophylaxis using non-absorbable polymyxin B (PB) (n = 106) or systemic levofloxacin (LVFX) (n = 140) after allogeneic SCT at our institute between 2004 and 2013. RESULTS: No significant difference was observed between the 2 groups in the cumulative incidences of failure of prophylaxis (P = 0.21), clinically documented infections (P = 0.70), or non-relapse mortality within the first 100 days after transplantation (P = 0.42). With bacteremia, the rate of resistance to LVFX was 82% in the PB group and 100% in the LVFX group (P = 0.41). Also, no significant difference was found in overall survival between the 2 groups (P = 0.78). CONCLUSION: Our results indicate no difference in the effectiveness of antibacterial prophylaxis between systemic antibiotic LVFX and non-absorbable antibiotic PB.

Factors Affecting Steady-state Plasma Concentrations of Enantiomeric Mirtazapine and its Desmethylated Metabolites in Japanese Psychiatric Patients.

INTRODUCTION: This study evaluated the effects of the CYP2D6*10 genotype on steady-state plasma concentrations of enantiomeric mirtazapine (MIR) and N-desmethylmirtazapine (DMIR) in Japanese patients. METHODS: Subjects were 77 Japanese patients treated with racemic MIR. Steady-state plasma concentrations of MIR and DMIR enantiomers were measured using stereoselective liquid chromatography. Polymerase chain reaction was used to determine the CYP2D6 genotypes. RESULTS: After correcting for dose and body weight, smokers (n=15) had significantly lower S-(+)-MIR than nonsmokers (n=55) (15.1±17.8 vs. 23.9±17.8 ng/mL/mg/kg, Kruskal-Wallis test, p=0.034). One-way analysis of variance revealed that CYP2D6*10 homozygotes had significantly higher corrected plasma concentrations of S-(+)-MIR than the no-variant allele group (p=0.034). Multiple regression analysis revealed a significant positive correlation between the number of CYP2D6*10 alleles and corrected plasma concentrations of S-(+)-MIR. These results yielded the following final model: corrected plasma concentration of S-(+)-MIR=15.9+7.30×(number of CYP2D6*10 alleles) (R=0.279, p=0.023, coefficient of determination (R(2))=0.078). CONCLUSION: Homozygous CYP2D6*10 alleles and smoking have a significant impact on the metabolism of S-(+)-MIR in Japanese patients.

Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony stimulating factor.

OBJECTIVES: Granulocyte-colony stimulating factor (G-CSF) has been shown to have combinatorial trophic effects with dental pulp stem cells for pulp regeneration. The aim of this investigation is to examine the effects of basic fibroblast growth factor (bFGF) in vitro and in vivo compared with those of G-CSF and to assess the potential utility of bFGF as an alternative to G-CSF for pulp regeneration. MATERIALS AND METHODS: Five different types of cells were examined in the in vitro effects of bFGF on cell migration, proliferation, anti-apoptosis, neurite outgrowth, angiogenesis, and odontogenesis compared with those of G-CSF. The in vivo regenerative potential of pulp tissue including vasculogenesis and odontoblastic differentiation was also compared using an ectopic tooth transplantation model. RESULTS: Basic fibroblast growth factor was similar to G-CSF in high migration, proliferation and anti-apoptotic effects and angiogenic and neurite outgrowth stimulatory activities in vitro. There was no significant difference between bFGF and G-CSF in the regenerative potential in vivo. CONCLUSIONS: The potential utility of bFGF for pulp regeneration is demonstrated as a homing/migration factor similar to the influence of G-CSF.