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).

Supermicrovascular anastomosis training using chicken wings and colored water.

Plastic surgeons require experience in supermicroscopic vascular anastomosis. Herein, we report a simple, rapid, and cost-effective training method using chicken wings and colored water. The avian ventral metacarpal artery was selected for dissection and anastomosis to mimic supermicrosurgery. Over 14 weeks (one anastomosis per day), the ulnar artery in 100 chicken wings was exposed by dissection, cut proximally, and injected with blue food dye-colored water by an inexperienced surgeon. After ligating the artery branches, it was cut and subjected to end-to-end anastomosis. Next, colored water was injected into the ulnar artery to check for suture sufficiency. The vessel was re-dissected to inspect the lumen and sutures qualitatively. Of the 100 wings, the first and last 20 wings' ventral metacarpal artery dissection, anastomosis times, and leakage frequency were compared. Avian ventral metacarpal artery diameter was recorded, and the cumulative anastomosis time where individual anastomosis times started decreasing was determined. Leakage rates before and after this point were compared. The avian ventral metacarpal artery diameter was 0.7-0.8 mm. The last 20 wings had significantly shorter median dissection times (12:27 vs. 17:45 min), anastomosis times (9:02 vs. 12:29 min), and leakage rates (15% vs. 70%); more even stitching and parallel ligature points; and less vessel layer inversion than the first 20 wings. After a cumulative anastomosis time of 10 h 26 min, individual times sharply decreased, and the leakage rate decreased significantly (58.3% vs. 23.8%). The proposed method significantly improved supermicrosurgical anastomosis. Thus, we believe that this method will help surgeons improve their supermicrosurgical skills.

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.

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.

Intraocular Ossification in the GSP/pe Chicken With Imperfect Albinism.

The eyes of 2 male and 2 female GSP/pe chickens, the imperfect albino strain, were investigated at 52 weeks of age. Aged chickens of the GSP/pe colony became blind with bilateral ocular enlargement and opaque lenses. Affected eyes (bilateral in 2 males and unilateral in 2 females) were hard and difficult to section; histologic specimens were processed after decalcification. A large portion of the posterior chamber was occupied by cancellous bone containing fibrous and cartilaginous foci. Osseous tissues developed adjacent to the choroid, and no retinal pigment epithelium (RPE) was detected between osseous tissues and the choroid. Small segments of degenerate neuronal retina were scattered in the osseous tissue. The irises and ciliary bodies were deformed by osseous tissue, and the lenses had severe cataracts. These observations suggest that the intraocular osseous tissue may be derived from RPE in the hereditary incomplete-albino strain of chickens.

Prognosis of arterial aneurysm after surgery in patients with Behçet's disease.

AIM: Despite improvements in therapeutic modalities, the treatment of arterial aneurysms complicating Behçet's disease (BD) is still challenging. This study examined the long-term prognosis after surgery for arterial aneurysms in BD. METHODS: This study included 9 patients with BD (8 men and 1 woman) who underwent surgery for arterial aneurysms between 1989 and 2008. The outcomes after the surgical intervention were assessed, including procedure-related complications and survival. RESULTS: The initial surgical procedures were performed for aortic or iliac aneurysms in 5 patients and for lower-extremity aneurysms in 4 patients. There was no operative mortality. The mean follow-up period was 135±69 months, ranging from 53 to 259 months. Patients with aortic or iliac aneurysms underwent graft interposition with Dacron prostheses. Their postoperative courses were uneventful, and all patients were alive during the follow-up with no procedure-related complications. Those treated for lower-extremity aneurysms tended to show perioperative and postoperative complications, including aneurysmal degeneration of the autogenous vein graft in 2 patients. One patient who initially underwent surgery for a popliteal artery aneurysm died due to the rupture of a dissecting aortic aneurysm after serial surgical interventions for multiple aneurysms. Concomitant aortic or iliac aneurysms in 2 patients were followed up without any change in size under medical treatment using colchicine and corticosteroids. CONCLUSION: Although we cannot draw a firm conclusion because of the small number of cases in the present series, graft interposition can lead to a favorable prognosis in BD patients with aortic or iliac aneurysms, whereas surgical treatment of BD-related lower-extremity aneurysms is frequently associated with short- and long-term postoperative complications. Immunosuppressive therapy might possibly improve treatment outcomes.

GATA3 inhibits lysyl oxidase-mediated metastases of human basal triple-negative breast cancer cells.

Discovery of mechanisms that impede the aggressive and metastatic phenotype of human basal triple-negative-type breast cancers (BTNBCs) could provide novel targets for therapy for this form of breast cancer that has a relatively poor prognosis. Previous studies have demonstrated that expression of GATA3, the master transcriptional regulator of mammary luminal differentiation, can reduce the tumorigenicity and metastatic propensity of the human BTNBC MDA-MB-231 cell line (MB231), although the mechanism for reduced metastases was not elucidated. We demonstrate through gene expression profiling that GATA3 expression in 231 cells resulted in the dramatic reduction in the expression of lysyl oxidase (LOX), a metastasis-promoting, matrix-remodeling protein, in part, through methylation of the LOX promoter. Suppression of LOX expression by GATA3 was further confirmed in the BTNBC Hs578T cell line. Conversely, reduction of GATA3 expression by small interfering RNA in luminal BT474 cells increased LOX expression. Reconstitution of LOX expression in 231-GATA3 cells restored metastatic propensity. A strong inverse association between LOX and GATA3 expression was confirmed in a panel of 51 human breast cancer cell lines. Similarly, human breast cancer microarray data demonstrated that high LOX/low GATA3 expression is associated with the BTNBC subtype of breast cancer and poor patient prognosis. Expression of GATA3 reprograms BTNBCs to a less aggressive phenotype and inhibits a major mechanism of metastasis through inhibition of LOX. Induction of GATA3 in BTNBC cells or novel approaches that inhibit LOX expression or activity could be important strategies for treating BTNBCs.

Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy.

To identify transcriptional profiles predictive of the clinical benefit of cisplatin and fluorouracil (CF) chemotherapy to gastric cancer patients, endoscopic biopsy samples from 96 CF-treated metastatic gastric cancer patients were prospectively collected before therapy and analyzed using high-throughput transcriptional profiling and array comparative genomic hybridization. Transcriptional profiling identified 917 genes that are correlated with poor patient survival after CF at P<0.05 (poor prognosis signature), in which protein synthesis and DNA replication/recombination/repair functional categories are enriched. A survival risk predictor was then constructed using genes, which are included in the poor prognosis signature and are contained within identified genomic amplicons. The combined expression of three genes-MYC, EGFR and FGFR2-was an independent predictor for overall survival of 27 CF-treated patients in the validation set (adjusted P=0.017), and also for survival of 40 chemotherapy-treated gastric cancer patients in a published data set (adjusted P=0.026). Thus, combined expression of MYC, EGFR and FGFR2 is predictive of poor survival in CF-treated metastatic gastric cancer patients.

Risk factors for intrahepatic cholangiocarcinoma: a possible role of hepatitis B virus.

There are several established risk factors for intrahepatic cholangiocarcinoma (ICC), namely primary sclerosing cholangitis, fibropolycystic liver disease, parasitic infection, intrahepatic biliary stones and chemical carcinogen exposure. However, the majority of patients with ICC do not have any of these risk factors. Therefore, identification of other risk factors is warranted for the prevention and early detection of ICC. We evaluated the risk factors for ICC in a large-scale cohort study in the province of Osaka, Japan. This retrospective cohort study included 154,814 apparently healthy individual blood donors, aged 40-64 years at the time of blood donation in the period 1991-1993. The average observation period was 7.6 years, resulting in 1.25 million person-years of observation. Incident ICC cases were identified by linking the blood-donor database to the records in the population-based cancer registry for the province. There were 11 incident ICC cases during follow-up, with an incidence rate of 0.88 per 100,000 person-years. Compared with subjects aged 40-49 years, the subjects aged 50-54 years and 55-59 years had a significantly higher risk for ICC (hazard ratio [HR] = 5.90; 95%CI:1.08-32.31 and 11.07; 95%CI:1.98-61.79, respectively). Compared with those with ALT level of 19 Karmen Units (KU) or less, subjects with ALT level of 40 KU or higher had a significantly higher risk for ICC (HR: 8.30; 95%CI:1.47-46.83). Compared with those who tested negative for both HBsAg and anti-HCV, those who tested HBsAg-positive had a significantly higher risk for ICC (HR: 8.56; 95%CI: 1.33-55.20). Our results suggest that HBV infection and liver inflammation are independently associated with ICC development. These findings need to be verified by further large cohort studies.

The localization of proteins encoded by CRYM, KIAA1199, UBA52, COL9A3, and COL9A1, genes highly expressed in the cochlea.

Genes that are highly expressed in the inner ear, as revealed by cDNA microarray analysis, may have a crucial functional role there. Those that are expressed specifically in auditory tissues are likely to be good candidates to screen for genetic alterations in patients with deafness, and several genes have been successfully identified as responsible for hereditary hearing loss. To understand the detailed mechanisms of the hearing loss caused by the mutations in these genes, the present study examined the immunocytochemical localization of the proteins encoded by Crym, KIAA1199 homolog, Uba52, Col9a3, and Col9a1 in the cochlea of rats and mice. Confocal microscopic immunocytochemistry was performed on cryostat sections. Ultrastructurally, postembedding immunogold cytochemistry was applied using Lowicryl sections. Crym protein was predominantly distributed in the fibrocytes in the spiral ligament, as well as the stria vascularis in rats. KIAA1199 protein homolog was localized in various supporting cells, including inner phalangeal, border, inner and outer pillar, and Deiters' cells. Uba52 protein was restrictedly localized within the surface of the marginal cells of the stria vascularis. Collagen type IX was found within the tectorial membrane as well as fibrocytes in the spiral ligament. The present results showed cell-specific localization of the encoded proteins of these highly expressed genes, indicating that the coordinated actions of various molecules distributed in different parts of the cochlea are essential for maintenance of auditory processing in the cochlea.

Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I.

Mutations in the human gene encoding cadherin23 (CDH23) cause Usher syndrome type 1D (USH1D) and nonsyndromic hearing loss. Individuals with Usher syndrome type I have profound congenital deafness, vestibular areflexia and usually begin to exhibit signs of RP in early adolescence. In the present study, we carried out the mutation analysis in all 69 exons of the CDH23 gene in 56 Usher type 1 probands already screened for mutations in MYO7A. A total of 18 of 56 subjects (32.1%) were observed to have one or two CDH23 variants that are presumed to be pathologic. Twenty one different pathologic genome variants were observed of which 15 were novel. Out of a total of 112 alleles, 31 (27.7%) were considered pathologic. Based on our results it is estimated that about 20% of patients with Usher syndrome type I have CDH23 mutations.

Relationship between age at onset and magnetic resonance image-defined hyperintensities in mood disorders.

OBJECTIVES: To examine in patients with mood disorders the relationship of age at onset with the location and degree of MRI-defined brain hyperintensities. METHOD: Fifty-two patients diagnosed as having mood disorders and 14 controls participated in the study. Brain MR images were analyzed according to semiquantitative ratings for the anatomical distribution and severity of T2-weighted hyperintensities. We compared these hyperintensities among the three age- and sex-matched groups of late-onset mood disorder patients (LOM), early-onset mood disorder patients (EOM), and controls. The time since the onset of disorder was significantly longer in the EOM than in the LOM group. We also conducted linear multiple regression analysis using the severity of hyperintensities as dependent variable to determine whether the clinical features correlate with vascular pathology. RESULTS: As for deep white matter hyperintensity (DWMH), LOM exhibited higher ratings than EOM; as for brain areas, significant between-group differences were detected in the bilateral frontal areas and in the left parieto-occipital area. No significant difference was observed between EOM and controls. As for periventricular hyperintensity, there was no difference among the three groups. We obtained a significant regression model to predict DWMH ratings; age, number of ECTs, and LOM were selected as significant variables. CONCLUSION: The present study suggests that the time since the onset of disorder does not affect the development of white matter lesions, but that white matter lesions are associated with late-onset mood disorders. The frontal areas and the left parieto-occipital area would be important for the development of late-onset mood disorders.

Brain metabolic changes associated with predispotion to onset of major depressive disorder and adjustment disorder in cancer patients--a preliminary PET study.

OBJECTIVES: To explore neurobiological risk factors for major depressive disorder (MDD) and adjustment disorder in cancer patients by examining regional brain metabolism before psychiatric manifestation using positron emission tomography and by prospectively observing depressive and anxiety symptoms. METHOD: Cancer patients who showed no psychiatric symptoms when they underwent 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) were followed up for one year using the Hospital Anxiety and Depression Scale (HADS). Fourteen patients who showed high HADS scores and 14 patients who showed low HADS scores were assessed by a psychiatrist 2 years after the PET scan and grouped into the deterioration group (n=10) and the no-change group (n=9). 18F-FDG PET images were analyzed to examine the difference in local brain glucose metabolism between the two groups. RESULTS: The deterioration group showed a decreased glucose metabolism in the right medial frontal gyrus (BA6) and an increased glucose metabolism in the right posterior cingulate (BA29), right anterior cingulate (BA25), left subcallosal gyrus (BA25), and left caudate compared with the no-change group. CONCLUSION: Cancer patients who later developed MDD or adjustment disorder showed regional brain metabolic changes. These regions may be associated with vulnerability to the onset of MDD or adjustment disorder in cancer patients.

CRYM mutations cause deafness through thyroid hormone binding properties in the fibrocytes of the cochlea.

BACKGROUND: In a search for mutations of mu-crystallin (CRYM), a taxion specific crystalline which is also known as an NADP regulated thyroid hormone binding protein, two mutations were found at the C-terminus in patients with non-syndromic deafness. OBJECTIVE: To investigate the mechanism of hearing loss caused by CRYM mutations METHODS: T3 binding activity of mutant mu-crystallin was compared with that of wild-type mu-crystallin, because mu-crystallin is known to be identical to T3 binding protein. To explore the sites within the cochlea where mu-crystallin is functioning, its localisation in the mouse cochlea was investigated immunocytochemically using a specific antibody. RESULTS: One mutant was shown to have no binding capacity for T3, indicating that CRYM mutations cause auditory dysfunction through thyroid hormone binding properties. Immunocytochemical results indicated that mu-crystallin was distributed within type II fibrocytes of the lateral wall, which are known to contain Na,K-ATPase. CONCLUSIONS: CRYM mutations may cause auditory dysfunction through thyroid hormone binding effects on the fibrocytes of the cochlea. mu-Crystallin may be involved in the potassium ion recycling system together with Na,K-ATPase. Future animal experiments will be necessary to confirm a causal relation between Na,K-ATPase, T3, and deafness.

HPA axis normalization, estimated by DEX/CRH test, but less alteration on cerebral glucose metabolism in depressed patients receiving ECT after medication treatment failures.

OBJECTIVE: To examine the clinical effects of electroconvulsive therapy (ECT) on depressed patients with medication treatment failures, we investigated the alterations in hypothalamic-pituitary-adrenocortical (HPA) function and regional cerebral metabolism rate of glucose (rCMRGlu) after ECT in these patients. METHOD: Before and after ECT, the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test was administered to seven patients who were referred for ECT. In the same patients, (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG PET) was also assessed. RESULTS: Cortisol response in the DEX/CRH test significantly decreased after a successful ECT. A significant hypometabolism in various frontal regions and hypermetabolism in the parietal regions of these patients when compared with controls remained after ECT. CONCLUSION: Depressed patients who failed trials of antidepressant medication showed a remission with ECT that was accompanied by resolution of HPA dysregulation. However, measures of cerebral brain metabolism did not resolve.

Attenuation of ganglioside GM1 accumulation in the brain of GM1 gangliosidosis mice by neonatal intravenous gene transfer.

A single intravenous injection with 4 x 10(7) PFU of recombinant adenovirus encoding mouse beta-galactosidase cDNA to newborn mice provided widespread increases of beta-galactosidase activity, and attenuated the development of the disease including the brain at least for 60 days. The beta-galactosidase activity showed 2-4 times as high a normal activity in the liver and lung, and 50 times in the heart. In the brain, while the activity was only 10-20% of normal, the efficacy of the treatment was distinct. At the 30th day after the injection, significant attenuation of ganglioside GM1 accumulation in the cerebrum was shown in three out of seven mice. At the 60th day after the injection, the amount of ganglioside GM1 was above the normal range in all treated mice, which was speculated to be the result of reaccumulation. However, the values were still definitely lower in most of the treated mice than those in untreated mice. In the histopathological study, X-gal-positive cells, which showed the expression of exogenous beta-galactosidase gene, were observed in the brain. It is noteworthy that neonatal administration via blood vessels provided access to the central nervous system because of the incompletely formed blood-brain barrier.