OPERA tau neutrino charged current interactions.

The OPERA experiment was designed to discover the vτ appearance in a vµ beam, due to neutrino oscillations. The detector, located in the underground Gran Sasso Laboratory, consisted of a nuclear photographic emulsion/lead target with a mass of about 1.25 kt, complemented by electronic detectors. It was exposed from 2008 to 2012 to the CNGS beam: an almost pure vµ beam with a baseline of 730 km, collecting a total of 1.8·1020 protons on target. The OPERA Collaboration eventually assessed the discovery of vµâ†’vτ oscillations with a statistical significance of 6.1 σ by observing ten vτ CC interaction candidates. These events have been published on the Open Data Portal at CERN. This paper provides a detailed description of the vτ data sample to make it usable by the whole community.

Bedrock sculpting under an active alpine glacier revealed from cosmic-ray muon radiography.

Mountain glaciers form landscapes with U-shaped valleys, roche moutonées and overdeepenings through bedrock erosion. However, little evidence for active glacial carving has been provided particularly for areas above the Equilibrium Line Altitude (ELA) where glaciers originate. This is mainly due to our lack of information about the shape of the bedrock underneath active glaciers in highly elevated areas. In the past years, the bedrock morphology underneath active glaciers has been studied by geophysical methods in order to infer the subglacial mechanisms of bedrock erosion. However, these comprise surveys on the glaciers' surface, from where it has been difficult to investigate the lateral boundary between the ice and the bedrock with sufficient resolution. Here we perform a muon-radiographic inspection of the Eiger glacier (Switzerland, European Alps) with the aid of cosmic-ray muon attenuation. We find a reach (600 × 300 m) within the accumulation area where strong lateral glacial erosion has cut nearly vertically into the underlying bedrock. This suggests that the Eiger glacier has profoundly sculpted its bedrock in its accumulation area. This also reveals that the cosmic-ray muon radiography is an ideal technology to reconstruct the shape of the bedrock underneath an active glacier.

Final Results of the OPERA Experiment on ν_{τ} Appearance in the CNGS Neutrino Beam.

The OPERA experiment was designed to study ν_{µ}→ν_{τ} oscillations in the appearance mode in the CERN to Gran Sasso Neutrino beam (CNGS). In this Letter, we report the final analysis of the full data sample collected between 2008 and 2012, corresponding to 17.97×10^{19} protons on target. Selection criteria looser than in previous analyses have produced ten ν_{τ} candidate events, thus reducing the statistical uncertainty in the measurement of the oscillation parameters and of ν_{τ} properties. A multivariate approach for event identification has been applied to the candidate events and the discovery of ν_{τ} appearance is confirmed with an improved significance level of 6.1σ. |Δm_{32}^{2}| has been measured, in appearance mode, with an accuracy of 20%. The measurement of the ν_{τ} charged-current cross section, for the first time with a negligible contamination from ν[over ¯]_{τ}, and the first direct evidence for the ν_{τ} lepton number are also reported.

Discovery of τ Neutrino Appearance in the CNGS Neutrino Beam with the OPERA Experiment.

The OPERA experiment was designed to search for ν_{µ}→ν_{τ} oscillations in appearance mode, i.e., by detecting the τ leptons produced in charged current ν_{τ} interactions. The experiment took data from 2008 to 2012 in the CERN Neutrinos to Gran Sasso beam. The observation of the ν_{µ}→ν_{τ} appearance, achieved with four candidate events in a subsample of the data, was previously reported. In this Letter, a fifth ν_{τ} candidate event, found in an enlarged data sample, is described. Together with a further reduction of the expected background, the candidate events detected so far allow us to assess the discovery of ν_{µ}→ν_{τ} oscillations in appearance mode with a significance larger than 5σ.

The TRIM-FLMN protein TRIM45 directly interacts with RACK1 and negatively regulates PKC-mediated signaling pathway.

The receptor for activated C-kinase (RACK1), a scaffolding protein that participates in the protein kinase C (PKC) signaling pathway, has an important role in shuttling active PKCs to its substrate. Indeed, recent studies have revealed that RACK1 has an important role in tumorigenesis and that enhancement of the feed-forward mechanism of the c-Jun N-terminal kinase (JNK)-Jun pathway via RACK1 is associated with constitutive activation of MEK (MAPK-ERK kinase)-ERK (extracellular signal-regulated kinase) signaling in human melanoma cells. Taken together, RACK1 additionally has a very important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Here, we show that one of the tripartite motif-containing (TRIM) family ubiquitin ligases, TRIM45, is a novel RACK1-interacting protein and downregulates MAPK signal transduction. Importantly, the expression of TRIM45 is induced when growth-promoting extracellular stimuli activate the MAPK signaling pathway, resulting in attenuation of activation of the MAPK pathway. These findings suggest that TRIM45 functions as a member of the negative feedback loop of the MAPK pathway.

A moiré deflectometer for antimatter.

The precise measurement of forces is one way to obtain deep insight into the fundamental interactions present in nature. In the context of neutral antimatter, the gravitational interaction is of high interest, potentially revealing new forces that violate the weak equivalence principle. Here we report on a successful extension of a tool from atom optics--the moiré deflectometer--for a measurement of the acceleration of slow antiprotons. The setup consists of two identical transmission gratings and a spatially resolving emulsion detector for antiproton annihilations. Absolute referencing of the observed antimatter pattern with a photon pattern experiencing no deflection allows the direct inference of forces present. The concept is also straightforwardly applicable to antihydrogen measurements as pursued by the AEgIS collaboration. The combination of these very different techniques from high energy and atomic physics opens a very promising route to the direct detection of the gravitational acceleration of neutral antimatter.

Precise measurement of the neutrino mixing parameter θ23 from muon neutrino disappearance in an off-axis beam.

New data from the T2K neutrino oscillation experiment produce the most precise measurement of the neutrino mixing parameter θ23. Using an off-axis neutrino beam with a peak energy of 0.6 GeV and a data set corresponding to 6.57×10(20) protons on target, T2K has fit the energy-dependent νµ oscillation probability to determine oscillation parameters. The 68% confidence limit on sin(2)(θ23) is 0.514(-0.056)(+0.055) (0.511±0.055), assuming normal (inverted) mass hierarchy. The best-fit mass-squared splitting for normal hierarchy is Δm32(2)=(2.51±0.10)×10(-3) eV(2)/c(4) (inverted hierarchy: Δm13(2)=(2.48±0.10)×10(-3) eV(2)/c(4)). Adding a model of multinucleon interactions that affect neutrino energy reconstruction is found to produce only small biases in neutrino oscillation parameter extraction at current levels of statistical uncertainty.

Observation of electron neutrino appearance in a muon neutrino beam.

The T2K experiment has observed electron neutrino appearance in a muon neutrino beam produced 295 km from the Super-Kamiokande detector with a peak energy of 0.6 GeV. A total of 28 electron neutrino events were detected with an energy distribution consistent with an appearance signal, corresponding to a significance of 7.3σ when compared to 4.92±0.55 expected background events. In the Pontecorvo-Maki-Nakagawa-Sakata mixing model, the electron neutrino appearance signal depends on several parameters including three mixing angles θ12, θ23, θ13, a mass difference Δm(32)(2) and a CP violating phase δ(CP). In this neutrino oscillation scenario, assuming |Δm(32)(2)|=2.4×10(-3) eV(2), sin(2)θ(23)=0.5, and Δm322>0 (Δm(32)(2)<0), a best-fit value of sin(2)2θ(13)=0.140(-0.032)(+0.038) (0.170(-0.037)(+0.045)) is obtained at δ(CP)=0. When combining the result with the current best knowledge of oscillation parameters including the world average value of θ(13) from reactor experiments, some values of δ(CP) are disfavored at the 90% C.L.

Measurement of neutrino oscillation parameters from muon neutrino disappearance with an off-axis beam.

The T2K Collaboration reports a precision measurement of muon neutrino disappearance with an off-axis neutrino beam with a peak energy of 0.6 GeV. Near detector measurements are used to constrain the neutrino flux and cross section parameters. The Super-Kamiokande far detector, which is 295 km downstream of the neutrino production target, collected data corresponding to 3.01×10(20) protons on target. In the absence of neutrino oscillations, 205±17 (syst) events are expected to be detected while only 58 muon neutrino event candidates are observed. A fit to the neutrino rate and energy spectrum, assuming three neutrino flavors and normal mass hierarchy yields a best-fit mixing angle sin2(θ23)=0.514±0.082 and mass splitting |Δm(32)(2)|=2.44(-0.15)(+0.17)×10(-3) eV2/c4. Our result corresponds to the maximal oscillation disappearance probability.

Activation of the brainstem precedes and outlasts the K-complex in humans.

A K-complex (KC) in the electroencephalographs (EEGs) indicates a moderate depth of slow-wave sleep (SWS) in humans and animals. The cortical activities are upregulated during the periods between the KCs ("up state"), and it is proposed that temporarily stored memories during wakeful periods will be consolidated during these periods. Although the underlying mechanism for KCs is proposed to be in the cortex itself, the involvement of the brainstem has not been explored. Here we investigate the excitability changes of the brainstem preceding, during, and after KCs in humans. We simultaneously recorded brainstem auditory evoked potentials (BAEPs) with EEGs, and sequentially analyzed BAEPs around the KCs. The results showed a transient activation of the ventral brainstem preceding the KC and a sustained activation of the dorsal brainstem outlasting the KC. Thus, it is suggested that KCs are triggered by the activation of the brainstem and that the "up state" is maintained by the sustained activation of the brainstem.

Indication of electron neutrino appearance from an accelerator-produced off-axis muon neutrino beam.

The T2K experiment observes indications of ν(µ) → ν(e) appearance in data accumulated with 1.43×10(20) protons on target. Six events pass all selection criteria at the far detector. In a three-flavor neutrino oscillation scenario with |Δm(23)(2)| = 2.4×10(-3) eV(2), sin(2)2θ(23) = 1 and sin(2)2θ(13) = 0, the expected number of such events is 1.5±0.3(syst). Under this hypothesis, the probability to observe six or more candidate events is 7×10(-3), equivalent to 2.5σ significance. At 90% C.L., the data are consistent with 0.03(0.04) < sin(2)2θ(13) < 0.28(0.34) for δ(CP) = 0 and a normal (inverted) hierarchy.

Successful reduced-intensity SCT from unrelated cord blood in three patients with X-linked SCID.

We describe three males with X-linked SCID (X-SCID) who were successfully treated by reduced-intensity SCT from unrelated cord blood (CB). Mean age at transplant was 5.7 months (range, 3-9 months). Pre-transplant conditioning for all patients consisted of fludarabine (FLU) (30 mg/m(2) per day) from day -7 to day -2 (total dose 180 mg/m(2)) and BU 4 mg/kg per day from day -3 to day -2 (total dose 8 mg/kg). All CB units were serologically matched at HLA-A, B and DR loci. Although two patients had suffered from fungal or bacterial pneumonia before transplantation, there were no other infectious complications during transplantation. All patients engrafted and achieved 100% donor chimerism. We also confirmed full donor chimerism of both T and B cells. Only one patient developed acute GVHD grade III, which was resolved by increasing the dose of oral corticosteroid. None of the patients has developed chronic GVHD during follow up for 21-77 months. None of the patient received i.v. Ig replacement post transplant, or showed delay in psychomotor development. Reduced-intensity conditioning consisting of FLU and BU and transplantation from unrelated CB was an effective and safe treatment for these patients with X-SCID.

Identification of the DSPP mutation in a new kindred and phenotype-genotype correlation.

OBJECTIVE: Hereditary dentin defects can be grouped into three types of dentinogenesis imperfecta (DGI) and two types of dentin dysplasia. Tooth enamel is considered normal in patients with hereditary dentin defects, but is easily worn down and fractured due to DSPP mutation-induced altered dentin properties. The purposes of this study were to identify genetic cause of a family with type II DGI and enamel defects. MATERIALS AND METHODS: We identified a family with type II DGI and a unique form of hypoplastic enamel defect affecting occlusal third of the crown. Family members were recruited for the genetic analysis and DNA was obtained from peripheral whole blood. RESULTS: Mutational analysis revealed a T to A transversion in exon 3 of the DSPP (c.53T>A, p.V18D). Haplotype analysis showed that the same mutation arose separately in two different families having DGI with similar enamel defects, indicating that this phenotype is associated with this specific DSPP mutation. Clinical features suggest that enamel formation was affected in the affected individuals during early amelogenesis, in addition to the dentin defect. CONCLUSIONS: We observed that a DSPP gene mutation not only influences dentinogenesis but also affects early stage amelogenesis.

The syndrome of inappropriate secretion of antidiuretic hormone associated with SCT: clinical differences following SCT using cord blood and BM/peripheral blood.

Previously, we reported the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) as an underestimated complication associated with SCT. In the present report, we analyzed detailed data on a larger number of patients with SIADH following SCT and found different SIADH clinical features following cord blood SCT (CBSCT) and BMT/PBSCT. The median onset of SIADH following CBSCT and BMT/PBSCT was 19 and 46 days after SCT, respectively, and the median numbers of WBC at the onset of SIADH were 1.0 and 3.1 x 10(9)/l, respectively. Furthermore, severe symptoms such as seizures, somnolence and rigidity of limbs were observed only in patients with CBSCT (8/15 vs 0/10). These differences were statistically significant (P<0.01). Although the precise basis for SIADH following SCT still remains unknown, the different features of SIADH observed following CBSCT and BMT/PBSCT may provide important clues to the disease mechanism following SCT. Additionally, we confirmed our previous results that patients with SIADH showed a higher overall survival and event-free survival rates. However, we first suggested that they had some neurological disorders and that neurological sequelae such as developmental delay and seizures would consequently occur.

5-Aza-2'-deoxycytidine suppresses human renal carcinoma cell growth in a xenograft model via up-regulation of the connexin 32 gene.

BACKGROUND AND PURPOSE: The connexin (Cx) 32 gene, a member of the gap junction gene family, acts as a tumour suppressor gene in human renal cell carcinoma (RCC) and is down-regulated by the hypermethylation of CpG islands in a promoter region of the Cx gene. The current study investigated whether the restoration of Cx32 silenced by hypermethylation in RCC by a DNA demethylating agent could be an effective treatment against RCC. EXPERIMENTAL APPROACH: Using nude mice bearing Caki-1 cells (a human metastatic RCC cell line), the effects of 5-aza-2'-deoxycytidine (5-aza-CdR), a DNA demethylase inhibitor, on Cx32 mRNA expression and tumour growth were examined by RT-PCR, and by measuring tumour weight and volume. Cx32 expression in Caki-1 tumours was inhibited by Cx32 short interfering (si) RNA, and the effect of siRNA on 5-aza-CdR-dependent suppression of tumour growth in nude mice was evaluated. KEY RESULTS: 5-aza-CdR treatment inhibited the growth of Caki-1 cells in nude mice by 70% and increased 7-fold the level of Cx32 mRNA. The intratumour injection of Cx32 siRNA almost totally inhibited the expression of Cx32 mRNA and significantly reduced the suppression of tumour growth in 5-aza-CdR-treated nude mice. CONCLUSIONS AND IMPLICATIONS: 5-aza-CdR suppressed the growth of Caki-1 tumours in a xenograft model, by restoring Cx32 expression. This finding suggests that treatment with 5-aza-CdR could be a new effective therapy against human metastatic RCC and that Cx32 could be a potential target for the treatment of RCC.

Severe phimosis as a notable sequela of allogeneic stem cell transplantation in boys.

Hematopoietic SCT has improved the survival rates of patients with hematologic and metabolic disorders, as well as those with malignancy or immunodeficiency. Although various complications have been reported following allogeneic SCT, phimosis has rarely been reported, and the predisposing risk factors for phimosis have not been determined. In this study, the occurrence of severe phimosis following allogeneic SCT in boys was analyzed, and its risk factors were determined. The patients were under 15 years of age. Phimosis was observed in 32.6% of 46 patients after allogeneic SCT; 13.0% of cases required surgery. On univariate analysis, risk factors for severe phimosis included chronic GVHD and the use of a conditioning regimen including anti-thymocyte globulin (ATG). Multivariate analysis showed that chronic GVHD was an independent risk factor for severe phimosis. Thus, severe phimosis is an important complication of SCT in boys, especially in patients with chronic GVHD.

A novel missense mutation (p.P52R) in amelogenin gene causing X-linked amelogenesis imperfecta.

Amelogenesis imperfecta (AI) is a hereditary disease with abnormal dental enamel formation. Here we report a Japanese family with X-linked AI transmitted over at least four generations. Mutation analysis revealed a novel mutation (p.P52R) in exon 5 of the amelogenin gene. The mutation was detected as heterozygous in affected females and as hemizygous in their affected father. The affected sisters exhibited vertical ridges on the enamel surfaces, whereas the affected father had thin, smooth, yellowish enamel with distinct widening of inter-dental spaces. To study the pathological cause underlying the disease in this family, we synthesized the mutant amelogenin p.P52R protein and evaluated it in vitro. Furthermore, we studied differences in the chemical composition between normal and affected teeth by x-ray diffraction analysis and x-ray fluorescence analysis. We believe that these results will greatly aid our understanding of the pathogenesis of X-linked AI.