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The inner detector of the future Hyper-Kamiokande experiment will be instrumented with 40000 20\" photo-multiplier tubes (PMTs). Two models of PMTs are considered: the R12860 from Hamamatsu Photonics (nominal option), and the GDB-6203 from North Night Vision Technology (alternative option). Both models show improved performances compared to the PMTs used in the currently running Super-Kamiokande experiment. We present here the measurements of the performance of the nominal and alternative option PMTs done in the context of the Hyper-Kamiokande project, as well as the first use of those new PMTs in a running experiment, and other on-going developments for their future use in the Hyper-Kamiokande detector.

Inverted CCAAT box-binding protein of 90 kDa (ICBP90) is over-expressed in several types of cancer, including breast, prostate and lung cancers. In search for proteins that interact with the set and ring-associated (SRA) domain of ICBP90, we used the two-hybrid system and screened a placental cDNA library. Several clones coding for a new domain of DNMT1 were found. The interaction, between the ICBP90 SRA domain and the DNMT1 domain, has been confirmed with purified proteins by glutathione- S -transferase pull-down experiments. We checked whether ICBP90 and DNMT1 are present in the same macro-molecular complexes in Jurkat cells and immortalized human vascular smooth muscle cells (HVTs-SM1). Co-immunoprecipitation experiments showed that ICBP90 and DNMT1 are present in the same molecular complex, which was further confirmed by co-localization experiments as assessed by immunocytochemistry. Downregulation of ICBP90 and DNMT1 decreased VEGF gene expression, a major pro-angiogenic factor, whereas those of p16 INK4A gene and RB1 gene were significantly enhanced. Together, these results indicate that DNMT1 and ICBP90 are involved in VEGF gene expression, possibly via an interaction of the SRA domain of ICBP90 with a novel domain of DNMT1 and an upregulation of p16 INK4A . They further suggest a new role of ICBP90 in the relationship between histone ubiquitination and DNA methylation in the context of tumoral angiogenesis and tumour suppressor genes silencing.

With recent suggestive physics results, compelling future physics opportunities, and the continued improvement of the J-PARC proton beam power, the T2K collaboration is proposing an extension of the T2K run from the currently approved full statistics of 7.8 × 1021 Protons-on-Target (POT) (expected by 2021) to 20 × 1021 POT (expected by 2027). The T2K collaboration also plans to increase the \"effective\" T2K Phase 2 statistics by improved analysis techniques and neutrino beamline hardware upgrades. The physics sensitivity of this extended run are shown, including the possibility of excluding sin δCP = 0 to 3σ or better in the case of maximal CP violation in the lepton sector. Improvements on the atmospheric neutrino oscillation parameter constraints will also be made by T2K Phase 2, where the final sensitivities depend on the true values of the oscillation parameters.

Background Kinesin motors hydrolyze ATP to produce force and move along microtubules, converting chemical energy into work by a mechanism that is only poorly understood. Key transitions and intermediate states in the process are still structurally uncharacterized, and remain outstanding questions in the field. Perturbing the motor by introducing point mutations could stabilize transitional or unstable states, providing critical information about these rarer states. Results Here we show that mutation of a single residue in the kinesin-14 Ncd causes the motor to release ADP and hydrolyze ATP faster than wild type, but move more slowly along microtubules in gliding assays, uncoupling nucleotide hydrolysis from force generation. A crystal structure of the motor shows a large rotation of the stalk, a conformation representing a force-producing stroke of Ncd. Three C-terminal residues of Ncd, visible for the first time, interact with the central β-sheet and dock onto the motor core, forming a structure resembling the kinesin-1 neck linker, which has been proposed to be the primary force-generating mechanical element of kinesin-1. Conclusions Force generation by minus-end Ncd involves docking of the C-terminus, which forms a structure resembling the kinesin-1 neck linker. The mechanism by which the plus- and minus-end motors produce force to move to opposite ends of the microtubule appears to involve the same conformational changes, but distinct structural linkers. Unstable ADP binding may destabilize the motor-ADP state, triggering Ncd stalk rotation and C-terminus docking, producing a working stroke of the motor.

Molecular motors undergo conformational changes to produce force and move along cytoskeletal filaments. Structural changes have been detected in kinesin motors; however, further changes are expected because previous crystal structures are in the same or closely related conformations. We report here a 2.5 Å crystal structure of the minus‐end kinesin, Ncd, with the coiled‐coil stalk/neck and one head rotated by ∼75° relative to the other head. The two heads are asymmetrically positioned with respect to the stalk and show asymmetry of nucleotide state: one head is fully occupied, but the other is unstably bound to ADP. Unlike previous structures, our new atomic model can be fit into cryoelectron microscopy density maps of the motor attached to microtubules, where it appears to resemble a one‐head‐bound motor with the stalk rotated towards the minus end. Interactions between neck and motor core residues, observed in the head that moves with the stalk, are disrupted in the other head, permitting rotation of the stalk/neck. The rotation could represent a force‐producing stroke that directs the motor to the minus end.

ICBP90 (Inverted CCAAT box Binding Protein of 90 kDa) is a recently identified nuclear protein that binds to one of the inverted CCAAT boxes of the topoisomerase II α (TopoII α ) gene promoter. Here, we show that ICBP90 shares structural homology with several other proteins, including Np95, the human and mouse NIRF, suggesting the emergence of a new family of nuclear proteins. Towards elucidating the functions of this family, we analysed the expression of ICBP90 in various cancer or noncancer cell lines and in normal or breast carcinoma tissues. We found that cancer cell lines express higher levels of ICBP90 and TopoII α than noncancer cell lines. By using cell-cycle phase-blocking drugs, we show that in primary cultured human lung fibroblasts, ICBP90 expression peaks at late G1 and during G2/M phases. In contrast, cancer cell lines such as HeLa, Jurkat and A549 show constant ICBP90 expression throughout the entire cell cycle. The effect of overexpression of E2F-1 is more efficient on ICBP90 and TopoII α expression in noncancer cells (IMR90, WI38) than in cancer cells (U2OS, SaOs). Together, these results show that ICBP90 expression is altered in cancer cell lines and is upregulated by E2F-1 overexpression with an efficiency depending on the cancer status of the cell line.

Keeping DNA methylation on track DNA methylation is a key epigenetic process and the faithful maintenance of DNA methylation patterns is essential to the wellbeing of mammalian cells. This means that cells need a mechanism to identify the partially methylated version of CpG once a new DNA strand has been replicated or repaired, so that it can be further methylated by the DNA methyltransferase, DNMT1. As part of this process the protein UHRF1 (or Np95/ICBP90) facilitates the loading of DNMT1 onto the hemimethylated CpG sequences during DNA replication. Three papers in this issue describe crystal structures of the SRA domain of UHRF1 bound to DNA containing a hemi-methylated CpG site. The structures show that methyl-cytosine is flipped out of the DNA helix and inserted into a binding pocket on the SRA domain. Epigenetic inheritance in mammals is characterized by high-fidelity replication of CpG methylation patterns during development 1 , 2 . UHRF1 (also known as ICBP90 in humans and Np95 in mouse) 3 is an E3 ligase important for the maintenance of global and local DNA methylation in vivo 4 , 5 . The preferential affinity of UHRF1 for hemi-methylated DNA over symmetrically methylated DNA by means of its SET and RING-associated (SRA) domain 6 and its association with the maintenance DNA methyltransferase 1 (DNMT1) suggests a role in replication of the epigenetic code 4 , 5 , 7 . Here we report the 1.7 Å crystal structure of the apo SRA domain of human UHRF1 and a 2.2 Å structure of its complex with hemi-methylated DNA, revealing a previously unknown reading mechanism for methylated CpG sites (mCpG). The SRA–DNA complex has several notable structural features including a binding pocket that accommodates the 5-methylcytosine that is flipped out of the duplex DNA. Two specialized loops reach through the resulting gap in the DNA from both the major and the minor grooves to read the other three bases of the CpG duplex. The major groove loop confers both specificity for the CpG dinucleotide and discrimination against methylation of deoxycytidine of the complementary strand. The structure, along with mutagenesis data, suggests how UHRF1 acts as a key factor for DNMT1 maintenance methylation through recognition of a fundamental unit of epigenetic inheritance, mCpG.

The Tokai-to-Kamioka (T2K) neutrino experiment measures neutrino oscillations by using an almost pure muon neutrino beam produced at the J-PARC accelerator facility. The T2K muon monitor was installed to measure the direction and stability of the muon beam which is produced in conjunction with the muon neutrino beam. The systematic error in the muon beam direction measurement was estimated, using data and MC simulation, to be 0.28 mrad. During beam operation, the proton beam has been controlled using measurements from the muon monitor and the direction of the neutrino beam has been tuned to within 0.3 mrad with respect to the designed beam-axis. In order to understand the muon beam properties, measurement of the absolute muon yield at the muon monitor was conducted with an emulsion detector. The number of muon tracks was measured to be $(4.06\\pm 0.05\\pm 0.10)\\times 10^4$cm$^{-2}$ normalized with $4\\times 10^{11}$ protons on target with 250 kA horn operation. The result is in agreement with the prediction, which is corrected based on hadron production data.

The T2K (Tokai-to-Kamioka) is a long baseline neutrino experiment designed to study various parameters that rule neutrino oscillations, with an intense beam of muon neutrinos. A near detector complex (ND280) is used to constrain non-oscillated flux and hence to predict the expected number of events in the far detector (Super-Kamiokande). The difference in the target material between the far (water) and near (scintillator, hydrocarbon) detectors leads to the main non-canceling systematic uncertainty for the oscillation analysis. In order to reduce this uncertainty a new water grid and scintillator detector, WAGASCI, has been proposed. The detector will be operated at the J-PARC neutrino beam line with the main physics goal to measure the charged current neutrino cross section ratio between water and hydrocarbon with a few percent accuracy. Further physics program may include high-precision measurements of different charged current neutrino interaction channels. The concept of the new detector will be covered together with the actual construction plan.

Hyper-Kamiokande consists of two identical water-Cherenkov detectors of total 520 kt, with the first one in Japan at 295 km from the J-PARC neutrino beam with 2.5$^\\circ$ off-axis angles (OAAs), and the second one possibly in Korea at a later stage. Having the second detector in Korea would benefit almost all areas of neutrino oscillation physics, mainly due to longer baselines. There are several candidate sites in Korea with baselines of 1000–1300 km and OAAs of 1$^\\circ$–3$^\\circ$. We conducted sensitivity studies on neutrino oscillation physics for a second detector, either in Japan (JD $\\times$ 2) or Korea (JD + KD), and compared the results with a single detector in Japan. Leptonic charge–parity (CP) symmetry violation sensitivity is improved, especially when the CP is non-maximally violated. The larger matter effect at Korean candidate sites significantly enhances sensitivities to non-standard interactions of neutrinos and mass ordering determination. Current studies indicate the best sensitivity is obtained at Mt. Bisul (1088 km baseline, $1.3^\\circ$ OAA). Thanks to a larger (1000 m) overburden than the first detector site, clear improvements to sensitivities for solar and supernova relic neutrino searches are expected.