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The full data set of the NEMO-3 experiment has been used to measure the half-life of the two-neutrino double beta decay of \\[^{100}\\]Mo to the ground state of \\[^{100}\\]Ru, \\[T_{1/2} = \\left[ 6.81 \\pm 0.01\\,\\left( \\text{ stat }\\right) ^{+0.38}_{-0.40}\\,\\left( \\text{ syst }\\right) \\right] \\times 10^{18}\\] year. The two-electron energy sum, single electron energy spectra and distribution of the angle between the electrons are presented with an unprecedented statistics of \\[5\\times 10^5\\] events and a signal-to-background ratio of \\[\\sim \\] 80. Clear evidence for the Single State Dominance model is found for this nuclear transition. Limits on Majoron emitting neutrinoless double beta decay modes with spectral indices of \\[\\mathrm{n}=2,3,7\\], as well as constraints on Lorentz invariance violation and on the bosonic neutrino contribution to the two-neutrino double beta decay mode are obtained.

The double beta decay experiment NEMO-3 has compleated data taking in January 2011. The aim of the experiment is to search for the neutrinoless double beta decay and investigate the two-neutrino double beta decay in seven different isotopes (100Mo, 82Se, 116Cd, 150Nd, 96Zr, 48Ca and 130Te). After analysis of the most part of available data corresponding to 4.5 yr no evidence for 0νββ decay in 100Mo and 82Se is found. The half-life limits at 90% C.L. are 1.0 × 1024 yr and 3.2 × 1023 yr respectively. The two-neutrino decay half live values were precisely measured for all investigated isotopes.

The NEMO-3 results for the double-$\\beta $ decay of $^{150}$Nd to the 0$^+_1$ and 2$^+_1$ excited states of $^{150}$Sm are reported. The data recorded during 5.25 year with 36.6 g of the isotope $^{150}$Nd are used in the analysis. The signal of the $2\\nu \\beta \\beta $ transition to the 0$^+_1$ excited state is detected with a statistical significance exceeding 5$\\sigma $. The half-life is measured to be $T_{1/2}^{2\\nu \\beta \\beta }(0^+_1) = \\left[ 1.11 ^{+0.19}_{-0.14} \\,\\left( \\hbox {stat}\\right) ^{+0.17}_{-0.15}\\,\\left( \\hbox {syst}\\right) \\right] \\times 10^{20}$ year, which is the most precise value that has been measured to date. 90% confidence-level limits are set for the other decay modes. For the $2\\nu \\beta \\beta $ decay to the 2$^+_1$ level the limit is $T^{2\\nu \\beta \\beta }_{1/2}(2^+_1) > 2.42 \\times 10^{20}~\\hbox {year}$. The limits on the $0\\nu \\beta \\beta $ decay to the 0$^+_1$ and 2$^+_1$ levels of $^{150}$Sm are significantly improved to $T_{1/2}^{0\\nu \\beta \\beta }(0^+_1) > 1.36 \\times 10^{22}~\\hbox {year}$ and $T_{1/2}^{0\\nu \\beta \\beta }(2^+_1) > 1.26 \\times 10^{22}~\\hbox {year}$.

The possibility to probe new physics scenarios of light Majorana neutrino exchange and right-handed currents at the planned next generation neutrinoless double β decay experiment SuperNEMO is discussed. Its ability to study different isotopes and track the outgoing electrons provides the means to discriminate different underlying mechanisms for the neutrinoless double β decay by measuring the decay half-life and the electron angular and energy distributions.

Cyclic peptide natural products have evolved to exploit diverse protein targets, many of which control essential cellular processes. Inspired by a series of cyclic peptides with partially elucidated structures, we designed synthetic variants of ternatin, a cytotoxic and anti-adipogenic natural product whose molecular mode of action was unknown. The new ternatin variants are cytotoxic toward cancer cells, with up to 500-fold greater potency than ternatin itself. Using a ternatin photo-affinity probe, we identify the translation elongation factor-1A ternary complex (eEF1A·GTP·aminoacyl-tRNA) as a specific target and demonstrate competitive binding by the unrelated natural products, didemnin and cytotrienin. Mutations in domain III of eEF1A prevent ternatin binding and confer resistance to its cytotoxic effects, implicating the adjacent hydrophobic surface as a functional hot spot for eEF1A modulation. We conclude that the eukaryotic elongation factor-1A and its ternary complex with GTP and aminoacyl-tRNA are common targets for the evolution of cytotoxic natural products. Many plants, fungi, and bacteria have evolved to produce small molecules that have powerful effects on the cells of other living organisms, and can even kill them. These naturally produced compounds are often used as starting points for developing new drugs. One such class of compounds are the cyclic peptides, which can be relatively easily produced in the laboratory and are able to penetrate cells. Some cyclic peptides have also proved to be useful for treating cancer and immune diseases, so researchers are keen to identify others that have similar effects. One promising prospect, called ternatin, is produced by several species of fungi. In high doses, ternatin can kill mammalian cells, but it was not clear how it does so. To learn more, Carelli et al. searched a chemical database for cyclic peptides related to ternatin and identified several similar compounds that were reported to kill cancer cells. Inspired by the structures of these cyclic peptides, Carelli et al. synthesized modified versions of ternatin. One of these was 500 times more potent than ternatin, which means a much lower dose of the compound is still able to kill cancer cells. Further experiments showed that ternatin blocks the production of new proteins in cells. Specifically, ternatin binds to a complex that includes a protein called elongation factor-1A (eEF1A). Mutations in a particular region of eEF1A prevent ternatin from killing cells, suggesting a potential binding site for ternatin. The next challenge is to dissect the mechanism by which compounds binding to this site on eEF1A block protein synthesis and kill cells. A related challenge is to understand why certain cancer cells are hypersensitive to ternatin and other eEF1A inhibitors, while other cancer cells are relatively resistant. These questions are relevant to the development of eEF1A inhibitors as cancer treatments.

The NEMO-3 results for the double- β decay of 150 Nd to the 0 1 + and 2 1 + excited states of 150 Sm are reported. The data recorded during 5.25 year with 36.6 g of the isotope 150 Nd are used in the analysis. The signal of the 2 ν β β transition to the 0 1 + excited state is detected with a statistical significance exceeding 5 σ . The half-life is measured to be T 1 / 2 2 ν β β ( 0 1 + ) = 1 . 11 - 0.14 + 0.19 stat - 0.15 + 0.17 syst × 10 20  year, which is the most precise value that has been measured to date. 90% confidence-level limits are set for the other decay modes. For the 2 ν β β decay to the 2 1 + level the limit is T 1 / 2 2 ν β β ( 2 1 + ) > 2.42 × 10 20 year . The limits on the 0 ν β β decay to the 0 1 + and 2 1 + levels of 150 Sm are significantly improved to T 1 / 2 0 ν β β ( 0 1 + ) > 1.36 × 10 22 year and T 1 / 2 0 ν β β ( 2 1 + ) > 1.26 × 10 22 year .

In 1956 Reines & Cowan discovered the neutrino using a liquid scintillator detector. The neutrinos interacted with the scintillator, producing light that propagated across transparent volumes to surrounding photo-sensors. This approach has remained one of the most widespread and successful neutrino detection technologies used since. This article introduces a concept that breaks with the conventional paradigm of transparency by confining and collecting light near its creation point with an opaque scintillator and a dense array of optical fibres. This technique, called LiquidO, can provide high-resolution imaging to enable efficient identification of individual particles event-by-event. A natural affinity for adding dopants at high concentrations is provided by the use of an opaque medium. With these and other capabilities, the potential of our detector concept to unlock opportunities in neutrino physics is presented here, alongside the results of the first experimental validation. Liquid scintillator detectors have been used to study neutrinos ever since their discovery in 1956. The authors introduce an opaque scintillator detector concept for future neutrino experiments with increased capacity for particle identification and a natural affinity for doping.

Replication of mammalian mitochondrial DNA (mtDNA) is an essential process that requires high fidelity and control at multiple levels to ensure proper mitochondrial function. Mutations in the mitochondrial genome maintenance exonuclease 1 ( MGME1 ) gene were recently reported in mitochondrial disease patients. Here, to study disease pathophysiology, we generated Mgme1 knockout mice and report that homozygous knockouts develop depletion and multiple deletions of mtDNA. The mtDNA replication stalling phenotypes vary dramatically in different tissues of Mgme1 knockout mice. Mice with MGME1 deficiency accumulate a long linear subgenomic mtDNA species, similar to the one found in mtDNA mutator mice, but do not develop progeria. This finding resolves a long-standing debate by showing that point mutations of mtDNA are the main cause of progeria in mtDNA mutator mice. We also propose a role for MGME1 in the regulation of replication and transcription termination at the end of the control region of mtDNA. It has been debated whether premature ageing in mitochondrial DNA mutator mice is driven by point mutations or deletions of mtDNA. Matic et al generate Mgme1 knockout mice and show here that these mice have tissue-specific replication stalling and accumulate deleted mtDNA, without developing progeria.

In mice lacking the interleukin-2 receptor β chain (IL-2Rβ), T cells were shown to be spontaneously activated, resulting in exhaustive differentiation of B cells into plasma cells and the appearance of high serum concentrations of immunoglobulins G1 and E as well as autoantibodies that cause hemolytic anemia. Marked infiltrative granulocytopoiesis was also apparent, and the animals died after about 12 weeks. Depletion of CD4$^+$ T cells in mutant mice rescued B cells without reversion of granulocyte abnormalities. T cells did not proliferate in response to polyclonal activators, nor could antigen-specific immune responses be elicited. Thus, IL-2Rβ is required to keep the activation programs of T cells under control, to maintain homeostasis, and to prevent autoimmunity.

Using data from the NEMO-3 experiment, we have measured the two-neutrino double beta decay (\\[2\\nu \\beta \\beta \\]) half-life of \\[^{82}\\]Se as \\[T_{\\smash {1/2}}^{2\\nu } \\!=\\! \\left[ 9.39 \\pm 0.17\\left( \\text{ stat }\\right) \\pm 0.58\\left( \\text{ syst }\\right) \\right] \\times 10^{19}\\] y under the single-state dominance hypothesis for this nuclear transition. The corresponding nuclear matrix element is \\[\\left| M^{2\\nu }\\right| = 0.0498 \\pm 0.0016\\]. In addition, a search for neutrinoless double beta decay (\\[0\\nu \\beta \\beta \\]) using 0.93 kg of \\[^{82}\\]Se observed for a total of 5.25 y has been conducted and no evidence for a signal has been found. The resulting half-life limit of \\[T_{1/2}^{0\\nu } > 2.5 \\times 10^{23} \\,\\text{ y } \\,(90\\%\\,\\text{ C.L. })\\] for the light neutrino exchange mechanism leads to a constraint on the effective Majorana neutrino mass of \\[\\langle m_{\\nu } \\rangle < \\left( 1.2{-}3.0\\right) \\,\\text{ eV }\\], where the range reflects \\[0\\nu \\beta \\beta \\] nuclear matrix element values from different calculations. Furthermore, constraints on lepton number violating parameters for other \\[0\\nu \\beta \\beta \\] mechanisms, such as right-handed currents, majoron emission and R-parity violating supersymmetry modes have been set.