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A bstract The Double Chooz collaboration presents a measurement of the neutrino mixing angle θ 13 using reactor ν e ¯ observed via the inverse beta decay reaction in which the neutron is captured on hydrogen. This measurement is based on 462.72 live days data, approximately twice as much data as in the previous such analysis, collected with a detector positioned at an average distance of 1050 m from two reactor cores. Several novel techniques have been developed to achieve significant reductions of the backgrounds and systematic uncertainties. Accidental coincidences, the dominant background in this analysis, are suppressed by more than an order of magnitude with respect to our previous publication by a multi-variate analysis. These improvements demonstrate the capability of precise measurement of reactor ν e ¯ without gadolinium loading. Spectral distortions from the ν e ¯ reactor flux predictions previously reported with the neutron capture on gadolinium events are confirmed in the independent data sample presented here. A value of sin 2 2 θ 13  = 0.095 − 0.039 + 0.038 (stat+syst) is obtained from a fit to the observed event rate as a function of the reactor power, a method insensitive to the energy spectrum shape. A simultaneous fit of the hydrogen capture events and of the gadolinium capture events yields a measurement of sin 2 2 θ 13 = 0 . 088 ± 0 . 033(stat+syst).

Neutrinos were assumed to be massless particles until the discovery of the neutrino oscillation process. This phenomenon indicates that the neutrinos have non-zero masses and the mass eigenstates (ν1, ν2, ν3) are mixtures of their flavour eigenstates (νe, νμ, ντ). The oscillations between different flavour eigenstates are described by three mixing angles (θ12, θ23, θ13), two differences of the squared neutrino masses of the ν2/ν1 and ν3/ν1 pairs and a charge conjugation parity symmetry violating phase δCP. The Double Chooz experiment, located near the Chooz Electricité de France reactors, measures the oscillation parameter θ13 using reactor neutrinos. Here, the Double Chooz collaboration reports the measurement of the mixing angle θ13 with the new total neutron capture detection technique from the full data set, yielding sin2(2θ13) = 0.105 ± 0.014. This measurement exploits the multidetector configuration, the isoflux baseline and data recorded when the reactors were switched off. In addition to the neutrino mixing angle measurement, Double Chooz provides a precise measurement of the reactor neutrino flux, given by the mean cross-section per fission 〈σf〉 = (5.71 ± 0.06) × 10−43 cm2 per fission, and reports an empirical model of the distortion in the reactor neutrino spectrum.

The yields and production rates of the radioisotopes$^{9}$Li and$^{8}$He created by cosmic muon spallation on$^{12}$C, have been measured by the two detectors of the Double Chooz experiment. The identical detectors are located at separate sites and depths, which means that they are subject to different muon spectra. The near (far) detector has an overburden of ∼120 m.w.e. (∼300 m.w.e.) corresponding to a mean muon energy of 32.1 ± 2.0 GeV (63.7 ± 5.5 GeV). Comparing the data to a detailed simulation of the$^{9}$Li and$^{8}$He decays, the contribution of the$^{8}$He radioisotope at both detectors is found to be compatible with zero. The observed$^{9}$Li yields in the near and far detectors are 5.51 ± 0.51 and 7.90 ± 0.51, respectively, in units of 10$^{−8}$μ$^{−1}$g$^{−1}$cm$^{2}$. The shallow overburdens of the near and far detectors give a unique insight when combined with measurements by KamLAND and Borexino to give the first multi-experiment, data driven relationship between the$^{9}$Li yield and the mean muon energy according to the power law $ Y = {Y}_0{\\left(\\left\\langle {E}_{\\mu}\\right\\rangle /1\\ GeV\\right)}^{\\overline{\\alpha}} $ , giving $ \\overline{\\alpha} = 0.72 \\pm 0.06 $ and Y$_{0}$ = (0.43 ± 0.11) × 10$^{−8}$μ$^{−1}$g$^{−1}$cm$^{2}$. This relationship gives future liquid scintillator based experiments the ability to predict their cosmogenic$^{9}$Li background rates.

We observed a measurement of the Double Chooz collaboration and the neutrino mixing angle θ13 using reactor $\\bar{v}$e via the inverse beta decay reaction in which the neutron is captured on hydrogen. Our measurement is based on 462.72 live days data, approximately twice as much data as in the previous such analysis, collected with a detector positioned at an average distance of 1050 m from two reactor cores. Several novel techniques have been developed to achieve significant reductions of the backgrounds and systematic uncertainties. Accidental coincidences, the dominant background in this analysis, are suppressed by more than an order of magnitude with respect to our previous publication by a multi-variate analysis. Furthermore, these improvements demonstrate the capability of precise measurement of reactor $\\bar{v}$e without gadolinium loading. Spectral distortions from the $\\bar{v}$e reactor flux predictions previously reported with the neutron capture on gadolinium events are confirmed in the independent data sample presented here. A value of sin2 2θ13= 0.0950.039+0.038 (stat+syst) is obtained from a fit to the observed event rate as a function of the reactor power, a method insensitive to the energy spectrum shape. A simultaneous fit of the hydrogen capture events and of the gadolinium capture events yields a measurement of sin2 2θ13 = 0.088 ± 0.033(stat+syst).

Monoclonal B-cell lymphocytosis (MBL) is a preclinical hematologic syndrome characterized by small accumulations of CD5 + B lymphocytes. Most MBL share phenotypic characteristics with chronic lymphocytic leukemia (CLL). Although some MBL progress to CLL, most MBL have apparently limited potential for progression to CLL, particularly those MBL with normal absolute B-cell counts (‘low-count’ MBL). Most CLL are monoclonal and it is not known whether MBL are monoclonal or oligoclonal; this is important because it is unclear whether MBL represent indolent CLL or represent a distinct premalignant precursor before the development of CLL. We used flow cytometry analysis and sorting to determine immunophenotypic characteristics, clonality and molecular features of MBL from familial CLL kindreds. Single-cell analysis indicated four of six low-count MBL consisted of two or more unrelated clones; the other two MBL were monoclonal. 87% of low-count MBL clones had mutated immunoglobulin genes, and no immunoglobulin heavy-chain rearrangements of V H family 1 were observed. Some MBL were diversified, clonally related populations with evidence of antigen drive. We conclude that although low-count MBL share many phenotypic characteristics with CLL, many MBL are oligoclonal. This supports a model for step-wise development of MBL into CLL.

Diarrhoeal disease is responsible for 8.6% of global child mortality. Recent epidemiological studies found the protozoan parasite Cryptosporidium to be a leading cause of paediatric diarrhoea, with particularly grave impact on infants and immunocompromised individuals. There is neither a vaccine nor an effective treatment. Here we establish a drug discovery process built on scalable phenotypic assays and mouse models that take advantage of transgenic parasites. Screening a library of compounds with anti-parasitic activity, we identify pyrazolopyridines as inhibitors of Cryptosporidium parvum and Cryptosporidium hominis . Oral treatment with the pyrazolopyridine KDU731 results in a potent reduction in intestinal infection of immunocompromised mice. Treatment also leads to rapid resolution of diarrhoea and dehydration in neonatal calves, a clinical model of cryptosporidiosis that closely resembles human infection. Our results suggest that the Cryptosporidium lipid kinase PI(4)K (phosphatidylinositol-4-OH kinase) is a target for pyrazolopyridines and that KDU731 warrants further preclinical evaluation as a drug candidate for the treatment of cryptosporidiosis. The establishment of a drug-discovery screening pipeline for cryptosporidiosis, and identification of pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K. Diarrhoea drug discovery The apicomplexan parasite Cryptosporidium is a leading cause of paediatric diarrhoea, with high mortality in infants and individuals with weak immune systems. Here, the authors report the establishment of a drug discovery screening pipeline for cryptosporidiosis, and identify pyrazolopyridines as selective ATP-competitive inhibitors of the Cryptosporidium lipid kinase PI(4)K. The lead candidate, KDU731, inhibits growth of C. parvum and C. hominis in vitro , and demonstrated in vivo efficacy in immunocompromised mice and neonatal calves (a clinical model of human disease). Moreover, KDU731 meets a broad range of safety and pharmacology criteria, and has potential as a much-needed therapeutic for treatment of cryptosporidiosis.

Monoclonal B-cell lymphocytosis (MBL) is a hematologic condition wherein small B-cell clones can be detected in the blood of asymptomatic individuals. Most MBL have an immunophenotype similar to chronic lymphocytic leukemia (CLL), and ‘CLL-like’ MBL is a precursor to CLL. We used flow cytometry to identify MBL from unaffected members of CLL kindreds. We identified 101 MBL cases from 622 study subjects; of these, 82 individuals with MBL were further characterized. In all, 91 unique MBL clones were detected: 73 CLL-like MBL (CD5 + CD20 dim sIg dim ), 11 atypical MBL (CD5 + CD20 + sIg + ) and 7 CD5 neg MBL (CD5 neg CD20 + sIg neg ). Extended immunophenotypic characterization of these MBL subtypes was performed, and significant differences in cell surface expression of CD23, CD49d, CD79b and FMC-7 were observed among the groups. Markers of risk in CLL such as CD38, ZAP70 and CD49d were infrequently expressed in CLL-like MBL, but were expressed in the majority of atypical MBL. Interphase cytogenetics was performed in 35 MBL cases, and del 13q14 was most common (22/30 CLL-like MBL cases). Gene expression analysis using oligonucleotide arrays was performed on seven CLL-like MBL, and showed activation of B-cell receptor associated pathways. Our findings underscore the diversity of MBL subtypes and further clarify the relationship between MBL and other lymphoproliferative disorders.

Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy. ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL [SD 20%]) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing. Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 [81%] of 77 patients receiving leriglitazone and 34 [87%] of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean [SD] change from baseline leriglitazone: –27·7 [41·4] m; placebo: –30·3 [60·5] m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 [70%] of 77 vs nine [23%] of 39 patients, respectively) and peripheral oedema (49 [64%] of 77 vs seven [18%] of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six [5%] of 116 patients, all of whom were in the placebo group. The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy. Minoryx Therapeutics.

We report here the identification of a cis-acting region involved in light regulation of the nuclear gene (GapB) encoding the B subunit of chloroplast glyceraldehyde 3-phosphate dehydrogenase from Arabidopsis thaliana. Our results show that a 664-bp GapB promoter fragment is sufficient to confer light induction and organ-specific expression of the Escherichia coli beta-glucuronidase reporter gene (Gus) in transgenic tobacco (Nicotiana tabacum) plants. Deletion analysis indicates that the -261 to -173 upstream region of the GapB gene is essential for light induction. This region contains four direct repeats with the consensus sequence 5'-ATGAA(A/G)A-3' (Gap boxes). Deletion of all four repeats abolishes light induction completely. In addition, we have linked a 109-bp (-263 to -152) GapB upstream fragment containing the four direct repeats in two orientations to the -92 to +6 upstream sequence of the cauliflower mosaic virus 35S basal promoter. The resulting chimeric promoters are able to confer light induction and to enhance leaf-specific expression of the Gus reporter gene in transgenic tobacco plants. Based on these results we conclude that Gap boxes are essential for light regulation and organ-specific expression of the GapB gene in A. thaliana. Using gel mobility shift assays we have also identified a nuclear factor from tobacco that interacts with GapA and GapB DNA fragments containing these Gap boxes. Competition assays indicate that Gap boxes are the binding sites for this factor. Although this binding activity is present in nuclear extracts from leaves and roots of light-grown or dark-treated tobacco plants, the activity is less abundant in nuclear extracts prepared from leaves of dark-treated plants or from roots of greenhouse-grown plants. In addition, our data show that this binding factor is distinct from the GT-1 factor, which binds to Box II and Box III within the light-responsive element of the RbcS-3A gene of pea

Nucleotide sequences for the nuclear genes encoding chloroplast (GapA and GapB) and cytosolic (GapC) glyceraldehyde-3-phosphate dehydrogenases (GAPDHs) from Arabidopsis thaliana were determined. Comparison of nucleotide sequences indicates that the divergence of chloroplast and cytosolic GAPDH genes preceded the divergence of prokaryotes and eukaryotes. In addition, some intron-exon junctions are conserved among GapB, GapC, and chicken GAPDH genes. These results provide evidence at the molecular level to support the idea that introns existed before the divergence of prokaryotes and eukaryotes