Requirement of Mouse BCCIP for Neural Development and Progenitor Proliferation

Multiple DNA repair pathways are involved in the orderly development of neural systems at distinct stages. The homologous recombination (HR) pathway is required to resolve stalled replication forks and critical for the proliferation of progenitor cells during neural development. BCCIP is a BRCA2 and CDKN1A interacting protein implicated in HR and inhibition of DNA replication stress. In this study, we determined the role of BCCIP in neural development using a conditional BCCIP knock-down mouse model. BCCIP deficiency impaired embryonic and postnatal neural development, causing severe ataxia, cerebral and cerebellar defects, and microcephaly. These development defects are associated with spontaneous DNA damage and subsequent cell death in the proliferative cell populations of the neural system during embryogenesis. With in vitro neural spheroid cultures, BCCIP deficiency impaired neural progenitor's self-renewal capability, and spontaneously activated p53. These data suggest that BCCIP and its anti-replication stress functions are essential for normal neural development by maintaining an orderly proliferation of neural progenitors

Search for astronomical neutrinos from blazar TXS 0506+056 in super-kamiokande

We report a search for astronomical neutrinos in the energy region from several GeV to TeV in the direction of the blazar TXS 0506+056 using the Super-Kamiokande detector following the detection of a 100 TeV neutrinos from the same location by the IceCube collaboration. Using Super-Kamiokande neutrino data across several data samples observed from 1996 April to 2018 February we have searched for both a total excess above known backgrounds across the entire period as well as localized excesses on smaller timescales in that interval. No significant excess nor significant variation in the observed event rate are found in the blazar direction. Upper limits are placed on the electron- and muon-neutrino fluxes at the 90% confidence level as 6.0 × 10−7 and 4.5 × 10−7–9.3 × 10−10 [erg cm−2 s−1], respectively

Successful bone marrow transplantation in a patient with DNA ligase IV deficiency and bone marrow failure

BACKGROUND: DNA Ligase IV deficiency syndrome is a rare autosomal recessive disorder caused by hypomorphic mutations in the DNA ligase IV gene (LIG4). The clinical phenotype shows overlap with a number of other rare syndromes, including Seckel syndrome, Nijmegen breakage syndrome, and Fanconi anemia. Thus the clinical diagnosis is often delayed and established by exclusion. METHODS: We describe a patient with pre- and postnatal growth retardation and dysmorphic facial features in whom the diagnoses of Seckel-, Dubowitz-, and Nijmegen breakage syndrome were variably considered. Cellular radiosensitivity in the absence of clinical manifestations of Ataxia telangiectasia lead to the diagnosis of DNA ligase IV (LIG4) deficiency syndrome, confirmed by compound heterozygous mutations in the LIG4 gene. At age 11, after a six year history of progressive bone marrow failure and increasing transfusion dependency the patient was treated with matched sibling donor hematopoetic stem cell transplantation (HSCT) using a fludarabine-based conditioning regimen without irradiation. RESULTS: The post-transplantation course was uneventful with rapid engraftment leading to complete and stable chimerism. Now at age 16, the patient has gained weight and is in good clinical condition. CONCLUSION: HSCT using mild conditioning without irradiation qualifies as treatment of choice in LIG4-deficient patients who have a matched sibling donor

The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1

Defective responses to DNA single strand breaks underlie various neurodegenerative diseases. However, the exact role of this repair pathway during the development and maintenance of the nervous system is unclear. Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons. This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation. Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function. Collectively, these data detail the in vivo link between DNA single strand break repair and neurogenesis and highlight the diverse consequences of specific types of genotoxic stress in the nervous system

Numt-Mediated Double-Strand Break Repair Mitigates Deletions during Primate Genome Evolution

Non-homologous end joining (NHEJ) is the major mechanism of double-strand break repair (DSBR) in mammalian cells. NHEJ has traditionally been inferred from experimental systems involving induced double strand breaks (DSBs). Whether or not the spectrum of repair events observed in experimental NHEJ reflects the repair of natural breaks by NHEJ during chromosomal evolution is an unresolved issue. In primate phylogeny, nuclear DNA sequences of mitochondrial origin, numts, are inserted into naturally occurring chromosomal breaks via NHEJ. Thus, numt integration sites harbor evidence for the mechanisms that act on the genome over evolutionary timescales. We have identified 35 and 55 lineage-specific numts in the human and chimpanzee genomes, respectively, using the rhesus monkey genome as an outgroup. One hundred and fifty two numt-chromosome fusion points were classified based on their repair patterns. Repair involving microhomology and repair leading to nucleotide additions were detected. These repair patterns are within the experimentally determined spectrum of classical NHEJ, suggesting that information from experimental systems is representative of broader genetic loci and end configurations. However, in incompatible DSBR events, small deletions always occur, whereas in 54% of numt integration events examined, no deletions were detected. Numts show a statistically significant reduction in deletion frequency, even in comparison to DSBR involving filler DNA. Therefore, numts show a unique mechanism of integration via NHEJ. Since the deletion frequency during numt insertion is low, native overhangs of chromosome breaks are preserved, allowing us to determine that 24% of the analyzed breaks are cohesive with overhangs of up to 11 bases. These data represent, to the best of our knowledge, the most comprehensive description of the structure of naturally occurring DSBs. We suggest a model in which the sealing of DSBs by numts, and probably by other filler DNA, prevents nuclear processing of DSBs that could result in deleterious repair

Atmospheric neutrino oscillation analysis with improved event reconstruction in Super-Kamiokande IV

A new event reconstruction algorithm based on a maximum likelihood method has been developed for Super-Kamiokande. Its improved kinematic and particle identification capabilities enable the analysis of atmospheric neutrino data in a detector volume 32% larger than previous analyses and increase the sensitivity to the neutrino mass hierarchy. Analysis of a 253.9 kton⋅ ⋅ year exposure of the Super-Kamiokande IV atmospheric neutrino data has yielded a weak preference for the normal hierarchy, disfavoring the inverted hierarchy at 74% assuming oscillations at the best fit of the analysis

Search for astronomical neutrinos from blazar TXS 0506+056 in Super-Kamiokande

We report a search for astronomical neutrinos in the energy region from several GeV to TeV in the direction of the blazar TXS 0506+056 using the Super-Kamiokande detector following the detection of a 100 TeV neutrinos from the same location by the IceCube collaboration. Using Super-Kamiokande neutrino data across several data samples observed from 1996 April to 2018 February we have searched for both a total excess above known backgrounds across the entire period as well as localized excesses on smaller timescales in that interval. No significant excess nor significant variation in the observed event rate are found in the blazar direction. Upper limits are placed on the electron- and muon-neutrino fluxes at the 90% confidence level as 6.0 × 10−7 and 4.5 × 10−7–9.3 × 10−10 [erg cm−2 s−1], respectively

Search for proton decay into three charged leptons in 0.37 megaton-years exposure of the Super-Kamiokande

A search for proton decay into three charged leptons has been performed by using 0.37 Mton⋅years of data collected in Super-Kamiokande. All possible combinations of electrons, muons, and their antiparticles consistent with charge conservation were considered as decay modes. No significant excess of events has been found over the background, and lower limits on the proton lifetime divided by the branching ratio have been obtained. The limits range between 9.2×10^33 and 3.4×10^34 years at 90% confidence level, improving by more than an order of magnitude upon limits from previous experiments. A first limit has been set for the p→μ^−e^+e^+ mode

Measurement of the tau neutrino cross section in atmospheric neutrino oscillations with Super-Kamiokande

Using 5326 days of atmospheric neutrino data, a search for atmospheric tau neutrino appearance has been performed in the Super-Kamiokande experiment. Super-Kamiokande measures the tau normalization to be 1.47 ± 0.32 under the assumption of normal neutrino hierarchy, relative to the expectation of unity with neutrino oscillation. The result excludes the hypothesis of no-tau appearance with a significance level of 4.6σ. The inclusive charged-current tau neutrino cross section averaged by the tau neutrino flux at SuperKamiokande is measured to be ð0.94 ± 0.20Þ × 10−38 cm2. The measurement is consistent with the Standard Model prediction, agreeing to within 1.5σ

Sensitivity of super-kamiokande with gadolinium to low energy antineutrinos from pre-supernova emission

Supernova detection is a major objective of the Super-Kamiokande (SK) experiment. In the next stage of SK (SK-Gd), gadolinium (Gd) sulfate will be added to the detector, which will improve the ability of the detector to identify neutrons. A core-collapse supernova (CCSN) will be preceded by an increasing flux of neutrinos and antineutrinos, from thermal and weak nuclear processes in the star, over a timescale of hours; some of which may be detected at SK-Gd. This could provide an early warning of an imminent CCSN, hours earlier than the detection of the neutrinos from core collapse. Electron antineutrino detection will rely on inverse beta decay events below the usual analysis energy threshold of SK, so Gd loading is vital to reduce backgrounds while maximizing detection efficiency. Assuming normal neutrino mass ordering, more than 200 events could be detected in the final 12 hr before core collapse for a 15–25 solar mass star at around 200 pc, which is representative of the nearest red supergiant to Earth, α-Ori (Betelgeuse). At a statistical false alarm rate of 1 per century, detection could be up to 10 hr before core collapse, and a pre-supernova star could be detected by SK-Gd up to 600 pc away. A pre-supernova alert could be provided to the astrophysics community following gadolinium loading