289 research outputs found
Concerted Loading of Mcm2â7 Double Hexamers around DNA during DNA Replication Origin Licensing
The licensing of eukaryotic DNA replication origins, which ensures once per cell cycle replication, involves the loading of six related minichromosome maintenance proteins (Mcm2-7) into prereplicative complexes (pre-RCs). Mcm2-7 forms the core of the replicative DNA helicase, which is inactive in the pre-RC. The ATP-dependent Mcm2-7 loading reaction requires the Origin Recognition Complex (ORC), Cdc6 and Cdt1. We have reconstituted Mcm2-7 loading with purified budding yeast proteins. Using biochemical approaches and electron microscopy, we show that single heptamers of Cdt1·Mcm2-7 are loaded cooperatively into stable, head-to-head Mcm2-7 double hexamers connected via N-terminal rings. DNA runs through a central channel in the double hexamer, and, once loaded, Mcm2-7 can slide passively along double-stranded DNA. Our work has significant implications for understanding how eukaryotic DNA replication origins are chosen and licensed, how replisomes assemble during initiation and how unwinding occurs during DNA replication
Connective tissue presentation in two families expands the phenotypic spectrum of PYROXD1 disorders
Recessive variants in the oxidoreductase PYROXD1 are reported to cause a myopathy in 22 affected individuals from 15 families. Here, we describe two female probands from unrelated families presenting with features of a congenital connective tissue disorder including osteopenia, blue sclera, soft skin, joint hypermobility and neuromuscular junction dysfunction in addition to known features of PYROXD1 myopathy including respiratory difficulties, weakness, hypotonia and oromotor dysfunction. Proband AII:1 is compound heterozygous for the recurrent PYROXD1 variant Chr12(GRCh38):g.21452130A\u3eG;NM_024854.5:c.464A\u3eG;p.(N155S) and Chr12(GRCh38):g.21462019_21462022del;NM_024854.5:c.892_895del;p.(V298Mfs*4) and proband BII:1 is compound heterozygous for Chr12(GRCh38):g.21468739-21468741del;NM_024854.5:c.1488_1490del;p.(E496del) and Chr12(GRCh38):g.21467619del;NM_024854.5:c.1254+1del. RNA studies demonstrate c.892_895del;p.(V298Mfs*4) is targeted by nonsense mediated decay and c.1254+1delG elicits in-frame skipping of exon-11. Western blot from cultured fibroblasts shows reduced PYROXD1 protein levels in both probands. Testing urine from BII:1 and six individuals with PYROXD1 myopathy showed elevated levels of deoxypyridinoline, a mature collagen crosslink, correlating with PYROXD1-disorder severity. Urine and serum amino acid testing of the same individuals revealed no reportable changes. In contrast to PYROXD1 knock-out, we find no evidence for disrupted tRNA ligase activity, as measured via XBP1 splicing, in fibroblasts expressing PYROXD1 variants. In summary, we expand the clinical spectrum of PYROXD1-related disorders to include an overlapping connective tissue and myopathy presentation, identify three novel, pathogenic PYROXD1 variants, and provide preliminary evidence that elevated urine DPD crosslinks may provide a clinical biomarker for PYROXD1 disorders. Our results advocate consideration of PYROXD1 variants in the differential diagnosis for undiagnosed individuals presenting with a connective tissue disorder and myopathy
Charged-Particle Multiplicities in Charged-Current Neutrino-- and Anti-Neutrino--Nucleus Interactions
The CHORUS experiment, designed to search for
oscillations, consists of a nuclear emulsion target and electronic detectors.
In this paper, results on the production of charged particles in a small sample
of charged-current neutrino-- and anti-neutrino--nucleus interactions at high
energy are presented. For each event, the emission angle and the ionization
features of the charged particles produced in the interaction are recorded,
while the standard kinematic variables are reconstructed using the electronic
detectors. The average multiplicities for charged tracks, the pseudo-rapidity
distributions, the dispersion in the multiplicity of charged particles and the
KNO scaling are studied in different kinematical regions. A study of
quasi-elastic topologies performed for the first time in nuclear emulsions is
also reported. The results are presented in a form suitable for use in the
validation of Monte Carlo generators of neutrino--nucleus interactions.Comment: 17 pages, 5 figure
Leading order analysis of neutrino induced dimuon events in the CHORUS experiment
We present a leading order QCD analysis of a sample of neutrino induced
charged-current events with two muons in the final state originating in the
lead-scintillating fibre calorimeter of the CHORUS detector. The results are
based on a sample of 8910 neutrino and 430 antineutrino induced opposite-sign
dimuon events collected during the exposure of the detector to the CERN Wide
Band Neutrino Beam between 1995 and 1998. % with GeV
and GeV collected %between 1995 and 1998. The analysis yields a
value of the charm quark mass of \mc = (1.26\pm 0.16 \pm 0.09) \GeVcc and a
value of the ratio of the strange to non-strange sea in the nucleon of , improving the results obtained in similar analyses
by previous experiments.Comment: Submitted to Nuclear Physics
Associated Charm Production in Neutrino-Nucleus Interactions
In this paper a search for associated charm production both in neutral and
charged current -nucleus interactions is presented. The improvement of
automatic scanning systems in the {CHORUS} experiment allows an efficient
search to be performed in emulsion for short-lived particles. Hence a search
for rare processes, like the associated charm production, becomes possible
through the observation of the double charm-decay topology with a very low
background. About 130,000 interactions located in the emulsion target
have been analysed. Three events with two charm decays have been observed in
the neutral-current sample with an estimated background of 0.180.05. The
relative rate of the associated charm cross-section in deep inelastic
interactions, has been
measured. One event with two charm decays has been observed in charged-current
interactions with an estimated background of 0.180.06 and the
upper limit on associated charm production in charged-current interactions at
90% C.L. has been found to be .Comment: 10 pages, 4 figure
Emulsion sheet doublets as interface trackers for the OPERA experiment
New methods for efficient and unambiguous interconnection between electronic
counters and target units based on nuclear photographic emulsion films have
been developed. The application to the OPERA experiment, that aims at detecting
oscillations between mu neutrino and tau neutrino in the CNGS neutrino beam, is
reported in this paper. In order to reduce background due to latent tracks
collected before installation in the detector, on-site large-scale treatments
of the emulsions ("refreshing") have been applied. Changeable Sheet (CSd)
packages, each made of a doublet of emulsion films, have been designed,
assembled and coupled to the OPERA target units ("ECC bricks"). A device has
been built to print X-ray spots for accurate interconnection both within the
CSd and between the CSd and the related ECC brick. Sample emulsion films have
been extensively scanned with state-of-the-art automated optical microscopes.
Efficient track-matching and powerful background rejection have been achieved
in tests with electronically tagged penetrating muons. Further improvement of
in-doublet film alignment was obtained by matching the pattern of low-energy
electron tracks. The commissioning of the overall OPERA alignment procedure is
in progress.Comment: 19 pages, 19 figure
Measurement of the atmospheric muon charge ratio with the OPERA detector
The OPERA detector at the Gran Sasso underground laboratory (LNGS) was used
to measure the atmospheric muon charge ratio in the TeV energy region. We
analyzed 403069 atmospheric muons corresponding to 113.4 days of livetime
during the 2008 CNGS run. We computed separately the muon charge ratio for
single and for multiple muon events in order to select different energy regions
of the primary cosmic ray spectrum and to test the charge ratio dependence on
the primary composition. The measured charge ratio values were corrected taking
into account the charge-misidentification errors. Data have also been grouped
in five bins of the "vertical surface energy". A fit to a simplified model of
muon production in the atmosphere allowed the determination of the pion and
kaon charge ratios weighted by the cosmic ray energy spectrum.Comment: 14 pages, 10 figure
First events from the CNGS neutrino beam detected in the OPERA experiment
The OPERA neutrino detector at the underground Gran Sasso Laboratory (LNGS)
was designed to perform the first detection of neutrino oscillations in
appearance mode, through the study of nu_mu to nu_tau oscillations. The
apparatus consists of a lead/emulsion-film target complemented by electronic
detectors. It is placed in the high-energy, long-baseline CERN to LNGS beam
(CNGS) 730 km away from the neutrino source. In August 2006 a first run with
CNGS neutrinos was successfully conducted. A first sample of neutrino events
was collected, statistically consistent with the integrated beam intensity.
After a brief description of the beam and of the various sub-detectors, we
report on the achievement of this milestone, presenting the first data and some
analysis results.Comment: Submitted to the New Journal of Physic
The detection of neutrino interactions in the emulsion/lead target of the OPERA experiment
The OPERA neutrino detector in the underground Gran Sasso Laboratory (LNGS)
was designed to perform the first detection of neutrino oscillations in
appearance mode through the study of oscillations. The
apparatus consists of an emulsion/lead target complemented by electronic
detectors and it is placed in the high energy long-baseline CERN to LNGS beam
(CNGS) 730 km away from the neutrino source. Runs with CNGS neutrinos were
successfully carried out in 2007 and 2008 with the detector fully operational
with its related facilities for the emulsion handling and analysis. After a
brief description of the beam and of the experimental setup we report on the
collection, reconstruction and analysis procedures of first samples of neutrino
interaction events
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