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Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis.
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 5' end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development
On the dynamics of planetesimals embedded in turbulent protoplanetary discs with dead zones
(abridged) Accretion in protoplanetary discs is thought to be driven by [...]
turbulence via the magnetorotational instability (MRI). Recent work has shown
that a planetesimal swarm embedded in a fully turbulent disc is subject to
strong excitation of the velocity dispersion, leading to collisional
destruction of bodies with radii R_p < 100 km. Significant diffusion of
planetesimal semimajor axes also arises, leading to large-scale spreading of
the planetesimal population throughout the inner regions of the protoplanetary
disc, in apparent contradiction of constraints provided by the distribution of
asteroids within the asteroid belt. In this paper, we examine the dynamics of
planetesimals embedded in vertically stratified turbulent discs, with and
without dead zones. Our main aims are to examine the turbulent excitation of
the velocity dispersion, and the radial diffusion, of planetesimals in these
discs. We employ three dimensional MHD simulations [...], along with an
equilibrium chemistry model [...] We find that planetesimals in fully turbulent
discs develop large random velocities that will lead to collisional
destruction/erosion for bodies with sizes below 100 km, and undergo radial
diffusion on a scale \sim 2.5 au over a 5 Myr disc life time. But planetesimals
in a dead zone experience a much reduced excitation of their random velocities,
and equilibrium velocity dispersions lie between the disruption thresholds for
weak and strong aggregates for sizes R_p < 100 km. We also find that radial
diffusion occurs over a much reduced length scale \sim 0.25 au over the disc
life time, this being consistent with solar system constraints. We conclude
that planetesimal growth via mutual collisions between smaller bodies cannot
occur in a fully turbulent disc. By contrast, a dead zone may provide a safe
haven in which km-sized planetesimals can avoid mutual destruction through
collisions.Comment: 18 pages, 13 figures, 3 tables, MNRAS in press, minor corrections to
match the published versio
The MRN complex is transcriptionally regulated by MYCN during neural cell proliferation to control replication stress
The MRE11/RAD50/NBS1 (MRN) complex is a major sensor of DNA double strand breaks, whose role in controlling faithful DNA replication and preventing replication stress is also emerging. Inactivation of the MRN complex invariably leads to developmental and/or degenerative neuronal defects, the pathogenesis of which still remains poorly understood. In particular, NBS1 gene mutations are associated with microcephaly and strongly impaired cerebellar development, both in humans and in the mouse model. These phenotypes strikingly overlap those induced by inactivation of MYCN, an essential promoter of the expansion of neuronal stem and progenitor cells, suggesting that MYCN and the MRN complex might be connected on a unique pathway essential for the safe expansion of neuronal cells. Here, we show that MYCN transcriptionally controls the expression of each component of the MRN complex. By genetic and pharmacological inhibition of the MRN complex in a MYCN overexpression model and in the more physiological context of the Hedgehog-dependent expansion of primary cerebellar granule progenitor cells, we also show that the MRN complex is required for MYCN-dependent proliferation. Indeed, its inhibition resulted in DNA damage, activation of a DNA damage response, and cell death in a MYCN- and replication-dependent manner. Our data indicate the MRN complex is essential to restrain MYCN-induced replication stress during neural cell proliferation and support the hypothesis that replication-born DNA damage is responsible for the neuronal defects associated with MRN dysfunctions.Cell Death and Differentiation advance online publication, 12 June 2015; doi:10.1038/cdd.2015.81
Hybrid SPECT/CT for the assessment of a painful hip after uncemented total hip arthroplasty
Background The diagnosis of hip pain after total hip replacement (THR)
represents a highly challenging question that is of increasing concern to
orthopedic surgeons. This retrospective study assesses bone scintigraphy with
Hybrid SPECT/CT for the diagnosis of painful THR in a selected cohort of
patients. Methods Bone SPECT/CT datasets of 23 patients (mean age 68.9 years)
with a painful hip after THR were evaluated. Selection of the patients
required an inconclusive radiograph, normal serum levels of inflammatory
parameters (CRP and ESR) or a negative aspiration of the hip joint prior to
the examination. The standard of reference was established by an
interdisciplinary adjudication-panel using all imaging data and clinical
follow-up data (>12 month). Pathological and physiological uptake patterns
were defined and applied. Results The cause of pain in this study group could
be determined in 18 out of 23 cases. Reasons were aseptic loosening (nâ=â5),
spine-related (nâ=â5), heterotopic ossification (nâ=â5), neuronal (nâ=â1),
septic loosening (nâ=â1) and periprosthetic stress fracture (nâ=â1). In (nâ=
5) cases the cause of hip pain could not be identified. SPECT/CT imaging
correctly identified the cause of pain in (nâ=â13) cases, in which the
integrated CT-information led to the correct diagnosis in (nâ=â4) cases,
mainly through superior anatomic correlation. Loosening was correctly assessed
in all cases with a definite diagnosis. Conclusions SPECT/CT of THA reliably
detects or rules out loosening and provides valuable information about
heterotopic ossifications. Furthermore differential diagnoses may be detected
with a whole-body scan and mechanical or osseous failure is covered by CT-
imaging. SPECT/CT holds great potential for imaging-based assessment of
painful prostheses
TEAD and YAP regulate the enhancer network of human embryonic pancreatic progenitors.
The genomic regulatory programmes that underlie human organogenesis are poorly understood. Pancreas development, in particular, has pivotal implications for pancreatic regeneration, cancer and diabetes. We have now characterized the regulatory landscape of embryonic multipotent progenitor cells that give rise to all pancreatic epithelial lineages. Using human embryonic pancreas and embryonic-stem-cell-derived progenitors we identify stage-specific transcripts and associated enhancers, many of which are co-occupied by transcription factors that are essential for pancreas development. We further show that TEAD1, a Hippo signalling effector, is an integral component of the transcription factor combinatorial code of pancreatic progenitor enhancers. TEAD and its coactivator YAP activate key pancreatic signalling mediators and transcription factors, and regulate the expansion of pancreatic progenitors. This work therefore uncovers a central role for TEAD and YAP as signal-responsive regulators of multipotent pancreatic progenitors, and provides a resource for the study of embryonic development of the human pancreas
ReadDepth: A Parallel R Package for Detecting Copy Number Alterations from Short Sequencing Reads
Copy number alterations are important contributors to many genetic diseases, including cancer. We present the readDepth package for R, which can detect these aberrations by measuring the depth of coverage obtained by massively parallel sequencing of the genome. In addition to achieving higher accuracy than existing packages, our tool runs much faster by utilizing multi-core architectures to parallelize the processing of these large data sets. In contrast to other published methods, readDepth does not require the sequencing of a reference sample, and uses a robust statistical model that accounts for overdispersed data. It includes a method for effectively increasing the resolution obtained from low-coverage experiments by utilizing breakpoint information from paired end sequencing to do positional refinement. We also demonstrate a method for inferring copy number using reads generated by whole-genome bisulfite sequencing, thus enabling integrative study of epigenomic and copy number alterations. Finally, we apply this tool to two genomes, showing that it performs well on genomes sequenced to both low and high coverage. The readDepth package runs on Linux and MacOSX, is released under the Apache 2.0 license, and is available at http://code.google.com/p/readdepth/
Searching for large-scale structures around high-redshift radio galaxies with Herschel
This paper presents the first results of a far-infrared search for protocluster-associated galaxy overdensities using the Spectral and Photometric Imaging REciever (SPIRE) instrument on-board the Herschel Space Observatory. Large (âŒ400âarcmin2) fields surrounding 26 powerful high-redshift radio galaxies (2.0 1028.5 WHzâ1) are mapped at 250, 350 and 500âÎŒm to give a unique wide-field sample. On average, the fields have a higher than expected, compared to blank fields, surface density of 500âÎŒm sources within 6 comoving Mpc of the radio galaxy. The analysis is then restricted to potential protocluster members only, which are identified using a far-infrared colour selection; this reveals significant overdensities of galaxies in two fields, neither of which are previously known protoclusters. The probability of finding two overdensities of this size by chance, given the number of fields observed, is 5 Ă 10â4. Overdensities here exist around radio galaxies with L500âMHz âł 1029 WHzâ1 and z 1014âMâ. However, the large uncertainty in the redshift estimation means that it is possible that these far-infrared overdensities consist of several structures across the redshift range searched
Attenuation of RNA polymerase II pausing mitigates BRCA1-associated R-loop accumulation and tumorigenesis
Most BRCA1-associated breast tumours are basal-like yet originate from luminal progenitors. BRCA1 is best known for its functions in double-strand break repair and resolution of DNA replication stress. However, it is unclear whether loss of these ubiquitously important functions fully explains the cell lineage-specific tumorigenesis. In vitro studies implicate BRCA1 in elimination of R-loops, DNA-RNA hybrid structures involved in transcription and genetic instability. Here we show that R-loops accumulate preferentially in breast luminal epithelial cells, not in basal epithelial or stromal cells, of BRCA1 mutation carriers. Furthermore, R-loops are enriched at the 50 end of those genes with promoter-proximal RNA polymerase II (Pol II) pausing. Genetic ablation of Cobra1, which encodes a Pol II-pausing and BRCA1-binding protein, ameliorates R-loop accumulation and reduces tumorigenesis in Brca1-knockout mouse mammary epithelium. Our studies show that Pol II pausing is an important contributor to BRCA1-associated R-loop accumulation and breast cancer development
LSST: from Science Drivers to Reference Design and Anticipated Data Products
(Abridged) We describe here the most ambitious survey currently planned in
the optical, the Large Synoptic Survey Telescope (LSST). A vast array of
science will be enabled by a single wide-deep-fast sky survey, and LSST will
have unique survey capability in the faint time domain. The LSST design is
driven by four main science themes: probing dark energy and dark matter, taking
an inventory of the Solar System, exploring the transient optical sky, and
mapping the Milky Way. LSST will be a wide-field ground-based system sited at
Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m
effective) primary mirror, a 9.6 deg field of view, and a 3.2 Gigapixel
camera. The standard observing sequence will consist of pairs of 15-second
exposures in a given field, with two such visits in each pointing in a given
night. With these repeats, the LSST system is capable of imaging about 10,000
square degrees of sky in a single filter in three nights. The typical 5
point-source depth in a single visit in will be (AB). The
project is in the construction phase and will begin regular survey operations
by 2022. The survey area will be contained within 30,000 deg with
, and will be imaged multiple times in six bands, ,
covering the wavelength range 320--1050 nm. About 90\% of the observing time
will be devoted to a deep-wide-fast survey mode which will uniformly observe a
18,000 deg region about 800 times (summed over all six bands) during the
anticipated 10 years of operations, and yield a coadded map to . The
remaining 10\% of the observing time will be allocated to projects such as a
Very Deep and Fast time domain survey. The goal is to make LSST data products,
including a relational database of about 32 trillion observations of 40 billion
objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures
available from https://www.lsst.org/overvie
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