The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is ...becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution.
Retrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods.
Abnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%.
Our results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
BRWD3 has been described as a cause of X‐linked intellectual disability, but relatively little is known about the specific phenotype. We report the largest BRWD3 patient series to date, comprising 17 ...males with 12 distinct null variants and 2 partial gene deletions. All patients presented with intellectual disability, which was classified as moderate (65%) or mild (35%). Behavioral issues were present in 75% of patients, including aggressive behavior, attention deficit/hyperactivity and/or autistic spectrum disorders. Mean head circumference was +2.8 SD (2.8 standard deviations above the mean), and mean BMI was +2.0 SD (in the context of a mean height of +1.3 SD), indicating a predominant macrocephaly/obesity phenotype. Shared facial features included a tall chin, prognathism, broad forehead, and prominent supraorbital ridge. Additional features, reported in a minority (<30%) of patients included cryptorchidism, neonatal hypotonia, and small joint hypermobility. This study delineates the clinical features associated with BRWD3 null variants and partial gene deletions, and suggests that BRWD3 should be included in the differential diagnosis of patients with an overgrowth‐intellectual disability (OGID) phenotype, particularly in male patients with a mild or moderate intellectual disability associated with macrocephaly and/or obesity.
Segmenting the nuclei of cells in microscopy images is often the first step in the quantitative analysis of imaging data for biological and biomedical applications. Many bioimage analysis tools can ...segment nuclei in images but need to be selected and configured for every experiment. The 2018 Data Science Bowl attracted 3,891 teams worldwide to make the first attempt to build a segmentation method that could be applied to any two-dimensional light microscopy image of stained nuclei across experiments, with no human interaction. Top participants in the challenge succeeded in this task, developing deep-learning-based models that identified cell nuclei across many image types and experimental conditions without the need to manually adjust segmentation parameters. This represents an important step toward configuration-free bioimage analysis software tools.
CellProfiler has enabled the scientific research community to create flexible, modular image analysis pipelines since its release in 2005. Here, we describe CellProfiler 3.0, a new version of the ...software supporting both whole-volume and plane-wise analysis of three-dimensional (3D) image stacks, increasingly common in biomedical research. CellProfiler's infrastructure is greatly improved, and we provide a protocol for cloud-based, large-scale image processing. New plugins enable running pretrained deep learning models on images. Designed by and for biologists, CellProfiler equips researchers with powerful computational tools via a well-documented user interface, empowering biologists in all fields to create quantitative, reproducible image analysis workflows.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Using state-of-the-art dynamical simulations of globular clusters, including radiation reaction during black hole encounters and a cosmological model of star cluster formation, we create a realistic ...population of dynamically formed binary black hole mergers across cosmic space and time. We show that in the local universe, 10% of these binaries form as the result of gravitational-wave emission between unbound black holes during chaotic resonant encounters, with roughly half of those events having eccentricities detectable by current ground-based gravitational-wave detectors. The mergers that occur inside clusters typically have lower masses than binaries that were ejected from the cluster many Gyrs ago. Gravitational-wave captures from globular clusters contribute 1 – 2 Gpc−3 yr−1 to the binary merger rate in the local universe, increasing to ≳ 10 Gpc−3 yr−1 at z ∼ 3 . Finally, we discuss some of the technical difficulties associated with post-Newtonian scattering encounters, and how care must be taken when measuring the binary parameters during a dynamical capture.
The formation and evolution of binary stars are critical components of several fields in astronomy. The most numerous sources for gravitational wave observatories are inspiraling or merging compact ...binaries, while binary stars are present in nearly every electromagnetic survey regardless of the target population. Simulations of large binary populations serve to both predict and inform observations of electromagnetic and gravitational wave sources. Binary population synthesis is a tool that balances physical modeling with simulation speed to produce large binary populations on timescales of days. We present a community-developed binary population synthesis suite, COSMIC, which is designed to simulate compact-object binary populations and their progenitors. As a proof of concept, we simulate the Galactic population of compact binaries and their gravitational wave signals observable by the Laser Interferometer Space Antenna.
Abstract
Theoretical modeling of massive stars predicts a gap in the black hole (BH) mass function above ∼40–50
M
⊙
for BHs formed through single star evolution, arising from (pulsational) ...pair-instability supernovae (PISNe). However, in dense star clusters, dynamical channels may exist that allow construction of BHs with masses in excess of those allowed from single star evolution. The detection of BHs in this so-called “upper-mass gap” would provide strong evidence for the dynamical processing of BHs prior to their eventual merger. Here, we explore in detail the formation of BHs with masses within or above the pair-instability gap through collisions of young massive stars in dense star clusters. We run a suite of 68 independent cluster simulations, exploring a variety of physical assumptions pertaining to growth through stellar collisions, including primordial cluster mass segregation and the efficiency of envelope stripping during collisions. We find that as many as ∼20% of all BH progenitors undergo one or more collisions prior to stellar collapse and up to ∼1% of all BHs reside within or above the pair-instability gap through the effects of these collisions. We show that these BHs readily go on to merge with other BHs in the cluster, creating a population of massive BH mergers at a rate that may compete with the “multiple-generation” merger channel described in other analyses. This has clear relevance for the formation of very massive BH binaries as recently detected by the Laser Interferometer Gravitational-Wave Observatory/Virgo in GW190521. Finally, we describe how stellar collisions in clusters may provide a unique pathway to PISNe and briefly discuss the expected rate of these events and other electromagnetic transients.
Globular clusters (GCs) in the Milky Way exhibit a well-observed bimodal distribution in core radii separating the so-called core-collapsed and non-core-collapsed clusters. Here, we use our ...Hénon-type Monte Carlo code, CMC, to explore initial cluster parameters that map into this bimodality. Remarkably, we find that by varying the initial size of clusters (specified in our initial conditions in terms of the initial virial radius, rv) within a relatively narrow range consistent with the measured radii of young star clusters in the local universe (rv 0.5-5 pc), our models reproduce the variety of present-day cluster properties. Furthermore, we show that stellar-mass black holes (BHs) play an intimate role in this mapping from initial conditions to the present-day structural features of GCs. We identify "best-fit" models for three GCs with known observed BH candidates, NGC 3201, M22, and M10, and show that these clusters harbor populations of ∼50-100 stellar-mass BHs at present. As an alternative case, we also compare our models to the core-collapsed cluster NGC 6752 and show that this cluster likely contains few BHs at present. Additionally, we explore the formation of BH binaries in GCs and demonstrate that these systems form naturally in our models in both detached and mass-transferring configurations with a variety of companion stellar types, including low-mass main-sequence stars, white dwarfs, and sub-subgiants.
Over 100 millisecond radio pulsars (MSPs) have been observed in globular clusters (GCs), motivating theoretical studies of the formation and evolution of these sources through stellar evolution ...coupled to stellar dynamics. Here we study MSPs in GCs using realistic N-body simulations with our Cluster Monte Carlo code. We show that neutron stars (NSs) formed in electron-capture supernovae (including both accretion-induced and merger-induced collapse of white dwarfs) can be spun up through mass transfer to form MSPs. Both NS formation and spin-up through accretion are greatly enhanced through dynamical interaction processes. We find that our models for average GCs at the present day with masses 2 × 105 M can produce up to 10-20 MSPs, while a very massive GC model with mass 106 M can produce close to 100. We show that the number of MSPs is anti-correlated with the total number of stellar-mass black holes (BHs) retained in the host cluster. The radial distributions are also affected: MSPs are more concentrated toward the center in a host cluster with a smaller number of retained BHs. As a result, the number of MSPs in a GC could be used to place constraints on its BH population. Some intrinsic properties of MSP systems in our models (such as the magnetic fields and spin periods) are in good overall agreement with observations, while others (such as the distribution of binary companion types) are less so, and we discuss the possible reasons for such discrepancies. Interestingly, our models also demonstrate the possibility of dynamically forming NS-NS and NS-BH binaries in GCs, although the predicted numbers are very small.
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