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Massively parallel profiling and predictive modeling of the outcomes of CRISPR/Cas9-mediated double-strand break repair.
Non-homologous end-joining (NHEJ) plays an important role in double-strand break (DSB) repair of DNA. Recent studies have shown that the error patterns of NHEJ are strongly biased by sequence context, but these studies were based on relatively few templates. To investigate this more thoroughly, we systematically profiled ∼1.16 million independent mutational events resulting from CRISPR/Cas9-mediated cleavage and NHEJ-mediated DSB repair of 6872 synthetic target sequences, introduced into a human cell line via lentiviral infection. We find that: (i) insertions are dominated by 1 bp events templated by sequence immediately upstream of the cleavage site, (ii) deletions are predominantly associated with microhomology and (iii) targets exhibit variable but reproducible diversity with respect to the number and relative frequency of the mutational outcomes to which they give rise. From these data, we trained a model that uses local sequence context to predict the distribution of mutational outcomes. Exploiting the bias of NHEJ outcomes towards microhomology mediated events, we demonstrate the programming of deletion patterns by introducing microhomology to specific locations in the vicinity of the DSB site. We anticipate that our results will inform investigations of DSB repair mechanisms as well as the design of CRISPR/Cas9 experiments for diverse applications including genome-wide screens, gene therapy, lineage tracing and molecular recording
Insulin Treatment Is Associated With Improved Fetal Placental Vascular Circulation in Obese and Non-obese Women With Gestational Diabetes Mellitus
Objective: The present study was designed to investigate the impact of carbohydrate restriction and insulin treatment on placental maternal and fetal vascular circulation in obese and non-obese women with gestational diabetes mellitus (GDM).Design and methods: One Hundred Ninety-One women with GDM who gave birth and underwent a placental histopathological examination at Wolfson Medical Center, Israel, were included in the study: 122 women who were treated with carbohydrate/calorie restriction diet (Group 1) and 69 women who were treated with diet plus insulin (Group 2). Additionally, each group was divided into two subgroups according to pre-pregnancy BMI: non-obese and obese.Results: Maternal vascular malperfusion lesions did not differ significantly between groups. Vascular lesions related to fetal malperfusion were significantly lower in GDM women treated by insulin and diet compared to women with diet alone (p = 0.027). Among fetal malperfusion lesions, villous changes consistent with fetal thrombo-occlusive disease (FTOD) were significantly lower in women treated with diet plus insulin and lowest in GDM women with pre-pregnancy BMI < 30 kg/m2 (p = 0.009). In the logistic regression analysis, insulin treatment was significantly associated with a decreased rate of villous changes consistent with FTOD (OR 0.97, 95% CI 0.12–0.80, p = 0.03). Prevalence of gestational hypertension was higher in obese women of both treatment groups (p = 0.024).Conclusion: Combination of obesity and GDM increased rate of FTOD and prevalence of gestational hypertension. Carbohydrate restriction diet plus insulin treatment was associated with improved fetal placental vascular circulation, especially in GDM women with pre-pregnancy BMI < 30 kg/m2
Stable Non-Supersymmetric Supergravity Solutions from Deformations of the Maldacena-Nunez Background
We study a deformation of the type IIB Maldacena-Nunez background which
arises as the near-horizon limit of NS5 branes wrapped on a two-cycle. This
background is dual to a "little string theory" compactified on a two-sphere, a
theory which at low energies includes four-dimensional N = 1 super Yang-Mills
theory. The deformation we study corresponds to a mass term for some of the
scalar fields in this theory, and it breaks supersymmetry completely. In the
language of seven-dimensional SO(4) gauged supergravity the deformation
involves (at leading order) giving a VEV, depending only on the radial
coordinate, to a particular scalar field. We explicitly construct the
corresponding solution at leading order in the deformation, both in
seven-dimensional and in ten-dimensional supergravity, and we verify that it
completely breaks supersymmetry. Since the original background had a mass gap
and we are performing a small deformation, the deformed background is
guaranteed to be stable even though it is not supersymmetric.Comment: 1+31 pages, one figure. v2: minor clarifications, refs adde
Strain-induced orbital energy shift in antiferromagnetic RuO2 revealed by resonant elastic x-ray scattering
In its ground state, RuO2 was long thought to be an ordinary metallic
paramagnet. Recent neutron and x-ray diffraction revealed that bulk RuO2 is an
antiferromagnet (AFM) with TN above 300 K. Furthermore, epitaxial strain
induces novel superconductivity in thin films of RuO2 below 2 K. Here, we
present a resonant elastic x-ray scattering (REXS) study at the Ru L2 edge of
the strained RuO2 films exhibiting the strain-induced superconductivity. We
observe an azimuthal modulation of the 100 Bragg peak consistent with canted
AFM found in bulk. Most notably, in the strained films displaying novel
superconductivity, we observe a ~1 eV shift of the Ru eg orbitals to a higher
energy. The energy shift is smaller in thicker, relaxed films and films with a
different strain direction. Our results provide further evidence of the utility
of epitaxial strain as a tuning parameter in complex oxides.Comment: 20 pages, 3 main figures, 3 supplementary figure
LayoutLM: Pre-training of Text and Layout for Document Image Understanding
Pre-training techniques have been verified successfully in a variety of NLP
tasks in recent years. Despite the widespread use of pre-training models for
NLP applications, they almost exclusively focus on text-level manipulation,
while neglecting layout and style information that is vital for document image
understanding. In this paper, we propose the \textbf{LayoutLM} to jointly model
interactions between text and layout information across scanned document
images, which is beneficial for a great number of real-world document image
understanding tasks such as information extraction from scanned documents.
Furthermore, we also leverage image features to incorporate words' visual
information into LayoutLM. To the best of our knowledge, this is the first time
that text and layout are jointly learned in a single framework for
document-level pre-training. It achieves new state-of-the-art results in
several downstream tasks, including form understanding (from 70.72 to 79.27),
receipt understanding (from 94.02 to 95.24) and document image classification
(from 93.07 to 94.42). The code and pre-trained LayoutLM models are publicly
available at \url{https://aka.ms/layoutlm}.Comment: KDD 202
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