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"Lee, Christina"
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Evaluation of vaginal microbiome equilibrium states identifies microbial parameters linked to resilience after menses and antibiotic therapy
The vaginal microbiome (VMB) is a complex microbial community that is closely tied to reproductive health. Optimal VMB communities have compositions that are commonly defined by the dominance of certain Lactobacillus spp. and can remain stable over time or transition to non-optimal states dominated by anaerobic bacteria and associated with bacterial vaginosis (BV). The ability to remain stable or undergo transitions suggests a system with either single (mono-stable) or multiple (multi-stable) equilibrium states, though factors that contribute to stability have been difficult to determine due to heterogeneity in microbial growth characteristics and inter-species interactions. Here, we use a computational model to determine whether differences in microbial growth and interaction parameters could alter equilibrium state accessibility and account for variability in community composition after menses and antibiotic therapies. Using a global uncertainty and sensitivity analysis that captures parameter sets sampled from a physiologically relevant range, model simulations predicted that 79.7% of microbial communities were mono-stable (gravitate to one composition type) and 20.3% were predicted to be multi-stable (can gravitate to more than one composition type, given external perturbations), which was not significantly different from observations in two clinical cohorts (HMP cohort, 75.2% and 24.8%; Gajer cohort, 78.1% and 21.9%, respectively). The model identified key microbial parameters that governed equilibrium state accessibility, such as the importance of non-optimal anaerobic bacteria interactions with Lactobacillus spp., which is largely understudied. Model predictions for composition changes after menses and antibiotics were not significantly different from those observed in clinical cohorts. Lastly, simulations were performed to illustrate how this quantitative framework can be used to gain insight into the development of new combinatorial therapies involving altered prebiotic and antibiotic dosing strategies. Altogether, dynamical models could guide development of more precise therapeutic strategies to manage BV.
Journal Article
Individualised prediction of major bleeding in patients with atrial fibrillation treated with anticoagulation
Anticoagulation in atrial fibrillation (AF) increases the risk of major bleeding. No predictive model has hitherto provided estimates of the absolute risk for individual patients.
To predict the individual 1-year risk of major bleeding in patients with AF taking anticoagulants and evaluate the importance of individual risk factors.
A nationwide register-based cohort study.
Danish patients with first-time non-valvular AF who redeemed anticoagulants within 7 days after diagnosis.
The individual absolute risk of major bleeding was estimated from a logistic regression model (the Calculator of Absolute Bleeding Risk/CABS model) utilising the same risk factors as HAS-BLED, except allowing non-linear age effects, and allowing effect modification of all factors according to history of bleeding. The logistic regression was assessed in term of discrimination using the Area Under the ROC curve (AUC) and calibration.
Among 76,102 patients with AF redeeming anticoagulants, 2,406 suffered a major bleeding within 1 year. History of bleeding was the strongest predictor, and age significantly modified the risk. The CABS model superseded HAS-BLED score with regards to discrimination (AUC 0.646 vs 0.615, p<0.001) and calibrated well. A typical male patient was 70-years old without any risk factors and he had a 1-year bleeding risk of 1.4% (1.2; 1.6) while a typical female patient was 73-years old, had hypertension and a 1-year bleeding risk of 2.2% (1.9;2.6).
We propose CABS as a tool for prediction of individual absolute risks of major bleeding in patients with AF taking anticoagulant. The predicted absolute risk can be used for patient counselling.
Journal Article
Made in Asian America : a history for young people
\"This book is a stirring account of the ordinary people and extraordinary acts that made Asian America and the young people who are remaking America today\"--Amazon.
Book
An in silico framework for the rational design of vaginal probiotic therapy
Bacterial vaginosis ( BV ) is a common condition characterized by a shift in vaginal microbiome composition that is linked to negative reproductive outcomes and increased susceptibility to sexually transmitted infections. Despite the commonality of BV, standard-of-care antibiotics provide limited control of recurrent BV episodes and development of new biotherapies is limited by the lack of controlled models needed to evaluate new dosing and treatment regimens. Here, we develop an in silico framework to evaluate selection criteria for potential probiotic strains, test adjunctive therapy with antibiotics, and alternative dosing strategies. This computational framework highlighted the importance of resident microbial species on the efficacy of hypothetical probiotic strains, identifying specific interaction parameters between resident non-optimal anaerobic bacteria (nAB) and Lactobacillus spp. with candidate probiotic strains as a necessary selection criterion. Model predictions were able to replicate results from a recent phase 2b clinical trial for the live biotherapeutic product, Lactin-V, demonstrating the relevance of the in silico platform. Results from the computational model support that the probiotic strain in Lactin-V requires adjunctive antibiotic therapy to be effective, and that increasing the dosing frequency of the probiotic could have a moderate impact on BV recurrence at 12 and 24 weeks. Altogether, this framework could provide evidence for the rational selection of probiotic strains and help optimize dosing frequency or adjunctive therapies.
Journal Article
Solar Energetic Electron Access to the Moon Within the Terrestrial Magnetotail and Shadowing by the Lunar Surface
We present measurements of 30–700 keV Solar Energetic Electrons (SEEs) near the Moon when within the terrestrial magnetotail by the Acceleration, Reconnection, Turbulence, and Electrodynamics of the Moon's Interaction with the Sun spacecraft. Despite their detection deep within the tail, the incident flux and spectral shape of these electrons are nearly identical to measurements taken upstream of Earth in the solar wind by the Wind spacecraft; however, their pitch angle distribution is isotropized compared to the more field‐aligned distribution upstream. We illustrate that SEEs initially traveling Earthward precipitate onto the lunar far‐side, generating extended shadows in the cis‐lunar electron distribution. By modeling the dynamics of these electrons, we show that their precipitation patterns on the lunar near‐side are comparatively reduced. The non‐uniform precipitation and accessibility of potentially hazardous electrons to the Moon's surface are highly relevant in the context of astronaut safety during the planned exploration of the lunar environment. Plain Language Summary The Moon is located within the tail of Earth's magnetosphere during one‐third of its orbit. Although the strong terrestrial magnetic field prevents high‐energy particles from reaching Earth's surface, the Moon does not receive the same protection when it is within the terrestrial magnetotail. Instead, we show that the high‐energy electron flux near the Moon is unchanged during intense solar energetic electron events compared to measurements taken far upstream of Earth. However, the precipitation of these particles onto the lunar surface is non‐uniform. Since these electrons gain access to the magnetosphere from down‐tail of the Moon, they preferentially bombard the lunar far‐side surface. This creates a shadow in the electrons on the nearside that extends far beyond the Moon toward Earth. Hence, despite the high flux of these particles that are potentially hazardous to future activities on the lunar surface, there exist regions across the lunar near‐side where the relative flux of these electrons is reduced relative to the upstream value when the Moon is within the magnetotail. These findings provide context for the fundamental scientific understanding of high‐energy solar electrons and their access to the lunar surface. Key Points High‐energy solar energetic electrons (SEEs) have direct access to the lunar environment when in the terrestrial magnetotail Precipitation onto the lunar nightside carves‐out electrons from the ambient distribution, generating extended shadows far from the Moon When in the tail, the lunar surface is non‐uniformly bombarded by Earthward‐traveling SEEs, with reduced access to the dayside hemisphere
Journal Article
Characterization of the interplay between DNA repair and CRISPR/Cas9-induced DNA lesions at an endogenous locus
The CRISPR–Cas9 system provides a versatile toolkit for genome engineering that can introduce various DNA lesions at specific genomic locations. However, a better understanding of the nature of these lesions and the repair pathways engaged is critical to realizing the full potential of this technology. Here we characterize the different lesions arising from each Cas9 variant and the resulting repair pathway engagement. We demonstrate that the presence and polarity of the overhang structure is a critical determinant of double-strand break repair pathway choice. Similarly, single nicks deriving from different Cas9 variants differentially activate repair: D10A but not N863A-induced nicks are repaired by homologous recombination. Finally, we demonstrate that homologous recombination is required for repairing lesions using double-stranded, but not single-stranded DNA as a template. This detailed characterization of repair pathway choice in response to CRISPR–Cas9 enables a more deterministic approach for designing research and therapeutic genome engineering strategies.
CRISPR-Cas9 has rapidly become a common molecular biology tool for modifying genomes and has been modified to generate single-strand nicks as well as double-strand breaks. Here the authors explore the DNA repair pathways activated by the different variants of Cas9.
Journal Article
Curved adhesions mediate cell attachment to soft matrix fibres in three dimensions
Integrin-mediated focal adhesions are the primary architectures that transmit forces between the extracellular matrix (ECM) and the actin cytoskeleton. Although focal adhesions are abundant on rigid and flat substrates that support high mechanical tensions, they are sparse in soft three-dimensional (3D) environments. Here we report curvature-dependent integrin-mediated adhesions called curved adhesions. Their formation is regulated by the membrane curvatures imposed by the topography of ECM protein fibres. Curved adhesions are mediated by integrin ɑvβ5 and are molecularly distinct from focal adhesions and clathrin lattices. The molecular mechanism involves a previously unknown interaction between integrin β5 and a curvature-sensing protein, FCHo2. We find that curved adhesions are prevalent in physiological conditions, and disruption of curved adhesions inhibits the migration of some cancer cell lines in 3D fibre matrices. These findings provide a mechanism for cell anchorage to natural protein fibres and suggest that curved adhesions may serve as a potential therapeutic target.
Zhang et al. report curved adhesions, which are integrin-based adhesions formed in response to membrane curvatures that can be imposed by the overlying extracellular matrix fibre geometry.
Journal Article