171 research outputs found
P1 bacteriophage-enabled delivery of CRISPR-Cas9 antimicrobial activity against shigella flexneri
The discovery of clustered, regularly interspaced, short palindromic repeats (CRISPR) and the Cas9 RNA-guided nuclease provides unprecedented opportunities to selectively kill specific populations or species of bacteria. However, the use of CRISPR-Cas9 to clear bacterial infections in vivo is hampered by the inefficient delivery of cas9 genetic constructs into bacterial cells. Here, we use a broad-host-range P1-derived phagemid to deliver the CRISPR-Cas9 chromosomal-targeting system into Escherichia coli and the dysentery-causing Shigella flexneri to achieve DNA sequence-specific killing of targeted bacterial cells. We show that genetic modification of the helper P1 phage DNA packaging site (pac) significantly enhances the purity of packaged phagemid and improves the Cas9-mediated killing of S. flexneri cells. We further demonstrate that P1 phage particles can deliver chromosomal-targeting cas9 phagemids into S. flexneri in vivo using a zebrafish larvae infection model, where they significantly reduce the bacterial load and promote host survival. Our study highlights the potential of combining P1 bacteriophage-based delivery with the CRISPR chromosomal-targeting system to achieve DNA sequence-specific cell lethality and efficient clearance of bacterial infection
Flt3L controls the development of radiosensitive dendritic cells in the meninges and choroid plexus of the steady-state mouse brain
As shown by analyses of morphology, gene expression, antigen-presenting function, and Flt3 dependence, the steady-state mouse brain contains a population of DCs that exhibits similarities to splenic DCs and differences from microglia
Schrodinger cat states prepared by Bloch oscillation in a spin-dependent optical lattice
We propose to use Bloch oscillation of ultra-cold atoms in a spin-dependent
optical lattice to prepare schrodinger cat states. Depending on its internal
state, an atom feels different periodic potentials and thus has different
energy band structures for its center-of-mass motion. Consequently, under the
same gravity force, the wave packets associated with different internal states
perform Bloch oscillation of different amplitudes in space and in particular
they can be macroscopically displaced with respect to each other. In this way,
a cat state can be prepared.Comment: 4 pages, 3 figures; slightly modifie
Squeeze-and-Breathe Evolutionary Monte Carlo Optimisation with Local Search Acceleration and its application to parameter fitting
Motivation: Estimating parameters from data is a key stage of the modelling
process, particularly in biological systems where many parameters need to be
estimated from sparse and noisy data sets. Over the years, a variety of
heuristics have been proposed to solve this complex optimisation problem, with
good results in some cases yet with limitations in the biological setting.
Results: In this work, we develop an algorithm for model parameter fitting
that combines ideas from evolutionary algorithms, sequential Monte Carlo and
direct search optimisation. Our method performs well even when the order of
magnitude and/or the range of the parameters is unknown. The method refines
iteratively a sequence of parameter distributions through local optimisation
combined with partial resampling from a historical prior defined over the
support of all previous iterations. We exemplify our method with biological
models using both simulated and real experimental data and estimate the
parameters efficiently even in the absence of a priori knowledge about the
parameters.Comment: 15 Pages, 3 Figures, 6 Tables; Availability: Matlab code available
from the authors upon reques
Association between serum keptin concentrations and insulin resistance: A population-based study from China
BACKGROUND Insulin resistance contributes to the cardio-metabolic risk. The effect of leptin in obese and overweight population on insulin resistance was seldom reported. METHODS A total of 1234 subjects (572 men and 662 women) aged ≥18 y was sampled by the procedure. Adiposity measures included BMI, waist circumference, hip circumference, WHR, upper arm circumference, triceps skinfold and body fat percentage. Serum leptin concentrations were measured by an ELISA method. The homeostasis model (HOMA-IR) was applied to estimate insulin resistance. RESULTS In men, BMI was the variable which was most strongly correlated with leptin, whereas triceps skinfold was most sensitive for women. More importantly, serum leptin levels among insulin resistant subjects were almost double compared to the subjects who had normal insulin sensitivity at the same level of adiposity in both men and women, after controlling for potential confounders. In addition, HOMA-IR increased significantly across leptin quintiles after adjustment for age, BMI, total energy intake, physical activity and smoking status in both men and women (p for trend <0.0001). CONCLUSIONS There was a significant association between HOMA-IR and serum leptin concentrations in Chinese men and women, independently of adiposity levels. This may suggest that serum leptin concentration is an important predictor of insulin resistance and other metabolic risks irrespective of obesity levels. Furthermore, leptin levels may be used to identify the cardio-metabolic risk in obese and overweight population.Hui Zuo, Zumin Shi, Baojun Yuan, Yue Dai, Gaolin Wu, Akhtar Hussai
European and multi-ancestry genome-wide association meta-analysis of atopic dermatitis highlights importance of systemic immune regulation
Atopic dermatitis (AD) is a common inflammatory skin condition and prior genome-wide association studies (GWAS) have identified 71 associated loci. In the current study we conducted the largest AD GWAS to date (discovery N = 1,086,394, replication N = 3,604,027), combining previously reported cohorts with additional available data. We identified 81 loci (29 novel) in the European-only analysis (which all replicated in a separate European analysis) and 10 additional loci in the multi-ancestry analysis (3 novel). Eight variants from the multi-ancestry analysis replicated in at least one of the populations tested (European, Latino or African), while two may be specific to individuals of Japanese ancestry. AD loci showed enrichment for DNAse I hypersensitivity and eQTL associations in blood. At each locus we prioritised candidate genes by integrating multi-omic data. The implicated genes are predominantly in immune pathways of relevance to atopic inflammation and some offer drug repurposing opportunities.</p
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