Liver cirrhosis is a major cause of death worldwide and is characterized by extensive fibrosis. There are currently no effective antifibrotic therapies available. To obtain a better understanding of ...the cellular and molecular mechanisms involved in disease pathogenesis and enable the discovery of therapeutic targets, here we profile the transcriptomes of more than 100,000 single human cells, yielding molecular definitions for non-parenchymal cell types that are found in healthy and cirrhotic human liver. We identify a scar-associated TREM2
CD9
subpopulation of macrophages, which expands in liver fibrosis, differentiates from circulating monocytes and is pro-fibrogenic. We also define ACKR1
and PLVAP
endothelial cells that expand in cirrhosis, are topographically restricted to the fibrotic niche and enhance the transmigration of leucocytes. Multi-lineage modelling of ligand and receptor interactions between the scar-associated macrophages, endothelial cells and PDGFRα
collagen-producing mesenchymal cells reveals intra-scar activity of several pro-fibrogenic pathways including TNFRSF12A, PDGFR and NOTCH signalling. Our work dissects unanticipated aspects of the cellular and molecular basis of human organ fibrosis at a single-cell level, and provides a conceptual framework for the discovery of rational therapeutic targets in liver cirrhosis.
Interest in electrical energy storage systems is increasing as the opportunities for their application become more compelling in an industry with a back-drop of ageing assets, increasing distributed ...generation and a desire to transform networks into Smart Grids. A field trial of an energy storage system designed and built by ABB is taking place on a section of 11
kV distribution network operated by EDF Energy Networks in Great Britain. This paper reports on the findings from simulation software developed at Durham University that evaluates the benefits brought by operating an energy storage system in response to multiple events on multiple networks. The tool manages the allocation of a finite energy resource to achieve the most beneficial shared operation across two adjacent areas of distribution network. Simulations account for the key energy storage system parameters of capacity and power rating. Results for events requiring voltage control and power flow management show how the choice of operating strategy influences the benefits achieved. The wider implications of these results are discussed to provide an assessment of the role of electrical energy storage systems in future Smart Grids.
DNA stretching induces Cas9 off-target activity Newton, Matthew D; Taylor, Benjamin J; Driessen, Rosalie P C ...
Nature Structural & Molecular Biology,
03/2019, Letnik:
26, Številka:
3
Journal Article
Recenzirano
Odprti dostop
CRISPR/Cas9 is a powerful genome-editing tool, but spurious off-target edits present a barrier to therapeutic applications. To understand how CRISPR/Cas9 discriminates between on-targets and ...off-targets, we have developed a single-molecule assay combining optical tweezers with fluorescence to monitor binding to λ-DNA. At low forces, the Streptococcus pyogenes Cas9 complex binds and cleaves DNA specifically. At higher forces, numerous off-target binding events appear repeatedly at the same off-target sites in a guide-RNA-sequence-dependent manner, driven by the mechanical distortion of the DNA. Using single-molecule Förster resonance energy transfer (smFRET) and cleavage assays, we show that DNA bubbles induce off-target binding and cleavage at these sites, even with ten mismatches, as well as at previously identified in vivo off-targets. We propose that duplex DNA destabilization during cellular processes (for example, transcription, replication, etc.) can expose these cryptic off-target sites to Cas9 activity, highlighting the need for improved off-target prediction algorithms.
Genetic progress will increase when breeders examine genotypes in addition to pedigrees and phenotypes. Genotypes for 38,416 markers and August 2003 genetic evaluations for 3,576 Holstein bulls born ...before 1999 were used to predict January 2008 daughter deviations for 1,759 bulls born from 1999 through 2002. Genotypes were generated using the Illumina BovineSNP50 BeadChip and DNA from semen contributed by US and Canadian artificial-insemination organizations to the Cooperative Dairy DNA Repository. Genomic predictions for 5 yield traits, 5 fitness traits, 16 conformation traits, and net merit were computed using a linear model with an assumed normal distribution for marker effects and also using a nonlinear model with a heavier tailed prior distribution to account for major genes. The official parent average from 2003 and a 2003 parent average computed from only the subset of genotyped ancestors were combined with genomic predictions using a selection index. Combined predictions were more accurate than official parent averages for all 27 traits. The coefficients of determination (R2) were 0.05 to 0.38 greater with nonlinear genomic predictions included compared with those from parent average alone. Linear genomic predictions had R2 values similar to those from nonlinear predictions but averaged just 0.01 lower. The greatest benefits of genomic prediction were for fat percentage because of a known gene with a large effect. The R2 values were converted to realized reliabilities by dividing by mean reliability of 2008 daughter deviations and then adding the difference between published and observed reliabilities of 2003 parent averages. When averaged across all traits, combined genomic predictions had realized reliabilities that were 23% greater than reliabilities of parent averages (50 vs. 27%), and gains in information were equivalent to 11 additional daughter records. Reliability increased more by doubling the number of bulls genotyped than the number of markers genotyped. Genomic prediction improves reliability by tracing the inheritance of genes even with small effects.
We study direct numerical simulations of turbulence arising from the interaction of an initial background shear, a linear background stratification and an external body force. In each simulation the ...turbulence produced is spatially intermittent, with dissipation rates varying over orders of magnitude in the vertical. We focus analysis on the statistically quasi-steady states achieved by applying large-scale body forcing to the domain, and compare flows forced by internal gravity waves with those forced by vertically uniform vortical modes. By considering the turbulent energy budgets for each simulation, we find that the injection of potential energy from the wave forcing permits a reversal in the sign of the mean buoyancy flux. This change in the sign of the buoyancy flux is associated with large, convective density overturnings, which in turn lead to more efficient mixing in the wave-forced simulations. The inhomogeneous dissipation in each simulation allows us to investigate localised correlations between the kinetic and potential energy dissipation rates. These correlations lead us to the conclusion that an appropriate definition of an instantaneous mixing efficiency, $\unicodeSTIX{x1D702}(t):=\unicodeSTIX{x1D712}/(\unicodeSTIX{x1D712}+\unicodeSTIX{x1D700})$ (where $\unicodeSTIX{x1D700}$ and $\unicodeSTIX{x1D712}$ are the volume-averaged turbulent viscous dissipation rate and fluctuation density variance destruction rate respectively) in the wave-forced cases is independent of an appropriately defined local turbulent Froude number, consistent with scalings proposed for low Froude number stratified turbulence.
To determine factors associated with outcomes following pelvic exenteration for advanced nonrectal pelvic malignancy.
The PelvEx Collaborative provides large volume data from specialist centers to ...ascertain factors associated with improved outcomes.
Consecutive patients who underwent pelvic exenteration for nonrectal pelvic malignancy between 2006 and 2017 were identified from 22 tertiary centers. Patient demographics, neoadjuvant therapy, histopathological assessment, length of stay, 30-day major complication/mortality rate were recorded.The primary endpoints were factors associated with survival. The secondary endpoints included the difference in margin rates across the cohorts, impact of neoadjuvant treatment on survival, associated morbidity, and mortality.
One thousand two hundred ninety-three patients were identified. 40.4% (n = 523) had gynecological malignancies (endometrial, ovarian, cervical, and vaginal), 35.7% (n = 462) urological (bladder), 18.1% (n = 234) anal, and 5.7% had sarcoma (n = 74).The median age across the cohort was 63 years (range, 23-85). The median 30-day mortality rate was 1.7%, with the highest rates occurring following exenteration for recurrent sarcoma or locally advanced cervical cancer (3.3% each). The median length of hospital stay was 17.5 days. 34.5% of patients experienced a major complication, with highest rate occurring in those having salvage surgery for anal cancer.Multivariable analysis showed R0 resection was the main factor associated with long-term survival. The 3-year overall-survival rate for R0 resection was 48% for endometrial malignancy, 40.6% for ovarian, 49.4% for cervical, 43.8% for vaginal, 59% for bladder, 48.3% for anal, and 48.1% for sarcoma.
Pelvic exenteration remains an important treatment in selected patients with advanced or recurrent nonrectal pelvic malignancy. The range in 3-year overall survival following R0 resection (40%-59%) reflects the diversity of tumor types.
To examine whether past and recent sun exposure and vitamin D status (serum 25-hydroxyvitamin D 25(OH)D levels) are associated with risk of first demyelinating events (FDEs) and to evaluate the ...contribution of these factors to the latitudinal gradient in FDE incidence in Australia.
This was a multicenter incident case-control study. Cases (n = 216) were aged 18-59 years with a FDE and resident within one of 4 Australian centers (from latitudes 27°S to 43°S), from November 1, 2003, to December 31, 2006. Controls (n = 395) were matched to cases on age, sex, and study region, without CNS demyelination. Exposures measured included self-reported sun exposure by life stage, objective measures of skin phenotype and actinic damage, and vitamin D status.
Higher levels of past, recent, and accumulated leisure-time sun exposure were each associated with reduced risk of FDE, e.g., accumulated leisure-time sun exposure (age 6 years to current), adjusted odds ratio (AOR) = 0.70 (95% confidence interval CI 0.53-0.94) for each ultraviolet (UV) dose increment of 1,000 kJ/m(2) (range 508-6,397 kJ/m(2)). Higher actinic skin damage (AOR = 0.39 95% CI 0.17-0.92, highest grade vs the lowest) and higher serum vitamin D status (AOR = 0.93 95% CI 0.86-1.00 per 10 nmol/L increase in 25(OH)D) were independently associated with decreased FDE risk. Differences in leisure-time sun exposure, serum 25(OH)D level, and skin type additively accounted for a 32.4% increase in FDE incidence from the low to high latitude regions.
Sun exposure and vitamin D status may have independent roles in the risk of CNS demyelination. Both will need to be evaluated in clinical trials for multiple sclerosis prevention.
We test the assumption of hydrostatic equilibrium in an X-ray luminosity selected sample of 50 galaxy clusters at 0.15 < z < 0.3 from the Local Cluster Substructure Survey (LoCuSS). Our weak-lensing ...measurements of M
500 control systematic biases to sub-4 per cent, and our hydrostatic measurements of the same achieve excellent agreement between XMM–Newton and Chandra. The mean ratio of X-ray to lensing mass for these 50 clusters is
$\mathrel {\beta _{\rm X}}\;= 0.95\pm 0.05$
, and for the 44 clusters also detected by Planck, the mean ratio of Planck mass estimate to LoCuSS lensing mass is
$\mathrel {\beta _{\rm P}}\;= 0.95\pm 0.04$
. Based on a careful like-for-like analysis, we find that LoCuSS, the Canadian Cluster Comparison Project, and Weighing the Giants agree on
$\mathrel {\beta _{\rm P}}\;\simeq 0.9{\rm -}0.95$
at 0.15 < z < 0.3. This small level of hydrostatic bias disagrees at ∼5σ with the level required to reconcile Planck cosmology results from the cosmic microwave background and galaxy cluster counts.
H₂O at the Phoenix Landing Site Smith, P.H; Tamppari, L.K; Arvidson, R.E ...
Science (American Association for the Advancement of Science),
07/2009, Letnik:
325, Številka:
5936
Journal Article
Recenzirano
The Phoenix mission investigated patterned ground and weather in the northern arctic region of Mars for 5 months starting 25 May 2008 (solar longitude between 76.5° and 148°). A shallow ice table was ...uncovered by the robotic arm in the center and edge of a nearby polygon at depths of 5 to 18 centimeters. In late summer, snowfall and frost blanketed the surface at night; H₂O ice and vapor constantly interacted with the soil. The soil was alkaline (pH = 7.7) and contained CaCO₃, aqueous minerals, and salts up to several weight percent in the indurated surface soil. Their formation likely required the presence of water.
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