502 research outputs found
Perivascular stem cells at the crossroads of tissue regeneration and pathology
Pericytes represent a population of potential mesenchymal stem cells (MSC) that reside
within a perivascular niche until they are required in normal homeostasis and the
response to injury. Their mesenchymal capacities for multipotent differentiation,
immune modulation and release of trophic factors hold great promise for regenerative
therapies. Pathological expression of these potentials has been described in disease
states, while acute or chronic inflammation following injury can lead to the production
of signalling molecules that ultimately drive these progenitors to a fibrotic fate. The aim
of this work was to explore how fate decisions of pericytes are regulated by their niche
(in the setting of osteogenesis), and in the response to acute and chronic injury (in the
setting of fibrosis).
It was hypothesized that interactions between pericytes and endothelial cells (EC)
within their perivascular niche are responsible for regulating mesenchymal
differentiation. The osteogenic, adipogenic and chondrogenic potential of pericytes
following isolation from multiple human organs was confirmed. The interactions
between pericytes and EC in 2D and 3D coculture and the production of basement
membrane proteins in these settings were confirmed. The osteogenic differentiation of
pericytes was accelerated by EC but no influence of EC on the adipogenic and
chondrogenic differentiation of pericytes was detected. Furthermore, data indicated
that the influence on pericyte osteogenic potential by EC may occur through wnt
signaling. The activation of TGFβ (transforming growth factor beta) through αv integrins has
been suggested as central mediator of fibrosis in multiple organs. We hypothesized that
selective αv integrin deletions in PDGFRβ (platelet derived growth factor receptor
beta) expressing pericytes identifies a targetable pathway regulating fibrosis in skeletal
muscle. We report that PDGFRβ-Cre inactivates genes in murine skeletal muscle
pericytes with high efficiency. Deletion of the αv integrin subunit in pericytes protected
mice from chemical injury induced skeletal muscle fibrosis. Pharmacological blockade
of αv integrins by a novel small molecule (CWHM 12) attenuated muscle fibrosis, even
when administered after fibrosis was established
Parallel MCMC with Generalized Elliptical Slice Sampling
Probabilistic models are conceptually powerful tools for finding structure in
data, but their practical effectiveness is often limited by our ability to
perform inference in them. Exact inference is frequently intractable, so
approximate inference is often performed using Markov chain Monte Carlo (MCMC).
To achieve the best possible results from MCMC, we want to efficiently simulate
many steps of a rapidly mixing Markov chain which leaves the target
distribution invariant. Of particular interest in this regard is how to take
advantage of multi-core computing to speed up MCMC-based inference, both to
improve mixing and to distribute the computational load. In this paper, we
present a parallelizable Markov chain Monte Carlo algorithm for efficiently
sampling from continuous probability distributions that can take advantage of
hundreds of cores. This method shares information between parallel Markov
chains to build a scale-mixture of Gaussians approximation to the density
function of the target distribution. We combine this approximation with a
recent method known as elliptical slice sampling to create a Markov chain with
no step-size parameters that can mix rapidly without requiring gradient or
curvature computations.Comment: 19 pages, 8 figures, 3 algorithm
Large cross-effect dynamic nuclear polarisation enhancements with kilowatt inverting chirped pulses at 94 GHz
This work was supported by UK Research Council EPSRC research grant EP/R13705/1 and Wellcome Trust 099149/Z/12/Z.Dynamic nuclear polarisation (DNP) is a process that transfers electron spin polarisation to nuclei by applying resonant microwave radiation, and has been widely used to improve the sensitivity of nuclear magnetic resonance (NMR). Here we demonstrate new levels of performance for static cross-effect proton DNP using high peak power chirped inversion pulses at 94 GHz to create a strong polarisation gradient across the inhomogeneously broadened line of the mono-radical 4-amino TEMPO. Enhancements of up to 340 are achieved at an average power of a few hundred mW, with fast build-up times (3 s). Experiments are performed using a home-built wideband kW pulsed electron paramagnetic resonance (EPR) spectrometer operating at 94 GHz, integrated with an NMR detection system. Simultaneous DNP and EPR characterisation of other mono-radicals and biradicals, as a function of temperature, leads to additional insights into limiting relaxation mechanisms and give further motivation for the development of wideband pulsed amplifiers for DNP at higher frequencies.Publisher PDFPeer reviewe
Compact corrugated feedhorns with high Gaussian coupling efficiency and -60 dB sidelobes
We demonstrate that very high performance, extremely compact, scalar corrugated feedhorns can be designed and constructed by optimizing the excitation and phasing of the HE11, HE12 and HE13 modes near the throat of the horn whilst limiting excitation of higher order modes. We present the design and measurement of two families of dual-profiled horn, both with a directivity of 20 dBi that couple with very high efficiency to a fundamental Gaussian mode. The first was optimized for sidelobe performance and features sidelobes approaching -60 dB for a horn length of only 15.6λ. The second was designed to minimize horn length and achieves sidelobe levels below -35 dB for a horn which is only 4.8λ long. The horns exhibit excellent coupling to the fundamental free-space Gaussian mode, with LG00 power coupling of 99.92% and 99.75% respectively. We demonstrate excellent agreement between simulation and experiment at 94 GHz and simulate the performance over a 20% bandwidth. High performance compact scalar horns are of interest because they reduce manufacturing risk at high frequencies, and reduce size and weight at lower frequencies, which can be important in horn arrays and space applications, where horn arrays often have serious weight and size restrictions.PostprintPeer reviewe
Shape dependent conformable holographic metasurfaces
Funding: European Research Council - 819346; Engineering and Physical Sciences Research Council - EP/V029975/1; Royal Society - URF\R\211033.In this paper, the design, fabrication, and experimental demonstration of conformable holographic metasurfaces are reported. Here, it is shown that the produced holographic image changes as the metasurface is applied to targets with different shapes. The demonstration is based on a reflective type metasurface, where the reflected polarization is perpendicular to that of the incident light. In addition, how the parameters of the metasurface determine the quality of the images produced and the ability to produce independent images are discussed critically.Publisher PDFPeer reviewe
An output coupler for a W-band high power wideband gyro-amplifier
This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) U.K. under Research Grant EP/K029746/1, and Science and Technology Facilities Council (STFC) U.K. under Research Grants ST/K006673/1 & ST/K006703/1, ST/N002326/1 & ST/N002318/1.An output coupler for a W-band high power wideband gyro-amplifier has been designed, manufactured and experimentally measured. It consists of a high performance sin2-parallel corrugated horn integrated with a broadband multi-layer window. The major design requirements are that the horn/window combination must have an input return loss lower than -30 dB over a 10 GHz bandwidth, provide a high quality output beam pattern, and operate under ultra-high vacuum conditions. The coupler converts a circular wave guide TE11 mode into the free space Laguerre Gaussian LG00 mode over the frequency band of 90–100 GHz with a measured return loss of between -30 and -40 dB and a simulated Gaussian coupling efficiency of over 99% at 94 GHz.PostprintPeer reviewe
A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype
Background Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis.
Methods Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed.
Results We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly.
Conclusions Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features—particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry—should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations
Cognitive health among older adults in the United States and in England
<p>Abstract</p> <p>Background</p> <p>Cognitive function is a key determinant of independence and quality of life among older adults. Compared to adults in England, US adults have a greater prevalence of cardiovascular risk factors and disease that may lead to poorer cognitive function. We compared cognitive performance of older adults in the US and England, and sought to identify sociodemographic and medical factors associated with differences in cognitive function between the two countries.</p> <p>Methods</p> <p>Data were from the 2002 waves of the US Health and Retirement Study (HRS) (n = 8,299) and the English Longitudinal Study of Ageing (ELSA) (n = 5,276), nationally representative population-based studies designed to facilitate direct comparisons of health, wealth, and well-being. There were differences in the administration of the HRS and ELSA surveys, including use of both telephone and in-person administration of the HRS compared to only in-person administration of the ELSA, and a significantly higher response rate for the HRS (87% for the HRS vs. 67% for the ELSA). In each country, we assessed cognitive performance in non-hispanic whites aged 65 and over using the same tests of memory and orientation (0 to 24 point scale).</p> <p>Results</p> <p>US adults scored significantly better than English adults on the 24-point cognitive scale (unadjusted mean: 12.8 vs. 11.4, P < .001; age- and sex-adjusted: 13.2 vs. 11.7, P < .001). The US cognitive advantage was apparent even though US adults had a significantly higher prevalence of cardiovascular risk factors and disease. In a series of OLS regression analyses that controlled for a range of sociodemographic and medical factors, higher levels of education and wealth, and lower levels of depressive symptoms, accounted for some of the US cognitive advantage. US adults were also more likely to be taking medications for hypertension, and hypertension treatment was associated with significantly better cognitive function in the US, but not in England (P = .014 for treatment × country interaction).</p> <p>Conclusion</p> <p>Despite methodological differences in the administration of the surveys in the two countries, US adults aged ≥ 65 appeared to be cognitively healthier than English adults, even though they had a higher burden of cardiovascular risk factors and disease. Given the growing number of older adults worldwide, future cross-national studies aimed at identifying the medical and social factors that might prevent or delay cognitive decline in older adults would make important and valuable contributions to public health.</p
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