The hypocholesterolemic effect of soy is well-documented and this has led to the regulatory approval of a health claim relating soy protein to a reduced risk of cardiovascular disease (CVD). However, ...soybeans contain additional components, such as isoflavones, lecithins, saponins and fiber that may improve cardiovascular health through independent mechanisms. This review summarizes the evidence on the cardiovascular benefits of non-protein soy components in relation to known CVD risk factors such as hypertension, hyperglycemia, inflammation, and obesity beyond cholesterol lowering. Overall, the available evidence suggests non-protein soy constituents improve markers of cardiovascular health; however, additional carefully designed studies are required to independently elucidate these effects. Further, work is also needed to clarify the role of isoflavone-metabolizing phenotype and gut microbiota composition on biological effect.
Osteoporosis is a common disease diagnosed primarily by measurement of bone mineral density (BMD). We undertook a genome-wide association study (GWAS) in 142,487 individuals from the UK Biobank to ...identify loci associated with BMD as estimated by quantitative ultrasound of the heel. We identified 307 conditionally independent single-nucleotide polymorphisms (SNPs) that attained genome-wide significance at 203 loci, explaining approximately 12% of the phenotypic variance. These included 153 previously unreported loci, and several rare variants with large effect sizes. To investigate the underlying mechanisms, we undertook (1) bioinformatic, functional genomic annotation and human osteoblast expression studies; (2) gene-function prediction; (3) skeletal phenotyping of 120 knockout mice with deletions of genes adjacent to lead independent SNPs; and (4) analysis of gene expression in mouse osteoblasts, osteocytes and osteoclasts. The results implicate GPC6 as a novel determinant of BMD, and also identify abnormal skeletal phenotypes in knockout mice associated with a further 100 prioritized genes.
A Reconciled Estimate of Ice-Sheet Mass Balance Shepherd, Andrew; Ivins, Erik R.; Geruo A ...
Science (American Association for the Advancement of Science),
11/2012, Letnik:
338, Številka:
6111
Journal Article
Recenzirano
Odprti dostop
We combined an ensemble of satellite altimetry, interferometry, and gravimetry data sets using common geographical regions, time intervals, and models of surface mass balance and glacial isostatic ...adjustment to estimate the mass balance of Earth's polar ice sheets. We find that there is good agreement between different satellite methods—especially in Greenland and West Antarctica—and that combining satellite data sets leads to greater certainty. Between 1992 and 2011, the ice sheets of Greenland, East Antarctica, West Antarctica, and the Antarctic Peninsula changed in mass by -152 ± 49, +14 ± 43, -65 ± 26, and -20 ± 14 gigatonnes year⁻¹, respectively. Since 1992, the polar ice sheets have contributed, on average, 0.59 ± 0.20 millimeter year⁻¹ to the rate of global sea-level rise.
Excessive lipid accumulation in Bruch's membrane (BrM) is a hallmark of ageing, the major risk factor for age-related macular degeneration (AMD). Retinal pigment epithelial (RPE) cells may utilise ...reverse cholesterol transport (RCT) activity to move lipid into BrM, mediated through ATP-binding cassette A1 (ABCA1) and scavenger receptor BI (SR-BI).
ABCA1 expression was assessed by reverse transcription polymerase chain reaction (RT-PCR) and western blotting of human RPE cell extracts. Lipid transport assays were performed using radiolabelled photoreceptor outer segments (POS). ABCA1 and SR-BI expression was examined in normal mouse eyes by immunofluorescence staining. BrMs of ABCA1 and SR-BI heterozygous mice were examined microscopically.
Human RPE cells expressed ABCA1 mRNA and protein. The ABCA1 and SR-BI inhibitor glyburide (also known as glibenclamide) abolished basal transport of POS-derived lipids in RPE cells in the presence of high-density lipoprotein. Mouse retina and RPE expressed ABCA1 and SR-BI. SR-BI was highly expressed in RPE. BrMs were significantly thickened in SR-BI heterozygous mice, but not in ABCA1 heterozygous mice.
RPE cells express ABCA1 and SR-BI. This implies a significant role for SR-BI and ABCA1 in lipid transport and RCT in the retina and RPE.
Dysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular ...mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot
FGFR1
mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline
FGFR1
mutation, p.R661P. Somatic activating
FGFR1
mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be
in cis
with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase
FGFR1
duplication and multiple mutants
in cis
(25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed,
FGFR1
alterations were less common (10/53; 19 %;
p
< 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (
p
< 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as
FGFR1
mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic
FGFR1
alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
Additive manufacturing (AM) technologies have long been recognized for their ability to fabricate complex geometric components directly from models conceptualized through computers, allowing for ...complicated designs and assemblies to be fabricated at lower costs, with shorter time to market, and improved function. Lacking behind the design complexity aspect is the ability to fully exploit AM processes for control over texture within AM components. Currently, standard heat-fill strategies utilized in AM processes result in largely columnar grain structures. Proposed in this work is a point heat source fill for the electron beam melting (EBM) process through which the texture in AM materials can be controlled. Through this point heat source strategy, the ability to form either columnar or equiaxed grain structures upon solidification through changes in the process parameters associated with the point heat source fill is demonstrated for the nickel-base superalloy, Inconel 718. Mechanically, the material is demonstrated to exhibit either anisotropic properties for the columnar-grained material fabricated through using the standard raster scan of the EBM process or isotropic properties for the equiaxed material fabricated using the point heat source fill.
An understanding of the relationship between radio-loud active galaxies and their large-scale environments is essential for realistic modelling of radio-galaxy evolution and environmental impact, for ...understanding AGN triggering and life cycles, and for calibrating galaxy feedback in cosmological models. We use the LOFAR Two-Metre Sky Survey (LoTSS) Data Release 1 catalogues to investigate this relationship. We cross-matched a sample of 8745 radio-loud AGN with 0.08 < z < 0.4, selected from LoTSS, with two Sloan Digital Sky Survey (SDSS) cluster catalogues, and find that only 10 percent of LoTSS AGN in this redshift range have a high-probability association, so that the majority of low-redshift AGN (including a substantial fraction of the most radio-luminous objects) must inhabit haloes with M < 1014 M⊙. We find that the probability of a cluster association, and the richness of the associated cluster, is correlated with AGN radio luminosity, and we also find that, for the cluster population, the number of associated AGN and the radio luminosity of the brightest associated AGN is richness-dependent. We demonstrate that these relations are not driven solely by host-galaxy stellar mass, supporting models in which large-scale environment is influential in driving AGN jet activity in the local Universe. At the lowest radio luminosities we find that the minority of objects with a cluster association are located at larger mean cluster-centre distances than more luminous AGN, an effect that appears to be driven primarily by host-galaxy mass. Finally, we also find that FRI radio galaxies inhabit systematically richer environments than FRIIs, consistent with previous work. The work presented here demonstrates the potential of LoTSS for AGN environmental studies. In future, the full northern-sky LoTSS catalogue, together with the use of deeper optical/IR imaging data and spectroscopic follow-up with WEAVE-LOFAR, will provide opportunities to extend this type of work to much larger samples and higher redshifts.
Multiple myeloma (MM) is a plasma cell cancer that develops in the skeleton causing profound bone destruction and fractures. The bone disease is mediated by increased osteoclastic bone resorption and ...suppressed bone formation. Bisphosphonates used for treatment inhibit bone resorption and prevent bone loss but fail to influence bone formation and do not replace lost bone, so patients continue to fracture. Stimulating bone formation to increase bone mass and fracture resistance is a priority; however, targeting tumor-derived modulators of bone formation has had limited success. Sclerostin is an osteocyte-specific Wnt antagonist that inhibits bone formation. We hypothesized that inhibiting sclerostin would prevent development of bone disease and increase resistance to fracture in MM. Sclerostin was expressed in osteocytes from bones from naive and myeloma-bearing mice. In contrast, sclerostin was not expressed by plasma cells from 630 patients with myeloma or 54 myeloma cell lines. Mice injected with 5TGM1-eGFP, 5T2MM, or MM1.S myeloma cells demonstrated significant bone loss, which was associated with a decrease in fracture resistance in the vertebrae. Treatment with anti-sclerostin antibody increased osteoblast numbers and bone formation rate but did not inhibit bone resorption or reduce tumor burden. Treatment with anti-sclerostin antibody prevented myeloma-induced bone loss, reduced osteolytic bone lesions, and increased fracture resistance. Treatment with anti-sclerostin antibody and zoledronic acid combined increased bone mass and fracture resistance when compared with treatment with zoledronic acid alone. This study defines a therapeutic strategy superior to the current standard of care that will reduce fractures for patients with MM.
•Anti-sclerostin treatment increases bone mass and fracture resistance in MM•Anti-sclerostin in combination with zoledronic acid is superior to zoledronic acid alone in increasing fracture resistance.
Context.
The LOFAR Two-metre Sky Survey (LoTSS) will eventually map the complete Northern sky and provide an excellent opportunity to study the distribution and evolution of the large-scale structure ...of the Universe.
Aims.
We test the quality of LoTSS observations through a statistical comparison of the LoTSS first data release (DR1) catalogues to expectations from the established cosmological model of a statistically isotropic and homogeneous Universe.
Methods.
We study the point-source completeness and define several quality cuts, in order to determine the count-in-cell statistics and differential source count statistics, and measure the angular two-point correlation function. We use the photometric redshift estimates, which are available for about half of the LoTSS-DR1 radio sources, to compare the clustering throughout the history of the Universe.
Results.
For the masked LoTSS-DR1 value-added source catalogue, we find a point-source completeness of 99% above flux densities of 0.8 mJy. The counts-in-cell statistic reveals that the distribution of radio sources cannot be described by a spatial Poisson process. Instead, a good fit is provided by a compound Poisson distribution. The differential source counts are in good agreement with previous findings in deep fields at low radio frequencies and with simulated catalogues from the SKA Design Study and the Tiered Radio Extragalactic Continuum Simulation. Restricting the value added source catalogue to low-noise regions and applying a flux density threshold of 2 mJy provides our most reliable estimate of the angular two-point correlation. Based on the distribution of photometric redshifts and the
Planck
2018 best-fit cosmological model, the theoretically predicted angular two-point correlation between 0.1 deg and 6 deg agrees reasonably well with the measured clustering for the sub-sample of radio sources with redshift information.
Conclusions.
The deviation from a Poissonian distribution might be a consequence of the multi-component nature of a large number of resolved radio sources and/or of uncertainties on the flux density calibration. The angular two-point correlation function is < 10
−2
at angular scales > 1 deg and up to the largest scales probed. At a 2 mJy flux density threshold and at a pivot angle of 1 deg, we find a clustering amplitude of
A
= (5.1 ± 0.6) × 10
−3
with a slope parameter of
γ
= 0.74 ± 0.16. For smaller flux density thresholds, systematic issues are identified, which are most likely related to the flux density calibration of the individual pointings. We conclude that we find agreement with the expectation of large-scale statistical isotropy of the radio sky at the per cent level. The angular two-point correlation agrees well with the expectation of the cosmological standard model.
Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus and all cause mortality. Long-term survivors of ...hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31-49% among HCT recipients. Although MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal of reviewing literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.
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