393 research outputs found
Reply: Randomised studies with translational end points are required to further elucidate the prognostic and predictive value of CA IX
Histiocytoid cardiomyopathy and microphthalmia with linear skin defects syndrome: phenotypes linked by truncating variants in NDUFB11
Variants in NDUFB11, which encodes a structural component of complex I of the mitochondrial respiratory chain (MRC), were recently independently reported to cause histiocytoid cardiomyopathy (histiocytoid CM) and microphthalmia with linear skin defects syndrome (MLS syndrome). Here we report an additional case of histiocytoid CM, which carries a de novo nonsense variant in NDUFB11 (ENST00000276062.8: c.262C > T; p.[Arg88*]) identified using whole-exome sequencing (WES) of a family trio. An identical variant has been previously reported in association with MLS syndrome. The case we describe here lacked the diagnostic features of MLS syndrome, but a detailed clinical comparison of the two cases revealed significant phenotypic overlap. Heterozygous variants in HCCS (which encodes an important mitochondrially targeted protein) and COX7B, which, like NDUFB11, encodes a protein of the MRC, have also previously been identified in MLS syndrome including a case with features of both MLS syndrome and histiocytoid CM. However, a systematic review of WES data from previously published histiocytoid CM cases, alongside four additional cases presented here for the first time, did not identify any variants in these genes. We conclude that NDUFB11 variants play a role in the pathogenesis of both histiocytoid CM and MLS and that these disorders are allelic (genetically related)
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The mass distribution of the unusual merging cluster Abell 2146 from strong lensing
Abell 2146 consists of two galaxy clusters that have recently collided close to the plane of the sky, and it is unique in showing two large shocks on images. With an early stage merger, shortly after first core passage, one would expect the cluster galaxies and the dark matter to be leading the X-ray emitting plasma. In this regard, the cluster Abell 2146-A is very unusual in that the X-ray cool core appears to lead, rather than lag, the brightest cluster galaxy (BCG) in their trajectories. Here we present a strong-lensing analysis of multiple-image systems identified on images. In particular, we focus on the distribution of mass in Abell 2146-A in order to determine the centroid of the dark matter halo. We use object colours and morphologies to identify multiple-image systems; very conservatively, four of these systems are used as constraints on a lens mass model. We find that the centroid of the dark matter halo, constrained using the strongly lensed features, is coincident with the BCG, with an offset of β2 kpc between the centres of the dark matter halo and the BCG. Thus from the strong-lensing model, the X-ray cool core also leads the centroid of the dark matter in Abell 2146-A, with an offset of β30 kpc.JEC acknowledges support from The University of Texas at Dallas, and NASA through a Fellowship of the Texas Space Grant Consortium. Based on observations made with the NASA/ESA HST, obtained through programme 12871 through the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. Additional funding supporting JEC, LJK, and DIC came from a grant from the Space Telescope Science Institute under the same programme 12871. Additional funding supporting JEC and LJK came from a grant from the National Science Foundation, number 1517954. This work was supported in part by World Premier International Research Center Initiative (WPI Initiative), MEXT, Japan, and JSPS KAKENHI Grant Number 26800093 and 15H05892
HST imaging of the dusty filaments and nucleus swirl in NGC4696 at the centre of the Centaurus Cluster
Narrow-band HST imaging has resolved the detailed internal structure of the
10 kpc diameter H alpha+[NII] emission line nebulosity in NGC4696, the central
galaxy in the nearby Centaurus cluster, showing that the dusty, molecular,
filaments have a width of about 60pc. Optical morphology and velocity
measurements indicate that the filaments are dragged out by the bubbling action
of the radio source as part of the AGN feedback cycle. Using the drag force we
find that the magnetic field in the filaments is in approximate pressure
equipartition with the hot gas. The filamentary nature of the cold gas
continues inward, swirling around and within the Bondi accretion radius of the
central black hole, revealing the magnetic nature of the gas flows in massive
elliptical galaxies. HST imaging resolves the magnetic, dusty, molecular
filaments at the centre of the Centaurus cluster to a swirl around and within
the Bondi radius.This is the accepted manuscript. It is currently embargoed pending publication
Killer immunoglobulin-like Receptors (KIR) haplogroups A and B track with Natural Killer Cells and Cytokine Profile in Aged Subjects: Observations from Octo/Nonagenarians in the Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST)
BACKGROUND: Natural Killer Cells (NK) play an important role in detection and elimination of virus-infected, damaged or cancer cells. NK cell function is guided by expression of Killer Immunoglobulin-like Receptors (KIRs) and contributed to by the cytokine milieu. KIR molecules are grouped on NK cells into stimulatory and inhibitory KIR haplotypes A and B, through which NKs sense and tolerate HLA self-antigens or up-regulate the NK-cytotoxic response to cells with altered HLA self-antigens, damaged by viruses or tumours. We have previously described increased numbers of NK and NK-related subsets in association with sIL-2R cytokine serum levels in BELFAST octo/nonagenarians. We hypothesised that changes in KIR A and B haplotype gene frequencies could explain the increased cytokine profiles and NK compartments previously described in Belfast Elderly Longitudinal Free-living Aging STudy (BELFAST) octo/nonagenarians, who show evidence of ageing well. RESULTS: In the BELFAST study, 24% of octo/nonagenarians carried the KIR A haplotype and 76% KIR B haplotype with no differences for KIR A haplogroup frequency between male or female subjects (23% v 24%; p=0.88) or for KIR B haplogroup (77% v 76%; p=0.99). Octo/nonagenarian KIR A haplotype carriers showed increased NK numbers and percentage compared to Group B KIR subjects (p=0.003; p=0.016 respectively). There were no KIR A/ B haplogroup-associated changes for related CD57+CD8 ((high or low)) subsets. Using logistic regression, KIR B carriers were predicted to have higher IL-12 cytokine levels compared to KIR A carriers by about 3% (OR 1.03, confidence limits CI 0.99β1.09; p=0.027) and 14% higher levels for TGF-Ξ² (active), a cytokine with an anti-inflammatory role, (OR 1.14, confidence limits CI 0.99β1.09; p=0.002). CONCLUSION: In this observational study, BELFAST octo/nonagenarians carrying KIR A haplotype showed higher NK cell numbers and percentage compared to KIR B carriers. Conversely, KIR B haplotype carriers, with genes encoding for activating KIRs, showed a tendency for higher serum pro-inflammatory cytokines compared to KIR A carriers. While the findings in this study should be considered exploratory they may serve to stimulate debate about the immune signatures of those who appear to age slowly and who represent a model for good quality survivor-hood
Strongly magnetized pulsars: explosive events and evolution
Well before the radio discovery of pulsars offered the first observational
confirmation for their existence (Hewish et al., 1968), it had been suggested
that neutron stars might be endowed with very strong magnetic fields of
-G (Hoyle et al., 1964; Pacini, 1967). It is because of their
magnetic fields that these otherwise small ed inert, cooling dead stars emit
radio pulses and shine in various part of the electromagnetic spectrum. But the
presence of a strong magnetic field has more subtle and sometimes dramatic
consequences: In the last decades of observations indeed, evidence mounted that
it is likely the magnetic field that makes of an isolated neutron star what it
is among the different observational manifestations in which they come. The
contribution of the magnetic field to the energy budget of the neutron star can
be comparable or even exceed the available kinetic energy. The most magnetised
neutron stars in particular, the magnetars, exhibit an amazing assortment of
explosive events, underlining the importance of their magnetic field in their
lives. In this chapter we review the recent observational and theoretical
achievements, which not only confirmed the importance of the magnetic field in
the evolution of neutron stars, but also provide a promising unification scheme
for the different observational manifestations in which they appear. We focus
on the role of their magnetic field as an energy source behind their persistent
emission, but also its critical role in explosive events.Comment: Review commissioned for publication in the White Book of
"NewCompStar" European COST Action MP1304, 43 pages, 8 figure
Suv4-20h Histone Methyltransferases Promote Neuroectodermal Differentiation by Silencing the Pluripotency-Associated Oct-25 Gene
Post-translational modifications (PTMs) of histones exert fundamental roles in regulating gene expression. During development, groups of PTMs are constrained by unknown mechanisms into combinatorial patterns, which facilitate transitions from uncommitted embryonic cells into differentiated somatic cell lineages. Repressive histone modifications such as H3K9me3 or H3K27me3 have been investigated in detail, but the role of H4K20me3 in development is currently unknown. Here we show that Xenopus laevis Suv4-20h1 and h2 histone methyltransferases (HMTases) are essential for induction and differentiation of the neuroectoderm. Morpholino-mediated knockdown of the two HMTases leads to a selective and specific downregulation of genes controlling neural induction, thereby effectively blocking differentiation of the neuroectoderm. Global transcriptome analysis supports the notion that these effects arise from the transcriptional deregulation of specific genes rather than widespread, pleiotropic effects. Interestingly, morphant embryos fail to repress the Oct4-related Xenopus gene Oct-25. We validate Oct-25 as a direct target of xSu4-20h enzyme mediated gene repression, showing by chromatin immunoprecipitaton that it is decorated with the H4K20me3 mark downstream of the promoter in normal, but not in double-morphant, embryos. Since knockdown of Oct-25 protein significantly rescues the neural differentiation defect in xSuv4-20h double-morphant embryos, we conclude that the epistatic relationship between Suv4-20h enzymes and Oct-25 controls the transit from pluripotent to differentiation-competent neural cells. Consistent with these results in Xenopus, murine Suv4-20h1/h2 double-knockout embryonic stem (DKO ES) cells exhibit increased Oct4 protein levels before and during EB formation, and reveal a compromised and biased capacity for in vitro differentiation, when compared to normal ES cells. Together, these results suggest a regulatory mechanism, conserved between amphibians and mammals, in which H4K20me3-dependent restriction of specific POU-V genes directs cell fate decisions, when embryonic cells exit the pluripotent state
Combined vertebral fracture assessment and bone mineral density measurement: a new standard in the diagnosis of osteoporosis in academic populations
Vertebral Fracture Analysis enables the detection of vertebral fractures in the same session as bone mineral density testing. Using this method in 2,424 patients, we found unknown vertebral fractures in approximately one out of each six patients with significant impact on management. The presence of osteoporotic vertebral fractures (VF) is an important risk factor for all future fractures independent of BMD. Yet, determination of the VF status has not become standard practice. Vertebral Fracture Assessment (VFA) is a new feature available on modern densitometers. In this study we aimed to determine the prevalence of VF using VFA in all patients referred for BMD testing in a university medical center and to evaluate its added clinical value. Prospective diagnostic evaluation study in 2,500 consecutive patients referred for BMD. Patients underwent VFA in supine position after BMD testing. Questionnaires were used to assess perceived added value of VFA. In 2,424 patients (1,573 women), results were evaluable. In 541 patients (22%), VFA detected a prevalent VF that was unknown in 69%. In women, the prevalence was 20% versus 27% found in men (p <0.0001). The prevalence of VF was 14% in patients with normal BMD (97/678), increased to 21% (229/1,100) in osteopenia and to 26% in those with osteoporosis (215/646) by WHO criteria. After excluding mild fractures VF prevalence was 13% (322/2,424). In 468 of 942 questionnaires (50% response rate), 27% of the referring physicians reported VFA results to impact on patient management. VFA is a patient friendly new tool with a high diagnostic yield, as it detected unknown VF in one out of each six patients, with significant impact on management. We believe these findings justify considering VFA in all new patients referred for osteoporosis assessment in similar populations
A Putative P-Type ATPase Required for Virulence and Resistance to Haem Toxicity in Listeria monocytogenes
Regulation of iron homeostasis in many pathogens is principally mediated by the ferric uptake regulator, Fur. Since acquisition of iron from the host is essential for the intracellular pathogen Listeria monocytogenes, we predicted the existence of Fur-regulated systems that support infection. We examined the contribution of nine Fur-regulated loci to the pathogenicity of L. monocytogenes in a murine model of infection. While mutating the majority of the genes failed to affect virulence, three mutants exhibited a significantly compromised virulence potential. Most striking was the role of the membrane protein we designate FrvA (Fur regulated virulence factor A; encoded by frvA [lmo0641]), which is absolutely required for the systemic phase of infection in mice and also for virulence in an alternative infection model, the Wax Moth Galleria mellonella. Further analysis of the ΞfrvA mutant revealed poor growth in iron deficient media and inhibition of growth by micromolar concentrations of haem or haemoglobin, a phenotype which may contribute to the attenuated growth of this mutant during infection. Uptake studies indicated that the ΞfrvA mutant is unaffected in the uptake of ferric citrate but demonstrates a significant increase in uptake of haem and haemin. The data suggest a potential role for FrvA as a haem exporter that functions, at least in part, to protect the cell against the potential toxicity of free haem
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