410 research outputs found
The role of parvovirus B19 in the pathogenesis of autoimmunity and autoimmune disease
Human parvovirus B19 is a single-stranded DNA virus which preferentially targets the erythroblasts in the bone marrow. B19 infection commonly causes erythema infectiosum, arthralgia, fetal death, transient aplastic crisis in patients with shortened red cell survival, and persistent infection in people who are immunocompromised. Less common clinical manifestations include atypical skin rashes, neurological syndromes, cardiac syndromes, and various cytopenias. B19 infection has also been associated with development of a variety of different autoimmune diseases, including rheumatological, neurological, neuromuscular, cardiovascular, haematological, nephrological and metabolic. Production of a variety of autoantibodies has been demonstrated to occur during B19 infection and these have been shown to be key to the pathogenesis of the particular disease process in a significant number of cases, for example, production of rheumatoid factor in cases of B19-associated rheumatoid arthritis and production of anti-glutamic acid decarboxylase (GAD) in patients with B19-associated type 1 diabetes mellitus. B19 infection has also been associated with the development of multiple autoimmune diseases in 12 individuals. Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibody to B19 proteins has been shown to cross react with a variety of recognised human autoantigens, including collagen II, keratin, angiotensin II type 1 receptor, myelin basic protein, cardiolipin, and platelet membrane glycoprotein IIb/IIIa), B19-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein
Acute effects of nitrate-rich beetroot juice on blood pressure, hemostasis and vascular inflammation markers in healthy older adults: A randomized, placebo-controlled crossover study
Aging is associated with a vasoconstrictive, pro-coagulant, and pro-inflammatory profile of arteries and a decline in the bioavailability of the endothelium-derived molecule nitric oxide. Dietary nitrate elicits vasodilatory, anti-coagulant and anti-inflammatory effects in younger individuals, but little is known about whether these benefits are evident in older adults. We investigated the effects of 140 mL of nitrate-rich (HI-NI; containing 12.9 mmol nitrate) versus nitrate-depleted beetroot juice (LO-NI; containing ≤0.04 mmol nitrate) on blood pressure, blood coagulation, vascular inflammation markers, plasma nitrate and nitrite before, and 3 h and 6 h after ingestion in healthy older adults (five males, seven females, mean age: 64 years, age range: 57–71 years) in a randomized, placebo-controlled, crossover study. Plasma nitrate and nitrite increased 3 and 6 h after HI-NI ingestion (p < 0.05). Systolic, diastolic and mean arterial blood pressure decreased 3 h relative to baseline after HI-NI ingestion only (p < 0.05). The number of blood monocyte-platelet aggregates decreased 3 h after HI-NI intake (p < 0.05), indicating reduced platelet activation. The number of blood CD11b-expressing granulocytes decreased 3 h following HI-NI beetroot juice intake (p < 0.05), suggesting a shift toward an anti-adhesive granulocyte phenotype. Numbers of blood CD14++CD16+ intermediate monocyte subtypes slightly increased 6 h after HI-NI beetroot juice ingestion (p < 0.05), but the clinical implications of this response are currently unclear. These findings provide new evidence for the acute effects of nitrate-rich beetroot juice on circulating immune cells and platelets. Further long-term research is warranted to determine if these effects reduce the risk of developing hypertension and vascular inflammation with aging
Long-term effects of a protein-enriched diet on blood pressure in older women
Short-term randomised, controlled trials have found that dietary protein relative to carbohydrate can reduce blood pressure. Our objective was to investigate the effects on blood pressure of an increase in protein intake from whey over 2 years in women aged over 70 years. From the general population, 219 women aged between 70 and 80 years were recruited to a 2-year randomised, double-blind, placebo-controlled parallel-design trial: 181 women completed the trial to the end of year 2. Participants were randomly assigned to consume a daily whey protein-based beverage (protein) or an energy-matched low-protein high-carbohydrate beverage (control). Blood pressure measurements were performed at baseline, year 1 and year 2. For protein relative to control, the estimated mean net differences in protein and carbohydrate intakes were 18 (95 % CI 13, 23) and − 22 (95 % CI − 9, − 35) g/d at year 1, and 22 (95 % CI 17, 28) and − 18 (95 % CI − 6, − 31) g/d at year 2. Intention-to-treat analysis found no overall differences between groups in blood pressure (P>0.5). Net differences in systolic and diastolic blood pressure were – 2.3 (95 % CI – 5.3, 0.7) and – 1.5 (95 % CI – 3.6, 0.6) mmHg at year 1, and 1.6 (95 % CI – 1.5, 4.7) and 0.3 (95 % CI – 1.9, 2.4) mmHg at year 2. Similar differences in systolic and diastolic blood pressure at years 1 and 2 were observed with per-protocol analysis. Therefore, the present study did not provide evidence that a higher whey protein intake in older women can have prolonged effects on blood pressure
Microbial infections in eight genomic subtypes of chronic fatigue syndrome/myalgic encephalomyelitis
Spontaneous DC Current Generation in a Resistively Shunted Semiconductor Superlattice Driven by a TeraHertz Field
We study a resistively shunted semiconductor superlattice subject to a
high-frequency electric field. Using a balance equation approach that
incorporates the influence of the electric circuit, we determine numerically a
range of amplitude and frequency of the ac field for which a dc bias and
current are generated spontaneously and show that this region is likely
accessible to current experiments. Our simulations reveal that the Bloch
frequency corresponding to the spontaneous dc bias is approximately an integer
multiple of the ac field frequency.Comment: 8 pages, Revtex, 3 Postscript figure
The physical constraints on a new LoBAL QSO at z=4.82
Very few low-ionization broad absorption line (LoBAL) QSOs have been found at
high redshifts to date. One high-redshift LoBAL QSO, J0122+1216, was recently
discovered at the Lijiang 2.4-m Telescope with an initial redshift
determination of 4.76. Aiming to investigate its physical properties, we
carried out follow-up observations in the optical and near-IR spectroscopy.
Near-IR spectra from UKIRT and P200 confirms that it is a LoBAL, with a new
redshift determination of based on the \mgii~ emission-line. The
new \mgii~ redshift determination reveals strong blueshifts and asymmetry of
the high-ionization emission lines. We estimated a black hole mass of and Eddington ratio of according to the
empirical \mgii-based single-epoch relation and bolometric correction factor.
It is possible that strong outflows are the result of an extreme quasar
environment driven by the high Eddington ratio. A lower limit on the outflowing
kinetic power () was derived from both emission and absorption
lines, indicating these outflows play a significant role in the feedback
process to regulate the growth of its black hole as well as host galaxy
evolution.Comment: 12 pages, 10 figures. Accepted for publication in The Astrophysical
Journa
ETV4 and ETV5 drive synovial sarcoma through cell cycle and DUX4 embryonic pathway control
Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGF receptor (FGFR) signaling. In genetic FGFR-knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Transcriptome analyses of BGJ398-treated cells and histological and expression analyses of mouse and human synovial sarcoma tumors revealed prevalent expression of two ETS factors and FGFR targets, ETV4 and ETV5. We further demonstrate that ETV4 and ETV5 acted as drivers of synovial sarcoma growth, most likely through control of the cell cycle. Upon ETV4 and ETV5 knockdown, we observed a striking upregulation of DUX4 and its transcriptional targets that activate the zygotic genome and drive the atrophy program in facioscapulohumeral dystrophy patients. In addition to demonstrating the importance of inhibiting all three FGFRs, the current findings reveal potential nodes of attack for the cancer with the discovery of ETV4 and ETV5 as appropriate biomarkers and molecular targets, and activation of the embryonic DUX4 pathway as a promising approach to block synovial sarcoma tumors
Loss of Tet1 associated 5-hydroxymethylcytosine is concomitant with aberrant promoter hypermethylation in liver cancer
Aberrant hypermethylation of CpG islands (CGI) in human tumors occurs predominantly at repressed genes in the host tissue, but the preceding events driving this phenomenon are poorly understood. In this study, we temporally tracked epigenetic and transcriptomic perturbations which occur in a mouse model of liver carcinogenesis. Hypermethylated CGI events in the model were predicted by enrichment of the DNA modification 5-hydroxymethylcytosine (5hmC) and the histone H3 modification H3K27me3 at silenced promoters in the host tissue. During cancer progression, CGI underwent hypo-hydroxymethylation prior to hypermethylation, whilst retaining H3K27me3. In livers from mice deficient in Tet1, a tumor suppressor involved in cytosine demethylation, we observed a similar loss of promoter core 5hmC, suggesting that reduced Tet1 activity at CGI may contribute to epigenetic dysregulation observed during hepatocarcinogenesis. Consistent with this possibility, mouse liver tumors exhibited reduced Tet1 protein levels. Similar to humans, DNA methylation changes at CGI in mice did not appear to be direct drivers of hepatocellular carcinoma progression, rather, dynamic changes in H3K27me3 promoter deposition correlated strongly with tumor-specific activation and repression of transcription. Overall, our results suggest that loss of promoter-associated 5hmC in liver tumors licenses reprogramming of DNA methylation at silent CGI during progression
Exploring the Origin and Fate of the Magellanic Stream with Ultraviolet and Optical Absorption
(Abridged) We present an analysis of ionization and metal enrichment in the
Magellanic Stream (MS), the nearest gaseous tidal stream, using HST/STIS and
FUSE ultraviolet spectroscopy of two background AGN, NGC 7469 and Mrk 335. For
NGC 7469, we include optical spectroscopy from VLT/UVES. In both sightlines the
MS is detected in low-ion and high-ion absorption. Toward NGC 7469, we measure
a MS oxygen abundance [O/H]_MS=[OI/HI]=-1.00+/-0.05(stat)+/-0.08(syst),
supporting the view that the Stream originates in the SMC rather than the LMC.
We use CLOUDY to model the low-ion phase of the Stream as a photoionized plasma
using the observed Si III/Si II and C III/C II ratios. Toward Mrk 335 this
yields an ionization parameter log U between -3.45 and -3.15 and a gas density
log (n_H/cm^-3) between -2.51 and -2.21. Toward NGC 7469 we derive sub-solar
abundance ratios for [Si/O], [Fe/O], and [Al/O], indicating the presence of
dust in the MS. The high-ion column densities are too large to be explained by
photoionization, but also cannot be explained by a single-temperature
collisional-ionization model (equilibrium or non-equilibrium). This suggests
the high-ion plasma is multi-phase. Summing over the low-ion and high-ion
phases, we derive conservative lower limits on the ratio N(total H II)/N(H I)
of >19 toward NGC 7469 and >330 toward Mrk 335, showing that along these two
directions the vast majority of the Stream has been ionized. The presence of
warm-hot plasma together with the small-scale structure observed at 21 cm
provides evidence for an evaporative interaction with the hot Galactic corona.
This scenario, predicted by hydrodynamical simulations, suggests that the fate
of the MS will be to replenish the Galactic corona with new plasma, rather than
to bring neutral fuel to the disk.Comment: Accepted for publication in ApJ. 18 pages, 7 figures, all in colo
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