Dynamics of gut microbiota in autoimmune lupus Zhang, Husen; Liao, Xiaofeng; Sparks, Joshua B ...
Applied and Environmental Microbiology,
12/2014, Letnik:
80, Številka:
24
Journal Article
Recenzirano
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Gut microbiota has been recognized as an important environmental factor in health, as well as in metabolic and immunological diseases, in which perturbation of the host gut microbiota is often ...observed in the diseased state. However, little is known on the role of gut microbiota in systemic lupus erythematosus. We investigated the effects of host genetics, sex, age, and dietary intervention on the gut microbiome in a murine lupus model. In young, female lupus-prone mice resembling women at childbearing age, a population with the highest risk for lupus, we found marked depletion of lactobacilli, and increases in Lachnospiraceae and overall diversity compared to age-matched healthy controls. The predicted metagenomic profile in lupus-prone mice showed a significant enrichment of bacterial motility- and sporulation-related pathways. Retinoic acid as a dietary intervention restored lactobacilli that were downregulated in lupus-prone mice, and this correlated with improved symptoms. The predicted metagenomes also showed that retinoic acid reversed many lupus-associated changes in microbial functions that deviated from the control. In addition, gut microbiota of lupus-prone mice were different between sexes, and an overrepresentation of Lachnospiraceae in females was associated with an earlier onset of and/or more severe lupus symptoms. Clostridiaceae and Lachnospiraceae, both harboring butyrate-producing genera, were more abundant in the gut of lupus-prone mice at specific time points during lupus progression. Together, our results demonstrate the dynamics of gut microbiota in murine lupus and provide evidence to suggest the use of probiotic lactobacilli and retinoic acid as dietary supplements to relieve inflammatory flares in lupus patients.
Active Cryovolcanism on Europa? Sparks, W. B.; Schmidt, B. E.; McGrath, M. A. ...
Astrophysical journal. Letters,
04/2017, Letnik:
839, Številka:
2
Journal Article
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Evidence for plumes of water on Europa has previously been found using the Hubble Space Telescope using two different observing techniques. Roth et al. found line emission from the dissociation ...products of water. Sparks et al. found evidence for off-limb continuum absorption as Europa transited Jupiter. Here, we present a new transit observation of Europa that shows a second event at the same location as a previous plume candidate from Sparks et al., raising the possibility of a consistently active source of erupting material on Europa. This conclusion is bolstered by comparison with a nighttime thermal image from the Galileo Photopolarimeter-Radiometer that shows a thermal anomaly at the same location, within the uncertainties. The anomaly has the highest observed brightness temperature on the Europa nightside. If heat flow from a subsurface liquid water reservoir causes the thermal anomaly, its depth is 1.8-2 km, under simple modeling assumptions, consistent with scenarios in which a liquid water reservoir has formed within a thick ice shell. Models that favor thin regions within the ice shell that connect directly to the ocean, however, cannot be excluded, nor modifications to surface thermal inertia by subsurface activity. Alternatively, vapor deposition surrounding an active vent could increase the thermal inertia of the surface and cause the thermal anomaly. This candidate plume region may offer a promising location for an initial characterization of Europa's internal water and ice and for seeking evidence of Europa's habitability.
Objective We sought to evaluate performance of a noninvasive prenatal test for fetal trisomy 21 (T21) and trisomy 18 (T18). Study Design A multicenter cohort study was performed whereby cell-free DNA ...from maternal plasma was analyzed. Chromosome-selective sequencing on chromosomes 21 and 18 was performed with reporting of an aneuploidy risk (High Risk or Low Risk) for each subject. Results Of the 81 T21 cases, all were classified as High Risk for T21 and there was 1 false-positive result among the 2888 normal cases, for a sensitivity of 100% (95% confidence interval CI, 95.5–100%) and a false-positive rate of 0.03% (95% CI, 0.002–0.20%). Of the 38 T18 cases, 37 were classified as High Risk and there were 2 false-positive results among the 2888 normal cases, for a sensitivity of 97.4% (95% CI, 86.5–99.9%) and a false-positive rate of 0.07% (95% CI, 0.02–0.25%). Conclusion Chromosome-selective sequencing of cell-free DNA and application of an individualized risk algorithm is effective in the detection of fetal T21 and T18.
It has long been recognized that the mammalian gut microbiota has a role in the development and activation of the host immune system. Much less is known on how host immunity regulates the gut ...microbiota. Here we investigated the role of adaptive immunity on the mouse distal gut microbial composition by sequencing 16 S rRNA genes from microbiota of immunodeficient Rag1(-/-) mice, versus wild-type mice, under the same housing environment. To detect possible interactions among immunological status, age and variability from anatomical sites, we analyzed samples from the cecum, colon, colonic mucus and feces before and after weaning. High-throughput sequencing showed that Firmicutes, Bacteroidetes and Verrucomicrobia dominated mouse gut bacterial communities. Rag1(-) mice had a distinct microbiota that was phylogenetically different from wild-type mice. In particular, the bacterium Akkermansia muciniphila was highly enriched in Rag1(-/-) mice compared with the wild type. This enrichment was suppressed when Rag1(-/-) mice received bone marrows from wild-type mice. The microbial community diversity increased with age, albeit the magnitude depended on Rag1 status. In addition, Rag1(-/-) mice had a higher gain in microbiota richness and evenness with increase in age compared with wild-type mice, possibly due to the lack of pressure from the adaptive immune system. Our results suggest that adaptive immunity has a pervasive role in regulating gut microbiota's composition and diversity.
Objective We sought to develop a novel biochemical assay and algorithm for the prenatal evaluation of risk for fetal trisomy 21 (T21) and trisomy 18 (T18) using cell-free DNA obtained from maternal ...blood. Study Design We assayed cell-free DNA from a training set and a blinded validation set of pregnant women, comprising 250 disomy, 72 T21, and 16 T18 pregnancies. We used digital analysis of selected regions in combination with a novel algorithm, fetal-fraction optimized risk of trisomy evaluation (FORTE), to determine trisomy risk for each subject. Results In all, 163/171 subjects in the training set passed quality control criteria. Using a Z statistic, 35/35 T21 cases and 7/7 T18 cases had Z statistic >3 and 120/121 disomic cases had Z statistic <3. FORTE produced an individualized trisomy risk score for each subject, and correctly discriminated all T21 and T18 cases from disomic cases. All 167 subjects in the blinded validation set passed quality control and FORTE performance matched that observed in the training set correctly discriminating 36/36 T21 cases and 8/8 T18 cases from 123/123 disomic cases. Conclusion Digital analysis of selected regions and FORTE enable accurate, scalable noninvasive fetal aneuploidy detection.
To determine whether brain volume, as assessed on MRI scans, differs between individuals with autism and control subjects, and whether such differences are affected by age.
Previous studies have ...found increased brain weight, head circumference, and MRI brain volume in children with autism. However, studies of brain size in adults with autism have yielded conflicting results. The authors hypothesize that enlargement of the brain may be a feature of brain development during early childhood in autism that normalizes with maturational processes.
The authors measured total brain volumes from 1.5-mm coronal MRI scans in 67 non-mentally retarded children and adults with autism and 83 healthy community volunteers, ranging in age from 8 to 46 years. Head circumference was also measured. Groups did not differ on age, sex, verbal IQ, or socioeconomic status.
Brain volumes were significantly larger for children with autism 12 years old and younger compared with normally developing children, when controlling for height. Brain volumes for individuals older than age 12 did not differ between the autism and control groups. Head circumference was increased in both younger and older groups of subjects with autism, suggesting that those subjects older than age 12 had increased brain volumes as children.
Brain development in autism follows an abnormal pattern, with accelerated growth in early life that results in brain enlargement in childhood. Brain volume in adolescents and adults with autism is, however, normal, and appears to be due to a slight decrease in brain volume for these individuals at the same time that normal children are experiencing a slight increase.
Chronic kidney disease (CKD) patients undergoing hemodialysis (HD) have a high risk of sudden cardiac death (SCD). A unique risk factor may be a longer interval between HD sessions (interdialytic ...period). Inherent in conventional HD (thrice-weekly) are two 48-hour short breaks (SIDP) and one 72-hour long break (LIDP) between HD sessions.
We used an implantable cardiac monitor (ICM) to define the incidence and timing of significant arrhythmias in an HD population.
Fifty CKD patients undergoing HD with left ventricular ejection fraction >35% had an ICM inserted, with intensive follow-up to record SCD events and predefined bradyarrhythmias and tachyarrhythmias.
Mean age of the patients was 67 ± 11 years; 72% were male, and the mean follow-up was 18 ± 4 months. There were 8 unexpected SCDs (16%), all during the LIDP. The terminal event was severe bradycardia with asystole in each recorded case. No episodes of polymorphic ventricular tachycardia (VT) occurred. A total of 7686 arrhythmia events were recorded in 43 patients (86%), including bradycardia in 15 patients (30%), sinus arrest in 14 (28%), second-degree atrioventricular block in 4 (8%), nonsustained VT in 10 (20%), and new-onset paroxysmal atrial fibrillation in 14 (28%). The LIDP was the highest-risk period for all arrhythmias (P < .001). The arrhythmia event rate per hour was greatest during the first pre-HD period of the week compared with any other peri-HD period (P < .001).
Risk of SCD and significant arrhythmias is greatest during the LIDP. SCD was attributable to severe bradycardia and asystole. Interventions to prevent this type of SCD or shorten the LIDP deserve further evaluation.
URL: https://www.anzctr.org.au (Unique identifier: ACTRN12613001326785).
We report an optical/UV jet and counterjet in M84, previously unreported in archival Hubble Space Telescope imaging. With archival VLA, ALMA, and Chandra imaging, we examine the first well-sampled ...spectral energy distribution of the inner jet of M84, where we find that multiple co-spatial spectral components are required. In particular, the ALMA data reveal that the radio spectrum of all four knots in the jet turns over at approximately 100 GHz, which requires a second component for the bright optical/UV emission. Further, the optical/UV has a soft spectrum and is inconsistent with the relatively flat X-ray spectrum, which indicates a third component at higher energies. Using archival VLA imaging, we have measured the proper motion of the innermost knots at 0.9 0.6 and 1.1 0.4c, which when combined with the low jet-to-counterjet flux ratio yields an orientation angle for the system of °. In the radio, we find high fractional polarization of the inner jet of up to 30% while in the optical no polarization is detected (<8%). We investigate different scenarios for explaining the particular multicomponent spectral energy distribution (SED) of the knots. Inverse Compton models are ruled out due to the extreme departure from equipartition and the unrealistically high total jet power required. The multicomponent SED can be naturally explained within a leptohadronic scenario, but at the cost of very high power in relativistic protons. A two-component synchrotron model remains a viable explanation, but more theoretical work is needed to explain the origin and properties of the electron populations.
Indoleamine 2,3-dioxygenase-1 (IDO1; IDO) mediates oxidative cleavage of tryptophan, an amino acid essential for cell proliferation and survival. IDO1 inhibition is proposed to have therapeutic ...potential in immunodeficiency-associated abnormalities, including cancer. Here, we describe INCB024360, a novel IDO1 inhibitor, and investigate its roles in regulating various immune cells and therapeutic potential as an anticancer agent. In cellular assays, INCB024360 selectively inhibits human IDO1 with IC50 values of approximately 10nM, demonstrating little activity against other related enzymes such as IDO2 or tryptophan 2,3-dioxygenase (TDO). In coculture systems of human allogeneic lymphocytes with dendritic cells (DCs) or tumor cells, INCB024360 inhibition of IDO1 promotes T and natural killer (NK)–cell growth, increases IFN-γ production, and reduces conversion to regulatory T (Treg)–like cells. IDO1 induction triggers DC apoptosis, whereas INCB024360 reverses this and increases the number of CD86high DCs, potentially representing a novel mechanism by which IDO1 inhibition activates T cells. Furthermore, IDO1 regulation differs in DCs versus tumor cells. Consistent with its effects in vitro, administration of INCB024360 to tumor-bearing mice significantly inhibits tumor growth in a lymphocyte-dependent manner. Analysis of plasma kynurenine/tryptophan levels in patients with cancer affirms that the IDO pathway is activated in multiple tumor types. Collectively, the data suggest that selective inhibition of IDO1 may represent an attractive cancer therapeutic strategy via up-regulation of cellular immunity.
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