Inflammatory bowel disease (IBD) is considered to result from interplay between host and intestinal microbiota. While IBD in adults has shown to be associated with marked changes in the intestinal ...microbiota, there are only a few studies in children, and particularly studies focusing on therapeutic responses are lacking. Hence, this prospective study addressed the intestinal microbiota in pediatric IBD especially related to the level of inflammation.
In total, 68 pediatric patients with IBD and 26 controls provided stool and blood samples in a tertiary care hospital and 32 received anti-tumor necrosis factor-α (anti-TNF-α). Blood inflammatory markers and fecal calprotectin levels were determined. The intestinal microbiota was characterized by phylogenetic microarray and qPCR analysis.
The microbiota varied along a gradient of increasing intestinal inflammation (indicated by calprotectin levels), which was associated with reduced microbial richness, abundance of butyrate producers, and relative abundance of Gram-positive bacteria (especially Clostridium clusters IV and XIVa). A significant association between microbiota composition and inflammation was indicated by a set of bacterial groups predicting the calprotectin levels (area under curve (AUC) of 0.85). During the induction of anti-TNF-α, the microbial diversity and similarity to the microbiota of controls increased in the responder group by week 6, but not in the non-responders (P<0.01; response related to calprotectin levels). The abundance of six groups of bacteria including those related to Eubacterium rectale and Bifidobacterium spp. predicted the response to anti-TNF-α medication.
Intestinal microbiota represents a potential biomarker for correlating the level of inflammation and therapeutic responses to be further validated.
We report the detection of an extrasolar planet of mass ratio image in microlensing event MOA-2007-BLG-192. The best-fit microlensing model shows both the microlensing parallax and finite source ...effects, and these can be combined to obtain the lens masses of image for the primary and image for the planet. However, the observational coverage of the planetary deviation is sparse and incomplete, and the radius of the source was estimated without the benefit of a source star color measurement. As a result, the 2 capital sigma limits on the mass ratio and finite source measurements are weak. Nevertheless, the microlensing parallax signal clearly favors a substellar mass planetary host, and the measurement of finite source effects in the light curve supports this conclusion. Adaptive optics images taken with the Very Large Telescope (VLT) NACO instrument are consistent with a lens star that is either a brown dwarf or a star at the bottom of the main sequence. Follow-up VLT and/or Hubble Space Telescope (HST) observations will either confirm that the primary is a brown dwarf or detect the low-mass lens star and enable a precise determination of its mass. In either case, the lens star, MOA-2007-BLG-192L, is the lowest mass primary known to have a companion with a planetary mass ratio, and the planet, MOA-2007-BLG-192Lb, is probably the lowest mass exoplanet found to date, aside from the lowest mass pulsar planet.
We present the analysis of four candidate short-duration binary microlensing events from the 2006-2007 MOA Project short-event analysis. Three of these events are determined to be microlensing ...events, while the fourth is most likely caused by stellar variability. One of these events, MOA-bin-1, is due to a planet, and it is the first example of a planetary event in which the stellar host is only detected through binary microlensing effects. This is one of the most massive and widest separation planets found by microlensing. The scarcity of such wide-separation planets also has implications for interpretation of the isolated planetary mass objects found by this analysis. In particular, if the entire isolated planet sample found by Sumi et al. consists of planets bound in wide orbits around stars, we find that it is likely that the median orbital semimajor axis is <30 AU.
We report the detection of sub-Saturn-mass planet MOA-2008-BLG-310Lb and argue that it is the strongest candidate yet for a bulge planet. Deviations from the single-lens fit are smoothed out by ...finite-source effects and therefore are not immediately apparent from the light curve. Nevertheless, we find that a model in which the primary has a planetary companion is favored over the single-lens model by DELTAchi{sup 2} {approx} 880 for an additional 3 degrees of freedom. Detailed analysis yields a planet/star mass ratio q = (3.3 +- 0.3) x 10{sup -4} and an angular separation between the planet and star within 10% of the angular Einstein radius. The small angular Einstein radius, theta{sub E} = 0.155 +- 0.011 mas, constrains the distance to the lens to be D{sub L} >6.0 kpc if it is a star (M{sub L} >0.08 M{sub sun}). This is the only microlensing exoplanet host discovered so far that must be in the bulge if it is a star. By analyzing VLT NACO adaptive optics images taken near the baseline of the event, we detect additional blended light that is aligned to within 130 mas of the lensed source. This light is plausibly from the lens, but could also be due to a companion to the lens or source, or possibly an unassociated star. If the blended light is indeed due to the lens, we can estimate the mass of the lens, M{sub L} = 0.67 +- 0.14 M{sub sun}, planet mass m = 74 +- 17 M{sub +}, and projected separation between the planet and host, 1.25 +- 0.10 AU, putting it right on the 'snow line'. If not, then the planet has lower mass, is closer to its host and is colder. To distinguish among these possibilities on reasonable timescales would require obtaining Hubble Space Telescope images almost immediately, before the source-lens relative motion of mu= 5 mas yr{sup -1} causes them to separate substantially.
Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes. MR studies can be straightforward; for ...example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease. However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret. In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease). Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol). We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations. In doing so, we hope to contribute towards more reliable evaluations of MR findings.
Highlights ► GMDP peptide mimic, RVPPRYHAKISPMVN (RN-peptide) as a new non-pyrogenic adjuvant. ► Structure-activity relationship studies of shortened and Ala-scan analogues of RN-peptide. ► PRYH is ...ultimately required for binding to anti-GMDP-antibodies. ► RVPPRYH is a minimal peptide segment possessing adjuvant activity. ► Ala-scan approach revealed K9, I10, S11, М13 contributions into RN adjuvant activity.
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Summary
The F1 antigen of Yersinia pestis belongs to a class of non‐pilus adhesins assembled via a classical chaperone–usher pathway. Such pathways consist of PapD‐like chaperones that bind subunits ...and pilot them to the outer membrane usher, where they are assembled into surface structures. In a recombinant Escherichia coli model system, chaperone–subunit (Caf1M:Caf1n) complexes accumulate in the periplasm. Three inde‐pendent methods showed that these complexes are rod‐ or coil‐shaped linear arrays of Caf1 subunits capped at one end by a single copy of Caf1M chaperone. Deletion and point mutagenesis identified an N‐terminal donor strand region of Caf1 that was essential for polymerization in vitro, in the periplasm and at the cell surface, but not for chaperone–subunit interaction. Partial protease digestion of periplasmic complexes revealed that this region becomes buried upon formation of Caf1:Caf1 contacts. These results show that, despite the capsule‐like appearance of F1 antigen, the basic structure is assembled as a linear array of subunits held together by intersubunit donor strand complementation. This example shows that strikingly different architectures can be achieved by the same general principle of donor strand complementation and suggests that a similar basic polymer organization will be shared by all surface structures assembled by classical chaperone–usher pathways.
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Insulin resistance has deleterious effects on cardiometabolic disease. We used Mendelian randomization analyses to clarify the causal relationships of insulin resistance (IR) on circulating ...blood-based metabolites to shed light on potential mediators of the IR to cardiometabolic disease relationship.
We used 53 single nucleotide polymorphisms associated with IR from a recent genome-wide association study (GWAS) to explore their effects on circulating lipids and metabolites. We used published summary-level data from two GWASs of European individuals; data on the exposure (IR) were obtained from meta-GWASs of 188,577 individuals, and data on the outcomes (58 metabolic measures assessed by nuclear magnetic resonance) were taken from a GWAS of 24,925 individuals.
One-SD genetically elevated IR (equivalent to 55% higher geometric mean of fasting insulin, 0.89 mmol/L higher triglycerides, and 0.46 mmol/L lower HDL cholesterol) was associated with higher concentrations of all branched-chain amino acids (BCAAs)-isoleucine (0.56 SD; 95% CI 0.43, 0.70), leucine (0.42 SD; 95% CI 0.28, 0.55), and valine (0.26 SD; 95% CI 0.12, 0.39)-as well as with higher glycoprotein acetyls (an inflammation marker) (0.47 SD; 95% CI 0.32, 0.62) (
< 0.0003 for each). Results were broadly consistent when using multiple sensitivity analyses to account for potential genetic pleiotropy.
We provide robust evidence that IR causally affects each individual BCAA and inflammation. Taken together with existing studies, this implies that BCAA metabolism lies on a causal pathway from adiposity and IR to type 2 diabetes.
Circulating lipoprotein lipids cause coronary heart disease (CHD). However, the precise way in which one or more lipoprotein lipid-related entities account for this relationship remains unclear. ...Using genetic instruments for lipoprotein lipid traits implemented through multivariable Mendelian randomisation (MR), we sought to compare their causal roles in the aetiology of CHD.
We conducted a genome-wide association study (GWAS) of circulating non-fasted lipoprotein lipid traits in the UK Biobank (UKBB) for low-density lipoprotein (LDL) cholesterol, triglycerides, and apolipoprotein B to identify lipid-associated single nucleotide polymorphisms (SNPs). Using data from CARDIoGRAMplusC4D for CHD (consisting of 60,801 cases and 123,504 controls), we performed univariable and multivariable MR analyses. Similar GWAS and MR analyses were conducted for high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. The GWAS of lipids and apolipoproteins in the UKBB included between 393,193 and 441,016 individuals in whom the mean age was 56.9 y (range 39-73 y) and of whom 54.2% were women. The mean (standard deviation) lipid concentrations were LDL cholesterol 3.57 (0.87) mmol/L and HDL cholesterol 1.45 (0.38) mmol/L, and the median triglycerides was 1.50 (IQR = 1.11) mmol/L. The mean (standard deviation) values for apolipoproteins B and A-I were 1.03 (0.24) g/L and 1.54 (0.27) g/L, respectively. The GWAS identified multiple independent SNPs associated at P < 5 × 10-8 for LDL cholesterol (220), apolipoprotein B (n = 255), triglycerides (440), HDL cholesterol (534), and apolipoprotein A-I (440). Between 56%-93% of SNPs identified for each lipid trait had not been previously reported in large-scale GWASs. Almost half (46%) of these SNPs were associated at P < 5 × 10-8 with more than one lipid-related trait. Assessed individually using MR, LDL cholesterol (odds ratio OR 1.66 per 1-standard-deviation-higher trait; 95% CI: 1.49-1.86; P < 0.001), triglycerides (OR 1.34; 95% CI: 1.25-1.44; P < 0.001) and apolipoprotein B (OR 1.73; 95% CI: 1.56-1.91; P < 0.001) had effect estimates consistent with a higher risk of CHD. In multivariable MR, only apolipoprotein B (OR 1.92; 95% CI: 1.31-2.81; P < 0.001) retained a robust effect, with the estimate for LDL cholesterol (OR 0.85; 95% CI: 0.57-1.27; P = 0.44) reversing and that of triglycerides (OR 1.12; 95% CI: 1.02-1.23; P = 0.01) becoming weaker. Individual MR analyses showed a 1-standard-deviation-higher HDL cholesterol (OR 0.80; 95% CI: 0.75-0.86; P < 0.001) and apolipoprotein A-I (OR 0.83; 95% CI: 0.77-0.89; P < 0.001) to lower the risk of CHD, but these effect estimates attenuated substantially to the null on accounting for apolipoprotein B. A limitation is that, owing to the nature of lipoprotein metabolism, measures related to the composition of lipoprotein particles are highly correlated, creating a challenge in making exclusive interpretations on causation of individual components.
These findings suggest that apolipoprotein B is the predominant trait that accounts for the aetiological relationship of lipoprotein lipids with risk of CHD.
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Breakthrough Listen is the most comprehensive and sensitive search for extraterrestrial intelligence (SETI) to date, employing a collection of international observational facilities including both ...radio and optical telescopes. During the first three years of the Listen program, thousands of targets have been observed with the Green Bank Telescope (GBT), Parkes Telescope and Automated Planet Finder. At GBT and Parkes, observations have been performed ranging from 700 MHz to 26 GHz, with raw data volumes averaging over 1 PB day−1. A pseudo-real time software spectroscopy suite is used to produce multi-resolution spectrograms amounting to approximately 400 GB h−1 GHz−1 beam−1. For certain targets, raw baseband voltage data is also preserved. Observations with the Automated Planet Finder produce both two-dimensional and one-dimensional high-resolution (R ∼ 105) echelle spectral data. Although the primary purpose of Listen data acquisition is for SETI, a range of secondary science has also been performed with these data, including studies of fast radio bursts. Other current and potential research topics include spectral line studies, searches for certain kinds of dark matter, probes of interstellar scattering, pulsar searches, radio transient searches and investigations of stellar activity. Listen data are also being used in the development of algorithms, including machine-learning approaches to modulation scheme classification and outlier detection, that have wide applicability not just for astronomical research but for a broad range of science and engineering. In this paper, we describe the hardware and software pipeline used for collection, reduction, archival, and public dissemination of Listen data. We describe the data formats and tools, and present Breakthrough Listen Data Release 1.0 (BLDR 1.0), a defined set of publicly available raw and reduced data totaling 1 PB.
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