Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN

Neutral Pion Asymmetry Analysis and Forward Upgrade Preparation at STAR

The Relativistic Heavy Ion Collider (RHIC) sited at Brookhaven National Lab in Upton, New York, is the only collider in the world capable of colliding beams of polarized protons. The Solenoidal Tracker at RHIC (STAR) detector analyzes properties of these collisions to investigate, among other things, the gluon’s spin contribution to the spin of the proton. The gluon contribution can be theoretically calculated from an experimentally measured asymmetry in the number of π0’s (a particle produced in the collisions) produced as a function of the protons’ spin configuration. STAR’s Endcap Electromagnetic Calorimeter (EEMC) can reconstruct a π0 , which decays in 10-16 s, by measuring the energy of its two decay photons. This summer, we performed Quality Assurance (QA) on the 2012 p+p data, made asymmetry calculations by fitting mass plots to a couple of different functions, helped prepare a forward upgrade at STAR, and processed some data from 2013. The QA involved plotting several characteristics of the π0 reconstruction process as a function of run number, which are segments of data. This summer 9,600 scintillators were polished and painted to be sent to Brookhaven for the update of the Forward Calorimeter System (FCS)

Creating an Effective Regional Alignment Strategy for the U.S. Army

View the Executive SummaryAs the war in Afghanistan draws to a close, the Army increasingly is focused upon “regionally aligning” its forces. To do so effectively, however, it must undertake several initiatives. First, the Army must acknowledge and liberate the unique productive capabilities (talents) of each individual. Second, it must shift from process-oriented, industrial age personnel management to productivity-focused, information age talent management. Third, the Army must foster enduring human relationships between its organizations and the governments, militaries, and populations to which they are regionally aligned. Hand in hand with this, it must redesign its Force Generation Model to create regional expertise at both individual and organizational levels. Finally, the Army must ensure that regional alignment does not degrade the worldwide “flex” capabilities of its forces.https://press.armywarcollege.edu/monographs/1474/thumbnail.jp

Onset of human preterm and term birth is related to unique inflammatory transcriptome profiles at the maternal fetal interface.

BackgroundPreterm birth is a main determinant of neonatal mortality and morbidity and a major contributor to the overall mortality and burden of disease. However, research of the preterm birth is hindered by the imprecise definition of the clinical phenotype and complexity of the molecular phenotype due to multiple pregnancy tissue types and molecular processes that may contribute to the preterm birth. Here we comprehensively evaluate the mRNA transcriptome that characterizes preterm and term labor in tissues comprising the pregnancy using precisely phenotyped samples. The four complementary phenotypes together provide comprehensive insight into preterm and term parturition.MethodsSamples of maternal blood, chorion, amnion, placenta, decidua, fetal blood, and myometrium from the uterine fundus and lower segment (n = 183) were obtained during cesarean delivery from women with four complementary phenotypes: delivering preterm with (PL) and without labor (PNL), term with (TL) and without labor (TNL). Enrolled were 35 pregnant women with four precisely and prospectively defined phenotypes: PL (n = 8), PNL (n = 10), TL (n = 7) and TNL (n = 10). Gene expression data were analyzed using shrunken centroid analysis to identify a minimal set of genes that uniquely characterizes each of the four phenotypes. Expression profiles of 73 genes and non-coding RNA sequences uniquely identified each of the four phenotypes. The shrunken centroid analysis and 10 times 10-fold cross-validation was also used to minimize false positive finings and overfitting. Identified were the pathways and molecular processes associated with and the cis-regulatory elements in gene's 5' promoter or 3'-UTR regions of the set of genes which expression uniquely characterized the four phenotypes.ResultsThe largest differences in gene expression among the four groups occurred at maternal fetal interface in decidua, chorion and amnion. The gene expression profiles showed suppression of chemokines expression in TNL, withdrawal of this suppression in TL, activation of multiple pathways of inflammation in PL, and an immune rejection profile in PNL. The genes constituting expression signatures showed over-representation of three putative regulatory elements in their 5'and 3' UTR regions.ConclusionsThe results suggest that pregnancy is maintained by downregulation of chemokines at the maternal-fetal interface. Withdrawal of this downregulation results in the term birth and its overriding by the activation of multiple pathways of the immune system in the preterm birth. Complications of the pregnancy associated with impairment of placental function, which necessitated premature delivery of the fetus in the absence of labor, show gene expression patterns associated with immune rejection

6-Bromo-3-methyl-2-phenyl-3H-imidazo[4,5-b]pyridine

The two fused five- and six-membered rings building the mol­ecule of the title compound, C13H10BrN3, are approximately planar, the largest deviation from the mean plane being 0.004 (2) Å. The dihedral angle between the imidazo[4,5-b]pyridine mean plane and that of the phenyl ring is 41.84 (11)°. The structure is held together by slipped π–π stacking between symmetry-related mol­ecules, with an inter­planar distance of 3.583 (1) Å and a centroid–centroid vector of 3.670 (2) Å

Architecture of the RNA polymerase II–TFIIF complex revealed by cross-linking and mass spectrometry

Higher-order multi-protein complexes such as RNA polymerase II (Pol II) complexes with transcription initiation factors are often not amenable to X-ray structure determination. Here, we show that protein cross-linking coupled to mass spectrometry (MS) has now sufficiently advanced as a tool to extend the Pol II structure to a 15-subunit, 670 kDa complex of Pol II with the initiation factor TFIIF at peptide resolution. The N-terminal regions of TFIIF subunits Tfg1 and Tfg2 form a dimerization domain that binds the Pol II lobe on the Rpb2 side of the active centre cleft near downstream DNA. The C-terminal winged helix (WH) domains of Tfg1 and Tfg2 are mobile, but the Tfg2 WH domain can reside at the Pol II protrusion near the predicted path of upstream DNA in the initiation complex. The linkers between the dimerization domain and the WH domains in Tfg1 and Tfg2 are located to the jaws and protrusion, respectively. The results suggest how TFIIF suppresses non-specific DNA binding and how it helps to recruit promoter DNA and to set the transcription start site. This work establishes cross-linking/MS as an integrated structure analysis tool for large multi-protein complexes

Concurrent validity of skin carotenoid status as a concentration biomarker of vegetable and fruit intake compared to multiple 24-h recalls and plasma carotenoid concentrations across one year: a cohort study

Background Biological markers of vegetable and fruit (VF) intake are needed both for nutrition surveillance and for the evaluation of nutrition interventions. Optically assessed skin carotenoid status (SCS) has been proposed as a marker of intake but there are few published validity studies to date. Therefore, the objective of the study was to examine the concurrent validity of multiple methods of assessing VF intake cross-sectionally and seasonally over one year and to discuss the relative merits and limitations of each method. Methods Fifty-two 40–60 y old women completed a 1-year longitudinal study that included 1) SCS assessment using resonance Raman spectroscopy (RRS) and using pressure-mediated reflection spectroscopy (RS) at 12 timepoints, 2) thirty-six 24-h recalls using the Automated Self-Administered 24-Hour Dietary Assessment Tool (ASA24; total 1866 recalls), and 3) plasma carotenoid concentrations measured every 3 months. Pearson correlation coefficients and mixed linear models were used to estimate pairwise correlations between RRS, RS, ASA24, and plasma carotenoids. Results RS and RRS were strongly correlated at baseline and over the year (r = 0.86 and 0.76; respectively, P < 0.001). RS was strongly correlated with plasma carotenoids at baseline (r = 0.70) and moderately across the year (r = 0.65), as was RRS (r = 0.77 and 0.69, respectively, all P < 0.001). At baseline, self-reported VF was weakly correlated with RRS (r = 0.33; P = 0.016), but not with RS or plasma carotenoids. Across the year, self-reported VF intake was weakly correlated with both RS (r = 0.37; P = 0.008), RRS (r = 0.37; P = 0.007), and with plasma carotenoids (r = 0.36; P < 0.008). Conclusions SCS as measured by RS and RRS is moderately to strongly correlated with plasma carotenoid concentrations both cross-sectionally and longitudinally, indicating that it can be a powerful tool to assess carotenoid-rich VF intake in populations

Gestational weight change and childhood body composition trajectories from pregnancy to early adolescence

ObjectiveA mother-child dyad trajectory model of weight and body composition spanning from conception to adolescence was developed to understand how early life exposures shape childhood body composition.MethodsAfrican American (49.3%) and Dominican (50.7%) pregnant mothers (n = 337) were enrolled during pregnancy, and their children (47.5% female) were followed from ages 5 to 14. Gestational weight gain (GWG) was abstracted from medical records. Child weight, height, percentage body fat, and waist circumference were measured. GWG and child body composition trajectories were jointly modeled with a flexible latent class model with a class membership component that included prepregnancy BMI.ResultsFour prenatal and child body composition trajectory patterns were identified, and sex-specific patterns were observed for the joint GWG-postnatal body composition trajectories with more distinct patterns among girls but not boys. Girls of mothers with high GWG across gestation had the highest BMI z score, waist circumference, and percentage body fat trajectories from ages 5 to 14; however, boys in this high GWG group did not show similar growth patterns.ConclusionsJointly modeled prenatal weight and child body composition trajectories showed sex-specific patterns. Growth patterns from childhood though early adolescence appeared to be more profoundly affected by higher GWG patterns in females, suggesting sex differences in developmental programming

Architecture of the RNA polymerase II–TFIIF complex revealed by cross-linking and mass spectrometry

Higher-order multi-protein complexes such as RNA polymerase II (Pol II) complexes with transcription initiation factors are often not amenable to X-ray structure determination. Here, we show that protein cross-linking coupled to mass spectrometry (MS) has now sufficiently advanced as a tool to extend the Pol II structure to a 15-subunit, 670 kDa complex of Pol II with the initiation factor TFIIF at peptide resolution. The N-terminal regions of TFIIF subunits Tfg1 and Tfg2 form a dimerization domain that binds the Pol II lobe on the Rpb2 side of the active centre cleft near downstream DNA. The C-terminal winged helix (WH) domains of Tfg1 and Tfg2 are mobile, but the Tfg2 WH domain can reside at the Pol II protrusion near the predicted path of upstream DNA in the initiation complex. The linkers between the dimerization domain and the WH domains in Tfg1 and Tfg2 are located to the jaws and protrusion, respectively. The results suggest how TFIIF suppresses non-specific DNA binding and how it helps to recruit promoter DNA and to set the transcription start site. This work establishes cross-linking/MS as an integrated structure analysis tool for large multi-protein complexes

Fetal Growth and Risk of Stillbirth: A Population-Based Case–Control Study

Background: Stillbirth is strongly related to impaired fetal growth. However, the relationship between fetal growth and stillbirth is difficult to determine because of uncertainty in the timing of death and confounding characteristics affecting normal fetal growth. Methods and Findings: We conducted a population-based case–control study of all stillbirths and a representative sample of live births in 59 hospitals in five geographic areas in the US. Fetal growth abnormalities were categorized as small for gestational age (SGA) (90th percentile) at death (stillbirth) or delivery (live birth) using population, ultrasound, and individualized norms. Gestational age at death was determined using an algorithm that considered the time-of-death interval, postmortem examination, and reliability of the gestational age estimate. Data were weighted to account for the sampling design and differential participation rates in various subgroups. Among 527 singleton stillbirths and 1,821 singleton live births studied, stillbirth was associated with SGA based on population, ultrasound, and individualized norms (odds ratio [OR] [95% CI]: 3.0 [2.2 to 4.0]; 4.7 [3.7 to 5.9]; 4.6 [3.6 to 5.9], respectively). LGA was also associated with increased risk of stillbirth using ultrasound and individualized norms (OR [95% CI]: 3.5 [2.4 to 5.0]; 2.3 [1.7 to 3.1], respectively), but not population norms (OR [95% CI]: 0.6 [0.4 to 1.0]). The associations were stronger with more severe SGA and LGA (95th percentile). Analyses adjusted for stillbirth risk factors, subset analyses excluding potential confounders, and analyses in preterm and term pregnancies showed similar patterns of association. In this study 70% of cases and 63% of controls agreed to participate. Analysis weights accounted for differences between consenting and non-consenting women. Some of the characteristics used for individualized fetal growth estimates were missing and were replaced with reference values. However, a sensitivity analysis using individualized norms based on the subset of stillbirths and live births with non-missing variables showed similar findings. Conclusions: Stillbirth is associated with both growth restriction and excessive fetal growth. These findings suggest that, contrary to current practices and recommendations, stillbirth prevention strategies should focus on both severe SGA and severe LGA pregnancies