Lipidomic profiling in Crohn's disease: abnormalities in phosphatidylinositols, with preservation of ceramide, phosphatidylcholine and phosphatidylserine composition.

Crohn's disease is a chronic inflammatory condition largely affecting the terminal ileum and large bowel. A contributing cause is the failure of an adequate acute inflammatory response as a result of impaired secretion of pro-inflammatory cytokines by macrophages. This defective secretion arises from aberrant vesicle trafficking, misdirecting the cytokines to lysosomal degradation. Aberrant intestinal permeability is also well-established in Crohn's disease. Both the disordered vesicle trafficking and increased bowel permeability could result from abnormal lipid composition. We thus measured the sphingo- and phospholipid composition of macrophages, using mass spectrometry and stable isotope labelling approaches. Stimulation of macrophages with heat-killed Escherichia coli resulted in three main changes; a significant reduction in the amount of individual ceramide species, an altered composition of phosphatidylcholine, and an increased rate of phosphatidylcholine synthesis in macrophages. These changes were observed in macrophages from both healthy control individuals and patients with Crohn's disease. The only difference detected between control and Crohn's disease macrophages was a reduced proportion of newly-synthesised phosphatidylinositol 16:0/18:1 over a defined time period. Shotgun lipidomics analysis of macroscopically non-inflamed ileal biopsies showed a significant decrease in this same lipid species with overall preservation of sphingolipid, phospholipid and cholesterol composition

The Paleoproterozoic Chibaisong Mafic-Ultramafic Intrusion and Cu-Ni Deposit, North China Craton: SHRIMP Zircon U-Pband Re-Os Geochronology and Geodynamic Implications

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Laser feedback interferometry in multi-mode terahertz quantum cascade lasers

The typical modal characteristics arising during laser feedback interferometry (LFI) in multi-mode terahertz (THz) quantum cascade lasers (QCLs) are investigated in this work. To this end, a set of multi-mode reduced rate equations with gain saturation for a general Fabry-Pérot multi-mode THz QCL under optical feedback is developed. Depending on gain bandwidth of the laser and optical feedback level, three different operating regimes are identified, namely a single-mode regime, a multi-mode regime, and a tuneable-mode regime. When the laser operates in the single-mode and multi-mode regimes, the self-mixing signal amplitude (peak to peak value of the self-mixing fringes) is proportional to the feedback coupling rate at each mode frequency. However, this rule no longer holds when the laser enters into the tuneable-mode regime, in which the feedback level becomes sufficiently strong (the boundary value of the feedback level depends on the gain bandwidth). The mapping of the identified feedback regimes of the multi-mode THz QCL in the space of the gain bandwidth and feedback level is investigated. In addition, the dependence of the aforementioned mapping of these three regimes on the linewidth enhancement factor of the laser is also explored, which provides a systematic picture of the potential of LFI in multi-mode THz QCLs for spectroscopic sensing applications

Incidence of rotavirus gastroenteritis by age in African, Asian and European children: Relevance for timing of rotavirus vaccination

© 2016 The Author(s). Published with license by Taylor & Francis. © GSK Biologicals SA.Variability in rotavirus gastroenteritis (RVGE) epidemiology can influence the optimal vaccination schedule. We evaluated regional trends in the age of RVGE episodes in low- to middle- versus high-income countries in three continents. We undertook a post-hoc analysis based on efficacy trials of a human rotavirus vaccine (HRV; Rotarix™, GSK Vaccines), in which 1348, 1641, and 5250 healthy infants received a placebo in Europe (NCT00140686), Africa (NCT00241644), and Asia (NCT00197210, NCT00329745). Incidence of any/severe RVGE by age at onset was evaluated by active surveillance over the first two years of life. Severity of RVGE episodes was assessed using the Vesikari-scale. The incidence of any RVGE in Africa was higher than in Europe during the first year of life (≤2.78% vs. ≤2.03% per month), but much lower during the second one (≤0.86% versus ≤2.00% per month). The incidence of severe RVGE in Africa was slightly lower than in Europe during the first year of life. Nevertheless, temporal profiles for the incidence of severe RVGE in Africa and Europe during the first (≤1.00% and ≤1.23% per month) and second (≤0.53% and ≤1.13% per month) years of life were similar to those of any RVGE. Any/severe RVGE incidences peaked at younger ages in Africa vs. Europe. In high-income Asian regions, severe RVGE incidence (≤0.31% per month) remained low during the study. The burden of any RVGE was higher earlier in life in children from low- to middle- compared with high-income countries. Differing rotavirus vaccine schedules are likely warranted to maximize protection in different settings

Impact of massive neutrinos on the Higgs self-coupling and electroweak vacuum stability

The presence of right-handed neutrinos in the type I seesaw mechanism may lead to significant corrections to the RG evolution of the Higgs self-coupling. Compared to the Standard Model case, the Higgs mass window can become narrower, and the cutoff scale become lower. Naively, these effects decrease with decreasing right-handed neutrino mass. However, we point out that the unknown Dirac Yukawa matrix may impact the vacuum stability constraints even in the low scale seesaw case not far away from the electroweak scale, hence much below the canonical seesaw scale of 10^15 GeV. This includes situations in which production of right-handed neutrinos at colliders is possible. We illustrate this within a particular parametrization of the Dirac Yukawas and with explicit low scale seesaw models. We also note the effect of massive neutrinos on the top quark Yukawa coupling, whose high energy value can be increased with respect to the Standard Model case.Comment: 17 pages, 7 figures, minor revisions, version to appear in JHE

Two-stage analyses of sequence variants in association with quantitative traits

We propose a two-stage design for the analysis of sequence variants in which a proportion of genes that show some evidence of association are identified initially and then followed up in an independent data set. We compare two different approaches. In both approaches the same summary measure (total number of minor alleles) is used for each gene in the initial analysis. In the first (simple) approach the same summary measure is used in the analysis of the independent data set. In the second (alternative) approach a more specific hypothesis is formed for the second stage; the summary measure used is the count of minor alleles in only those variants that in the initial data showed the same direction of association as was seen overall. We applied the methods to the simulated quantitative traits of Genetic Analysis Workshop 17, blind to the simulation model, and then evaluated their performance once the underlying model was known. Performance was similar for most genes, but the simple strategy considerably out-performed the alternative strategy for one gene, where most of the effect was due to very rare variants; this suggests that the alternative approach would not be advisable when the effect is seen in very rare variants. Further simulations are needed to investigate the potential superior power of the alternative method when some variants within a gene have opposing effects. Overall, the power to detect associations was low; this was also true when using a more powerful joint analysis that combined the two stages of the study

Defining Fatty Acid Changes Linked to Rumen Development, Weaning and Growth in Holstein-Friesian Heifers

After birth, as effectively monogastric animals, calves undergo substantial physiological changes to become ruminants by 3 months of age and reach sexual maturity at approximately 15 months of age. Herein, we assess longitudinal metabolomic changes in Holstein-Friesian (HF) heifers from birth until sexual maturity during this developmental process. Sera from 20 healthy, HF heifers were sampled biweekly from 2 weeks of age until 13 months of age and then monthly until 19 months of age. Sera were assessed using flow infusion electrospray high-resolution mass spectrometry (FIE-HRMS) on a Q Exactive hybrid quadrupole-Orbitrap mass spectrometer for high-throughput, sensitive, non-targeted metabolite fingerprinting. Partial least squares discriminant analysis (PLS-DA) and unsupervised hierarchical clustering analysis (HCA) of the derived metabolomes indicated changes detectable in heifers’ sera over time. Time series analyses identified 30 metabolites that could be related to rumen development and weaning at ~3 months of age. Further time series analysis identified 40 metabolites that could be correlated with growth. These findings highlight the role of acetic acid and 3-phenylpropionate (3-PP) in rumen development and growth, suggest that weaning induces elevated levels of fatty acyls in response to a post-weaning stress-induced innate immune response and demonstrate the utilization of fatty acyls in growth. The identified metabolites offer serum metabolites which could inform the nutrition and healthy development of heifers

Metal-Metal Terahertz Quantum Cascade Laser with Hybrid Mode Section

A hybrid mode section is integrated into the end of the metal-metal (MM) waveguide of a terahertz (THz) frequency quantum cascade laser (QCL) by removing sub-wavelength portions of the top metal layer. This allows a hybrid mode to penetrate into the air, which reduces the effective index of the mode and improves the out-coupling performance at the facet. The transmission of the processed metal-metal hybrid section (MMHS) waveguide is further increased by ensuring its length fulfills the criterion for constructive interference. These simple modifications to a 2.5 THz MM QCL waveguide result in a significant increase in the output emission power. In addition, simulations show that further improvements in out-coupling efficiency can be achieved for lower frequencies with effective refractive indices close to the geometric mean of the indices of the MM waveguide and air

Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation

The force-dependent interaction between talin and vinculin plays a crucial role in the initiation and growth of focal adhesions. Here we use magnetic tweezers to characterise the mechano-sensitive compact N-terminal region of the talin rod, and show that the three helical bundles R1-R3 in this region unfold in three distinct steps consistent with the domains unfolding independently. Mechanical stretching of talin R1-R3 enhances its binding to vinculin and vinculin binding inhibits talin refolding after force is released. Mutations that stabilize R3 identify it as the initial mechano-sensing domain in talin, unfolding at ~5 pN, suggesting that 5 pN is the force threshold for vinculin binding and adhesion progression

Impaired decisional impulsivity in pathological videogamers

Abstract Background Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. Methods Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. Results In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. Conclusions We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management