Association of snRNA genes with coiled bodies is mediated by nascent snRNA transcripts

AbstractBackground: Coiled bodies are nuclear organelles that are highly enriched in small nuclear ribonucleoproteins (snRNPs) and certain basal transcription factors. Surprisingly, coiled bodies not only contain mature U snRNPs but also associate with specific chromosomal loci, including gene clusters that encode U snRNAs and histone messenger RNAs. The mechanism(s) by which coiled bodies associate with these genes is completely unknown.Results: Using stable cell lines, we show that artificial tandem arrays of human U1 and U2 snRNA genes colocalize with coiled bodies and that the frequency of the colocalization depends directly on the transcriptional activity of the array. Association of the genes with coiled bodies was abolished when the artificial U2 arrays contained promoter mutations that prevent transcription or when RNA polymerase II transcription was globally inhibited by α-amanitin. Remarkably, the association was also abolished when the U2 snRNA coding regions were replaced by heterologous sequences.Conclusions: The requirement for the U2 snRNA coding region indicates that association of snRNA genes with coiled bodies is mediated by the nascent U2 RNA itself, not by DNA or DNA-bound proteins. Our data provide the first evidence that association of genes with a nuclear organelle can be directed by an RNA and suggest an autogenous feedback regulation model

Intimal smooth muscle cells are a source but not a sensor of anti-inflammatory CYP450 derived oxylipins

AbstractVascular pathologies are associated with changes in the presence and expression of morphologically distinct vascular smooth muscle cells. In particular, in complex human vascular lesions and models of disease in pigs and rodents, an intimal smooth muscle cell (iSMC) which exhibits a stable epithelioid or rhomboid phenotype in culture is often found to be present in high numbers, and may represent the reemergence of a distinct developmental vascular smooth muscle cell phenotype. The CYP450-oxylipin - soluble epoxide hydrolase (sEH) pathway is currently of great interest in targeting for cardiovascular disease. sEH inhibitors limit the development of hypertension, diabetes, atherosclerosis and aneurysm formation in animal models. We have investigated the expression of CYP450-oxylipin-sEH pathway enzymes and their metabolites in paired intimal (iSMC) and medial (mSMC) cells isolated from rat aorta. iSMC basally released significantly larger amounts of epoxy-oxylipin CYP450 products from eicosapentaenoic acid > docosahexaenoic acid > arachidonic acid > linoleic acid, and expressed higher levels of CYP2C12, CYP2B1, but not CYP2J mRNA compared to mSMC. When stimulated with the pro-inflammatory TLR4 ligand LPS, epoxy-oxylipin production did not change greatly in iSMC. In contrast, LPS induced epoxy-oxylipin products in mSMC and induced CYP2J4. iSMC and mSMC express sEH which metabolizes primary epoxy-oxylipins to their dihydroxy-counterparts. The sEH inhibitors TPPU or AUDA inhibited LPS-induced NFκB activation and iNOS induction in mSMC, but had no effect on NFκB nuclear localization or inducible nitric oxide synthase in iSMC; effects which were recapitulated in part by addition of authentic epoxy-oxylipins. iSMCs are a rich source but not a sensor of anti-inflammatory epoxy-oxylipins. Complex lesions that contain high levels of iSMCs may be more resistant to the protective effects of sEH inhibitors

Amorphous Systems in Athermal, Quasistatic Shear

We present results on a series of 2D atomistic computer simulations of amorphous systems subjected to simple shear in the athermal, quasistatic limit. The athermal quasistatic trajectories are shown to separate into smooth, reversible elastic branches which are intermittently broken by discrete catastrophic plastic events. The onset of a typical plastic event is studied with precision, and it is shown that the mode of the system which is responsible for the loss of stability has structure in real space which is consistent with a quadrupolar source acting on an elastic matrix. The plastic events themselves are shown to be composed of localized shear transformations which organize into lines of slip which span the length of the simulation cell, and a mechanism for the organization is discussed. Although within a single event there are strong spatial correlations in the deformation, we find little correlation from one event to the next, and these transient lines of slip are not to be confounded with the persistent regions of localized shear -- so-called "shear bands" -- found in related studies. The slip lines gives rise to particular scalings with system length of various measures of event size. Strikingly, data obtained using three differing interaction potentials can be brought into quantitative agreement after a simple rescaling, emphasizing the insensitivity of the emergent plastic behavior in these disordered systems to the precise details of the underlying interactions. The results should be relevant to understanding plastic deformation in systems such as metallic glasses well below their glass temperature, soft glassy systems (such as dense emulsions), or compressed granular materials.Comment: 21 pages, 18 figure

Increased brain activation during working memory processing after pediatric mild traumatic brain injury (mTBI).

Purpose: The neural substrate of post-concussive symptoms following the initial injury period after mild traumatic brain injury (mTBI) in pediatric populations remains poorly elucidated. This study examined neuropsychological, behavioral, and brain functioning in adolescents post-mTBI to assess whether persistent differences were detectable up to a year post-injury. Methods: Nineteen adolescents (mean age 14.7 years) who experienced mTBI 3–12 months previously (mean 7.5 months) and 19 matched healthy controls (mean age 14.0 years) completed neuropsychological testing and an fMRI auditory-verbal N-back working memory task. Parents completed behavioral ratings. Results: No between-group differences were found for cognition, behavior, or N-back task performance, though the expected decreased accuracy and increased reaction time as task difficulty increased were apparent. However, the mTBI group showed significantly greater brain activation than controls during the most difficult working memory task condition. Conclusion: Greater working memory task-related activation was found in adolescents up to one year post-mTBI relative to controls, potentially indicating compensatory activation to support normal task performance. Differences in brain activation in the mTBI group so long after injury may indicate residual alterations in brain function much later than would be expected based on the typical pattern of natural recovery, which could have important clinical implications

Scaling law in the Standard Map critical function. Interpolating hamiltonian and frequency map analysis

We study the behaviour of the Standard map critical function in a neighbourhood of a fixed resonance, that is the scaling law at the fixed resonance. We prove that for the fundamental resonance the scaling law is linear. We show numerical evidence that for the other resonances $p/q$, $q \geq 2$, $p \neq 0$ and $p$ and $q$ relatively prime, the scaling law follows a power--law with exponent $1/q$.Comment: AMS-LaTeX2e, 29 pages with 8 figures, submitted to Nonlinearit

Decreased cerebral blood flow in chronic pediatric mild TBI: an MRI perfusion study

We evaluated cerebral blood flow (CBF) in chronic pediatric mild traumatic brain injury (mTBI) using arterial spin labeling (ASL) magnetic resonance imaging perfusion. mTBI patients showed lower CBF than controls in bilateral frontotemporal regions, with no between-group cognitive differences. Findings suggest ASL may be useful to assess functional abnormalities in pediatric mTBI

Associated Production of a Z Boson and a Single Heavy-Quark Jet

The leading-order process for the production of a Z boson and a heavy-quark jet at hadron colliders is gQ -> ZQ (Q=c,b). We calculate this cross section at next-to-leading order at the Tevatron and the LHC, and compare it with other sources of ZQ events. This process is a background to new physics, and can be used to measure the heavy-quark distribution function.Comment: 15 pages, 9 figures. Version to appear in Phys. Rev.

Differential Cross Section for Higgs Boson Production Including All-Orders Soft Gluon Resummation

The transverse momentum $Q_T$ distribution is computed for inclusive Higgs boson production at the energy of the CERN Large Hadron Collider. We focus on the dominant gluon-gluon subprocess in perturbative quantum chromodynamics and incorporate contributions from the quark-gluon and quark-antiquark channels. Using an impact-parameter $b$-space formalism, we include all-orders resummation of large logarithms associated with emission of soft gluons. Our resummed results merge smoothly at large $Q_T$ with the fixed-order expectations in perturbative quantum chromodynamics, as they should, with no need for a matching procedure. They show a high degree of stability with respect to variation of parameters associated with the non-perturbative input at low $Q_T$. We provide distributions $d\sigma/dy dQ_T$ for Higgs boson masses from $M_Z$ to 200 GeV. The average transverse momentum at zero rapidity $y$ grows approximately linearly with mass of the Higgs boson over the range $M_Z < m_h \simeq 0.18 m_h + 18$~GeV. We provide analogous results for $Z$ boson production, for which we compute $\simeq 25$ GeV. The harder transverse momentum distribution for the Higgs boson arises because there is more soft gluon radiation in Higgs boson production than in $Z$ production.Comment: 42 pages, latex, 26 figures. All figures replaced. Some changes in wording. Published in Phys. Rev. D67, 034026 (2003

Biannual versus annual mass azithromycin distribution and malaria seroepidemiology among preschool children in Niger: a sub-study of a cluster randomized trial.

BACKGROUND: Biannual mass azithromycin administration to preschool children reduces all-cause mortality, but the mechanism for the effect is not understood. Azithromycin has activity against malaria parasites, and malaria is a leading cause of child mortality in the Sahel. The effect of biannual versus annual azithromycin distribution for trachoma control on serological response to merozoite surface protein 1 (MSP-119), a surrogate for malaria incidence, was evaluated among children in Niger. METHODS: Markers of malaria exposure were measured in two arms of a factorial randomized controlled trial designed to evaluate targeted biannual azithromycin distribution to children under 12 years of age compared to annual azithromycin to the entire community for trachoma control (N = 12 communities per arm). Communities were treated for 36 months (6 versus 3 distributions). Dried blood spots were collected at 36 months among children ages 1-5 years, and MSP-119 antibody levels were assessed using a bead-based multiplex assay to measure malaria seroprevalence. RESULTS: Antibody results were available for 991 children. MSP-119 seropositivity was 62.7% in the biannual distribution arm compared to 68.7% in the annual arm (prevalence ratio 0.91, 95% CI 0.83 to 1.00). Mean semi-quantitative antibody levels were lower in the biannual distribution arm compared to the annual arm (mean difference - 0.39, 95% CI - 0.05 to - 0.72). CONCLUSIONS: Targeted biannual azithromycin distribution was associated with lower malaria seroprevalence compared to that in a population that received annual distribution. Trial Registration Clinicaltrials.gov NCT00792922

On-chip single-copy real-time reverse-transcription PCR in isolated picoliter droplets

The first lab-on-chip system for picoliter droplet generation and RNA isolation, followed by reverse transcription, and PCR amplification with real-time fluorescence detection in the trapped droplets has been developed. The system utilized a shearing T-junction in a fused silica device to generate a stream of monodisperse picoliter-scale droplets that were isolated from the microfluidic channel walls and each other by the oil phase carrier. An off-chip valving system stopped the droplets on-chip, allowing thermal cycling for reverse transcription and subsequent PCR amplification without droplet motion. This combination of the established real-time reverse transcription-PCR assay with digital microfluidics is ideal for isolating single-copy RNA and virions from a complex environment, and will be useful in viral discovery and gene-profiling applications