583 research outputs found
Universal Flow-Driven Conical Emission in Ultrarelativistic Heavy-Ion Collisions
The double-peak structure observed in soft-hard hadron correlations is
commonly interpreted as a signature for a Mach cone generated by a supersonic
jet interacting with the hot and dense medium created in ultrarelativistic
heavy-ion collisions. We show that it can also arise due to averaging over many
jet events in a transversally expanding background. We find that the
jet-induced away-side yield does not depend on the details of the
energy-momentum deposition in the plasma, the jet velocity, or the system size.
Our claim can be experimentally tested by comparing soft-hard correlations
induced by heavy-flavor jets with those generated by light-flavor jets.Comment: 4 pages, 3 figure
Dirac Quantization Condition for Monopole in Noncommutative Space-Time
Since the structure of space-time at very short distances is believed to get
modified possibly due to noncommutativity effects and as the Dirac Quantization
Condition (DQC), , probes the magnetic field point
singularity, a natural question arises whether the same condition will still
survive. We show that the DQC on a noncommutative space in a model of dynamical
noncommutative quantum mechanics remains the same as in the commutative case to
first order in the noncommutativity parameter , leading to the
conjecture that the condition will not alter in higher orders.Comment: 11 page
Model evaluation for glycolytic oscillations in yeast biotransformations of xenobiotics
Anaerobic glycolysis in yeast perturbed by the reduction of xenobiotic
ketones is studied numerically in two models which possess the same topology
but different levels of complexity. By comparing both models' predictions for
concentrations and fluxes as well as steady or oscillatory temporal behavior we
answer the question what phenomena require what kind of minimum model
abstraction. While mean concentrations and fluxes are predicted in agreement by
both models we observe different domains of oscillatory behavior in parameter
space. Generic properties of the glycolytic response to ketones are discussed
Quantitative assessment of device-clot interaction for stent retriever thrombectomy
PURPOSE: Rapid revascularization in emergent large vessel occlusion with endovascular embolectomy has proven clinical benefit. We sought to measure device-clot interaction as a potential mechanism for efficient embolectomy.
METHODS: Two different radiopaque clot models were injected to create a middle cerebral artery occlusion in a patient-specific vascular phantom. A radiopaque stent retriever was deployed within the clot by unsheathing the device or a combination of unsheathing followed by pushing the device (n=8/group). High-resolution cone beam CT was performed immediately after device deployment and repeated after 5 min. An image processing pipeline was created to quantitatively evaluate the volume of clot that integrates with the stent, termed the clot integration factor (CIF).
RESULTS: The CIF was significantly different for the two deployment variations when the device engaged the hard clot (p=0.041), but not the soft clot (p=0.764). In the hard clot, CIF increased significantly between post-deployment and final imaging datasets when using the pushing technique (p=0.019), but not when using the unsheathing technique (p=0.067). When we investigated the effect of time on CIF in the different clot models disregarding the technique, the CIF was significantly increased in the final dataset relative to the post-deployment dataset in both clot models (p=0.004-0.007).
CONCLUSIONS: This study demonstrates in an in vitro system the benefit of pushing the Trevo stent during device delivery in hard clot to enhance integration. Regardless of delivery technique, clot-device integration increased in both clot models by waiting 5 min
Interaction of Cannabis Use Disorder and Striatal Connectivity in Antipsychotic Treatment Response
Antipsychotic (AP) medications are the mainstay for the treatment of schizophrenia spectrum disorders (SSD), but their efficacy is unpredictable and widely variable. Substantial efforts have been made to identify prognostic biomarkers that can be used to guide optimal prescription strategies for individual patients. Striatal regions involved in salience and reward processing are disrupted as a result of both SSD and cannabis use, and research demonstrates that striatal circuitry may be integral to response to AP drugs. In the present study, we used functional magnetic resonance imaging (fMRI) to investigate the relationship between a history of cannabis use disorder (CUD) and a striatal connectivity index (SCI), a previously developed neural biomarker for AP treatment response in SSD. Patients were part of a 12-week randomized, double-blind controlled treatment study of AP drugs. A sample of 48 first-episode SSD patients with no more than 2 weeks of lifetime exposure to AP medications, underwent a resting-state fMRI scan pretreatment. Treatment response was defined a priori as a binary (response/nonresponse) variable, and a SCI was calculated in each patient. We examined whether there was an interaction between lifetime CUD history and the SCI in relation to treatment response. We found that CUD history moderated the relationship between SCI and treatment response, such that it had little predictive value in SSD patients with a CUD history. In sum, our findings highlight that biomarker development can be critically impacted by patient behaviors that influence neurobiology, such as a history of CUD
The effects of main-ion dilution on turbulence in low q95 C-Mod ohmic plasmas, and comparisons with nonlinear GYRO
Recent experiments on C-mod seeding nitrogen into ohmic plasmas with [subscript q]95 = 3.4 found that the seeding greatly reduced long-wavelength (ITG-scale) turbulence. The long-wavelength turbulence that was reduced by the nitrogen seeding was localized to the region of r/a≈0.85, where the turbulence is well above marginal stability (as evidenced by Q[subscript i]/Q[subscript GB]≫1). The nonlinear gyrokinetic code GYRO was used to simulate the expected turbulence in these plasmas, and the simulated turbulent density fluctuations and turbulent energy fluxes quantitatively agreed with the experimental measurements both before and after the nitrogen seeding. Unexpectedly, the intrinsic rotation of the plasma was also found to be affected by the nitrogen seeding, in a manner apparently unrelated to a change in the electron-ion collisionality that was proposed by other experiments.United States. Dept. of Energy. Office of Fusion Energy Sciences (Award E-FG02-94-ER54235
Some gating potentiators, including VX-770, diminish ΔF508-CFTR functional expression.
Cystic fibrosis (CF) is caused by mutations in the CF transmembrane regulator (CFTR) that result in reduced anion conductance at the apical membrane of secretory epithelia. Treatment of CF patients carrying the G551D gating mutation with the potentiator VX-770 (ivacaftor) largely restores channel activity and has shown substantial clinical benefit. However, most CF patients carry the ΔF508 mutation, which impairs CFTR folding, processing, function, and stability. Studies in homozygous ΔF508 CF patients indicated little clinical benefit of monotherapy with the investigational corrector VX-809 (lumacaftor) or VX-770, whereas combination clinical trials show limited but significant improvements in lung function. We show that VX-770, as well as most other potentiators, reduces the correction efficacy of VX-809 and another investigational corrector, VX-661. To mimic the administration of VX-770 alone or in combination with VX-809, we examined its long-term effect in immortalized and primary human respiratory epithelia. VX-770 diminished the folding efficiency and the metabolic stability of ΔF508-CFTR at the endoplasmic reticulum (ER) and post-ER compartments, respectively, causing reduced cell surface ΔF508-CFTR density and function. VX-770-induced destabilization of ΔF508-CFTR was influenced by second-site suppressor mutations of the folding defect and was prevented by stabilization of the nucleotide-binding domain 1 (NBD1)-NBD2 interface. The reduced correction efficiency of ΔF508-CFTR, as well as of two other processing mutations in the presence of VX-770, suggests the need for further optimization of potentiators to maximize the clinical benefit of corrector-potentiator combination therapy in CF
New therapeutic approach to heart failure due to myocardial infarction based on targeting growth hormone-releasing hormone receptor
Background We previously showed that growth hormone-releasing hormone (GHRH) agonists are cardioprotective following myocardial infarction (MI). Here, our aim was to evaluate the in vitro and in vivo activities of highly potent new GHRH agonists, and elucidate their mechanisms of action in promoting cardiac repair. Methods and Results H9c2 cells were cultured in serum-free medium, mimicking nutritional deprivation. GHRH agonists decreased calcium influx and significantly improved cell survival. Rats with cardiac infarction were treated with GHRH agonists or placebo for four weeks. MI size was reduced by selected GHRH agonists (JI-38, MR-356, MR-409); this accompanied an increased number of cardiac c-kit+ cells, cellular mitotic divisions, and vascular density. One week post-MI, MR-409 significantly reduced plasma levels of IL-2, IL-6, IL-10 and TNF-? compared to placebo. Gene expression studies revealed favorable outcomes of MR-409 treatment partially result from inhibitory activity on pro-apoptotic molecules and pro-fibrotic systems, and by elevation of bone morphogenetic proteins. Conclusions Treatment with GHRH agonists appears to reduce the inflammatory responses post-MI and may consequently improve mechanisms of healing and cardiac remod eling by regulating pathways involved in fibrosis, apoptosis and cardiac repair. Patients with cardiac dysfunction could benefit from treatment with novel GHRH agonists
Hard underlying event correction to inclusive jet cross sections
Jets observed in hadron-hadron scattering contain a contribution from the
underlying event that is produced by spectator interactions taking place
incoherently with the major parton-parton collision, due to the extended
composite structure of the colliding hadrons. Using a recent measurement of the
double parton interaction rate, we calculate that the underlying event may be 2
- 3 times stronger than generally assumed, as a result of semi-hard
perturbative multiple-parton interactions. This can have an important influence
on the inclusive jet cross section at moderate values of E_T, persisting at the
5 - 10% level to the largest observable E_T. We show how the underlying event
can be measured accurately using a generalization of the method first proposed
by Marchesini and Webber.Comment: 19 pages, revtex, 8 PostScript figure
Quantifying and Mitigating Motor Phenotypes Induced by Antisense Oligonucleotides in the Central Nervous System [preprint]
Antisense oligonucleotides (ASOs) are emerging as a promising class of therapeutics for neurological diseases. When injected directly into the cerebrospinal fluid, ASOs distribute broadly across brain regions and exert long-lasting therapeutic effects. However, many phosphorothioate (PS)-modified gapmer ASOs show transient motor phenotypes when injected into the cerebrospinal fluid, ranging from reduced motor activity to ataxia or acute seizure-like phenotypes. The effect of sugar and phosphate modifications on these phenotypes has not previously been systematically studied. Using a behavioral scoring assay customized to reflect the timing and nature of these effects, we show that both sugar and phosphate modifications influence acute motor phenotypes. Among sugar analogues, PS-DNA induces the strongest motor phenotype while 2’-substituted RNA modifications improve the tolerability of PS-ASOs. This helps explain why gapmer ASOs have been more challenging to develop clinically relative to steric blocker ASOs, which have a reduced tendency to induce these effects. Reducing the PS content of gapmer ASOs, which contain a stretch of PS-DNA, improves their toxicity profile, but in some cases also reduces their efficacy or duration of effect. Reducing PS content improved the acute tolerability of ASOs in both mice and sheep. We show that this acute toxicity is not mediated by the major nucleic acid sensing innate immune pathways. Formulating ASOs with calcium ions before injecting into the CNS further improved their tolerability, but through a mechanism at least partially distinct from the reduction of PS content. Overall, our work identifies and quantifies an understudied aspect of oligonucleotide toxicology in the CNS, explores its mechanism, and presents platform-level medicinal chemistry approaches that improve tolerability of this class of compounds
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