290 research outputs found
Efficacy and Safety of Vibegron for the Treatment of Overactive Bladder in Women: A Subgroup Analysis From the Double-Blind, Randomized, Controlled EMPOWUR Trial
Importance The international phase 3 EMPOWUR trial demonstrated efficacy and safety of vibegron, a newer b3-adrenergic receptor agonist, in adults with overactive bladder (OAB). Women are disproportionately affected by OAB, especially those with bothersome symptoms, such as urge urinary incontinence (UUI). Objective This subgroup analysis from EMPOWUR assessed efficacy and safety of vibegron in women. Study Design In EMPOWUR, patients with OAB were randomized 5:5:4 to 12 weeks of treatment with once-daily vibegron 75 mg, placebo, or tolterodine 4-mg extended release. Efficacy end points included change from baseline at week 12 in mean daily number of micturitions, UUI episodes, and urgency episodes. Safety was assessed through adverse events (AEs). Results Of the patients included in the analysis, 1286 (84.9%) were women (vibegron, n = 463; placebo, n = 459; tolterodine, n = 364). At week 12, women receiving vibegron showed significant reductions (95% confidence intervals of least squares mean differences does not include 0) from baseline versus placebo in mean daily micturitions, UUI episodes, and urgency episodes, with least squares mean differences (95% confidence intervals) of −0.5 (−0.8 to −0.2), −0.7 (−1.0 to −0.4), and −0.8 (−1.3 to −0.4), respectively. Treatment-emergent AE incidence was similar with vibegron (39%) and placebo (35%); the most common AE with incidence higher with vibegron (4.3%) than placebo (2.6%) was headache. Conclusions In this subgroup analysis, women receiving vibegron showed significant reductions in key efficacy end points versus placebo and favorable safety profile, consistent with the overall results from EMPOWUR, suggesting that vibegron is efficacious and safe for the treatment of OAB in this patient population
Some Variations on Maxwell's Equations
In the first sections of this article, we discuss two variations on Maxwell's
equations that have been introduced in earlier work--a class of nonlinear
Maxwell theories with well-defined Galilean limits (and correspondingly
generalized Yang-Mills equations), and a linear modification motivated by the
coupling of the electromagnetic potential with a certain nonlinear Schroedinger
equation. In the final section, revisiting an old idea of Lorentz, we write
Maxwell's equations for a theory in which the electrostatic force of repulsion
between like charges differs fundamentally in magnitude from the electrostatic
force of attraction between unlike charges. We elaborate on Lorentz'
description by means of electric and magnetic field strengths, whose governing
equations separate into two fully relativistic Maxwell systems--one describing
ordinary electromagnetism, and the other describing a universally attractive or
repulsive long-range force. If such a force cannot be ruled out {\it a priori}
by known physical principles, its magnitude should be determined or bounded
experimentally. Were it to exist, interesting possibilities go beyond Lorentz'
early conjecture of a relation to (Newtonian) gravity.Comment: 26 pages, submitted to a volume in preparation to honor Gerard Emch
v. 2: discussion revised, factors of 4\pi corrected in some equation
Statins in unconventional secretion of insulin-degrading enzyme and degradation of the amyloid-β peptide.
Population-based studies demonstrated that statins might decrease the risk of developing Alzheimer's disease (AD). Statins inhibit the 3-hydroxy-3-methyl-glutaryl-coenzyme-A reductase and thereby de novo synthesis of cholesterol. Cell culture and animal studies indicated that cholesterol affects the proteolytic processing of the amyloid precursor protein and the generation of amyloid-β (Aβ). Recently, we have demonstrated that statins can also stimulate the degradation of Aβ. The statin-induced clearance of Aβ could be attributed to increased release of the insulin-degrading enzyme (IDE) via an exosome-related unconventional secretory pathway. Interestingly, this statin-induced secretion of exosome-associated IDE was independent of cellular cholesterol concentrations, but rather caused by impairment of isoprenoid biosynthesis and protein prenylation. We further identified a new hexapeptide sequence in the C-terminal region of IDE, named the SlyX motif that is critically involved in IDE secretion. Taken these findings together, the increased clearance of Aβ by stimulated secretion of IDE might contribute to the protective effects of statins against AD
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FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC
A purine metabolic checkpoint that prevents autoimmunity and autoinflammation.
Still's disease, the paradigm of autoinflammation-cum-autoimmunity, predisposes for a cytokine storm with excessive T lymphocyte activation upon viral infection. Loss of function of the purine nucleoside enzyme FAMIN is the sole known cause for monogenic Still's disease. Here we discovered that a FAMIN-enabled purine metabolon in dendritic cells (DCs) restrains CD4+ and CD8+ T cell priming. DCs with absent FAMIN activity prime for enhanced antigen-specific cytotoxicity, IFNγ secretion, and T cell expansion, resulting in excessive influenza A virus-specific responses. Enhanced priming is already manifest with hypomorphic FAMIN-I254V, for which ∼6% of mankind is homozygous. FAMIN controls membrane trafficking and restrains antigen presentation in an NADH/NAD+-dependent manner by balancing flux through adenine-guanine nucleotide interconversion cycles. FAMIN additionally converts hypoxanthine into inosine, which DCs release to dampen T cell activation. Compromised FAMIN consequently enhances immunosurveillance of syngeneic tumors. FAMIN is a biochemical checkpoint that protects against excessive antiviral T cell responses, autoimmunity, and autoinflammation
FAMIN is a multifunctional purine enzyme enabling the purine nucleotide cycle
Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases risk for Crohn’s disease and leprosy. We developed an unbiased liquid chromatography mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic paralogues additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronises mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.Includes ERC. Wellcome Trust and MRC
Single Spin Asymmetry in Polarized Proton-Proton Elastic Scattering at GeV
We report a high precision measurement of the transverse single spin
asymmetry at the center of mass energy GeV in elastic
proton-proton scattering by the STAR experiment at RHIC. The was measured
in the four-momentum transfer squared range \GeVcSq, the region of a significant interference between the
electromagnetic and hadronic scattering amplitudes. The measured values of
and its -dependence are consistent with a vanishing hadronic spin-flip
amplitude, thus providing strong constraints on the ratio of the single
spin-flip to the non-flip amplitudes. Since the hadronic amplitude is dominated
by the Pomeron amplitude at this , we conclude that this measurement
addresses the question about the presence of a hadronic spin flip due to the
Pomeron exchange in polarized proton-proton elastic scattering.Comment: 12 pages, 6 figure
Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in 200 GeV Au+Au Collisions
A data-driven method was applied to measurements of Au+Au collisions at
200 GeV made with the STAR detector at RHIC to isolate
pseudorapidity distance -dependent and -independent
correlations by using two- and four-particle azimuthal cumulant measurements.
We identified a component of the correlation that is -independent,
which is likely dominated by anisotropic flow and flow fluctuations. It was
also found to be independent of within the measured range of
pseudorapidity . The relative flow fluctuation was found to be for particles of transverse momentum
less than GeV/. The -dependent part may be attributed to
nonflow correlations, and is found to be relative to the
flow of the measured second harmonic cumulant at
Beam energy dependent two-pion interferometry and the freeze-out eccentricity of pions in heavy ion collisions at STAR
We present results of analyses of two-pion interferometry in Au+Au collisions
at = 7.7, 11.5, 19.6, 27, 39, 62.4 and 200 GeV measured in the
STAR detector as part of the RHIC Beam Energy Scan program. The extracted
correlation lengths (HBT radii) are studied as a function of beam energy,
azimuthal angle relative to the reaction plane, centrality, and transverse mass
() of the particles. The azimuthal analysis allows extraction of the
eccentricity of the entire fireball at kinetic freeze-out. The energy
dependence of this observable is expected to be sensitive to changes in the
equation of state. A new global fit method is studied as an alternate method to
directly measure the parameters in the azimuthal analysis. The eccentricity
shows a monotonic decrease with beam energy that is qualitatively consistent
with the trend from all model predictions and quantitatively consistent with a
hadronic transport model.Comment: 27 pages; 27 figure
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