Measurement of the Positive Muon Anomalous Magnetic Moment to 0.20 ppm.

We present a new measurement of the positive muon magnetic anomaly, a_{μ}≡(g_{μ}-2)/2, from the Fermilab Muon g-2 Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, ω[over ˜]_{p}^{'}, and of the anomalous precession frequency corrected for beam dynamics effects, ω_{a}.

Observation of high-energy neutrinos from the Galactic plane.

The origin of high-energy cosmic rays, atomic nuclei that continuously impact Earth's atmosphere, is unknown. Because of deflection by interstellar magnetic fields, cosmic rays produced within the Milky Way arrive at Earth from random directions. However, cosmic rays interact with matter near their sources and during propagation, which produces high-energy neutrinos.

Strong Constraints on Neutrino Nonstandard Interactions from TeV-Scale ν_{μ} Disappearance at IceCube.

We report a search for nonstandard neutrino interactions (NSI) using eight years of TeV-scale atmospheric muon neutrino data from the IceCube Neutrino Observatory. By reconstructing incident energies and zenith angles for atmospheric neutrino events, this analysis presents unified confidence intervals for the NSI parameter ε_{μτ}. The best-fit value is consistent with no NSI at a p value of 25.

Search for Relativistic Magnetic Monopoles with Eight Years of IceCube Data.

We present an all-sky 90% confidence level upper limit on the cosmic flux of relativistic magnetic monopoles using 2886 days of IceCube data. The analysis was optimized for monopole speeds between 0.750c and 0.

Measurement of the Positive Muon Anomalous Magnetic Moment to 0.46 ppm.

We present the first results of the Fermilab National Accelerator Laboratory (FNAL) Muon g-2 Experiment for the positive muon magnetic anomaly a_{μ}≡(g_{μ}-2)/2. The anomaly is determined from the precision measurements of two angular frequencies. Intensity variation of high-energy positrons from muon decays directly encodes the difference frequency ω_{a} between the spin-precession and cyclotron frequencies for polarized muons in a magnetic storage ring.

A review of the pharmacology and clinical profile of lumateperone for the treatment of schizophrenia.

Schizophrenia is associated with a tremendous individual and societal burden. The disease is characterized by a complex set of symptoms including psychosis, hallucinations, delusions and related positive symptoms combined with social function deficits, cognitive disturbances and, often, devastating mood disorder, such as comorbid depression. Management of the disease often requires lifelong pharmacotherapy.

eV-Scale Sterile Neutrino Search Using Eight Years of Atmospheric Muon Neutrino Data from the IceCube Neutrino Observatory.

The results of a 3+1 sterile neutrino search using eight years of data from the IceCube Neutrino Observatory are presented. A total of 305 735 muon neutrino events are analyzed in reconstructed energy-zenith space to test for signatures of a matter-enhanced oscillation that would occur given a sterile neutrino state with a mass-squared differences between 0.01 and 100  eV^{2}.

An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep.

Unlabelled: Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices.

Methylphenidate restores novel object recognition in DARPP-32 knockout mice.

Previously, we have shown that Dopamine- and cAMP-regulated phosphoprotein of 32kDa (DARPP-32) knockout mice required significantly more trials to reach criterion than wild-type mice in an operant reversal-learning task. The present study was conducted to examine adult male and female DARPP-32 knockout mice and wild-type controls in a novel object recognition test. Wild-type and knockout mice exhibited comparable behavior during the initial exploration trials.

Muscarinic receptors acting at pre- and post-synaptic sites differentially regulate dopamine/DARPP-32 signaling in striatonigral and striatopallidal neurons.

Muscarinic receptors, activated by acetylcholine, play critical roles in the functional regulation of medium spiny neurons in the striatum. However, the muscarinic receptor signaling pathways are not fully elucidated due to their complexity. In this study, we investigated the function of muscarinic receptors in the striatum by monitoring DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32 kDa) phosphorylation at Thr34 (the PKA-site) using mouse striatal slices.

Forebrain overexpression of CK1delta leads to down-regulation of dopamine receptors and altered locomotor activity reminiscent of ADHD.

Dopamine neurotransmission controls motor and perseverative behavior, is mediated by protein phosphorylation, and may be perturbed in disorders of attention and hyperactivity. To assess the role of casein kinase I (CK1) in the regulation of dopamine signaling, we generated a genetically modified mouse line that overexpresses CK1delta (CK1delta OE) specifically in the forebrain. Overexpression was confirmed both at the mRNA and at the protein levels.

Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling.

Recent reports have shown that the selective dopamine D(1)-like agonist SKF 83822 [which stimulates adenylate cyclase, but not phospholipase C] induces prominent behavioral seizures in mice, whereas its benzazepine congener SKF 83959 [which stimulates phospholipase C, but not adenylate cyclase] does not. To investigate the relative involvement of D(1) vs D(5) receptors in mediating seizures, ethological behavioral topography and cortical EEGs were recorded in D(1), D(5) and DARPP-32 knockout mice in response to a convulsant dose of SKF 83822. SKF 83822-induced behavioral and EEG seizures were gene dose-dependently abolished in D(1) knockouts.

Phosphodiesterase 1B differentially modulates the effects of methamphetamine on locomotor activity and spatial learning through DARPP32-dependent pathways: evidence from PDE1B-DARPP32 double-knockout mice.

Mice lacking phosphodiesterase 1B (PDE1B) exhibit an exaggerated locomotor response to D-methamphetamine and increased in vitro phosphorylation of DARPP32 (dopamine- and cAMP-regulated phosphoprotein, M r 32 kDa) at Thr34 in striatal brain slices treated with the D1 receptor agonist, SKF81297. These results indicated a possible regulatory role for PDE1B in pathways involving DARPP32. Here, we generated PDE1B x DARPP32 double-knockout (double-KO) mice to test the role of PDE1B in DARPP32-dependent pathways in vivo.

Disruption of orofacial movement topographies in congenic mutants with dopamine D5 but not D4 receptor or DARPP-32 transduction 'knockout'.

The role of D(1)-like [D(1), D(5)] and D(2)-like [D(2), D(3), D(4)] dopamine receptors and dopamine transduction via DARPP-32 in topographies of orofacial movement was assessed in restrained mice with congenic D(4) vs. D(5) receptor vs. DARPP-32 'knockout'.

Cannabinoid action depends on phosphorylation of dopamine- and cAMP-regulated phosphoprotein of 32 kDa at the protein kinase A site in striatal projection neurons.

Herbal cannabis, smoked in the form of marihuana or hashish, is the most common illicit drug consumed in the Western world. In the brain, cannabinoids interact with neuronal CB1 receptors, thereby producing a marked reduction of motor activity. Here, we report that the motor depressant effect produced by the cannabinoid receptor agonist (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]trans-4-(3-hydroxypropyl)cyclohexanol (CP55,940) is attenuated by genetic inactivation of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), which is abundantly expressed in the medium spiny neurons of the striatum.

Phosphorylation of DARPP-32 at Threonine-34 is required for cocaine action.

Mice lacking DARPP-32, a striatal-enriched phosphoprotein, show abnormal behavioral and biochemical responses to cocaine, but the role of individual phosphorylation sites in DARPP-32 in these responses is unknown. We show here that mutation of Thr-34 in DARPP-32 mimicked the behavioral phenotype of the constitutive DARPP-32 knockout in cocaine-induced place conditioning, locomotor activity, and sensitization paradigms. In contrast, mutations of Thr75 did not affect conditioned place preference or the acute locomotor response to cocaine, but DARPP-32 Thr-75 mutants showed no locomotor sensitization in response to repeated cocaine administration.

DARPP-32 phosphorylation opposes the behavioral effects of nicotine.

Background: The addictive properties of nicotine are mediated via dopaminergic pathways and their post-synaptic neurons in the striatum. Because post-synaptic neurons within the striatum contain high levels of the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), we hypothesized that DARPP-32 may functionally contribute to the behavioral effects of nicotine.

Methods: We examined the behavioral effects of nicotine and the phosphorylation state of DARPP-32 in wild-type (WT) and DARPP-32 knockout (KO) mice.

A network of control mediated by regulator of calcium/calmodulin-dependent signaling.

Calmodulin (CaM) is a major effector for the intracellular actions of Ca2+ in nearly all cell types. We identified a CaM-binding protein, designated regulator of calmodulin signaling (RCS). G protein-coupled receptor (GPCR)-dependent activation of protein kinase A (PKA) led to phosphorylation of RCS at Ser55 and increased its binding to CaM.

Characterization of stanniocalcin 2, a novel target of the mammalian unfolded protein response with cytoprotective properties.

Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces a highly conserved homeostatic response in all eukaryotic cells, termed the unfolded-protein response (UPR). Here we describe the characterization of stanniocalcin 2 (STC2), a mammalian homologue of a calcium- and phosphate-regulating hormone first identified in fish, as a novel target of the UPR. Expression of STC2 gene is rapidly upregulated in cultured cells after exposure to tunicamycin and thapsigargin, by ATF4 after activation of the ER-resident kinase PERK.

Ovarian function and morphology after deletion of the DARPP-32 gene in mice.

A plethora of systemic and local signaling molecules regulate ovarian function, but how different signaling molecules interact within an ovarian target cell is not known. Here we report that endocrine cells of the ovary express a phosphoprotein, DARPP-32 (dopamine and cyclic AMP-regulated phosphoprotein of Mr 32,000), which integrates signaling molecules in neurons. We thus hypothesized that DARPP-32 might act in a similar way in ovarian endocrine cells and therefore studied whether DARPP-32 gene deletion has consequences for ovarian functions in mice.

Molecular characterization of recombinant mouse adenosine kinase and evaluation as a target for protein phosphorylation.

The regulation of adenosine kinase (AK) activity has the potential to control intracellular and interstitial adenosine (Ado) concentrations. In an effort to study the role of AK in Ado homeostasis in the central nervous system, two isoforms of the enzyme were cloned from a mouse brain cDNA library. Following overexpression in bacterial cells, the corresponding proteins were purified to homogeneity.

Ethologically based resolution of D2-like dopamine receptor agonist-versus antagonist-induced behavioral topography in dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa "knockout" mutants congenic on the C57BL/6 genetic background.

Given the critical role of dopamine- and adenosine 3',5'-monophosphate-regulated phosphoprotein of 32 kDa (DARPP-32) in the regulation of dopaminergic function, DARPP-32-null mutant mice congenic on the inbred C57BL/6 strain for 10 generations were examined phenotypically for their ethogram of responsivity to the selective D2-like receptor agonist RU 24213 (N-n-propyl-N-phenylethyl-p-3-hydroxyphenylethylamine) and the selective D2-like receptor antagonist YM 09151-2 (cis-N-[1-benzyl-2-methyl-pyrrolidin-3-yl]-5-chloro-2-methoxy-4-methylaminobenzamide), using procedures that resolve all topographies of behavior in the natural repertoire. After vehicle challenge, levels of sniffing and rearing seated were reduced in DARPP-32 mutants; the injection procedure seems to constitute a "stressor" that reveals phenotypic effects of DARPP-32 deletion not apparent under natural conditions. Topographical effects of 0.