Spectroscopy along Multiple, Lensed Sightlines through Outflowing Winds in the Quasar SDSS J1029+2623

We study the origin of absorption features on the blue side of the C IV broad emission line of the large-separation lensed quasar SDSS J1029+2623 at z_em ~ 2.197. The quasar images, produced by a foreground cluster of galaxies, have a maximum separation angle of ~ 22".5. The large angular separation suggests that the sight-lines to the quasar central source can go through different regions of outflowing winds from the accretion disk of the quasar, providing a unique opportunity to study the structure of outflows from the accretion disk, a key ingredient for the evolution of quasars as well as for galaxy formation and evolution. Based on medium- and high-resolution spectroscopy of the two brightest images conducted at the Subaru telescope, we find that each image has different intrinsic levels of absorptions, which can be attributed either to variability of absorption features over the time delay between the lensed images, ~ 774 days, or to the fine structure of quasar outflows probed by the multiple sight-lines toward the quasar. While both these scenarios are consistent with the current data, we argue that they can be distinguished with additional spectroscopic monitoring observations.Comment: 17 pages, including 7 figures; accepted for publication in the Astronomical Journa

Recent Progress on the Molecular Mechanism of Quality Controls Induced by Ribosome Stalling

Accurate gene expression is a prerequisite for all cellular processes. Cells actively promote correct protein folding, which prevents the accumulation of abnormal and non-functional proteins. Translation elongation is the fundamental step in gene expression to ensure cellular functions, and abnormal translation arrest is recognized and removed by the quality controls. Recent studies demonstrated that ribosome plays crucial roles as a hub for gene regulation and quality controls. Ribosome-interacting factors are critical for the quality control mechanisms responding to abnormal translation arrest by targeting its products for degradation. Aberrant mRNAs are produced by errors in mRNA maturation steps and cause aberrant translation and are eliminated by the quality control system. In this review, we focus on recent progress on two quality controls, Ribosome-associated Quality Control (RQC) and No-Go Decay (NGD), for abnormal translational elongation. These quality controls recognize aberrant ribosome stalling and induce rapid degradation of aberrant polypeptides and mRNAs thereby maintaining protein homeostasis and preventing the protein aggregation

Prescribing Pattern of Hypnotic Medications in Patients Initiating Treatment at Japanese Hospitals: A Nationwide, Retrospective, Longitudinal, Observational Study Using a Claims Database

Background Prolonged treatment of insomnia using benzodiazepine (BZD) receptor agonists, including BZD and non-BZD hypnotic drugs, can cause drug dependence, tolerance, abuse and other adverse events. These side effects are more common and/or severe in older adults taking different hypnotic drugs concomitantly. Therefore, a single prescription is limited to 30 daily doses for most BZD receptor agonists and restrictions apply to the prescription of more than three types of hypnotic drugs in Japan. Little is known, however, about the real-world prescribing pattern of hypnotic drugs in Japan. Objective We analysed prescribing patterns for hypnotic drugs in Japan to evaluate whether real-world use differs from guideline recommendations. Methods In this nationwide, retrospective, longitudinal, observational study, we analysed the types of hypnotic drugs prescribed, duration of medication and treatment setting in a subset of hospitals in Japan using a hospital-based administrative claims database (Medical Data Vision). Patients initiating treatment with hypnotic drugs between January 2012 and December 2016 were included in the analyses to assess the duration of medication and occurrence of co-prescription of a second and third hypnotic drug, within a year from prescription of the first hypnotic drugs. Results In 261,167 patients analysed, the first hypnotic drugs prescribed were BZDs (59.7%), non-BZDs (36.8%), a melatonin receptor agonist [MRA] (3.1%) and an orexin receptor antagonist [ORA] (0.4%). Benzodiazepine and non-BZD hypnotic drugs were mostly prescribed in inpatient settings (57.7% and 63.0%, respectively) and the MRA and ORA mostly in outpatient settings (62.6% and 65.4%, respectively). The departments that prescribed the most patients their first hypnotic drugs were internal medicine (23.6%), general surgery (11.8%), orthopaedic surgery (11.4%) and urology (5.3%). Of the total prescriptions of MRA and ORA as the first hypnotic drugs, 22.0% and 31.8% were in internal medicine, 4.4% each in general surgery, 6.0% and 4.5% in orthopaedic surgery, 9.7% and 4.4% in neurology, and 10.1% and 12.2% in psychiatry departments, respectively. Mean duration of medication was 1.13 months for non-BZDs, 1.15 months for BZDs, 1.29 months for the ORA and 1.83 months for the MRA. Overall, 5.3% (95% confidence interval 5.2–5.4) of patients were prescribed a second hypnotic drug; of these, 8.4% (95% confidence interval 8.0–8.9) were prescribed at least three hypnotic drugs within a year. Patients who were prescribed three or more hypnotic drugs received higher doses of the first drug than patients who received fewer hypnotic drugs. Conclusions Benzodiazepine receptor agonists were the most common hypnotic drugs prescribed as the first drug to patients in Japan. Further education and awareness may be needed on the risk of complications and adverse events associated with these therapies. The duration of BZD receptor agonist use was shorter than for the MRA and ORA, in accordance with prescribing guidelines. Long-term use and co-prescribing of hypnotic drugs were also uncommon. Key Points The side effects of prolonged benzodiazepine receptor agonist use are more common and/or severe in older adults who take multiple hypnotic drugs concomitantly. This study revealed that benzodiazepine receptor agonists are the most commonly prescribed first-line treatments and are mostly prescribed in the inpatient setting in hospital departments such as internal medicine, general surgery, orthopaedic surgery and urology. A melatonin receptor agonist and an orexin receptor antagonist were commonly prescribed to patients in an outpatient setting in internal medicine, psychiatry and neurology departments

Simultaneous Evaluation of Three-Dimensional Lip Kinetics and Tongue Pressure during Swallowing

Objectives: The purpose of this study was to evaluate the amount of lip movement and simultaneous tongue pressure changes on an artificial palatal plate during swallowing. Methods: Subjects were 9 healthy males (25.4 ± 2.1 years of age). Three-dimensional lip movement was measured by a wireless optoelectronic system, and tongue pressure was simultaneously recorded by a sensor sheet attached to the incisive papilla of an artificial palatal plate. Reflective markers were attached to the right and left corners of the mouth to measure the distance between them. All subjects were instructed to swallow 5 mL and 20 mL samples of water at will. The maximum change of distance between the corners of mouth, the maximum tongue pressure, and the time interval between the two maxima (lip-tongue interval) were calculated. Wilcoxon’s test was used to detect significant differences in these measurements between the two volumes. Results: Maximum tongue pressure did not differ significantly between swallowed volumes. The maximum change of distance between the corners of mouth was larger and the lip-tongue interval was significantly shorter with the larger volume. Conclusions: We suggest that swallowing a larger volume is accomplished by larger lip movement rather than larger tongue movement. These results indicate that lip movement during swallowing can be evaluated objectively

Seizure responses and induction of Fos by the NMDA Agonist (tetrazol-5-yl)glycine in a genetic model of NMDA receptor hypofunction

Effects of the direct NMDA agonist (tetrazol-5-yl)glycine (TZG) were examined in a genetic mouse model of reduced NMDA receptor function. In this model, expression of the NR1 subunit is reduced but not eliminated and the mice are therefore designated as NR1 hypomorphic. Previous work suggested that the reduced NR1 subunit expression produced a functional subsensitivity as judged by a blunted Fos induction response to a sub-seizure dose of TZG. In the present study seizure threshold doses of TZG were tested in the wild type and mutant mice. Surprisingly, there was no difference in the seizure sensitivity between the wild type mice and mice presumed to express very low levels of the NR1 subunit. An extensive neuroanatomical analysis of Fos induction was conducted after the threshold seizure doses of TZG. The results demonstrate that some brain regions of the NR1 -/- mice exhibit much lower Fos induction in comparison to the NR1 +/+ mice. These regions include hippocampus, amygdala, and cerebral cortical regions. However, in other regions, similar induction of Fos was observed in both genotypes in response to the NMDA agonist. Regions showing similar Fos induction in the NR1 +/+ and NR1 -/- mice include the lateral septum, nucleus of the solitary tract, and medial hypothalamic regions. The results suggest that the NMDA receptor hypofunction in the NR1 -/- mice is not global but regionally specific and that subcortical structures are responsible for the seizure-inducing effects of TZG

Increased sensitivity to kainic acid in a genetic model of reduced NMDA receptor function

The pathophysiology of schizophrenia may involve reduced NMDA receptor function and experimental models of NMDA receptor hypofunction have proven useful for characterizing neurobiological abnormalities potentially relevant to schizophrenia. The present study assessed behavioral responses and induction of Fos after administration of kainic acid to wild type mice (NR1+/+) and mice with genetically reduced NMDA receptor expression (NR1neo/neo). At a dose of 20 mg/kg kainic acid induced lethal seizures in 100% of the NR1neo/neo mice tested but produced no lethal seizures in the wild type mice. The NR1neo/neo mice also exhibited enhanced behavioral responses to kainic acid at a dose of 15 mg/kg but no lethal seizures were produced by this dose. A greater induction of Fos was observed in neocortical and limbic cortical regions of the NR1neo/neo compared to NR1+/+ mice after administration of 15 mg/kg kainic acid. In contrast, there were no differences between the genotypes in kainic acid induced of Fos in the amygdala, hippocampus, lateral septum, and nucleus accumbens. In order to determine if altered behavioral phenotypes of the NR1neo/neo mice could be related to increased sensitivity of kainate receptors to endogenous glutamate, effects of the highly selective kainate antagonist LY382884 were examined. The kainate antagonist reduced the exaggerated acoustic startle responses, deficits in prepulse inhibition of acoustic startle, and motor hyperactivity in the NR1neo/neo mice. These findings suggest that selective kainate receptor antagonists could be novel therapeutic candidates for schizophrenia

Patterns of hypnotic prescribing for residual insomnia and recurrence of major depressive disorder: a retrospective cohort study using a Japanese health insurance claims database

Background: Major depressive disorder (MDD) is highly prevalent in Japan and frequently accompanied by insomnia that may persist even with MDD remission. Hypnotics are used for the pharmacological treatment of insomnia, but their influence on MDD recurrence or residual insomnia following MDD remission is unclear. This retrospective, longitudinal, cohort study utilized a large Japanese health insurance claims database to investigate patterns of hypnotic prescriptions among patients with MDD, and the influence of hypnotic prescription pattern on MDD recurrence. Methods: Eligible patients (20–56 years) were those registered in the Japan Medical Data Center database between 1 January 2005 and 31 December 2018, and prescribed antidepressant and hypnotic therapy after being diagnosed with MDD. Patients who had ceased antidepressant therapy for > 180 days were followed for 1 year to evaluate depression recurrence, as assessed using Kaplan-Meier estimates. Logistic regression modelling was used to analyze the effect of hypnotic prescription pattern on MDD recurrence. Results: Of the 179,174 patients diagnosed with MDD who initiated antidepressant treatment between 1 January 2006 and 30 June 2017, complete prescription information was available for 2946 eligible patients who had been prescribed hypnotics. More patients were prescribed hypnotic monotherapy (70.8%) than combination therapy (29.2%). The most prescribed therapies were benzodiazepine monotherapy (26.2%), non-benzodiazepine monotherapy (28.9%), and combination therapy with two drugs (21.1%). Among patients prescribed multiple hypnotics, concomitant prescriptions for anxiolytics, antipsychotics, mood stabilizers and sedative antidepressants were more common. The 1-year recurrence rate for MDD was approximately 20%, irrespective of hypnotic monoversus combination therapy or class of hypnotic therapy. Being a spouse (odds ratio [OR], 1.44; 95% confidence interval [CI], 1.03–2.02) or other family member (OR, 1.46, 95% CI, 0.99–2.16) of the insured individual, or being prescribed a sedative antidepressant (OR, 1.50, 95% CI, 1.24–1.82) conferred higher odds of MDD recurrence within 1 year of completing antidepressant therapy. Conclusions: Benzodiazepines are the most prescribed hypnotic among Japanese patients with MDD, though combination hypnotic therapy is routinely prescribed. Hypnotic prescription pattern does not appear to influence real-world MDD recurrence, though hypnotics should be appropriately prescribed given class differences in efficacy and safety

Neural activation deficits in a mouse genetic model of NMDA receptor hypofunction in tests of social aggression and swim stress

Mice with reduced expression of the NR1 subunit of the NMDA receptor (NR1 hypomorphic mice) display altered behavioral phenotypes that may relate to behavioral characteristics of schizophrenia. Altered phenotypes in the NR1 hypomorphs include marked deficits in species-typical behavioral interactions in tests of social aggression and social affiliation. To gain insight into neuroanatomical circuits disrupted by reduced NMDA receptor function, the present work compared regional brain activation in NR1 hypomorphic mice and their wild type controls after a resident-intruder test. Induction of Fos protein was used as an index of neuronal activation. Wild type mice exhibited robust induction of Fos in select brain regions, including specific nuclei of the hypothalamus and amygdala, lateral septum, and widespread regions of the cerebral cortex. Although the behavioral patterns were different for male and female mice, neuroanatomical patterns of Fos induction were remarkably similar for the two sexes. To determine socially specific components of Fos induction by the resident-intruder test, responses were compared for mice assessed in a test of general arousal and stress involving forced swim. Some common brain regions were activated by both tests but regionally specific differences were also found. The NR1 hypomorphic mice tested in the resident-intruder procedure displayed distinctly different behavioral interactions compared to the wild type mice and exhibited a significantly blunted Fos response in almost all brain regions. The mutant mice also exhibited reduced Fos in response to swim stress in specific brain regions. These data suggest that the NR1 hypomorphic mice have functional activation deficits in response to social challenge and swim stress