bluuebunny/crossref_metadata_2025_split huggingface dataset:
Secreted APE1/Ref-1 inhibits TNF-α-stimulated endothelial inflammation via thiol-disulfide exchange in TNF receptor
Authors: Park Myoung Soo , Choi Sunga , Lee Yu Ran , Joo Hee Kyoung , Kang Gun , Kim Cuk-Seong , Kim Soo Jin , Lee Sang Do , Jeon Byeong Hwa 
Published: March 2016

AbstractApurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a multifunctional protein with redox activity and is proved to be secreted from stimulated cells. The aim of this study was to evaluate the functions of extracellular APE1/Ref-1 with respect to leading anti-inflammatory signaling in TNF-α-stimulated endothelial cells in response to acetylation. Treatment of TNF-α-stimulated endothelial cells with an inhibitor of deacetylase that causes intracellular acetylation, considerably suppressed vascular cell adhesion molecule-1 (VCAM-1). During TSA-mediated acetylation in culture, a time-dependent increase in secreted APE1/Ref-1 was confirmed. The acetyl moiety of acetylated-APE1/Ref-1 was rapidly removed based on the removal kinetics. Additionally, recombinant human (rh) APE1/Ref-1 with reducing activity induced a conformational change in rh TNF-α receptor 1 (TNFR1) by thiol-disulfide exchange. Following treatment with the neutralizing anti-APE1/Ref-1 antibody, inflammatory signals via the binding of TNF-α to TNFR1 were remarkably recovered, leading to up-regulation of reactive oxygen species generation and VCAM-1, in accordance with the activation of p66shc and p38 MAPK. These results strongly indicate that anti-inflammatory effects in TNF-α-stimulated endothelial cells by acetylation are tightly linked to secreted APE1/Ref-1, which inhibits TNF-α binding to TNFR1 by reductive conformational change, with suggestion as an endogenous inhibitor of vascular inflammation.
Exploring the structure of glutamate racemase from Mycobacterium tuberculosis as a template for anti-mycobacterial drug discovery
Authors: Poen Sinothai , Nakatani Yoshio , Opel-Reading Helen K. , Lassé Moritz , Dobson Renwick C.J. , Krause Kurt L. 
Published: March 2016

Glutamate racemase (MurI) is responsible for providing D-glutamate for peptidoglycan biosynthesis in bacteria and has been a favoured target in pharmaceutical drug design efforts. It has recently been proven to be essential in Mycobacterium tuberculosis, the causative organism of tuberculosis, a disease for which new medications are urgently needed. In the present study, we have determined the protein crystal structures of MurI from both M. tuberculosis and Mycobacterium smegmatis in complex with D-glutamate to 2.3 Å and 1.8 Å resolution respectively. These structures are conserved, but reveal differences in their active site architecture compared with that of other MurI structures. Furthermore, compounds designed to target other glutamate racemases have been screened but do not inhibit mycobacterial MurI, suggesting that a new drug design effort will be needed to develop inhibitors. A new type of MurI dimer arrangement has been observed in both structures, and this arrangement becomes the third biological dimer geometry for MurI found to date. The mycobacterial MurI dimer is tightly associated, with a KD in the nanomolar range. The enzyme binds D- and L-glutamate specifically, but is inactive in solution unless the dimer interface is mutated. We created triple mutants of this interface in the M. smegmatis glutamate racemase (D26R/R105A/G194R or E) that have appreciable activity (kcat=0.056–0.160 min−1 and KM=0.26–0.51 mM) and can be utilized to screen proposed antimicrobial candidates for inhibition.
Temporally chimeric mice reveal flexibility of circadian period-setting in the suprachiasmatic nucleus
Authors: Smyllie Nicola J. , Chesham Johanna E. , Hamnett Ryan , Maywood Elizabeth S. , Hastings Michael H. 
Published: March 2016

Significance
The suprachiasmatic nucleus (SCN) is the principal circadian clock of the mammalian brain. To function effectively, SCN neurons must operate as a synchronized circuit. How cell-autonomous and circuit-level circadian mechanisms interact to achieve this is unclear. Here, we used intersectional genetics to create temporally chimeric mice where both 24-h and 20-h clock neurons were present in the SCN, in different cell populations. The 24-h dopamine receptor-positive cells set the speed of the SCN, imposing their cell-autonomous 24-h period on all cells in the circuit. Exposure to a 20-h lighting cycle, however, inverted this dominance, reprograming the circuit to 20 h. These results show how robust circuit-level signaling underlies complex, nonlinear computations of circadian period that also exhibit a remarkable level of plasticity.
Desert in liberal justice: beyond institutional guarantees
Authors: Messina J. P. 
Published: March 2016

AbstractI argue that a theory of distributive justice is sensitive to desert if and only if it (1) does not require an institutional scheme thatpreventsindividuals from treating one another as they deserve, and (2) requires a desertethos. A desertethosis a set of principles that, though not embodied in a society’s basic coercive structure, nevertheless governs interpersonal relations between citizens. These two necessary conditions are jointly sufficient for ‘giving desert its due’ in a theory of justice. I therefore reject the received view that a desert-sensitive theory must endeavor to guarantee distributions patterned according to desert.
A Lactobacillus mutant capable of accumulating long-chain polyphosphates that enhance intestinal barrier function
Authors: Saiki Asako , Ishida Yasuaki , Segawa Shuichi , Hirota Ryuichi , Nakamura Takeshi , Kuroda Akio 
Published: March 2016

Abstract
Inorganic polyphosphate (polyP) was previously identified as a probiotic-derived substance that enhances intestinal barrier function. PolyP-accumulating bacteria are expected to have beneficial effects on the human gastrointestinal tract. In this study, we selected Lactobacillus paracasei JCM 1163 as a strain with the potential to accumulate polyP, because among the probiotic bacteria stored in our laboratory, it had the largest amount of polyP. The chain length of polyP accumulated in L. paracasei JCM 1163 was approximately 700 phosphate (Pi) residues. L. paracasei JCM 1163 accumulated polyP when Pi was added to Pi-starved cells. We further improved the ability of L. paracasei JCM 1163 to accumulate polyP by nitrosoguanidine mutagenesis. The mutant accumulated polyP at a level of 1500 nmol/mg protein—approximately 190 times that of the wild-type strain. PolyP extracted from the L. paracasei JCM 1163 significantly suppressed the oxidant-induced intestinal permeability in mouse small intestine. In conclusion, we have succeeded in breeding the polyP-accumulating Lactobacillus mutant that is expected to enhance intestinal barrier function.
Searching for novel ATF4 target genes in human hepatoma cells by microarray analysis
Authors: Maruyama Ryuto , Shimizu Makoto , Ishijima Tomoko , Nakai Yuji , Inoue Jun , Sato Ryuichiro 
Published: March 2016

Abstract
Activating transcription factor 4 (ATF4) is a transcription factor with an important biological activity. ATF4 is induced by various stresses, such as endoplasmic reticulum stress, through the phosphorylation of eukaryotic translation initiation factor 2α. ATF4 is also involved in lipid metabolism. In the present study, we performed a microarray experiment to identify new ATF4 target genes, particularly those involved in lipid metabolism, and identified C12orf39, CSTA, and CALCB as novel ATF4 target genes. An amino acid response element (AARE) as an ATF4-binding site is present in the promoter regions of these genes. In a detailed analysis using luciferase assay, we showed that ATF4 activated C12orf39 promoter activity and that this activation was diminished by deletion or mutation of the AARE sequence in the promoter region. Our results suggest that C12orf39, CSTA, and CALCB are novel ATF4 target genes and that C12orf39 promoter activity is activated by ATF4 through AARE.
Naringin lauroyl ester inhibits lipopolysaccharide-induced activation of nuclear factor κB signaling in macrophages
Authors: Hattori Hiromi , Tsutsuki Hiroyasu , Nakazawa Masami , Ueda Mitsuhiro , Ihara Hideshi , Sakamoto Tatsuji 
Published: March 2016

Abstract
Naringin (Nar) has antioxidant and anti-inflammatory properties. It was recently reported that enzymatic modification of Nar enhanced its functions. Here, we acylated Nar with fatty acids of different sizes (C2–C18) using immobilized lipase from Rhizomucor miehei and investigated the anti-inflammatory effects of these molecules. Treatment of murine macrophage RAW264.7 cells with Nar alkyl esters inhibited lipopolysaccharide (LPS)-induced nitric oxide (NO) production, with Nar lauroyl ester (Nar-C12) showing the strongest effect. Furthermore, Nar-C12 suppressed the LPS-induced expression of inducible NO synthase by blocking the phosphorylation of inhibitor of nuclear factor (NF)-κB-α as well as the nuclear translocation of NF-κB subunit p65 in macrophage cells. Analysis of Nar-C12 uptake in macrophage cells revealed that Nar-C12 ester bond was partially degraded in the cell membrane and free Nar was translocated to the cytosol. These results indicate that Nar released from Nar-C12 exerts anti-inflammatory effects by suppressing NF-κB signaling pathway.
An ethanol extract of Ramulus mori improves blood circulation by inhibiting platelet aggregation
Authors: Lee Jiyun , Kwon Gayeung , Park Jieun , Kim Jeong-Keun , Choe Soo Young , Seo Yoonhee , Lim Young-Hee 
Published: March 2016

Abstract
Inappropriate platelet aggregation can cause blood coagulation and thrombosis. In this study, the effect of an ethanol extract of Ramulus mori (ERM) on blood circulation was investigated. The antithrombotic activity of ERM on rat carotid arterial thrombosis was evaluated in vivo, and the effect of ERM on platelet aggregation and blood coagulation time was evaluated ex vivo. To evaluate the safety of ERM, its cytotoxicity to platelets and its effect on tail bleeding time were assessed; ERM was not toxic to rat platelets and did not prolong bleeding time. Moreover, administering ERM to rats had a significant preventive effect on carotid arterial thrombosis in vivo, and significantly inhibited adenosine diphosphate- and collagen-induced platelet aggregation ex vivo, whereas it did not prolong coagulation periods, such as prothrombin time and activated partial thromboplastin time. The results suggest that ERM is effective in improving blood circulation via antiplatelet activity rather than anticoagulation activity.
Assessment of the Effects of Hepatic Impairment and Smoking on the Pharmacokinetics of a Single Oral Dose of the Soluble Guanylate Cyclase Stimulator Riociguat (BAY 63‐2521)
Authors: Frey Reiner , Becker Corina , Unger Sigrun , Schmidt Anja , Wensing Georg , Mück Wolfgang 
Published: March 2016

Riociguat, a soluble guanylate cyclase stimulator developed for the treatment of pulmonary hypertension, is metabolized in part by the liver. Expression of one of the metabolizing enzymes, CYP1A1, is induced by aromatic hydrocarbons in tobacco smoke. Two non‐∗∗∗randomized, nonblinded studies were conducted to investigate the pharmacokinetics of riociguat in individuals with mild (Child‐Pugh A) or moderate (Child‐Pugh B) hepatic impairment associated with liver cirrhosis compared with that in age‐, weight‐, and sex‐matched healthy controls: study 1 included smokers and nonsmokers, and study 2 included nonsmokers only. Data from these studies were integrated for analysis. All participants (N = 64) received a single oral dose of riociguat 1.0 mg. Riociguat exposure was significantly higher in individuals with Child‐Pugh B hepatic impairment than in healthy controls (ratio: 153% [90% confidence interval: 103%‐228%]) but was similar in those with Child‐Pugh A hepatic impairment and controls. The half‐life of the riociguat metabolite M1 was prolonged in patients with Child‐Pugh B or A hepatic impairment compared with that in controls by approximately 43% and 24%, respectively. Impaired hepatic function was associated with higher riociguat exposure in nonsmokers compared with the population of smokers and nonsmokers combined. Riociguat's safety profile was similar in individuals with impaired or normal liver function. In conclusion, moderate hepatic impairment was associated with increased riociguat exposure compared with that in controls, probably as a result of reduced clearance of the metabolite M1. This suggests that dose titration of riociguat should be administered with particular care in patients with moderate hepatic impairment.
Assessment of the Effects of Renal Impairment and Smoking on the Pharmacokinetics of a Single Oral Dose of the Soluble Guanylate Cyclase Stimulator Riociguat (BAY 63‐2521)
Authors: Frey Reiner , Becker Corina , Unger Sigrun , Schmidt Anja , Wensing Georg , Mück Wolfgang 
Published: March 2016

Renal impairment is a common comborbidity in patients with pulmonary hypertension. The breakdown of riociguat, an oral soluble guanylate cyclase stimulator used to treat pulmonary hypertension, may be affected by smoking because polycyclic aromatic hydrocarbons in tobacco smoke induce expression of one of the metabolizing enzymes, CYP1A1. Two nonrandomized, nonblinded studies were therefore performed to investigate the pharmacokinetics and safety of a single oral dose of riociguat 1.0 mg in individuals with mild, moderate, or severe renal impairment compared with age‐, weight‐, and sex‐matched healthy controls, including either smokers and nonsmokers (study I) or nonsmokers alone (study II). Pharmacokinetic analyses focused on the integrated per‐protocol data set of both studies (N = 63). In patients with renal impairment, the renal clearance of riociguat was reduced and its terminal half‐life prolonged compared with those in healthy controls. There was a monotonic relationship between creatinine clearance on treatment day and riociguat renal clearance (R2 = 0.62). However, increased riociguat exposure with decreasing renal function was not strictly proportional. Riociguat exposure appeared to be greater in nonsmokers than in the combined population of smokers and nonsmokers, irrespective of renal function. Adverse events were mild to moderate and in line with the mode of action of riociguat. No serious adverse events occurred. In conclusion, renal impairment was associated with reduced riociguat clearance compared with that in controls; however, riociguat exposure in patients with renal impairment was highly variable, and ranges overlapped with those observed in healthy controls.
Population Pharmacokinetics and the Pharmacokinetic/Pharmacodynamic Relationship of Riociguat in Patients with Pulmonary Arterial Hypertension or Chronic Thromboembolic Pulmonary Hypertension
Authors: Saleh Soundos , Becker Corina , Frey Reiner , Mück Wolfgang 
Published: March 2016

This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies—PATENT‐1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase‐Stimulator Trial 1; 12 weeks; PAH) and CHEST‐1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase–Stimulator Trial 1; 16 weeks; CTEPH)—and long‐term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed‐effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one‐compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time‐ or dose‐dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan‐treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6‐minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one‐compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT‐1, NCT00810693; PATENT‐2, NCT00863681; CHEST‐1, NCT00855465; CHEST‐2, NCT00910429.)
Pharmacokinetic Interaction Study between Riociguat and the Combined Oral Contraceptives Levonorgestrel and Ethinylestradiol in Healthy Postmenopausal Women
Authors: Frey Reiner , Unger Sigrun , van der Mey Dorina , Becker Corina , Saleh Soundos , Wensing Georg , Mück Wolfgang 
Published: March 2016

Female patients requiring treatment for pulmonary arterial hypertension (PAH) are advised to avoid pregnancy because of the high associated mortality rate. Oral contraception is one of the main methods of preventing pregnancy in this context, mandating pharmacokinetic and safety studies for new agents in this setting. Riociguat is a soluble guanylate cyclase stimulator approved for treatment of PAH and inoperable and persistent or recurrent chronic thromboembolic pulmonary hypertension. This single‐center, randomized, nonblinded study involving healthy postmenopausal women investigated the effect of riociguat on plasma concentrations of levonorgestrel (0.15 mg) and ethinylestradiol (0.03 mg) in a combined oral contraceptive. Treatment A was a single oral tablet of levonorgestrel‐ethinylestradiol. In treatment B, subjects received 2.5 mg riociguat 3 times daily for 12 days. On the eighth day, they also received a single oral tablet of levonorgestrel‐ethinylestradiol. Subjects received both regimens in a crossover design. There was no change in area under the plasma concentration—time curves of levonorgestrel or ethinylestradiol or maximum concentration in plasma (Cmax) of levonorgestrel during combined administration versus levonorgestrel‐ethinylestradiol alone. A 20% increase in the Cmax of ethinylestradiol was noted during coadministration; this is not anticipated to adversely impact the contraceptive efficacy or to require any dose adjustment for ethinylestradiol. Plasma concentrations and exposures of riociguat were within the expected range and were not influenced by coadministration with levonorgestrel‐ethinylestradiol. Combined treatment was safe and well tolerated. In conclusion, riociguat did not change the exposure to levonorgestrel or ethinylestradiol relative to oral contraceptive administered alone.
Radiological properties of nanocomposite Fricke gel dosimeters for heavy ion beams
Authors: Maeyama Takuya , Fukunishi Nobuhisa , Ishikawa Kenichi L. , Fukasaku Kazuaki , Fukuda Shigekazu 
Published: March 2016

Abstract
The radiological properties of nanocomposite Fricke gel (NC-FG) dosimeters prepared with different concentrations of nano-clay, perchloric acid and ferrous ions in deaerated conditions were investigated under carbon and argon ion beam irradiation covering a linear-energy-transfer (LET) range of 10 to 3000 eV/nm. We found that NC-FG exhibits radiological properties distinct from those of conventional Fricke gel. The radiation sensitivity of NC-FG is independent of the LET and is nearly constant even at very high LET (3000 eV/nm) values in the Bragg peak region of the argon ion beam. In addition, whereas conventional Fricke gel dosimeters only operate under acidic conditions, NC-FG dosimeters function under both acidic and neutral conditions. The radiation sensitivity decreases with decreasing nano-clay concentration in NC-FG, which indicates that the nano-clay plays a vital role in the radiation-induced oxidation of Fe 2+ .
Effective Assessment and Evaluation for Shared Accountability in University Music Programs
Authors: Hourigan Ryan M. 
Published: March 2016

Abstract
This article examines the basic framework for program assessment and evaluation in preparation for university annual reporting, accreditation, and reflection on curriculum and teaching practice among professors within the music school. The discussion focuses on twenty-first-century accountability standards and student expectations, with a concentration on assessing student-learning objectives in music at the university level. Strategies are provided for simple workflow, reporting, and cloud storage to promote a common understanding among the professor, student, and administrator. Strategies for determining appropriate events to assess as well as direct and indirect measures are examined within the framework of applied music. Examples of processes to establish student learning objectives and example instruments are provided, and common terminology is operationally defined.
A Binational Multicenter Pilot Feasibility Randomized Controlled Trial of Early Goal-Directed Mobilization in the ICU*
Authors: Hodgson Carol L. , Bailey Michael , Bellomo Rinaldo , Berney Susan , Buhr Heidi , Denehy Linda , Gabbe Belinda , Harrold Megan , Higgins Alisa , Iwashyna Theodore J. , Papworth Rebecca , Parke Rachael , Patman Shane , Presneill Jeffrey , Saxena Manoj , Skinner Elizabeth , Tipping Claire , Young Paul , Webb Steven 
Published: March 2016

Objectives:
To determine if the early goal-directed mobilization intervention could be delivered to patients receiving mechanical ventilation with increased maximal levels of activity compared with standard care.

Design:
A pilot randomized controlled trial.

Setting:
Five ICUs in Australia and New Zealand.

Participants:
Fifty critically ill adults mechanically ventilated for greater than 24 hours.

Intervention:
Patients were randomly assigned to either early goal-directed mobilization (intervention) or to standard care (control). Early goal-directed mobilization comprised functional rehabilitation treatment conducted at the highest level of activity possible for that patient assessed by the ICU mobility scale while receiving mechanical ventilation.

Measurements and Main Results:
The ICU mobility scale, strength, ventilation duration, ICU and hospital length of stay, and total inpatient (acute and rehabilitation) stay as well as 6-month post-ICU discharge health-related quality of life, activities of daily living, and anxiety and depression were recorded. The mean age was 61 years and 60% were men. The highest level of activity (ICU mobility scale) recorded during the ICU stay between the intervention and control groups was mean (95% CI) 7.3 (6.3–8.3) versus 5.9 (4.9–6.9), p = 0.05. The proportion of patients who walked in ICU was almost doubled with early goal-directed mobilization (intervention n = 19 [66%] vs control n = 8 [38%]; p = 0.05). There was no difference in total inpatient stay (d) between the intervention versus control groups (20 [15–35] vs 34 [18–43]; p = 0.37). There were no adverse events.

Conclusions:
Key Practice Points: Delivery of early goal-directed mobilization within a randomized controlled trial was feasible, safe and resulted in increased duration and level of active exercises.