bluuebunny/crossref_metadata_2025_split huggingface dataset:
The novel μ‐opioid receptor agonist PZM21 depresses respiration and induces tolerance to antinociception
Authors: Hill Rob , Disney Alex , Conibear Alex , Sutcliffe Katy , Dewey William , Husbands Stephen , Bailey Chris , Kelly Eamonn , Henderson Graeme 
Published: March 2018

Background and PurposePZM21 is a novel μ‐opioid receptor ligand that has been reported to induce minimal arrestin recruitment and be devoid of the respiratory depressant effects characteristic of classical μ receptor ligands such as morphine. We have re‐examined the signalling profile of PZM21 and its ability to depress respiration.Experimental ApproachG protein (Gi) activation and arrestin‐3 translocation were measured in vitro, using BRET assays, in HEK 293 cells expressing μ receptors. Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole‐body plethysmography, and antinociception was measured by the hot plate test.Key ResultsPZM21 (10−9 – 3 × 10−5 M) produced concentration‐dependent Gi activation and arrestin‐3 translocation. Comparison with responses evoked by morphine and DAMGO revealed that PZM21 was a low efficacy agonist in both signalling assays. PZM21 (10–80 mg·kg−1) depressed respiration in a dose‐dependent manner. The respiratory depression was due to a decrease in the rate of breathing not a decrease in tidal volume. On repeated daily administration of PZM21 (twice daily doses of 40 mg·kg−1), complete tolerance developed to the antinociceptive effect of PZM21 over 3 days but no tolerance developed to its respiratory depressant effect.Conclusion and ImplicationsThese data demonstrate that PZM21 is a low efficacy μ receptor agonist for both G protein and arrestin signalling. Contrary to a previous report, PZM21 depresses respiration in a manner similar to morphine, the classical opioid receptor agonist.
Modulation of the nutritional value of lupine wholemeal and protein isolates using submerged and solid‐state fermentation with Pediococcus pentosaceus strains
Authors: Bartkiene Elena , Sakiene Vytaute , Bartkevics Vadims , Juodeikiene Grazina , Lele Vita , Wiacek Claudia , Braun Peggy G. 
Published: March 2018

SummaryThe influence of different factors (submerged and/or solid‐state fermentation, pediococci strain, lupine variety and protein isolation process) on the protein digestibility, total phenolic compounds (TPC) content and radical scavenging activity of Lupinus luteus and angustifolius wholemeal and protein isolates was evaluated. As safety factor, biogenic amines (Bas) formation was analysed. The Pediococcus pentosaceus strains No. 8, No. 9 and No. 10 are suitable starters for lupine wholemeal fermentation and both applied processes (fermentation and protein isolation) increase protein digestibility (by 10%). Higher TPC content in fermented wholemeal can be obtained, compare to isolates. In SMF isolates by 58.3%, 68.2%, 95.6%, 76.6%, lower content of phenylethylamine, putrescine, cadaverine and histamine, respectively was found. The highest protein digestibility and the lowest BAs content using submerged fermentation with pediococcus No. 8 in lupine variety Vilnius protein isolates can be obtained and this technology for high‐quality lupine proteins preparation can be recommended.
Targeting Alzheimer's disease with gene and cell therapies
Authors: Loera‐Valencia R. , Piras A. , Ismail M. A. M. , Manchanda S. , Eyjolfsdottir H. , Saido T. C. , Johansson J. , Eriksdotter M. , Winblad B. , Nilsson P. 
Published: March 2018

AbstractAlzheimer's disease (AD) causes dementia in both young and old people affecting more than 40 million people worldwide. The two neuropathological hallmarks of the disease, amyloid beta (Aβ) plaques and neurofibrillary tangles consisting of protein tau are considered the major contributors to the disease. However, a more complete picture reveals significant neurodegeneration and decreased cell survival, neuroinflammation, changes in protein and energy homeostasis and alterations in lipid and cholesterol metabolism. In addition, gene and cell therapies for severe neurodegenerative disorders have recently improved technically in terms of safety and efficiency and have translated to the clinic showing encouraging results. Here, we review broadly current data within the field for potential targets that could modify AD through gene and cell therapy strategies. We envision that not only Aβ will be targeted in a disease‐modifying treatment strategy but rather that a combination of treatments, possibly at different intervention times may prove beneficial in curing this devastating disease. These include decreased tau pathology, neuronal growth factors to support neurons and modulation of neuroinflammation for an appropriate immune response. Furthermore, cell based therapies may represent potential strategies in the future.
Synthesis and biological evaluation of novel cyclopropyl derivatives as subtype-selective ligands for estrogen receptor
Authors: Wang Zunyuan , Yang Yewei , Zheng Xiaoliang , Zhang Tao , Huang Wenhai , Yan Dongmei , Zhang Wenjun , Wang Xiaoju , Shen Zhengrong 
Published: March 2018

Abstract

Objectives
Tamoxifen is the most commonly used selective estrogen receptor modulators (SERMs); however, patients often develop the acquired drug resistance on tamoxifen therapy. The aim of this study was to develop new SERMs.

Methods
Several novel cyclopropyl derivatives were designed and synthesized. The binding affinities of these compounds as well as the selectivity on subtype of estrogen receptor (ER) were assessed by fluorescence polarization. The antagonistic activity was also evaluated by dual-luciferase reporter assay.

Key findings
Our data identified five compounds (9a, 9b, 9d, 9e and 9f) with a higher selectivity on ERα than ERβ subtype, warranting further development as a subtype-selective ER modulator. The study of antiestrogen activity also demonstrated that compounds 9a, 9c-f acted as full functional antagonists for ERα. These compounds had no or very low cytotoxicity.

Conclusions
Although these cyclopropyl derivatives showed lower binding affinities on ERs compared to 17β-estradiol, five of these compounds exhibited binding to ERα only and therefore might serve as a promising lead compound for further development of novel subtype-selective SERMs.
Combining long‐acting bronchodilators with different mechanisms of action: A pharmacological approach to optimize bronchodilation of equine airways
Authors: Calzetta L. , Rogliani P. , Pistocchini E. , Mattei M. , Cito G. , Alfonsi P. , Page C. , Matera M. G. 
Published: March 2018

The ultra long‐acting β2‐adrenoceptor agonist olodaterol plus the ultra long‐acting muscarinic antagonist tiotropium bromide are known to relax equine airways. In human bronchi combining these drugs elicits a positive interaction, thus we aimed to characterize this information further in equine isolated airways stimulated by electrical field stimulation (EFS) and using the Concentration‐Reduction Index (CRI) and Combination Index (CI) equations. The drugs were administered alone and together by reproducing ex vivo the concentration‐ratio delivered by the currently available fixed‐dose combination (1:1). The single agents elicited a significant (p < .05) concentration‐dependent reduction in the EFS‐induced contractility, that was synergistically improved (CI 0.18) when administered in combination (0.9 logarithms more potent, 24% more effective than the monocomponents). The drugs mixture allowed a reduction in the concentration of olodaterol from ≃1 to ≃2.3 logarithms. A favorable CRI was detected also for tiotropium bromide, whose concentration can be reduced ≃1 logarithm at medium effect levels, remaining positive up to submaximal relaxant effect in the presence of olodaterol. The combination of tiotropium bromide/olodaterol allows the reduction in the concentration of the monocomponents to achieve airway smooth muscle relaxation, thus potentially decreases the risk of adverse events when these drugs are used to treat severe asthmatic horses.
Education on invasive mechanical ventilation involving intensive care nurses: a systematic review
Authors: Guilhermino Michelle C , Inder Kerry J , Sundin Deborah 
Published: March 2018

ABSTRACTBackgroundIntensive care unit nurses are critical for managing mechanical ventilation. Continuing education is essential in building and maintaining nurses' knowledge and skills, potentially improving patient outcomes.AimsThe aim of this study was to determine whether continuing education programmes on invasive mechanical ventilation involving intensive care unit nurses are effective in improving patient outcomes.MethodsFive electronic databases were searched from 2001 to 2016 using keywords such as mechanical ventilation, nursing and education. Inclusion criteria were invasive mechanical ventilation continuing education programmes that involved nurses and measured patient outcomes. Primary outcomes were intensive care unit mortality and in‐hospital mortality. Secondary outcomes included hospital and intensive care unit length of stay, length of intubation, failed weaning trials, re‐intubation incidence, ventilation‐associated pneumonia rate and lung‐protective ventilator strategies. Studies were excluded if they excluded nurses, patients were ventilated for less than 24 h, the education content focused on protocol implementation or oral care exclusively or the outcomes were participant satisfaction. Quality was assessed by two reviewers using an education intervention critical appraisal worksheet and a risk of bias assessment tool. Data were extracted independently by two reviewers and analysed narratively due to heterogeneity.ResultsTwelve studies met the inclusion criteria for full review: 11 pre‐ and post‐intervention observational and 1 quasi‐experimental design. Studies reported statistically significant reductions in hospital length of stay, length of intubation, ventilator‐associated pneumonia rates, failed weaning trials and improvements in lung‐protective ventilation compliance. Non‐statistically significant results were reported for in‐hospital and intensive care unit mortality, re‐intubation and intensive care unit length of stay.ConclusionLimited evidence of the effectiveness of continuing education programmes on mechanical ventilation involving nurses in improving patient outcomes exists. Comprehensive continuing education is required.Relevance to clinical practiceWell‐designed trials are required to confirm that comprehensive continuing education involving intensive care nurses about mechanical ventilation improves patient outcomes.
Regulation of melanocyte stem cell behavior by the niche microenvironment
Authors: Li Huirong , Hou Ling 
Published: March 2018

SummarySomatic stem cells are regulated by their niches to maintain tissue homeostasis and repair throughout the lifetime of an organism. An excellent example to study stem cell/niche interactions is provided by the regeneration of melanocytes during the hair cycle and in response to various types of injury. These processes are regulated by neighboring stem cells and multiple signaling pathways, including WNT/β‐catenin, KITL/KIT, EDNs/EDNRB, TGF‐β/TGF‐βR, α‐MSH/MC1R, and Notch signaling. In this review, we highlight recent studies that have advanced our understanding of the molecular crosstalk between melanocyte stem cells and their neighboring cells, which collectively form the niche microenvironment, and we focus on the question of how McSCs/niche interactions shape the responses to genotoxic damages and mechanical injury.
Characterization of Porphyra lucasii pigment mutant induced by gamma irradiation
Authors: Lee Hak‐Jyung , Choi Jong‐il , Kim Gwang H. 
Published: March 2018

SUMMARYThe present study describes the isolation of a pigment mutant strain of Porphyra lucasii, which was obtained using gamma irradiation. Gametophytic blades of this seaweed were irradiated with gamma rays at doses of 500 and 1000 Gy. After irradiation, red color was observed in the blades exposed to the 500 Gy dose. Single somatic cells from these irradiated blades were isolated from archespores and then cultured to obtain pigment mutant blades that are referred to as 500GR in this investigation. Evaluation of genetic variations in these blades was performed using random amplification of polymorphic DNA (RAPD) analysis. Chlorophyll content, antioxidant activity, and total phenolic content were found to be higher in 500GR than in the wild type (WT) algal strain. Protein extracts obtained from the blades were examined using 2D gel electrophoresis; changes in the proteome were finally analyzed using MS/MS. A total of 216 proteins were detected. From these, nine proteins were over‐expressed in the pigment spots in 500GR as compared to WT. These results indicate that the over‐expressed proteins are either antioxidant enzymes or photosynthesis‐related proteins.
The role of services in globalisation
Authors: Bohn Timon , Brakman Steven , Dietzenbacher Erik 
Published: March 2018

AbstractThis paper explores the role of services in international trade and global value chains, and adds to our knowledge on recent trends in globalisation. We employ indicators for trade in value‐added (VA) and for gross exports, and address the following two questions: (i) has trade ofVAin services (i.e., theVAcreated by domestic service industries and embodied in foreign consumption of final products) grown more than trade ofVAin manufacturing; and (ii) does trade ofVAin services travel further than trade ofVAin manufacturing. Based on the World Input‐Output Database (WIOD), we find, in general, that for the period 2000–14, the share of services in exports ofVAgrew over time, whilst the share of manufacturing remained constant (or grew relatively less). Second, throughout the entire period, services had a larger share in interregional exports ofVAthan in intraregional exports ofVA, whilst the opposite was true for manufacturing. Services were thus more global than manufacturing.
Improvements of Shooting Performance in Adolescent Air Rifle Athletes After 6-Week Balance and Respiration Training Programs
Authors: Park Han-Kyu , Kim Dong-Woo , Kim Tae-Ho 
Published: March 2018

Context:Several factors, such as balance and respiration training programs, have been identified as contributing to a shooting performance. However, little is known about the benefits of these programs on the shooting records of adolescent air rifle athletes.Objective:The purpose of this study was to investigate whether balance and respiration training can contribute to the shooting performance required for adolescent air rifle shooting athletes.Design:Case-control study.Setting:Shooting range.Participants:A total of 21 adolescent air rifle athletes were recruited from the local school community and assigned to an experimental (n = 11; EG) or control (n = 10; CG) group.Intervention:The EG performed respiration and balance training for 30 minutes 3 times a week for 6 weeks, and the CG performed balance training only.Main Outcome Measures:Data were collected on the respiratory function, muscle activity, and shooting record before and after the 6-week intervention.Results:The forced vital capacity (FVC), forced expired volume in 1 second (FEV1), FEV1as a percentage of FVC, peak expiratory flow, and maximum voluntary ventilation were significantly increased in the EG, and FEV1as a percentage of FVC was significantly increased in the CG (P < .05). The FVC and peak expiratory flow postintervention were significantly different between the groups (P < .05). The activity of the right internal oblique (IO) and left IO muscles of the FVC were significantly different in the EG (P < .05). Within-group changes in right external oblique, right IO, and left IO of the maximum voluntary ventilation were significantly increased in the EG (P < .05). The right IO and left IO activity improved more significantly in the EG than CG (P < .05). There was no difference between the groups with respect to the shooting records.Conclusions:The clinical significance of this study is the balance and respiration training affected the respiration function capacity and muscle activity, but did not affect the shooting record. Nevertheless, these training are a potential approach method to improve athletes’ shooting record.
Reliability and Validity of Tethered Swimming Lactate Minimum Test and Their Relationship With Performance in Young Swimmers
Authors: Kalva-Filho Carlos Augusto , Toubekis Argyris , Zagatto Alessandro Moura , Silva Adelino Sanchez Ramos da , Loures João Paulo , Campos Eduardo Zapaterra , Papoti Marcelo 
Published: March 2018

Purpose: To test the reliability and validity of tethered swimming lactate minimum test in young swimmers. Methods: Lactate minimum test was performed twice to test the reliability (experiment 1; n = 13). In addition, the validity was investigated through lactate minimum test relationships with tethered swimming lactate threshold and peak force obtained during graded exercise test (experiment 2; n = 11). Finally, the correlations with mean speeds observed during 200-m (s200m) and 30-minute continuous efforts (s30min) were also analyzed (experiment 3; n = 15). In all experiments, the lactate minimum test began with 3-minute all-out effort to induce lactatemia, followed by an exhaustive graded exercise test. Results: The lactate minimum intensity and mean force during the entire 3-minute all-out effort (MF) showed high reliability (coefficient of variation < 8.9% and intraclass correlation coefficient > .93). The lactate minimum intensity was not different compared with lactate threshold (P = .22), presenting high correlations (r = .92) and agreement (95% limits of agreement = ±7.9 N). The mean force during the entire 3-minute all-out effort was similar to peak force obtained during graded exercise test (P = .41), presenting significant correlations (r = .88) and high indices of agreement (95% limits of agreement = ±11.3 N). In addition, lactate minimum test parameters correlated both with mean speeds observed during 200-m (r > .74) and 30-minute continuous efforts (r > .70). Conclusion: Thus, tethered swimming lactate minimum test can be used for training recommendations and to monitor aerobic adaptations in young swimmers.
Dextromethorphan Attenuates NADPH Oxidase-Regulated Glycogen Synthase Kinase 3β and NF-κB Activation and Reduces Nitric Oxide Production in Group A Streptococcal Infection
Authors: Chen Chia-Ling , Cheng Miao-Huei , Kuo Chih-Feng , Cheng Yi-Lin , Li Ming-Han , Chang Chih-Peng , Wu Jiunn-Jong , Anderson Robert , Wang Shuying , Tsai Pei-Jane , Liu Ching-Chuan , Lin Yee-Shin 
Published: March 2018

ABSTRACT

Group A
Streptococcus
(GAS) is an important human pathogen that causes a wide spectrum of diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), an antitussive drug, has been demonstrated to efficiently reduce inflammatory responses, thereby contributing to an increased survival rate of GAS-infected mice. However, the anti-inflammatory mechanisms underlying DM treatment in GAS infection remain unclear. DM is known to exert neuroprotective effects through an NADPH oxidase-dependent regulated process. In the present study, membrane translocation of NADPH oxidase subunit p47
phox
and subsequent reactive oxygen species (ROS) generation induced by GAS infection were significantly inhibited via DM treatment in RAW264.7 murine macrophage cells. Further determination of proinflammatory mediators revealed that DM effectively suppressed inducible nitric oxide synthase (iNOS) expression and NO, tumor necrosis factor alpha, and interleukin-6 generation in GAS-infected RAW264.7 cells as well as in air-pouch-infiltrating cells from GAS/DM-treated mice. GAS infection caused AKT dephosphorylation, glycogen synthase kinase-3β (GSK-3β) activation, and subsequent NF-κB nuclear translocation, which were also markedly inhibited by treatment with DM and an NADPH oxidase inhibitor, diphenylene iodonium. These results suggest that DM attenuates GAS infection-induced overactive inflammation by inhibiting NADPH oxidase-mediated ROS production that leads to downregulation of the GSK-3β/NF-κB/NO signaling pathway.
Catabolism of 2-Hydroxypyridine by Burkholderia sp. Strain MAK1: a 2-Hydroxypyridine 5-Monooxygenase Encoded by
hpdABCDE
Catalyzes the First Step of Biodegradation
Authors: Petkevičius Vytautas , Vaitekūnas Justas , Stankevičiūtė Jonita , Gasparavičiūtė Renata , Meškys Rolandas 
Published: March 2018

ABSTRACT

Microbial degradation of 2-hydroxypyridine usually results in the formation of a blue pigment (nicotine blue). In contrast, the
Burkholderia
sp. strain MAK1 bacterium utilizes 2-hydroxypyridine without the accumulation of nicotine blue. This scarcely investigated degradation pathway presumably employs 2-hydroxypyridine 5-monooxygenase, an elusive enzyme that has been hypothesized but has yet to be identified or characterized. The isolation of the mutant strain
Burkholderia
sp. MAK1 ΔP5 that is unable to utilize 2-hydroxypyridine has led to the identification of a gene cluster (designated
hpd
) which is responsible for the degradation of 2-hydroxypyridine. The activity of 2-hydroxypyridine 5-monooxygenase has been assigned to a soluble diiron monooxygenase (SDIMO) encoded by a five-gene cluster (
hpdA
,
hpdB
,
hpdC
,
hpdD
, and
hpdE
). A 4.5-kb DNA fragment containing all five genes has been successfully expressed in
Burkholderia
sp. MAK1 ΔP5 cells. We have proved that the recombinant HpdABCDE protein catalyzes the enzymatic turnover of 2-hydroxypyridine to 2,5-dihydroxypyridine. Moreover, we have confirmed that emerging 2,5-dihydroxypyridine is a substrate for HpdF, an enzyme similar to 2,5-dihydroxypyridine 5,6-dioxygenases that are involved in the catabolic pathways of nicotine and nicotinic acid. The proteins and genes identified in this study have allowed the identification of a novel degradation pathway of 2-hydroxypyridine. Our results provide a better understanding of the biodegradation of pyridine derivatives in nature. Also, the discovered 2-hydroxypyridine 5-monooxygenase may be an attractive catalyst for the regioselective synthesis of various
N
-heterocyclic compounds.

IMPORTANCE
The degradation pathway of 2-hydroxypyridine without the accumulation of a blue pigment is relatively unexplored, as, to our knowledge, no genetic data related to this process have ever been presented. In this paper, we describe genes and enzymes involved in this little-studied catabolic pathway. This work provides new insights into the metabolism of 2-hydroxypyridine in nature. A broad-range substrate specificity of 2-hydroxypyridine 5-monooxygenase, a key enzyme in the degradation, makes this biocatalyst attractive for the regioselective hydroxylation of pyridine derivatives.