bluuebunny/crossref_metadata_2025_split huggingface dataset:
Suppression of cell membrane permeability by suramin: involvement of its inhibitory actions on connexin 43 hemichannels
Authors: Chi Yuan , Gao Kun , Zhang Hui , Takeda Masayuki , Yao Jian 
Published: March 2014

Background and PurposeSuramin is a clinically prescribed drug for treatment of human African trypanosomiasis, cancer and infection. It is also a well‐known pharmacological antagonist of P2 purinoceptors. Despite its clinical use and use in research, the biological actions of this molecule are still incompletely understood. Here, we investigated the effects of suramin on membrane channels, as exemplified by its actions on non‐junctional connexin43 (Cx43) hemichannels, pore‐forming α‐haemolysin and channels involved in ATP release under hypotonic conditions.Experimental ApproachHemichannels were activated by removing extracellular Ca2+. The influences of suramin on hemichannel activities were evaluated by its effects on influx of fluorescent dyes and efflux of ATP. The membrane permeability and integrity were assessed through cellular retention of preloaded calcein and LDH release.Key ResultsSuramin blocked Cx43 hemichannel permeability induced by removal of extracellular Ca2+ without much effect on Cx43 expression and gap junctional intercellular communication. This action of suramin was mimicked by its analogue NF023 and NF449 but not by another P2 purinoceptor antagonist PPADS. Besides hemichannels, suramin also significantly blocked intracellular and extracellular exchanges of small molecules caused by α‐haemolysin from Staphylococcus aureus and by exposure of cells to hypotonic solution. Furthermore, it prevented α‐haemolysin‐ and hypotonic stress‐elicited cell injury.Conclusion and ImplicationsSuramin blocked membrane channels and protected cells against toxin‐ and hypotonic stress‐elicited injury. Our finding provides novel mechanistic insights into the pharmacological actions of suramin. Suramin might be therapeutically exploited to protect membrane integrity under certain pathological situations.
Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis
Authors: Baliga R S , Scotton C J , Trinder S L , Chambers R C , MacAllister R J , Hobbs A J 
Published: March 2014

Background and PurposeIdiopathic pulmonary fibrosis (IPF) is a progressive fibro‐proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti‐fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life‐threatening disorder.Experimental ApproachPulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild‐type (WT) and natriuretic peptide receptor (NPR)‐A knockout (KO) mice exposed to bleomycin (1 mg·kg−1). Human myofibroblast differentiation was studied in vitro.Key ResultsExacerbated cardiac, vascular and fibrotic pathology was observed in NPR‐A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide‐dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR‐A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ‐induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.Conclusions and ImplicationsThese data highlight an endogenous host‐defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.
Analgesic synergy between opioid and α2‐adrenoceptors
Authors: Chabot‐Doré A‐J , Schuster D J , Stone L S , Wilcox G L 
Published: March 2014

Opioid and α2‐adrenoceptor agonists are potent analgesic drugs and their analgesic effects can synergize when co‐administered. These supra‐additive interactions are potentially beneficial clinically; by increasing efficacy and/or reducing the total drug required to produce sufficient pain relief, undesired side effects can be minimized. However, combination therapies of opioids and α2‐adrenoceptor agonists remain underutilized clinically, in spite of a large body of preclinical evidence describing their synergistic interaction. One possible obstacle to the translation of preclinical findings to clinical applications is a lack of understanding of the mechanisms underlying the synergistic interactions between these two drug classes. In this review, we provide a detailed overview of the interactions between different opioid and α2‐adrenoceptor agonist combinations in preclinical studies. These studies have identified the spinal cord as an important site of action of synergistic interactions, provided insights into which receptors mediate these interactions and explored downstream signalling events enabling synergy. It is now well documented that the activation of both μ and δ opioid receptors can produce synergy with α2‐adrenoceptor agonists and that α2‐adrenoceptor agonists can mediate synergy through either the α2A or the α2C adrenoceptor subtypes. Current hypotheses surrounding the cellular mechanisms mediating opioid–adrenoceptor synergy, including PKC signalling and receptor oligomerization, and the evidence supporting them are presented. Finally, the implications of these findings for clinical applications and drug discovery are discussed.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
In vivo profiling of seven common opioids for antinociception, constipation and respiratory depression: no two opioids have the same profile
Authors: Kuo A , Wyse B D , Meutermans W , Smith M T 
Published: March 2014

Background and PurposeFor patients experiencing inadequate analgesia and intolerable opioid‐related side effects on one strong opioid analgesic, pain relief with acceptable tolerability is often achieved by rotation to a second strong opioid. These observations suggest subtle pharmacodynamic differences between opioids in vivo. This study in rats was designed to assess differences between opioids in their in vivo profiles.Experimental ApproachMale Sprague Dawley rats were given single i.c.v. bolus doses of morphine, morphine‐6‐glucuronide (M6G), fentanyl, oxycodone, buprenorphine, DPDPE ([D‐penicillamine2,5]‐enkephalin) or U69,593. Antinociception, constipation and respiratory depression were assessed using the warm water tail‐flick test, the castor oil‐induced diarrhoea test and whole body plethysmography respectively.Key ResultsThese opioid agonists produced dose‐dependent antinociception, constipation and respiratory depression. For antinociception, morphine, fentanyl and oxycodone were full agonists, buprenorphine and M6G were partial agonists, whereas DPDPE and U69,593 had low potency. For constipation, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, morphine produced a bell‐shaped dose–response curve, whereas DPDPE and U69,593 were inactive. For respiratory depression, morphine, M6G, fentanyl and buprenorphine were full agonists, oxycodone was a partial agonist, whereas DPDPE and U69,593 were inactive. The respiratory depressant effects of fentanyl and oxycodone were of short duration, whereas morphine, M6G and buprenorphine evoked prolonged respiratory depression.Conclusion and ImplicationsFor the seven opioids we assessed, no two had the same profile for evoking antinociception, constipation and respiratory depression, suggesting that these effects are differentially regulated. Our findings may explain the clinical success of ‘opioid rotation’.Linked ArticlesThis article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2
Discovery and Structure Optimization of a Series of Isatin Derivatives as Mycobacterium tuberculosis Chorismate Mutase Inhibitors
Authors: Jeankumar Variam U. , Alokam Reshma , Sridevi Jonnalagadda P. , Suryadevara Priyanka , Matikonda Siddharth S. , Peddi Santosh , Sahithi Seedarala , Alvala Mallika , Yogeeswari Perumal , Sriram Dharmarajan 
Published: March 2014

In this study, the crystal structure of the Mycobacterium tuberculosis (MTB) enzyme chorismate mutase (CM) bound to transition state analogue (PDB: 2FP2) was used as a framework for virtual screening of the BITS‐Pilani in‐house database (2500 compounds) to identify new scaffold. We identified isatin as novel small molecule MTB CM inhibitors; further twenty‐four isatin derivatives were synthesized and evaluated in vitro for their ability to inhibit MTB CM, and activity against M. tuberculosis as steps towards the derivation of structure–activity relationships (SAR) and lead optimization. Compound 3‐(4‐nitrobenzylidene)indolin‐2‐one, 24 emerged as the most promising lead with an IC50 of 1.01 ± 0.22 μm for purified CM and MIC of 23.5 μm for M. tuberculosis, with little or no cytotoxicity.
Invisible Losses and the Logics of Resettlement Compensation
Authors: WITTER REBECCA , SATTERFIELD TERRE 
Published: March 2014

AbstractThe necessity of compensating people negatively affected by conservation and other development projects has been widely acknowledged. It is less widely acknowledged that because conventional compensation assessments focus on material resources and their economic equivalents, many important losses incurred by resettlers are invisible to project authorities. Through ethnographic observations and interviews, we documented losses identified by people facing resettlement from Mozambique's Limpopo National Park. We also examined resettlement planning documents to determine why decision makers’ assessments of natural resource use and value neglect losses residents identified as critical. Identifying, preventing, and mitigating invisible losses in resettlement planning necessitates a better understanding of intangible benefits residents derive from resources, which are often as or more important than their readily apparent material properties. These benefits include but are not limited to decision‐making authority linked to owning land versus having the use of fields; ancestral identity and social belonging linked to gravesites; the importance of tree roots that provide a powerful sense of security because they suppress hunger in periods of scarcity; and the importance of people's location within social networks and hierarchies as they determine the benefits versus risks that will be incurred through resettlement.Pérdidas Invisibles y la Lógica de la Compensación de Repoblación
The extent of inflammation is a predictor for pouch‐related complications in ileal pouches in patients with ulcerative or indeterminate colitis
Authors: Tan K.‐K. , Ravindran P. , Young C. J. , Solomon M. J. 
Published: March 2014

AbstractAimLimited data are available on the relationship between the histological features of the resected specimens in patients with ulcerative colitis (UC) or indeterminate colitis (IC) and the outcome of restorative proctocolectomy. The aim of our study was to determine if the histological features of the resected specimen in patients with UC and IC can predict ileal‐pouch‐related outcome.MethodA review of all patients who had a restorative proctocolectomy created following completion proctectomy or proctocolectomy for UC and IC was performed.ResultsBetween 1992 and 2011, 142 patients (132 with UC and 10 with IC) were reviewed. After a median follow‐up of 36 (3–149) months, 51 (35.9%) developed a pouch‐related complication. Forty‐two (29.7%) developed pouchitis while three (2.1%) developed a pouch‐cutaneous fistula. Four (2.8%) had pouch failure, while stricture of the anastomosis was seen in three (2.1%) patients. The presence of extension of the inflammation into the muscularis propria of the resected specimen was associated with an increased risk of pouch‐related complications (P = 0.01). The presence of submucosal oedema was also a significant risk factor (P = 0.03).ConclusionThe extension of inflammation into the muscularis propria appears to predict pouch‐related complications following restorative proctocolectomy for UC or IC.
Investigating Constituent Order Change With Elicited Pantomime: A Functional Account of SVO Emergence
Authors: Hall Matthew L. , Ferreira Victor S. , Mayberry Rachel I. 
Published: March 2014

AbstractOne of the most basic functions of human language is to convey who did what to whom. In the world's languages, the order of these three constituents (subject [S], verb [V], and object [O]) is uneven, with SOV and SVO being most common. Recent experiments using experimentally elicited pantomime provide a possible explanation of the prevalence of SOV, but extant explanations for the prevalence of SVO could benefit from further empirical support. Here, we test whether SVO might emerge because (a) SOV is not well suited for describing reversible events (a woman pushing a boy) and (b) pressures to be efficient and mention subjects before objects conspire to rule out many other alternatives. We tested this by asking participants to describe reversible and non‐reversible events in pantomime, and we instructed some participants to be consistent in the form of their gestures and to teach them to the experimenter. These manipulations led to the emergence of SVO in speakers of both English (SVO) and Turkish (SOV).
The impact of childhood emotional abuse on violence among people who inject drugs
Authors: Lake Stephanie , Wood Evan , Dong Huiru , Dobrer Sabina , Montaner Julio , Kerr Thomas 
Published: March 2014

AbstractIntroduction and AimsChildhood emotional abuse is a known risk factor for various poor social and health outcomes. While people who inject drugs (IDU) report high levels of violence, in addition to high rates of childhood maltreatment, the relationship between childhood emotional abuse and later life violence within this population has not been examined.Design and MethodsCross‐sectional data were derived from an open prospective cohort of IDU in Vancouver, Canada. Childhood emotional abuse was measured using the Childhood Trauma Questionnaire. We used multivariate logistic regression to examine potential associations between childhood emotional abuse and being a recent victim or perpetrator of violence.ResultsBetween December 2005 and May 2013, 1437 IDU were eligible for inclusion in this analysis, including 465 (32.4%) women. In total, 689 (48.0%) reported moderate to severe history of childhood emotional abuse, whereas 333 (23.2%) reported being a recent victim of violence and 173 (12.0%) reported being a recent perpetrator of violence. In multivariate analysis, being a victim of violence (adjusted odds ratio = 1.49, 95% confidence interval 1.15–1.94) and being a perpetrator of violence (adjusted odds ratio = 1.58, 95% confidence interval 1.12–2.24) remained independently associated with childhood emotional abuse.Discussion and ConclusionsWe found high rates of childhood emotional abuse and subsequent adult violence among this sample of IDU. Emotional abuse was associated with both victimisation and perpetration of violence. These findings highlight the need for policies and programmes that address both child abuse and historical emotional abuse among adult IDU. [Lake S, Wood E, Dong H, Dobrer S, Montaner J, Kerr T. The impact of childhood emotional abuse on violence among people who inject drugs. Drug Alcohol Rev 2015;34:4–9]
5‐(2‐aminopropyl)indole: A new player in the drama of ‘legal highs’ alerts the community
Authors: Katselou Maria , Papoutsis Ioannis , Nikolaou Panagiota , Spiliopoulou Chara , Athanaselis Sotiris 
Published: March 2014

AbstractIssues5‐(2‐aminopropyl)indole (5‐IT) is a new psychoactive substance, a ‘legal high’, that recently invaded the drug arena in Europe and has already led to numerous intoxications and fatalities. Knowledge upon its pharmacology and toxicity is non‐existent or restricted; the only available information involves very few published scientific articles, official reports from the European Monitoring Centre for Drugs and Drug Addiction and drug abusers' experiences expressed in online drug forums.ApproachA review of the existing knowledge on 5‐IT is reported, concerning its chemistry and synthesis, its pharmacological and toxicological aspects, as well as information concerning the fatal and toxic consequences of its use. The existing methodologies for the determination of 5‐IT in biological and seized samples as well as its legal status are also presented. All the relative data were gathered through a detailed search of PubMed and the Internet.Key FindingsNo original studies have investigated and/or confirmed its pharmacological properties, acute and chronic toxicity, physiological and behavioural effects or the dependence potential of the drug. Thus, it is difficult to specify the physical effects of 5‐IT in humans. This drug is a phenomenon with global significance for public health as its use can lead to intoxication and fatalities.ImplicationsSignificant information on 5‐IT is provided for pharmacologists, toxicologists, forensic pathologists and regulatory authorities.Conclusion5‐IT is a current public health challenge. Better international collaboration, effective legislation and continuous community alertness are needed to tackle this current growing phenomenon. [Katselou M, Papoutsis I, Nikolaou P, Spiliopoulou C, Athanaselis S. 5‐(2‐aminopropyl)indole: A new player in the drama of ‘legal highs’ alerts the community. Drug Alcohol Rev 2015;34:51–57]
Interaction strengths in balanced carbon cycles and the absence of a relation between ecosystem complexity and stability
Authors: Neutel Anje‐Margriet , Thorne Michael A.S. 
Published: March 2014

AbstractThe strength of interactions is crucial to the stability of ecological networks. However, the patterns of interaction strengths in mathematical models of ecosystems have not yet been based upon independent observations of balanced material fluxes. Here we analyse two Antarctic ecosystems for which the interaction strengths are obtained: (1) directly, from independently measured material fluxes, (2) for the complete ecosystem and (3) with a close match between species and ‘trophic groups’. We analyse the role of recycling, predation and competition and find that ecosystem stability can be estimated by the strengths of the shortest positive and negative predator‐prey feedbacks in the network. We show the generality of our explanation with another 21 observed food webs, comparing random‐type parameterisations of interaction strengths with empirical ones. Our results show how functional relationships dominate over average‐network topology. They make clear that the classic complexity‐instability paradox is essentially an artificial interaction‐strength result.
Evolutionary history underlies plant physiological responses to global change since the last glacial maximum
Authors: Becklin Katie M. , Medeiros Juliana S. , Sale Kayla R. , Ward Joy K. 
Published: March 2014

AbstractAssessing family‐ and species‐level variation in physiological responses to global change across geologic time is critical for understanding factors that underlie changes in species distributions and community composition. Here, we used stable carbon isotopes, leaf nitrogen content and stomatal measurements to assess changes in leaf‐level physiology in a mixed conifer community that underwent significant changes in composition since the last glacial maximum (LGM) (21 kyr BP). Our results indicate that most plant taxa decreased stomatal conductance and/or maximum photosynthetic capacity in response to changing conditions since the LGM. However, plant families and species differed in the timing and magnitude of these physiological responses, and responses were more similar within families than within co‐occurring species assemblages. This suggests that adaptation at the level of leaf physiology may not be the main determinant of shifts in community composition, and that plant evolutionary history may drive physiological adaptation to global change over recent geologic time.
Distribution patterns ofPacific halibut (Hippoglossus stenolepis) in relation to environmental variables along the continental shelf waters of theUS WestCoast and southernBritishColumbia
Authors: Sadorus Lauri L. , Mantua Nathan J. , Essington Timothy , Hickey Barbara , Hare Steven 
Published: March 2014

AbstractKnowing howPacific halibut (Hippoglossus stenolepis) distribute in relation to ocean conditions is of primary importance to halibut managers, as they are tasked with estimating stock size and designing effective monitoring programs amidst a changing climate. This research examined near‐bottom environmental data alongside halibut survey catch data for the years 2006–2009 on the continental shelf ofOregon,Washington, and southernBritishColumbia. The objectives of the research were to: (1) characterize summer environmental conditions and halibut distribution; (2) explore ranges and possible tolerance thresholds for halibut in relation to temperature, dissolved oxygen (DO), salinity, andpH; and (3) identify the primary environmental factors affecting distribution of halibut and model the observed relationships. Seasonal hypoxia is an annual feature of the study area and results suggest halibut exhibited an apparentDOminimum threshold of 0.9 mL L−1. Ordinary least squares multiple regression analysis indicated that depth, temperature, andDOwere significant variables in predicting halibut distribution, whereas salinity and bottom type were not. Ambiguity in model results led to the use of two additional analytical methods, geographically weighted regression (GWR) and tree regression, to examine regional variation and the overarching structure of halibut distribution. The three models yielded similar results indicating the importance ofDOand temperature as variables describing structure. TheGWRmodel yielded the best fit of the three when usingDOas a predictor variable, indicating that regional variation is a factor. These results suggest that low, but above‐threshold,DOmay be contributing to catchability differences in the survey.