bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecule chemokine mimetics suggest a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3
Authors: Nedjai Belinda , Li Hubert , Stroke Ilana L , Wise Emma L , Webb Maria L , Merritt J Robert , Henderson Ian , Klon Anthony E , Cole Andrew G , Horuk Richard , Vaidehi Nagarajan , Pease James E 
Published: September 2011

BACKGROUND AND PURPOSEThe chemokine receptor CXCR3 directs migration of T‐cells in response to the ligands CXCL9/Mig, CXCL10/IP‐10 and CXCL11/I‐TAC. Both ligands and receptors are implicated in the pathogenesis of inflammatory disorders, including atherosclerosis and rheumatoid arthritis. Here, we describe the molecular mechanism by which two synthetic small molecule agonists activate CXCR3.EXPERIMENTAL APPROACHAs both small molecules are basic, we hypothesized that they formed electrostatic interactions with acidic residues within CXCR3. Nine point mutants of CXCR3 were generated in which an acidic residue was mutated to its amide counterpart. Following transient expression, the ability of the constructs to bind and signal in response to natural and synthetic ligands was examined.KEY RESULTSThe CXCR3 mutants D112N, D195N and E196Q were efficiently expressed and responsive in chemotaxis assays to CXCL11 but not to CXCL10 or to either of the synthetic agonists, confirmed with radioligand binding assays. Molecular modelling of both CXCL10 and CXCR3 suggests that the small molecule agonists mimic a region of the ‘30s loop’ (residues 30–40 of CXCL10) which interacts with the intrahelical CXCR3 residue D112, leading to receptor activation. D195 and E196 are located in the second extracellular loop and form putative intramolecular salt bridges required for a CXCR3 conformation that recognizes CXCL10. In contrast, CXCL11 recognition by CXCR3 is largely independent of these residues.CONCLUSION AND IMPLICATIONSWe provide here a molecular basis for the observation that CXCL10 and CXCL11 are allosteric ligands of CXCR3. Such findings may have implications for the design of CXCR3 antagonists.LINKED ARTICLEThis article is commented on by O'Boyle, pp. 895–897 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2011.01759.x
Functional selectivity of central Gα‐subunit proteins in mediating the cardiovascular and renal excretory responses evoked by central α2‐adrenoceptor activation in vivo
Authors: Wainford RD , Kapusta DR 
Published: September 2011

BACKGROUND AND PURPOSE Activation of brain α2‐adrenoceptors in conscious rodents decreases heart rate (HR) and mean arterial blood pressure (MAP) and increases urine output and urinary sodium excretion. In vitro, α2‐adrenoceptor stimulation activates Gαi(1–3), Gαo and Gαs‐subunit protein‐gated signal transduction pathways. Here we have investigated whether these same Gα‐subunit protein‐gated pathways mediate the cardiovascular and renal excretory responses to central α2‐adrenoceptor activation in conscious Sprague‐Dawley rats.EXPERIMENTAL APPROACH Rats were pre‐treated by intracerebroventricular injection (i.c.v.) with an oligodeoxynucleotide (ODN) targeted to a Gαi1, Gαi2, Gαi3, Gαo, Gαs or a scrambled (SCR) ODN sequence (25 µg, 24 h). On the day of study, the α2‐adrenoceptor agonist guanabenz (50 µg) or saline vehicle, was injected i.c.v. into ODN‐pre‐treated conscious rats. MAP and HR were recorded, and urine was collected for 150 min.KEY RESULTS In vehicle‐ and SCR ODN‐pre‐treated rats, i.c.v. guanabenz decreased MAP and HR, and produced marked diuretic and natriuretic responses. Selective ODN‐mediated down‐regulation of brain Gαi2‐subunit proteins abolished the central guanabenz‐induced hypotension and natriuresis. In contrast, following selective Gαs down‐regulation, the characteristic hypotensive response to i.c.v. guanabenz was converted to an immediate increase in MAP. The bradycardic and diuretic responses to i.c.v. guanabenz were not blocked by pre‐treatment with any ODN.CONCLUSIONS AND IMPLICATIONS There was functional selectivity of Gαi2 and Gαs subunit protein‐gated signal transduction pathways in mediating the hypotensive and natriuretic, but not bradycardic or diuretic, responses evoked by central α2‐adrenoceptor activation in vivo.
The Biometric Measurement of Alcohol Consumption
Authors: Snell Lawrence D. , Ramchandani Vijay A. , Saba Laura , Herion David , Heilig Markus , George David T. , Pridzun Lutz , Helander Anders , Schwandt Melanie L. , Phillips Monte J. , Hoffman Paula L. , Tabakoff Boris ,   and the WHO/ISBRA Study on State and Trait Markers of Alcohol Use and Dependence Investigators
Published: September 2011

Background:  Proper ascertainment of the history of alcohol consumption by an individual is an important component of medical diagnosis of disease and influences the implementation of appropriate treatment strategies that include prescription of medication, as well as intervention for the negative physical and social consequences of hazardous/harmful levels of alcohol consumption. Biological (biometric) diagnostic tests that provide information on current and past quantity and frequency of alcohol consumption by an individual, prior to onset of organ damage, continue to be sought.
Methods:  Platelet monoamine oxidase B (MAO‐B) protein was quantitated in 2 populations of subjects who had histories of different levels of alcohol consumption. Levels were assayed by immunoblotting or by ELISA. The development and evaluation of the new ELISA‐based measure of platelet MAO‐B protein levels is described.
Results:  One subject population constituted a nontreatment‐seeking, cross‐sectional subject sample, and the other population was a longitudinally followed, hospitalized group of subjects. An algorithm combining measures of platelet MAO‐B protein with the plasma levels of carbohydrate‐deficient transferrin (CDT) and with liver enzymes (aspartate aminotransferase or γ‐glutamyltransferase [GGT]) can detect hazardous/harmful alcohol use (HHAU) with the highest sensitivity and specificity in the cross‐sectional nontreatment‐seeking population. In the treatment‐seeking population, low MAO‐B protein levels at admission are associated with heavy drinking prior to admission, and these protein levels increase over a period of abstinence from alcohol.
Conclusions:  The platelet MAO‐B protein measurement is particularly effective for male alcohol consumers. The combined use of MAO‐B protein measures together with measures of CDT and GGT does, however, improve the diagnostic utility of both markers for ascertaining HHAU in women. Furthermore, measurement of changes in platelet MAO‐B protein levels during treatment for alcohol dependence may help monitor the success of the treatment program.
Reward and Relapse: Complete Gene‐Induced Dissociation in an Animal Model of Alcohol Dependence
Authors: Quintanilla María E. , Tampier Lutske , Karahanian Eduardo , Rivera‐Meza Mario , Herrera‐Marschitz Mario , Israel Yedy 
Published: September 2011

Background:  In animal models of continuous alcohol self‐administration, in which physical dependence does not constitute the major factor of ethanol intake, 2 factors likely contribute to the perpetuation of alcohol self‐administration: (i) the rewarding effects of ethanol and (ii) the contextual conditioning cues that exist along with the process of self‐administration. Present studies are aimed at understanding the relative contribution of these factors on the perpetuation of heavy alcohol self‐administration, as an indication of relapse.
Methods:  Wistar‐derived UChB high ethanol drinker rats were allowed access to 10% ethanol and water on a 24‐hour basis. In initial studies, an anticatalase shRNA gene‐coding lentiviral vector aimed at inhibiting acetaldehyde generation was administered into the ventral tegmental area (VTA) of the animals prior to ethanol access. In subsequent studies, the lentiviral vector was administered to animals, which had consumed ethanol on a 24‐hour basis, or a 1‐hour basis, after the animals had reached high levels of ethanol intake for 60 to 80 days. In final studies, quinine (0.01%) was added to the ethanol solution to alter the conditioning taste/smell cues of alcohol that animals had chronically ingested.
Results:  Data indicate that the administration of an anticatalase vector into the VTA of naïve animals blocked reward and alcohol self‐administration, while it was, nevertheless, inactive in inhibiting alcohol self‐administration in rats that had been conditioned to ingest ethanol for over 2 months. The lack of inhibitory effect of the anticatalase vector on ethanol intake in animals that had chronically self‐administered ethanol was fully reversed when the contextual conditioning cues of the alcohol solution were changed.
Conclusions:  Data highlight the importance of conditioning factors in relapse and suggest that only abolishing or blunting it, along with long‐lasting pharmacological treatment to reduce ethanol reward, may have protracted effects in reducing alcohol self‐administration.
Corticotropin‐Releasing Factor Acting on Corticotropin‐Releasing Factor Receptor Type 1 is Critical for Binge Alcohol Drinking in Mice
Authors: Kaur Simranjit , Li Ju , Stenzel‐Poore Mary P. , Ryabinin Andrey E. 
Published: September 2011

Background:  The corticotropin‐releasing factor (CRF) system has been implicated in the regulation of alcohol consumption. However, previous mouse knockout (KO) studies using continuous ethanol access have failed to conclusively confirm this. Recent studies have shown that CRF receptor type 1 (CRFR1) antagonists attenuate alcohol intake in the limited access “drinking in the dark” (DID) model of binge drinking. To avoid the potential nonspecific effects of antagonists, in this study, we tested alcohol drinking in CRFR1, CRFR2, CRF, and urocortin 1 (Ucn1) KO and corresponding wild‐type (WT) littermates using the DID paradigm.
Methods:  On days 1 to 3, the CRFR1, CRFR2, Ucn1, and CRF KO mice and their respective WT littermates were provided with 20% ethanol or 10% sucrose for 2 hours with water available at all other times. On day 4, access to ethanol or sucrose was increased to 4 hours. At the end of each drinking session, the volume of ethanol consumed was recorded, and at the conclusion of the last session, blood was also collected for blood ethanol concentration (BEC) analysis.
Results:  CRFR1 KO mice had lower alcohol intakes and BECs and higher intakes of sucrose compared with WTs. In contrast, CRFR2 KO mice, while having reduced intakes initially, had similar alcohol intakes on days 2 to 4 and similar BECs as the WTs. To determine the ligand responsible, Ucn1 and CRF KO and WT mice were tested next. While Ucn1 KOs had similar alcohol intakes and BECs to their WTs, CRF KO mice showed reduced alcohol consumption and lower BECs compared with WTs.
Conclusions:  Our results confirm that CRFR1 plays a key role in binge drinking and identify CRF as the ligand critically involved in excessive alcohol consumption.
Alcohol Dehydrogenase‐1B Arg47His Polymorphism and Upper Aerodigestive Tract Cancer Risk: A Meta‐Analysis Including 24,252 Subjects
Authors: Guo Haipeng , Zhang Guohong , Mai Ruiqin 
Published: September 2011

Background:  Cancers of the upper aerodigestive tract (UADT) include malignant tumors of the oral cavity, pharynx, larynx, and esophagus, account for approximately 4% of all new cancers in world. Alcohol drinking is an established risk factor for UADT cancers, and the rate of alcohol metabolism could significantly been influenced by genetic polymorphisms of alcohol dehydrogenase‐1B (ADH1B) His47Arg (rs1229984). To evaluate whether combined evidence shows ADH1B His47Arg as a common genetic variant that influenced the risk of UADT cancers, we considered all available studies in a meta‐analysis.
Methods:  Eighteen studies were combined representing data of 8,539 cases and 15,713 controls for meta‐analysis. Stratified analyses were carried out to determine the gene–environment interaction between ADH1B His47Arg and alcohol drinking and gene–gene interaction between ADH1B His47Arg and aldehyde dehydrogenase‐2 (ALDH2) Glu/Lys related to UADT cancer risk. Potential sources of heterogeneity between studies were explored; sensitivity analysis and publication bias was also evaluated.
Results:  The ADH1B 47Arg allele was found to be associated with increased risk of UADT cancers, the pooled odds ratios (ORs) being 1.66 (95% CI: 1.54 to 1.79) and 3.47 (95% CI: 2.76 to 4.36) for the His/Arg and Arg/Arg genotypes compared with the His/His genotype, respectively. An 18.48‐fold increase in OR (95% CI: 12.95 to 26.40) for UADT cancers among alcohol drinkers with Arg/Arg genotype was found, when compared among nondrinkers with the His/His genotype. Significant interaction between carriers with ADH1B 47Arg and ALDH2 487Lys allele related to risk for UADT cancers was more evident, compared with noncarriers (OR = 10.31, 95% CI: 5.45 to 18.85).
Conclusions:  ADH1B 47Arg allele is a common genetic variant that increased the risk of UADT cancers; furthermore, it modulates the susceptibility to UADT cancers coupled with alcohol drinking and interaction with the ALDH2 487Lys allele.
GABAA Receptor Modulation During Adolescence Alters Adult Ethanol Intake and Preference in Rats
Authors: Hulin Mary W. , Amato Russell J. , Winsauer Peter J. 
Published: September 2011

Background:  To address the hypothesis that GABAA receptor modulation during adolescence may alter the abuse liability of ethanol during adulthood, the effects of adolescent administration of both a positive and negative GABAA receptor modulator on adult alcohol intake and preference were assessed.
Methods:  Three groups of adolescent male rats received 12 injections of lorazepam (3.2 mg/kg), dehydroepiandrosterone (DHEA, 56 mg/kg), or vehicle on alternate days starting on postnatal day (PD) 35. After this time, the doses were increased to 5.6 and 100 mg/kg, respectively, for 3 more injections on alternate days. Subjects had access to 25 to 30 g of food daily, during the period of the first 6 injections, and 18 to 20 g thereafter. Food intake of each group was measured 60 minutes after food presentation, which occurred immediately after drug administration on injection days or at the same time of day on noninjection days. When subjects reached adulthood (PD 88), ethanol preference was determined on 2 separate occasions, an initial 3‐day period and a 12‐day period, in which increasing concentrations of ethanol were presented. During each preference test, intake of water, saccharin, and an ethanol/saccharin solution was measured after each 23‐hour access period.
Results:  During adolescence, lorazepam increased 60‐minute food intake, and this effect was enhanced under the more restrictive feeding schedule. DHEA had the opposite effect on injection days, decreasing food intake compared with noninjection days. In adulthood, the lorazepam‐treated group preferred the 2 lowest concentrations of ethanol/saccharin more than saccharin alone compared with vehicle‐treated subjects, which showed no preference for any concentration of ethanol/saccharin over saccharin. DHEA‐treated subjects showed no preference among the 3 solutions.
Conclusions:  These data demonstrate that GABAA receptor modulation during adolescence can alter intake and preference for ethanol in adulthood and highlights the importance of drug history as an important variable in the liability for alcohol abuse.
Mineral Carbonation as the Core of an Industrial Symbiosis for Energy‐Intensive Minerals Conversion
Authors: Brent Geoffrey F. , Allen Daniel J. , Eichler Brent R. , Petrie James G. , Mann Jason P. , Haynes Brian S. 
Published: September 2011

SummaryThe longer term sustainability of the minerals sector may hinge, in large part, on finding innovative solutions to the challenges of energy intensity and carbon dioxide (CO2) management. This article outlines the need for large‐scale “carbon solutions” that might be shared by several colocated energy‐intensive and carbon‐intensive industries. In particular, it explores the potential for situating a mineral carbonation plant as a carbon sink at the heart of a minerals and energy complex to form an industrial symbiosis. Several resource‐intensive industries can be integrated synergistically in this way, to enable a complex that produces energy and mineral products with low net CO2 emissions. An illustrative hypothetical case study of such a system within New South Wales, Australia, has been constructed, on the basis of material and energy flows derived from Aspen modeling of a serpentine carbonation process. The synergies and added value created have the potential to significantly offset the energy and emission penalties and direct costs of CO2 capture and storage. This suggests that greenfield minerals beneficiation and metals refining plants should consider closer integration with the power production and energy provision plants on which they depend, together with a carbon solution, such as mineral carbonation, as a critical element of such integration. Other sustainability considerations are highlighted.
Simon Patten on Public Infrastructure and Economic Rent Capture
Authors: HUDSON MICHAEL 
Published: September 2011

AbstractReflecting the Progressive Era's reform agenda Simon Patten (1852–1922) argued that freeing markets from one source of economic rent (by taxing land rent) would merely leave the surplus to be taken by other monopolists and rent extractors (railroads, Wall Street trusts, and basic privatized utilities). To prevent unearned income (economic rent) from adding to the economy's cost of living and doing business, potentially rent‐yielding infrastructure should be kept in the public domain as a “fourth factor of production.” Instead of rentiers making a profit by charging access fees and user fees, the return to public investment should take the form of reducing the economy's overall price structure.
Does the Lack of a Profit Motive Affect Hiring in Academe? Evidence from the Market for Lawyers
Authors: PJESKY REX J. , SUTTER DANIEL 
Published: September 2011

AbstractThe comparative performance of academic and economic markets continues to be debated. One factor potentially distinguishing academic markets is the profit motive. Profit and competition have been shown to curb discrimination in markets, and the absence of profit discipline could result in myriad forms of prejudice in academic hiring. We explore the role of the profit motive in the performance of academic markets by comparing the pedigree of employees of top law schools and top law firms. Top law schools are much more likely to employ graduates of top ranked law schools than elite law firms, and the difference exists at both the junior and senior levels. We find no evidence that the graduates of top 5 law schools outperform grads of less prestigious schools in publications or citations. In the absence of a profit motive, academic hiring appears more likely to indulge a preference for pedigree, and by implication, this may explain other scholarly prejudices in the academy.
Perspective: Physiological Role(s) of the Vascular Myogenic Response
Authors: DAVIS MICHAEL J. 
Published: September 2011

Please cite this paper as: Davis MJ. Perspective: Physiological Role(s) of the Vascular Myogenic Response. Microcirculation 19: 99–114, 2012.AbstractThe vascular myogenic response is an inherent property of VSM in the walls of small arteries and arterioles, allowing these principal resistance segments of the microcirculation to respond to changes in transmural pressure. Elevated intraluminal pressure leads to myogenic constriction, whereas reduced pressure leads to myogenic dilation. This review focuses on the physiological significance of the myogenic response in microvascular networks. First, historical concepts related to the detection of stretch by the vessel wall are reviewed, including the wall tension hypothesis, and the implications of the proposal that the arteriolar network responds to Pp changes as a system of series‐coupled myogenic effectors. Next, the role of the myogenic response in the local regulation of blood flow and/or Pc is examined. Finally, the interaction of myogenic constriction and dilation with other local control mechanisms, including metabolic, neural and shear‐dependent mechanisms, is discussed. Throughout the review, an attempt is made to integrate historical and current literature with an emphasis on the physiological role, rather than the underlying signaling mechanisms, of this important component of vascular control.
Hormonal response to restraint in rhesus monkeys
Authors: Gauquelin‐Koch Guillemette , Blanquie Jean‐Pierre , Viso Michel , Florence Geneviòve , Milhaud Claude , Gharib Claude 
Published: September 2011

Abstract: The purpose of this study was to characterize the hormonal responses to a restraining system in four adult male rhesus monkeys (Macaca mulatta) in preparation for a spaceflight project. After the monkeys were accustomed to food and water (Phase I), blood‐volume‐regulating hormones were measured during three phases: 10 days in a metabolic cage (Phase II), 16 days sitting in a restrained position in a specially designed metabolism chair (Phase III) and 10 days in metabolic cage (Phase IV). An increase of active renin (30%) and vasopressin (25%) was observed at the end of Phase III. A decrease of atrial natriuretic peptide (ANP), urodilatin, and sodium excretion occurred during the first days of Phase III. Catecholamines were unchanged. A dramatic increase (tenfold) in urinary excretion of growth hormone occurred during all of Phase III and at the beginning of Phase IV.These findings are similar to those found in man during isolation inactivity and during confinement stress.
Tumors of the respiratory tract observed at the German Primate Center, 1978–1994
Authors: Brack Manfred , Schwartz Peter , Heinrichs Till , Schultz Michael , Fuchs Eberhard 
Published: September 2011

Abstract: Eight spontaneous pulmonary tumors (four bronchiolar tubular adenomas, two bronchiolar adenocarcinomas, two squamous‐cell carcinomas) occurred in a total of 54 adult tree shrews (Tupaia belangeri) of the GPC colonies between 1978 and 1994. The adenomas and adenocarcinomas consisted of tubularly or trabecularly arranged cuboidal to cylindrical cells interspersed with some PAS‐positive goblet cells, thus resembling the epithelial lining of respiratory bronchioles of tree shrews. The two squamous‐cell carcinomas probably originated from the pulmonary alveoles.Three more pulmonary tumors (one small‐cell carcinoma, one bronchial adenoma, one squamous‐cell carcinoma) developed in 409 adult callitrichids of the GPC colonies during the same period, and one more bronchial adenoma was observed in a common marmoset (Callithrix jacchus) of another colony located in Göttingen. With regard to the adenomas and squamous‐cell carcinomas, a similar cellular origin with the tree shrews is assumed. The small‐cell carcinoma possibly developed from the bronchial epithelium, provided a pathogenesis parallel to that of human small‐cell carcinoma is suggested.Four of the tree shrew pulmonary adenomas/adenocarcinomas and the small‐cell Ca were macroscopically visible as yellowish‐grey nodules of 1 mm × 1 mm to 15 mm × 15 mm diameter, predominantly involving the main lobes (2 × right main lobes, 2 × left main lobes, 1 × all lobes). The pulmonary tumors of the other animals were below macroscopical detectability.