bluuebunny/crossref_metadata_2025_split huggingface dataset:
Simultaneous determination of MK‐0767 and seven metabolites in rat urine using liquid chromatography/tandem mass spectrometry
Authors: Shen Zhongzhou , Kochansky Christopher , Bakhtiar Ray , Franklin Ronald B. , Vincent Stella H. 
Published: September 2004

AbstractMK‐0767, 5‐[2,4‐dioxothiazolidin‐5‐yl)methyl]‐2‐methoxy‐N‐[[(4‐trifluoromethyl)phenyl]methyl]benzamide (I, Table 1), is a dual peroxisome proliferator‐activated receptor (PPAR) α/γ agonist previously studied for the treatment of type 2 diabetes and dyslipidemia. To support further toxicological studies in one of the animal species used in chronic testing of I, a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method for the simultaneous quantification of I and seven metabolites in rat urine was developed and validated. In this method, urine samples were diluted with acetonitrile/methanol (50:50, v/v) and injected directly onto the column of an LC system. Detection was achieved by MS/MS using a turbo ion spray probe monitoring precursor → product ion combinations in selected reaction monitoring (SRM) mode. The linear range for I and three metabolites was 0.8–800 ng/mL, and 8–8000 ng/mL for four other metabolites found to be present in urine at higher concentrations than I. Intra‐day and inter‐day variation using this method were ≤13.0%. The method exhibited good linearity, reproducibility, specificity and sufficient sensitivity when used for the analysis of rat urine samples. Concentrations of I and its major metabolites in rat urine were determined in samples collected between 0–24 h after dosing on the last day of administration of nine daily oral doses to three male (1000 mg/kg/day) and three female (300 mg/kg/day) Sprague‐Dawley rats. The urinary concentrations of I and its metabolites were similar in male and female rats. The average concentrations of I were 0.51 and 0.33 μg/mL in male and female rats, respectively. Concentrations of four of the seven metabolites quantified were 6‐ to 45‐fold higher than those of I. The most abundant metabolite, with concentrations of 24.2 and 13.3 μg/mL in male and female rat urine, respectively, was a methyl sulfoxide derivative formed by oxidative cleavage of the thiazolidinedione ring, followed by S‐methylation and oxidation of the sulfide intermediate. Copyright © 2004 John Wiley & Sons, Ltd.

Molecular weight (MW), SRM transitions and structures of MK‐0767 (I) and its metabolites
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MS1, MS2, and SQT—three unified, compact, and easily parsed file formats for the storage of shotgun proteomic spectra and identifications
Authors: McDonald W. Hayes , Tabb David L. , Sadygov Rovshan G. , MacCoss Michael J. , Venable John , Graumann Johannes , Johnson Jeff R. , Cociorva Daniel , Yates John R. 
Published: September 2004

AbstractAs the speed with which proteomic labs generate data increases along with the scale of projects they are undertaking, the resulting data storage and data processing problems will continue to challenge computational resources. This is especially true for shotgun proteomic techniques that can generate tens of thousands of spectra per instrument each day. One design factor leading to many of these problems is caused by storing spectra and the database identifications for a given spectrum as individual files. While these problems can be addressed by storing all of the spectra and search results in large relational databases, the infrastructure to implement such a strategy can be beyond the means of academic labs. We report here a series of unified text file formats for storing spectral data (MS1 and MS2) and search results (SQT) that are compact, easily parsed by both machine and humans, and yet flexible enough to be coupled with new algorithms and data‐mining strategies. Copyright © 2004 John Wiley & Sons, Ltd.
Process modeling: A systems engineering tool for analyzing complex systems
Authors: Osmundson John S. , Gottfried Russell , Kum Chee Yang , Boon Lau Hui , Lian Lim Wei , Patrick Poh Seng Wee , Thye Tan Choo 
Published: September 2004

AbstractThis paper presents a method for performing architectural analyses of complex systems‐of‐systems using process modeling. A process is a series of actions undertaken by a system‐of‐systems to produce one or more end results, typically products and services. The method applies to systems‐of systems whose effectiveness and performance depend strongly on process timelines, such as distributed information systems, logistics systems, and manufacturing and distribution systems. A fundamental tool in this method is the development of a unified modeling language (UML) related view of the system‐of‐system processes of interest and the subsequent conversion of the UML related view into an end‐to‐end system‐of‐systems executable object‐oriented simulation model. This method is illustrated by applying process modeling and simulation to analysis of a military systems‐of‐systems, an expeditionary warfare system envisioned for the 2015–2020 time frame. Expeditionary warfare is the operation of an armed force in an area far from a supportable home base and supported by temporarily established means. The U.S. military has conducted expeditionary warfare in the past by building up forces, equipment, and supplies at a beachhead before moving on to an objective. There is current interest in the U.S. military to shift from the concept of establishing a beachhead and then movement to an objective to a concept of sea‐based launching and supporting forces and sea‐to‐objective maneuver for fighting forces. A fundamental tool in this analysis is an end‐to‐end object‐oriented simulation model emulating the full implementation of these force architectures and design factors as well as accounting for the impact of varying levels of operational intensity, attrition of personnel and transport vehicles, weather, mining sea lanes, transport vehicle operating and availability constraints, landing spot constraints, and transit and communications delays. This paper focuses on the framework of the simulation model and its most significant findings as applied to expeditionary warfare concepts as an example of the application of process modeling to architectural analyses of complex systems‐of‐systems. © 2004 Wiley Periodicals, Inc. Syst Eng 7: 320–337, 2004
Opioid analgesia in the newborn
Authors: Nandi R. , Fitzgerald M. 
Published: September 2004

AbstractPain in neonates is now well established. Studies of the developmental neurobiology of pain have revealed that pain processing in the immature is very different from that in the mature nervous system. Neonates undergo considerable maturation of peripheral, spinal and supraspinal afferent pain transmission over the early postnatal period but are able to respond to tissue injury with specific behaviour and with autonomic, hormonal and metabolic signs of stress and distress. Opioid analgesia is now widely used in neonates. There is evidence that morphine requirements may be low in the youngest patients. Sensory threshold testing in rat pups has shown that the analgesic potency of systemic morphine mechanical stimulation is significantly greater in the neonate and declines with postnatal age. The changing morphine sensitivity in the postnatal period may be part of a general reorganisation in the structure and function of primary afferent synapses, neurotransmitter/receptor expression and function and excitatory and inhibitory modulation from higher brain centres. Importantly opioid receptor expression undergoes significant developmental regulation — mu opioid receptors, observed to be exuberantly expressed in the neonatal rat, have been found to be functional. These findings have important implications for the human neonate as they provide a possible explanation for the differences in morphine requirements observed in the youngest patients. The study of the underlying mechanisms of pain and analgesia in development has enabled important changes in clinical practice. However, pain in the newborn remains poorly understood and continued research and intensive study in this area is essential for further effective analgesic intervention and the discovery of new targets for therapy.
Severe acute maternal morbidity in rural South Africa
Authors: Gandhi M.N. , Welz T. , Ronsmans C. 
Published: September 2004

AbstractObjective: Our objective was to identify the frequency, causes, and avoidable factors of severe acute maternal morbidity (SAMM) in four non‐specialist hospitals in rural South Africa. Method: We conducted a prospective audit using criteria for SAMM suited to the diagnostic and treatment facilities available in the primary hospital setting. For each case of SAMM, a local audit team assessed the standard of care against local management guidelines and examined avoidable factors. An external specialist also retrospectively examined avoidable factors. Result The facility‐based incidence of SAMM was 541 cases per 100,000 births (95% CI 368–767). The commonest organ systems involved were cerebral (42%), coagulation (19%), and vascular dysfunctions (16%). The commonest obstetric diagnoses were eclampsia (39%) and obstetric haemorrhage (32%). Approximately 65% of cases were avoidable. Conclusion: A qualitative case review audit of SAMM in a non‐specialist rural setting appears feasible and sustainable, and provides valuable information towards improving deficiencies in maternal care.
Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation
Authors: Costa Barbara , Giagnoni Gabriella , Franke Chiara , Trovato Anna Elisa , Colleoni Mariapia 
Published: September 2004

Cannabidiol (CBD), a nonpsychoactive marijuana constituent, was recently shown as an oral antihyperalgesic compound in a rat model of acute inflammation. We examined whether the CBD antihyperalgesic effect could be mediated by cannabinoid receptor type 1 (CB1) or cannabinoid receptor type 2 (CB2) and/or by transient receptor potential vanilloid type 1 (TRPV1). Rats received CBD (10 mg kg−1) and the selective antagonists: SR141716 (N‐(piperidin‐1‐yl)‐5‐(4‐chlorophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide) for CB1, SR144528 (N‐[(1S)‐endo‐1,3,3‐trimethylbicyclo[2.2.1]heptan‐2‐yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)pyrazole‐3 carboxamide) for CB2 and capsazepine (CPZ) for TRPV1 receptors. The intraplantar injection of carrageenan in rats induced a time‐dependent thermal hyperalgesia, which peaked at 3 h and decreased at the following times. CBD, administered 2 h after carrageenan, abolished the hyperalgesia to the thermal stimulus evaluated by plantar test. Neither SR141716 (0.5 mg kg−1) nor SR144528 (3 and 10 mg kg−1) modified the CBD‐induced antihyperalgesia; CPZ partially at the lowest dose (2 mg kg−1) and fully at the highest dose (10 mg kg−1) reversed this effect. These results demonstrate that TRPV1 receptor could be a molecular target of the CBD antihyperalgesic action.British Journal of Pharmacology (2004) 143, 247–250. doi:10.1038/sj.bjp.0705920
Actions of two naturally occurring saturated N‐acyldopamines on transient receptor potential vanilloid 1 (TRPV1) channels
Authors: De Petrocellis Luciano , Chu Constance J , Moriello Aniello Schiano , Kellner Juliane C , Walker J Michael , Di Marzo Vincenzo 
Published: September 2004

Four long‐chain, linear fatty acid dopamides (N‐acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N‐arachidonoyl‐dopamine (NADA) and N‐oleoyl‐dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N‐palmitoyl‐ and N‐stearoyl‐dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 (‘entourage’ effect).
When pre‐incubated for 5 min with cells, both compounds dose‐dependently enhanced NADA's TRPV1‐mediated effect on intracellular Ca2+ in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1–10 μM), the EC50 of NADA was lowered from ∼90 to ∼30 nM.
The effect on intracellular Ca2+ by another endovanilloid, N‐arachidonoyl‐ethanolamine (anandamide, 50 nM), was also enhanced dose‐dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0–6.7) to enhance intracellular Ca2+ via TRPV1.
When co‐injected with NADA (0.5 μg) in rat hind paws, STEARDA (5 μg) potentiated NADA's TRPV1‐mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 μg) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain.
These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as ‘entourage’ compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain.

British Journal of Pharmacology (2004) 143, 251–256. doi:10.1038/sj.bjp.0705924
Effects of inhaled thrombin receptor agonists in mice
Authors: Moffatt James D , Lever Rebecca , Page Clive P 
Published: September 2004

Active thrombin is found in the airways of patients with a variety of inflammatory lung diseases. However, whether thrombin contributes to the pathologies of these diseases is unknown, although thrombin is a potent inflammatory mediator in other organ systems. In the present study we have assessed the acute inflammatory effect of inhaled thrombin and investigated the possible receptors mediating any effects in mice.
Thrombin (200–2000 U kg−1 intranasally), induced the recruitment of a small, but significant, number of neutrophils into the airways as assessed by differential counts of cells retrieved by bronchoalveolar lavage (BAL). This small response was mimicked by peptide agonists of proteinase‐activated receptor‐4 (PAR4; GYPGKF, AYPGKF; 2–20 mg kg−1), but not PAR1 (SFLLRN; 2–20 mg kg−1). By contrast, trypsin (200–2000 U kg−1) caused profound inflammation and lung damage.
Concentrations of tumour necrosis factor‐α (TNF‐α) were elevated in BAL fluid from thrombin‐treated mice, and a TNF‐α‐neutralising antibody inhibited the influx of neutrophils in response to thrombin.
Although isolated alveolar macrophages appeared to express PAR1‐ and PAR4‐immunoreactivity, these cells failed to release TNF‐α above baseline levels in response to thrombin, trypsin or any of the peptide PAR agonists.
Neither thrombin (2000 U kg−1) nor trypsin (200 U kg−1) modified the airway neutrophilia in response to intranasal bacterial lipopolysaccharide (LPS; 100 μg kg−1).
In conclusion, exogenous thrombin has only a modest acute inflammatory action in the lung that appears to be mediated by PAR4 and involve release of TNF‐α from an unknown source.

British Journal of Pharmacology (2004) 143, 269–275. doi:10.1038/sj.bjp.0705926
The evolving role of lipid rafts and caveolae in G protein‐coupled receptor signaling: implications for molecular pharmacology
Authors: Ostrom Rennolds S , Insel Paul A 
Published: September 2004

The many components of G‐protein‐coupled receptor (GPCR) signal transduction provide cells with numerous combinations with which to customize their responses to hormones, neurotransmitters, and pharmacologic agonists. GPCRs function as guanine nucleotide exchange factors for heterotrimeric (α, β, γ) G proteins, thereby promoting exchange of GTP for GDP and, in turn, the activation of ‘downstream’ signaling components. Recent data indicate that individual cells express mRNA for perhaps over 100 different GPCRs (out of a total of nearly a thousand GPCR genes), several different combinations of G‐protein subunits, multiple regulators of G‐protein signaling proteins (which function as GTPase activating proteins), and various isoforms of downstream effector molecules. The differential expression of such protein combinations allows for modulation of signals that are customized for a specific cell type, perhaps at different states of maturation or differentiation. In addition, in the linear arrangement of molecular interactions involved in a given GPCR–G‐protein–effector pathway, one needs to consider the localization of receptors and post‐receptor components in subcellular compartments, microdomains, and molecular complexes, and to understand the movement of proteins between these compartments. Co‐localization of signaling components, many of which are expressed at low overall concentrations, allows cells to tailor their responses by arranging, or spatially organizing in unique and kinetically favorable ways, the molecules involved in GPCR signal transduction. This review focuses on the role of lipid rafts and a subpopulation of such rafts, caveolae, as a key spatial compartment enriched in components of GPCR signal transduction. Recent data suggest cell‐specific patterns for expression of those components in lipid rafts and caveolae. Such domains likely define functionally important, cell‐specific regions of signaling by GPCRs and drugs active at those GPCRs.British Journal of Pharmacology (2004) 143, 235–245. doi:10.1038/sj.bjp.0705930
Investigation of the effect of the farnesyl protein transferase inhibitor R115777 on isoprenylation and intracellular signalling by the prostacyclin receptor
Authors: O'Meara Sarah J , Kinsella B Therese 
Published: September 2004

The human (h) and mouse (m) prostacyclin receptors (IPs) undergo isoprenylation through attachment of a C‐15 farnesyl moiety within their conserved carboxyl terminal ‐CSLC sequences.
Herein, the effects of a novel farnesyl transferase inhibitor R115777 on signalling by the hIP and mIP, overexpressed in human embryonic kidney 293 cells, and by the hIP endogenously expressed in human erythroleukaemia cells were investigated.
R115777 significantly impaired IP‐mediated cyclic AMP generation (IC50 0.37–0.60 nM) and intracellular calcium ([Ca2+]i) mobilization (IC50 37–65 nM), but had no effect on signalling by the control nonisoprenylated β2 adrenergic receptor or the α or β isoforms of the human thromboxane A2 receptor (TP).
Additionally, R115777 significantly reduced IP‐mediated cross‐desensitization of signalling by the TPα, but not by the TPβ, isoform of the human TP and impaired the farnesylation‐dependent processing of the chaperone HDJ‐2 protein (IC50 4.5 nM).
Furthermore, R115777 fully impaired isoprenylation of both the Ha‐RasWT and Ha‐RasCSLC in vitro and in whole cells confirming that, unlike N‐Ras and Ki‐Ras, the ‐CSLC motif associated with the IP cannot support alternative geranylgeranylation in the presence of R115777 and does not act as a substrate for geranylgeranyl transferase 1 in vitro or in whole cells.
In conclusion, these data confirm that R115777 potently impairs IP isoprenylation and signalling, and suggest that clinically it may not only target Ras proteins but may also disrupt IP isoprenylation, events which could impact on physiologic processes in which prostacyclin and its receptor are implicated.

British Journal of Pharmacology (2004) 143, 318–330. doi:10.1038/sj.bjp.0705956
Pharmacological evidence for a key role of voltage‐gated K+ channels in the function of rat aortic smooth muscle cells
Authors: Tammaro Paolo , Smith Amy L , Hutchings Simon R , Smirnov Sergey V 
Published: September 2004

The role of voltage‐dependent (IKv) and large conductance Ca2+‐activated (BKCa) K+ currents in the function of the rat aorta was investigated using specific BKCa and KV channel inhibitors in single rat aortic myocytes (RAMs) with patch‐clamp technique and in endothelium‐denuded aortic rings with isometric tension measurements.
The whole‐cell K+ currents were recorded in RAMs dialysed with 200 and 444 nM Ca2+ and in perforated‐patch configuration. Electrophysiological analysis demonstrated that IKv appeared at −40 mV, while BKCa (isolated using 1 μM paxilline) were seen positive to −20 mV in all conditions.
Voltage‐dependent characteristics, but not maximal conductance, of IKv was significantly altered in increased [Ca2+]i. Correolide (1 μM) (a KV1 channel blocker) did not inhibit the IKv, whereas millimolar concentration of TEA (IC50=3.1±0.6 mM, n=5) and 4‐aminopyridine (4‐AP, IC50=5.9±1.9 mM, n=7) suppressed IKv. These results and immunocytochemical analysis suggest the KV2.1 channel to be a molecular correlate for IKv.
In nonstimulated aortic rings 1–5 mM TEA and 4‐AP (inhibitors of IKv), but not paxilline (1 μM), caused contraction. The frequency of contractile responses to TEA and 4‐AP was increased in the presence of 10 mM KCl, which itself did not significantly affect the aortic basal tone.
Phenylephrine (15–40 nM) induced sustained tension with superimposed slow oscillatory contractions (termed OWs). OWs were blocked by diltiazem, ryanodine and cyclopiazonic acid, suggesting the involvement of L‐type Ca2+ channels and ryanodine‐sensitive Ca2+ stores in this process.
TEA and 4‐AP, but not IbTX, paxilline or correolide, increased the duration and amplitude of OWs, indicating that IKv is involved in the control of oscillatory activity.
In conclusion, our findings suggest that the KV2.1‐mediated IKv, and not BKCa, plays an important role in the regulation of the excitability and contractility of rat aorta.

British Journal of Pharmacology (2004) 143, 303–317. doi:10.1038/sj.bjp.0705957
Microarray Analysis in Alzheimer's Disease and Normal Aging
Authors: Ricciarelli Roberta , d'Abramo Cristina , Massone Sara , Marinari Umberto M. , Pronzato Maria A. , Tabaton Massimo 
Published: September 2004

AbstractThe purpose of this study was to investigate gene expression in Alzheimer's disease (AD), the most common form of senile dementia. We utilized the microarray technology to simultaneously compare the expression profile of 12,000 human genes in cerebral cortex of AD and normal aging. To identify gene expression related to neurodegeneration, beside the presence of amyloid deposition, we used control brains with abundant amyloid plaques, derived from cognitively normal elderly subjects. The microarray analysis indicated that 314 genes were differentially expressed in AD cerebral cortex, with differences greater than 5 folds in 25 genes. RT‐PCR performed on a selected group of genes confirmed the increased expression of the interferon‐induced protein 3 in AD brain. This protein, which is highly inducible by both type I and type II interferons, was not previously associated with the neurodegenerative disease.
IUBMB Life, 56: 349‐354, 2004
A memory-efficient algorithm for multiple sequence alignment with constraints
Authors: Lu Chin Lung , Huang Yen Pin 
Published: September 2004

Abstract
Motivation: Recently, the concept of the constrained sequence alignment was proposed to incorporate the knowledge of biologists about structures/functionalities/consensuses of their datasets into sequence alignment such that the user-specified residues/nucleotides are aligned together in the computed alignment. The currently developed programs use the so-called progressive approach to efficiently obtain a constrained alignment of several sequences. However, the kernels of these programs, the dynamic programming algorithms for computing an optimal constrained alignment between two sequences, run in 𝒪(γn2) memory, where γ is the number of the constraints and n is the maximum of the lengths of sequences. As a result, such a high memory requirement limits the overall programs to align short sequences~only.
Results: We adopt the divide-and-conquer approach to design a memory-efficient algorithm for computing an optimal constrained alignment between two sequences, which greatly reduces the memory requirement of the dynamic programming approaches at the expense of a small constant factor in CPU time. This new algorithm consumes only 𝒪(αn) space, where α is the sum of the lengths of constraints and usually α ≪ n in practical applications. Based on this algorithm, we have developed a memory-efficient tool for multiple sequence alignment with constraints.
Availability: http://genome.life.nctu.edu.tw/MUSICME
Contact: cllu@mail.nctu.edu.tw