bluuebunny/crossref_metadata_2025 huggingface dataset:
HIV‐1 viral fitness estimation using exchangeable on subsets priors and prior model selection
Authors: Kitchen Christina M. R. , Weiss Robert E. , Liu Gang , Wrin Terri
Published: June 2006

The phenotype–genotype problem is a fundamental problem of biology where an organism's genotype (genetic information) predicts its phenotype (observable characteristic). Viral fitness, defined as the reproductive capacity of a virus compared to a standard, is a continuous phenotype. We construct models to predict viral fitness as a function of mutation away from the standardwildtypevirus. Data of this nature are difficult to analyse because there are potentially many more parameters than observations. We treat this issue as a regression problem using a prior with both a shrinkage component and a variable selection component. The key to practical implementation of the model is the prior specification for the regression coefficients. We use results from the scientific literature to construct several informative exchangeable within subsets priors (ESP). We use prior model selection (PMS) to select among our priors. Two novel graphics present results from five models each with 71 predictors. Copyright © 2006 John Wiley & Sons, Ltd.
Appropriateness of some resampling‐based inference procedures for assessing performance of prognostic classifiers derived from microarray data
Authors: Lusa Lara , McShane Lisa M. , Radmacher Michael D. , Shih Joanna H. , Wright George W. , Simon Richard
Published: June 2006

The goal of many gene‐expression microarray profiling clinical studies is to develop a multivariate classifier to predict patient disease outcome from a gene‐expression profile measured on some biological specimen from the patient. Often some preliminary validation of the predictive power of a profile‐based classifier is carried out using the same data set that was used to derive the classifier. Techniques such as cross‐validation or bootstrapping can be used in this setting to assess predictive power, and if applied correctly, can result in a less biased estimate of predictive accuracy of a classifier. However, some investigators have attempted to apply standard statistical inference procedures to assess the statistical significance of associations between true and cross‐validated predicted outcomes. We demonstrate in this paper that naïve application of standard statistical inference procedures to these measures of association under null situations can result in greatly inflated testing type I error rates. Under alternatives of small to moderate associations, confidence interval coverage probabilities may be too low, although for very large associations coverage probabilities approach their intended values. Our results suggest that caution should be exercised in interpreting some of the claims of exceptional prognostic classifier performance that have been reported in prominent biomedical journals in the past few years. Copyright © 2006 John Wiley & Sons, Ltd.
Misspecified regression model for the subdistribution hazard of a competing risk
Authors: Latouche A. , Boisson V. , Chevret S. , Porcher R.
Published: June 2006

We consider a competing risks setting, when evaluating the prognostic influence of an exposure on a specific cause of failure. Two main regression models are used in such analyses, the Cox cause‐specific proportional hazards model and the subdistribution proportional hazards model. They are exemplified in a real data example focusing on relapse‐free interval in acute leukaemia patients. We examine the properties of the estimator based on the latter model when the true model is the former. An explicit relationship between subdistribution hazards ratio and cause‐specific hazards ratio is derived, assuming a flexible parametric distribution for latent failure times. Copyright © 2006 John Wiley & Sons, Ltd.
Re‐examining the precepts of the blade element momentum theory for coning rotors
Authors: Crawford Curran
Published: June 2006

Blade element momentum (BEM) theory remains the core analytic approach behind most wind turbine analysis codes. The development of the theory extends over 100 years and thus bears re‐examination for applications involving coned rotors, for which it was never designed. This article reviews the underlying assumptions of BEM with a view to properly formulating a modified BEM theory for coned rotors. The postulate is that the critical limitation of BEM is the usual assumed relation between disc and far wake induction. Proper consideration of the relative placement of the wake and radially induced velocity, using potential flow theory, yields corrections to the BEM method. Using the modified BEM method, results are presented and compared with computational fluid dynamics (CFD) studies for ideal and real rotors to validate the new approach. It is found that the main limitation of BEM in application to coned rotors is in the assumed wake position, not the planar disc or the independence of stream‐tube assumptions. The latter is found only to have a strong effect at high induction factors and thrust coefficients, which are manifest in deficient local thrust coefficient models that seek to model transient recirculating flow conditions within the confines of a steady stream‐tube method. Copyright © 2006 John Wiley &Sons, Ltd.
Case and word order in Lithuanian
Authors: FRANKS STEVEN , LAVINE JAMES E.
Published: June 2006

This paper examines the unusual case and word order behavior of objects of infinitives in Lithuanian. In addition to lexically determined case idiosyncrasy, Lithuanian exhibits syntactically determined case idiosyncrasy: with infinitives in three distinct constructions, case possibilities other than accusative obtain. These cases (dative, genitive, and nominative) depend on the general clause structure rather than on the particular infinitive. Moreover, unlike ordinary direct objects, these objects appear in a position preceding rather than following the verb. It is argued that they move to this position in order potentially to be accessible for Case assignment by some higher Case-assigning head. In this way we unify the two superficially unrelated properties of non-canonical word order and Case. This movement, however, is not feature-driven in the sense of standard minimalist Case-licensing mechanisms. We characterize it as ‘agnostic’ in that it applies to an object with unvalued Case features, if that object reaches a point in the derivation where it has no recourse but to move because failure to do so would be fatal.
Trapped morphology
Authors: HARRIS ALICE C. , FAARLUND JAN TERJE
Published: June 2006

We argue that there is a diachronic process, distinct from phonological erosion, that results in the loss of inflectional morphology that is trapped when a clitic attaches to a host, becoming an affix. This is supported with attested examples from Mainland Scandinavian, Georgian, Spanish, and Greek, as well as shallow, well-accepted reconstructions from Slavic and Georgian. It is further supported by new reconstructions from Zoque (Mixe-Zoquean) and Andi (Northeast Caucasian). For example, in Old Norse the postposed article is a clitic, and there is a case ending between the noun stem and the article: hest-s=in-s ‘the horse (gen)’. The first s is trapped morphology, and it is subsequently lost: hest-en-s. Similarly, in pre-Georgian, the postposed article traps the ergative case marker, *-n: *k'ac-n=ma-n ‘the man (erg)’; it is subsequently lost: k'ac-man. We argue that the loss of trapped morphology is not sound change or another phonological process, but a morphological process.
Emissions from open biomass burning in India: Integrating the inventory approach with high‐resolution Moderate Resolution Imaging Spectroradiometer (MODIS) active‐fire and land cover data
Authors: Venkataraman C. , Habib G. , Kadamba D. , Shrivastava M. , Leon J.‐F. , Crouzille B. , Boucher O. , Streets D. G.
Published: June 2006

Climatological mean estimates of forest burning and crop waste burning based on broad assumptions of the amounts burned have so far been used for India in global inventories. Here we estimate open biomass burning representative of 1995–2000 from forests using burned area and biomass density specific for Indian ecosystems and crop waste burning as a balance between generation and known uses as fuel and fodder. High‐resolution satellite data of active fires and land cover classification from MODIS, both on a scale of 1 km × 1 km, were used to capture the seasonal variability of forest and crop waste burning and in conjunction with field reporting. Correspondence in satellite‐detected fire cycles with harvest season was used to identify types crop waste burned in different regions. The fire season in forest areas was from February to May, and that in croplands varied with geographical location, with peaks in April and October, corresponding to the two major harvest seasons. Spatial variability in amount of forest biomass burned differed from corresponding forest fire counts with biomass burned being largest in central India but fire frequency being highest in the east‐northeast. Unutilized crop waste and MODIS cropland fires were predominant in the western Indo‐Gangetic plain. However, the amounts of unutilized crop waste in the four regions were not strictly proportional to the fire counts. Fraction crop waste burned in fields ranged from 18 to 30% on an all‐India basis and had a strong regional variation. Open burning contributes importantly (about 25%) to black carbon, organic matter, and carbon monoxide emissions, a smaller amount (9–13%) to PM2.5(particulate mass in particles smaller than 2.5 micron diameter) and CO2emissions, and negligibly to SO2emissions (1%). However, it cannot explain a large “missing source” of BC or CO from India.
The Planetary rate of sprite events
Authors: Ignaccolo Massimiliano , Farges Thomas , Mika Agnes , Allin Thomas H. , Chanrion Olivier , Blanc Elisabeth , Neubert Torsten , Fraser‐Smith Antony C. , Füllekrug Martin
Published: June 2006

We propose a new formula to calculate the planetary rate of sprite events, based on observations with sprite detectors. This formula uses the number of detected sprites, the detection efficiency and the false alarm rate of the detector and spatial and temporal effectiveness functions. The role of these elements in the formula is discussed for optical and non‐optical recordings. We use the formula to calculate an average planetary rate of sprite events of ∼2.8 per minute with an accuracy of a factor ∼2–3 by use of observations reported in the literature. The proposed formula can be used to calculate the occurrence rate of any physical event detected by remote sensing.
Ionospheric signatures of internal reconnection for northward interplanetary magnetic field: Observation of “reciprocal cells” and magnetosheath ion precipitation
Authors: Watanabe Masakazu , Sofko George J. , André Dieter A. , Ruohoniemi J. Michael , Hairston Marc R. , Kabin Konstantin
Published: June 2006

Magnetic reconnection that involves overdraped lobe field lines is called internal reconnection since it occurs inside the magnetopause. When the interplanetary magnetic field (IMF) is due northward and the Earth's dipole is tilted significantly, internal reconnection occurs in the winter hemisphere, not only between a summer lobe field line and a winter lobe field line but also between a summer lobe field line and a closed field line. The latter internal reconnection drives “reciprocal cells” in the winter ionosphere that circulate exclusively in the closed field line region. The reciprocal cells are intimately related to the lobe cells in the summer ionosphere in that in the steady state, the reconnection voltage associated with merging of IMF and open field lines is equal to the sum of the lobe cell potential and the reciprocal cell potential. In this paper we present observations of convection patterns consistent with those expected for reciprocal cells, using ionospheric radar and low‐altitude satellite data. We also show the concurrence of lobe cells and reciprocal cells. The observations of reciprocal cells provide support for the internal reconnection between a summer lobe field line and a closed field line. In addition, we show that equatorward of the polar cap boundary, magnetosheath‐like ions are drifting from noon toward the flankside in both hemispheres. We suggest that these ions are of magnetosheath origin and that they entered the closed region of the magnetosphere through the rotational discontinuity associated with internal reconnection. These magnetosheath‐like ion observations strongly support the occurrence of internal reconnection.
Estimation of fractional sky cover from broadband shortwave radiometer measurements
Authors: Long C. N. , Ackerman T. P. , Gaustad K. L. , Cole J. N. S.
Published: June 2006

We outline a methodology for estimating fractional sky cover for an effective 160° field of view from an analysis of surface measurements of downwelling total and diffuse shortwave (SW) irradiance. The data are screened for optically thicker overcast cases, after which an empirically derived formulation is used to estimate the fractional sky cover for the remaining data. The retrieved fractional sky cover time series is then evaluated to mitigate times of anomalous behavior caused by the thick overcast screening. The resultant sky cover estimates show a high degree of repeatability given nominally well maintained and operated radiometer systems and the use of the Long and Ackerman (2000) methodology for estimating the clear‐sky total and diffuse SW. Thus the resultant fractional sky‐cover estimates appear to be fairly independent of the particular climate regime and model of radiometers used, at least for the climate regimes we have tested so far. The sky‐cover estimates agree to better than 10% root mean square sky cover amount with sky imager retrievals and human observations, which is as good as the agreement between sky imaging systems and observers themselves. As such, this methodology becomes a powerful tool for satellite and model validations and climatological analyses including the study of trends in cloud amount. Analysis shows that the technique also produces realistic frequency distributions, showing that the continental midlatitude regimes included in the study are typified by clear‐sky occurring about 1/3 of the time, overcast about 1/3 of the time, and partly cloudy skies to varying extent occurring the remaining 1/3 of the time. By contrast, the tropical western Pacific oceanic regime during the Nauru99 field experiment exhibits far more frequent occurrence of partly cloudy skies, with sky cover amounts of 20% to 50% occurring about half the time.
Temporal trend and long‐range transport of particulate polycyclic aromatic hydrocarbons at Gosan in northeast Asia between 2001 and 2004
Authors: Lee Ji Yi , Kim Yong Pyo , Kang Chang‐Hee , Ghim Young Sung , Kaneyasu Naoki
Published: June 2006

The temporal trend of the particulate polycyclic aromatic hydrocarbon (PAH) level was observed at Gosan, a background site in Korea, for 4 years between November 2001 and January 2004. The total average concentration of ambient particulate PAH compounds was 3.65 ± 4.74 ng m−3, which was mainly affected by a rather small number of very high PAH level samples. The PAH level at Gosan was 1 or 2 orders higher than those at other remote sites and 1 or 2 orders lower than those in urban areas in northeast Asia. The particulate PAH concentrations were high during cold periods mainly because of the seasonal variation of fossil fuel usage amount in northeast Asia. When the PAH levels were high, the ratio of BeP‐to‐BaP was also high, which is an indicator of particle residence time in the air. On the basis of the backward trajectory and upper wind direction analyses, it was observed that when air parcels were from China, the PAH levels were high. Also, the compositions of PAH compound ratios were similar to those in Beijing in winter. These indicate influence of emissions from China, especially from coal combustion and long‐range transport. The relationship between the concentrations of PAHs and non‐sea‐salt‐(nss)‐SO42− was generally good when the PAH levels were high. However, the periods of peaks were different, implying different emission patterns.
Extending Greenland temperature records into the late eighteenth century
Authors: Vinther B. M. , Andersen K. K. , Jones P. D. , Briffa K. R. , Cappelen J.
Published: June 2006

At present, continuous instrumental temperature records for Greenland reach back to the late nineteenth century at a few sites. Combining early observational records from locations along the south and west coasts, it has been possible to extend the overall record back to the year 1784. The new extended Greenland temperature record is 9% incomplete. There are, however, sufficient new data (an additional 74 complete winters and 52 complete summers) to provide a valuable indication of late eighteenth century and nineteenth century seasonal trends. Comparison of the previously published records with additional observational series digitized from Danish Meteorological Institute Yearbooks has also revealed inhomogeneities in some of the existing twentieth century temperature records. These problems have been eliminated in the new extended Greenland temperature record. A long homogeneous west Greenland instrumental temperature record is of great value for the interpretation of the growing number of Greenland ice core records. A first comparison of the new record with highly resolved Greenland ice core data is presented. Correlations between west Greenland winter temperatures and the ice core winter season proxy are found to be r = 0.67 and r = 0.60 for the periods 1785–1872 and 1873–1970, respectively.
New insights into Arctic paleogeography and tectonics from U‐Pb detrital zircon geochronology
Authors: Miller Elizabeth L. , Toro Jaime , Gehrels George , Amato Jeffrey M. , Prokopiev Andrei , Tuchkova Marianna I. , Akinin Vyacheslav V. , Dumitru Trevor A. , Moore Thomas E. , Cecile Michael P.
Published: June 2006

To test existing models for the formation of the Amerasian Basin, detrital zircon suites from 12 samples of Triassic sandstone from the circum‐Arctic region were dated by laser ablation‐inductively coupled plasma‐mass spectrometry (ICP‐MS). The northern Verkhoyansk (NE Russia) has Permo‐Carboniferous (265–320 Ma) and Cambro‐Silurian (410–505 Ma) zircon populations derived via river systems from the active Baikal Mountain region along the southern Siberian craton. Chukotka, Wrangel Island (Russia), and the Lisburne Hills (western Alaska) also have Permo‐Carboniferous (280–330 Ma) and late Precambrian‐Silurian (420–580 Ma) zircons in addition to Permo‐Triassic (235–265 Ma), Devonian (340–390 Ma), and late Precambrian (1000–1300 Ma) zircons. These ages suggest at least partial derivation from the Taimyr, Siberian Trap, and/or east Urals regions of Arctic Russia. The northerly derived Ivishak Formation (Sadlerochit Mountains, Alaska) and Pat Bay Formation (Sverdrup Basin, Canada) are dominated by Cambrian–latest Precambrian (500–600 Ma) and 445–490 Ma zircons. Permo‐Carboniferous and Permo‐Triassic zircons are absent. The Bjorne Formation (Sverdrup Basin), derived from the south, differs from other samples studied with mostly 1130–1240 Ma and older Precambrian zircons in addition to 430–470 Ma zircons. The most popular plate tectonic model for the origin of the Amerasian Basin involves counterclockwise rotation of the Arctic Alaska–Chukotka microplate away from the Canadian Arctic margin. The detrital zircon data suggest that the Chukotka part of the microplate originated closer to the Taimyr and Verkhoyansk, east of the Polar Urals of Russia, and not from the Canadian Arctic.
Measurement of Cl2 in coastal urban air
Authors: Finley B. D. , Saltzman E. S.
Published: June 2006

Measurements of Cl2 in coastal urban air were made in Irvine, California from Aug.‐Nov., 2005, using negative ion atmospheric pressure chemical ionization with tandem mass spectrometry. Cl2 ranged from <2.5 to 20 ppt with a two month mean of 3.5 ± 3.5 ppt (1σ) and an average noon photolysis rate of 44 ppt hr−1 Cl2. Model calculations suggest that Cl2 photochemistry results in an increase of 5–8 ppb in daily maximum O3 levels, relative to a base case scenario without Cl2.
Independent active microplate tectonics of northeast Asia from GPS velocities and block modeling
Authors: Apel E. V. , Bürgmann R. , Steblov G. , Vasilenko N. , King R. , Prytkov A.
Published: June 2006

Independent Okhotsk and Amurian microplate motions are tested using velocities from 123 GPS sites (80 from within the proposed OKH and AMU plate boundaries) used to constrain the plate kinematics of northeast Asia. A block modeling approach is used to incorporate both rigid block rotation and near‐boundary elastic strain accumulation effects in a formal inversion of the GPS velocities. Models include scenarios with and without independent OKH and AMU plate motion. Our modeling favors scenarios with independent OKH and AMU motion, based on the application of F‐test statistics. The independent OKH plate rotates 0.231 deg/Myr clockwise with respect to North America about a pole located north of Sakhalin. The modeled AMU plate rotates 0.298 deg/Myr counterclockwise with respect to NAM about a pole located west of the Magadan region. The plate‐motion parameters of the independent plates are consistent with the kinematics inferred from earthquake focal mechanism solutions along their boundaries.
Earthquake recurrence as a record breaking process
Authors: Davidsen Jörn , Grassberger Peter , Paczuski Maya
Published: June 2006

Extending the central concept of recurrence times for a point process to recurrent events in space‐time allows us to characterize seismicity as a record breaking process using only spatiotemporal relations among events. Linking record breaking events with edges between nodes in a graph generates a complex dynamical network isolated from any length, time or magnitude scales set by the observer. For Southern California, the network of recurrences reveals new statistical features of seismicity with robust scaling laws. The rupture length and its scaling with magnitude emerges as a generic measure for distance between recurrent events. Further, the relative separations for subsequent records in space (or time) form a hierarchy with unexpected scaling properties.
Phase transitions and compressibility of NaMgF3 (Neighborite) in perovskite‐ and post‐perovskite‐related structures
Authors: Martin C. David , Crichton Wilson A. , Liu Haozhe , Prakapenka Vitali , Chen Jiuhua , Parise John B.
Published: June 2006

Monochromatic x‐ray diffraction data collected in‐situ within the diamond anvil cell show perovskite structured Neighborite (NaMgF3) transforms to the CaIrO3‐type post‐perovskite structure between 28 and 30 GPa. Upon laser heating, the CaIrO3‐type structure transforms further to an unknown structure (Pnnm, designated N‐phase). Upon pressure release, N‐phase NaMgF3 becomes x‐ray amorphous. A structure transformation in post‐perovskite MgSiO3 and MgGeO3 to N‐phase may account for previous observations of extra x‐ray reflections during high pressure experiments and tomographic observations of an additional boundary in the lower mantle below the D″ discontinuity.
The PPARα/γ dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats
Authors: Li Ping‐Ping , Shan Song , Chen Yue‐Teng , Ning Zhi‐Qiang , Sun Su‐Juan , Liu Quan , Lu Xian‐Ping , Xie Ming‐Zhi , Shen Zhu‐Fang
Published: June 2006

The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L‐glutamate (MSG) obese rats and to determine whether its lipid‐lowering effect is mediated through its activation of PPARα.

Chiglitazar is a PPARα/γ dual agonist.

The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats.

Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets.

Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein‐cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARα, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats.

These data suggest that PPARα/γ coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARγ agonists.

British Journal of Pharmacology (2006) 148, 610–618. doi:10.1038/sj.bjp.0706745
Group I mGlu receptor stimulation inhibits activation‐induced cell death of human T lymphocytes
Authors: Chiocchetti Annalisa , Miglio Gianluca , Mesturini Riccardo , Varsaldi Federica , Mocellin Marco , Orilieri Elisabetta , Dianzani Chiara , Fantozzi Roberto , Dianzani Umberto , Lombardi Grazia
Published: June 2006

The effects ofL‐glutamate on activation‐induced cell death (AICD) of human activated (1 μg ml−1phytohemagglutinin plus 2 U ml−1interleukin‐2; 8 days) T lymphocytes were studied by measuring anti‐CD3 monoclonal antibody (10 μg ml−1; 18 h)‐induced cell apoptosis (Annexin V and propidium iodide staining).

L‐Glutamate (1 × 10−8–1 × 10−4 M) significantly (P0.01) inhibited AICD in a concentration‐dependent manner (EC50=6.3 × 10−8 M; maximum inhibition 54.8±6.3% at 1 × 10−6 M).

TheL‐glutamate inhibitory effect was pharmacologically characterized as mediated by group I mGlu receptors, since mGlu receptor agonists reproduced this effect. The EC50values were: 3.2 × 10−7 Mfor (1S,3R)‐ACPD; 4.5 × 10−8 Mfor quisqualate; 1.0 × 10−6 Mfor (S)‐3,5‐DHPG; 2.0 × 10−5 Mfor CHPG.

Group I mGlu receptor antagonists inhibited the effects of quisqualate 1.0 × 10−6 M. The IC50values calculated were: 8.7 × 10−5, 4.3 × 10−6and 6.3 × 10−7 Mfor AIDA, LY 367385 and MPEP, respectively.

L‐Glutamate (1 × 10−6M; 18 h) significantly (P0.05) inhibited FasL expression (40.8±11.3%) (cytofluorimetric analysis), whereas it did not affect Fas signalling.

Expression of both mGlu1and mGlu5receptor mRNA by T lymphocytes and T‐cell lines, as demonstrated by reverse transcriptase–PCR analysis, suggests thatL‐glutamate‐mediated inhibition of AICD was exerted on T cells.

These data depict a novel role forL‐glutamate in the regulation of the immune response through group I mGlu receptor‐mediated mechanisms.

British Journal of Pharmacology(2006)148, 760–768. doi:10.1038/sj.bjp.0706746
Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder
Authors: Abrams Paul , Andersson Karl‐Erik , Buccafusco Jerry J , Chapple Christopher , de Groat William Chet , Fryer Alison D , Kay Gary , Laties Alan , Nathanson Neil M , Pasricha Pankaj Jay , Wein Alan J
Published: June 2006

The effectiveness of antimuscarinic agents in the treatment of the overactive bladder (OAB) syndrome is thought to arise through blockade of bladder muscarinic receptors located on detrusor smooth muscle cells, as well as on nondetrusor structures.

Muscarinic M3receptors are primarily responsible for detrusor contraction. Limited evidence exists to suggest that M2receptors may have a role in mediating indirect contractions and/or inhibition of detrusor relaxation. In addition, there is evidence that muscarinic receptors located in the urothelium/suburothelium and on afferent nerves may contribute to the pathophysiology of OAB. Blockade of these receptors may also contribute to the clinical efficacy of antimuscarinic agents.

Although the role of muscarinic receptors in the bladder, other than M3receptors, remains unclear, their role in other body systems is becoming increasingly well established, with emerging evidence supporting a wide range of diverse functions. Blockade of these functions by muscarinic receptor antagonists can lead to similarly diverse adverse effects associated with antimuscarinic treatment, with the range of effects observed varying according to the different receptor subtypes affected.

This review explores the evolving understanding of muscarinic receptor functions throughout the body, with particular focus on the bladder, gastrointestinal tract, eye, heart, brain and salivary glands, and the implications for drugs used to treat OAB. The key factors that might determine the ideal antimuscarinic drug for treatment of OAB are also discussed. Further research is needed to show whether the M3selective receptor antagonists have any advantage over less selective drugs, in leading to fewer adverse events.

British Journal of Pharmacology(2006)148, 565–578. doi:10.1038/sj.bjp.0706780
Citrobacter rodentium‐induced NF‐κB activation in hyperproliferating colonic epithelia: role of p65 (Ser536) phosphorylation
Authors: Wang Yu , Xiang Guang‐Sheng , Kourouma Famourou , Umar Shahid
Published: June 2006

The transcription factors of the NF‐κB/Rel family form dimeric complexes that control expression of various genes involved in inflammation and proliferation.

During transmissible murine colonic hyperplasia (TMCH) induced by Citrobacter rodentium, nuclear translocation of NF‐κB in isolated colonic crypts increased 3 day's post‐infection and continued over 12 days paralleling peak hyperplasia. Antibody supershifts for both p65/p50 hetero‐ and p50/p50 homodimers occurred. Expression levels of both p50 and p65 subunits increased in cytosolic/nuclear extracts and correlated with NF‐κB activation kinetics. IκBα levels decreased during this time.

Phosphorylation of IKKα (at Ser176/180) and ‐β (at Ser177/181) increased significantly during TMCH suggesting activation in vivo.

p65‐Ser536 (p65536) exhibited increased phosphorylation on immunoblotting and immunohistochemistry (IHC) both at day 6 and 12 TMCH. p65536 translocated to nucleus and interacted with transcriptional coactivator CREB binding protein (CBP).

Proteasomal inhibitor bortezomib (Velcade®) caused accumulation of Ser32/36‐phosphorylated IκBα and significant inhibition of NF‐κB activity in vivo. Velcade® also blocked nuclear translocation of activated p65: both immunoblotting and IHC failed to detect p65536 nuclear immunoreactivity. Velcade®, however, did not abrogate TMCH.

p65 interacted strongly with ribosomal S6 kinase 1 (RSK‐1) during coimmunoprecipitation but not with IKKα or ‐β.

Thus, NF‐κB activation during TMCH involves both IκBα degradation and p65‐Ser536 phosphorylation. p65/RSK‐1 interaction and concomitant increase in p65536 complexed with CBP may be important in modulating NF‐κB activity in vivo. Activated NF‐κB, besides modulating proliferation, may aid in providing protective immunity against C. rodentium infection in vivo.

British Journal of Pharmacology (2006) 148, 814–824. doi:10.1038/sj.bjp.0706784
Phenobarbital increases monkeyin vivonicotine disposition and induces liver and brain CYP2B6 protein
Authors: Lee Anna M , Miksys Sharon , Tyndale Rachel F
Published: June 2006

CYP2B6 is a drug‐metabolizing enzyme expressed in the liver and brain that can metabolize bupropion (Zyban®, a smoking cessation drug), activate tobacco‐smoke nitrosamines, and inactivate nicotine. Hepatic CYP2B6 is induced by phenobarbital and induction may affectin vivonicotine disposition, while brain CYP2B6 induction may affect local levels of centrally acting substrates. We investigated the effect of chronic phenobarbital treatment on induction ofin vivonicotine disposition and CYP2B6 expression in the liver and brain of African Green (Vervet) monkeys.

Monkeys were split into two groups (n=6 each) and given oral saccharin daily for 22 days; one group was supplemented with 20 mg kg−1phenobarbital. Monkeys were given a 0.1 mg kg−1nicotine dose subcutaneously before and after treatment.

Phenobarbital treatment resulted in a significant, 56%, decrease (P=0.04) in the maximum nicotine plasma concentration and a 46% decrease (P=0.003) in the area under the concentration–time curve. Phenobarbital also increased hepatic CYP2B6 protein expression. In monkey brain, significant induction (P<0.05) of CYP2B6 protein levels was observed in all regions tested (caudate, putamen, hippocampus, cerebellum, brain stem and frontal cortex) ranging from 2‐fold to 150‐fold. CYP2B6 expression was induced in specific cells, such as frontal cortical pyramidal cells and thalamic neurons.

In conclusion, chronic phenobarbital treatment in monkeys resulted in increasedin vivonicotine disposition, and induced hepatic and brain CYP2B6 protein levels and cellular expression. This induction may alter the metabolism of CYP2B6 substrates including peripherally acting drugs such as cyclophosphamide and centrally acting drugs such as bupropion, ecstasy and phencyclidine.

British Journal of Pharmacology(2006)148, 786–794. doi:10.1038/sj.bjp.0706787
Lysophosphatidylcholine reduces the organ injury and dysfunction in rodent models of Gram‐negative and Gram‐positive shock
Authors: Murch Oliver , Collin Marika , Sepodes Bruno , Foster Simon J , Mota‐Filipe Helder , Thiemermann Christoph
Published: June 2006

Lysophosphatidylcholine (LPC) modulates the inflammatory response and reduces mortality in animal models of sepsis. Here, we investigate the effects of LPC from synthetic (sLPC) and natural, soy bean derived LPC, (nLPC) sources on the organ injury/dysfunction caused by systemic administration of lipopolysaccharide (LPS) or peptidoglycan (PepG) and lipoteichoic acid (LTA).

Rats were subjected to (i) endotoxaemia (LPS 6 mg kg–1 i.v.) and treated with sLPC (1–100 mg kg−1), (ii) endotoxaemia and treated with nLPC (10 mg kg−1) or (iii) Gram‐positive shock (PepG 10 mg kg–1 and LTA 3 mg kg–1 i.v.) and treated with sLPC (10 mg kg−1).

Endotoxaemia or Gram‐positive shock for 6 h resulted in increases in serum makers of renal dysfunction and liver, pancreatic and neuromuscular injury.

Administration of sLPC, at 1 or 2 h after LPS, dose dependently (1–10 mg kg−1) reduced the organ injury/dysfunction. High doses of sLPC (30 and 100 mg kg−1) were shown to be detrimental in endotoxaemia. sLPC also afforded protection against the organ injury/dysfunction caused by Gram‐positive shock. nLPC was found to be protective in endotoxaemic animals.

The beneficial effects of sLPC were associated with an attenuation in circulating levels of interleukin‐1β (IL‐1β).

In conclusion, LPC dose and time dependently reduces the organ injury and circulating IL‐1β levels caused by Gram‐negative or Gram‐positive shock in the rat. Thus, we speculate that appropriate doses of LPC may be useful in reducing the degree of organ injury and dysfunction associated with shock of various aetiologies.

British Journal of Pharmacology (2006) 148, 769–777. doi:10.1038/sj.bjp.0706788
The orexin system regulates alcohol‐seeking in rats
Authors: Lawrence Andrew J , Cowen Michael S , Yang Hong‐Ju , Chen Feng , Oldfield Brian
Published: June 2006

Orexin‐containing neurons have been implicated in feeding, sleep–wake cycles and more recently in drug‐seeking behaviour.

Pretreatment of alcohol‐preferring (iP) rats with an orexin1 receptor antagonist (SB‐334867, 20 mg kg−1, intraperitoneally) completely abolished an olfactory cue‐induced reinstatement of alcohol‐seeking behaviour, and also attenuated alcohol responding under an operant fixed ratio regimen without affecting water responding.

The mRNA encoding orexin within the hypothalamus was expressed at a similar density in iP and non‐preferring (NP) rats; chronic consumption of ethanol in iP rats did not significantly regulate the density of this expression, but did increase the area of expression within the lateral, but not medial, hypothalamus.

These data indicate that while orexin may not be implicated in the development of an alcohol preference, re‐exposure of cues previously associated with alcohol availability is sufficient and adequate to activate orexin‐containing neurons and drive reinstatement of alcohol‐seeking.

British Journal of Pharmacology (2006) 148, 752–759. doi:10.1038/sj.bjp.0706789
Electrochemical hydrogen storage in Li-doped pentacene
Authors: Fang Baizeng , Zhou Haoshen , Honma Itaru
Published: June 2006

Porous metal-incorporated nanostructured organic compounds represent an innovative concept in hydrogen storage. This work reports in detail the first practical realization of electrochemical hydrogen storage in such a material, Li-doped pentacene. Although lithium doping is at a very low level the conductivity of pentacene increases considerably after the doping of lithium, which makes ordered layer-stacked Li-doped pentacene very promising as electrode material for electrochemical hydrogen storage. A discharge capacity of ca. 238mAhg−1 has been achieved in 6M KOH for the Li-doped pentacene electrode, which is comparable to that obtained from commonly used electrode material, LaNi5 alloy for electrochemical hydrogen storage. Furthermore, a great improvement in the hydrogen storage capacity can be expected from the Li-doped pentacene by simply raising the lithium doping level.
Structure of poly(propyl ether imine) dendrimer from fully atomistic molecular dynamics simulation and by small angle x-ray scattering
Authors: Jana Chandan , Jayamurugan G. , Ganapathy Rajesh , Maiti Prabal K. , Jayaraman N. , Sood A. K.
Published: June 2006

We study the structure of carboxylic acid terminated neutral poly(propyl ether imine) (PETIM) dendrimer from generations 1–6 (G1–G6) in a good solvent (water) by fully atomistic molecular dynamics (MD) simulations. We determine as a function of generation the structural properties such as radius of gyration, shape tensor, asphericity, fractal dimension, monomer density distribution, and end-group distribution functions. The sizes obtained from the MD simulations have been validated by small angle x-ray scattering experiment on dendrimer of generations 2–4 (G2–G4). A good agreement between the experimental and theoretical value of radius of gyration has been observed. We find a linear increase in radius of gyration with the generation. In contrast, Rg scales as ∼Nx with the number of monomers. We find two distinct exponents depending on the generations, x=0.47 for G1–G3 and x=0.28 for G3–G6, which reveal their nonspace filling nature. In comparison with the amine terminated poly(amidoamine) (PAMAM) dendrimer, we find that Rg of Gth generation PETIM dendrimer is nearly equal to that of (G+1)th generation of PAMAM dendrimer as observed by Maiti et al. [Macromolecules 38, 979 (2005)]. We find substantial back folding of the outer subgenerations into the interior of the dendrimer. Due to their highly flexible nature of the repeating branch units, the shape of the PETIM dendrimer deviates significantly from the spherical shape and the molecules become more and more spherical as the generation increases. The interior of the dendrimer is quite open with internal cavities available for accommodating guest molecules, suggesting the use of PETIM dendrimer for guest-host applications. We also give a quantitative measure of the number of water molecules present inside the dendrimer.
Probing photochemical transformations at TiO2∕Pt and TiO2∕Ir interfaces using x-ray absorption spectroscopy
Authors: Lahiri Debdutta , Subramanian V. , Bunker Bruce A. , Kamat Prashant V.
Published: June 2006

Structural transformations at the TiO2∕Pt and TiO2∕Ir interfaces during UV-irradiation have been probed by X-ray absorption spectroscopy. Oxidation by the photogenerated holes results in the intercalation of Pt and Ir into the Titania matrix. The structural transformations observed with Pt and Ir nanoparticles anchored on TiO2 is different than the clustering of gold atoms observed in the TiO2/Au system. Implications of such structural transformations on the photocatalytic activity of semiconductor photocatalyts are discussed.
Analyzing energy landscapes for folding model proteins
Authors: Cox Graham A. , Johnston Roy L.
Published: June 2006

A new benchmark 20-bead HP model protein sequence (on a square lattice), which has 17 distinct but degenerate global minimum (GM) energy structures, has been studied using a genetic algorithm (GA). The relative probabilities of finding particular GM conformations are determined and related to the theoretical probability of generating these structures using a recoil growth constructor operator. It is found that for longer successful GA runs, the GM probability distribution is generally very different from the constructor probability, as other GA operators have had time to overcome any initial bias in the originally generated population of structures. Structural and metric relationships (e.g., Hamming distances) between the 17 distinct GM are investigated and used, in conjunction with data on the connectivities of the GM and the pathways that link them, to explain the GM probability distributions obtained by the GA. A comparison is made of searches where the sequence is defined in the normal (forward) and reverse directions. The ease of finding mirror image solutions are also compared. Finally, this approach is applied to rationalize the ease or difficulty of finding the GM for a number of standard benchmark HP sequences on the square lattice. It is shown that the relative probabilities of finding particular members of a set of degenerate global minima depend critically on the topography of the energy landscape in the vicinity of the GM, the connections and distances between the GM, and the nature of the operators used in the chosen search method.
Excitation spectra of nitro-diphenylaniline: Accurate time-dependent density functional theory predictions for charge-transfer dyes
Authors: Jacquemin Denis , Bouhy Michaël , Perpète Eric A.
Published: June 2006

Using time-dependent density functional theory (TD-DFT) and the polarizable continuum model (PCM), we have computed the absorption spectra of nitro-diphenylamine dyes. It turns out that the 6-311+G(2d,p) and 6-311G(d,p) basis sets provide, respectively, almost perfectly converged excitation spectra and geometries. Using the PBE0 hybrid functional, we obtain a valuable correlation between PCM-TD-DFT and experimental λmax with mean signed/absolute deviations of −4nm (0.03eV)∕8nm (0.06eV) and relatively small extreme discrepancies, although the excitations responsible for the color of this class of dyes present a charge-transfer character. The changes in the electron density upon absorption are analyzed through an orbital picture. In addition, a relationship between the light fastness and a well-identified vibrational frequency is proposed.
Generating long-lasting H1 and C13 hyperpolarization in small molecules with parahydrogen-induced polarization
Authors: Jonischkeit Thorsten , Bommerich Ute , Stadler Jörg , Woelk Klaus , Niessen Heiko G. , Bargon Joachim
Published: June 2006

Recently, Levitt and co-workers demonstrated that conserving the population of long-lasting nuclear singlet states in weak magnetic fields can lead to a preservation of nuclear spin information over times substantially longer than governed by the (high-field) spin-lattice relaxation time T1. Potential benefits of the prolonged spin information for magnetic resonance imaging and spectroscopy were pointed out, particularly when combined with the parahydrogen induced polarization (PHIP) methodology. In this contribution, we demonstrate that an increase of the effective relaxation time by a factor up to three is achieved experimentally, when molecules hyperpolarized by PHIP are kept in a weak magnetic field instead of the strong field of a typical NMR magnet. This increased lifetime of spin information makes the known PHIP phenomena more compatible with the time scales of biological processes and, thus, more attractive for future investigations.
Deterrence and System Management: The Case of North Korea
Authors: Morgan Patrick M.
Published: June 2006

The recent North Korean crisis is the latest phase in a lengthy U.S.-North Korean deterrence relationship. That relationship, particularly its problems and limitations, is reviewed and the effectiveness of each side's contemporary deterrence posture is assessed. It is noted that deterrence and compellence have not prevented the emergence of the North's nuclear proliferation efforts, nor has it brought North Korea a large improvement in security. The recent crisis is also examined to assess the mistakes in U.S. efforts to further pursue deterrence and compellence to end the North Korean nuclear weapons program. Lessons of the crisis for the use of deterrence for system security management are briefly discussed.
Bargaining and the Failure of Asymmetric Deterrence: Trading off the Risk of War for the Promise of a Better Deal
Authors: Langlois Catherine C. , Langlois Jean-Pierre P.
Published: June 2006

We propose that fully informed rivals' ability to bargain on the terms of an alternative status quo can lead to the failure of asymmetric deterrence. The model we develop to support this claim allows repeated rounds of bargaining, crisis, and war until one of the rivals agrees to the other side's last offer. The defender holds and enjoys possession of the prize coveted by the challenger. We argue that the defender's incentive to drag his feet and the challenger's resulting need to resort to threats if she is to obtain anything at all, yield inefficient equilibria that involve costly wars. Credibility requires that the rivals make good on their deterrent threats of war with some probability, and this probability depends on the two sides respective bargaining positions. We therefore identify a tradeoff between bargaining and deterrence that leave the rivals indifferent between a whole continuum of possible inefficient equilibria. However, we distinguish between the ex ante expected utility calculations on which the rivals make forward looking, optimal, decisions and the evaluation of the ex post consequences of these choices. The ex post evaluation captures the expected consequence of a strategy choice by evaluating the endgame outcome net of all costs incurred. In those equilibrium strategies that also optimize expected ex post prospects, the defender may well choose to make low compromise offers in case of challenge despite the risk of war, while the challenger remains aggressive but contains his demands.
Sequential Analysis of Deterrence Games with a Declining Status Quo
Authors: Carlson Lisa J. , Dacey Raymond
Published: June 2006

The model developed in this paper provides a formal prospect theory account of Challenger's behavior in the traditional deterrence game played under sequential decision analysis. The model is used to analyze two basic claims commonly made in the international relations literature regarding the importation of prospect theory into the analysis of crisis games. These claims pertain to Challenger's behavior when the valuation of the status quo is positive and Challenger's behavior when the valuation of the status quo is negative.

We model the traditional deterrence game between Challenger and Defender as a one-sided incomplete information game where Challenger is uncertain about Defender's preference ordering. We examine the behavior of Challenger under the condition that the status quo is declining, using a von Neumann—Morgenstern decision rule as specified by expected utility theory, and a Kahneman—Tverksy decision rule as specified by prospect theory.

The formal results show that these claims do not hold unconditionally and must be stated more precisely. Furthermore, there exist conditions under which the claims are false. We show that in addition to specifying the valuation of the status quo and the value of the probability of loss, as per the claims, a fuller understanding of Challenger's behavior also requires a specification of Challenger's valuation of the status quo vis-à-vis the valuations of other major payoffs in the game. In so doing, we capture many of the details relevant to a more complete analysis of Challenger's behavior in the deterrence game.