bluuebunny/crossref_metadata_2025 huggingface dataset:
Health economic evaluations alongside clinical trials: A review of study protocols at the Swedish Medical Products Agency
Authors: Lindfors Anne , Feltelius Nils , Lundkvist Jonas
Published: June 2007

Objectives: Conducting economic evaluation in the context of clinical studies is common but has been the subject of extensive discussion due to its limitations. Various standard approaches and guidelines how such studies should be conducted have been proposed, but there is very limited information available about how common these studies are, what type of data that is collected, and how the quality of the protocols compares to the suggested standards. This study examines the prevalence and study design of health economic evaluations conducted alongside clinical trials in Sweden between 1995 and 2005.

Methods: A systematic assessment of clinical trial protocols that had arrived as applications to the Medical Products Agency between 1995 and 2005 was performed. Only protocols arriving during the first half of odd years within the time period were included.

Results: A total number of 680 protocols from 1995 to 2005 were examined, and among them, 14.4 percent included a health economic part. With the exception of year 2001, a trend toward an increased prevalence of economic evaluations next to clinical trials can be seen.

Conclusions: This study shows that economic evaluations alongside clinical trials are becoming more common, although most trials still lack a health economic part of the protocol. The information about the economic evaluation provided in the protocols is in many cases scarce, possibly due to the fact that there currently are no generally accepted and applied guidelines for economic evaluations in clinical trial protocols. Introducing requirements for detailed study plans also for the economic evaluation should improve the quality of economic evaluations alongside clinical trials.
Effective early warning systems for new and emerging health technologies: Developing an evaluation framework and an assessment of current systems
Authors: Murphy Kieran , Packer Claire , Stevens Andrew , Simpson Sue
Published: June 2007

Objectives: The aim of this study was to define an effective early warning system, to identify and rank the characteristics of an effective early warning system for emerging health technologies, and to evaluate current early warning systems against these characteristics.

Methods: An iterative Delphi-type process with the thirteen members of the International Information Network on New and Changing Health Technologies (EuroScan). We synthesized key characteristics that network members had graded. Members were then asked whether these characteristics were present or fulfilled in their system.

Results: The definition of an effective early warning system developed was the following: a system that identifies innovations in the field of health technology likely to have a significant impact; and disseminates information relevant to the needs of the customer which is timely, so as to enable appropriate decision making (such as resource allocation), facilitate appropriate adoption, and identify further research requirements. Five primary and eleven secondary components of effective early warning systems were identified. The five primary characteristics concerned relevance, independence, resourcing, a clear pathway for the outputs to reach decision makers, and defined customers. Although the primary characteristics were present or fulfilled to some extent in the majority of evaluated early warning systems, there was considerable variability in the presence of the secondary characteristics in the evaluated systems.

Conclusions: Our study provides a definition for an effective early warning system and a shared understanding of the important characteristics and components of such systems. This work should provide guidance to those setting up new early warning systems as well as for those managing and reviewing current systems.
Determinants of adolescents’ soft drink consumption
Authors: Bere Elling , Sørli Glomnes Elin , te Velde Saskia J , Klepp Knut-Inge
Published: June 2007

Objective

To identify determinants of adolescents’ consumption of carbonated
soft drinks (regular and diet), both of total consumption and of consumption
at school.

Design/Setting/Subjects

Regular and diet soft drink consumption was measured by food frequency
questions that were dichotomised. Several potential environmental and
personal determinants of consumption were measured. A total of 2870
(participation rate: 85%) 9th and 10th graders, within 33 Norwegian schools,
participated in the study. Multilevel logistic regression analyses were
preformed for total soft drink consumption (twice a week or more vs. less)
and for consumption at school (once a week or more vs. less).

Results

A total of 63% and 27% of the participants reported to drink respectively
regular and diet soft drinks twice a week or more, and 24% and 8%,
respectively, reported to drink soft drinks once a week or more at school.
Preferences, accessibility, modelling and attitudes were the strongest
determinants of both regular and diet soft drink consumption. In addition,
gender, educational plans and dieting were related to both total soft drink
consumption and consumption at school. Pupils with longer distance from
school to shop and those in schools with rules concerning soft drink
consumption tended to have lower odds of drinking both regular and diet soft
drinks at school.

Conclusion

This study shows that gender, educational plans, dieting, accessibility,
modelling, attitudes and preferences all seem to be strong determinants of
adolescents’ soft drink consumption. Parents and the home
environment appear as great potential intervention targets.
Development and validation of a short questionnaire to assess sodium intake
Authors: Charlton Karen E , Steyn Krisela , Levitt Naomi S , Jonathan Deborah , Zulu Jabulisiwe V , Nel Johanna H
Published: June 2007

Objectives

To develop and validate a short food-frequency questionnaire to assess habitual dietary salt intake in South Africans and to allow classification of individuals according to intakes above or below the maximum recommended intake of 6 g salt day−1.

Design

Cross-sectional validation study in 324 conveniently sampled men and women.

Methods

Repeated 24-hour urinary Na values and 24-hour dietary recalls were obtained on three occasions. Food items consumed by >5% of the sample and which contributed ≥50 mg Na serving−1were included in the questionnaire in 42 categories. A scoring system was devised, based on Na content of one index food per category and frequency of consumption.

Results

Positive correlations were found between Na content of 35 of the 42 food categories in the questionnaire and total Na intake, calculated from 24-hour recall data. Total Na content of the questionnaire was associated with Na estimations from 24-hour recall data (r= 0.750;P< 0.0001;n= 328) and urinary Na (r= 0.152;P= 0.0105;n= 284). Urinary Na was higher for subjects in tertile 3 than tertile 1 of questionnaire Na content (P< 0.05). Questionnaire Na content of <2400 and ≥2400 mg day−1equated to a reference cut-off score of 48 and corresponded to mean (standard deviation) urinary Na values of 145 (68) and 176 (99) mmol day−1, respectively (P< 0.05). Sensitivity and specificity against urinary Na ≥100 and <100 mmol day−1was 12.4% and 93.9%, respectively.

Conclusion

A 42-item food-frequency questionnaire has been shown to have content-, construct- and criterion-related validity, as well as internal consistency, with regard to categorising individuals according to their habitual salt intake; however, the devised scoring system needs to show improved sensitivity.
Experimenting with recursive queries in database and logic programming systems
Authors: TERRACINA G. , LEONE N. , LIO V. , PANETTA C.
Published: June 2007

This article considers the problem of reasoning on massive amounts of (possibly distributed) data. Presently, existing proposals show some limitations: (i) the quantity of data that can be handled contemporarily is limited, because reasoning is generally carried out in main-memory; (ii) the interaction with external (and independent) Database Management Systems is not trivial and, in several cases, not allowed at all; and (iii) the efficiency of present implementations is still not sufficient for their utilization in complex reasoning tasks involving massive amounts of data. This article provides a contribution in this setting; it presents a new system, called DLVDB, which aims to solve these problems. Moreover, it reports the results of a thorough experimental analysis we have carried out for comparing our system with several state-of-the-art systems (both logic and databases) on some classical deductive problems; the other tested systems are LDL++, XSB, Smodels, and three top-level commercial Database Management Systems. DLVDB significantly outperforms even the commercial database systems on recursive queries.
Simulation of the sporadic E layer response to prereversal associated evening vertical electric field enhancement near dip equator
Authors: Carrasco A. J. , Batista I. S. , Abdu M. A.
Published: June 2007

The role of the molecular and metallic ions in the formation of sporadic E layers (Es layers) has been an active area of research for many years. Ionosonde data of the Es layer parameter, fbEs (the blanketing frequency of sporadic layer), and ftEs (the top frequency of Es trace), obtained over the Brazilian sites, Fortaleza, and São Luis, show that the diurnal variations of these parameters often present a disruption that is coincident with the evening prereversal electric field/vertical drift enhancement, to reappear after about 2 hours. In this work we have developed a model of the E region with the objective to describe all the phases of the life cycle of the sporadic layer and its relation to the evening vertical electric field enhancement that is associated with the development of the prereversal zonal electric field enhancement. The model calculates the densities of NO+, O2+, O+, N2+, and Fe+ in the height region 86–140 km by simultaneously solving the continuity and momentum equations for each of the species. For low latitudes this model shows that winds and electric fields each play distinct roles in the vertical transport of plasma leading to Es layer formation. The results of our numerical simulation confirm the dominant role of the vertical electric field as the cause of the inhibition/disruption of the sporadic layer in the evening. More specifically, the results reveal that an upward directed (positive) vertical electric field is capable of disrupting an ongoing sporadic layer, whereas a downward (negative) electric field favors its formation or even intensification, thus corroborating the conclusions of the recent study by Abdu et al. (2003).
Geoeffectiveness of halo coronal mass ejections
Authors: Gopalswamy N. , Yashiro S. , Akiyama S.
Published: June 2007

We studied the geoeffectiveness, speed, solar source, and flare association of a set of 378 halo coronal mass ejections (CMEs) of cycle 23 (1996–2005, inclusive). We compiled the minimum Dst values occurring within 1–5 days after the CME onset. We compared the distributions of such Dst values for the following subsets of halo CMEs: disk halos (within 45 deg from disk center), limb halos (beyond 45 degrees but within 90 deg from disk center), and backside halo CMEs. Defining that a halo CME is geoeffective if it is followed by Dst ≤ −50 nT, moderately geoeffective if −50 nT < Dst < −100 nT, and strongly geoeffective if Dst ≤ −100 nT, we find that the disk halos are followed by strong storms, limb halos are followed by moderate storms, and backside halos are not followed by significant storms. The Dst distribution for a random sample is nearly identical to the case of backside halos. About 71% of all frontside halos are geoeffective, supporting the high rate of geoeffectiveness of halo CMEs. A larger fraction (75%) of disk halos are geoeffective. Intense storms are generally due to disk halos and the few intense storms from limb halos occur only in the maximum and declining phases. Most intense storms occur when there are successive CMEs. The delay time between CME onset and minimum Dst value is the smallest for limb halos, suggesting that the sheath is geoeffective in these cases. The geoeffectiveness rate has prominent dips in 1999 and 2002 (the beginning and end years of the solar maximum phase). The numbers of all frontside and geoeffective frontside halos show a triple peak structure similar to the number of intense geomagnetic storms. The difference in flare sizes among geoeffective and nongeoeffective halos is not significant. The nongeoeffective CMEs are generally slower and have more easterly or limbward solar sources compared to the geoeffective ones; source location and speed are the most important parameters for geoeffectiveness.
Risks due to X‐ray flares during astronaut extravehicular activity
Authors: Smith David S. , Scalo John M.
Published: June 2007

Solar hard X‐ray flares can expose astronauts on lunar and deep space extravehicular activities (EVAs) to dangerous acute biological doses. We combine calculations of radiative transfer through shielding materials with subsequent transfer through tissue to show that hazardous doses, taken as ≥0.1 Gy, should occur with a probability of about 10% per 100 hours of accumulated EVA inside the current spacesuit. The rapid onset and short duration of X‐ray flares and the lack of viable precursor events require strategies for quick retreat, in contrast to solar proton events, which usually take hours to deliver significant fluence and can often be anticipated by flares or other light speed precursors. Our results contrast with the view that only particle radiation poses dangers for human space exploration. Heavy‐element shields provide the most efficient protection from X‐ray flares, since X rays produce no significant secondary radiation. We calculate doses due to X‐ray flares behind aluminum shields and estimate the required shield masses to accompany EVA rovers.
Are plasma depletions in Saturn's ionosphere a signature of time‐dependent water input?
Authors: Moore Luke , Mendillo Michael
Published: June 2007

Recent radio occultation measurements by the Cassini spacecraft reveal the presence of numerous “ionospheric holes”, or plasma depletions, in Saturn's upper atmosphere that cannot be explained with standard photochemical theory. The holes are remarkably similar in size and shape to artificially‐created depletions first observed in the terrestrial ionosphere during the 1970s. At Earth, such vertical structures are typically caused by the enhanced loss of electrons and ions resulting from the introduction of spacecraft exhaust products (e.g., H2O) into the atmosphere. Using a new model of Saturn's upper atmosphere, we show that a time‐variable influx of water into Saturn's ionosphere could explain the observed plasma depletions. The required influxes present a target to assess for the possible sources and consequences of water processes throughout the Saturnian system.
Positive surface temperature feedback in the stable nocturnal boundary layer
Authors: Walters Justin T. , McNider Richard T. , Shi Xingzhong , Norris William B. , Christy John R.
Published: June 2007

The techniques of nonlinear analysis are used to examine the behavior of the stable nocturnal boundary layer (SNBL) when it is subjected to changes in incoming radiation or in surface characteristics. A single‐column model and nonlinear bifurcation techniques are used to demonstrate that any atmospheric forcing, such as weak radiative forcing from greenhouse gases or cloud cover, can trigger a potentially significant positive feedback. Multiple solutions occur in some parameter spaces. This analysis shows that any forcing that decreases the stability, whether by increasing greenhouse gases or surface heat capacity, can cause large increases in surface temperature as the SNBL shifts from a weak turbulent regime, which allows the surface to cool, to a turbulent regime, which mixes warm air from aloft. Positive feedback may be a key factor in interpreting the long‐term observed nocturnal warming trend in the SNBL.
Interferogram formation in the presence of complex and large deformation
Authors: Yun Sang‐Ho , Zebker Howard , Segall Paul , Hooper Andrew , Poland Michael
Published: June 2007

Sierra Negra volcano in Isabela island, Galápagos, erupted from October 22 to October 30 in 2005. During the 8 days of eruption, the center of Sierra Negra's caldera subsided about 5.4 meters. Three hours prior to the onset of the eruption, an earthquake (Mw 5.4) occurred, near the caldera. Because of the large and complex phase gradient due to the huge subsidence and the earthquake, it is difficult to form an interferogram inside the caldera that spans the eruption. The deformation is so large and spatially variable that the approximations used in existing InSAR software (ROI, ROI_PAC, DORIS, GAMMA) cannot properly coregister SAR image pairs spanning the eruption. We have developed here a two‐step algorithm that can form intra‐caldera interferograms from these data. The first step involves a “rubber‐sheeting” SAR image coregistration. In the second step we use range offset estimates to mitigate the steep phase gradient. Using this new algorithm, we retrieve an interferogram with the best coverage to date inside the caldera of Sierra Negra.
Remote sensing retrievals of fine mode aerosol optical depth and impacts on its correlation with CO from biomass burning
Authors: Kampe Thomas U. , Sokolik Irina N.
Published: June 2007

It has been suggested that simultaneous satellite measurements of mid‐visible fine mode aerosol optical depth τf and CO concentrations can aid in improving the characterization of biomass burning in chemical transport models. However different approaches for retrieving τf have recently been proposed. Using MODIS and MOPITT data, we examine the impact these have on the regression slope between enhancements of τf and CO (Δτf/ΔCO) for representative biomass burning cases, including savanna and extratropical forests. Both MODIS Collection 4 and recent Collection 5 aerosol products are used in our study. We find that τf varies systematically with retrieval method causing systematic differences in the slope of regression. Regardless of method used, noticeable differences in regression slope are observed for different types of biomass burning. Our results point out the need for consistency in defining τf between satellite measurements and models if the Δτf/ΔCO ratio is to be used as a constraint.
Crustal thicknesses and Poisson's ratios in China by joint analysis of teleseismic receiver functions and Rayleigh wave dispersion
Authors: Ma Yanlu , Zhou Huilan
Published: June 2007

A new grid search scheme, which extends the stacking H‐κ algorithm to multi‐layered crustal models and fits observed dispersion of surface wave group velocity simultaneously, is proposed to estimate the thickness, Poisson's ratio, and average P wave speed of the crust. We first apply it to a synthetic data of a 2‐layered crustal model. Then we show the results analyzing records from 45 permanent broadband seismic stations in China. The estimates at six stations agree well with results from deep seismic sounding profiles. The crustal thicknesses agree in general with the Crust 2.0 model. We find that the Poisson's ratio in the Yangtze platform is rather low compared with the other two platforms. The stations along the southeast coast of China have higher Poisson's ratios. The Poisson's ratio of the whole region tends to increase as the average P‐wave velocity.
Phyloclimatic Modelling: Phylogenies, Palaeo-climate and Environmental Preferences
Authors: Yesson Chris , Culham Alastair
Published: June 2007

A new technique is demonstrated for the interpretation of the role played by climate in plant diversity through the optimisation of climate variables on phylogenetic trees. This is achieved by calculating climate preferences for individual species based on established bioclimatic modelling techniques using pointdistribution data from distributed sources. We demonstrate a new technique for optimising the component parameters on phylogenetic trees. These parameters can be re-combined intobioclimatic models for ancestral nodes throughout the phylogenetic tree. The combination of DNA-sequence data and the fossil record is used to establish time-calibrated phylogenies. Using these chronograms, bioclimatic models can in turn can be projected into the relevant palaeo-climate scenario to establish possible areas of palaeo-distribution. This technique is demonstrated using exemplar plant groups from Mediterranean-type winter-wet climate zones.
A revision of Australia' s hammer orchids (Drakaea: Orchidaceae), with some field data on species-specific sexually deceived wasp pollinators
Authors: Hopper Stephen D. , Brown Andrew P.
Published: June 2007

Drakaea Lindley, 1840 is a genus of 10 species of geophytic orchids endemic to the South-west Australian Floristic Region. The genus is renowned for its morphological and chemical adaptations, achieving pollination by sexual deception of male thynnid wasps. The history of taxa in Drakaea has been one of dispute and confusion right to the present day. Here we provide a revision of the genus, the first made by using modern collections and field data, formalising names for undescribed taxa featured by Hoffman and Brown (1992, 1998), several of which are threatened with extinction. We describe six new species: D. andrewsiae, D. concolor, D. confluens, D. gracilis, D. isolata and D. micrantha. Experimental baiting of male wasps has helped show the specific status of some of these new taxa. Molecular phylogenetic research is needed to clarify relationships and patterns of speciation in the genus. Five of the 10 Drakaea species are legally protected under the Western Australian Wildlife Conservation Act and the Commonwealth Environment Protection and Biodiversity Conservation Act, signalling the ongoing need for research and management to ensure the conservation of this unique part of Australia’s orchid heritage. D. andrewsiae has been recorded only three times from the Gnowangerup–Tunney district. Urgent surveys are needed to establish its conservation status.
Systematics of the Rubus fruticosus aggregate (Rosaceae) and other exotic Rubus taxa in Australia
Authors: Evans Katherine J. , Symon David E. , Whalen Molly A. , Hosking John R. , Barker Robyn M. , Oliver Julie A.
Published: June 2007

Exotic Rubus taxa in Australia have been revised following consultation with European and North American experts in Rubus, allied with studies of variation in patterns of DNA restriction fragments and morphology. Many of these taxa have names that are applied for the first time in Australia (prefaced with a †). The major focus of the work was the Rubus fruticosus L. aggregate and taxa of this aggregate covered here are R. anglocandicans A. Newton, R. cissburiensis W.C. Barton & Ridd., †R. echinatus Lindl., †R. erythrops Edees & A. Newton, R. laciniatus Willd., R. leightonii Lees ex Leight. †R. leucostachys Schleich. ex Sm., †R. phaeocarpus W.C.R. Watson, R. polyanthemus Lindeb., †R. riddelsdellii Rilstone, †R. rubritinctus W.C.R. Watson, R. ulmifolius Schott (including R. ulmifolius var. ulmifolius and †R. ulmifolius var. anoplothyrsus Sudre), and R. vestitus Weihe, along with two undescribed taxa, Rubus sp. Scott Creek (D.E. Symon 16504) and Rubus sp. Tasmania (J.R. Hosking 1551). Other naturalised taxa are R. alceifolius Poir., R. ellipticus Sm., R. idaeus L., †R. laudatus A. Berger, †R. loganobaccus L.H. Bailey, †R. philadelphicus Blanch., R. roribaccus (L.H. Bailey) Rydb. and R. rugosus Sm. Patterns of morphological and molecular variation among individuals of the R. fruticosus agg. in Australia were examined. In phenetic analyses based on examination of 137 herbarium specimens and 27 morphological characters, taxa showed varying degrees of separation. Some taxa, for example R. anglocandicans and the two varieties of R. ulmifolius, formed distinct groups in these analyses whereas there was considerable overlap among individuals of other species. Fifty M13/HaeIII DNA-banding patterns (phenotypes) were identified among 198 collections from the R. fruticosus agg. across Australia. Thirty-five DNA phenotypes were correlated with 15 taxa of the R. fruticosus agg.; the remaining 15 DNA types correlated poorly or were determined with only a moderate level of confidence. R. anglocandicans, R. echinatus, R. leightonii, R. leucostachys, R. sp. Tasmania, R. ulmifolius and R. vestitus had two or more DNA phenotypes whereas only one DNA phenotype was observed for the remaining eight taxa. Taxa that were more distinct with respect to their DNA phenotypes also tended to be more distinct with respect to morphology based on a Mantel matrix correlation test. Within taxa that were difficult to tell apart morphologically, those sharing the same DNA phenotype were considered members of the same Rubus taxon. These results are discussed in the context of the evolution and ecology of the R. fruticosus agg. in Australia and in relation to the incomplete taxonomy of Rubus in Europe and North America.
Induction of Cullin 7 by DNA damage attenuates p53 function
Authors: Jung Peter , Verdoodt Berlinda , Bailey Aaron , Yates John R. , Menssen Antje , Hermeking Heiko
Published: June 2007

The p53 tumor suppressor gene encodes a transcription factor, which is translationally and posttranslationally activated after DNA damage. In a proteomic screen for p53 interactors, we found that the cullin protein Cul7 efficiently associates with p53. After DNA damage, the level of Cul7 protein increased in a caffeine-sensitive, but p53-independent, manner. Down-regulation of Cul7 by conditional microRNA expression augmented p53-mediated inhibition of cell cycle progression. Ectopic expression of Cul7 inhibited activation of p53 by DNA damaging agents and sensitized cells to adriamycin. Although Cul7 recruited the F-box protein FBX29 to p53, the combined expression of Cul7/FBX29 did not promote ubiquitination and degradation of p53
in vivo
. Therefore, the inhibition of p53 activity by Cul7 is presumably mediated by alternative mechanisms. The interplay between p53 and Cul7 resembles the negative feedback loop described for p53 and Mdm2. Pharmacological modulation of Cul7 function may allow the sensitization of cancer cells expressing wild-type p53 to genotoxic agents used in cancer therapy.
The yeast DNA damage checkpoint proteins control a cytoplasmic response to DNA damage
Authors: Dotiwala Farokh , Haase Julian , Arbel-Eden Ayelet , Bloom Kerry , Haber James E.
Published: June 2007

A single HO endonuclease-induced double-strand break (DSB) is sufficient to activate the DNA damage checkpoint and cause
Saccharomyces
cells to arrest at G
2
/M for 12–14 h, after which cells adapt to the presence of the DSB and resume cell cycle progression. The checkpoint signal leading to G
2
/M arrest was previously shown to be nuclear-limited. Cells lacking ATR-like Mec1 exhibit no DSB-induced cell cycle delay; however, cells lacking Mec1's downstream protein kinase targets, Rad53 or Chk1, still have substantial G
2
/M delay, as do cells lacking securin, Pds1. This delay is eliminated only in the triple mutant
chk1
Δ
rad53
Δ
pds1
Δ, suggesting that Rad53 and Chk1 control targets other than the stability of securin in enforcing checkpoint-mediated cell cycle arrest. The G
2
/M arrest in
rad53
Δ and
chk1
Δ revealed a unique cytoplasmic phenotype in which there are frequent dynein-dependent excursions of the nucleus through the bud neck, without entering anaphase. Such excursions are infrequent in wild-type arrested cells, but have been observed in cells defective in mitotic exit, including the semidominant
cdc5-ad
mutation. We suggest that Mec1-dependent checkpoint signaling through Rad53 and Chk1 includes the repression of nuclear movements that are normally associated with the execution of anaphase.
High-field MRI of brain cortical substructure based on signal phase
Authors: Duyn Jeff H. , van Gelderen Peter , Li Tie-Qiang , de Zwart Jacco A. , Koretsky Alan P. , Fukunaga Masaki
Published: June 2007

The ability to detect brain anatomy and pathophysiology with MRI is limited by the contrast-to-noise ratio (CNR), which depends on the contrast mechanism used and the spatial resolution. In this work, we show that in MRI of the human brain, large improvements in contrast to noise in high-resolution images are possible by exploiting the MRI signal phase at high magnetic field strength. Using gradient-echo MRI at 7.0 tesla and a multichannel detector, a nominal voxel size of 0.24 × 0.24 × 1.0 mm
3
(58 nl) was achieved. At this resolution, a strong phase contrast was observed both between as well as within gray matter (GM) and white matter (WM). In gradient-echo phase images obtained on normal volunteers at this high resolution, the CNR between GM and WM ranged from 3:1 to 20:1 over the cortex. This CNR is an almost 10-fold improvement over conventional MRI techniques that do not use image phase, and it is an ≈100-fold improvement when including the gains in resolution from high-field and multichannel detection. Within WM, phase contrast appeared to be associated with the major fiber bundles, whereas contrast within GM was suggestive of the underlying layer structure. The observed phase contrast is attributed to local variations in magnetic susceptibility, which, at least in part, appeared to originate from iron stores. The ability to detect cortical substructure from MRI phase contrast at high field is expected to greatly enhance the study of human brain anatomy
in vivo
.
Recognition of trimethyllysine by a chromodomain is not driven by the hydrophobic effect
Authors: Hughes Robert M. , Wiggins Kimberly R. , Khorasanizadeh Sepideh , Waters Marcey L.
Published: June 2007

Posttranslational modifications of histone proteins regulate gene expression via complex protein–protein and protein–DNA interactions with chromatin. One such modification, the methylation of lysine, has been shown to induce binding to chromodomains in an aromatic cage [Nielsen PR,
et al.
(2002)
Nature
416:103–107]. The binding generally is attributed to the presence of cation–π interactions between the methylated lysine and the aromatic pocket. However, whether the cationic component of the interaction is necessary for binding in the aromatic cage has not been addressed. In this article, the interaction of trimethyllysine with tryptophan is compared with that of its neutral analog, tert-butylnorleucine (2-amino-7,7-dimethyloctanoic acid), within the context of a β-hairpin peptide model system. These two side chains have near-identical size, shape, and polarizabilities but differ in their charges. Comparison of the two peptides reveals that the neutral side chain has no preference for interacting with tryptophan, unlike trimethyllysine, which interacts strongly in a defined geometry.
In vitro
binding studies of the histone 3A peptide containing trimethyllysine or tert-butylnorleucine to HP1 chromodomain indicate that the cationic moiety is critical for binding in the aromatic cage. This difference in binding affinities demonstrates the necessity of the cation–π interaction to binding with the chromodomain and its role in providing specificity. This article presents an excellent example of synergy between model systems and
in vitro
studies that allows for the investigation of the key forces that control biomolecular recognition.
Cleavage of the transactivation-inhibitory domain of p63 by caspases enhances apoptosis
Authors: Sayan Berna S. , Sayan A. Emre , Yang Ai Li , Aqeilan Rami I. , Candi Eleonora , Cohen Gerald M. , Knight Richard A. , Croce Carlo M. , Melino Gerry
Published: June 2007

p63 is a p53-related transcription factor. Utilization of two different promoters and alternative splicing at the C terminus lead to generation of six isoforms. The α isoforms of TAp63 and ΔNp63 contain a transactivation-inhibitory (TI) domain at the C termini, which can bind to the transactivation (TA) domain and inhibit its transcriptional activity. Consequently, TAp63α can directly inhibit its activity through an intramolecular interaction; similarly, ΔNp63α can inhibit the activity of the active TAp63 isoforms through an intermolecular interaction. In this work, we demonstrate that after induction of apoptosis, the TI domain of the p63α isoforms is cleaved by activated caspases. Cleavage of ΔNp63α relieves its inhibitory effect on the transcriptionally active p63 proteins, and the cleavage of TAp63α results in production of a TAp63 protein with enhanced transcriptional activity. In agreement with these data, generation of the N-terminal TAp63 fragment has a role in apoptosis because stable cell lines expressing wild-type TAp63 are more sensitive to apoptosis compared with cells expressing the noncleavable mutant. We also used a model system in which TAp63 expression was induced by trichostatin-A treatment in HCT116 cells. Trichostatin-A sensitized these cells to apoptosis, and this sensitization was associated with cleavage of up-regulated p63.
A model of Internet topology usingk-shell decomposition
Authors: Carmi Shai , Havlin Shlomo , Kirkpatrick Scott , Shavitt Yuval , Shir Eran
Published: June 2007

We study a map of the Internet (at the autonomous systems level), by introducing and using the method ofk-shell decomposition and the methods of percolation theory and fractal geometry, to find a model for the structure of the Internet. In particular, our analysis uses information on the connectivity of the network shells to separate, in a unique (no parameters) way, the Internet into three subcomponents: (i) a nucleus that is a small (≈100 nodes), very well connected globally distributed subgraph; (ii) a fractal subcomponent that is able to connect the bulk of the Internet without congesting the nucleus, with self-similar properties and critical exponents predicted from percolation theory; and (iii) dendrite-like structures, usually isolated nodes that are connected to the rest of the network through the nucleus only. We show that our method of decomposition is robust and provides insight into the underlying structure of the Internet and its functional consequences. Our approach of decomposing the network is general and also useful when studying other complex networks.
Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling
Authors: Knezevic Dejan , Zhang Wengeng , Rochette Patrick J. , Brash Douglas E.
Published: June 2007

Sunlight's UVB radiation triggers cell signaling at multiple sites to induce apoptosis. The integration of these signal entry sites is not understood. Here we show that P53 and E2f1 constitute a UV-inducible apoptosis switch. At low-UV doses, wild-type cells resemble the OFF state of an siP53-treated cell, whereas at high-UV doses, the apoptosis frequency transitions to the fully ON behavior of an siE2f1-treated cell. The switch's target is Bcl-2: Rapid Bcl-2 down-regulation in response to UVB-induced DNA photoproducts is lost in P53-deficient cells, but, as for apoptosis, is restored when both P53 and its inhibited target E2f1 are absent. P53's down-regulation of Bcl-2 is mediated entirely through E2f1. Bcl-2 is also down-regulated by a separate pathway triggered by DNA photoproducts in the absence of P53 and E2f1. Four UV pathways terminating on Bcl-2 contribute to apoptosis after UVB irradiation. The apoptosis lost in
p53
−/−
is completely restored by siBcl-2, implying that Bcl-2 is a rate-limiting member of this network. These results identify Bcl-2 as an integrator of several UV-induced proapoptotic signals and show that it, in turn, suppresses a direct UV–apoptosis pathway. UV-induced apoptosis requires both UV activation of the direct pathway and a separate UV disinhibition of this pathway through P53–E2f1–Bcl-2.
Chronic exposure to paclitaxel diminishes phosphoinositide signaling by calpain-mediated neuronal calcium sensor-1 degradation
Authors: Boehmerle Wolfgang , Zhang Kun , Sivula Michael , Heidrich Felix M. , Lee Yashang , Jordt Sven-Eric , Ehrlich Barbara E.
Published: June 2007

Paclitaxel (Taxol) is a well established chemotherapeutic agent for the treatment of solid tumors, but it is limited in its usefulness by the frequent induction of peripheral neuropathy. We found that prolonged exposure of a neuroblastoma cell line and primary rat dorsal root ganglia with therapeutic concentrations of Taxol leads to a reduction in inositol trisphosphate (Ins
P
3
)-mediated Ca
2+
signaling. We also observed a Taxol-specific reduction in neuronal calcium sensor 1 (NCS-1) protein levels, a known modulator of Ins
P
3
receptor (Ins
P
3
R) activity. This reduction was also found in peripheral neuronal tissue from Taxol treated animals. We further observed that short hairpin RNA-mediated NCS-1 knockdown had a similar effect on phosphoinositide-mediated Ca
2+
signaling. When NCS-1 protein levels recovered, so did Ins
P
3
-mediated Ca
2+
signaling. Inhibition of the Ca
2+
-activated protease μ-calpain prevented alterations in phosphoinositide-mediated Ca
2+
signaling and NCS-1 protein levels. We also found that NCS-1 is readily degraded by μ-calpain
in vitro
and that μ-calpain activity is increased in Taxol but not vehicle-treated cells. From these results, we conclude that prolonged exposure to Taxol activates μ-calpain, which leads to the degradation of NCS-1, which, in turn, attenuates Ins
P
3
mediated Ca
2+
signaling. These findings provide a previously undescribed approach to understanding and treating Taxol-induced peripheral neuropathy.
Reorientional dynamics of water molecules in anionic hydration shells
Authors: Laage Damien , Hynes James T.
Published: June 2007

Water molecule rotational dynamics within a chloride anion's first hydration shell are investigated through simulations. In contrast to recent suggestions that the ion's hydration shell is rigid during a water's reorientation, we find a labile hydration sphere, consistent with previous assessments of chloride as a weak structure breaker. The nondiffusive reorientation mechanism found involves a hydrogen-bond partner switch with a large amplitude angular jump and the water's departure from the anion's shell. An analytic extended jump model accounts for the simulation results, as well as available NMR and ultrafast spectroscopic data, and resolves the discrepancy between them.
Regulation of the protein disulfide proteome by mitochondria in mammalian cells
Authors: Yang Yi , Song Yanli , Loscalzo Joseph
Published: June 2007

The majority of protein disulfides in cells is considered an important inert structural, rather than a dynamic regulatory, determinant of protein function. Here, we show that some disulfides in proteins also are regulated by cell redox status with functional consequences. We find that reactive oxygen species (ROS) produced by mitochondria are actively used by cells to facilitate cell-surface protein disulfide formation, as well as folding and transport, in mammalian cells. Inhibition of mitochondrial ROS production suppresses protein disulfide formation and induces reductive stress, leading to dysfunction and retention (possibly in the Golgi, in part) of a group of cell-surface disulfide-containing proteins. Sparsely cultured cells produce less ROS than confluent cells do, which leads to decreased disulfide formation and decreased activity of a subgroup of disulfide-containing cell-surface receptors. These data support the concept of two subproteomes comprising the disulfide proteome, a structural group and a redox-sensitive regulatory group, with the latter having direct functional consequences for the cell.
Coupling of hydrogenic tunneling to active-site motion in the hydrogen radical transfer catalyzed by a coenzyme B12-dependent mutase
Authors: Dybala-Defratyka Agnieszka , Paneth Piotr , Banerjee Ruma , Truhlar Donald G.
Published: June 2007

Hydrogen transfer reactions catalyzed by coenzyme B12-dependent methylmalonyl-CoA mutase have very large kinetic isotope effects, indicating that they proceed by a highly quantal tunneling mechanism. We explain the kinetic isotope effect by using a combined quantum mechanical/molecular mechanical potential and semiclassical quantum dynamics calculations. Multidimensional tunneling increases the magnitude of the calculated intrinsic hydrogen kinetic isotope effect by a factor of 3.6 from 14 to 51, in excellent agreement with experimental results. These calculations confirm that tunneling contributions can be large enough to explain even a kinetic isotope effect >50, not because the barrier is unusually thin but because corner-cutting tunneling decreases the distance over which the system tunnels without a comparable increase in either the effective potential barrier or the effective mass for tunneling.
Biologically inspired crack trapping for enhanced adhesion
Authors: Glassmaker Nicholas J. , Jagota Anand , Hui Chung-Yuen , Noderer William L. , Chaudhury Manoj K.
Published: June 2007

We present a synthetic adaptation of the fibrillar adhesion surfaces found in nature. The structure consists of protruding fibrils topped by a thin plate and shows an experimentally measured enhancement in adhesion energy of up to a factor of 9 over a flat control. Additionally, this structure solves the robustness problems of previous mimic structures and has preferred contact properties (i.e., a large surface area and a highly compliant structure). We show that this geometry enhances adhesion because of its ability to trap interfacial cracks in highly compliant contact regimes between successive fibril detachments. This results in the requirement that the externally supplied energy release rate for interfacial separation be greater than the intrinsic work of adhesion, in a manner analogous to lattice trapping of cracks in crystalline solids.
Behavioral improvement in a primate Parkinson's model is associated with multiple homeostatic effects of human neural stem cells
Authors: Redmond D. Eugene , Bjugstad Kimberly B. , Teng Yang D. , Ourednik Vaclav , Ourednik Jitka , Wakeman Dustin R. , Parsons Xuejun H. , Gonzalez Rodolfo , Blanchard Barbara C. , Kim Seung U. , Gu Zezong , Lipton Stuart A. , Markakis Eleni A. , Roth Robert H. , Elsworth John D. , Sladek John R. , Sidman Richard L. , Snyder Evan Y.
Published: June 2007

Stem cells have been widely assumed to be capable of replacing lost or damaged cells in a number of diseases, including Parkinson's disease (PD), in which neurons of the substantia nigra (SN) die and fail to provide the neurotransmitter, dopamine (DA), to the striatum. We report that undifferentiated human neural stem cells (hNSCs) implanted into 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian primates survived, migrated, and had a functional impact as assessed quantitatively by behavioral improvement in this DA-deficit model, in which Parkinsonian signs directly correlate to reduced DA levels. A small number of hNSC progeny differentiated into tyrosine hydroxylase (TH) and/or dopamine transporter (DAT) immunopositive cells, suggesting that the microenvironment within and around the lesioned adult host SN still permits development of a DA phenotype by responsive progenitor cells. A much larger number of hNSC-derived cells that did not express neuronal or DA markers was found arrayed along the persisting nigrostriatal path, juxtaposed with host cells. These hNSCs, which express DA-protective factors, were therefore well positioned to influence host TH+ cells and mediate other homeostatic adjustments, as reflected in a return to baseline endogenous neuronal number-to-size ratios, preservation of extant host nigrostriatal circuitry, and a normalizing effect on α-synuclein aggregation. We propose that multiple modes of reciprocal interaction between exogenous hNSCs and the pathological host milieu underlie the functional improvement observed in this model of PD.
Extreme ultraviolet spectroscopy of highly charged argon ions at the Berlin EBIT
Authors: Biedermann C , Radtke R , Fussmann G , Allen F I
Published: June 2007

Extreme ultraviolet radiation from highly charged argon was investigated at the Berlin Electron Beam Ion Trap with a 2 m grazing incidence spectrometer. Lines in the wavelength range 150 to 660 Å originating from C-like Ar12+to Li-like Ar15+ions have been identified and are compared with database information from solar line lists and predictions. Line ratios for the observed resonance, intercombination and forbidden lines offer important diagnostic capabilities for low density, hot plasmas.
The Formation of the cAMP/Protein Kinase A-dependent Annexin 2–S100A10 Complex with Cystic Fibrosis Conductance Regulator Protein (CFTR) Regulates CFTR Channel Function
Authors: Borthwick Lee A. , Mcgaw Jean , Conner Gregory , Taylor Christopher J. , Gerke Volker , Mehta Anil , Robson Louise , Muimo Richmond
Published: June 2007

Cystic fibrosis results from mutations in the cystic fibrosis conductance regulator protein (CFTR), a cAMP/protein kinase A (PKA) and ATP-regulated Cl−channel. CFTR is increasingly recognized as a component of multiprotein complexes and although several inhibitory proteins to CFTR have been identified, protein complexes that stimulate CFTR function remain less well characterized. We report that annexin 2 (anx 2)–S100A10 forms a functional cAMP/PKA/calcineurin (CaN)-dependent complex with CFTR. Cell stimulation with forskolin/3-isobutyl-1-methylxanthine significantly increases the amount of anx 2–S100A10 that reciprocally coimmunoprecipitates with cell surface CFTR and calyculin A. Preinhibition with PKA or CaN inhibitors attenuates the interaction. Furthermore, we find that the acetylated peptide (STVHEILCKLSLEG, Ac1-14), but not the nonacetylated equivalent N1-14, corresponding to the S100A10 binding site on anx 2, disrupts the anx 2–S100A10/CFTR complex. Analysis of 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid (DIDS) and CFTRinh172-sensitive currents, taken as indication of the outwardly rectifying Cl−channels (ORCC) and CFTR-mediated currents, respectively, showed that Ac1-14, but not N1-14, inhibits both the cAMP/PKA-dependent ORCC and CFTR activities. CaN inhibitors (cypermethrin, cyclosporin A) discriminated between ORCC/CFTR by inhibiting the CFTRinh172-, but not the DIDS-sensitive currents, by >70%. Furthermore, peptide Ac1-14 inhibited acetylcholine-induced short-circuit current measured across a sheet of intact intestinal biopsy. Our data suggests that the anx 2–S100A10/CFTR complex is important for CFTR function across epithelia.
G protein signaling governing cell fate decisions involves opposing Gα subunits inCryptococcus neoformans
Authors: Hsueh Yen-Ping , Xue Chaoyang , Heitman Joseph
Published: June 2007

Communication between cells and their environments is often mediated by G protein-coupled receptors and cognate G proteins. In fungi, one such signaling cascade is the mating pathway triggered by pheromone/pheromone receptor recognition. Unlike Saccharomyces cerevisiae, which expresses two Gα subunits, most filamentous ascomycetes and basidiomycetes have three Gα subunits. Previous studies have defined the Gα subunit acting upstream of the cAMP-protein kinase A pathway, but it has been unclear which Gα subunit is coupled to the pheromone receptor and response pathway. Here we report that in the pathogenic basidiomycetous yeast Cryptococcus neoformans, two Gα subunits (Gpa2, Gpa3) sense pheromone and govern mating. gpa2 gpa3 double mutants, but neither gpa2 nor gpa3 single mutants, are sterile in bilateral crosses. By contrast, deletion of GPA3 (but not GPA2) constitutively activates pheromone response and filamentation. Expression of GPA2 and GPA3 is differentially regulated: GPA3 expression is induced by nutrient-limitation, whereas GPA2 is induced during mating. Based on the phenotype of dominant active alleles, Gpa2 and Gpa3 signal in opposition: Gpa2 promotes mating, whereas Gpa3 inhibits. The incorporation of an additional Gα into the regulatory circuit enabled increased signaling complexity and facilitated cell fate decisions involving choice between yeast growth and filamentous asexual/sexual development.