bluuebunny/crossref_metadata_2025_split huggingface dataset:
CONTROLLED PERTURBATION FOR ARRANGEMENTS OF CIRCLES
Authors: HALPERIN DAN , LEISEROWITZ ERAN 
Published: October 2004

Given a collection [Formula: see text] of circles in the plane, we wish to construct the arrangement [Formula: see text] (namely the subdivision of the plane into vertices, edges and faces induced by [Formula: see text]) using floating point arithmetic. We present an efficient scheme, controlled perturbation, that perturbs the circles in [Formula: see text] slightly to form a collection [Formula: see text], so that all the predicates that arise in the construction of [Formula: see text] are computed accurately and [Formula: see text] is degeneracy free.We introduced controlled perturbation several years ago, and already applied it to certain types of arrangements. The major contribution of the current work is the derivation of a good (small) resolution bound, that is, a bound on the minimum separation of features of the arrangement that is required to guarantee that the predicates involved in the construction can be safely computed with the given (limited) precision arithmetic. A smaller resolution bound leads to smaller perturbation of the original input.We present the scheme, describe how the resolution bound is determined and how it effects the perturbation magnitude. We implemented the perturbation scheme and the construction of the arrangement and we report on experimental results.
Sexual selection and predator avoidance in an acoustic moth: discriminating females take fewer risks
Authors: Greenfield Michael , Greig Emma 
Published: October 2004

AbstractSexual activities in both males and females are expected to incur energetic costs and risk. We tested the expectation that females who exhibit a higher level of discrimination of potential mates' signals incur greater risk than females who are relatively indiscriminate by assaying mate choice and predator evasion in an acoustic moth, Achroia grisella. Female A. grisella evaluate males on the basis of their song, only orienting toward males whose ultrasonic songs are delivered at pulse rates above a lower threshold value. Non-flying females also respond negatively, by ceasing all movement, upon hearing ultrasonic pulses delivered at rates below an upper threshold value; this response is assumed to represent evasion of predatory bats, specifically gleaning species. We found that both the lower and upper pulse-rate thresholds varied considerably among individual females and that the upper pulse-rate threshold for defensive response was always equal to or slightly lower than the lower pulse-rate threshold for a mating response. Thus, females who exhibit heightened discrimination of potential mates' signals experience less, not more, predatory risk. This relationship may reflect the evolutionary origin of acoustic sexual communication in A. grisella as a coöption of the ancestral function of hearing in evasion of predatory bats.
Social play in kaka (Nestor meridionalis) with comparisons to kea (Nestor notabilis)
Authors: Bond Alan , Diamond Judy 
Published: October 2004

AbstractSocial play in the kaka (Nestor meridionalis), a New Zealand parrot, is described and contrasted with that of its closest relative, the kea (Nestor notabilis), in one of the first comparative studies of social play in closely related birds. Most play action patterns were clearly homologous in these two species, though some contrasts in the form of specific play behaviors, such as kicking or biting, could be attributed to morphological differences. Social play in kakas is briefer, more predictable, and less sequentially diverse than that shown by keas. Kaka play also appears to be restricted to fledglings and juveniles, while the behavior is more broadly distributed among age groups in keas. Play initiation behaviors were relatively more frequent in kakas and more tightly intercorrelated in occurrence. A primary grouping of action patterns in kakas consisted of arboreal play, which was rare in keas. The most striking species difference was exhibited in social object play, which is pervasive among keas, but which was not observed in kakas. Although the two species are morphologically similar, they differ strikingly in several aspects of their ecology and social behavior, including the duration of the association between juveniles and adults, the degree of exploratory behavior, and the flexibility of their foraging strategies. The observed species differences in play behavior are discussed in relation to the contrasting life histories in the two species, suggesting that many features of social play may reflect evolutionary responses to particular ontogenetic and ecological constraints.
Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro
Authors: La Motte-Mohs Ross N. , Herer Elaine , Zúñiga-Pflücker Juan Carlos 
Published: October 2004

AbstractThe Notch signaling pathway plays a key role at several stages of T-lymphocyte differentiation. However, it remained unclear whether signals induced by the Notch ligand Delta-like 1 could support full T-cell differentiation from a defined source of human hematopoietic stem cells (HSCs) in vitro. Here, we show that human cord blood–derived HSCs cultured on Delta-like 1–expressing OP9 stromal cells undergo efficient T-cell lineage commitment and sustained T-cell differentiation. A normal stage-specific program of T-cell development was observed, including the generation of CD4 and CD8 αβ–T-cell receptor (TCR)–bearing cells. Induction of T-cell differentiation was dependent on the expression of Delta-like 1 by the OP9 cells. Stimulation of the in vitro–differentiated T cells by TCR engagement induced the expression of T-cell activation markers and costimulatory receptors. These results establish an efficient in vitro coculture system for the generation of T cells from human HSCs, providing a new avenue for the study of early T-cell differentiation and function.
Extracellular nucleotide signaling by P2 receptors inhibits IL-12 and enhances IL-23 expression in human dendritic cells: a novel role for the cAMP pathway
Authors: Schnurr Max , Toy Tracey , Shin Amanda , Wagner Moritz , Cebon Jonathan , Maraskovsky Eugene 
Published: October 2004

AbstractThe interleukin-12 (IL-12) cytokine family plays important roles in the orchestration of innate and adaptive immunity by dendritic cells (DCs). The regulation of IL-12 expression has been thoroughly studied, but little is known about factors governing the expression of IL-23 and IL-27, 2 novel IL-12 family members acting on memory and naive T cells, respectively. We report that the expression of these cytokines by DCs was critically dependent on the mode of activation. DC activation by CD40L predominantly induced IL-12. Ligands of the Toll-like receptor (TLR) 3 and TLR4 induced IL-12 and IL-27, whereas exposure to intact Escherichia coli resulted in high expression of IL-12, IL-27, and IL-23. The nucleotide adenosine triphosphate (ATP) has been shown to inhibit IL-12 production by P2 receptors. We found that ATP also inhibited IL-27 expression but enhanced IL-23 expression. Interestingly, the reciprocal regulation of IL-12/IL-27 and IL-23 by ATP was mediated by 2 distinct P2 receptors and was also induced by prostaglandin E2 by cyclic adenosine monophosphate (cAMP)–elevating EP2/EP4 receptors. As a consequence, DCs were selectively impaired in their ability to induce interferon-γ (IFN-γ) in naive T cells but continued to promote IFN-γ and IL-17 production in memory T cells. These studies identify P2 receptors as promising targets for the design of novel strategies to manipulate specific stages of T-cell responses and to treat IL-12– and IL-23–mediated disorders.
Tumor metastasis but not tumor growth is dependent on Src-mediated vascular permeability
Authors: Criscuoli Michele L. , Nguyen Mai , Eliceiri Brian P. 
Published: October 2004

AbstractVascular endothelial growth factor (VEGF)–induced vascular permeability (VP) is a hallmark of tumor growth and metastasis. Previous studies have shown a requirement for Src kinase in VEGF-mediated VP and signaling in blood vessels. In this study, we have examined the effect of Src-mediated reduced VP on tumor growth and metastasis. The growth and spontaneous metastasis of VEGF-expressing tumor cells were determined in Src-knockout (src–/–) or control mice (src+/+ or src+/–). In comparison to control mice, src-null mice had a significant reduction in tumor-induced VP as well as a subsequent reduction in spontaneous metastasis. In contrast, primary tumor weight and vascular density were unchanged between src-null and control mice. Consistent with a role for Src in the extravasation of tumor cells from the circulation, direct intravenous injection of lung carcinoma cells resulted in a more than 2-fold reduction in lung tumor burden in src-null mice compared to control mice. The comparison of the results from the experimental metastasis and the spontaneous metastasis models suggests that there are defects in VP in the primary site of Src-deficient mice and that there may be an essential role for Src and Src-mediated VP in tumor metastasis to the lung.
Induction of tolerance using Fas ligand: a double-edged immunomodulator
Authors: Askenasy Nadir , Yolcu Esma S. , Yaniv Isaac , Shirwan Haval 
Published: October 2004

AbstractApoptosis mediated by Fas ligand (FasL) interaction with Fas receptor plays a pivotal regulatory role in immune homeostasis, immune privilege, and self-tolerance. FasL, therefore, has been extensively exploited as an immunomodulatory agent to induce tolerance to both autoimmune and foreign antigens with conflicting results. Difficulties associated with the use of FasL as a tolerogenic factor may arise from (1) its complex posttranslational regulation, (2) the opposing functions of different forms of FasL, (3) different modes of expression, systemic versus localized and transient versus continuous, (4) the level and duration of expression, (5) the sensitivity of target tissues to Fas/FasL-mediated apoptosis and the efficiency of antigen presentation in these tissues, and (6) the types and levels of cytokines, chemokines, and metalloproteinases in the extracellular milieu of the target tissues. Thus, the effective use of FasL as an immunomodulator to achieve durable antigen-specific immune tolerance requires careful consideration of all of these parameters and the design of treatment regimens that maximize tolerogenic efficacy, while minimizing the non-tolerogenic and toxic functions of this molecule. This review summarizes the current status of FasL as a tolerogenic agent, problems associated with its use as an immunomodulator, and new strategies to improve its therapeutic potential.
Dendritic-cell activation by secretory phospholipase A2
Authors: Ramoner Reinhold , Putz Thomas , Gander Hubert , Rahm Andrea , Bartsch Georg , Schaber Claudia , Thurnher Martin 
Published: October 2004

AbstractDendritic cells (DCs), also referred to as the sentinels of the immune system, induce and coordinate important functions of immune surveillance. DCs acquire immunity-initiating capacity only after a process of maturation usually induced by ligands that bind to members of the tumor necrosis factor (TNF) or toll-like receptor families. Secretory phospholipase A2 (sPLA2), which hydrolyzes the sn-2 ester bond of glycerophospholipids, regulates a variety of cellular functions including migration of endothelial cells and neurite outgrowth. In the present study we investigated the role of sPLA2 in DC biology. We report that human monocyte-derived DC cultures lack sPLA2 activity but respond to exogenous sPLA2. sPLA2 alone and in cooperation with TNF-α and interleukin 1 β (IL-1β) induced fatty acid release from DC membranes, which was accompanied by upregulation of surface markers and by an increase in the migratory and immunostimulatory capacity of the DCs. Our findings indicate that secreted enzymes such as sPLA2 can contribute to DC maturation and emphasize the role of lipid mediators in the regulation of immune responses. This observation may also have implications for DC-based vaccine development.
Rank Difference Analysis of Microarrays (RDAM), a novel approach to statistical analysis of microarray expression profiling data
Authors: Martin Dietmar E , Demougin Philippe , Hall Michael N , Bellis Michel 
Published: October 2004

Abstract
Background
A key step in the analysis of microarray expression profiling data is the identification of genes that display statistically significant changes in expression signals between two biological conditions.

Results
We describe a new method, Rank Difference Analysis of Microarrays (RDAM), which estimates the total number of truly varying genes and assigns a p-value to each signal variation. Information on a group of differentially expressed genes includes the sensitivity and the false discovery rate. We demonstrate the feasibility and efficiency of our approach by applying it to a large synthetic expression data set and to a biological data set obtained by comparing vegetatively-growing wild type and tor2-mutant yeast strains. In both cases we observed a significant improvement of the power of analysis when our method is compared to another popular nonparametric method.

Conclusions
This study provided a valuable new statistical method to analyze microarray data. We conclude that the good quality of the results obtained by RDAM is mainly due to the quasi-perfect equalization of variation distribution, which is related to the standardization procedure used and to the measurement of variation by rank difference.
Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote
Authors: Ward Pauline , Equinet Leila , Packer Jeremy , Doerig Christian 
Published: October 2004

Abstract
Background
Malaria, caused by the parasitic protist Plasmodium falciparum, represents a major public health problem in the developing world. The P. falciparum genome has been sequenced, which provides new opportunities for the identification of novel drug targets. Eukaryotic protein kinases (ePKs) form a large family of enzymes with crucial roles in most cellular processes; hence malarial ePKS represent potential drug targets. We report an exhaustive analysis of the P. falciparum genomic database (PlasmoDB) aimed at identifying and classifying all ePKs in this organism.

Results
Using a variety of bioinformatics tools, we identified 65 malarial ePK sequences and constructed a phylogenetic tree to position these sequences relative to the seven established ePK groups. Predominant features of the tree were: (i) that several malarial sequences did not cluster within any of the known ePK groups; (ii) that the CMGC group, whose members are usually involved in the control of cell proliferation, had the highest number of malarial ePKs; and (iii) that no malarial ePK clustered with the tyrosine kinase (TyrK) or STE groups, pointing to the absence of three-component MAPK modules in the parasite. A novel family of 20 ePK-related sequences was identified and called FIKK, on the basis of a conserved amino acid motif. The FIKK family seems restricted to Apicomplexa, with 20 members in P. falciparum and just one member in some other Apicomplexan species.

Conclusion
The considerable phylogenetic distance between Apicomplexa and other Eukaryotes is reflected by profound divergences between the kinome of malaria parasites and that of yeast or mammalian cells.
In vitro pharmacokinetics of anti-psoriatic fumaric acid esters
Authors: Litjens Nicolle HR , van Strijen Elisabeth , van Gulpen Co , Mattie Herman , van Dissel Jaap T , Thio H Bing , Nibbering Peter H 
Published: October 2004

Abstract
Background
Psoriasis is a chronic inflammatory skin disease that can be successfully treated with a mixture of fumaric acid esters (FAE) formulated as enteric-coated tablets for oral use. These tablets consist of dimethylfumarate (DMF) and salts of monoethylfumarate (MEF) and its main bioactive metabolite is monomethylfumarate (MMF). Little is known about the pharmacokinetics of these FAE. The aim of the present study was to investigate the hydrolysis of DMF to MMF and the stability of MMF, DMF and MEF at in vitro conditions representing different body compartments.

Results
DMF is hydrolyzed to MMF in an alkaline environment (pH 8), but not in an acidic environment (pH 1). In these conditions MMF and MEF remained intact during the period of analysis (6 h). Interestingly, DMF was hardly hydrolyzed to MMF in a buffer of pH 7.4, but was rapidly hydrolyzed in human serum having the same pH. Moreover, in whole blood the half-life of DMF was dramatically reduced as compared to serum. The concentrations of MMF and MEF in serum and whole blood decreased with increasing time. These data indicate that the majority of the FAE in the circulation are metabolized by one or more types of blood cells. Additional experiments with purified blood cell fractions resuspended in phosphate buffered saline (pH 7.4) revealed that at concentrations present in whole blood monocytes/lymphocytes, but not granulocytes and erythrocytes, effectively hydrolyzed DMF to MMF. Furthermore, in agreement with the data obtained with the pure components of the tablet, the enteric-coated tablet remained intact at pH 1, but rapidly dissolved at pH 8.

Conclusion
Together, these in vitro data indicate that hydrolysis of DMF to MMF rapidly occurs at pH 8, resembling that within the small intestines, but not at pH 1 resembling the pH in the stomach. At both pHs MMF and MEF remained intact. These data explain the observation that after oral FAE intake MMF and MEF, but not DMF, can be readily detected in the circulation of human healthy volunteers and psoriasis patients.
Length of sick leave – Why not ask the sick-listed? Sick-listed individuals predict their length of sick leave more accurately than professionals
Authors: Fleten Nils , Johnsen Roar , Førde Olav Helge 
Published: October 2004

Abstract
Background
The knowledge of factors accurately predicting the long lasting sick leaves is sparse, but information on medical condition is believed to be necessary to identify persons at risk. Based on the current practice, with identifying sick-listed individuals at risk of long-lasting sick leaves, the objectives of this study were to inquire the diagnostic accuracy of length of sick leaves predicted in the Norwegian National Insurance Offices, and to compare their predictions with the self-predictions of the sick-listed.

Methods
Based on medical certificates, two National Insurance medical consultants and two National Insurance officers predicted, at day 14, the length of sick leave in 993 consecutive cases of sick leave, resulting from musculoskeletal or mental disorders, in this 1-year follow-up study. Two months later they reassessed 322 cases based on extended medical certificates. Self-predictions were obtained in 152 sick-listed subjects when their sick leave passed 14 days. Diagnostic accuracy of the predictions was analysed by ROC area, sensitivity, specificity, likelihood ratio, and positive predictive value was included in the analyses of predictive validity.

Results
The sick-listed identified sick leave lasting 12 weeks or longer with an ROC area of 80.9% (95% CI 73.7–86.8), while the corresponding estimates for medical consultants and officers had ROC areas of 55.6% (95% CI 45.6–65.6%) and 56.0% (95% CI 46.6–65.4%), respectively. The predictions of sick-listed males were significantly better than those of female subjects, and older subjects predicted somewhat better than younger subjects. Neither formal medical competence, nor additional medical information, noticeably improved the diagnostic accuracy based on medical certificates.

Conclusion
This study demonstrates that the accuracy of a prognosis based on medical documentation in sickness absence forms, is lower than that of one based on direct communication with the sick-listed themselves.
Prospective study of clinician-entered research data in the Emergency Department using an Internet-based system after the HIPAA Privacy Rule
Authors: Kline Jeffrey A , Johnson Charles L , Webb William B , Runyon Michael S 
Published: October 2004

Abstract
Background
Design and test the reliability of a web-based system for multicenter, real-time collection of data in the emergency department (ED), under waiver of authorization, in compliance with HIPAA.

Methods
This was a phase I, two-hospital study of patients undergoing evaluation for possible pulmonary embolism. Data were collected by on-duty clinicians on an HTML data collection form (prospective e-form), populated using either a personal digital assistant (PDA) or personal computer (PC). Data forms were uploaded to a central, offsite server using secure socket protocol transfer. Each form was assigned a unique identifier, and all PHI data were encrypted, but were password-accessible by authorized research personnel to complete a follow-up e-form.

Results
From April 15, 2003-April 15 2004, 1022 prospective e-forms and 605 follow-up e-forms were uploaded. Complexities of PDA use compelled clinicians to use PCs in the ED for data entry for most forms. No data were lost and server log query revealed no unauthorized entry. Prospectively obtained PHI data, encrypted upon server upload, were successfully decrypted using password-protected access to allow follow-up without difficulty in 605 cases. Non-PHI data from prospective and follow-up forms were available to the study investigators via standard file transfer protocol.

Conclusions
Data can be accurately collected from on-duty clinicians in the ED using real-time, PC-Internet data entry in compliance with the Privacy Rule. Deidentification-reidentification of PHI was successfully accomplished by a password-protected encryption-deencryption mechanism to permit follow-up by approved research personnel.
The evolution of drug-activated nuclear receptors: one ancestral gene diverged into two xenosensor genes in mammals
Authors: Handschin Christoph , Blättler Sharon , Roth Adrian , Looser Renate , Oscarson Mikael , Kaufmann Michel R , Podvinec Michael , Gnerre Carmela , Meyer Urs A 
Published: October 2004

Abstract
Background
Drugs and other xenobiotics alter gene expression of cytochromes P450 (CYP) by activating the pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in mammals. In non-mammalian species, only one xenosensor gene has been found. Using chicken as a model organism, the aim of our study was to elucidate whether non-mammalian species only have one or two xenosensors like mammals.

Results
To explore the evolutionary aspect of this divergence, we tried to identify additional xenobiotic sensing nuclear receptors in chicken using various experimental approaches. However, none of those revealed novel candidates. Ablation of chicken xenobiotic receptor (CXR) function by RNAi or dominant-negative alleles drastically reduced drug-induction in a chicken hepatoma cell line. Subsequently, we functionally and structurally characterized CXR and compared our results to PXR and CAR. Despite the high similarity in their amino acid sequence, PXR and CAR have very distinct modes of activation. Some aspects of CXR function, e.g. direct ligand activation and high promiscuity are very reminiscent of PXR. On the other hand, cellular localization studies revealed common characteristics of CXR and CAR in terms of cytoplasmic-nuclear distribution. Finally, CXR has unique properties regarding its regulation in comparison to PXR and CAR.

Conclusion
Our finding thus strongly suggest that CXR constitutes an ancestral gene which has evolved into PXR and CAR in mammals. Future studies should elucidate the reason for this divergence in mammalian versus non-mammalian species.