bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic and genomic dissection of diabetes in the Cohen rat
Authors: Yagil Chana , Barkalifa Ronit , Sapojnikov Marina , Wechsler Alexander , Ben-Dor David , Weksler-Zangen Sarah , Kaiser Nurit , Raz Itamar , Yagil Yoram
Published: January 2007

We investigated the metabolic and genetic basis of diabetes in the Cohen Diabetic rat, a model of diet-induced diabetes, as a means to identify the molecular mechanisms involved. By altering individual components in the diabetogenic diet, we established that the dietary susceptibility that leads to the development of diabetes in this model is directly related to the high casein and low copper content in chow. The development of diabetes is accompanied by depletion of the acini from the exocrine pancreas and replacement with fat cells, while the appearance of the islets of Langerhans remains intact. With reversion back from diabetogenic to regular diet, the diabetic phenotype disappears but the histological changes in the exocrine pancreas prevail. Using positional cloning, we detected a major quantitative trait locus (QTL) on rat chromosome 4 with a chromosomal span of 4.9 cM, and two additional loci on chromosomes 7 and X. A screen for genes within that QTL in the rat and in the syntenic regions in mouse and man revealed only 23 candidate genes. Notable among these genes is Ica1, which has been causally associated with diabetes and bovine casein. We conclude that the development of diabetes in our model is dependent upon high casein and low copper in diet, that it is accompanied by histomorphological changes in the exocrine but not endocrine pancreas, that it is reversible, and that it is associated with a major QTL on chromosome 4 in which we detected Ica1, a high priority candidate gene.
Microarray and real-time PCR analysis of adrenal gland gene expression in the 7-day-old rat: effects of hypoxia from birth
Authors: Bruder Eric D. , Lee Julie J. , Widmaier Eric P. , Raff Hershel
Published: January 2007

We hypothesize that changes in adrenal gene expression mediate the increased plasma corticosterone and steroidogenesis in rat pups exposed to hypoxia from birth. In the current study, rat pups (with their dams) were exposed to hypoxia from birth and compared with pups from normoxic dams fed ad libitum or pair fed to match the decreased maternal food intake that occurs during hypoxia. Microarray analysis was performed, followed by verification with real-time PCR. Furthermore, the expression of selected genes involved in adrenal function was analyzed by real-time PCR, regardless of microarray results. Hypoxia increased plasma ACTH and corticosterone, while food restriction had no effect. Microarray revealed that many of the genes affected by hypoxia encode proteins that require molecular oxygen (monooxygenases, oxidoreductases, and electron transport), whereas only a few genes known to be involved in adrenal steroidogenesis were affected. Interestingly, the expression of genes involved in mitochondrial function and intermediary metabolism was increased by hypoxia. Real-time PCR detected a small but significant increase in the expression of Cyp21a1 mRNA in the hypoxic adrenal. When decreased maternal food intake was controlled for, the effects of hypoxia were more pronounced, in that real-time PCR detected significant increases in the expression of Star (244%), Cyp21a1 (208%), and Ldlr (233%). The present study revealed that increased plasma corticosterone in rat pups was due to hypoxia per se, and not as a result of decreased food intake by the hypoxic dam. Furthermore, hypoxia induced changes in gene expression that account for more productive and efficient steroidogenesis.
“Sequence Agnosia” in Bálint's Syndrome: Defects in Visuotemporal Processing after Bilateral Parietal Damage
Authors: Malcolm George L. , Barton Jason J. S.
Published: January 2007

Bálint's syndrome is characterized by visuospatial dysfunction, with failure to attend to multiple objects in space and poor spatial localization manifested as impaired reaching and saccadic targeting. Less investigated in this disorder is perceptual processing along the dimension of time. We studied the performance of a patient with Bálint's syndrome on two oddity paradigms in which she had to indicate which of three objects was different in color, shape, or structure. Her initial difficulty with processing multiple objects present simultaneously in different locations recovered, but she had persistent difficulty processing objects seen sequentially at the same location. Further studies showed that this deficit was not due to impairments in sustained attention or in distributing attention over time, but to impaired processing of temporal sequences. The deficit was also present with auditory stimuli, indicating a multimodal failure of temporal sequencing. These findings show that bilateral parietal lesions affect not only the spatial but also the temporal organization of perception.
Selective Attention Supports Working Memory Maintenance by Modulating Perceptual Processing of Distractors
Authors: Sreenivasan Kartik K. , Jha Amishi P.
Published: January 2007

Selective attention has been shown to bias sensory processing in favor of relevant stimuli and against irrelevant or distracting stimuli in perceptual tasks. Increasing evidence suggests that selective attention plays an important role during working memory maintenance, possibly by biasing sensory processing in favor of to-be-remembered items. In the current study, we investigated whether selective attention may also support working memory by biasing processing against irrelevant and potentially distracting information. Event-related potentials (ERPs) were recorded while subjects (n = 22) performed a delayed-recognition task for faces and shoes. The delay period was filled with face or shoe distractors. Behavioral performance was impaired when distractors were congruent with the working memory domain (e.g., face distractor during working memory for faces) relative to when distractors were incongruent with the working memory domain (e.g., face distractor during shoe working memory). If attentional biasing against distractor processing is indeed functionally relevant in supporting working memory maintenance, perceptual processing of distractors is predicted to be attenuated when distractors are more behaviorally intrusive relative to when they are nonintrusive. As such, we predicted that perceptual processing of distracting faces, as measured by the face-sensitive N170 ERP component, would be reduced in the context of congruent (face) working memory relative to incongruent (shoe) working memory. The N170 elicited by distracting faces demonstrated reduced amplitude during congruent versus incongruent working memory. These results suggest that perceptual processing of distracting faces may be attenuated due to attentional biasing against sensory processing of distractors that are most behaviorally intrusive during working memory maintenance.
Intercomparison Study of the Land Surface Process Model and the Common Land Model for a Prairie Wetland in Florida
Authors: Whitfield B. , Jacobs J. M. , Judge J.
Published: January 2007

Common Land Model (CLM) and Land Surface Process (LSP) model simulations are compared to measured values for a 13-day dry-down period with a rapidly decreasing near-surface water table for a marsh wetland community in Florida. LSP was able to provide reasonable estimates without any modifications to the model physics. To obtain reasonable simulations using CLM, the baseline TOPMODEL baseflow generation and the bottom drainage mechanisms were not employed and the lower layers were allowed to remain saturated. In addition, several of CLM’s default wetland vegetation parameters were replaced with grassland parameters. Even after these modifications, CLM underestimated soil water storage. However, both model-simulated soil temperatures showed very good agreement as compared to measured temperatures, capturing both the soil warming during the study period and the diurnal fluctuations. Modeled surface energy fluxes also agreed well with measured values. LSP’s inability to consistently capture latent heat fluxes appears to be linked to its canopy resistance scaling functions. Other minor issues were that CLM’s rooting depth greatly exceeded observed depths and that CLM did not move water in the vadose zone from lower to upper layers during the nighttime as observed in the measurements. Overall, these results suggest that LSP can be applied to characterize a marsh dry down, but that minor modifications could greatly improve results. CLM demonstrated considerable potential, but requires some changes to model physics and default parameters prior to application to wetlands at a subgrid scale.
A Distributed Snow-Evolution Modeling System (SnowModel)
Authors: Liston Glen E. , Elder Kelly
Published: January 2007

SnowModel is a spatially distributed snow-evolution modeling system designed for application in landscapes, climates, and conditions where snow occurs. It is an aggregation of four submodels: MicroMet defines meteorological forcing conditions, EnBal calculates surface energy exchanges, SnowPack simulates snow depth and water-equivalent evolution, and SnowTran-3D accounts for snow redistribution by wind. Since each of these submodels was originally developed and tested for nonforested conditions, details describing modifications made to the submodels for forested areas are provided. SnowModel was created to run on grid increments of 1 to 200 m and temporal increments of 10 min to 1 day. It can also be applied using much larger grid increments, if the inherent loss in high-resolution (subgrid) information is acceptable. Simulated processes include snow accumulation; blowing-snow redistribution and sublimation; forest canopy interception, unloading, and sublimation; snow-density evolution; and snowpack melt. Conceptually, SnowModel includes the first-order physics required to simulate snow evolution within each of the global snow classes (i.e., ice, tundra, taiga, alpine/mountain, prairie, maritime, and ephemeral). The required model inputs are 1) temporally varying fields of precipitation, wind speed and direction, air temperature, and relative humidity obtained from meteorological stations and/or an atmospheric model located within or near the simulation domain; and 2) spatially distributed fields of topography and vegetation type. SnowModel’s ability to simulate seasonal snow evolution was compared against observations in both forested and nonforested landscapes. The model closely reproduced observed snow-water-equivalent distribution, time evolution, and interannual variability patterns.
A Multimodel Analysis, Validation, and Transferability Study of Global Soil Wetness Products
Authors: Gao Xiang , Dirmeyer Paul A.
Published: January 2007

Multimodel ensemble forecasting has been shown to offer a systematic improvement in the skill of climate prediction with atmosphere and ocean circulation models. However, little such work has been done for the land surface component, an important lower boundary for weather and climate forecast models. In this study, the authors examine and evaluate several methods of combining individual global soil wetness products from uncoupled land surface model calculations and coupled land–atmosphere model reanalyses to produce an ensemble analysis. Analyses are verified against observations from the Global Soil Moisture Data Bank (GSMDB) with skill measured by correlation coefficient and root-mean-square error (RMSE). A preliminary transferability study is conducted as well for investigating the feasibility of transferring ensemble regression parameters within two specific regions (Illinois and east-central China) and between these two regions of similar climate and land use. The results show that when sufficient validation data are available, one can use a seasonally dependent linear regression to improve the skill of any individual model simulation of soil wetness. Further improvements in skill can be achieved with more sophisticated ensembling methods, such as the regression-adjusted multimodel ensemble mean analysis and regression-adjusted multimodel analysis. However, all the ensembling schemes involving regression usually do not help improve the skill scores as far as the simulation of anomalies of soil wetness is concerned. In the absence of calibration data, the simple arithmetic ensemble mean across multiple soil wetness products generally does as well or better than the best individual model at any location in the representation of both soil wetness and its anomaly. Transferability from one subset of stations from the Illinois or east-central China dataset to another gives satisfactory results. However, results are poor when transferring regression weights between different regions, even with similar climate regimes and land cover. Such an exercise helps us to understand better the virtues and limitations of various ensembling techniques and enables progress toward creating an optimum, model-independent analysis from a practical point of view.
Community Assessment of Senior Health Using a Telephone Survey and Supplementary Methods
Authors: Jensen Christine J. , Finifter David H. , Wilson Carol E. , Koenig Bryan L.
Published: January 2007

Because of the dramatic growth in the senior population, a community's assessment of the health needs of its older adults has become increasingly important. Telephone surveys have been routinely used to assess a variety of senior issues. Identified limitations of telephone surveys, however, suggest the importance of using supplementary methods. This article reports the findings of an assessment of health issues of seniors in a community with a rapidly increasing population of seniors. The core assessment tool was a telephone survey of a randomly selected sample of community-residing seniors. The two supplementary methods were a survey of those who provide regular care for seniors and focus groups of minority and low-income seniors. These three methods provided valuable information individually and collectively. These findings support the assertion made by the authors that supplementary evaluation of especially informative subgroups is valuable for a comprehensive characterization of the health of community-residing seniors.
Long-Term Care Providers and Their Perceptions of the External Environment: Rural Versus Urban Differences
Authors: Weech-Maldonado Robert , Shea Dennis , Elmendorf Kris
Published: January 2007

Long-term care organizations are facing rapid environmental changes given recent market and policy changes, which include the implementation of the Balanced Budget Act (BBA; 1997), the growthof managed care, the increased number of nursing home alternatives, and nurse staffing shortages. Using survey data, this study examined urban and/or rural differences in the environment perceptions across long-term care provider types in Pennsylvania: nursing homes, home health agencies, and assisted living facilities. In addition, it analyzed how long-term care organizations have responded to the implementation of the BBA (1997). Results show that urban and rural long-term care providers have similarities and differences in their environmental perceptions and in their response to environmental changes. Workforce issues were identified almost universally by rural and urban facilities as the critical industry problem. On the other hand, there were also differences, with rural nursing home providers showing the greatest vulnerability among long-term care organizations.
Food for Thought: Nourishing the Publication of Qualitative Research
Authors: Schoenberg Nancy E. , Shenk Dena , Kart Cary S.
Published: January 2007

In recent years, journal editors have issued loud and earnest calls for high-quality manuscripts based on qualitative methods. Yet, in reviewing the past several years of gerontological journals, including the Journal of Applied Gerontology (JAG), the authors noticed that the rate at which qualitative papers are published has held steady at modest percentages of the total number of published works. This essay explores this seemingly contradictory situation by providing insights into several key questions: Why are not more research articles published that use qualitative methods? Why is it important that qualitative researchers publish their works in applied venues like the JAG? What should authors of qualitative pieces keep in mind when developing their manuscripts?
Flame Retardancy of Thermoplastic Polyurethane and Polyvinyl Chloride by Organoclays
Authors: Beyer Günter
Published: January 2007

Thermooxidative stability and peak of heat release rates of thermoplastic polyurethane nanocomposites are improved by organoclays; but time to ignition of these composites is reduced. A cable with a thermoplastic polyurethane nanocomposite jacket does not pass a simple flame spread test by a Bunsen burner, indicating that the reduction of the peak of heat release rate does not prevent the flame spread. Polyvinyl chloride (PVC) with organoclays shows a fast HCl release by an accelerated chain-stripping reaction of the polymer catalyzed by the quaternary ammonium compound within the organoclays resulting in strong discolorations. Synthesis routes based on ethylene-vinyl acetate copolymer (EVA) or thermoplastic polyurethane (TPU) masterbatches of organoclays strongly diminish the darkening of the PVC compounds. Cone calorimeter experiments do not show remarkably improved flame retardancy properties of PVC filled with organoclays.
Finite Element Analysis of Composite Worm Gears
Authors: Maheedhara S. S. , Pourboghrat F.
Published: January 2007

Worm gears are commonly used in windshield wipers and power windows of automobiles. The goal of this work is to study several material problems, such as production bottlenecks and excessive scrap, resulting from the production of steel worm shafts. A possible solution is explored in this work by characterizing material properties of a promising candidate (glass reinforced acetal copolymer) that can replace steel in worm gears. Finite element analysis of the worm thread under static loading and constant temperature is performed in order to calculate the size of the new composite part. The results obtained in this work support the possibility of manufacturing composite worm shafts that could operate at elevated temperatures without sacrificing part performance, while reducing part weight leading to improved fuel economy, noise reduction, and manufacturing problems associated with the steel part. The finite element analysis shows that compared to a steel gear, the axial pitch of a composite worm gear must be increased by 250% in order for it to operate without failure for 10 years at a constant temperature of 23%C. This increase in the axial pitch would ramp up to 400%, if the composite worm gear is expected to operate for 10 years at a constant temperature of 100 C.
Effect of Plasticizers Content on the Mechanical Properties of Unsaturated Polyester Resin
Authors: Bakar M. , Djaider F.
Published: January 2007

The present work investigates the effect of plasticizers on the mechanical properties of unsaturated polyester (UP) resin. After the curing behavior analysis, several compositions based on UP resin and different amounts of plasticizers are studied. The tensile strength, elastic modulus, elongation at break, impact strength, critical stress intensity factor, hardness as well as glass transition temperature are evaluated as functions of plasticizer content. The results obtained reveal that the impact resistance is maximally improved by approximately 65 and 55%, when 5 and 15 phr dioctyl phthalate (DOP) and tricresyl phosphate (TCP), respectively, are added. The enhancement is more pronounced for the critical stress intensity factor. However, a decrease in hardness and glass transition temperature, but an increase in elongation at break are noticed as expected. In general, TCP compositions exhibit better mechanical properties when compared to that containing DOP.
Relationship of Coping Styles With Quality of Life and Depressive Symptoms in Older Heart Failure Patients
Authors: Klein Dawn M. , Turvey Carolyn L. , Pies Carla J.
Published: January 2007

This study examines the relationship between coping styles, quality of life, and depressive symptoms in older heart failure patients. Eighty heart failure patients seeking treatment in an outpatient heart failure or family practice clinic participated in a study examining depression, disability, and heart failure. Patients completed a clinical interview and questionnaires about mood, functional impairment, comorbid illness, quality of life, and coping. Heart failure severity and maladaptive coping styles, including denial, self-distraction, and self-blame, negatively affected quality of life and depressive symptoms. The use of maladaptive coping strategies involves efforts that divert attention from the illness and suggests the need to provide heart failure patients the skills to directly address the stress associated with their illness. Interventions that target these coping strategies may help patients take a more active role in their heart failure management and may improve psychological and cardiac outcomes.
Influence of Nonwoven Fabrics' Physical Parameters on Thermal and Water Vapor Resistance
Authors: Mazzuchetti Giorgio , Lopardo Giuseppina , Demichelis Roberto
Published: January 2007

This article takes into consideration some constructive parameters of needled nonwoven fabrics used as padding in winter clothes, and their influence on thermal resistance Rct and water vapor resistance Ret. The nonwoven fabric features taken into consideration were the following: substance fibers, their average linear density, and their bulk density. Nonwoven fabrics examined had a fiber content varying from 0.5% to 4% of the total volume of the sample. In these particular conditions, the results obtained showed that the fiber substance has little influence on Rct and Ret. Instead, the average fiber linear density and bulk density of nonwoven fabrics are very important for an accurate design in order to optimize comfort performance.
Nongenomic signaling of the retinoid X receptor through binding and inhibiting Gq in human platelets
Authors: Moraes Leonardo A. , Swales Karen E. , Wray Jessica A. , Damazo Amilcar , Gibbins Jonathan M. , Warner Timothy D. , Bishop-Bailey David
Published: January 2007

Retinoid X receptors (RXRs) are important transcriptional nuclear hormone receptors, acting as either homodimers or the binding partner for at least one fourth of all the known human nuclear receptors. Functional nongenomic effects of nuclear receptors are poorly understood; however, recently peroxisome proliferator-activated receptor (PPAR) \#947;, PPAR\#946;, and the glucocorticoid receptor have all been found active in human platelets. Human platelets express RXR\#945; and RXR\#946;. RXR ligands inhibit platelet aggregation and TXA2 release to ADP and the TXA2 receptors, but only weakly to collagen. ADP and TXA2 both signal via the G protein, Gq. RXR rapidly binds Gq but not Gi/z/o/t/gust in a ligand-dependent manner and inhibits Gq-induced Rac activation and intracellular calcium release. We propose that RXR ligands may have beneficial clinical actions through inhibition of platelet activation. Furthermore, our results demonstrate a novel nongenomic mode for nuclear receptor action and a functional cross-talk between G-protein and nuclear receptor signaling families.
FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly expressed by lymphocytes following HIV-1 infection
Authors: Wilson Timothy J. , Presti Rachel M. , Tassi Ilaria , Overton Edgar T. , Cella Marina , Colonna Marco
Published: January 2007

Fc receptor–like proteins (FcRLs) are a growing family of molecules homologous to FcγRI. Whereas all 7 previously reported Fc receptor homologs are expressed by B cells, here we report a new receptor, FcRL6, that is expressed by cytolytic cells including natural killer (NK) cells and effector and effector-memory CD8+ T cells. FcRL6 contains a novel cytoplasmic cysteine-rich motif and recruits SHP-2 through a phosphorylated ITIM, indicating a potential signaling function in effector lymphocytes. In vitro, FcRL6 does not greatly influence NK-cell or CD8+ T-cell–mediated cytotoxicity and has minimal impact on cytokine secretion. However, FcRL6 expression among T lymphocytes is greatly expanded in human immunodeficiency virus type 1 (HIV-1)–infected individuals, and includes not only effector and effector-memory CD8+ T cells but also populations of CD4+ T cells. Expansion of FcRL6-positive lymphocytes is not related to viral load, but is indicative of the dysregulated expansion of terminally differentiated effector lymphocyte populations in response to chronic HIV-1 infection and may serve as an important marker for chronic immune activation and for tracking the generation of effector cells following immune stimulation.
Donor T-cell alloreactivity against host thymic epithelium limits T-cell development after bone marrow transplantation
Authors: Hauri-Hohl Mathias M. , Keller Marcel P. , Gill Jason , Hafen Katrin , Pachlatko Esther , Boulay Thomas , Peter Annick , Holländer Georg A. , Krenger Werner
Published: January 2007

Acute graft-versus-host disease (aGVHD) impairs thymus-dependent T-cell regeneration in recipients of allogeneic bone marrow transplants through yet to be defined mechanisms. Here, we demonstrate in mice that MHC-mismatched donor T cells home into the thymus of unconditioned recipients. There, activated donor T cells secrete IFN-γ, which in turn stimulates the programmed cell death of thymic epithelial cells (TECs). Because TECs themselves are competent and sufficient to prime naive allospecific T cells and to elicit their effector function, the elimination of host-type professional antigen-presenting cells (APCs) does not prevent donor T-cell activation and TEC apoptosis, thus precluding normal thymopoiesis in transplant recipients. Hence, strategies that protect TECs may be necessary to improve immune reconstitution following allogeneic bone marrow transplantation.
Targeting aurora kinases as therapy in multiple myeloma
Authors: Shi Yijiang , Reiman Tony , Li Weiqun , Maxwell Christopher A. , Sen Subrata , Pilarski Linda , Daniels Tracy R. , Penichet Manuel L. , Feldman Rick , Lichtenstein Alan
Published: January 2007

The aurora kinases facilitate transit from G2 through cytokinesis and, thus, are targets in cancer therapy. Multiple myeloma (MM) is a malignancy characterized by genetic instability, suggesting a disruption of checkpoints that arrest cells at G2M when injury to the mitotic machinery occurs. Since deficient checkpoints would prevent cell cycle arrest and may render cells susceptible to apoptosis in mitosis and since aurora kinases are intermediaries in checkpoint pathways, we tested antimyeloma effects of 2 agents that inhibit aurora kinases. Both inhibited growth of MM lines and primary myeloma samples at nanomolar concentrations while having less of an effect on proliferating lymphocytes and hematopoietic cells. MM cells were not protected by IL-6 or activating mutations of Ras. Antimyeloma effects included induction of tetraploidy followed by apoptosis. Apoptosis correlated with inhibition of aurora activity as shown by reduction of histone 3B phosphorylation. Ectopic expression of aurora A protected MM cells against aurora inhibitors but had no effect on apoptosis induced by bortezomib. As expression of RHAMM in MM contributes to genetic instability, we tested effects of RHAMM. RHAMM overexpression enhanced sensitivity to apoptosis and RHAMM silencing decreased sensitivity. These results suggest potential for aurora kinase inhibitors in MM especially in patients in whom RHAMM is overexpressed.
Involvement of Fyn kinase in Kit and integrin-mediated Rac activation, cytoskeletal reorganization, and chemotaxis of mast cells
Authors: Samayawardhena Lionel A. , Kapur Reuben , Craig Andrew W. B.
Published: January 2007

Kit receptor and its ligand stem cell factor (SCF) are critical regulators of mast cell production, proliferation, degranulation, and chemotaxis. In this study, we investigated how Fyn kinase regulates chemotaxis of mast cells toward SCF. On β1-integrin engagement, Fyn-deficient (fyn−/−) mast cells displayed a striking defect in cell spreading and lamellipodia formation compared to wild-type mast cells. The hematopoietic-specific Src family kinases (Lyn/Fgr/Hck) were not required for initial SCF-induced cell spreading. Reduced SCF-induced activation of Rac1 and Rac2 GTPases, p38 mitogen-activated protein kinase, and filamentous actin polymerization was observed in fyn−/− mast cells compared to wild-type mast cells. Retroviral-mediated expression of Fyn, constitutively active forms of Rac2 or phosphatidylinositol 3-kinase (PI3K) in fyn−/− mast cells rescued defects in SCF-induced cell polarization and chemotaxis of Fyn-deficient mast cells. Thus, we conclude that Fyn kinase plays a unique role upstream of PI3K and Rac GTPases to promote the reorganization of the cytoskeleton during mast cell spreading and chemotaxis.
Least-squares methods for identifying biochemical regulatory networks from noisy measurements
Authors: Kim Jongrae , Bates Declan G , Postlethwaite Ian , Heslop-Harrison Pat , Cho Kwang-Hyun
Published: January 2007

Background

We consider the problem of identifying the dynamic interactions in biochemical networks from noisy experimental data. Typically, approaches for solving this problem make use of an estimation algorithm such as the well-known linear Least-Squares (LS) estimation technique. We demonstrate that when time-series measurements are corrupted by white noise and/or drift noise, more accurate and reliable identification of network interactions can be achieved by employing an estimation algorithm known as Constrained Total Least Squares (CTLS). The Total Least Squares (TLS) technique is a generalised least squares method to solve an overdetermined set of equations whose coefficients are noisy. The CTLS is a natural extension of TLS to the case where the noise components of the coefficients are correlated, as is usually the case with time-series measurements of concentrations and expression profiles in gene networks.

Results

The superior performance of the CTLS method in identifying network interactions is demonstrated on three examples: a genetic network containing four genes, a network describing p53 activity and mdm2 messenger RNA interactions, and a recently proposed kinetic model for interleukin (IL)-6 and (IL)-12b messenger RNA expression as a function of ATF3 and NF-κ B promoter binding. For the first example, the CTLS significantly reduces the errors in the estimation of the Jacobian for the gene network. For the second, the CTLS reduces the errors from the measurements that are corrupted by white noise and the effect of neglected kinetics. For the third, it allows the correct identification, from noisy data, of the negative regulation of (IL)-6 and (IL)-12b by ATF3.

Conclusion

The significant improvements in performance demonstrated by the CTLS method under the wide range of conditions tested here, including different levels and types of measurement noise and different numbers of data points, suggests that its application will enable more accurate and reliable identification and modelling of biochemical networks.
Inter-population variability of DEFA3 gene absence: correlation with haplotype structure and population variability
Authors: Ballana Ester , González Juan Ramón , Bosch Nina , Estivill Xavier
Published: January 2007

Background

Copy number variants (CNVs) account for a significant proportion of normal phenotypic variation and may have an important role in human pathological variation. The α-defensin cluster on human chromosome 8p23.1 is one of the better-characterized CNVs, in which high copy number variability affecting the DEFA1 and DEFA3 genes has been reported. Moreover, the DEFA3 gene has been found to be absent in a significant proportion of control population subjects. CNVs involving immune genes, such as α-defensins, are possibly contributing to innate immunity differences observed between individuals and influence predisposition and susceptibility to disease.

Results

We have tested the DEFA3 absence in 697 samples from different human populations. The proportion of subjects lacking DEFA3 has been found to vary from 10% to 37%, depending on the population tested, suggesting differences in innate immune function between populations. Absence of DEFA3 was correlated with the region's haplotype block structure. African samples showed a higher intra-populational variability together with the highest proportion of subjects without DEFA3 (37%). Association analysis of DEFA3 absence with 136 SNPs from a 100-kb region identified a conserved haplotype in the Caucasian population, extending for the whole region.

Conclusion

Complexity and variability are essential genomic features of the α-defensin cluster at the 8p23.1 region. The identification of population differences in subjects lacking the DEFA3 gene may be suggestive of population-specific selective pressures with potential impact on human health.
Phylogenetic distribution of translational GTPases in bacteria
Authors: Margus Tõnu , Remm Maido , Tenson Tanel
Published: January 2007

Background

Translational GTPases are a family of proteins in which GTPase activity is stimulated by the large ribosomal subunit. Conserved sequence features allow members of this family to be identified.

Results

To achieve accurate protein identification and grouping we have developed a method combining searches with Hidden Markov Model profiles and tree based grouping. We found all the genes for translational GTPases in 191 fully sequenced bacterial genomes. The protein sequences were grouped into nine subfamilies.

Analysis of the results shows that three translational GTPases, the translation factors EF-Tu, EF-G and IF2, are present in all organisms examined. In addition, several copies of the genes encoding EF-Tu and EF-G are present in some genomes. In the case of multiple genes for EF-Tu, the gene copies are nearly identical; in the case of multiple EF-G genes, the gene copies have been considerably diverged. The fourth translational GTPase, LepA, the function of which is currently unknown, is also nearly universally conserved in bacteria, being absent from only one organism out of the 191 analyzed. The translation regulator, TypA, is also present in most of the organisms examined, being absent only from bacteria with small genomes.

Surprisingly, some of the well studied translational GTPases are present only in a very small number of bacteria. The translation termination factor RF3 is absent from many groups of bacteria with both small and large genomes. The specialized translation factor for selenocysteine incorporation – SelB – was found in only 39 organisms. Similarly, the tetracycline resistance proteins (Tet) are present only in a small number of species.

Proteins of the CysN/NodQ subfamily have acquired functions in sulfur metabolism and production of signaling molecules. The genes coding for CysN/NodQ proteins were found in 74 genomes. This protein subfamily is not confined to Proteobacteria, as suggested previously but present also in many other groups of bacteria.

Conclusion

Four of the translational GTPase subfamilies (IF2, EF-Tu, EF-G and LepA) are represented by at least one member in each bacterium studied, with one exception in LepA. This defines the set of translational GTPases essential for basic cell functions.
Energetics of the protein-DNA-water interaction
Authors: Spyrakis Francesca , Cozzini Pietro , Bertoli Chiara , Marabotti Anna , Kellogg Glen E , Mozzarelli Andrea
Published: January 2007

Background

To understand the energetics of the interaction between protein and DNA we analyzed 39 crystallographically characterized complexes with the HINT (Hydropathic INTeractions) computational model. HINT is an empirical free energy force field based on solvent partitioning of small molecules between water and 1-octanol. Our previous studies on protein-ligand complexes demonstrated that free energy predictions were significantly improved by taking into account the energetic contribution of water molecules that form at least one hydrogen bond with each interacting species.

Results

An initial correlation between the calculated HINT scores and the experimentally determined binding free energies in the protein-DNA system exhibited a relatively poor r2 of 0.21 and standard error of ± 1.71 kcal mol-1. However, the inclusion of 261 waters that bridge protein and DNA improved the HINT score-free energy correlation to an r2 of 0.56 and standard error of ± 1.28 kcal mol-1. Analysis of the water role and energy contributions indicate that 46% of the bridging waters act as linkers between amino acids and nucleotide bases at the protein-DNA interface, while the remaining 54% are largely involved in screening unfavorable electrostatic contacts.

Conclusion

This study quantifies the key energetic role of bridging waters in protein-DNA associations. In addition, the relevant role of hydrophobic interactions and entropy in driving protein-DNA association is indicated by analyses of interaction character showing that, together, the favorable polar and unfavorable polar/hydrophobic-polar interactions (i.e., desolvation) mostly cancel.
Emergency correction of coagulation before major surgery in two elderly patients on oral anticoagulation
Authors: Angelo Marzia , Gutmann Bernhard , Adami Michele , Zagler Bernd , Zelger Anton , Pechlaner Christoph , Wiedermann Christian J
Published: January 2007

Recommendations for urgent reversal of oral anticoagulation with vitamin K1 antagonists are largely derived from case series employing empirical dosing regimens with vitamin K1 and prothrombin complex concentrates. Data on the use of prothrombin complex concentrates in this indication are scarce in the elderly who are at high risk of both hemorrhagic and thrombotic complications. The two cases presented here describe patients older than 75 years who underwent rapid International Normalized Ratio (INR) reversal with prothrombin complex concentrates for surgical treatment of a bleeding ruptured spleen and for emergency surgery of a dissecting aorta. Both patients had their INRs rapidly corrected to ≤ 1.6 and underwent operation without complications. Evidence on treatment of patients who present with elevated INR and who have major bleeding or need to undergo emergency surgery is based mainly on observational studies. The two elderly patients presented here underwent successful emergency surgery after their INRs had been corrected with the intravenous use of vitamin K1 in combination with prothrombin complex concentrate that was administered according to current guideline recommendations.
Progress and Future of Molecular Pain
Authors: Gu Jianguo , Zhuo Min
Published: January 2007

Since its launch at the beginning of 2005, Molecular Pain has published pain research articles that cover broad areas including: genetics, molecular and cellular biology, synaptic and neuronal mechanisms, novel animal models and human functional imaging studies. One important feature of Molecular Pain is its high speed in manuscript processing and publication, making the journal one of the best places for pain researchers to publish their novel findings.
Effects of hyaluronan treatment on lipopolysaccharide-challenged fibroblast-like synovial cells
Authors: Santangelo Kelly S , Johnson Amanda L , Ruppert Amy S , Bertone Alicia L
Published: January 2007

Numerous investigations have reported the efficacy of exogenous hyaluronan (HA) in modulating acute and chronic inflammation. The current study was performed to determine the in vitro effects of lower and higher molecular weight HA on lipopolysaccharide (LPS)-challenged fibroblast-like synovial cells. Normal synovial fibroblasts were cultured in triplicate to one of four groups: group 1, unchallenged; group 2, LPS-challenged (20 ng/ml); group 3, LPS-challenged following preteatment and sustained treatment with lower molecular weight HA; and group 4, LPS-challenged following pretreatment and sustained treatment with higher molecular weight HA. The response to LPS challenge and the influence of HA were compared among the four groups using cellular morphology scoring, cell number, cell viability, prostaglandin E2 (PGE2) production, IL-6 production, matrix metalloproteinase 3 (MMP3) production, and gene expression microarray analysis. As expected, our results demonstrated that LPS challenge induced a loss of characteristic fibroblast-like synovial cell culture morphology (P < 0.05), decreased the cell number (P < 0.05), increased PGE2 production 1,000-fold (P < 0.05), increased IL-6 production 15-fold (P < 0.05), increased MMP3 production threefold (P < 0.05), and generated a profile of gene expression changes typical of LPS (P < 0.005). Importantly, LPS exposure at this concentration did not alter the cell viability. Higher molecular weight HA decreased the morphologic change (P < 0.05) associated with LPS exposure. Both lower and higher molecular weight HA significantly altered a similar set of 21 probe sets (P < 0.005), which represented decreased expression of inflammatory genes (PGE2, IL-6) and catabolic genes (MMP3) and represented increased expression of anti-inflammatory and anabolic genes. The molecular weight of the HA product did not affect the cell number, the cell viability or the PGE2, IL-6, or MMP3 production. Taken together, the anti-inflammatory and anticatabolic gene expression profiles of fibroblast-like synovial cells treated with HA and subsequently challenged with LPS support the pharmacologic benefits of treatment with HA regardless of molecular weight. The higher molecular weight HA product provided a cellular protective effect not seen with the lower molecular weight HA product.
From Parallel Universes to Possible Worlds: Ontological Pluralism in Physics, Narratology, and Narrative
Authors: Ryan Marie-Laure
Published: January 2007

This essay explores how theoretical physics, narratology, and narrative itself deal with the idea that reality consists of a plurality of worlds. In physics, the existence of parallel universes has been postulated on the cosmic level to describe what lies on the other side of black holes and, on the level of subatomic particles, to avoid the paradoxes of quantum mechanics. In narratology, the philosophical idea of a plurality of possible worlds and the contrast between the actual and the possible provide a model of the cognitive pattern into which readers organize information in order to interpret it as a story. But the many-worlds interpretation of physics and the possible worlds (PW) model of narrative differ in their conception of the ontological status of the multiple worlds: in physics they are all actual, while narrative theory stresses the contrast between actuality and mere possibility. This does not mean that the PW model is incompatible with the many-worlds cosmology proposed by physics: faced with a narrative that presents multiple realities as existing objectively, the theory would simply claim that the actual domain is made up of a number of different worlds and that the distinction actual/nonactual repeats itself within each of these parts. The last section of the essay explores what it takes for a narrative to impose a many-worlds cosmology, distinguishing these narratives from other texts that present contradictory versions of facts and situating them with respect to three types of story common in fantasy and science fiction: the narrative of transworld exploration, the narrative of alternate history, and the time-travel narrative.
Wolfgang Iser's Eighteenth Century
Authors: Folkenflik Robert
Published: January 2007

A stage in the history of reading underlies the origins of Wolfgang Iser's method. His distinctive theory of reading is adumbrated in the writings of the period of his original specialty, the eighteenth century. In The Implied Reader Iser takes his theoretical hints and directions from the narrators of Fielding and Sterne. Through an examination of the chapters on eighteenth-century novels in The Implied Reader (and of Laurence Sterne: Tristram Shandy) as well as the theoretical position of The Act of Reading, this essay argues that by utilizing a range of eighteenth-century writers who insist upon the role of the reader's imagination in a process that leads to different meanings for each, Iser proposes that readers should read as they demonstrably did read during the eighteenth century rather than as they read in the nineteenth and early twentieth centuries. The importance of Wolfgang Iser's early work in the history of Anglo-German aesthetics is that he recovered, brought to consciousness, theorized, and extended the implications of a mode of reading largely bypassed during the last several centuries.
AIDS and the Postmodern Subject: Joan Retallack's “AID/I/SAPPEARANCE”
Authors: Walpert Bryan
Published: January 2007

In the context of growing interest in the use of science in contemporary poetry, this essay offers a close reading of Joan Retallack's poem “AID/I/SAPPEARANCE” (1998a) as an extended case study of one use of science: the subversion of scientific language. Retallack uses two connected lines of the postmodern critique of science—linguistic slippage and paradigm-dependency—not to subvert or to critique science as an end in itself but to return attention to the human subject, specifically in the context of AIDS, suggesting that the individual becomes lost in the analytical, object-centered epistemology of science. The essay suggests that, in doing so, Retallack offers a defense of the subject on the basis of postmodern theories known for their critique of subjectivity.
The glycosyltransferase Fringe promotes Delta-Notch signaling between neurons and glia, and is required for subtype-specific glial gene expression
Authors: Thomas Graham B. , van Meyel Donald J.
Published: January 2007

The development, organization and function of central nervous systems depend on interactions between neurons and glial cells. However, the molecular signals that regulate neuron-glial communication remain elusive. In the ventral nerve cord of Drosophila, the close association of the longitudinal glia (LG) with the neuropil provides an excellent opportunity to identify and characterize neuron-glial signals in vivo. We have found that the activity and restricted expression of the glycosyltransferase Fringe (Fng)renders a subset of LG sensitive to activation of signaling through the Notch(N) receptor. This is the first report showing that modulation of N signaling by Fng is important for central nervous system development in any organism. In each hemisegment of the nerve cord the transcription factor Prospero (Pros) is selectively expressed in the six most anterior LG. Pros expression is specifically reduced in fng mutants, and is blocked by antagonism of the N pathway. The N ligand Delta (Dl), which is expressed by a subset of neurons, cooperates with Fng for N signaling in the anterior LG, leading to subtype-specific expression of Pros. Furthermore, ectopic Pros expression in posterior LG can be triggered by Fng, and by Dl derived from neurons but not glia. This effect can be mimicked by direct activation of the N pathway within glia. Our genetic studies suggest that Fng sensitizes N on glia to axon-derived Dl and that enhanced neuron-glial communication through this ligand-receptor pair is required for the proper molecular diversity of glial cell subtypes in the developing nervous system.