bluuebunny/crossref_metadata_2025 huggingface dataset:
Paradoxical effects of interleukin-18 on the severity of acute graft-versus-host disease mediated by CD4+ and CD8+ T-cell subsets after experimental allogeneic bone marrow transplantation
Authors: Min Chang-Ki , Maeda Yoshinobu , Lowler Kathleen , Liu Chen , Clouthier Shawn , Lofthus David , Weisiger Elizabeth , Ferrara James L. M. , Reddy Pavan
Published: July 2004

Administration of exogenous interleukin-18 (IL-18) regulates experimental acute graft-versus-host disease (GVHD) in a Fas-dependent manner when donor CD4+ T cells are required for mortality after experimental allogeneic bone marrow transplantation (BMT). However, CD4+ and CD8+ T cells can induce acute GVHD after clinical allogeneic BMT, and the role of IL-18 in CD8+-mediated acute GVHD is unknown. We, therefore, determined the role of IL-18 in GVHD mediated by CD4+ or CD8+ T cells across major histocompatibility complex (MHC) class II- and class I-disparate allogeneic BMT, respectively. Administering IL-18 significantly increased survival in CD4+-mediated GVHD but reduced survival in CD8+-mediated GVHD. This increase in deaths was associated with significantly greater clinical, biochemical, and histopathologic parameters of GVHD damage and was independent of Fas expression on donor T cells. Administering IL-18 significantly enhanced allospecific cytotoxic function and expansion of CD8+ cells. Endogenous IL-18 was critical to GVHD mediated by CD8+ donor T cells because IL-18 receptor-deficient donors caused significantly less GVHD but exacerbated CD4+-mediated, GVHD-related death. Furthermore, administering anti-IL-18 monoclonal antibody significantly reduced CD8+-mediated, GVHD-related death. Together these findings demonstrate that IL-18 has paradoxical effects on CD4+ and CD8+ cell-mediated GVHD. (Blood. 2004;104:3393-3399)
G6PD is indispensable for erythropoiesis after the embryonic-adult hemoglobin switch
Authors: Paglialunga Francesca , Fico Annalisa , Iaccarino Ingram , Notaro Rosario , Luzzatto Lucio , Martini Giuseppe , Filosa Stefania
Published: July 2004

Glucose 6-phosphate dehydrogenase (G6PD) (EC 1.1.1.42) is an essential enzyme for the rapid production of NADPH, as required on exposure to oxidative stress. Mouse embryonic stem (ES) cells can produce all embryonic and fetal/adult cell types. By studying the in vitro differentiation of embryoid bodies produced from G6pdΔ ES cells that are totally unable to produce G6PD protein, we found that these cells are able to differentiate into mesodermal cells, cardiomyocytes, hepatocytes, and primitive erythroid cells. However, we show here that, after the hemoglobin switch has taken place, definitive erythrocytes die by apoptosis. This apoptotic death is delayed by reducing agents and by a caspase inhibitor, but it is prevented only by the restoration of G6PD activity. Thus, G6PD proves indispensable for definitive erythropoiesis.
Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ibα
Authors: Kanaji Taisuke , Russell Susan , Cunningham Janet , Izuhara Kenji , Fox Joan E. B. , Ware Jerry
Published: July 2004

We have investigated the ability of glycoprotein (GP) Ibα, a megakaryocytic gene product, to sequester the signal transduction protein 14-3-3ξ and to influence megakaryocytopoiesis. Using a Gp1ba–/– mouse colony, we compared the rescued phenotypes produced by a wild-type human GP Ibα allele or a similar allele containing a 6-residue cytoplasmic tail truncation that abrogates binding to 14-3-3ξ. The observed phenotypes illustrate an involvement for GP Ibα in thrombopoietin-mediated events of megakaryocyte proliferation, polyploidization, and the expression of apoptotic markers in maturing megakaryocytes. We developed a hypothesis for the involvement of a GP Ibα/14-3-3ξ/PI-3 kinase complex in regulating thrombopoietin-mediated responses. An observed increase in thrombopoietin-mediated Akt phosphorylation in the truncated variant supported the hypothesis and led to the development of a model in which the GP Ibα cytoplasmic tail sequestered signaling proteins during megakaryocytopoiesis and, as such, became a critical regulator in the temporal sequence of events that led to normal megakaryocyte maturation.
Mouse CD99 participates in T-cell recruitment into inflamed skin
Authors: Bixel Gabriele , Kloep Stephan , Butz Stefan , Petri Björn , Engelhardt Britta , Vestweber Dietmar
Published: July 2004

Human CD99 is a small highly O-glycosylated cell-surface protein expressed on most leukocytes. It was recently found to be expressed at endothelial cell contacts and to participate in the transendothelial migration (TEM) of monocytes in vitro. In order to analyze the physiologic relevance of CD99 in vivo we searched for the mouse homolog. We cloned a mouse cDNA coding for a protein 45% identical in its sequence with human CD99. Based on the cDNA, we generated antibodies against this mouse homolog of CD99, which detected the antigen on most leukocytes, on endothelia of various tissues, and at cell contacts of cultured endothelial cells. Cell aggregation of CD99-transfected Chinese hamster ovary (CHO) cells was completely blocked by anti-CD99 antibodies. The same antibodies inhibited TEM of lymphocytes in vitro, independent of whether T cells or endothelial cells were preincubated with antibodies. In a cutaneous delayed-type hypersensitivity (DTH) reaction, anti-CD99 antibodies inhibited the recruitment of in vivo–activated T cells into inflamed skin as well as edema formation. We conclude that mouse CD99 participates in the TEM of lymphocytes and in their recruitment to inflamed skin in vivo. This establishes CD99 as a valid target for interference with cutaneous inflammatory processes.
PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis
Authors: Uutela Marko , Wirzenius Maria , Paavonen Karri , Rajantie Iiro , He Yulong , Karpanen Terhi , Lohela Marja , Wiig Helge , Salven Petri , Pajusola Katri , Eriksson Ulf , Alitalo Kari
Published: July 2004

Platelet-derived growth factor-D (PDGF-D) is a recently characterized member of the PDGF family with unknown in vivo functions. We investigated the effects of PDGF-D in transgenic mice by expressing it in basal epidermal cells and then analyzed skin histology, interstitial fluid pressure, and wound healing. When compared with control mice, PDGF-D transgenic mice displayed increased numbers of macrophages and elevated interstitial fluid pressure in the dermis. Wound healing in the transgenic mice was characterized by increased cell density and enhanced recruitment of macrophages. Macrophage recruitment was also the characteristic response when PDGF-D was expressed in skeletal muscle or ear by an adeno-associated virus vector. Combined expression of PDGF-D with vascular endothelial growth factor-E (VEGF-E) led to increased pericyte/smooth muscle cell coating of the VEGF-E–induced vessels and inhibition of the vascular leakiness that accompanies VEGF-E–induced angiogenesis. These results show that full-length PDGF-D is activated in tissues and is capable of increasing interstitial fluid pressure and macrophage recruitment and the maturation of blood vessels in angiogenic processes.
Long-term acquisition of allergen-specific IgE and asthma following allogeneic bone marrow transplantation from allergic donors
Authors: Hallstrand Teal S. , Sprenger Jay D. , Agosti Jan M. , Longton Gary M. , Witherspoon Robert P. , Henderson William R.
Published: July 2004

Adoptive transfer of allergen-specific immunoglobulin E (IgE) from atopic donors to nonatopic recipients occurs during the first year following bone marrow transplantation (BMT). Mature B- and T-cell clones with allergen-specific memory and hematopoietic progenitor cells are transferred through BMT. The objective of this study was to characterize the long-term rate of allergic sensitization and development of clinical allergic diseases following BMT from atopic donors. A long-term follow-up study was conducted in a cohort of donor and recipient pairs with moderate-to-severe allergic disease in the donor prior to BMT. Assessments of allergen-specific IgE, clinical rhinitis, and asthma were made in the donors prior to BMT and in the recipients with a mean follow-up of 15.5 years after BMT. From an initial cohort of 12 bone marrow transplant recipients who received marrow from allergic donors, 5 long-term survivors were identified. Allergen-specific IgE transferred from donor to recipient following BMT frequently persisted, and a high rate of de novo allergic sensitization was observed between 1 and 14 years after BMT. These events were associated with elevation in total IgE, and development of allergic rhinitis and asthma at long-term follow-up. We conclude that marrow-derived immune cells from allergic donors can transfer the predisposition to allergy and asthma.
New strategies to improve exercise tolerance in chronic obstructive pulmonary disease
Authors: Ambrosino N. , Strambi S.
Published: July 2004

Breathlessness is the most common symptom limiting exercise in patients with chronic obstructive pulmonary disease (COPD). Exercise training can improve both exercise tolerance and health status in these patients, intensity being of key importance. Nevertheless, in these patients extreme breathlessness and/or peripheral muscle fatigue may prevent patients from higher levels of intensity. In this review article the literature concerning the different ways to optimise exercise tolerance in patients with COPD, with the objective of enhancing the tolerance to higher exercise training intensity, is summarised.

Continuous positive airway pressure and different modalities of noninvasive positive pressure ventilation (NPPV) may reduce breathlessness and increase exercise tolerance in these patients. Respiratory muscle unloading and reduction in intrinsic positive end-expiratory pressure have been considered among mechanisms underlying these effects. Nevertheless, the role of NPPV in pulmonary rehabilitation, if any, is still controversial. The addition of nocturnal domiciliary NPPV during a daily exercise programme in patients with severe COPD resulted in an improvement in exercise tolerance and quality of life.

In patients with severe COPD application of electrical stimulation combined with active limb mobilisation significantly improved muscle strength, and interval training has been shown capable of inducing physiological training effects.

Oxygen supplementation in patients who do not desaturate during exercise seems to be the most promising treatment, since it allows for higher exercise intensities and, therefore, superior training efficacy.

In conclusion, further studies are needed to define the appropriate patients in order to generalise such interventions. The modalities discussed should be used as adjuncts to a well designed comprehensive respiratory rehabilitation programme.
Sarcoidosis and granuloma genes: a family-based study in African-Americans
Authors: Rybicki B.A. , Maliarik M.J. , Poisson L.M. , Iannuzzi M.C.
Published: July 2004

The evidence for a genetic component in the aetiology of sarcoidosis includes familial aggregation, associations with genetic polymorphisms, and linkage to the major histocompatibility complex class region on chromosome 6p. Unfortunately, the majority of genetic associations with sarcoidosis have not been consistently replicated.

In the present study, using a family-based study design, which controls for population stratification, the authors attempted to replicate previously reported associations between sarcoidosis and three attractive candidate genes studied primarily in case-control samples.

In 225 nuclear families, ascertained through African Americans with a history of sarcoidosis, no evidence was found for an association between sarcoidosis susceptibility and polymorphisms in the angiotensin converting enzyme, vitamin D receptor and tumour necrosis factor‐α genes. Further analyses of chronic and acute disease phenotypes failed to reveal any notable associations. Assuming an underlying inheritance model with an additive allelic effect on disease risk, the current study had ∼80–90% statistical power to detect a 3‐fold increased risk associated with the putative risk allele of the polymorphisms under study.

The present authors conclude that in African-Americans, the angiotensin converting enzyme, vitamin D receptor, and tumour necrosis factor‐α genes are not significant risk factors for sarcoidosis susceptibility.
Dyspnoea at rest and at the end of different exercises in patients with near-fatal asthma
Authors: Barreiro E. , Gea J. , Sanjuás C. , Marcos R. , Broquetas J. , Milic-Emili J.
Published: July 2004

Blunted perception of dyspnoea under resistive loading has been observed in patients with a history of near-fatal asthma (NFA). The perception of dyspnoea at rest and at the end point of various exercises was assessed in such patients.

Respiratory function and exercise capacity (6‐min walking distance, incremental cycloergometry and inspiratory threshold loading) were assessed in seven NFA and eight non-NFA patients. Dyspnoea (Borg scale) was measured at rest and at the end point of the various exercises.

Dyspnoea at rest was significantly lower in NFA patients. Although exercise tolerance was similarly reduced in both the NFA and non-NFA groups, dyspnoea at peak cycle exercise was significantly lower in the former (2.6±2versus6.1±3.8 (Borg scale; mean±sd)), who mainly (86%) stopped because of leg discomfort. A similar trend was observed in the 6‐min walking distance and inspiratory threshold loading tests. Dyspnoea at peak exercise was the best indicator of the NFA condition, with a sensitivity of 100% and specificity of 63% for a Borg scale score of ≤6.

Perception of dyspnoea is blunted in near-fatal asthma patients at both rest and the end point of various forms of exercise. Dyspnoea at peak exercise is the best indicator of the near-fatal asthma condition.
Performance vigilance task and sleepiness in patients with sleep-disordered breathing
Authors: Sforza E. , Haba-Rubio J. , De Bilbao F. , Rochat T. , Ibanez V.
Published: July 2004

Altered vigilance performance has been documented in patients with sleep-related breathing disorders (SRBDs). Sleep fragmentation, sleepiness, respiratory disturbances and nocturnal hypoxaemia have been suggested as the pathogenesis of these deficits, yet it remains difficult to find a good correlation between performance deficits and the above factors. In the present study, which performance measure better characterised SRBD patients and the main factors implicated in these disturbances were examined.

The study group consisted of 152 patients and 45 controls, all examined using a performance vigilance task and subjective sleepiness assessment. Speed and accuracy in the psychomotor vigilance task (PVT) were measured in patients and controls. Objective daytime sleepiness was assessed in the patient group using the maintenance of wakefulness test.

In comparison with controls, PVT accuracy rather than speed seems to be affected in SRBD patients, with lapses and false responses significantly greater in patients with more severe objective sleepiness and higher apnoea/hypopnoea index. Although slowing and increased variability in reaction time were associated with shorter sleep latency in the maintenance of wakefulness test, subjective sleepiness, sleep fragmentation, nocturnal hypoxaemia and apnoea/hypopnoea index influenced mainly PVT accuracy.

It is concluded that vigilance impairment, sleep fragmentation and severity of disease may partially and differentially contribute to the diurnal performance consequences found in sleep-related breathing disorders. Since the psychomotor vigilance task worsening is more marked in accuracy that in speed, measurement of lapses and false responses would better characterise the degree of diurnal impairment in these patients.
Airway iron and iron-regulatory cytokines in cystic fibrosis
Authors: Reid D.W. , Lam Q.T. , Schneider H. , Walters E.H.
Published: July 2004

Iron availability is critical toPseudomonas aeruginosa. The current authors determined sputum iron, ferritin, microalbumin levels and total cell counts (TCC) in 19 adult patients with cystic fibrosis (CF) during an acute exacerbation and repeated analyses following a median of 12 days antibiotic treatment. The current authors also determined sputum interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α levels because of their putative role in intracellular iron homeostasis. Additional data were obtained from 17 stable CF patients, eight patients with stable chronic obstructive pulmonary disease (COPD) and six normal subjects.

Overall, sputum iron, ferritin, microalbumin, IL‐1β and TNF‐α concentrations and TCCs were significantly elevated in the CF patients compared to those with COPD and normal controls. Sputum ferritin levels were significantly elevated in acuteversusstable CF patients and there was a trend for sputum TCC to be higher, but all other inflammatory indices were similar. In the CF patients, sputum iron was positively and strongly related to IL‐1β, TNF‐α, ferritin and microalbumin levels, but negatively related to forced expiratory volume in one second % predicted. In those acute patients who clinically improved with antibiotics (n=14), there were significant decreases in sputum TCC, iron, ferritin and IL‐1β content, but not TNF‐α or albumin levels. However, changes in sputum TNF‐α in acute patients were still closely related to changes in iron, ferritin and albumin content, and changes in IL‐1β were related to changes in sputum ferritin content.

Iron and iron-regulatory cytokines may play a role in cystic fibrosis lung disease and the increased iron content may even facilitatePseudomonas aeruginosainfection.
Multiple system atrophy presenting as central sleep apnoea: Fig. 1.—
Authors: Cormican L.J. , Higgins S. , Davidson A.C. , Howard R. , Williams A.J.
Published: July 2004

A 61‐yr-old male presented with apparent idiopathic central sleep apnoea but after 4 yrs developed features of autonomic, cerebellar and extrapyramidal dysfunction consistent with a diagnosis of multiple system atrophy (MSA).

Though central sleep apnoea can occur in multiple sleep apnoea, it is less frequent than obstructive sleep apnoea and occurs in the later stages of the disease.

The pathogenesis of MSA involves gliosis and neuronal cell loss in specific areas of the central nervous system. Central sleep apnoea in MSA may be due to the depletion of cholinergic neurons in the arcuate nucleus of the medulla by apoptosis.

This is the first description of multiple system atrophy presenting as central sleep apnoea. The current authors believe that multiple system atrophy should be considered in the differential diagnosis of late onset central sleep apnoea and progressive hypoventilation.
Umbilical cord trace elements and minerals and risk of early childhood wheezing and eczema
Authors: Shaheen S.O. , Newson R.B. , Henderson A.J. , Emmett P.M. , Sherriff A. , Cooke M. ,   the ALSPAC Study Team
Published: July 2004

It has been suggested that foetal nutrition might influence the inception of wheezing and atopic disorders in childhood but specific nutrients have not been implicated.

In the Avon Longitudinal Study of Parents and Children umbilical cord samples were assayed for trace elements and minerals, and mothers were asked about wheezing and eczema in their children. Associations of cord concentrations of selenium, zinc, copper, manganese, magnesium, iron, lead and mercury with wheezing at 30–42 months, with wheezing patterns defined by the presence or absence of transient infant, later onset or persistent wheezing at 0–6 months and 30–42 months, respectively (n=2,044), and with eczema at 18–30 months (n=2,173), were analysed.

Cord selenium was negatively associated with persistent wheeze (adjusted odds ratio (OR) per doubling concentration: 0.67). Cord iron was negatively associated with later onset wheeze (OR: 0.86) and with eczema (OR: 0.90). Children with high cord concentrations of selenium and iron were less likely than those with low concentrations to wheeze transiently in infancy.

The level of foetal exposure to selenium and iron may possibly influence the risk of wheezing and eczema in early childhood although, in view of the multiple analyses carried out, it is possible that the main findings occurred by chance.
The TORCH (TOwards a Revolution in COPD Health) survival study protocol: Fig. 1.—
Authors:   The TORCH Study Group
Published: July 2004

Only long-term home oxygen therapy has been shown in randomised controlled trials to increase survival in chronic obstructive pulmonary disease (COPD). There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators, alone or in combination, on mortality in patients with COPD, despite their known benefit in reducing symptoms and exacerbations. The “TOwards a Revolution in COPD Health” (TORCH) survival study is aiming to determine the impact of salmeterol/fluticasone propionate (SFC) combination and the individual components on the survival of COPD patients.

TORCH is a multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Approximately 6,200 patients with moderate-to-severe COPD were randomly assigned tob.i.d.treatment with either SFC (50/500 µg), fluticasone propionate (500 µg), salmeterol (50 µg) or placebo for 3 yrs. The primary end-point is all-cause mortality; secondary end-points are COPD morbidity relating to rate of exacerbations and health status, using the St George's Respiratory Questionnaire. Other end-points include other mortality and exacerbation end-points, requirement for long-term oxygen therapy, and clinic lung function. Safety end-points include adverse events, with additional information on bone fractures.

The first patient was recruited in September 2000 and results should be available in 2006. This paper describes the “TOwards a Revolution in COPD Health” study and explains the rationale behind it.
Effect of freezing of sputum samples on flow cytometric analysis of lymphocyte subsets
Authors: Jaksztat E. , Holz O. , Paasch K. , Kelly M.M. , Hargreave F.E. , Cox G. , Magnussen H. , Jörres R.A.
Published: July 2004

Sputum samples should be processed shortly after induction to prevent cell degradation. For intermediate storage, freezing of homogenised samples or immediate fixation have been shown to be suitable for cytospins. The aim of this study was to investigate whether freezing or immediate fixation of sputum affect the analysis of lymphocyte subsets by flow cytometry.

Selected plugs from 24 sputum samples were homogenised. One aliquot was processed immediately and analysed by flow cytometry. A second aliquot was homogenised, frozen at −20°C after addition of dimethylsulfoxide and stored for a median time of 6 days. In six samples a third aliquot was fixed in formalin after induction and stored for up to 72 h before further processing.

Compared to immediate processing, percentages of total lymphocytes and T‐suppressor cells were elevated after being frozen, with a minor decrease in the T4/T8 ratio. Proportions of total lymphocytes, T‐helper and T‐suppressor cells correlated between native and frozen samples, intra-class correlation coefficients being 0.74, 0.85 and 0.70, respectively. The formalin-fixed aliquots could not be analysed with the antibodies used.

In conclusion, freezing seems to be a suitable technique to store sputum samples for flow cytometry of CD3, CD4 and CD8 lymphocyte subsets. Its effects were minor compared to the variation between subjects.
Reduced inspiratory flow attenuates IL‐8 release and MAPK activation of lung overstretch
Authors: Kotani M. , Kotani T. , Li Z. , Silbajoris R. , Piantadosi C.A. , Huang Y-C.T.
Published: July 2004

Lung overstretch involves mechanical factors, including large tidal volumes (VT), which induce inflammatory responses. The current authors hypothesised that inspiratory flow contributes to ventilator-induced inflammation.

Buffer-perfused rabbit lungs were ventilated for 2 h with 21% O2+5% CO2, positive end-expiratory pressure of 2–3 cmH2O and randomly assigned to either: 1) normalVT(6 mL·kg−1) at respiratory rate (RR) 30, inspiration:expiration time ratio (I:E) 1:1, low inspiratory flow 6 mL·kg−1·s−1; 2) largeVT(12 mL·kg−1) at RR 30, I:E 1:1, high inspiratory flow 12 mL·kg−1·s−1(HRHF); 3) largeVTat RR 15, I:E 1:1, low inspiratory flow 6 mL·kg−1·s−1(LRLF); or 4) largeVTat RR 15, I:E 1:2.3, high inspiratory flow 10 mL·kg−1·s−1(LRHF). Physiological parameters, tumour necrosis factor (TNF)‐α, interleukin (IL)‐8 and activation of mitogen-activated protein kinases (extracellular signal-regulated kinase (ERK)1/2, p38 and stress-activated protein kinase (SAPK)/c‐Jun N‐terminal kinase (JNK)) were measured.

HRHF increased weight gain, perfusate IL‐8 and phosphorylation of ERK1/2, p38 and SAPK/JNK. These responses were absent during LRLF but present during LRHF. Changes in TNF‐α were small. Tissue IL‐8 and phospho‐ERK1/2 staining was localised primarily to smooth muscle, adventitia and bronchial epithelium within larger bronchioles and arterioles.

These results indicate that mild overstretch of perfused lungs during high inspiratory flow enhances inflammatory signalling by cells in lung regions most affected by strong turbulent airflow.
Structural characterization of genomes by large scale sequence-structure threading: application of reliability analysis in structural genomics
Authors: Cherkasov Artem , Ho Sui Shannan J , Brunham Robert C , Jones Steven JM
Published: July 2004

Background

We establish that the occurrence of protein folds among genomes can be accurately described with a Weibull function. Systems which exhibit Weibull character can be interpreted with reliability theory commonly used in engineering analysis. For instance, Weibull distributions are widely used in reliability, maintainability and safety work to model time-to-failure of mechanical devices, mechanisms, building constructions and equipment.

Results

We have found that the Weibull function describes protein fold distribution within and among genomes more accurately than conventional power functions which have been used in a number of structural genomic studies reported to date.

It has also been found that the Weibull reliability parameter β for protein fold distributions varies between genomes and may reflect differences in rates of gene duplication in evolutionary history of organisms.

Conclusions

The results of this work demonstrate that reliability analysis can provide useful insights and testable predictions in the fields of comparative and structural genomics.
Two-stage normalization using background intensities in cDNA microarray data
Authors: Yoon Dankyu , Yi Sung-Gon , Kim Ju-Han , Park Taesung
Published: July 2004

Background

In the microarray experiment, many undesirable systematic variations are commonly observed. Normalization is the process of removing such variation that affects the measured gene expression levels. Normalization plays an important role in the earlier stage of microarray data analysis. The subsequent analysis results are highly dependent on normalization. One major source of variation is the background intensities. Recently, some methods have been employed for correcting the background intensities. However, all these methods focus on defining signal intensities appropriately from foreground and background intensities in the image analysis. Although a number of normalization methods have been proposed, no systematic methods have been proposed using the background intensities in the normalization process.

Results

In this paper, we propose a two-stage method adjusting for the effect of background intensities in the normalization process. The first stage fits a regression model to adjust for the effect of background intensities and the second stage applies the usual normalization method such as a nonlinear LOWESS method to the background-adjusted intensities. In order to carry out the two-stage normalization method, we consider nine different background measures and investigate their performances in normalization. The performance of two-stage normalization is compared to those of global median normalization as well as intensity dependent nonlinear LOWESS normalization. We use the variability among the replicated slides to compare performance of normalization methods.

Conclusions

For the selected background measures, the proposed two-stage normalization method performs better than global or intensity dependent nonlinear LOWESS normalization method. Especially, when there is a strong relationship between the background intensity and the signal intensity, the proposed method performs much better. Regardless of background correction methods used in the image analysis, the proposed two-stage normalization method can be applicable as long as both signal intensity and background intensity are available.
Integrated web service for improving alignment quality based on segments comparison
Authors: Plewczynski Dariusz , Rychlewski Leszek , Ye Yuzhen , Jaroszewski Lukasz , Godzik Adam
Published: July 2004

Background

Defining blocks forming the global protein structure on the basis of local structural regularity is a very fruitful idea, extensively used in description, and prediction of structure from only sequence information. Over many years the secondary structure elements were used as available building blocks with great success. Specially prepared sets of possible structural motifs can be used to describe similarity between very distant, non-homologous proteins. The reason for utilizing the structural information in the description of proteins is straightforward. Structural comparison is able to detect approximately twice as many distant relationships as sequence comparison at the same error rate.

Results

Here we provide a new fragment library for Local Structure Segment (LSS) prediction called FRAGlib which is integrated with a previously described segment alignment algorithm SEA. A joined FRAGlib/SEA server provides easy access to both algorithms, allowing a one stop alignment service using a novel approach to protein sequence alignment based on a network matching approach. The FRAGlib used as secondary structure prediction achieves only 73% accuracy in Q3 measure, but when combined with the SEA alignment, it achieves a significant improvement in pairwise sequence alignment quality, as compared to previous SEA implementation and other public alignment algorithms. The FRAGlib algorithm takes ~2 min. to search over FRAGlib database for a typical query protein with 500 residues. The SEA service align two typical proteins within circa ~5 min. All supplementary materials (detailed results of all the benchmarks, the list of test proteins and the whole fragments library) are available for download on-line at http://ffas.ljcrf.edu/darman/results/.

Conclusions

The joined FRAGlib/SEA server will be a valuable tool both for molecular biologists working on protein sequence analysis and for bioinformaticians developing computational methods of structure prediction and alignment of proteins.
The FU gene and its possible protein isoforms
Authors: Østerlund Torben , Everman David B , Betz Regina C , Mosca Monica , Nöthen Markus M , Schwartz Charles E , Zaphiropoulos Peter G , Toftgård Rune
Published: July 2004

Background

FU is the human homologue of the Drosophila gene fused whose product fused is a positive regulator of the transcription factor Cubitus interruptus (Ci). Thus, FU may act as a regulator of the human counterparts of Ci, the GLI transcription factors. Since Ci and GLI are targets of Hedgehog signaling in development and morphogenesis, it is expected that FU plays an important role in Sonic, Desert and/or Indian Hedgehog induced cellular signaling.

Results

The FU gene was identified on chromosome 2q35 at 217.56 Mb and its exon-intron organization determined. The human developmental disorder Syndactyly type 1 (SD1) maps to this region on chromosome 2 and the FU coding region was sequenced using genomic DNA from an affected individual in a linked family. While no FU mutations were found, three single nucleotide polymorphisms were identified. The expression pattern of FU was thoroughly investigated and all examined tissues express FU. It is also clear that different tissues express transcripts of different sizes and some tissues express more than one transcript. By means of nested PCR of specific regions in RT/PCR generated cDNA, it was possible to verify two alternative splicing events. This also suggests the existence of at least two additional protein isoforms besides the FU protein that has previously been described. This long FU and a much shorter isoform were compared for the ability to regulate GLI1 and GLI2. None of the FU isoforms showed any effects on GLI1 induced transcription but the long form can enhance GLI2 activity. Apparently FU did not have any effect on SUFU induced inhibition of GLI.

Conclusions

The FU gene and its genomic structure was identified. FU is a candidate gene for SD1, but we have not identified a pathogenic mutation in the FU coding region in a family with SD1. The sequence information and expression analyses show that transcripts of different sizes are expressed and subjected to alternative splicing. Thus, mRNAs may contain different 5'UTRs and encode different protein isoforms. Furthermore, FU is able to enhance the activity of GLI2 but not of GLI1, implicating FU in some aspects of Hedgehog signaling.
Age-associated alterations in CXCL1 chemokine expression by murine B cells
Authors: Hu Lina , Dixit Vishwa Deep , de Mello-Coelho Valeria , Taub Dennis D
Published: July 2004

Background

The CXCL1 chemokines, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (KC), have been shown to play a role in a number of pathophysiological disease states including endotoxin-induced inflammation and bacterial meningitis. While the expression of these chemokines has been identified in a variety of cell types in the mouse, little is known about their expression with murine B-lymphocytes.

Results

Here, we demonstrate that highly purified murine splenic B cells are capable of expressing both MIP-2 and KC protein and mRNA upon activation with lipopolysaccharide (LPS) but not in response to anti-μ and anti-CD40 in combination with interleukin-4 (IL-4) stimulation. Moreover, these chemokines are expressed at higher levels in B cells derived from young (4 m) compared to old (24–29 m) mice. Upon fractionation into distinct B-cell subsets, we found that the expression of MIP-2 and KC by aged follicular (FO) B cells is significantly decreased when compared to the same cells from younger mice, while only MIP-2 production was found to be diminished in aged marginal zone (MZ) B cells. Interestingly, MIP-2 and KC production by newly formed (NF) B cells did not significantly differ with age. Moreover, the potential relevance of these findings is supported by the poor ability of LPS-activated aged B cells to specifically mediate CXCL1-dependent leukocyte recruitment when compared to younger B cells.

Conclusion

Overall, the decreased expression of CXCL1 chemokines by aged B cells in response to LPS may have potential implications on the secondary recruitment of leukocytes to sites of microbial infections and inflammation possibly contributing to the increased susceptibility of older subjects to pathogen challenge.
Family-based clusters of cognitive test performance in familial schizophrenia
Authors: Hoti Fabian , Tuulio-Henriksson Annamari , Haukka Jari , Partonen Timo , Holmström Lasse , Lönnqvist Jouko
Published: July 2004

Background

Cognitive traits derived from neuropsychological test data are considered to be potential endophenotypes of schizophrenia. Previously, these traits have been found to form a valid basis for clustering samples of schizophrenia patients into homogeneous subgroups. We set out to identify such clusters, but apart from previous studies, we included both schizophrenia patients and family members into the cluster analysis. The aim of the study was to detect family clusters with similar cognitive test performance.

Methods

Test scores from 54 randomly selected families comprising at least two siblings with schizophrenia spectrum disorders, and at least two unaffected family members were included in a complete-linkage cluster analysis with interactive data visualization.

Results

A well-performing, an impaired, and an intermediate family cluster emerged from the analysis. While the neuropsychological test scores differed significantly between the clusters, only minor differences were observed in the clinical variables.

Conclusions

The visually aided clustering algorithm was successful in identifying family clusters comprising both schizophrenia patients and their relatives. The present classification method may serve as a basis for selecting phenotypically more homogeneous groups of families in subsequent genetic analyses.
Evaluation of reporting timeliness of public health surveillance systems for infectious diseases
Authors: Jajosky Ruth Ann , Groseclose Samuel L
Published: July 2004

Background

Timeliness is a key performance measure of public health surveillance systems. Timeliness can vary by disease, intended use of the data, and public health system level. Studies were reviewed to describe methods used to evaluate timeliness and the reporting timeliness of National Notifiable Diseases Surveillance System (NNDSS) data was evaluated to determine if this system could support timely notification and state response to multistate outbreaks.

Methods

Published papers that quantitatively measured timeliness of infectious disease surveillance systems operating in the U.S. were reviewed. Median reporting timeliness lags were computed for selected nationally notifiable infectious diseases based on a state-assigned week number and various date types. The percentage of cases reported within the estimated incubation periods for each disease was also computed.

Results

Few studies have published quantitative measures of reporting timeliness; these studies do not evaluate timeliness in a standard manner. When timeliness of NNDSS data was evaluated, the median national reporting delay, based on date of disease onset, ranged from 12 days for meningococcal disease to 40 days for pertussis. Diseases with the longer incubation periods tended to have a higher percentage of cases reported within its incubation period. For acute hepatitis A virus infection, which had the longest incubation period of the diseases studied, more than 60% of cases were reported within one incubation period for each date type reported. For cryptosporidiosis, Escherichia coli O157:H7 infection, meningococcal disease, salmonellosis, and shigellosis, less than 40% of cases were reported within one incubation period for each reported date type.

Conclusion

Published evaluations of infectious disease surveillance reporting timeliness are few in number and are not comparable. A more standardized approach for evaluating and describing surveillance system timeliness should be considered; a recommended methodology is presented. Our analysis of NNDSS reporting timeliness indicated that among the conditions evaluated (except for acute hepatitis A infection), the long reporting lag and the variability across states limits the usefulness of NNDSS data and aberration detection analysis of those data for identification of and timely response to multistate outbreaks. Further evaluation of the factors that contribute to NNDSS reporting timeliness is warranted.
Pressure‐dependent seismic response of fractured rock
Authors: Kozlov Evgenii A.
Published: July 2004

Effects of external stress and pore pressure variations on the seismic signature of fractured rocks remain of interest to geoscientists and practicing geophysicists. Commonly, the effects are modeled theoretically, assuming fracture faces to be rough surfaces contacting each other via the surface asperities. The model proposed here differs from other models of this kind in that (1) fracture roughness is described by a single parameter and (2) a controlled degree of hydraulic connectivity between fractures and equant pores is introduced. This adds to the model's convenience and makes it applicable to a wide variety of reservoirs. The model predictions of seismic velocities in fractured rock at variable stress are consistent with experimental data. For fixed effective stress, the model predictions coincide with those obtained using the model with ellipsoidal fractures of certain average aspect ratio and the same fracture porosity.

Apart from known effects, the model introduced predicts an amplification of the stress variation influence on fracturing‐induced anisotropy with an increase of connected equant porosity, a decrease of VP/VSwith effective stress, and implicit frequency dependence of the VP/VSrelation. It is also shown that amplitude versus offset (AVO) anomalies caused by fluid replacement can be seriously distorted if the fluid replacement is accompanied by significant variations of pore pressure, as, for example, at intense gas production. Neglecting these effects can lead to erroneous conclusions on shear modulus dependence on the pore fluid type. Qualitatively, in rocks with azimuthally aligned fracturing, the increase of effective stress affects AVO gradient in about the same way as the increase of water saturation parameter Vw. In contrast, the AVO intercept is not affected by variations of effective stress, while fluid replacement effect on the intercept is significant. Potentially, this can help distinguish the effects of pore pressure variations and fluid replacement on the AVO attributes.
Evidence of electrical anisotropy in limestone formations using the RMT technique
Authors: Linde Niklas , Pedersen Laust B.
Published: July 2004

Azimuthal resistivity surveys are often applied to complement hydrological information or to improve the location of observation boreholes in pump tests. Symmetric electrode configurations cannot distinguish anisotropy from lateral changes or dipping layers, but asymmetric arrays (e.g., the offset Wenner array) can. Tensor radiomagnetotellurics (RMT) is presented as an alternative method in studies of electrical anisotropy in the shallow subsurface. The electromagnetic and geomagnetic transfer functions provide information about the dimensionality of the data. These transfer functions can also be used to find the directions of anisotropy. Data with an anisotropic signature can be inverted for a one‐dimensional (1D) azimuthal anisotropy model. The method is faster than the azimuthal resistivity method.

A 380‐m‐long profile of tensor RMT data (12.7–243 kHz) from limestones that overlie shale on the island of Gotland, Sweden, is used to show the merits of the method. The data have a clear anisotropic signature. The data are inverted for a three‐layer 1D model with azimuthal anisotropy using two different approaches: (1) a moving median filter of five neighboring stations and neglecting static shift parameters; and (2) treating each station separately and including static shifts of the electric field in the inversion. Both inversions show models having a marked anisotropy with anisotropy factors of 3.7 and 4.5, respectively, in the limestones. The second approach has a significantly better data fit. However, the first approach is preferred because the models are smoother from station to station.
Three‐dimensional regularized focusing inversion of gravity gradient tensor component data
Authors: Zhdanov Michael S. , Ellis Robert , Mukherjee Souvik
Published: July 2004

We develop a new method for interpretation of tensor gravity field component data, based on regularized focusing inversion. The focusing inversion makes its possible to reconstruct a sharper image of the geological target than conventional maximum smoothness inversion. This new technique can be efficiently applied for the interpretation of gravity gradiometer data, which are sensitive to local density anomalies. The numerical modeling and inversion results show that the resolution of the gravity method can be improved significantly if we use tensor gravity data for interpretation. We also apply our method for inversion of the gradient gravity data collected by BHP Billiton over the Cannington Ag‐Pb‐Zn orebody in Queensland, Australia. The comparison with the drilling results demonstrates a remarkable correlation between the density anomaly reconstructed by the gravity gradient data and the true structure of the orebody. This result indicates that the emerging new geophysical technology of the airborne gravity gradient observations can improve significantly the practical effectiveness of the gravity method in mineral exploration.
Automatic determination of the magnetization–density ratio and magnetization inclination from the joint interpretation of 2D gravity and magnetic anomalies
Authors: Mendonça Carlos Alberto
Published: July 2004

The Poisson theorem establishes a linear relationship between the gravity and magnetic potentials arising from common dense and magnetized bodies with constant magnetization–density ratio and magnetization direction. For geological formations satisfying such constraints (i.e., the Poisson conditions), this theorem provides suitable relationships between the gravity and magnetic anomalies that are useful in interpreting the related data sets. In such applications, both magnetization–density ratio (MDR) and magnetization direction can be estimated, thus helping the subsurface geological mapping from potential field data acquired on the earth's surface. However, no existing method is fully automatic, which has hampered extensive use in routine applications. Such a drawback follows the adoption of equations that, although obeying the Poisson theorem, relate particular components of the gravity and magnetic fields, thus requiring either a known magnetization direction or the implementation of iterative procedures to determine it.

To allow one‐pass estimates for both MDR and magnetization direction (more precisely, its inclination projected on the plane normal to the source strike), this paper presents simple analytical solutions for these parameters by relating suitable gravity and magnetic vector fields that are derived from the gravity and magnetic data sets. Because current geophysical surveys usually provide only a single‐field component, a data processing scheme is developed to determine the required components in evaluating the desired vector fields. This is done by applying suitable linear transformations on the measured components according to well‐established filtering techniques in processing gravity and magnetic data. Except for distortions from noise, the proposed method automatically determines the MDR and the projected magnetization inclination for the underlying rocks everywhere the Poisson conditions are satisfied. Two‐dimensional sources are assumed, but no constraint upon their depth and cross‐section shape is required. Distorted estimates only appear close to the sources where at least one of the Poisson conditions is violated. In this case, the proposed technique furnishes apparent values for the rock properties. The abrupt changes of apparent values over contacts detect edges, thus facilitating the mapping of geological boundaries.

The proposed technique is used to interpret two profiles across the Appalachian fold belt from the eastern portion of the State of Georgia, and the results are compared with some of the geological information available for the area.