bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Protein Kinase C on T Lymphocyte Proliferation and Apoptosis in Acute Idiopathic Thrombocytopenic Purpura
Authors: Liu Fang , Wu Chang-lin , Xiao Hong , Yang Xiao-meng , Lv Xue-wen , Chen Qun
Published: September 2006

Previous studies have shown that T lymphocyte proliferation and apoptosis are abnormal in idiopathic thrombocytopenic purpura (ITP) children; however, the underlying regulated mechanisms in signal transductions remain unknown. In this paper, we investigated the changes of protein kinase C (PKC) activity in peripheral blood T lymphocytes and the effect of PKC on the peripheral blood T lymphocyte proliferation and apoptosis in ITP children. We demonstrated that T lymphocytes from ITP children were more susceptible to the activator (phorbol myristate acetate) and the inhibitor (H-7) of PKC. In ITP children, phorbol myristate acetate and H-7 dramatically affected T lymphocyte proliferation and apoptosis, but altered little in healthy children. Compared with healthy children, PKC activity was significantly enhanced in ITP children, increasing the expressions of Fas ligand on CD3+, CD4+ and CD8+ T cells, indicating positive correlations between PKC activity and the expressions of Fas ligand on T cells, while the relations between PKC activity and platelet count showed negative correlations. Taken together, our findings suggest that PKC signal transductions may participate in the procedure of T lymphocyte proliferation and apoptosis in ITP children. PKC activation may enhance T lymphocyte activity, suppress T cell apoptosis, and be involved in thrombocyte damage, which can be related to the immunity pathogenesis of ITP.
Lack of Very Strong Association between Pre-Treatment Fibrinogen and PAI-1 with Long-Term Mortality after Coronary Bypass Surgery
Authors: Sjöland Helen , Tengborn Lilian , Stensdotter Lillemor , Herlitz Johan
Published: September 2006

Aim: To explore the association between the coagulation protein fibrinogen and the fibrinolytic biomarker plasminogen activator inhibitor-1 (PAI-1) and the long-term mortality after coronary artery bypass grafting (CABG). Patients and Methods: In 729 patients undergoing CABG at Sahlgrenska University Hospital, a blood sample for fibrinogen and PAI-1 was collected prior to the procedure. Patients were followed for 10 years. Results: Among patients with high levels of fibrinogen (>3.6 g/l; median), the 10-year mortality was 32.3 vs. 20.7% among patients with fibrinogen levels below the median (p = 0.0005). However, patients with higher levels of fibrinogen were older and had an adverse risk factor pattern. When adjusting for these differences, pre-operative fibrinogen levels did not clearly appear as an independent predictor of long-term mortality. The 10-year mortality was similar in patients with high (25.3%) and low (26.5%) levels of PAI-1. Conclusion: Our results do not suggest that fibrinogen and PAI-1, when evaluated prior to the operative procedure, are strongly associated with increased mortality in the long-term after CABG, when other co-morbidity factors are simultaneously considered.
Cardiac Arrhythmias and Atrioventricular Block in a Cohort of Asymptomatic Individuals without Heart Disease
Authors: DePaula Rogério Silva , Antelmi Ivana , Vincenzi Marcos Antonio , André Carmen D.S. , Artes Rinaldo , Grupi César José , Mansur Alfredo José
Published: September 2006

Aims: To evaluate cardiac arrhythmias and rhythm disturbances on 24 h ambulatory electrocardiographic monitoring in a cohort of asymptomatic healthy individuals with normal clinical examination. Methods and Results: 625 asymptomatic healthy individuals, in the age range 15–83 (mean 42, SD 11.9) years; 276 (44.2%) men and 349 (55.8%) women were submitted to 24-hour ambulatory electrocardiographic monitoring. Statistical analysis was performed with likelihood ratio test and automatic backward logistic regression. The frequency of atrial arrhythmias (p < 0.0001; OR 1.059; 95% CI 1.050–1068) and of ventricular arrhythmias (p < 0.0001; OR 1.023; 95% CI 1.017–1.029) increased for each age increase of 1 year; neither atrial nor ventricular arrhythmias demonstrated a statistically significant difference relative to gender. Transient second-degree atrioventricular block (Mobitz I) was observed in 14 (2.2%) individuals and was more frequent in individuals with resting heart rate <60 bpm (p = 0.006; OR 6.7, 95% CI 1.7–25.5). Conclusion: The frequency of atrial and ventricular arrhythmias increased with age and did not demonstrate a significant difference relative to gender. Transient atrioventricular block was more frequent in individuals with lower resting heart rate.
Inhibition of Hypoxia-Inducible Factor-1α and Endothelial Progenitor Cell Differentiation by Adenoviral Transfer of Small Interfering RNA in vitro
Authors: Jiang Meng , Wang Binyao , Wang Changqian , He Ben , Fan Huahua , Guo Taylor B. , Shao Qin , Gao Li , Liu Yan
Published: September 2006

RNA interference is applied to study gene function in different organisms and in various cell types. Little is known about the effect of RNA interference on human endothelial progenitor cells (EPCs) in vitro. To address this issue, short hairpin RNA targeting the human hypoxia inducible factor-1α (HIF-1α) was transferred into human EPCs by an adenoviral vector. HIF-1α mRNA and protein expression was dramatically and specifically downregulated after adeno-small interfering RNA (siRNA)-HIF-1α infection in cells under hypoxia, a condition in which HIF-1α would have been induced. This effect persisted for at least 72 h and was accompanied by suppression of vascular endothelial growth factor (VEGF) mRNA and protein expression. The expression of endothelial cell markers CD31, VEGF receptor 2 (Flk-1) and eNOS as well as NO production were also markedly decreased. Functional studies showed HIF-1α knockdown via adenoviral siRNA transfer inhibited EPC colony formation, differentiation, proliferation and migration. These data indicate that specific gene knockdown via adenoviral transfer of siRNA is feasible in EPCs, and the effect is long-lasting. Our findings raise the possibility that such long-term modified human EPCs may be used to treat hypoxic tumor metastases that are known to be resistant to conventional therapeutic regimes.
Measuring the Refractoriness of the Electrically Stimulated Auditory Nerve
Authors: Morsnowski Andre , Charasse Basile , Collet Lionel , Killian Matthijs , Müller-Deile Joachim
Published: September 2006

Intracochlear recordings in cochlear implant recipients provide access to the electrically evoked compound action potential (ECAP). ECAP thresholds are potential predictors of speech processor map’s threshold and comfortable loudness levels. The auditory nerve’s refractory properties can influence these levels due to high-rate stimulation with interpulse intervals within the relative refractory period. Recovery functions were investigated at 84 stimulation sites in 14 Nucleus CI24 recipients using neural response telemetry and a modified forward masking technique. This technique introduces a reference masker-probe interval (MPI). In our study, an appropriate value between 300 and 375 µs was determined for this reference MPI, and the use of a reference MPI of 300 µs is suggested for recovery and amplitude growth functions. A median absolute refractory period of about 390 µs and a median time constant of about 425 µs were obtained by fitting an exponential model to the data. Hence, the auditory nerve is usually in relative refractory state when standard neural response telemetry forward masking is selected because of its default MPI of 500 µs. This can bias the measurement of ECAP thresholds. Additionally, the shape of standard forward masking recovery functions was explained by the influence of latency shift of the neural response.
Mechanism of Inflammation in Murine Eosinophilic Myocarditis Produced by Adoptive Transfer with Ovalbumin Challenge
Authors: Hirasawa Masao , Ito Yuko , Shibata Masa-Aki , Otsuki Yoshinori
Published: September 2006

Background: Interleukin (IL)-5, RANTES and CC chemokine receptor 3 (CCR3) are essential for induction of eosinophil recruitment in organs, but the precise pathogenesis of eosinophilic myocarditis is still unclear. We investigated the relationships between these cytokines and receptors in the development of inflammation in murine myocarditis produced by adoptive transfer, with reference to eosinophil infiltration and signal transduction. Methods: The splenocytes from male donor DBA/2 mice were separated after ovalbumin (OVA) sensitization. These cells had a CD4/CD8 ratio of approximately 3.0. Cells (2.0 × 107) were individually transfused to recipient adoptive male DBA/2 mice, and OVA challenge was performed serially. The heart and spleen of the recipient were analyzed to determine the kinetics of IL-5, RANTES, CCR3 and eosinophil production with simultaneous determination of Janus kinase 3 (JAK3) mRNA. Results: Approximately 85% of recipient mice developed myocarditis; 35% had recognizable cell infiltration in the left ventricular endocardium, an effect which was absent in control mice. Eosinophilic myocarditis was usually associated with animals having several degenerative changes in myocardial cells, and IL-5, RANTES and CCR3 expressions were usually present in these eosinophils (p < 0.05). CCR3 and JAK3 mRNAs were detected in the spleens and hearts of recipient animals providing histological evidence for kinetics related to eosinophil infiltration. Conclusion: The murine model of adoptive transferred myocarditis is suitable for studying the mechanism of eosinophilic myocarditis. A unique pathogenesis of this disorder may be controlled by the synergism of CD4 dominancy in the donor and JAK-STAT signaling in the recipient, which may cause recruitment of eosinophils into heart lesions.
In vitro Induction of Apoptosis in U937 Cells by Perillyl Alcohol with Sensitization by Pentoxifylline: Increased BCL-2 and BAX Protein Expression
Authors: Gómez-Contreras P.C. , Hernández-Flores G. , Ortiz-Lazareno P.C. , del Toro-Arreola S. , Delgado-Rizo V. , Lerma-Díaz J.M. , Barba-Barajas M. , Domínguez-Rodríguez J.R. , Bravo Cuellar A.
Published: September 2006

Background: Chemotherapy is effective against a wide variety of tumor cells, although its use is limited by side effects. In vitro experiments and phase I and II trials have shown that phytochemicals such as perillyl alcohol (P-OH) have antitumor effects. Pentoxifylline (PTX), a synthetic methylxanthine used mainly to treat pathologies associated with hematological diseases, sensitizes tumor cells to chemotherapy. The aim of this study was to determine whether PTX amplifies the antitumor effects of P-OH in U937 human myelomonocytic leukemia cells. Methods: Apoptosis was measured by the loss of mitochondrial membrane potential determined by flow cytometry using dihexyloxacarbocyanine iodide (DiOC6) and propidium iodide. Bcl-2 and Bax protein expression was also assessed by Western blot analysis. Results: P-OH and PTX induced loss of the mitochondrial membrane potential in U937 cells in vitro. Culturing the cells in the presence of both compounds caused a significant increase (p < 0.001) in apoptosis and expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax proteins. However, despite their coexistence, Bax expression prevailed in our experiments. These data suggest that the effects of PTX might be attributable to changes in the mitochondrial membrane potential. Conclusion: PTX sensitizes tumor cells to the anti-neoplastic action of P-OH. These observations may have clinical relevance in the treatment of cancer patients.
Histone Deacetylase Inhibitor Reduces Monocyte Adhesion to Endothelium Through the Suppression of Vascular Cell Adhesion Molecule-1 Expression
Authors: Inoue Kenji , Kobayashi Mika , Yano Kiichiro , Miura Mai , Izumi Akashi , Mataki Chikage , Doi Takeshi , Hamakubo Takao , Reid Patrick C. , Hume David A. , Yoshida Minoru , Aird William C. , Kodama Tatsuhiko , Minami Takashi
Published: September 2006

Objective—Tumor necrosis factor (TNF)-α initiates numerous changes in endothelial cell (EC) gene expression that contributes to the pathology of various diseases including inflammation. We hypothesized that TNF-α–mediated gene induction involves multiple signaling pathways, and that inhibition of one or more of these pathways may selectively target subsets of TNF-α–responsive genes and functions.

Methods and Results—Human umbilical vein endothelial cells (ECs) were preincubated with inhibitors of PI3 kinase (LY294002), histone deacetylases (HDAC) (trichostatin A [TSA]), de novo protein synthesis (CHX), proteasome (MG-132), and GATA factors (K-11430) before exposure to TNF-α at 4 hours and analyzed by microarray. TNF-α–mediated induction of vascular cell adhesion molecule-1 (VCAM-1) was attenuated by all of these inhibitors, whereas in contrast, stimulation of intercellular adhesion molecule-1 (ICAM-1) was blocked by MG-132 alone. Moreover TSA blocked TNF-α–mediated induction of monocyte adhesion both in vitro and in vivo through the suppression of VCAM-1. Further analysis demonstrated that HDAC3 plays a significant role in the regulation of TNF-α–mediated VCAM-1 expression.

Conclusions—TNF-α activates ECs via multiple signaling pathways, and these pathways may be selectively targeted to modulate EC function. Moreover, TSA treatment reduced monocyte adhesion via VCAM-1 suppression in vitro and in vivo, suggesting that TSA might be useful for the attenuation of the inflammatory response in EC.
Asp92Asn Polymorphism in the Myeloid IgA Fc Receptor Is Associated With Myocardial Infarction in Two Disparate Populations
Authors: Iakoubova Olga A. , Tong Carmen H. , Chokkalingam Anand P. , Rowland Charles M. , Kirchgessner Todd G. , Louie Judy Z. , Ploughman Lynn M. , Sabatine Marc S. , Campos Hannia , Catanese Joseph J. , Leong Diane U. , Young Bradford A. , Lew David , Tsuchihashi Zenta , Luke May M. , Packard Christopher J. , Zerba Kim E. , Shaw Peter M. , Shepherd James , Devlin James J. , Sacks Frank M.
Published: September 2006

Objective—Statins reduce inflammation and risk of myocardial infarction (MI). Because the myeloid IgA Fc receptor encoded byFCARmediates inflammation, we hypothesized that theFCAR Asp92Asn polymorphism is associated with risk of MI and that this risk would be modified by pravastatin.

Methods and Results—In the placebo arm of the Cholesterol and Recurrent Events (CARE) study, male carriers of the 92Asn allele had an adjusted hazard ratio for incident MI of 1.68 (95% CI 1.10 to 2.57); relative risk reduction by pravastatin was 69% in carriers and 12% in noncarriers (Pinteraction=0.007). In the placebo arm of the all-male West of Scotland Coronary Prevention Study (WOSCOPS), carriers had an adjusted odds ratio for incident coronary heart disease (CHD) of 1.46 (90% CI 1.05 to 2.03); for pravastatin compared with placebo treatment, the adjusted odds ratios were 0.55 (95% CI 0.32 to 0.93) in carriers and 0.65 (95% CI 0.51 to 0.83) in noncarriers (Pinteraction=0.55).

Conclusions—Carriers of 92Asn had increased risk of MI in CARE and increased odds of CHD in WOSCOPS. Pravastatin significantly reduced risk in carriers in both CARE and WOSCOPS. A genotype by treatment interaction was observed in CARE but not in WOSCOPS.
Endotoxin Induces Toll-Like Receptor 4 Expression in Vascular Smooth Muscle Cells via NADPH Oxidase Activation and Mitogen-Activated Protein Kinase Signaling Pathways
Authors: Lin Feng-Yen , Chen Yung-Hsiang , Tasi Jen-Sung , Chen Jaw-Wen , Yang Tung-Lin , Wang Hsiao-Jung , Li Chi-Yuan , Chen Yuh-Lien , Lin Shing-Jong
Published: September 2006

Objective—Toll-like receptor 4 (TLR4) plays a major role mediating endotoxin-induced cellular inflammation and regulates vascular smooth muscle cell (VSMC) proliferation, which is related to atherogenesis and restenosis. This study was conducted to investigate the mechanisms involved in lipopolysaccharide (LPS)-induced TLR4 expression in VSMCs.

Methods and Results—Stimulation of human aortic smooth muscle cells (HASMCs) with LPS significantly increased TLR4 expression. The increase was regulated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (including the activation of subunits p47phoxand Rac1), which mediates the production of reactive oxygen species and the activation of intracellular mitogen-activated protein kinase signaling pathways. Treatment with polyethylene-glycol-conjugated superoxide dismutase,N-acetylcysteine (NAC), diphenylene iodonium (DPI), or apocynin significantly decreased LPS-induced TLR4 expression. An actinomycin D chase experiment showed that LPS increased the half-life of TLR4 mRNA. Inhibition of NADPH oxidase activity by DPI, apocynin, or NAC significantly decreased TLR4 mRNA stability, as did the knock-down ofRAC1gene expression by RNA interference. We also demonstrated in an animal model that LPS administration led to a significant elevation of balloon-injury–induced neointimal hyperplasia, and of TLR4 expression, in rabbit aorta.

Conclusion—These findings suggest that NADPH oxidase activation, mRNA stabilization, and MAPK signaling pathways play critical roles in LPS-enhanced TLR4 expression in HASMCs, which contributes to vascular inflammation and cardiovascular disorders.
Increased Concentrations of C-Reactive Protein and IL-6 but not IL-18 Are Independently Associated With Incident Coronary Events in Middle-Aged Men and Women
Authors: Koenig Wolfgang , Khuseyinova Natalie , Baumert Jens , Thorand Barbara , Loewel Hannelore , Chambless Lloyd , Meisinger Christa , Schneider Andrea , Martin Stephan , Kolb Hubert , Herder Christian
Published: September 2006

Objectives—

We performed a prospective case–cohort study in initially healthy, middle-aged men and women from the MONICA/KORA Augsburg studies conducted between 1984 and 2002 to assess the role of IL-18 in comparison with IL-6 and CRP in the prediction of incident coronary heart disease (CHD).

Methods and Results—

Concentrations of IL-18 were measured in 382 case subjects with incident CHD and 1980 noncases. Mean follow-up was 11 years. Baseline concentrations of IL-18 were slightly higher in cases than in noncases (172.4 [1.0] versus 161.3 [1.0] pg/mL, respectively;
P
=0.114), but were clearly elevated for C-reactive protein (CRP) and IL-6 in cases compared with noncases. In multivariable analyses, accounting for classical cardiovascular risk factors and inflammatory markers, no statistically significant association was seen between increased concentrations of IL-18 and incident CHD both in men (hazard ratio [HR] and 95% confidence intervals [CIs] comparing extreme tertiles, 1.20; 95% CI, 0.85 to 1.69), and in women (HR, 1.25; 95% CI, 0.67 to 2.34). However, in this population increased concentrations of CRP and IL-6 were found to be independent predictors of future CHD events, even after multivariable adjustment.

Conclusions—

Elevated concentrations of CRP and IL-6, but not IL-18, were independently associated with risk of CHD in subjects from an area with moderate absolute risk.
Carotid Plaque Surface Irregularity Predicts Ischemic Stroke
Authors: Prabhakaran Shyam , Rundek Tatjana , Ramas Romel , Elkind Mitchell S.V. , Paik Myunghee Cho , Boden-Albala Bernadette , Sacco Ralph L.
Published: September 2006

Background and Purpose—

There is scant population-based evidence regarding extracranial carotid plaque surface irregularity and ischemic stroke. Using a prospective cohort design, we evaluated the association of carotid plaque surface irregularity and the risk of ischemic stroke in a multiethnic population.

Methods—

High-resolution B-mode ultrasound of the carotid arteries was performed in 1939 stroke-free subjects (mean age 69±10.0 years; 59% women; 53% Hispanic, 25% black, 22% white). Plaque was defined as a focal protrusion 50% greater than the surrounding area and localized along the extracranial carotid tree (internal carotid artery/bifurcation vs common carotid artery). Plaque surface was categorized as regular or irregular. Cox proportional hazard models were used to assess the association of surface characteristics and the risk of ischemic stroke.

Results—

Among 1939 total subjects, carotid plaque was visualized in 56.3% (1 plaque: 21.6%, >1 plaque: 34.7%, irregular plaque: 5.5%). During a mean follow up of 6.2 years after ultrasound examination, 69 ischemic strokes occurred. Unadjusted cumulative 5-year risks of ischemic stroke were: 1.3%, 3.0%, and 8.5% for no plaque, regular plaque, and irregular plaque, respectively. After adjusting for demographics, traditional vascular risk factors, degree of stenosis, and plaque thickness, presence of irregular plaque (vs no plaque) was independently associated with ischemic stroke (Hazard ratio, 3.1; 95% CI, 1.1 to 8.5).

Conclusions—

The presence of irregular carotid plaque independently predicted ischemic stroke in a multiethnic cohort. Plaque surface irregularities assessed by B-mode ultrasonography may help identify intermediate- to high-risk individuals beyond their vascular risk assessed by the presence of traditional risk factors.
Heritability of MRI Lesion Volume in CADASIL
Authors: Opherk Christian , Peters Nils , Holtmannspötter Markus , Gschwendtner Andreas , Müller-Myhsok Bertram , Dichgans Martin
Published: September 2006

Background and Purpose—

The phenotypic expressivity shows striking variability among individuals with CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), a small vessel disease caused by mutations in
NOTCH3
. However, little is known about the factors that underlie this variability. We sought to quantify the contribution of modifying genetic effects to individual differences in the volume of cerebral ischemic lesions.

Methods—

One hundred and fifty-one affected individuals (mean age±SD=45.7±10.4) from 95 unrelated families with CADASIL underwent MRI. The volume of lesions visible on T2-weighted images and the intracranial volume (ICV) were quantified and vascular risk factors were assessed. Because of a skewed distribution, lesion volume measures were square-root transformed. Variance component methods were used to estimate the heritability of lesion volumes (ie, the proportion of variation caused by additive genetic factors) after adjusting for covariates.

Results—

In multivariate analyses, higher age, a larger ICV, and a higher diastolic blood pressure were independently associated with a larger volume of T2-visible lesions (all
P
<0.05). After adjustment for age the point estimate for the heritability of the square-root-transformed measure of T2 lesion volume was 0.634 (SE=±0.286). Adjustment for age, sex, ICV, and diastolic blood pressure increased the estimated heritability to 0.738 (SE±0.255).

Conclusions—

Heritability estimates in CADASIL suggest a strong modifying influence of genetic factors distinct from the causative
NOTCH3
mutation on the amount of ischemic brain lesions. These findings justify a systematic search for genetic variants that modify disease progression.
Modulation of Dilator Responses of Cerebral Arterioles by Extracellular Superoxide Dismutase
Authors: Kitayama Jiro , Yi Chu , Faraci Frank M. , Heistad Donald D.
Published: September 2006

Background and Purpose—

Extracellular superoxide dismutase (ECSOD) is highly expressed in the wall of blood vessels and plays an important role in modulation of vascular function in extracranial arteries. Expression of ECSOD appears to affect cerebral vascular responses during disease states. Effects of ECSOD on dilator function in cerebral arterioles, however, have not been fully elucidated. In the present study, we examined effects of ECSOD deficiency on cerebrovascular reactivity under control conditions and during oxidative stress.

Methods—

Dilator responses of cerebral arterioles were examined in cranial windows in vivo in anesthetized ECSOD-deficient (−/−) and wild-type (+/+) mice under normal conditions and during oxidative stress induced by angiotensin II.

Results—

Total SOD activity in the aorta in ECSOD−/− mice (176±24 [mean±SEM] U/mg) was approximately 30% lower than in ECSOD+/+ mice (270±38,
P
=0.051). Dilator responses to acetylcholine (10 μmol/L) in cerebral arterioles were similar under control conditions in ECSOD+/+ (34±5% changes in diameter) and −/− mice (32±4%). Angiotensin II (500 nmol/L for 30 minutes) tended to reduce responses to acetylcholine in ECSOD+/+ mice (not significant) and significantly impaired responses in ECSOD−/− mice (42% reduction,
P
<0.05). Tempol (1 mmol/L), a scavenger of superoxide, restored the impaired dilator responses in ECSOD−/− mice. Responses to nitroprusside in cerebral arterioles were similar in ECSOD+/+ and −/− mice and were not affected by angiotensin II nor by tempol.

Conclusions—

ECSOD deficiency has little effect on cerebrovascular reactivity in control conditions but plays an important role in the regulation of vascular tone during oxidative stress produced by angiotensin II.
Corporeal Mélange: Aesthetics and Ethics of Biomaterials in Stelarc and Nina Sellars's Blender
Authors: Clarke Julie
Published: September 2006

Contemporary artists who use biomaterials to make art objects provide a valuable occasion for raising provocative questions about the value and use of human and nonhuman tissue in the biotechnological age. By disseminating ideas from the insular space of the laboratory to the general public, artists are able to broach philosophical, political, social and ethical questions that surround human ontology. The author considers the aesthetic aspects of Stelarc and Nina Sellars's Blender installation alongside the work of artists who assert an ethical position in their use of biomaterials.
Extending Contexts, Making Possibilities: An Introduction to Evaluating the Projects
Authors: Leach James
Published: September 2006

The author, an anthropologist, discusses his role as an observer attached to a collaborative arts/science research fellowship program. He examines the role of collaboration in research and in the Fellowships and explores new ways of conducting collaboration so that the research process itself becomes part of a project's output.
Mindscape: An Attempt to Visualize the Workings of the Brain
Authors: O'Shea Michael , Sneltvedt Sol
Published: September 2006

The authors describe Mindscape, an artwork in the form of an audiovisual installation. The work visualizes complex brain activity, attempting to bridge the distance between scientific imagery and artistic representations. Starting with images and data drawn from nerve cell activity, artist Sol Sneltvedt and neuroscientist Michael O'Shea collaborate to create a visualization of the unlimited scale of human thought.
Drawing the Line: Some Observations on an Art/Science Collaboration
Authors: Barnett Heather , Whittle Robert
Published: September 2006

The authors describe their project Metamorphosis & Design, an examination of the place of design and transformation in biological systems across research areas from nanofibers to cuttlefish display. They also discuss the collaborative process between artist and scientists.
Extremities of Perception
Authors: Wall Alan , Jones Gron Tudor
Published: September 2006

The authors present their collaborative exploration of the use of metaphor in science. If scientific writing is dependent to a large degree on metaphor, then to what extent is scientific thought itself dependent on metaphoric or analogical perception? The authors discuss the use of metaphor in scientific thought as a process of transferred pattern recognition.
Making Material Culture
Authors: Blackwell Alan , Biggs Simon
Published: September 2006

The authors present their collaborative investigation into the creative applications of liquid crystal elastomers. They explore the process of making these new materials as well as the question of how artists and scientists can work together to develop new materials and to use them in artistic or architectural applications.
Bodies Meet Minds: Choreography and Cognition
Authors: McCarthy Rosaleen , Blackwell Alan , deLahunta Scott , Wing Alan , Hollands Kristen , Barnard Philip , Nimmo-Smith Ian , Marcel Anthony
Published: September 2006

The article describes a collaborative research project between choreographer Wayne McGregor and a team of neuroscientists and psychologists concerned with the relationship between mind and bodily movement. The project comprised several areas of research into the neurological and cognitive basis of movement. The article also discusses the mutual benefits of collaboration between the dancers and scientists.
Willing Conversations: The Process of Being Between
Authors: deLahunta Scott
Published: September 2006

The author argues that the role of facilitation within art and science collaboration projects is perhaps best described not as a function or position, that of the facilitator, but as a framework for thinking about relations and how to encourage a certain quality of exchange. The article reflects on how the themes of willingness, inter-profession, conversations and wording, empathy, and collaborative writing relate to the conditions for interdisciplinary collaboration. This is based on the author's experience with collaborative projects, most recently as research organizer and facilitator for Choreography and Cognition, one of the first Arts and Science Research Fellowships jointly funded by the Arts Council England and Arts and Humanities Research Board (U.K.).
Three-Dimensional Structure and Dynamics of African Easterly Waves. Part I: Observations
Authors: Kiladis George N. , Thorncroft Chris D. , Hall Nicholas M. J.
Published: September 2006

The mean structure of African easterly waves (AEWs) over West Africa and the adjacent Atlantic is isolated by projecting dynamical fields from reanalysis and radiosonde data onto space–time-filtered satellite-derived outgoing longwave radiation. These results are compared with previous studies and an idealized modeling study in a companion paper, which provides evidence that the waves bear a close structural resemblance to the fastest-growing linear normal mode of the summertime basic-state flow over Africa. There is a significant evolution in the three-dimensional structure of AEWs as they propagate along 10°N across West Africa. At this latitude, convection occurs in northerly flow to the east of the Greenwich meridian, then shifts into the wave trough, and finally into southerly flow as the waves propagate offshore into the Atlantic ITCZ. In contrast, to the north of the African easterly jet along 15°N convection remains in southerly flow throughout the waves’ trajectory. Along 10°N over West Africa, the location of convection is consistent with the adiabatic dynamical forcing implied by the advection of perturbation vorticity by the mean thermal wind in the zonal direction, as in the companion paper. Offshore, and along 15°N, the relationship between the convection and dynamics is more complex, and not as easily explained in terms of dynamical forcing alone.
Tropical Cyclone Initialization and Prediction Based on Four-Dimensional Variational Data Assimilation
Authors: Wu Chun-Chieh , Chou Kun-Hsuan , Wang Yuqing , Kuo Ying-Hwa
Published: September 2006

Issues on the initialization and simulation of tropical cyclones (TCs) have been studied here based on four-dimensional variational data assimilation. In particular, experiments have been carried out to assess 1) what the most critical parameters for the so-called bogus data assimilation are and 2) how the current procedures for the bogus data assimilation can be further improved.

It is shown that the assimilation of wind fields is more successful than that of pressure fields in improving the initial structure and prediction of TCs. It is emphasized that the geostrophic adjustment favors the pressure field to adjust to the wind field because the TC vortex is much smaller than the radius of Rossby deformation. The results suggest that a better initial condition in the wind field is critical to the simulation of TCs.

Experiments from this study also show that inclusion of the initial TC movement in the data assimilation window can help improve the track prediction, particularly during the early integration period. This method is able to shed light on the improvement of TC simulation based on the bogus data assimilation.

In all, the results add a theoretical interpretation of the importance of the wind field to the sea level pressure field in terms of geostrophic adjustment, as well as a time dimension of the bogus data assimilation, by assimilating a movable vortex in the four-dimensional variational data assimilation.
Observed Boundary Layer Wind Structure and Balance in the Hurricane Core. Part I: Hurricane Georges
Authors: Kepert Jeffrey D.
Published: September 2006

The GPS dropsonde allows observations at unprecedentedly high horizontal and vertical resolution, and of very high accuracy, within the tropical cyclone boundary layer. These data are used to document the boundary layer wind field of the core of Hurricane Georges (1998) when it was close to its maximum intensity. The spatial variability of the boundary layer wind structure is found to agree very well with the theoretical predictions in the works of Kepert and Wang. In particular, the ratio of the near-surface wind speed to that above the boundary layer is found to increase inward toward the radius of maximum winds and to be larger to the left of the track than to the right, while the low-level wind maximum is both more marked and at lower altitude on the left of the storm track than on the right. However, the expected supergradient flow in the upper boundary layer is not found, with the winds being diagnosed as close to gradient balance.

The tropical cyclone boundary layer model of Kepert and Wang is used to simulate the boundary layer flow in Hurricane Georges. The simulated wind profiles are in good agreement with the observations, and the asymmetries are well captured. In addition, it is found that the modeled flow in the upper boundary layer at the eyewall is barely supergradient, in contrast to previously studied cases. It is argued that this lack of supergradient flow is a consequence of the particular radial structure in Georges, which had a comparatively slow decrease of wind speed with radius outside the eyewall. This radial profile leads to a relatively weak gradient of inertial stability near the eyewall and a strong gradient at larger radii, and hence the tropical cyclone boundary layer dynamics described by Kepert and Wang can produce only marginally supergradient flow near the radius of maximum winds. The lack of supergradient flow, diagnosed from the observational analysis, is thus attributed to the large-scale structure of this particular storm. A companion paper presents a similar analysis for Hurricane Mitch (1998), with contrasting results.
Three MCS Cases Occurring in Different Synoptic Environments in the Sub-Sahelian Wet Zone during the 2002 West African Monsoon
Authors: Schrage Jon M. , Fink Andreas H. , Ermert Volker , Ahlonsou Epiphane D.
Published: September 2006

Three mesoscale convective systems (MCSs) occurring in the sub-Sahelian wet zone of West Africa are examined using observations from the 2002 Integrated Approach to the Efficient Management of Scarce Water Resources in West Africa (IMPETUS) field campaign, the European Centre for Medium-Range Weather Forecasts (ECMWF) operational analyses, and Meteosat infrared imagery. These datasets enable the analysis of the synoptic-scale environment in which the MCSs were embedded, along with a high-resolution monitoring of surface parameters during the systems’ passages. The available data imply that cases I and II were of a squall-type nature. Case I propagated into a moderately sheared and rather moist lower and middle troposphere over the Upper Ouémé Valley (UOV). In contrast, case II was associated with a well-sheared and dry lower troposphere and a large, moist instability. In either case, behind the convective cluster a westward-propagating cyclonic vorticity maximum that was likely captured by the ECMWF analysis as a result of the special upper-air station at Parakou (Benin). In case I, the fast-moving vorticity signal slowed down over the Guinean Highlands where convection dissipated. Farther downstream, it might have played a role in the consolidation of an African easterly waves (AEW) trough over the West African coast and the eastern Atlantic. Case III proved to be a more stationary pattern of convection associated with a vortex in the monsoon flow. It also exhibited a moist and low shear environment.
The immunosuppressant drug FTY720 inhibits cytosolic phospholipase A2 independently of sphingosine-1-phosphate receptors
Authors: Payne Shawn G. , Oskeritzian Carole A. , Griffiths Rachael , Subramanian Preeti , Barbour Suzanne E. , Chalfant Charles E. , Milstien Sheldon , Spiegel Sarah
Published: September 2006

FTY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FTY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (S1P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD2 and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the biosynthesis of all eicosanoids is the phospholipase A2 (PLA2)–mediated release of arachidonic acid from glycerol phospholipids. Although FTY720 also reduced arachidonic acid release in response to antigen, it had no effect on translocation of cPLA2 or ERK1/2 activation, suggesting that it does not interfere with FcϵRI-mediated events leading to cPLA2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA2α activity, whereas FTY720-phosphate, sphingosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA2α and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FTY720 in eicosanoid-driven inflammatory disorders such as asthma and multiple sclerosis.
Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function
Authors: Brogdon Jennifer L. , Xu Yongyao , Szabo Susanne J. , An Shaojian , Buxton Francis , Cohen Dalia , Huang Qian
Published: September 2006

Histone deacetylases (HDACs) play a critical role in regulating gene expression and key biological processes. However, how HDACs are involved in innate immunity is little understood. Here, in this first systematic investigation of the role of HDACs in immunity, we show that HDAC inhibition by a small-molecule HDAC inhibitor (HDACi), LAQ824, alters Toll-like receptor 4 (TLR4)–dependent activation and function of macrophages and dendritic cells (DCs). Surprisingly, pan-HDAC inhibition modulates only a limited set of genes involved in distinct arms of immune responses. Specifically, it inhibited DC-controlled T helper 1 (Th1) effector but not Th2 effector cell activation and migration. It also inhibited macrophage- and DC-mediated monocyte but not neutrophil chemotaxis. These unexpected findings demonstrate the high specificity of HDAC inhibition in modulating innate and adaptive immune responses, and highlight the potential for HDACi to alter the Th1 and Th2 balance in therapeutic settings.
Annexin-1 modulates T-cell activation and differentiation
Authors: D'Acquisto Fulvio , Merghani Ahmed , Lecona Emilio , Rosignoli Guglielmo , Raza Karim , Buckley Christopher D. , Flower Roderick J. , Perretti Mauro
Published: September 2006

Annexin-1 is an anti-inflammatory protein that plays an important homeostatic role in innate immunity; however, its potential actions in the modulation of adaptive immunity have never been explored. Although inactive by itself, addition of annexin-1 to stimulated T cells augmented anti-CD3/CD28-mediated CD25 and CD69 expression and cell proliferation. This effect was paralleled by increased nuclear factor-κB (NF-κB), nuclear factor of activated T cells (NFATs), and activator protein-1 (AP-1) activation and preceded by a rapid T-cell receptor (TCR)–induced externalization of the annexin-1 receptor. Interestingly, differentiation of naive T cells in the presence of annexin-1 increased skewing in Th1 cells; in the collagen-induced arthritis model, treatment of mice with annexin-1 during the immunization phase exacerbated signs and symptoms at disease onset. Consistent with these findings, blood CD4+ cells from patients with rheumatoid arthritis showed a marked up-regulation of annexin-1 expression. Together these results demonstrate that annexin-1 is a molecular “tuner” of TCR signaling and suggest this protein might represent a new target for the development of drugs directed to pathologies where an unbalanced Th1/Th2 response or an aberrant activation of T cells is the major etiologic factor.
Glycoprotein Ibα forms disulfide bonds with 2 glycoprotein Ibβ subunits in the resting platelet
Authors: Luo Shi-Zhong , Mo Xi , Afshar-Kharghan Vahid , Srinivasan Sankaranarayanan , López José A. , Li Renhao
Published: September 2006

It is widely accepted that glycoprotein (GP) Ib contains one Ibα and one Ibβ subunit that are connected by a disulfide bond. It is unclear which Cys residue in Ibα, C484 or C485, forms the disulfide bond with Ibβ. Using mutagenesis studies in transfected Chinese hamster ovary (CHO) cells, we found that both C484 and C485 formed a disulfide bond with C122 in Ibβ. In the context of isolated peptides containing the Ibα or Ibβ transmembrane domain and nearby Cys residue, C484 and C485 in the Ibα peptide were both capable of forming a disulfide bond with the Ibβ peptide. Furthermore, coimmunoprecipitation of epitope-tagged subunits showed that at least 2 Ibβ subunits but only 1 Ibα and 1 IX subunit were present in the GP Ib-IX complex. Finally, the size difference between GP Ib from transfected CHO cells and human platelets was attributed to a combination of sequence polymorphism and glycosylation difference in Ibα, not the number of Ibβ subunits therein. Overall, these results demonstrate that Ibα is covalently connected to 2 Ibβ subunits in the resting platelet, necessitating revision of the subunit stoichiometry of the GP Ib-IX-V complex. The αβ2 composition in GP Ib may provide the basis for possible disulfide rearrangement in the receptor complex.
Dynamic posttranscriptional regulation of ϵ-globin gene expression in vivo
Authors: He Zhenning , Russell J. Eric
Published: September 2006

Functional studies of embryonic ϵ-globin indicate that individuals with β thalassemia or sickle cell disease are likely to benefit from therapeutic, transcriptional derepression of its encoding gene. The success of ϵ-globin gene-reactivation strategies, however, will be tempered by the stability that ϵ-globin mRNA exhibits in developmental stage-discordant definitive erythroid progenitors. Using cell culture and transgenic mouse model systems, we demonstrate that ϵ-globin mRNA is modestly unstable in immature, transcriptionally active erythroid cells, but that this characteristic has relatively little impact on the accumulation of ϵ-globin mRNA at subsequent stages of terminal differentiation. Importantly, the constitutive stability of ϵ-globin mRNA increases in transgenic mouse models of β thalassemia, suggesting that ϵ- and β-globin mRNAs are coregulated through a shared posttranscriptional mechanism. As anticipated, relevant cis-acting determinants of ϵ-globin mRNA stability map to its 3′ UTR, consistent with the positioning of functionally related elements in other globin mRNAs. These studies demonstrate that posttranscriptional processes do not pose a significant practical barrier to ϵ-globin gene reactivation and, moreover, indicate that related therapeutic strategies may be particularly effective in individuals carrying β-thalassemic gene defects.
Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia
Authors: Kay Neil E. , Geyer Susan M. , Call Timothy G. , Shanafelt Tait D. , Zent Clive S. , Jelinek Diane F. , Tschumper Renee , Bone Nancy D. , Dewald Gordon W. , Lin Thomas S. , Heerema Nyla A. , Smith Lisa , Grever Michael R. , Byrd John C.
Published: September 2006

Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity.
Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension
Authors: Hoeper M. M. , Leuchte H. , Halank M. , Wilkens H. , Meyer F. J. , Seyfarth H. J. , Wensel R. , Ripken F. , Bremer H. , Kluge S. , Hoeffken G. , Behr J.
Published: September 2006

Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension (IPAH). A multicentre, open, randomised, controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan.

The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size. At that time, 40 patients were randomised to receive either bosentan alone (control group) or bosentan plus inhaled iloprost (combination group) for a 12-week period.

The primary end-point, change in 6-min walking distance, was not met (mean changes +1 m and -9 m in the control and combination group, respectively). These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening. None of the secondary end-points including functional class, peak oxygen uptake, and time to clinical worsening differed significantly between groups.

The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients. Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension.