bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymorphisms in the CNTF and CNTF receptor genes are associated with muscle strength in men and women
Authors: De Mars Gunther , Windelinckx An , Beunen Gaston , Delecluse Christophe , Lefevre Johan , Thomis Martine A. I.
Published: February 2007

Genotypic associations between polymorphisms in the ciliary neurotrophic factor (CNTF) and CNTF receptor (CNTFR) genes and muscular strength phenotypes in 154 middle-aged men (45–49 yr) and 138 women (38–44 yr) and 99 older men (60–78 yr) and 102 older women (60–80 yr) were tested to validate earlier association studies. Allelic interaction effects were hypothesized between alleles of CNTF and CNTFR. We performed analysis of covariance with age, height, and fat-free mass (FFM) as covariates. FFM was anthropometrically estimated by the equation of Durnin-Womersley. Isometric, concentric, and eccentric torques for the knee flexors (KF) and extensors (KE) were measured using Biodex dynamometry. In the older male group, T-allele carriers of the C-1703T polymorphism in CNTFR performed significantly better on all noncorrected KF torques, whereas only noncorrected KE isometric torque at 120° and concentric torque at 240°/s were higher than the C/C homozygotes ( P < 0.05). When age, height, and FFM were used as covariates, T-allele carriers performed only better on KE and KF isometric torque at 120° ( P < 0.05). Concentric KF torque at 180°/s was lower in middle-aged female A-allele carriers compared with the T/T subjects for the T1069A polymorphism in CNTFR. After correction for age, height, and FFM, middle-aged female A-allele carriers exhibited lower values on all concentric KF strength measures and isometric torque at 120°. There was a lack of association with the CNTF G-6A polymorphism in men, with inconclusive results for a limited number of phenotypes in women. No significant CNTF/CNTFR allele interaction effects were found. Results indicate that CNTFR C-1703T and T1069A polymorphisms are significantly associated with muscle strength in humans.
Effects of intermittent hypoxia on oxidative stress-induced myocardial damage in mice
Authors: Park Ah-Mee , Suzuki Yuichiro J.
Published: February 2007

Obstructive sleep apnea is associated with increased risk for cardiovascular diseases. As obstructive sleep apnea is characterized by episodic cycles of hypoxia and normoxia during sleep, we investigated effects of intermittent hypoxia (IH) on ischemia-reperfusion-induced myocardial injury. C57BL/6 mice were subjected to IH (2 min 6% O2and 2 min 21% O2) for 8 h/day for 1, 2, or 4 wk; isolated hearts were then subjected to ischemia-reperfusion. IH for 1 or 2 wk significantly enhanced ischemia-reperfusion-induced myocardial injury. However, enhanced cardiac damage was not seen in mice treated with 4 wk of IH, suggesting that the heart has adapted to chronic IH. Ischemia-reperfusion-induced lipid peroxidation and protein carbonylation were enhanced with 2 wk of IH, while, with 4 wk, oxidative stress was normalized to levels in animals without IH. H2O2scavenging activity in adapted hearts was higher after ischemia-reperfusion, suggesting the increased antioxidant capacity. This might be due to the involvement of thioredoxin, as the expression level of this protein was increased, while levels of other antioxidant enzymes were unchanged. In the heart from mice treated with 2 wk of IH, ischemia-reperfusion was found to decrease thioredoxin. Ischemia-reperfusion injury can also be enhanced when thioredoxin reductase was inhibited in control hearts. These results demonstrate that IH changes the susceptibility of the heart to oxidative stress in part via alteration of thioredoxin.
Speed Dependence of Tuning to One-Dimensional Features in V1
Authors: Mechler Ferenc , Ohiorhenuan Ifije E. , Victor Jonathan D.
Published: January 2007

Using drifting compound grating stimuli matched in energy and frequency spectrum, we previously showed that neurons in the primary visual cortex (V1) were tuned to line-like, edge-like, and intermediate one-dimensional features. Because these compound grating stimuli were drifting, allowing for potential interaction between shape and motion, we examine here the dependence of V1 feature tuning on drift speed. We find that the feature selectivity and specificity of individual V1 neurons strongly depend on speed. A simple model explains these observations in terms of an interaction between linear filtering by the receptive field and the static nonlinearity of spike threshold, embedded in a recurrent network. Although the speed-dependent behaviors in single V1 neurons preclude their acting as extractors of one-dimensional features, the population as a whole retains a representation of a full suite of features.
Early Detection and Rapid Isolation of Leukemia-Reactive Donor T Cells for Adoptive Transfer Using the IFN-γ Secretion Assay
Authors: Jedema Inge , Meij Pauline , Steeneveld Esther , Hoogendoorn Mels , Nijmeijer Bart A. , van de Meent Marian , van Luxemburg-Heijs Simone A.P. , Willemze Roel , Falkenburg J.H. Frederik
Published: January 2007

Purpose: The poor immunogenicity of most leukemias and the lack of specificity of the donor T cells limit the in vivo effectiveness of conventional donor lymphocyte infusions in many patients suffering from persistent or recurrent leukemia after allogeneic stem cell transplantation. These limitations may be overcome by the adoptive transfer of in vitro generated leukemia-reactive T cells. Although the potential clinical efficacy of this approach has been shown previously, lack of reproducibility of the procedure and the inability to show persistence and survival of the transferred T cells hampered further clinical application. The purpose of this study was to develop a new, broadly applicable strategy for the efficient generation and isolation of leukemia-reactive T cells with a better probability to survive and expand in vivo.

Experimental Design: Myeloid and B-cell leukemias were modified into professional immunogenic antigen-presenting cells, and used to stimulate HLA-matched donor T cells. After two stimulations, responding donor T cells were isolated based on their secretion of IFN-γ and tested for their capacity to recognize and kill the primary leukemia.

Results: Using one universal stimulation and isolation protocol for various forms of leukemia, T-cell populations containing high frequencies of leukemia-reactive T cells could reproducibly be generated and early isolated under mild stimulatory conditions. Isolated T cells still had high proliferative potential and their reactivity seemed to be restricted to cells of the patient's hematopoiesis.

Conclusion: We here show a new robust procedure for the generation and isolation of leukemia-reactive T cells for adoptive transfer.
Biological Aspects and Binding Strategies of Vascular Endothelial Growth Factor in Renal Cell Carcinoma
Authors: Rini Brian I. , Rathmell W.Kimryn
Published: January 2007

Vascular endothelial growth factor (VEGF) is a key mediator in the pathogenesis of renal cell carcinoma (RCC). VEGF is up-regulated in clear cell RCC as a result of loss of the von Hippel-Lindau tumor suppressor gene and subsequent activation of the hypoxia response pathway. VEGF expression drives the migration and proliferation of endothelial cells to support the extensive angiogenesis in RCC. Strategies have been developed to bind and neutralize VEGF and have been investigated in RCC with promising results. Bevacizumab, a VEGF ligand-binding antibody, has shown prolonged time-to-progression versus placebo in treatment-refractory RCC patients and is being investigated currently in multiple RCC settings. VEGF-Trap is also a VEGF binding molecule with ongoing investigation in RCC.
A novel three-dimensional model to quantify metastatic melanoma invasion
Authors: Ghajar Cyrus M. , Suresh Vinod , Peyton Shelly R. , Raub Christopher B. , Meyskens Frank L. , George Steven C. , Putnam Andrew J.
Published: February 2007

Although attempts to develop any viable chemotherapeutic approaches to combat metastatic cancers have largely failed, potential genetic targets to halt metastatic progression continue to be identified. As drugs are developed to address these targets, there is a need for high-throughput systems that accurately reproduce in vivo microenvironments to gauge their efficacy. Accordingly, we have developed a three-dimensional in vitro culture system representative of the environment present upon secondary metastasis to quantitatively measure tumor cell invasion in this setting three-dimensionally. Culturing melanomas of different metastatic capacities within the system showed that each cell type invades the matrix in a manner commensurate to its known metastatic potential in vivo. Moreover, the developed quantitative schemes were put to use to characterize the effect of microenvironmental influences (i.e., matrix components, interstitial cell presence) on planar and vertical melanoma invasion. We propose this novel, quantitative system as a useful tool to assess the effects of pharmacologic and/or microenvironmental influences on tumor cell invasion at a metastatic site. [Mol Cancer Ther 2007;6(2):552–61]
CD44 Regulates Vascular Gene Expression in a Proatherogenic Environment
Authors: Zhao Liang , A. Hall Jason , Levenkova Natasha , Lee Eric , Middleton Melissa K. , Zukas Alicia M. , Rader Daniel J. , Rux John J. , Puré Ellen
Published: February 2007

Objective—To identify early changes in vascular gene expression mediated by CD44 that promote atherosclerotic disease in apolipoprotein E (apoE)–deficient (apoE−/−) mice.

Methods and Results—We demonstrate that CD44 is upregulated and functionally activated in aortic arch in the atherogenic environment of apoE−/− mice relative to wild-type (C57BL/6) controls. Moreover, CD44 activation even in apoE−/− mice is selective to lesion-prone regions because neither the thoracic aorta from apoE−/− mice nor the aortic arch of C57BL/6 mice exhibited upregulation of CD44 compared with thoracic aorta of CD57BL/6 mice. Consistent with these observations, gene expression profiling using cDNA microarrays and quantitative polymerase chain reaction revealed that ≈155 of 19 200 genes analyzed were differentially regulated in the aortic arch, but not in the thoracic aorta, in apoE−/− CD44−/− mice compared with apoE−/− CD44+/+ mice. However, these genes were not regulated by CD44 in the context of a C57BL/6 background, illustrating the selective impact of CD44 on gene expression in a proatherogenic environment. The patterns of differential gene expression implicate CD44 in focal adhesion formation, extracellular matrix deposition, and angiogenesis, processes critical to atherosclerosis.

Conclusions—CD44 is an early mediator of atherogenesis by virtue of its ability to regulate vascular gene expression in response to a proatherogenic environment.
Antibody and Complement in Transplant Vasculopathy
Authors: Wehner Jennifer , Morrell Craig N. , Reynolds Taylor , Rodriguez E. Rene , Baldwin William M.
Published: February 2007

Advances in immunosuppression have decreased the incidence of acute rejection, but the development of vasculopathy in the coronary arteries of transplants continues to limit the survival of cardiac allografts. Transplant vasculopathy has also been referred to as accelerated graft arteriosclerosis because it has features of arteriosclerosis, but it is limited to the graft and develops over a period of months to years. Although the pathological features of transplant vasculopathy are well defined, the causative mechanisms are not completely understood. This review focuses on the mechanisms by which antibody and complement can cause or contribute to coronary vasculopathy in cardiac transplants. Antibodies and complement can have independent effects, but the combination of antibodies and complement with inflammatory cells has greater pathogenic potential for the endothelial and smooth muscle cells of the coronary arteries. For example, stimulation through receptors for IgG or complement split products can activate macrophages, but stimulation through combinations of these receptors generates synergistic results. Together, antibodies and complement efficiently integrate the activation of endothelial cells, platelets, and macrophages, which are 3 of the primary components in the pathogenesis of transplant vasculopathy. Recent findings indicate that antibodies and complement produced within the transplant may contribute to vascular pathology in some transplants. Acute rejection caused by antibodies and complement has been treated by combinations of plasmapheresis, intravenous γ -globulin and monoclonal antibodies to CD20 on B lymphocytes. The effect of these treatment modalities on the development of coronary vasculopathy is unknown.
Adolescent Feline Heart Contains a Population of Small, Proliferative Ventricular Myocytes With Immature Physiological Properties
Authors: Chen Xiongwen , Wilson Rachel M. , Kubo Hajime , Berretta Remus M. , Harris David M. , Zhang Xiaoying , Jaleel Naser , MacDonnell Scott M. , Bearzi Claudia , Tillmanns Jochen , Trofimova Irina , Hosoda Toru , Mosna Federico , Cribbs Leanne , Leri Annarosa , Kajstura Jan , Anversa Piero , Houser Steven R.
Published: February 2007

Recent studies suggest that rather than being terminally differentiated, the adult heart is a self-renewing organ with the capacity to generate new myocytes from cardiac stem/progenitor cells (CS/PCs). This study examined the hypotheses that new myocytes are generated during adolescent growth, to increase myocyte number, and these newly formed myocytes are initially small, mononucleated, proliferation competent, and have immature properties. Ventricular myocytes (VMs) and cKit
+
(stem cell receptor) CS/PCs were isolated from 11- and 22-week feline hearts. Bromodeoxyuridine incorporation (in vivo) and p16
INK4a
immunostaining were measured to assess myocyte cell cycle activity and senescence, respectively. Telomerase activity, contractions, Ca
2+
transients, and electrophysiology were compared in small mononucleated (SMMs) and large binucleated (LBMs) myocytes. Heart mass increased by 101% during adolescent growth, but left ventricular myocyte volume only increased by 77%. Most VMs were binucleated (87% versus 12% mononucleated) and larger than mononucleated myocytes. A greater percentage of SMMs was bromodeoxyuridine positive (SMMs versus LBMs: 3.1% versus 0.8%;
P
<0.05), and p16
INK4a
negative and small myocytes had greater telomerase activity than large myocytes. Contractions and Ca
2+
transients were prolonged in SMMs versus LBMs and Ca
2+
release was disorganized in SMMs with reduced transient outward current and T-tubule density. The T-type Ca
2+
current, usually seen in fetal/neonatal VMs, was found exclusively in SMMs and in myocytes derived from CS/PC. Myocyte number increases during adolescent cardiac growth. These new myocytes are initially small and functionally immature, with patterns of ion channel expression normally found in the fetal/neonatal period
Prior Statin Use May Be Associated With Improved Stroke Outcome After Tissue Plasminogen Activator
Authors: Álvarez-Sabín José , Huertas Rafael , Quintana Manolo , Rubiera Marta , Delgado Pilar , Ribó Marc , Molina Carlos A. , Montaner Joan
Published: February 2007

Background and Purpose—

Statins may exert some neuroprotection, because use before stroke onset has been related to better outcome and reduced mortality. The purpose of this study was to evaluate whether patients who receive tissue plasminogen activator have better outcome when statins were taken before stroke.

Methods—

We evaluated 145 patients with a stroke involving the middle cerebral artery (who received tissue plasminogen activator treatment (<3 hours).

Results—

Fifty-eight patients (40%) became functionally independent at 3 months. Factors associated with good outcome were age (68 versus 74.4 years,
P
<0.001), baseline National Institutes of Health Stroke Scale score (13 versus 18,
P
<0.001), and proximal middle cerebral artery occlusion (56.1% versus 84.3%,
P
<0.001). Statins were the only drug taken before stroke that conditioned neurologic outcome. In fact, among patients who were functionally independent, 27.3% were under statins at the time of the index stroke as compared with 13.6% among the group of patients who were dependent or dead by the end of the study period (
P
=0.046). A logistic regression model identified baseline National Institutes of Health Stroke Scale score <15 (OR: 5.8, 95% CI: 2.05 to 16.36,
P
=0.001), age <70 years (OR: 2.93, 95% CI: 1.13 to 7.59,
P
=0.027), and previous treatment with statins (OR: 5.26, 95% CI: 1.48 to 18.72,
P
=0.027) as independent predictors of good functional outcome.

Conclusions—

Patients under statins at the moment of stroke who received thrombolytics had an improved neurologic outcome.
Wh-in-Situ Does Not Correlate with Wh-Indefinites or Question Particles
Authors: Bruening Benjamin
Published: February 2007

Two theories, the Clausal Typing Hypothesis (Cheng 1991) and the unselective binding theory of wh-in-situ, have linked wh-in-situ to two other phenomena typologically: the use of a question particle, and the use of wh-words as indefinites. This article shows, through a typological survey and a detailed comparison of Passamaquoddy and Mandarin Chinese, that there is no connection between wh-in-situ and either property. Passamaquoddy uses wh-words as indefinites in all the contexts Chinese does, but it is a robust wh-movement language. Crosslinguistically, languages of all possible types are attested: most crucially, wh-in-situ languages without question particles exist, and wh-in-situ languages that do not use wh-words as indefinites also exist. In fact, most languages, regardless of whether they are wh-movement or wh-in-situ languages, have question particles, and most languages use wh-words as indefinites.
Asymmetries in Scrambling and Cyclic Linearization
Authors: Ko Heejeong
Published: February 2007

I argue that linear order in constructions with scrambling is constrained by Cyclic Linearization of syntactic structure at the interface, and I show that this proposal provides a unified account for a variety of asymmetries in scrambling. Arguments in this article establish novel evidence for the thesis that the architecture of grammar requires linearization in phonology to be cyclically determined by the syntax. The article also sheds light on the distribution of floating quantifiers, possessor-raising constructions, and formal properties of scrambling.
Direct Estimation of the Reynolds Stress Vertical Structure in the Nearshore
Authors: Feddersen Falk , Williams A. J.
Published: January 2007

Measurements of the vertical Reynolds stress components in the wave-dominated nearshore are required to diagnose momentum and turbulence dynamics. Removing wave bias from Reynolds stress estimates is critical to a successful diagnosis. Here two existing Reynolds stress estimation methods (those of Trowbridge, and Shaw and Trowbridge) for wave-dominated environments and an extended method (FW) that is a combination of the two are tested with a vertical array of three current meters deployed in 3.2-m water depth off an ocean beach. During the 175-h-long experiment the instruments were seaward of the surfzone and the alongshore current was wind driven. Intercomparison of Reynolds stress methods reveals that the Trowbridge method is wave bias dominated. Tests of the integrated cospectra are used to reject bad Reynolds stress estimates, and the Shaw and Trowbridge estimates are rejected more often than FW estimates. With the FW method, wave bias remains apparent in the cross-shore component of the Reynolds stress. However, the alongshore component of Reynolds stress measured at the three current meters are related to each other with a vertically uniform first EOF containing 73% of the variance, indicating the presence of a constant stress layer. This is the first time the vertical structure of Reynolds stress has been measured in a wave-dominated environment. The Reynolds stress is, albeit weakly, related to the wind stress and a parameterized bottom stress. Using derived wave bias and bottom stress parameterizations, the effect of wave bias on Reynolds stress estimates is shown to be weaker for more typical surfzone conditions (with both stronger waves and currents than those observed here).
Turbulence Anisotropy Determined by Wind Profiler Radar and Its Correlation with Rain Events in Montreal, Canada
Authors: Hocking Anna , Hocking Wayne K.
Published: January 2007

Turbulence inhomogeneities at 3-m scales can be either isotropic or anisotropic, and the degree of anisotropy can be measured with VHF wind profiler radars. Studies over a period of two years in Montreal, Quebec, Canada, have shown that for this site during nonwinter months, the occurrence of isotropic turbulence at 3-m scales serves as a useful diagnostic for the occurrence of rainfall. Turbulent eddies are expected to be most isotropic when wind shears are weak and the atmosphere is either unstable or close to instability. The measurements show that when the turbulence is most isotropic, rainfall is very common. Furthermore, the development of quasi-isotropic turbulence usually occurs before the onset of precipitation. Lead times are typically of the order of 1 to 6 h. Correlation coefficients between the occurrence of strong isotropy and the development of rain generally exceed 0.6, and can be as high as 0.7. Further studies will be required to determine whether this phenomenon is specific to the Montreal area, or can be applied to other locations as well.
Toward Next-Generation, Simulation-Based Computational Tools for Conflict and Peace Studies
Authors: Yilmaz Levent
Published: January 2007

Human, social, and international conflicts are inescapable facts of life. This article elaborates on how advances in simulation theory and methodology can improve exploring and studying the dynamics of conflicts. The premise of the proposed strategy is based on the observation that agent-based social simulation, which enables high-level and powerful problem-solving capabilities, needs to be significantly enhanced to model complex, multilevel, and multistaged conflicts. To this end, the issues, challenges, and rationale underlying a novel simulation methodology, called multisimulation, are explained. The conceptual foundations needed for the realization of multisimulation are presented to contribute to the development of advanced simulation-based computational laboratories for conflict studies. Finally, by using the Bloomfield-Leiss dynamic phase model of conflict, the author argues for the utility of multisimulation.
A multicenter phase 2 study of the farnesyltransferase inhibitor tipifarnib in intermediate- to high-risk myelodysplastic syndrome
Authors: Fenaux Pierre , Raza Azra , Mufti Ghulam J. , Aul Carlo , Germing Ulrich , Kantarjian Hagop , Cripe Larry , Kerstens René , De Porre Peter , Kurzrock Razelle
Published: February 2007

This multicenter phase 2 study evaluated the use of tipifarnib (R115777) in patients with poor-risk myelodysplastic syndrome (MDS; French-American-British classification). Patients (n = 82) received tipifarnib 300 mg orally twice daily for the first 21 days of each 28-day cycle. Twenty-six patients (32%) responded to tipifarnib: 12 (15%) complete responses (CRs) and 14 (17%) hematologic improvements; 37 patients (45%) had stable disease (modified International Working Group criteria, 2006). Among the 12 CRs, the median response duration was 11.5 months (range, 2.0-21.9 months), the median time to progression was 12.4 months (range, 3.9-23.8 months), and 7 were still alive at time of analysis (all > 3 years). Median overall survival was 11.7 months (95% CI, 9.4-15.0). Grade 3-4 neutropenia (18%) and thrombocytopenia (32%) were the most common treatment-related adverse events; severe nonhematologic adverse events were rarely reported. In this study, durable responses and acceptable side effects were observed. Tipifarnib is an active agent for the treatment of patients with intermediate- to high-risk MDS.
Physiologic systemic iron metabolism in mice deficient for duodenal Hfe
Authors: Spasic Maja Vujic , Kiss Judit , Herrmann Thomas , Kessler Regina , Stolte Jens , Galy Bruno , Rathkolb Birgit , Wolf Eckhard , Stremmel Wolfgang , Hentze Matthias W. , Muckenthaler Martina U.
Published: February 2007

Mutations in the Hfe gene result in hereditary hemochromatosis (HH), a disorder characterized by increased duodenal iron absorption and tissue iron overload. Identification of a direct interaction between Hfe and transferrin receptor 1 in duodenal cells led to the hypothesis that the lack of functional Hfe in the duodenum affects TfR1-mediated serosal uptake of iron and misprogramming of the iron absorptive cells. Contrasting this view, Hfe deficiency causes inappropriately low expression of the hepatic iron hormone hepcidin, which causes increased duodenal iron absorption. We specifically ablated Hfe expression in mouse enterocytes using Cre/LoxP technology. Mice with efficient deletion of Hfe in crypt- and villi-enterocytes maintain physiologic iron metabolism with wild-type unsaturated iron binding capacity, hepatic iron levels, and hepcidin mRNA expression. Furthermore, the expression of genes encoding the major intestinal iron transporters is unchanged in duodenal Hfe-deficient mice. Our data demonstrate that intestinal Hfe is dispensable for the physiologic control of systemic iron homeostasis under steady state conditions. These findings exclude a primary role for duodenal Hfe in the pathogenesis of HH and support the model according to which Hfe is required for appropriate expression of the “iron hormone” hepcidin which then controls intestinal iron absorption.
Functional characterization of natural killer cells in type I leukocyte adhesion deficiency
Authors: Castriconi Roberta , Dondero Alessandra , Cantoni Claudia , Della Chiesa Mariella , Prato Carola , Nanni Marina , Fiorini Maurilia , Notarangelo Lucia , Parolini Silvia , Moretta Lorenzo , Notarangelo Luigi , Moretta Alessandro , Bottino Cristina
Published: February 2007

In this study, we analyzed IL-2–activated polyclonal natural killer (NK) cells derived from 2 patients affected by leukocyte adhesion deficiency type I (LAD1), an immunodeficiency characterized by mutations of the gene coding for CD18, the β subunit shared by major leukocyte integrins. We show that LAD1 NK cells express normal levels of various triggering NK receptors (and coreceptors) and that mAb-mediated engagement of these receptors results in the enhancement of both NK cytolytic activity and cytokine production. Moreover, these activating NK receptors were capable of recognizing their specific ligands on target cells. Thus, LAD1 NK cells, similarly to normal NK cells, were capable of killing most human tumor cells analyzed and produced high amounts of IFN-γ when cocultured in presence of target cells. Murine target cells represented a common exception, as they were poorly susceptible to LAD1 NK cells. Finally, LAD1 NK cells could efficiently kill or induce maturation of monocyte-derived immature dendritic cells (DCs). Altogether our present study indicates that in LAD1 patients, 3 important functions of NK cells (eg, cytotoxicity, IFN-γ production, and DC editing) are only marginally affected and provides new insight on the cooperation between activating receptors and LFA-1 in the induction of NK cell activation and function.
Distinctive NK-cell receptor repertoires sustain high-level constitutive NK-cell activation in HIV-exposed uninfected individuals
Authors: Ravet Sophie , Scott-Algara Daniel , Bonnet Elodie , Tran Hung Khiem , Tran Ton , Nguyen Ngai , Truong Lien Xuan , Theodorou Ioannis , Barré-Sinoussi Françoise , Pancino Gianfranco , Paul Pascale
Published: February 2007

We have previously associated high natural killer (NK)–cell activity and protection against HIV-1 infection in Vietnamese exposed uninfected intravascular drug users (EUs). Considering that activating and inhibitory signals sensed by NK-cell receptors regulate NK-cell activation, we performed phenotypic and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) transcript analyses of the NK-cell receptor (NKR) repertoire in 25 EUs, 19 HIV+ intravenous drug users, and 26 uninfected blood donors. Although NK-cell activation was not linked to a unique NKR repertoire in EUs, various patterns consistent with NK-cell activation were detected in EUs: high KIR3DS1/KIR3DL1 ratio associated with down-regulated KIR3DL1 transcript levels, KIR2DL3+ low-affinity receptor expansion associated to group HLA-C1 ligand in 2DS2−/2DL2− EUs, enhanced NKG2C/NKG2A ratio, and increased CD69 expression. Remarkably, EUs exhibited high constitutive degranulation activity in the absence of exogenous stimulation, as shown by the CD107a assay. Furthermore, CD161 expression was increased within the CD107a+ NK-cell compartment. Our results suggest that in response to viral exposition, particular genetic or regulated features of the NKR repertoire of EUs contribute to their high constitutive NK-cell potential. This might allow NK cells to generate a more rapid and effective immune response to HIV-1, thereby contributing to prevention toward infection.
Ancestry and pharmacogenetics of antileukemic drug toxicity
Authors: Kishi Shinji , Cheng Cheng , French Deborah , Pei Deqing , Das Soma , Cook Edwin H. , Hijiya Nobuko , Rizzari Carmelo , Rosner Gary L. , Frudakis Tony , Pui Ching-Hon , Evans William E. , Relling Mary V.
Published: February 2007

Treatment-related toxicity in acute lymphoblastic leukemia (ALL) can not only be life threatening but may also affect relapse risk. In 240 patients, we determined whether toxicities were related to 16 polymorphisms in genes linked to the pharmacodynamics of ALL chemotherapy, adjusting for age, race (self-reported or via ancestry-informative markers), sex, and disease risk group (lower- vs higher-risk therapy). Toxicities (gastrointestinal, infectious, hepatic, and neurologic) were assessed in each treatment phase. During the induction phase, when drugs subject to the steroid/cytochrome P4503A pathway predominated, genotypes in that pathway were important: vitamin D receptor (odds ratio [OR], 6.85 [95% confidence interval [CI], 1.73-27.0]) and cytochrome P4503A5 (OR, 4.61 [95% CI, 1.11-19.2]) polymorphisms were related to gastrointestinal toxicity and infection, respectively. During the consolidation phase, when antifolates predominated, the reduced folate carrier polymorphism predicted gastrointestinal toxicity (OR, 10.4 [95% CI, 1.35-80.4]) as it also did during continuation (OR, 2.01 [95% CI, 1.06-4.11]). In all 3 treatment phases, a glucuronosyltransferase polymorphism predicted hyperbilirubinemia (P = .017, P < .001, and P < .001) and methotrexate clearance (P = .028), which was also independently associated with hyperbilirubinemia (P = .026). The genotype-phenotype associations were similar whether analyses were adjusted by self-reported race or ancestry-informative genetic markers. Germ-line polymorphisms are significant determinants of toxicity of antileukemic therapy.
Road tunnel air pollution induces bronchoalveolar inflammation in healthy subjects
Authors: Larsson B-M. , Sehlstedt M. , Grunewald J. , Sköld C. M. , Lundin A. , Blomberg A. , Sandström T. , Eklund A. , Svartengren M.
Published: January 2007

Traffic-related air pollution is associated with adverse respiratory effects. The aim of the present study was to investigate whether exposure to air pollution in a road tunnel causes airway inflammatory and blood coagulation responses.

A total of 16 healthy subjects underwent bronchoscopy with bronchial mucosal biopsies and bronchoalveolar lavage (BAL) on two occasions, in random order: once at 14 h after a 2-h exposure to air pollution in a busy road tunnel, and once after a control day with subjects exposed to urban air during normal activities. Peripheral blood was sampled prior to bronchoscopy.

The road tunnel exposures included particulate matter with a 50% cut-off aerodynamic diameter of 2.5 μm, particulate matter with a 50% cut-off aerodynamic diameter of 10 μm and nitrogen dioxide which had median concentrations of 64, 176 and 230 µg·m−3, respectively. Significantly higher numbers of BAL fluid total cell number, lymphocytes and alveolar macrophages were present after road tunnel exposureversuscontrol. Significantly higher nuclear expression of the transcription factor component c-Jun was found in the bronchial epithelium after exposure. No upregulation of adhesion molecules or cellular infiltration was present and blood coagulation factors were unaffected.

In conclusion, exposure of healthy subjects to traffic-related air pollution resulted in a lower airway inflammatory response with cell migration, together with signs of an initiated signal transduction in the bronchial epithelium.
Resistance of quiescent and proliferating airway epithelial cells to H2O2challenge
Authors: Smit-de Vries M. P. , van der Toorn M. , Bischoff R. , Kauffman H. F.
Published: January 2007

Alveolar epithelial cell injury and recovery are important in the pathogenesis of oxidant-induced lung damage. The alveolar cell line A549 was used to study responses of proliferating and quiescent cells in culture to time- and dose-dependent hydrogen peroxide (H2O2) challenges.

Recovery was monitored after 24 h of incubation in fresh medium with 10% serum. The adherent cells were counted and the resistance and recovery of the attached cells was assessed by appearance, by measuring the number of viable, apoptotic and necrotic cells using fluorescent-activated cell sorting, and by determining the intracellular free thiol content.

A549 cells recovered from a 1-h challenge with up to 1 mM H2O2but could not sustain a more prolonged challenge (6 or 24 h) with 0.5 mM or 1.0 mM H2O2. These more severe conditions resulted in: loss of cells by detachment from the plate surface; reduced numbers of viable cells primarily due to necrosis; and a strong reduction of the intracellular free thiol content.

Quiescent cells proved to be more sensitive to oxidative stress than proliferating cells. Intracellular free thiol levels apparently play a decisive role in cell survival, preferentially protecting proliferating cells.
Motif kernel generated by genetic programming improves remote homology and fold detection
Authors: Håndstad Tony , Hestnes Arne JH , Sætrom Pål
Published: January 2007

Background

Protein remote homology detection is a central problem in computational biology. Most recent methods train support vector machines to discriminate between related and unrelated sequences and these studies have introduced several types of kernels. One successful approach is to base a kernel on shared occurrences of discrete sequence motifs. Still, many protein sequences fail to be classified correctly for a lack of a suitable set of motifs for these sequences.

Results

We introduce the GPkernel, which is a motif kernel based on discrete sequence motifs where the motifs are evolved using genetic programming. All proteins can be grouped according to evolutionary relations and structure, and the method uses this inherent structure to create groups of motifs that discriminate between different families of evolutionary origin. When tested on two SCOP benchmarks, the superfamily and fold recognition problems, the GPkernel gives significantly better results compared to related methods of remote homology detection.

Conclusion

The GPkernel gives particularly good results on the more difficult fold recognition problem compared to the other methods. This is mainly because the method creates motif sets that describe similarities among subgroups of both the related and unrelated proteins. This rich set of motifs give a better description of the similarities and differences between different folds than do previous motif-based methods.
The rheumatoid arthritis shared epitope increases cellular susceptibility to oxidative stress by antagonizing an adenosine-mediated anti-oxidative pathway
Authors: Ling Song , Li Zhanguo , Borschukova Olga , Xiao Liqun , Pumpens Paul , Holoshitz Joseph
Published: January 2007

We have recently demonstrated that the rheumatoid arthritis (RA) shared epitope (SE) acts as a ligand that triggers nitric oxide (NO) signaling in opposite cells. Given the known pro-oxidative effect of NO and the proposed role of oxidative stress in the pathogenesis of RA, this study explores whether SE-triggered signaling can increase cellular oxidative stress. cAMP levels, adenylyl cyclase activity, and protein kinase A activity were measured using commercial kits. Generation of reactive oxygen species (ROS) was quantified using the fluorochrome dichlorofluorescein diacetate. Oxidative DNA damage was quantified using the single-cell electrophoresis technique. Here, we report that cells exposed to cell surface SE-positive HLA-DR (human leukocyte antigen-DR) molecules, to cell-free recombinant proteins genetically engineered to express the SE motif, or to SE-positive synthetic peptide showed diminished cAMP-dependent signaling, increased ROS levels, and higher vulnerability to oxidative DNA damage. Introduction of single amino acid substitutions into SE-positive peptides revealed a consensus five-amino acid sequence motif of Q/R-K/R-X-X-A that is necessary and sufficient for SE-triggered signaling. The pro-oxidative effect of the SE could be reversed by inhibiting NO production. We conclude that the SE acts as a signaling ligand that activates an NO-mediated pro-oxidative pathway. The potential contribution of this signaling aberration to RA pathogenesis is discussed.
Simplified electrophysiological evaluation of peripheral nerves in critically ill patients: the Italian multi-centre CRIMYNE study
Authors: Latronico Nicola , Bertolini Guido , Guarneri Bruno , Botteri Marco , Peli Elena , Andreoletti Serena , Bera Paola , Luciani Davide , Nardella Anna , Vittorielli Elena , Simini Bruno , Candiani Andrea
Published: January 2007

Introduction

Critical illness myopathy and/or neuropathy (CRIMYNE) is frequent in intensive care unit (ICU) patients. Although complete electrophysiological tests of peripheral nerves and muscles are essential to diagnose it, they are time-consuming, precluding extensive use in daily ICU practice. We evaluated whether a simplified electrophysiological investigation of only two nerves could be used as an alternative to complete electrophysiological tests.

Methods

In this prospective, multi-centre study, 92 ICU patients were subjected to unilateral daily measurements of the action potential amplitude of the sural and peroneal nerves (compound muscle action potential [CMAP]). After the first ten days, complete electrophysiological investigations were carried out weekly until ICU discharge or death. At hospital discharge, complete neurological and electrophysiological investigations were performed.

Results

Electrophysiological signs of CRIMYNE occurred in 28 patients (30.4%, 95% confidence interval [CI] 21.9% to 40.4%). A unilateral peroneal CMAP reduction of more than two standard deviations of normal value showed the best combination of sensitivity (100%) and specificity (67%) in diagnosing CRIMYNE. All patients developed the electrophysiological signs of CRIMYNE within 13 days of ICU admission. Median time from ICU admission to CRIMYNE was six days (95% CI five to nine days). In 10 patients, the amplitude of the nerve action potential dropped progressively over a median of 3.0 days, and in 18 patients it dropped abruptly within 24 hours. Multi-organ failure occurred in 21 patients (22.8%, 95% CI 15.4% to 32.4%) and was strongly associated with CRIMYNE (odds ratio 4.58, 95% CI 1.64 to 12.81). Six patients with CRIMYNE died: three in the ICU and three after ICU discharge. Hospital mortality was similar in patients with and without CRIMYNE (21.4% and 17.2%; p = 0.771). At ICU discharge, electrophysiological signs of CRIMYNE persisted in 18 (64.3%) of 28 patients. At hospital discharge, diagnoses in the 15 survivors were critical illness myopathy (CIM) in six cases, critical illness polyneuropathy (CIP) in four, combined CIP and CIM in three, and undetermined in two.

Conclusion

A peroneal CMAP reduction below two standard deviations of normal value accurately identifies patients with CRIMYNE. These should have full neurological and neurophysiological evaluations before discharge from the acute hospital.
Information-based management of mental health services: a two-stage model for improving funding mechanisms and clinical governance
Authors: Elphick Martin , Elphick Martin
Published: February 2007

The government and commissioners have a responsibility to distribute resources for healthcare services to ensure equity across the country. They should also be concerned about quality, cost-effectiveness and safety. However, at present these tasks are seriously hampered by a lack of good-quality information about what is happening within services. Internal trust management is also poorly informed.
Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis
Authors: Leslie Jonathan D. , Ariza-McNaughton Linda , Bermange Adam L. , McAdow Ryan , Johnson Stephen L. , Lewis Julian
Published: January 2007

Notch signalling by the ligand Delta-like 4 (Dll4) is essential for normal vascular remodelling, yet the precise way in which the pathway influences the behaviour of endothelial cells remains a mystery. Using the embryonic zebrafish, we show that, when Dll4-Notch signalling is defective, endothelial cells continue to migrate and proliferate when they should normally stop these processes. Artificial overactivation of the Notch pathway has opposite consequences. When vascular endothelial growth factor (Vegf) signalling and Dll4-Notch signalling are both blocked, the endothelial cells remain quiescent. Thus, Dll4-Notch signalling acts as an angiogenic `off' switch by making endothelial cells unresponsive to Vegf.
Syne-1andSyne-2play crucial roles in myonuclear anchorage and motor neuron innervation
Authors: Zhang Xiaochang , Xu Rener , Zhu Binggen , Yang Xiujuan , Ding Xu , Duan Shumin , Xu Tian , Zhuang Yuan , Han Min
Published: February 2007

Proper nuclear positioning is important to cell function in many biological processes during animal development. In certain cells, the KASH-domain-containing proteins have been shown to be associated with the nuclear envelope, and to be involved in both nuclear anchorage and migration. We investigated the mechanism and function of nuclear anchorage in skeletal muscle cells by generating mice with single and double-disruption of the KASH-domain-containing genes Syne1 (also known as Syne-1)and Syne2 (also known as Syne-2). We showed that the deletion of the KASH domain of Syne-1 abolished the formation of clusters of synaptic nuclei and disrupted the organization of non-synaptic nuclei in skeletal muscle. Further analysis indicated that the loss of synaptic nuclei in Syne-1 KASH-knockout mice significantly affected the innervation sites and caused longer motor nerve branches. Although disruption of neither Syne-1 nor Syne-2 affected viability or fertility, Syne-1; Syne-2 double-knockout mice died of respiratory failure within 20 minutes of birth. These results suggest that the KASH-domain-containing proteins Syne-1 and Syne-2 play crucial roles in anchoring both synaptic and non-synaptic myonuclei that are important for proper motor neuron innervation and respiration.
Sdf1a patterns zebrafish melanophores and links the somite and melanophore pattern defects inchokermutants
Authors: Svetic Valentina , Hollway Georgina E. , Elworthy Stone , Chipperfield Thomas R. , Davison Claire , Adams Richard J. , Eisen Judith S. , Ingham Philip W. , Currie Peter D. , Kelsh Robert N.
Published: February 2007

Pigment pattern formation in zebrafish presents a tractable model system for studying the morphogenesis of neural crest derivatives. Embryos mutant for choker manifest a unique pigment pattern phenotype that combines a loss of lateral stripe melanophores with an ectopic melanophore `collar' at the head-trunk border. We find that defects in neural crest migration are largely restricted to the lateral migration pathway, affecting both xanthophores (lost) and melanophores (gained) in choker mutants. Double mutant and timelapse analyses demonstrate that these defects are likely to be driven independently, the collar being formed by invasion of melanophores from the dorsal and ventral stripes. Using tissue transplantation, we show that melanophore patterning depends upon the underlying somitic cells, the myotomal derivatives of which - both slow- and fast-twitch muscle fibres - are themselves significantly disorganised in the region of the ectopic collar. In addition, we uncover an aberrant pattern of expression of the gene encoding the chemokine Sdf1a in choker mutant homozygotes that correlates with each aspect of the melanophore pattern defect. Using morpholino knock-down and ectopic expression experiments, we provide evidence to suggest that Sdf1a drives melanophore invasion in the choker mutant collar and normally plays an essential role in patterning the lateral stripe. We thus identify Sdf1 as a key molecule in pigment pattern formation, adding to the growing inventory of its roles in embryonic development.
MDMX: from bench to bedside
Authors: Marine Jean-Christophe W. , Dyer Michael A. , Jochemsen Aart G.
Published: January 2007

The tumor suppressor protein p53 is negatively regulated by Mdm2, a ubiquitin ligase protein that targets p53 for degradation. Mdmx (also known as Mdm4) is a relative of Mdm2 that was identified on the basis of its ability to physically interact with p53. An increasing body of evidence, including recent genetic studies, suggests that Mdmx also acts as a key negative regulator of p53. Aberrant expression of MDMX could thus contribute to tumor formation. Indeed, MDMX amplification and/or overexpression occurs in several diverse tumors. Strikingly, recent work identifies MDMX as a specific chemotherapeutic target for treatment of retinoblastoma. Specific MDMX antagonists should therefore be developed as a tool to ensure activation of `dormant' p53 activity in tumors that retain wild-type p53.
Preorganization in biological systems: Are conformational constraints worth the energy?
Authors: Martin Stephen F.
Published: February 2007

It is generally assumed that preorganizing a flexible ligand in the three-dimensional shape it adopts when bound to a macromolecular receptor will provide a derivative having an increased binding affinity, primarily because the rigidified molecule is expected to benefit from a lesser entropic penalty during complexation. We now provide the first experimental evidence that demonstrates this common belief is not universally true. Indeed, we find that ligand preorganization may be accompanied by an unfavorable entropy of binding, even when the constrained ligand exhibits a higher binding affinity than its flexible control. Thus, the effects that ligand preorganization have upon energetics and structure in protein-ligand interactions must be reevaluated.
Modified mesoporous materials as Pd scavengers and catalyst supports
Authors: Crudden Cathleen M. , McEleney Kevin , MacQuarrie Stephanie L. , Blanc Alexandre , Sateesh Mutyala , Webb Jonathan D.
Published: February 2007

The use of mesoporous molecular sieves (MMSs) modified by mercaptopropyl trimethoxysilane (MPTMS) to scavenge Pd is described. The ordered mesoporous material displays excellent ability to remove Pd from organic and aqueous solutions. After only one treatment, a 500-ppm solution of PdCl2 in water can be reduced to 1 ppb. In addition, the resulting material is an effective, leach-proof catalyst for the Suzuki-Miyaura and Mizoroki-Heck reactions. Thus, the Suzuki-Miyaura reaction can be conducted in water at 80 °C with as little as 3 ppb Pd leaching. Hot filtrations and three-phase tests confirm that the catalyst acts without leaching Pd from the surface.
Widening the usefulness of epoxides and aziridines in synthesis
Authors: Hodgson David M. , Humphreys Philip G. , Hughes Steven P.
Published: February 2007

Deprotonation of terminal epoxides and aziridines with organolithium/diamine combinations or lithium amides allows the regio- and stereoselective formation of α-lithiated species. Judicious choice of reaction conditions allows these species to operate as nucleophiles, enolate equivalents, vinyl cation equivalents, or carbenes.