bluuebunny/crossref_metadata_2025 huggingface dataset:
Perils and pitfalls of permutation tests for distinguishing the effects of neighbouring polymorphisms
Authors: Biernacka Joanna M. , Cordell Heather J.
Published: July 2006

In a small region several marker loci may be associated with a trait, either because they directly influence the trait or because they are in linkage disequilibrium (LD) with a causal variant. Having established a potentially causal effect at a primary variant, we may ask if any other variants in the region appear to further contribute to the trait, indicating that the additional variant is either causal or is in LD with another causal locus. Methods of approaching this problem using case‐parent trio data include the stepwise conditional logistic regression approach described by Cordell and Clayton ([2002] Am. J. Hum. Genet. 70:124–141), and a constrained‐permutation method recently proposed by Spijker et al. ([2005] Ann. Hum. Genet. 69:90–101). Through simulation we demonstrate that the procedure described by Spijker et al. [2005], as well as unconditional logistic regression with “affected family‐based controls” (AFBACs), can lead to inflated type 1 errors in situations when haplotypes are not inferable for all trios, whereas the conditional logistic regression approach gives correct significance levels. We propose an alternative to the permutation method of Spijker et al. [2005], which does not rely on haplotyping, and results in correct type 1 errors and potentially high power when assumptions of random mating, Hardy‐Weinberg Equilibrium, and multiplicative effects of disease alleles are satisfied. Genet. Epidemiol. 2006. © 2006 Wiley‐Liss, Inc.
Sentinel node detection in breast cancer using contrast‐enhanced sonography with 25% albumin—Initial clinical experience
Authors: Omoto Kiyoka , Hozumi Yasuo , Omoto Yawara , Taniguchi Nobuyuki , Itoh Kouichi , Fujii Yasutomo , Mizunuma Hirobumi , Nagai Hideo
Published: July 2006

Purpose.

To determine the clinical usefulness of a sentinel lymph node (SLN) identification technique using contrast‐enhanced sonography (CEUS) with 25% albumin.

Methods.

The subjects were 23 women with breast cancer. Each was injected subcutaneously with 5 ml of 25% albumin solution as a negative contrast agent directly superficial to the breast tumor. The area was massaged, and the inferior axillary hairline was examined continuously using gray‐scale sonography with a 7.5‐ or 10‐MHz transducer. Any contrast‐enhanced lymph node was considered a CEUS‐detected SLN, was differentiated from other level I and II nodes, and was resected and pathologically assessed.

Results.

In all 23 patients, 1 or 2 CEUS‐detected SLNs (mean, 1.3 SLNs) were identified. Their sizes ranged from 5 mm to 25 mm (mean, 11.3 mm), and their depths (from the skin surface) ranged from 5mm to 20 mm (mean, 12.6 mm). Pathologic examination revealed a metastasis in 5 of the 23 patients, all in CEUS‐detected SLNs.

Conclusions.

In a clinical study using CEUS with 25% albumin, contrast‐enhanced nodes were identified in all subjects. The pathologic findings suggested that any metastatic nodes observed were SLNs, indicating that this technique may represent a new modality for SLN identification. © 2006 Wiley Periodicals, Inc. J Clin Ultrasound 34:317–326, 2006
Possible role of scavenger receptor SRCL in the clearance of amyloid‐βin Alzheimer's disease
Authors: Nakamura Kenji , Ohya Wakana , Funakoshi Hiroshi , Sakaguchi Gaku , Kato Akira , Takeda Masatoshi , Kudo Takashi , Nakamura Toshikazu
Published: July 2006

Accumulation of β‐amyloid protein (Aβ) in the brain is a hallmark of Alzheimer's disease (AD), and Aβ‐mediated pathogenesis could result from increased production of Aβ or insufficient Aβ clearance by microglia, astrocytes, or the vascular system. Cell‐surface receptors, such as scavenger receptors, might play a critical role in the binding and clearing of Aβ; however, the responsible receptors have yet to be identified. We show that scavenger receptor with C‐type lectin (SRCL), a member of the scavenger receptor family containing coiled‐coil, collagen‐like, and C‐type lectin/carbohydrate recognition domains, is expressed in cultured astrocytes and microglia. In contrast to the low expression of SRCL in the wild‐type mouse brain, in a double transgenic mouse model of AD (Tg‐APP/PS1), immunohistochemistry showed that SRCL was markedly induced in Aβ‐positive astrocytes and Aβ‐positive vascular/perivascular cells, which are associated closely with cerebral amyloid angiopathy. In patients with AD, the distribution of SRCL was similar to that seen in the Tg‐APP/PS1 temporal cortex. The presence of a large number of SRCL/Aβ double‐positive particles in the intracellular compartments of reactive astrocytes and vascular/perivascular cells in Tg‐APP/PS1 mice and AD patients suggests a role for SRCL in Aβ clearance. Moreover, CHO‐K1 cells transfected with SRCL isoforms were found to bind fibrillar Aβ1–42. These findings suggest that SRCL could be the receptor involved in the binding or clearing of Aβ by glial and vascular/perivascular cells in AD. © 2006 Wiley‐Liss, Inc.
Tetracycline‐inducible gene expression in nuclear transfer embryos derived from porcine fetal fibroblasts transformed with retrovirus vectors
Authors: Choi Bok Ryul , Koo Bon Chul , Ahn Kwang Sung , Kwon Mo Sun , Kim Jin‐Hoi , Cho Seong‐Keun , Kim Kyoung Mi , Kang Jee Hyun , Shim Hosup , Lee Hyuna , Uhm Sang Jun , Lee Hoon Taek , Kim Teoan
Published: July 2006

A critical problem of transgenic livestock production is uncontrollable constitutive expression of the foreign gene, which usually results in serious physiological disturbances in transgenic animals. One of the best solutions for this problem may be use of controllable gene expression system. In this study, using retrovirus vectors designed to express the enhanced green fluorescent protein (EGFP) gene under the control of the tetracycline‐inducible promoter, we examined whether the expression of the transgene could be controllable in fibroblast cells and nuclear transfer (NT) embryos of porcine. Transformed fibroblast cells were cultured in medium supplemented with or without doxycycline (a tetracycline analog) for 48 hr, and the induction efficiency was measured by comparing EGFP gene expression using epifluorescence microscopy and Western and Northern blot analyses. After the addition of doxycycline, EGFP expression increased up to 17‐fold. The nuclei of transformed fibroblast cells were transferred into enucleated oocytes. Fluorescence emission data revealed strong EGFP gene expression in embryos cultured with doxycycline, but little or no expression in the absence of the antibiotic. Our results demonstrate the successful regulation of transgene expression in porcine nuclear transfer embryos, and support the application of an inducible expression system in transgenic pig production to solve the inherent problems of side‐effects due to constitutive expression of the transgene. Mol. Reprod. Dev. © 2006 Wiley‐Liss, Inc.
Ubiquitin ligase gene expression in healthy volunteers with 20‐day bedrest
Authors: Ogawa Takayuki , Furochi Harumi , Mameoka Mai , Hirasaka Katsuya , Onishi Yuko , Suzue Naoto , Oarada Motoko , Akamatsu Motoki , Akima Hiroshi , Fukunaga Tetsuo , Kishi Kyoichi , Yasui Natsuo , Ishidoh Kazumi , Fukuoka Hideoki , Nikawa Takeshi
Published: July 2006

In animal models, several ubiquitin ligases play an important role in skeletal muscle atrophy caused by unloading. In this study we examined protein ubiquitination and ubiquitin ligase gene expression in quadriceps femoris muscle from healthy volunteers after 20‐day bedrest to clarify ubiquitin‐dependent proteolysis in human muscles after unloading. During bedrest, thickness and cross‐sectional area of the quadriceps femoris muscle decreased significantly by 4.6% and 3.7%, respectively. Ubiquitinated proteins accumulated in these atrophied human muscles. A real‐time reverse transcription–polymerase chain reaction system showed that bedrest significantly upregulated expression of two ubiquitin ligase genes, Cbl‐b and atrogin‐1. We also performed DNA microarray analysis to examine comprehensive gene expression in the atrophied muscle. Bedrest mainly suppressed the expression of muscle genes associated with control of gene expression in skeletal muscle. Our results suggest that, in humans, Cbl‐b– or atrogin‐1–mediated ubiquitination plays an important role in unloading‐induced muscle atrophy, and that unloading stress may preferentially inhibit transcriptional responses in skeletal muscle. Muscle Nerve, 2006
An awkward threesome—donors, governments and non‐state providers of health in low income countries
Authors: Palmer Natasha
Published: July 2006

Bilateral and multilateral donors make frequent reference to collaboration with non‐state providers (NSPs) in the health sector, and the desirability of so‐called public private partnerships. Governments of many low‐income countries are also increasingly committed to this goal in their policy statements. This article presents a range of cases from six countries of how governments, donors and NSPs interact. It describes examples of what type of engagement is taking place between governments and NSPs, highlights some common themes and reflects on common motivations for collaboration and constraints to it. Examples are examined under the original study design headings of dialogue, regulation, facilitation and contracting. These categories were not easy to sustain. Much government support to NSPs was characterised by donor involvement, fostering a ‘pilot project’ style of approach. In other cases, it was not so much a case of governments pursuing a specific intervention to support or regulate NSPs, as NGOs taking an initiative to fill a gap in government provision. The article highlights the main gap in interaction with NSPs as a comprehensive framework for regulating services provided by small scale, for profit NSPs. This is a serious shortcoming given that they deliver the bulk of basic health care in most of the countries examined. Copyright © 2006 John Wiley & Sons, Ltd.
Engaged or divorced? Cross‐service findings on government relations with non‐state service‐providers
Authors: Batley Richard
Published: July 2006

Non‐state provision (NSP) of basic services is an important substitute for government services in most developing countries. The international policy environment favours the idea that service levels could be improved if government and non‐state providers collaborated. This article examines the experience based on studies of basic education and healthcare, water and sanitation in six African and South Asian countries. It finds that, while policy is now generally in support of NSP, practice is more often unsupportive and relationships are surrounded by mistrust. The main providers of non‐state services—local entrepreneurs, individual practitioners, community organisations and small NGOs—are largely absent from any dialogue with government. They are exposed to forms of regulation that are largely repressive and effectively designed to protect established interests. Nevertheless, the article identifies positive examples of alternative forms of regulation that advance improved service standards, of facilitation by large NGOs acting in an intermediary role in support of local actors, and of replicable forms of collaboration between government and non‐state providers. Copyright © 2006 John Wiley & Sons, Ltd.
Plant safety and risk with temporary equipment
Authors: Cadwallader L.C.
Published: July 2006

Temporary equipment may be brought onto a plant site for a variety of process needs. The risk profile of the facility is altered by use of such temporary equipment, but since the time durations of temporary equipment usage are generally small, usually fewer than 90 days per year, the risk increase is also small and is typically not modeled in a probabilistic risk assessment. This article describes some risk issues with temporary equipment in long‐term use, gives a case study of a temporary, diesel‐driven air compressor under extended use at the Idaho National Laboratory, and suggests the need to model temporary equipment in the facility risk assessment if the equipment is used more than a few months. © 2006 American Institute of Chemical Engineers Process Saf Prog, 2006
Assessing design instability in iterative (agile) object‐oriented projects
Authors: Olague Hector M. , Etzkorn Letha H. , Li Wei , Cox Glenn
Published: July 2006

Assessing progress and stability in rapid, highly iterative and agile object‐oriented software development processes is difficult because program evolution appears somewhat disorderly. With agile software development methods, the expected time to reach software stability is obscured by the dynamic nature of the agile process itself. The System Design Instability (SDI) metric was developed to help analyze object‐oriented software evolution under these conditions. In this paper we examine a new version of SDI, called SDIe, based on the maximum entropy in a system. We believe our new measure is easier to calculate than the original version of SDI since it is based on data that are more commonly available than those used by SDI; also, SDIe gives a more accurate indication of software stability and maturity since it suffers less from data spikes. To validate the new metric, we use maintenance data from a commercial software project, developed using an agile process; these are the same data that were collected and analyzed in the original SDI study. In addition, we apply the refined SDI metric to the evolution of a well‐established, open‐source, iteratively‐developed software product. The results of our case study indicate our new SDIe metric is a viable measure of system design stability. Copyright © 2006 John Wiley & Sons, Ltd.
Serum HER2 levels are increased in patients with chronic heart failure
Authors: Perik Patrick J. , de Vries Elisabeth G.E. , Gietema Jourik A. , van der Graaf Winette T.A. , Smilde Tom D.J. , Sleijfer Dirk T. , van Veldhuisen Dirk J.
Published: July 2006

Background

The use of trastuzumab, an antibody against the human epidermal growth factor receptor 2 (HER2), in patients with HER2 positive metastatic breast cancer, is related to cardiotoxicity.

Aims

To investigate whether serum HER2 is increased in heart failure patients and related to disease severity.

Methods

Serum HER2, plasma tumor necrosis factor (TNF)‐α and its soluble (s) receptors (sTNF‐R1 and 2) were determined with ELISA in chronic heart failure patients and age and gender‐matched healthy controls.

Results

Serum HER2 was higher (P=0.013) in 50 heart failure patients (18 female; median age 57 (range 33–77) years), mean 12.1±S.D. 2.3 ng/mL, than in 15 controls, 10.4±2.6 ng/mL. Serum HER2 levels correlated inversely with left ventricular ejection fraction (P=0.037) and were highest among NYHA class III patients, followed by NYHA class II patients and controls (P=0.029, Kruskal–Wallis test). STNF‐R1 (P<.001) and sTNF‐R2 (P=0.015) were higher in patients than controls, and correlated positively with HER2 (P=0.027 and P=0.036, respectively).

Conclusions

Serum HER2 levels are increased in chronic heart failure patients. Further research is necessary to determine whether HER2 plays a role in the pathophysiology of heart failure.
Elongation factor Tu‐targeted antibiotics: Four different structures, two mechanisms of action
Authors: Parmeggiani Andrea , Nissen Poul
Published: July 2006

Elongation factor Tu (EF‐Tu), the carrier of aa‐tRNA to the mRNA‐programmed ribosome, is the target of four families of antibiotics of unrelated structure, of which the action is supported by two basic mechanisms. Kirromycin and enacyloxin block EF‐Tu · GDP on the ribosome; pulvomycin and GE2270 A inhibit the interaction of EF‐Tu · GTP with aa‐tRNA. The crystallographic analysis has unveiled the structural background of their actions, explaining how antibiotics of unrelated structures and binding modes and sites can employ similar mechanism of action. The selective similarities and differences of their binding sites and the induced EF‐Tu conformations make understand how nature can affect the activities of a complex regulatory enzyme by means of low‐molecular compounds, and have proposed a suitable approach for drug design.
Pellino proteins are more than scaffold proteins in TLR/IL‐1R signalling: A role as novel RING E3–ubiquitin‐ligases
Authors: Schauvliege Reinout , Janssens Sophie , Beyaert Rudi
Published: July 2006

Members of the Toll‐like receptor (TLR) and IL‐1 receptor (IL‐1R) family initiate signalling pathways that shape innate immunity. Pellino proteins have recently been implicated as evolutionary conserved scaffold proteins in TLR/IL‐1R signalling leading to nuclear factor‐κB and mitogen activated protein kinase‐dependent gene expression. We found that Pellino proteins contain a new RING‐like motif. Because RING motifs are a feature of a subclass of E3–ubiquitin‐ligases that target specific proteins for ubiquitination, we suggest that Pellino proteins are involved in TLR/IL‐1R signalling not only as scaffold proteins but also as RING E3–ubiquitin‐ligases. In support of this hypothesis we show that Pellino proteins induce IRAK‐1 polyubiquitination in a RING‐dependent manner. We further propose a model in which Pellino‐mediated IRAK‐1 polyubiquitination regulates TLR/IL‐1R signalling.
Congestive heart failure associated with a large transverse left ventricular moderator band in a cat
Authors: Wray Jonathan D. , Gajanayake Isuru , Smith Sionagh H.
Published: July 2006

Cardiomyopathy associated with abnormal trabecular bands of tissue traversing one or both ventricles is reported rarely in cats. The case of a 9-year-old cat which presented in congestive heart failure is reported. Multiple cardiac abnormalities were found, including a large trabecular tissue bridge which bisected the left ventricle. Other findings included arrhythmia, thrombocytopaenia and raised serum creatine kinase. The cat was euthanased due to clinical deterioration. Necropsy findings included increased cardiac weight, the division of the left ventricle by a large trabecular band composed of connective tissue and cardiac myofibres consistent with a moderator band, nodular thickening of the mitral valve, left atrial dilation, and fibroplasia/fibrosis of the left ventricular myocardium associated with widespread myofibre necrosis due to infarction. Pathological findings in this case differ from previous reports of ventricular transverse bridging tissue in cats with cardiac disease.
The Aryan clause, the Confessing Church, and the ecumenical movement: Barth and Bonhoeffer on natural theology, 1933–1935
Authors: Ballor Jordan J.
Published: July 2006

In this article I argue that the essential relationship between Dietrich Bonhoeffer and Karl Barth stands in need of reassessment. This argument is based on a survey of literature dealing with Bonhoeffer and Barth in three basic areas between the critically important years of 1933 and 1935. These three areas come into sharp relief given the political background of the German Christian victory in the church elections of 1933. Their respective positions, both theological and political, on the Aryan clause differ greatly. For Bonhoeffer, the imposition of the Aryan clause on the German churches represented a clear status confessionis, and Bonhoeffer favoured a very public schism. For Barth, while the Aryan clause was certainly troublesome, it was deemed better to wait for a ‘more central’ point, namely, that of the question of natural theology. Barth's emphasis on the importance of the question of natural theology carries over in his position regarding the significance and role of both the Confessing Church and the ecumenical movement. We see that Bonhoeffer explicitly questions the validity of Barth's emphasis on natural theology with respect to the Confessing Church and to the ecumenical movement. While many scholars have argued for the basic agreement between Barth and Bonhoeffer, especially on the question of natural theology, a closer examination of the two in the period 1933–35 calls such conclusions into question.
Oligodendrocytes regulate formation of nodes of Ranvier via the recognition molecule OMgp
Authors: NIE DU-YU , MA QUAN-HONG , LAW JANICE W.S. , CHIA CHERN-PANG , DHINGRA NARENDER K. , SHIMODA YASUSHI , YANG WU-LIN , GONG NENG , CHEN QING-WEN , XU GANG , HU QI-DONG , CHOW PIERCE K.H. , NG YEE-KONG , LING ENG-ANG , WATANABE KAZUTADA , XU TIAN-LE , HABIB AMYN A. , SCHACHNER MELITTA , XIAO ZHI-CHENG
Published: July 2006

The molecular mechanisms underlying the involvement of oligodendrocytes in formation of the nodes of Ranvier (NORs) remain poorly understood. Here we show that oligodendrocyte-myelin glycoprotein (OMgp) aggregates specifically at NORs. Nodal location of OMgp does not occur along demyelinated axons of either Shiverer or proteolipid protein (PLP) transgenic mice. Over-expression of OMgp in OLN-93 cells facilitates process outgrowth. In transgenic mice in which expression of OMgp is down-regulated, myelin thickness declines, and lateral oligodendrocyte loops at the node-paranode junction are less compacted and even join together with the opposite loops, which leads to shortened nodal gaps. Notably, each of these structural abnormalities plus modest down-regulation of expression of Na+ channel α subunit result in reduced conduction velocity in the spinal cords of the mutant mice. Thus, OMgp that is derived from glia has distinct roles in regulating nodal formation and function during CNS myelination.
Modeling the geomagnetic effects caused by the solar eclipse of 11 August 1999
Authors: Curto J. J. , Heilig B. , Piñol M.
Published: July 2006

The solar eclipse of 11 August 1999 was total along a belt crossing Central Europe, where there is a high density of magnetic observatories. We studied the transient geomagnetic effects produced by the temporary cutoff of the ionizing solar radiations during the eclipse. It is the first case in which the phenomenon has been analysed in a multisite context. For observatories along the umbra path, a model based on the equivalent electric current schema is proposed.
Observations of upper tropospheric/lower stratospheric water vapor and its isotopes
Authors: Coffey M. T. , Hannigan J. W. , Goldman A.
Published: July 2006

Airborne observations of high‐resolution infrared absorption, recorded between 1978 and 2005, are used to retrieve column amounts of H216O, H217O, H218O and HDO. Observations span a wide range of years, seasons and latitudes, all made with essentially the same spectrometer system. A spectral optimal estimator fitting technique, SFIT2, has been used uniformly to analyze all the data. The latitudinal distributions of H216O, H217O and H218O are similar and much like those from other observations (e.g., SPARC (Kley et al., 2000)). The column of HDO above 13 km exhibits a distribution with latitude that is much less pronounced. From 1978 to 2005 the long‐term increase in the column of Northern Hemisphere H216O above 13 km is found to be 1.16 ± 0.4%/year, consistent with previous observations. HDO is found to decrease by about 0.4%/year during the same period. In low latitudes, from 35°S to 35°N, large depletions of HDO relative to H216O, δD (−460 ± 21‰), and H218O relative to H216O (−104 ± 47‰) are determined. δD shows an unexpected trend of enhanced depletion of about 5–6‰ per year for the period from 1978 to 2005.
Variations and sources of the equivalent black carbon in the high Arctic revealed by long‐term observations at Alert and Barrow: 1989–2003
Authors: Sharma S. , Andrews E. , Barrie L. A. , Ogren J. A. , Lavoué D.
Published: July 2006

Fifteen years of “equivalent” black carbon (EBC) measurements (derived from aethalometer measurements of light absorption) made at Alert in Nunavut, Canada, and Point Barrow in Alaska, United States, were compared for the long‐term trends and seasonal cycle. Over the 15‐year period from 1989 to 2003, the results revealed a downward trend in EBC concentrations by as much as 54% at Alert and 27% at Barrow for the all‐year data, by 49% at Alert and 33% at Barrow for the winter data, and by 53% at Alert for the summer. It was difficult to quantify if there was a decline during the summer for Barrow since there was no clear trend. The difference in trends might be related to changes in circulation in the Arctic, variable source contribution, and/or scavenging of particles. The results revealed that EBC concentrations were 40% higher during the positive phase of the North Atlantic Oscillation than during the negative phase. The source contributions at the two sites were determined by using trajectory analysis techniques, which revealed that Alert came under the influence of Siberia/Europe transport while Barrow showed influence from Siberian and Pacific/Asian transport.
Large forest fires in Canada and the relationship to global sea surface temperatures
Authors: Skinner W. R. , Shabbar A. , Flannigan M. D. , Logan K.
Published: July 2006

Relationships between variations in peak Canadian forest fire season (JJA) severity and previous winter (DJF) global sea surface temperature (SST) variations are examined for the period 1953 to 1999. Coupled modes of variability between the seasonal severity rating (SSR) index and the previous winter global SSTs are analyzed using singular value decomposition (SVD) analysis. The robustness of the relationship is established by the Monte Carlo technique. The importance of the leading three SVD modes, accounting for approximately 90% of the squared covariance, to Canadian summer forest fire severity is identified. The first mode relates strongly to the global long‐term trend, especially evident in the warming of the Southern Hemisphere oceans, and shows significant positive correlation in the forested regions of northwestern, western and central Canada, while southern B.C., the extreme northwest coastal regions of B.C. and Yukon, and the Great Lakes region are identified as having significant negative correlation. The second mode relates to the multidecadal variation of Atlantic SST (AMO) and shows highly significant negative correlation extending from the western NWT and Canadian Prairie Provinces across northern Ontario and Quebec. The third mode is related to Pacific Ocean processes and the interrelationship between El Niño–Southern Oscillation (ENSO) and the Pacific Decadal Oscillation (PDO) and shows strong positive correlation in western Canada and negative correlation in the lower Great Lakes region of southern Ontario and southern Quebec. A 6‐month lag relationship between Canadian forest fire variability and large‐scale SSTs may provide the basis for developing long‐range forecasting schemes for fire severity in Canada.
Synthesis of bulk metallic glass foam by powder extrusion with a fugitive second phase
Authors: Lee Min Ha , Sordelet Daniel J.
Published: July 2006

Bulk metallic glass foams with 12mm in diameter and 30mm in length having a density of 4.62g∕cm3 (approximately 58.3% of theoretical) were fabricated by extruding a powder mixture comprised of 60vol% Ni59Zr20Ti16Si2Sn3 metallic glass blended with 40vol% brass followed by dissolution of the fugitive brass in an aqueous HNO3 solution. The final structure consists of continuously connected, high aspect ratio metallic glass struts surrounded by ∼40vol% of homogeneously distributed ellipsoid-shaped pores having nominal diameters between 10 and 50μm.
Scanning transmission electron microscope study on vertically correlated InGaAs∕GaAs quantum dots
Authors: Sauerwald A. , Kümmell T. , Peskes D. , Bacher G. , Löffler A. , Reithmaier J. P. , Forchel A.
Published: July 2006

Vertically stacked self-organized InGaAs∕GaAs quantum dots have been investigated by chemically sensitive scanning transmission electron microscopy combined with electron energy loss spectroscopy. While the probability of a laterally correlated growth is strongly enhanced with decreasing spacer layer thickness, no measurable variation of both the size and the average In alloy concentration of the quantum dots within the stacks is found, making the structures ideally suited for potential applications in quantum information processing.
Effects of nanoparticle clustering and alignment on thermal conductivities of Fe3O4 aqueous nanofluids
Authors: Zhu Haitao , Zhang Canying , Liu Shiquan , Tang Yaming , Yin Yansheng
Published: July 2006

Thermal conductivities of Fe3O4 aqueous nanofluids were studied. The results show that Fe3O4 nanofluids have higher thermal conductivities than other oxide aqueous nanofluids at the same volume fraction. The experimental values are higher than those predicted by the existing models. The abnormal thermal conductivities of Fe3O4 nanofluids are attributed to the observed nanoparticle clustering and alignment.
Role of the
Arabidopsis
DNA glycosylase/lyase ROS1 in active DNA demethylation
Authors: Agius Fernanda , Kapoor Avnish , Zhu Jian-Kang
Published: July 2006

DNA methylation is a stable epigenetic mark for transcriptional gene silencing in diverse organisms including plants and many animals. In contrast to the well characterized mechanism of DNA methylation by methyltransferases, the mechanisms and function of active DNA demethylation have been controversial. Genetic evidence suggested that the DNA glycosylase domain-containing protein ROS1 of
Arabidopsis
is a putative DNA demethylase, because loss-of-function
ros1
mutations cause DNA hypermethylation and enhance transcriptional gene silencing. We report here the biochemical characterization of ROS1 and the effect of its overexpression on the DNA methylation of target genes. Our data suggest that the DNA glycosylase activity of ROS1 removes 5-methylcytosine from the DNA backbone and then its lyase activity cleaves the DNA backbone at the site of 5-methylcytosine removal by successive β- and δ-elimination reactions. Overexpression of ROS1 in transgenic plants led to a reduced level of cytosine methylation and increased expression of a target gene. These results demonstrate that ROS1 is a 5-methylcytosine DNA glycosylase/lyase important for active DNA demethylation in
Arabidopsis
.
Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries
Authors: Inglese James , Auld Douglas S. , Jadhav Ajit , Johnson Ronald L. , Simeonov Anton , Yasgar Adam , Zheng Wei , Austin Christopher P.
Published: July 2006

High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration–response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration–response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure–activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>10
5
compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.
Nanodiscs separate chemoreceptor oligomeric states and reveal their signaling properties
Authors: Boldog Thomas , Grimme Stephen , Li Mingshan , Sligar Stephen G. , Hazelbauer Gerald L.
Published: July 2006

Bacterial chemoreceptors are transmembrane homodimers that can form trimers, higher order arrays, and extended clusters as part of signaling complexes. Interactions of dimers in oligomers are thought to confer cooperativity and cross-receptor influences as well as a 35-fold gain between ligand binding and altered kinase activity. In addition, higher order interactions among dimers are necessary for the observed patterns of assistance in adaptational modification among different receptors. Elucidating mechanisms underlying these properties will require defining which receptor functions can be performed by dimers and which require specific higher order interactions. However, such an assignment has not been possible. Here, we used Nanodiscs, an emerging technology for manipulating membrane proteins, to prepare small particles of lipid bilayer containing one or only a few chemoreceptor dimers. We found that receptor dimers isolated in individual Nanodiscs were readily modified, bound ligand, and performed transmembrane signaling. However, they were hardly able to activate the chemotaxis histidine kinase. Instead, maximal activation and thus full-range control of kinase occurred preferentially in discs containing approximately three chemoreceptor dimers. The sharp dependence of kinase activation on this number of receptors per dimer implies that the core structural unit of kinase activation and control is a trimer of dimers. Thus, our observations demonstrate that chemoreceptor transmembrane signaling does not require oligomeric organization beyond homodimers and implicate a trimer of dimers as the unit of downstream signaling.
Co‐Occurring Disorders: Policy and Practice in Germany
Authors: Hintz Thomas , Mann Karl
Published: July 2006

The occurrence of substance use disorders (SUD) with other mental disorders—what is often referred to as co‐occurring disorders (COD)—is a common phenomenon, but for a long time, little attention has been paid to this problem in Germany. During the last 25 years, however, COD awareness has increased due to a shift toward community‐based services. Scientific research has also demonstrated the significance and clinical relevance of COD. High prevalence rates and evidence of poor clinical outcomes were found in German studies. Many practitioners as well as policymakers acknowledge that changes in systems of care are necessary to meet the requirements of COD patients. The traditional German system is currently divided into addiction services and mental health services (predominantly in inpatient settings), often resulting in ineffective sequential treatment for COD patients. Research demonstrates that integrative treatment models are more appropriate, and the division of services should be reorganized to help COD patients appropriately. Efforts have already been made to restructure healthcare systems toward a more flexible approach with improved networking between in‐and outpatient services. A further issue is the general attitude toward SUD patients. Many practitioners continue to hold negative opinions (eg, “SUD patients are only weak‐minded”) or feel insecure when confronted with SUD. This results in SUD problems being frequently ignored or depreciated. Educational programs have been intensive over recent years to address this problem (eg, Fachkunde Sucht, an advanced training program on SUD). In general, treatment conditions for COD patients are improving, but further efforts are necessary. Guidelines and treatment strategies for COD patients have been recently published in Germany.
Relationship of DSM‐IV‐Based Depressive Disorders to Smoking Cessation and Smoking Reduction in Pregnant Smokers
Authors: Blalock Janice A. , Robinson Jason D. , Wetter David W. , Cinciripini Paul M.
Published: July 2006

This study investigated DSM‐IV depressive disorders as predictors of smoking cessation and reduction in 81 pregnant smokers participating in a smoking cessation trial. Thirty‐two percent of the sample met criteria for current dysthymia, major depressive disorder in partial remission, or minor depression. There was no significant reduction in smoking among women with or without current depressive disorders. Unexpectedly, as compared to women without depressive disorders, women with dysthymia significantly increased the mean number of cigarettes smoked (from 8 to 23 cigarettes per day during the 2 to 30 days post‐targeted quit date period) and were smoking significantly more cigarettes at 30 days. A main effect approaching significance suggested that women with current depressive disorders were less likely to be abstinent than women without current depressive disorders (OR = 6.3; 3.9% vs. 12.7% at 30 days post‐targeted quit date; 0% vs. 6.2% at 30 days post‐partum). Results add to previous findings indicating a correlation between depressive symptoms and continued smoking in pregnant women. Further investigation of mood‐focused smoking cessation interventions may be warranted.
Substance Use Disorder Comorbidity in Major Depressive Disorder: A Confirmatory Analysis of the STAR*D Cohort
Authors: Davis Lori L. , Frazier Elizabeth , Husain Mustafa M. , Warden Diane , Trivedi Madhukar , Fava Maurizio , Cassano Paolo , McGrath Patrick J. , Balasubramani G. K. , Wisniewski Stephen R. , Rush A. John
Published: July 2006

The demographics and clinical features were compared between those with (29.4%) and without concurrent substance use disorder (SUD) in 2541 outpatients with major depression (MDD) enrolled in the Sequenced Treatment Alternatives to Relieve Depression study. Compared to those without SUD, MDD patients with concurrent SUD were more likely to be younger, male, divorced or never married, and at greater current suicide risk, and have an earlier age of onset of depression, greater depressive symptomatology, more previous suicide attempts, more frequent concurrent anxiety disorders, and greater functional impairment (p = 0.048 to < 0.0001). They were also less likely to be Hispanic and endorse general medical comorbidities (p = 0.006 and 0.002, respectively).
One‐Year Follow‐Up Study of Suicide Attempters Treated for Drug Dependence
Authors: Agosti Vito , Levin Frances R.
Published: July 2006

A large proportion of patients treated for substance dependencies have attempted suicide. Scarce empirical evidence exists regarding their prognosis. Data from the Drug Abuse Treatment Outcome Survey were analyzed to determine the course of depression and substance dependence of 416 suicide attempters one year after discharge. The likelihood of recovery from drug dependence did not differ between patients who did or did not attempt suicide. Among suicide attempters who recovered from substance dependence, the frequency of Major Depression Disorder was significantly lower compared to admission, but its prevalence was nearly three times higher than that found in the general community.
Risk Factors for Suicide Ideation and Attempts Among Pathological Gamblers
Authors: Hodgins David C. , Mansley Chrystal , Thygesen Kylie
Published: July 2006

The link between pathological gambling and suicide is poorly understood. The current study has two major goals: to provide descriptive information about suicide ideation and attempts among pathological gamblers trying to quit, and to identify predictors of suicidal ideation and attempts, with a particular emphasis on mood and substance use disorders. A community sample of 101 individuals with gambling problems who had made a recent quit attempt was assessed using structured instruments. Of these, 28.7% reported no history of suicide ideation or attempts, 38.6% reported having only thoughts of suicide, and 32.7% reported a suicide attempt. Ideation predated the onset of gambling problems by an average of greater than ten years. History of ideation was increasingly likely with a greater severity of gambling problem as determined by DSM criteria. Those experiencing ideation were also more likely to over gamble on gambling days and five times more likely to have a history of depression. Substance abuse history was the only factor that distinguished between individuals who had a history of suicide attempts versus ideation only. Having a drug history was related to a more than six times greater likelihood of having made a suicide attempt. Gambling‐related suicide attempts were relatively rare−21.2% of attempters, or 7% of the total sample. These findings are consistent with the common factor model of etiology in which the suicidality of gambling is related to prior mental health disorders. More research on the relationship between alcohol and other drug disorders and their complex relationship to pathological gambling and suicide is crucial.
Testing the representation of time in reference memory in the bisection and the generalization task: The utility of a developmental approach
Authors: De Lurdes Delgado Maria , Droit-Volet Sylvie
Published: July 2006

This study examined the effect of the variability of representation of durations in reference memory on temporal discrimination performance in children aged 5 and 8 years as well as in adults using a bisection (Experiment 1) and a generalization task (Experiment 2). In each task, the participants were familiarized before the blocks of tested trials with either the same referent duration values (fixed condition) or a distribution of referent duration values, with a mean equal to the referent durations used in the fixed condition and a .20 coefficient of variation (variable condition). The results showed that the sensitivity to duration was lower in the variable than in the fixed condition in the children and, to a lesser extent, in the adults. The modelling of the data indicated that this effect was due to the increase in the variability of the representation of durations in reference memory, but also to changes in the decisional processes.
Requirement of dendritic Akt degradation by the ubiquitin–proteasome system for neuronal polarity
Authors: Yan Dong , Guo Li , Wang Yizheng
Published: July 2006

Asymmetric distributions of activities of the protein kinases Akt and glycogen synthase kinase 3β (GSK-3β) are critical for the formation of neuronal polarity. However, the mechanisms underlying polarized regulation of this pathway remain unclear. In this study, we report that the instability of Akt regulated by the ubiquitin–proteasome system (UPS) is required for neuron polarity. Preferential distribution in the axons was observed for Akt but not for its target GSK-3β. A photoactivatable GFP fused to Akt revealed the preferential instability of Akt in dendrites. Akt but not p110 or GSK-3β was ubiquitinated. Suppressing the UPS led to the symmetric distribution of Akt and the formation of multiple axons. These results indicate that local protein degradation mediated by the UPS is important in determining neuronal polarity.
Flexible Interaction Model for Complex Interactions of Multiple Anesthetics
Authors: Fidler Matthew , Kern Steven E.
Published: July 2006

Background

Minto et al. (Anesthesiology 2000) described a mathematical approach based on response surface methods for characterizing drug-drug interactions between several intravenous anesthetic drugs. To extend this effort, the authors developed a flexible interaction model based on the general Hill dose-response relation that includes a set of parameters that can be statistically assessed for interaction significance.

Methods

This new model was developed to identify pharmacologically meaningful interaction-related parameters and address mathematical limitations in previous models. The flexible interaction model and the model of Minto et al. were compared in their assessment of additivity using simulated sample data sets. The flexible interaction model was also compared with the Minto model in describing drug interactions using data from several other clinical studies of propofol, opioids, and benzodiazepines from Short et al. (Anesthesiology 2002) and Kern et al. (Anesthesiology 2004).

Results

The flexible interaction model was able to accurately classify an additive interaction based on the classic definition proposed by Loewe, with at most an 8% difference between the two surfaces. Also, the proposed model fit the clinical interaction data as well or slightly better than that of Minto et al.

Conclusions

The new model can accurately classify additive and synergistic drug interactions. It also can classify antagonistic interactions with biologically rational surfaces. This has been a problem for other interaction models in the past. The statistically assessable interaction parameters provide a quantitative manner to assess the interaction significance.
Effectiveness of interferon plus ribavirin combination in the treatment of naive patients with hepatitis C virus type 5. A French multicentre retrospective study
Authors: BONNY C. , FONTAINE H. , POYNARD T. , HÉZODE C. , LARREY D. , MARCELLIN P. , BOURLIÈRE M. , BRONOWICKI J. P. , MERLE P. , ZARSKI J. P. , SAPEY T. , GUILLEMARD C. , UGHETTO S. , HENQUELL C. , NICOLAS C. , ROCHE C. , RANDL K. , BOMMELAER G. , ABERGEL A.
Published: July 2006

Aim

To assess the rate of sustained virological response in naïve hepatitis C virus‐type 5 patients treated by standard interferon or percutaneous endoscopic gastrostomy‐interferon (peg‐interferon) and ribavirin combination for 48 weeks.

Patients and methods

A total of 87 hepatitis C virus patients were included from 12 centres in France; 28 patients received interferon plus ribavirin and 59 were treated with peg‐interferon plus ribavirin.

Results

Baseline characteristics were: mean age 58 ± 11 years, sex ratio 1, 66% had metavir fibrosis score ≥F2, 21% were cirrhotics and 53% had pretherapeutic viral load ≥800 000 IU/mL. Sustained virological response was achieved in 64% and 58% of hepatitis C virus‐5 patients treated with interferon and peg‐interferon, respectively (NS). In adherent patients, sustained virological response was obtained in 75% of patients. Sustained virological response in hepatitis C virus‐5 patients (60%) was significantly higher than sustained virological response in hepatitis C virus‐1 patients (37%) (P = 0.0499) and not significantly different from sustained virological response in hepatitis C virus‐2–3 patients (63%) (P = 0.8098).

Conclusions

Combination therapy is effective in 60% of hepatitis C virus‐5‐infected patients. Sustained virological response seems better in hepatitis C virus‐5 patients than in hepatitis C virus‐1 patients, and is similar to that of hepatitis C virus‐2–3 patients. More studies are needed to determine optimal duration of treatment in hepatitis C virus‐5 patients.