bluuebunny/crossref_metadata_2025 huggingface dataset:
Does a one-size recommendation system fit all? the effectiveness of collaborative filtering based recommendation systems across different domains and search modes
Authors: Im Il , Hars Alexander
Published: December 2007

Collaborative filtering (CF) is a personalization technology that generates recommendations for users based on others' evaluations. CF is used by numerous e-commerce Web sites for providing personalized recommendations. Although much research has focused on refining collaborative filtering algorithms, little is known about the effects of user and domain characteristics on the accuracy of collaborative filtering systems. In this study, the effects of two factors—product domain and users' search mode—on the accuracy of CF are investigated. The effects of those factors are tested using data collected from two experiments in two different product domains, and from two large CF datasets, EachMovie and Book-Crossing. The study shows that the search mode of the users strongly influences the accuracy of the recommendations. CF works better when users look for specific information than when they search for general information. The accuracy drops significantly when data from different modes are mixed. The study also shows that CF is more accurate for knowledge domains than for consumer product domains. The results of this study imply that for more accurate recommendations, collaborative filtering systems should be able to identify and handle users' mode of search, even within the same domain and user group.
Error correction vs. query garbling for Arabic OCR document retrieval
Authors: Darwish Kareem , Magdy Walid
Published: December 2007

Due to the existence of large numbers of legacy documents (such as old books and newspapers), improving retrieval effectiveness for OCR'ed documents continues to be an important problem. This article compares the effect of OCR error correction with and without language modeling and the effect of query garbling with weighted structured queries on the retrieval of OCR degraded Arabic documents. The results suggest that moderate error correction does not yield statistically significant improvement in retrieval effectiveness when indexing and searching using n-grams. Also, reversing error correction models to perform query garbling in conjunction with weighted structured queries yields improved retrieval effectiveness. Lastly, using very good error correction that utilizes language modeling yields the best improvement in retrieval effectiveness.
Semantic annotation of frequent patterns
Authors: Mei Qiaozhu , Xin Dong , Cheng Hong , Han Jiawei , Zhai Chengxiang
Published: December 2007

Using frequent patterns to analyze data has been one of the fundamental approaches in many data mining applications. Research in frequent pattern mining has so far mostly focused on developing efficient algorithms to discover various kinds of frequent patterns, but little attention has been paid to the important next step—interpreting the discovered frequent patterns. Although the compression and summarization of frequent patterns has been studied in some recent work, the proposed techniques there can only annotate a frequent pattern with nonsemantical information (e.g., support), which provides only limited help for a user to understand the patterns.

In this article, we study the novel problem of generating semantic annotations for frequent patterns. The goal is to discover the hidden meanings of a frequent pattern by annotating it with in-depth, concise, and structured information. We propose a general approach to generate such an annotation for a frequent pattern by constructing its context model, selecting informative context indicators, and extracting representative transactions and semantically similar patterns. This general approach can well incorporate the user's prior knowledge, and has potentially many applications, such as generating a dictionary-like description for a pattern, finding synonym patterns, discovering semantic relations, and summarizing semantic classes of a set of frequent patterns. Experiments on different datasets show that our approach is effective in generating semantic pattern annotations.
Measuring and extracting proximity graphs in networks
Authors: Koren Yehuda , North Stephen C. , Volinsky Chris
Published: December 2007

Measuring distance or some other form of proximity between objects is a standard data mining tool. Connection subgraphs were recently proposed as a way to demonstrate proximity between nodes in networks. We propose a new way of measuring and extracting proximity in networks called “cycle-free effective conductance” (CFEC). Importantly, the measured proximity is accompanied with a
proximity subgraph
which allows assessing and understanding measured values. Our proximity calculation can handle more than two endpoints, directed edges, is statistically well behaved, and produces an effectiveness score for the computed subgraphs. We provide an efficient algorithm to measure and extract proximity. Also, we report experimental results and show examples for four large network datasets: a telecommunications calling graph, the IMDB actors graph, an academic coauthorship network, and a movie recommendation system.
Learning to detect events with Markov-modulated poisson processes
Authors: Ihler Alexander , Hutchins Jon , Smyth Padhraic
Published: December 2007

Time-series of count data occur in many different contexts, including Internet navigation logs, freeway traffic monitoring, and security logs associated with buildings. In this article we describe a framework for detecting anomalous events in such data using an unsupervised learning approach. Normal periodic behavior is modeled via a time-varying Poisson process model, which in turn is modulated by a hidden Markov process that accounts for bursty events. We outline a Bayesian framework for learning the parameters of this model from count time-series. Two large real-world datasets of time-series counts are used as testbeds to validate the approach, consisting of freeway traffic data and logs of people entering and exiting a building. We show that the proposed model is significantly more accurate at detecting known events than a more traditional threshold-based technique. We also describe how the model can be used to investigate different degrees of periodicity in the data, including systematic day-of-week and time-of-day effects, and to make inferences about different aspects of events such as number of vehicles or people involved. The results indicate that the Markov-modulated Poisson framework provides a robust and accurate framework for adaptively and autonomously learning how to separate unusual bursty events from traces of normal human activity.
Time lower bounds for implementations of multi-writer snapshots
Authors: Ellen Faith , Fatourou Panagiota , Ruppert Eric
Published: December 2007

A snapshot object is an abstraction of the problem of obtaining a consistent view of the contents of shared memory in a distributed system, despite concurrent changes to the memory. There are implementations of
m
-component snapshot objects shared by
n
≥
m
processes using
m
registers. This is the minimum number of registers possible. We prove a time lower bound for implementations that use this minimum number of registers. It matches the time taken by the fastest such implementation. Our proof yields insight into the structure of any such implementation, showing that processes must access the registers in a very constrained way. We also prove a time lower bound for snapshot implementations using single-writer registers in addition to
m
historyless objects (such as registers and swap objects).
Priority sampling for estimation of arbitrary subset sums
Authors: Duffield Nick , Lund Carsten , Thorup Mikkel
Published: December 2007

From a high-volume stream of weighted items, we want to create a generic sample of a certain limited size that we can later use to estimate the total weight of arbitrary subsets. Applied to Internet traffic analysis, the items could be records summarizing the flows of packets streaming by a router. Subsets could be flow records from different time intervals of a worm attack whose signature is later determined. The samples taken in the past thus allow us to trace the history of the attack even though the worm was unknown at the time of sampling.

Estimation from the samples must be accurate even with heavy-tailed distributions where most of the weight is concentrated on a few heavy items. We want the sample to be weight sensitive, giving priority to heavy items. At the same time, we want sampling without replacement in order to avoid selecting heavy items multiple times. To fulfill these requirements we introduce priority sampling, which is the first weight-sensitive sampling scheme without replacement that works in a streaming context and is suitable for estimating subset sums. Testing priority sampling on Internet traffic analysis, we found it to perform an order of magnitude better than previous schemes.

Priority sampling is simple to define and implement: we consider a steam of items
i
= 0,…,
n
− 1 with weights
w

i

. For each item
i
, we generate a random number α

i

∈ (0,1] and create a priority
q

i

=
w

i

/α

i

. The sample
S
consists of the
k
highest priority items. Let τ be the (
k
+ 1)th highest priority. Each sampled item
i
in
S
gets a weight estimate
ŵ

i

= max{
w

i

, τ}, while nonsampled items get weight estimate
ŵ

i

= 0.

Magically, it turns out that the weight estimates are unbiased, that is, E[
ŵ

i

] =
w

i

, and by linearity of expectation, we get unbiased estimators over any subset sum simply by adding the sampled weight estimates from the subset. Also, we can estimate the variance of the estimates, and find, surprisingly, that the covariance between estimates
ŵ

i

and
ŵ

j

of different weights is zero.

Finally, we conjecture an extremely strong near-optimality; namely that for any weight sequence, there exists no specialized scheme for sampling
k
items with unbiased weight estimators that gets smaller variance sum than priority sampling with
k
+ 1 items. Szegedy settled this conjecture at STOC'06.
Simple off the shelf abstractions for XML schema
Authors: Martens Wim , Neven Frank , Schwentick Thomas
Published: December 2007

Although the advent of XML Schema [25] has rendered DTDs obsolete, research on practical XML optimization is mostly biased towards DTDs and tends to largely ignore XSDs (some notable exceptions non-withstanding). One of the underlying reasons is most probably the perceived simplicity of DTDs versus the alleged impenetrability of XML Schema. Indeed, optimization w.r.t. DTDs has a local flavor and usually reduces to reasoning about the accustomed formalism of regular expressions. XSDs, on the other hand, even when sufficiently stripped down, are related to the less pervious class of unranked regular tree automata [6, 19, 20, 21]. Recent results on the structural expressiveness of XSDs [19], however, show that XSDs are in fact much closer to DTDs than to tree automata, leveraging the possibility to directly extend techniques for DTD-based XML optimization to the realm of XML Schema. The goal of the present paper is to present the results in [19] in an easy and accessible way. At the same time, we discuss possible applications, related research, and future research directions. Throughout the paper, we try to restrict notation to a minimum. We refer to [19] for further details.
Overview and semantic issues of text mining
Authors: Stavrianou Anna , Andritsos Periklis , Nicoloyannis Nicolas
Published: December 2007

Text mining refers to the discovery of previously unknown knowledge that can be found in text collections. In recent years, the text mining field has received great attention due to the abundance of textual data. A researcher in this area is requested to cope with issues originating from the natural language particularities. This survey discusses such semantic issues along with the approaches and methodologies proposed in the existing literature. It covers syntactic matters, tokenization concerns and it focuses on the different text representation techniques, categorisation tasks and similarity measures suggested.
Community systems research at Yahoo!
Authors: Community Systems Group
Published: December 2007

The web and its continued evolution present unprecedented opportunities for database researchers and practitioners to deliver unique user experiences that are not possible traditionally, e.g., mass collaborations through (automatically) established online communities and exploration of large scale structured information. Along with these opportunities, however, come significant challenges. The challenges are two-fold:
systems
, the infrastructures that allow us to deliver information at scale; and
community
, the applications that deliver the next generation of web experiences centered around people and social networks. In this paper, we describe the ongoing research efforts within the
Community Systems
group here at Yahoo! Research to address these challenges.
Report on the First International Workshop on Database Preservation (PresDB'07)
Authors: Christophides Vassilis , Buneman Peter
Published: December 2007

The need to preserve scientific, scholarly and cultural data has long been recognized. These data sets are valuable and many of them are either impossible to reproduce (e.g. climate and demographic data) or can only be recovered at enormous costs (e.g. data from high energy physics experiments). While substantial investment has been made in archiving and preserving conventional forms of these objects, such as documents, images and numerical data in some file format, the need to preserve entire
databases
has only recently emerged. Databases differ from fixed digital objects studied in the past, in that they change over time, they have internal structure, and they include schemas and integrity constraints, which are basic for the
current
and
future interpretation
of the data. Increasingly, database technology is being used in the storage of large numerical scientific data sets.
Routing and network design with robustness to changing or uncertain traffic demands
Authors: Chekuri Chandra
Published: December 2007

A new class of network design problems were introduced by Fingerhut et al. [26], and independently by Duffield et al. [20], to address, among other things, the issue of uncertainty in the demand matrix. The so-called hose model (the term was coined in [20]) for demand matrices from [26, 20] was subsequently generalized to the polyhedral model by Ben-Ameur and Kerivin [11, 10]. In a different direction, Räacke [51] showed the existence of good randomized oblivious routings in all undirected graphs. This was followed by a proof of the polynomial time solvability of an optimal oblivious routing scheme [7].

One can view the above developments in a common framework of robust optimization. We give a survey of these developments and related work with the aim of providing a unified picture. We also highlight the remaining open problems.
Mechanisms of oxidant production in esophageal squamous cell and Barrett's cell lines
Authors: Feagins Linda A. , Zhang Hui Ying , Zhang Xi , Hormi-Carver Kathy , Thomas Tojo , Terada Lance S. , Spechler Stuart J. , Souza Rhonda F.
Published: December 2007

We hypothesized that differences among individuals in reflux-induced oxidant production by esophageal squamous epithelial cells might contribute to the development of Barrett's esophagus. We studied the effects of acid and bile acids on the production of reactive oxygen species (ROS) in esophageal squamous cell lines derived from gastroesophageal reflux disease patients with (NES-B3T) and without (NES-G2T) Barrett's esophagus and in a Barrett's epithelial cell line (BAR-T). Cells were incubated with an ROS-sensitive probe and exposed to acidic medium, neutral bile acid medium, or acidic bile acid medium. ROS were quantified in the presence and absence of diphenyleneiodonium chloride (DPI, an NADPH oxidase inhibitor), NG-monomethyl-l-arginine (l-NMMA, a nitric oxide synthase inhibitor), and rotenone (a mitochondrial electron transport chain inhibitor). Acidic bile acid medium induced ROS production in both squamous cell lines; however, only DPI blocked ROS production by NES-B3T cells, whereas both DPI and l-NMMA blocked ROS production by NES-G2T cells. In BAR-T cells, acidic medium and acidic bile acid medium induced the production of ROS; l-NMMA prevented ROS production after exposure to acidic medium, whereas ROS production induced by acidic bile acid medium was blocked by DPI. These studies demonstrate that there are differences between esophageal squamous cells and Barrett's epithelial cells and between esophageal squamous cells from gastroesophageal reflux disease patients with and without Barrett's esophagus in the mechanisms of oxidant production induced by exposure to acid and bile acids.
Purinergic receptors in gastrointestinal inflammation
Authors: Kolachala Vasantha L. , Bajaj Rahul , Chalasani Meghana , Sitaraman Shanthi V.
Published: December 2007

Purinergic receptors comprise a family of transmembrane receptors that are activated by extracellular nucleosides and nucleotides. The two major classes of purinergic receptors, P1 and P2, are expressed widely in the gastrointestinal tract as well as immune cells. The purinergic receptors serve a variety of functions from acting as neurotransmitters, to autocoid and paracrine signaling, to cell activation and immune response. Nucleosides and nucleotide agonist of purinergic receptors are released by many cell types in response to specific physiological signals, and their levels are increased during inflammation. In the past decade, the advent of genetic knockout mice and the development of highly potent and selective agonists and antagonists for the purinergic receptors have significantly advanced the understanding of purinergic receptor signaling in health and inflammation. In fact, agonist/antagonists of purinergic receptors are emerging as therapeutic modalities to treat intestinal inflammation. In this article, the distribution of the purinergic receptors in the gastrointestinal tract and their physiological and pathophysiological role in intestinal inflammation will be reviewed.
Interruption of endothelin signaling modifies membrane type 1 matrix metalloproteinase activity during ischemia and reperfusion
Authors: Deschamps Anne M. , Zavadzkas Juozas , Murphy Rebecca L. , Koval Christine N. , McLean Julie E. , Jeffords Laura , Saunders Stuart M. , Sheats Nina J. , Stroud Robert E. , Spinale Francis G.
Published: December 2007

The matrix metalloproteinases (MMPs), in particular, membrane type 1 MMP (MT1-MMP), are increased in the context of myocardial ischemia and reperfusion (I/R) and likely contribute to myocardial dysfunction. One potential upstream induction mechanism for MT1-MMP is endothelin (ET) release and subsequent protein kinase C (PKC) activation. Modulation of ET and PKC signaling with respect to MT1-MMP activity with I/R has yet to be explored. Accordingly, this study examined in vivo MT1-MMP activation during I/R following modification of ET signaling and PKC activation. With the use of a novel fluorogenic microdialysis system, myocardial interstitial MT1-MMP activity was measured in pigs (30 kg; n = 9) during I/R (90 min I/120 min R). Local ETA receptor antagonism (BQ-123, 1 μM) and PKC inhibition (chelerythrine, 1 μM) were performed in parallel microdialysis probes. MT1-MMP activity was increased during I/R by 122 ± 10% ( P < 0.05) and was unchanged from baseline with ET antagonism and/or PKC inhibition. Selective PKC isoform induction occurred such that PKC-βII increased by 198 ± 31% ( P < 0.05). MT1-MMP phosphothreonine, a putative PKC phosphorylation site, was increased by 121 ± 8% ( P < 0.05) in the I/R region. These studies demonstrate for the first time that increased interstitial MT1-MMP activity during I/R is a result of the ET/PKC pathway and may be due to enhanced phosphorylation of MT1-MMP. These findings identify multiple potential targets for modulating a local proteolytic pathway operative during I/R.
Thromboxane Receptor Activates the AMP-Activated Protein Kinase in Vascular Smooth Muscle Cells via Hydrogen Peroxide
Authors: Zhang Miao , Dong Yunzhou , Xu Jian , Xie Zhonglin , Wu Yong , Song Ping , Guzman Melissa , Wu Jiliang , Zou Ming-Hui
Published: December 2007

Thromboxane A
2
receptor (TPr) stimulation induces cellular hypertrophy in vascular smooth muscle cells (VSMCs); however, regulation of VSMC hypertrophy remains poorly understood. Here we show that TPr stimulation activates AMP-activated kinase (AMPK), which in turn limits TPr-induced protein synthesis in VSMCs. Exposure of cultured VSMCs to either TPr agonists, IBOP and U46619, or exogenous hydrogen peroxide (H
2
O
2
) caused time- and dose-dependent AMPK activation, as evidenced by increased phosphorylation of both AMPK-Thr172 and acetyl-coenzyme A carboxylase–Ser79, a downstream enzyme of AMPK, whereas SQ29548, a selective TPr antagonist, significantly attenuated TPr-enhanced AMPK activation. In parallel, both IBOP and U46619 significantly increased the production of reactive oxygen species such as H
2
O
2
. Furthermore, adenoviral overexpression of catalase (an H
2
O
2
scavenger) abolished, whereas superoxide dismutase (which catalyzes H
2
O
2
formation) enhanced, IBOP-induced AMPK activation, suggesting that TPr-activated AMPK was mediated by H
2
O
2
. Consistently, exposure of VSMCs to either TPr agonists or exogenous H
2
O
2
dose-dependently increased the phosphorylation of LKB1 (at serines 428 and 307), an AMPK kinase, as well as coimmunoprecipitation of AMPK with LKB1. In addition, direct mutagenesis of either Ser428 or Ser307 of LKB1 into alanine, like the kinase-dead LKB1 mutant, abolished both TPr-stimulated AMPK activation and coimmunoprecipitation. Finally, genetic inhibition of AMPK significantly accentuated IBOP-enhanced protein synthesis, whereas adenoviral overexpression of constitutively active AMPK abolished IBOP-enhance protein synthesis in VSMCs. We conclude that TPr stimulation triggers reactive oxygen species–mediated LKB1-dependent AMPK activation, which in return inhibits cellular protein synthesis in VSMCs.
Association Between Apolipoprotein E Genotype and Carotid Intima-Media Thickness May Suggest a Specific Effect on Large Artery Atherothrombotic Stroke
Authors: Paternoster Lavinia , Martínez González Nahara Anáni , Lewis Steff , Sudlow Cathie
Published: December 2007

Background and Purpose—

Apolipoprotein E genotype (
APOE
) influences cholesterol levels and ischemic heart disease. Although there is no convincing overall association with ischemic stroke,
APOE
may influence large artery (atherothrombotic) stroke, for which carotid intima-media thickness (CIMT) is an informative intermediate phenotype. We therefore performed a systematic review and meta-analysis of the association between
APOE
and CIMT.

Methods—

We sought all published studies assessing the association between
APOE
and CIMT. From each study, we extracted available data on study methods, subjects’ characteristics, and mean (and standard deviation) CIMT for each genotype or genotype group. We calculated study-specific and random effects pooled differences in mean CIMT between genotype groups, and assessed heterogeneity between studies and predefined subgroups using I
2
and χ
2
statistics.

Results—

Meta-analysis of 22 published studies (30 879 subjects) showed a significant association between
APOE
and CIMT (pooled mean difference ε4- versus ε2-allele containing genotypes 46 μm, 95% CI 29 to 62,
P
<0.00001). We found evidence of small study (mainly publication) bias, with a diminished (but still highly statistically significant) association in studies of >1000 subjects (pooled mean difference 17 μm, 95% CI 12 to 23,
P
<0.00001). The association was larger among high vascular risk and eastern Asian populations, but this may simply reflect the smaller size of these studies.

Conclusion—

Our results show a clear association of
APOE
with CIMT, even though publication bias means that this is overestimated by the published literature. These findings suggest the possibility of a specific association with large artery ischemic stroke.
Public Theology, the Ethics of Belief and the Challenge of Divine Hiddenness
Authors: Anderson Owen
Published: December 2007

This article considers the claim made by William Clifford that no belief should be held without sufficient reason and its implications for belief in God and public theology. Responses to Clifford, notably by William James, have tended to emphasize the personal side of religious belief. Public theology assumes a means for settling disputes through rational argument. However, David Hume and Immanuel Kant raised significant challenges to belief in God, and this developed during the nineteenth century into a rejection of public theology. This article traces the intellectual history behind Clifford's claim, and argues that, by the time that Freud offers his claim that belief in God is immature, the justification for public theology has been undermined. By clearly identifying the challenge facing public theology, this article lays the framework for constructing a response to the critique of reason given by Kant and the scepticism of Hume. If public theology is to be defended, this response is both necessary and timely.
Notions of the Public and Doing Theology
Authors: Smit Dirkie
Published: December 2007

The notion 'public' can have widely different meanings and, accordingly, many also understand the notion 'public theology' in different ways. Why would some who regard themselves as doing public theology prefer certain notions of 'public', while others prefer different understandings? In the first part, the article distinguishes three broad types of understanding the notion 'public'; ranging from a technical and almost prescriptive sense, following Habermas' description of the public sphere, to a vague and almost descriptive sense, following Tracy's description of all theological discourse as public. The second part serves as reminder of the similar range of possible meanings of the notion 'public theology', roughly corresponding to this wide spectrum of uses of 'public'. The third and final section then briefly reflects on the question why certain theologians prefer to do certain forms of public theology, suggesting both sociological reasons, like Tracy's 'elective affinities', as well as theological reasons; fundamentally different ways of viewing God and divine involvement in the world.
Effect of Twist, Fineness, Loading Rate and Length on Tensile Behavior of Multifilament Yarns (A Multivariate Study)
Authors: Chudoba Rostislav , Vořechovský Miroslav , Eckers Vera , Gries Thomas
Published: December 2007

The purpose of the present study was a multivariate experimental analysis of continuous multifilament glass yarns. The experimental design involved four main factors affecting the yarn tensile behavior, namely twist, fineness, loading rate and specimen length. In the evaluation, both the main effects and their interactions were considered. In the initial test design, each factor had been covered by at least two levels. The performed analysis of variance on the constructed response surface allowed us to exclude some factors and interactions and to narrow the test design space in the second step. The interaction effect of twist and fineness could be well documented. In particular, the nonlinear effect of twist with a pronounced maximum allowed us to discuss the role of local interactions due to pressure sensitive frictional bond that gets amplified at a particular level of twist.
Objective Grading of Fabric Pilling with Wavelet Texture Analysis
Authors: Junmin Zhang  , Xungai Wang  , Palmer Stuart
Published: December 2007

A new objective fabric pilling grading method based on wavelet texture analysis was developed. The new method created a complex texture feature vector based on the wavelet detail coefficients from all decomposition levels and horizontal, vertical and diagonal orientations, permitting a much richer and more complete representation of pilling texture in the image to be used as a basis for classification. Standard multi-factor classification techniques of principal components analysis and discriminant analysis were then used to classify the pilling samples into five pilling degrees. The preliminary investigation of the method was performed using standard pilling image sets of knitted, woven and non-woven fabrics. The results showed that this method could successfully evaluate the pilling intensity of knitted, woven and non-woven fabrics by selecting the suitable wavelet and associated analysis scale.
Communicating Corporate Social Responsibility on the Internet
Authors: Chaudhri Vidhi , Jian Wang
Published: December 2007

The need for and benefits of proactive and transparent communication about corporate social responsibility (CSR) are widely acknowledged. This study examines CSR communication undertaken by the top 100 information technology (IT) companies in India on their corporate Web sites, with an analytical focus on the dimensions of prominence of communication, extent of information, and style of presentation. The findings indicate that the number of companies with CSR information on their Web sites is strikingly low and that these leading companies do not leverage the Web sites to their advantage in terms of the quantity and style of CSR communication. Although the findings do not necessarily imply absence of CSR action on the part of IT companies in India, they attest to a general lack of proactive CSR communication. The article concludes with managerial implications for CSR communication on corporate Web sites.
The Role of School Professionals in Implementing Section 504 for Students With Disabilities
Authors: Madaus Joseph W. , Shaw Stan F.
Published: December 2007

There is a paucity of research related to the implementation of the procedural regulations of Section 504 of the Rehabilitation Act of 1973 in public schools. Section 504 is a general education civil rights law designed to provide access for students with disabilities. This study presents data from a survey that was distributed to a range of school-based professionals (general education teachers, school administrators, school counselors, school psychologists, social workers, and special education teachers) in one northeastern state. Based on a response rate of 46% ( n = 259), results indicate that 84% had served on a Section 504 team. Responsibility for managing Section 504 plans falls to a wide range of professionals. Analysis of item mean scores reveals that most components of the regulations are properly implemented, but analysis of item frequencies indicates areas of concern. Implications and areas for additional research are discussed.
αB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis
Authors: Dimberg Anna , Rylova Svetlana , Dieterich Lothar C. , Olsson Anna-Karin , Schiller Petter , Wikner Charlotte , Bohman Svante , Botling Johan , Lukinius Agneta , Wawrousek Eric F. , Claesson-Welsh Lena
Published: December 2007

Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone αB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA–mediated knockdown of αB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. αB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in αB-crystallin−/− mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in αB-crystallin−/− mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate αB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.
Escape from suppression: tumor-specific effector cells outcompete regulatory T cells following stem-cell transplantation
Authors: Mirmonsef Paria , Tan Gladys , Zhou Gang , Morino Tricia , Noonan Kimberly , Borrello Ivan , Levitsky Hyam I.
Published: December 2007

Immune reconstitution of autologous hematopoietic stem-cell transplant recipients with the progeny of mature T cells in the graft leads to profound changes in the emerging functional T-cell repertoire. In the steady state, the host is frequently tolerant to tumor antigens, reflecting dominant suppression of naive and effector T cells by regulatory T cells (Tregs). We examined the relative frequency and function of these 3 components within the tumor-specific T-cell compartment during immune reconstitution. Grafts from tumor-bearing donors exerted a significant antitumor effect in irradiated, syngeneic tumor-bearing recipients. This was associated with dramatic clonal expansion and interferon-γ (IFNγ) production by previously tolerant tumor-specific T cells. While donor-derived Tregs expanded in recipients, they did not inhibit the antigen-driven expansion of effector T cells in the early posttransplantation period. Indeed, the repopulation of tumor-specific effector T cells significantly exceeded that of Tregs, the expansion of which was limited by IL-2 availability. Although the intrinsic suppressive capacity of Tregs remained intact, their diminished frequency was insufficient to suppress effector cell function. These findings provide an explanation for the reversal of tolerance leading to tumor rejection in transplant recipients and likely contribute to the efficacy of adoptive T-cell therapies in lymphopenic hosts.
Differential context-dependent effects of friend of GATA-1 (FOG-1) on mast-cell development and differentiation
Authors: Sugiyama Daijiro , Tanaka Makoto , Kitajima Kenji , Zheng Jie , Yen Hilo , Murotani Tomotaka , Yamatodani Atsushi , Nakano Toru
Published: December 2007

Friend of GATA-1 (FOG-1) is a binding partner of GATA-1, a zinc finger transcription factor with crucial roles in erythroid, megakaryocytic, and mast-cell differentiation. FOG-1 is indispensable for the function of GATA-1 during erythro/megakaryopoiesis, but FOG-1 is not expressed in mast cells. Here, we analyzed the role of FOG-1 in mast-cell differentiation using a combined experimental system with conditional gene expression and in vitro hematopoietic induction of mouse embryonic stem cells. Expression of FOG-1 during the progenitor period inhibited the differentiation of mast cells and enhanced the differentiation of neutrophils. Analysis using a mutant of PU.1, a transcription factor that positively or negatively cooperates with GATA-1, revealed that this lineage skewing was caused by disrupted binding between GATA-1 and PU.1, which is a prerequisite for mast-cell differentiation. However, FOG-1 expression in mature mast cells brought approximately a reversible loss of the mast-cell phenotype. In contrast to the lineage skewing, the loss of the mast-cell phenotype was caused by down-regulation of MITF, a basic helix-loop-helix transcription factor required for mast-cell differentiation and maturation. These results indicate that FOG-1 inhibits mast-cell differentiation in a differentiation stage-dependent manner, and its effects are produced via different molecular mechanisms.
Canada's implementation of the Paragraph 6 Decision: is it sustainable public policy?
Authors: Cohen-Kohler Jillian C , Esmail Laura C , Cosio Andre Perez
Published: December 2007

Background

Following the Implementation of Paragraph 6 of the Doha Declaration on TRIPS and Public Health, Canada was among the first countries globally to amend its patent law, which resulted in Canada's Access to Medicines Regime (CAMR). CAMR allows the production and export of generic drugs to developing countries without the requisite manufacturing capacity to undertake a domestic compulsory license. CAMR has been the subject of much criticism lodged at its inability to ensure fast access to urgent medicines for least developing and developing countries in need. Only recently did the Canadian government grant Apotex the compulsory licenses required under CAMR to produce and export antiretroviral therapy to Rwanda's population.

Methods

The objective of this research is to investigate whether the CAMR can feasibly achieve its humanitarian objectives given the political interests embedded in the crafting of the legislation. We used a political economy framework to analyze the effect of varied institutions, political processes, and economic interests on public policy outcomes. In-depth, semi-structured interviews were conducted with nineteen key stakeholders from government, civil society and industry. Qualitative data analysis was performed using open-coding for themes, analyzing by stakeholder group.

Results

CAMR is removed from the realities of developing countries and the pharmaceutical market. The legislation needs to include commercial incentives to galvanize the generic drug industry to make use of this legislation. CAMR assumes that developing country governments have the requisite knowledge and human resource capacity to make use of the regime, which is not the case. The legislation does not offer sufficient incentives for countries to turn to Canada when needed drugs may be procured cheaply from countries such as India. In the long term, developing and least developing countries seek sustainable solutions to meet the health needs of their population, including developing their own capacity and local industries.

Conclusion

CAMR is symbolically meaningful but in practice, limited. The Rwanda case will be noteworthy in terms of the future of the legislation. To meet its intended international health objectives, this legislation needs to be better informed of developing country needs and global pharmaceutical market imperatives. Finally, we contend that serious public policy change cannot strike a balance between all vested interests. Above all, any feasible policy that aims to facilitate compulsory licensing must prioritize public health over trade or economic interests.
Contribution of telomerase RNA retrotranscription to DNA double-strand break repair during mammalian genome evolution
Authors: Nergadze Solomon G , Santagostino Marco Andrea , Salzano Alberto , Mondello Chiara , Giulotto Elena
Published: December 2007

Background

In vertebrates, tandem arrays of TTAGGG hexamers are present at both telomeres and intrachromosomal sites (interstitial telomeric sequences (ITSs)). We previously showed that, in primates, ITSs were inserted during the repair of DNA double-strand breaks and proposed that they could arise from either the capture of telomeric fragments or the action of telomerase.

Results

An extensive comparative analysis of two primate (Homo sapiens and Pan troglodytes) and two rodent (Mus musculus and Rattus norvegicus) genomes allowed us to describe organization and insertion mechanisms of all the informative ITSs present in the four species. Two novel observations support the hypothesis of telomerase involvement in ITS insertion: in a highly significant fraction of informative loci, the ITSs were introduced at break sites where a few nucleotides homologous to the telomeric hexamer were exposed; in the rodent genomes, complex ITS loci are present in which a retrotranscribed fragment of the telomerase RNA, far away from the canonical template, was inserted together with the telomeric repeats. Moreover, mutational analysis of the TTAGGG arrays in the different species suggests that they were inserted as exact telomeric hexamers, further supporting the participation of telomerase in ITS formation.

Conclusion

These results strongly suggest that telomerase was utilized, in some instances, for the repair of DNA double-strand breaks occurring in the genomes of rodents and primates during evolution. The presence, in the rodent genomes, of sequences retrotranscribed from the telomerase RNA strengthens the hypothesis of the origin of telomerase from an ancient retrotransposon.
TNF-related apoptosis-inducing ligand (TRAIL) is expressed throughout myeloid development, resulting in a broad distribution among neutrophil granules
Authors: Simons Mark P , Leidal Kevin G , Nauseef William M , Griffith Thomas S
Published: December 2007

TRAIL induces apoptosis in a variety of tumor cells. Our laboratory found that human neutrophils contain an intracellular reservoir of prefabricated TRAIL that is released after stimulation with Mycobacterium bovis bacillus Calmette-Guérin. In this study, we examined the subcellular distribution of TRAIL in freshly isolated neutrophils. Neutrophil granules, secretory vesicles (SV), and plasma membrane vesicles were isolated by subcellular fractionation, followed by free-flow electrophoresis, and examined by ELISA and immunoblot. TRAIL was found in all membrane-bound fractions with the highest amounts in the fractions enriched in azurophilic granule (AG) and SV. Immunofluorescence confocal microscopy showed that TRAIL colocalized independently with myeloperoxidase (MPO), lactoferrin (LF), and albumin, respective markers of AG, specific granules, and SV. Furthermore, immunotransmission electron microscopy demonstrated that TRAIL colocalized intracellularly with MPO and albumin. We examined TRAIL expression in PLB-985 cells induced with dimethylformamide and in CD34-positive stem cells treated with G-CSF. Quantitative RT-PCR analysis showed that TRAIL was expressed in each stage of development, whereas MPO and LF were only expressed at distinct times during differentiation. Collectively, these findings suggest that TRAIL is expressed throughout neutrophil development, resulting in a broad distribution among different granule subtypes.
γδ T cells mitigate the organ injury and mortality of sepsis
Authors: Tschöp Johannes , Martignoni André , Goetzman Holly S , Choi Lisa G , Wang Quan , Noel John G , Ogle Cora K , Pritts Timothy A , Johannigman Jay A , Lentsch Alex B , Caldwell Charles C
Published: December 2007

Sepsis is a difficult condition to treat and is associated with a high mortality rate. Sepsis is known to cause a marked depletion of lymphocytes, although the function of different lymphocyte subsets in the response to sepsis is unclear. γδ T cells are found largely in epithelial-rich tissues, and previous studies of γδ T cells in models of sepsis have yielded divergent results. In the present study, we examined the function of γδ T cells during sepsis in mice using cecal ligation and puncture (CLP). Mice deficient in γδ T cells had decreased survival times and increased tissue damage after CLP compared with wild-type mice. Furthermore, bacterial load was increased in γδ T cell-deficient mice, yet antibiotic treatment did not change mortality. Additionally, we found that recruitment of neutrophils and myeloid suppressor cells to the site of infection was diminished in γδ T cell-deficient mice. Finally, we found that circulating levels of IFN-γ were increased, and systemic levels of IL-10 were decreased in γδ T cell-deficient mice after CLP compared with wild-type mice. γδ T cell-deficient mice also had increased intestinal permeability after CLP compared with wild-type mice. Neutralization of IFN-γ abrogated the increase in intestinal permeability in γδ T cell-deficient mice. The intestines taken from γδ T cell-deficient mice had decreased myeloperoxidase yet had increased tissue damage as compared with wild-type mice. Collectively, our data suggest that γδ T cells modulate the response to sepsis and may be a potential therapeutic target.
Cooperative Binding of Insulin-Like Peptide 3 to a Dimeric Relaxin Family Peptide Receptor 2
Authors: Svendsen Angela Manegold , Vrecl Milka , Ellis Tina M. , Heding Anders , Kristensen Jesper Bøggild , Wade John D. , Bathgate Ross A. D. , De Meyts Pierre , Nøhr Jane
Published: December 2007

Insulin-like peptide 3 (INSL3) binds to a G protein-coupled receptor (GPCR) called relaxin family peptide receptor 2 (RXFP2). RXFP2 belongs to the leucine-rich repeat-containing subgroup (LGR) of class A GPCRs. Negative cooperativity has recently been demonstrated in other members of the LGR subgroup. In this work, the kinetics of INSL3 binding to HEK293 cells stably transfected with RXFP2 (HEK293-RXFP2) have been investigated in detail to study whether negative cooperativity occurs and whether this receptor functions as a dimer. Our results show that negative cooperativity is present and that INSL3-RXFP2 binding shows both similarities and differences with insulin binding to the insulin receptor. A dose-response curve for the negative cooperativity of INSL3 binding had a reverse bell shape reminiscent of that seen for the negative cooperativity of insulin binding to its receptor. This suggests that binding of INSL3 may happen in a trans rather than in a cis way in a receptor dimer. Bioluminescence resonance energy transfer (BRET2) experiments confirmed that RXFP2 forms constitutive homodimers. Heterodimerization between RXFP2 and RXFP1 was also observed.
Impairment of the Natriuretic Peptide System in Follitropin Receptor Knockout Mice and Reversal by Estradiol: Implications for Obesity-Associated Hypertension in Menopause
Authors: Belo Najara O. , Sairam M. Ram , dos Reis Adelina M.
Published: December 2007

Estrogen is considered a major regulator of adipose tissue in females. Estrogen increases circulating levels of atrial natriuretic peptide (ANP), a hormone with renal and cardiovascular effects. The aim of this study was to determine the status of the natriuretic peptide system in female follitropin-receptor knockout (FORKO) mice that could be associated with obesity and hypertension observed in these mutants. Furthermore, estradiol treatment was used to reverse alterations observed. FORKO and wild-type (WT) mice received daily injections of estradiol for 4 d. On the fifth day, blood was collected for determination of plasma ANP levels, and selected tissues were collected for determination of ANP, natriuretic peptide receptor type-A (NPR-A) and type-C (NPR-C) gene expression by RT-PCR and binding of [125I]ANP by autoradiography. At 5 months of age, FORKO mice were heavier and had more adipose tissue than WT mice. FORKO mice had lower plasma ANP levels and atrial ANP gene expression and higher renal and adipocyte NPR-C gene expression than WT mice. Estradiol treatment reduced weight gain and increased atrial ANP synthesis as well as decreased ANP clearance NPR-C receptors, resulting in elevation of circulating ANP level. In conclusion, this study shows that FORKO females have an impaired natriuretic peptide system, which may contribute to the susceptibility of FORKO mice to developing age-related hypertension previously shown in these animals. This study establishes a relation between estrogen, adipose tissue, and ANP, which may have important implications in menopausal women.