bluuebunny/crossref_metadata_2025 huggingface dataset:
What's in a name? Commonalities and differences in public understanding of “climate change” and “global warming”
Authors: Whitmarsh Lorraine
Published: September 2008

This paper reports on findings from a survey of public understanding of climate change and global warming amongst residents in the south of England. Whereas much previous research has relied on survey checklists to measure public understanding of climate change, this study employed a more qualitative approach to reveal participants' unprompted conceptions of climate change and global warming. Overall, the findings show a tendency for the public to dissociate themselves from the causes, impacts, and responsibility for tackling climate change/global warming. This research gave particular attention to how terminology is understood by the public. The findings point to important qualitative, as well as quantitative, differences between public understanding of “climate change” and public understanding of “global warming.” Furthermore, the latter term was found to evoke more concern than the former. As discussed in the article, these results have important implications for both researchers and communicators.
Manufacturing doubt: journalists' roles and the construction of ignorance in a scientific controversy
Authors: Stocking S. Holly , Holstein Lisa W.
Published: September 2008

In recent decades, corporate and special interests have developed a wide repertoire of methods to manufacture doubt about science that threatens their interests. In the case presented here, a trade association issued a rich assortment of rhetorical claims intended to sow public confusion about university studies that threatened to undermine its industry's activities. Journalists' use of these claims appeared to vary largely as a function of their perceptions of their journalistic roles and of their audiences, though their knowledge of science also appeared to play a role. Our findings offer insight into how and why reporters respond to rhetorical claims about scientific ignorance and uncertainty that actors use to discredit threatening science. In so doing, they contribute to growing scholarship on journalists' contributions to the social construction of ignorance in scientific controversies.
Guardians of our future: New Zealand mothers and sustainable biotechnology
Authors: Gamble Joanna C.
Published: September 2008

In year two of a three-year project, New Zealand mothers of children aged 10 and under were interviewed to examine the social, cultural and spiritual dimensions of biotechnology. Ten focus groups were conducted and used “sustainable biotechnology” as a center-point for discussion, concentrating on four different biotechnology scenarios. The findings of the research were consistent with year one and with findings on the general public throughout the world. Further insights revealed in year two suggested that women saw their and future generations' quality of life as intimately intertwined with the health of the environment, making the environment particularly important. Because of this, anything that had potentially negative consequences on the ecosystem was perceived to pose a threat to the woman, her family and future generations. The need for strict controls to be put in place by regulatory and research authorities was therefore seen as an important step in allaying her fears. True partnership and participation was seen as critical, since it would only be by such means that mothers would feel they were in control of the safety of their own children.
Visualizing nanotechnology: the impact of visual images on lay American audience associations with nanotechnology
Authors: Landau Jamie , Groscurth Christopher R. , Wright Lanelle , Condit Celeste M.
Published: September 2008

Developments in nanotechnology are attracting the attention of scholars of science communication who can play a strategic role in understanding technology adoption by the public. This paper begins to address a critical gap in that research by studying the impact of visual images on lay American audience associations with nanotechnology. An inductive qualitative analysis of semi-structured interviews about participants' general knowledge of nanotechnology and their reactions to two different visual images of nanotechnology revealed 10 themes, which were sometimes valenced positively or negatively: science, (medicinal) machines, technology, very small, sky, motion, (childhood) toys, bodily blood, injecting (disease), and foreign (insect). We argue that these findings illustrate a specific “visual” domain of “science” images, that this domain is organized to contain polarities, and that this leads to volatility in public attitudes but also flexibility in responses to a range of visual images of new sciences such as nanotechnology.
Bias in the exchange of arguments: the case of scientists’ evaluation of lay viewpoints on GM food
Authors: Cuppen Eefje , Hisschemöller Matthijs , Midden Cees
Published: September 2008

Most perspectives on public participation share the notion that dialogues should be open, allowing participants to articulate and evaluate different views and knowledge claims. We hypothesize that participants’ evaluation of claims may be biased because participants have a preference for a particular type or source of a claim. This would hamper an open dialogue. We tested the effect of three variables on scientists’ evaluation of claims of the general public about GM food: the claim’s favorability towards GM food, the phrasing, and the source of the claim. Results are based on a survey-experiment among 73 biotechnology-scientists. Biased processing occurred when scientists evaluated claims. Claims that were corresponding with the attitude of the scientists and that were phrased in a cognitive way were evaluated more positively than claims that were contrasting the attitude of the scientists and that were phrased in an affective way. Contrary to our expectation, scientists evaluated claims of the public more positively than claims of experts.
An analysis of the Public Scientific Literacy study in China
Authors: Fajun Chen  , Yumin Shi  , Fei Xu
Published: September 2008

In March 2006, the State Council of the People’s Republic of China issued The Outline of the Action Plan for Improving Scientific Literacy for All (From 2006—2010 and then 2010—2020) (the Scientific Literacy Outline), in which the official notion of scientific literacy named “Public Scientific Literacy in China” was put forward for the first time in the history of China. Subsequently, the program of “Study on Measurement Indicators of Scientific Literacy of Chinese Citizens and its Demonstration” was funded by the China Association for Science and Technology the following September. However, the notion as well as its measurement indicators still need more clarification. After reviewing some relevant literature and introducing the historical background to the concept of “Public Scientific Literacy in China” along with a detailed interpretation of its connotation, the authors do a closer examination of the measurement indicators established by the Research and Development Center for Science Communication at the University of Science and Technology of China, based on a systematical analysis of the sample surveys.
Postsecondary Education for Individuals With Disabilities
Authors: Katsiyannis Antonis , Dalun Zhang  , Landmark Leena , Reber Anne
Published: September 2008

Participation of students with disabilities in postsecondary education has been increasing steadily in the past two decades. Many of these students need reasonable accommodations and other assistance in order to stay enrolled and graduate with a degree. However, recent studies indicate that faculty in higher education have little knowledge about legislative mandates regarding their obligation in serving students with disabilities. When faculty members are ignorant of the legislative mandates pertaining to students with disabilities, accessibility to learning may be compromised. Lack of disability legislative knowledge may also lead to a failure to provide reasonable accommodations and may ultimately result in litigation. This article provides an overview of legislative mandates, examines relevant litigation, and discusses practice considerations regarding the participation of students with disabilities in postsecondary settings.
Time and Exigence in Temporal Genres
Authors: Markel Mike
Published: September 2008

Genre use entails a rhetorical response to an exigence in the writer's context. In one category of genres, which the author calls temporal genres, linear time constitutes a major exigence to which writers must respond. Temporal genres, such as annual reports and status reports, call for writers to publish texts because a certain amount of time has passed, even if they are not yet ready to do so. The first annual report of the Privacy Office of the Department of Homeland Security reveals an ineffective ethos and discontinuities between the mission of the office and that of the department. But the second annual report reveals a more effective ethos and greater harmony between the missions. This study shows how the requirement to report can force writers to decide existential issues of identity and mission.
Squaring the Learning Circle
Authors: Ward Mark
Published: September 2008

Student compositions traditionally are written for the teacher. Yet instructors of professional communication genres have discovered that students' motivation may be enhanced when they write assignments for audiences of peers within the classroom or professionals outside the campus. Yet client-based projects require writing students who have never yet written for an external audience to make a leap beyond the classroom. To bridge the gap between writing for classroom peers and writing for professional clients, this article describes a third and intermediate choice of audience, namely, external peers in cross-classroom collaborations that occur via telecommunication. The author places this intermediate-audience strategy within the larger conversation about the impact of audience on student writing outcomes, applies the strategy to professional writing pedagogy, and reports the results of a small pilot study that provide some preliminary support for the strategy.
Single Nucleotide Polymorphisms That Affect Homocysteine Levels in Turkish Population
Authors: Koç Yasemin L. , Akar Nejat
Published: September 2008

In this study, single nucleotide polymorphisms (SNPs) involved in homocysteine metabolism such as CT replacement in the 677th nucleotide in 5,10-methylenetetrahydrofolate reductase (MTHFR) enzyme; 68-bp insertion in the 844th nucleotide of cystathionine β-synthase (CBS) enzyme; 6-bp insertion/deletion in the region of 3′UTR in thymidylate synthase (TYMS) enzyme and 19-bp deletion in dihydrofolate reductase (DHFR) enzyme were investigated. The effects of these mutations on homocysteine levels were studied. As a result; we found that TT genotype of MTHFR 677 CT is an influencing factor on homocysteine levels in Turkish population. Furthermore, there seems to be another MTHFR 677 TT haplotype, which does not have an effect on homocysteine levels .Our data revealed that other SNPs did not have any influence on homocysteine levels.
Type and Location of Venous Thromboembolism in Carriers of Factor V Leiden or Prothrombin G20210A Mutation Versus Patients With No Mutation
Authors: Kovac Mirjana , Mitic Gorana , Mikovic Zeljko , Antonijevic Nebojsa , Djordjevic Valentina , Mikovic Danijela , Mandic Vesna , Rakicevic Ljiljana , Radojkovic Dragica
Published: September 2008

Factor V Leiden (FVLeiden) and prothrombin G20210A are the most common genetic causes of thrombophilia and established risk factors for different clinical manifestations of venous thromboembolism (VTE). This study investigated whether the clinical manifestation of VTE, the extension of deep vein thrombosis (DVT) and the presence of transient risk factors at the time of the first VTE, differed among patients with mutations (97 with FVLeiden; 33 with prothrombin G20210A) and in 109 patients without thrombophilia. Isolated pulmonary embolism (PE) was less prevalent in patients with FVLeiden (6%) and no thrombophilia (6%) than in those with prothrombin G20210A (15%). No difference was found in the incidence of distal DVT. Regarding the extension of proximal DVT, the lowest incidence for isolated popliteal vein and the highest for iliofemoral vein were observed in patients with prothrombin G20210A. No difference was observed between groups of patients with or without thrombophilia by unprovoked VTE. The pregnancy/puerperium was the most prevalent risk factor in carriers of prothrombin G20210A. Among FVLeiden carriers, the most prevalent risk factor was surgery, and in patients without thrombophilia, it was trauma ( P < .05). Thrombosis of the upper limb was more frequent in a group without thrombophilia than in patients with mutations ( P < .01). Transverse sinus venous thrombosis was present only in patients with prothrombin G20210A. Carriers of prothrombin G20210A have an increased risk of developing isolated PE and more severe clinical manifestations than those with FVLeiden or without thrombophilia.
Cangrelor Attenuates Coated-Platelet Formation
Authors: Norgard Nicholas B. , Hann Callie L. , Dale George L.
Published: September 2008

P2Y12 inhibitors were introduced clinically as effective inhibitors of adenosine-5′-diphosphate (ADP) mediated platelet activation and aggregation. This class of pharmacological agents has enjoyed considerable success. Cangrelor is a recently developed P2Y12 inhibitor that has the advantage of being an active drug not requiring metabolic conversion, although it is not orally available. Coated-platelets are a subclass of activated platelets generated on dual agonist activation with collagen plus thrombin; the primary hallmark of coated-platelets is their ability to support prothrombinase activity. Interestingly, we recently observed that the relatively weak agonist ADP potentiates the production of coated-platelets by the very strong agonists collagen plus thrombin, a previously unknown role for ADP. The authors sought in this study to determine if P2Y12 inhibitors, such as cangrelor, were capable of attenuating this augmentation of coated-platelet generation. Cangrelor, at physiologically relevant concentrations, was able to eliminate the ADP-dependent increase in coated-platelet production with an IC50 of 1.4 nM. Cangrelor, however, had no effect on thrombin-dependent platelet activation as measured by P-selectin expression. Although this in vitro study does not address the question of whether the effectiveness of cangrelor in vivo is partially due to an attenuation of coated-platelet production in addition to its documented antiaggregatory effects, it does reveal an unexpected action of cangrelor. Additional studies will be required to determine if all P2Y12 inhibitors are equally effective in attenuating coated-platelet production.
Ocular Vascular Thrombotic Events: A Diagnostic Window to Familial Thrombophilia (Compound Factor V Leiden and Prothrombin Gene Heterozygosity) and Thrombosis
Authors: Glueck Charles J. , Ping Wang
Published: September 2008

In a 12-member, 3-generation kindred with conjoint inheritance of G1691A factor V Leiden (FVL) and G20210A prothrombin gene (PTG) mutations, identified through a proband with amaurosis fugax and his father with nonarteritic ischemic optic neuropathy (NAION), the authors' hypothesis was that ocular thrombosis was a diagnostic window to familial thrombophilia—thrombosis. The authors used polymerase chain reaction (PCR) measures for thrombophilia (FVL, PTG, C677T-A1298C methylenetetrahydrofolate reductase [MTHFR], platelet glycoprotein PLA1A2) and hypofibrinolysis (plasminogen activator inhibitor-1 4G4G). The 39-year-old white male proband, with amaurosis fugax and transient ischemic attacks (TIA), was found to be a compound heterozygote for FVL and PTG mutations. His symptoms resolved only after coumadin. His 44-year-old brother (deep venous thrombosis [DVT]) and 46-year-old sister (DVT, pulmonary embolus [PE]) were compound FVL—PTG gene heterozygotes. Of 4 asymptomatic children born to these 3 siblings, 2 were FVL heterozygotes and 2 PTG heterozygotes. The proband's 69-year-old father, with NAION and ischemic stroke, had PTG heterozygosity, familial high factor VIII, and compound MTHFR C677T-A1298C mutation with homocysteinemia. The proband's 61-year-old aunt had PTG heterozygosity, recurrent DVT, and mesenteric artery thrombosis. The proband's 67-year-old mother, free of thrombotic events, was a FVL heterozygote, had high factor VIII, and PAI-1 4G4G homozygosity. In this extended kindred, ocular thrombotic events (amaurosis fugax, NAION) were associated with variegated thrombotic events, including TIA, ischemic stroke, DVT, PE, and mesenteric artery thrombosis, and opened a diagnostic window to family screening and treatment for complex thrombophilias, which had previously been undiagnosed.
Parenting Children With Autism Spectrum Disorders
Authors: Brobst Jennifer B. , Clopton James R. , Hendrick Susan S.
Published: September 2008

Balancing the roles of parent and partner is challenging for most people and may be especially challenging when extra time and effort are required in the parenting role. The current research compared 25 couples whose children have autism spectrum disorders (ASD) with 20 couples whose children do not have developmental disorders. Comparisons were made for both stressor (e.g., child's behavior problems) and relational (e.g., relationship satisfaction) variables. Results indicated that parents of children with ASD experienced more intense child behavior problems, greater parenting stress, and lower relationship satisfaction. In contrast, the two groups of couples did not differ on perceived spousal support, respect for their partners, and commitment. The implications of the findings of this study and other related research are discussed.
Rethinking Historical Trauma: Narratives of Resilience
Authors: Denham Aaron R.
Published: September 2008

There is significant variation in how people experience, emplot and intergenerationally transmit trauma experiences. Despite this variation, the literature rarely illustrates alternative manifestations or resilient responses to the construct of historical trauma. Based upon person-centered ethnographic research, this article highlights how a four-generation American Indian family contextualizes historical trauma and, specifically, how they frame their traumatic past into an ethic that functions in the transmission of resilience strategies, family identity, and as a framework for narrative emplotment. In conclusion, the author clarifies the distinction between historical trauma — the precipitating conditions or experiences — and the historical trauma response — the pattern of diverse responses that may result from exposure to historical trauma.
Usefulness of the Construct of Social Network to Explain Mental Health Service Utilization by the Maori Population in New Zealand
Authors: Kumar Shailesh , Oakley Browne Mark A.
Published: September 2008

This article briefly reviews the literature on the relationship between social network and mental health, and presents a theoretical framework outlining the role social networks may play in explaining the differential mental health service utilization rates between Maori and European people of New Zealand. By buffering individuals from the ill effects of stressful events, social networks may have a protective effect on people's mental health. In addition, social networks influence the way people with mental illnesses use mental health services. An inverse relationship between the size of an individual's social network and the rate of utilization of in-patient services has been reported. Despite having a larger and presumably more supportive social networks, Maori are over-represented in mental health service utilization statistics. Using the Maori example, we demonstrate that ethnic differences exist in the structure of social networks and the provision of social support to their members. Such differences may be based on the degree of emphasis placed on kinship or on individualism by cultures and on the receptivity or prejudice of the host community. We examine the sources of stress on Maori social networks that may adversely affect the network's ability to support its members experiencing mental illnesses. Caution must be exercised in using service utilization rates as measures of the mental health needs of different ethnic groups because of problems with help seeking and the detection of mental health issues in different ethnic groups.
Difficulties and Coping Strategies of Sudanese Refugees: A Qualitative Approach
Authors: Khawaja Nigar G. , White Katherine M. , Schweitzer Robert , Greenslade Jaimi
Published: September 2008

A qualitative approach was used to interview 23 Sudanese refugees residing in Brisbane, Australia. Semi-structured interviews were conducted to examine the participants' pre-migration, transit and post-migration experiences. Refugees reported traumatic and life-threatening experiences during the pre-migration and transit phases, and difficulties with resettlement during the post-migration phase. Nevertheless, participants reported using a number of coping strategies across all phases, including: reliance on religious beliefs, cognitive strategies such as reframing the situation, relying on their inner resources, and focusing on future wishes and aspirations. Social support also emerged as a salient coping strategy. The findings are useful for mental health professionals as they highlight the difficulties experienced by refugees across phases of migration as well as strategies they use to manage these traumas and stresses.
Collaborating With Chinese Families of Children With Hearing Impairments
Authors: Lo Lusa
Published: September 2008

Developing a collaborative home-school partnership in the special education process is one of the crucial indicators of successful educational planning. Special education laws and regulations strongly emphasize the importance of parental roles in the process. However, as is well documented in existing literature, it can be challenging for many culturally and linguistically diverse families to be schools' equal partners and to be actively involved in the process of developing their children's educational programs. As the number of Asian students with disabilities continues to increase, the purpose of this article is to illustrate two Chinese families' experiences and identify what educators and service providers could do to strengthen their partnerships with Chinese families of children with hearing impairments.
Task-Evoked BOLD Responses Are Normal in Areas of Diaschisis After Stroke
Authors: Fair Damien A. , Snyder Abraham Z. , Connor Lisa Tabor , Nardos Binyam , Corbetta Maurizio
Published: September 2008

Objective. Cerebral infarction can cause diaschisis, a reduction of blood flow and metabolism in areas of the cortex distant from the site of the lesion. Although the functional magnetic resonance imaging (fMRI) blood oxygen level dependent (BOLD) signal is increasingly used to examine the neural correlates of recovery in stroke, its reliability in areas of diaschisis is uncertain. Design. The effect of chronic diaschisis as measured by resting positron emission tomography on task-evoked BOLD responses during word-stem completion in a block design fMRI study was examined in 3 patients, 6 months after a single left hemisphere stroke involving the inferior frontal gyrus and operculum. Results. The BOLD responses were minimally affected in areas of chronic diaschisis. Conclusions. Within the confines of this study, the mechanism underlying the BOLD signal, which includes a mismatch between neuronally driven increases in blood flow and a corresponding increase in oxygen use, appears to be intact in areas of chronic diaschisis.
Limitations of Intrathecal Baclofen for Spastic Hemiparesis Following Stroke
Authors: Kofler Markus , Quirbach Ellen , Schauer Robert , Singer Markus , Saltuari Leopold
Published: September 2008

Objective. Intrathecal baclofen (ITB) has become the first choice in the management of deleterious spasticity that does not respond to oral and intramuscular medications following spinal cord injury, traumatic brain injury, and cerebral palsy. The usefulness of ITB in severe spastic hemiparesis following stroke is studied. Methods. A total of 8 patients underwent clinical and video assessment following ITB bolus application (n = 5) and during continuous infusion via a temporary catheter system (n = 3). Results. The mean daily dosage alleviating spasticity on the hemiparetic side—without affecting the nonparetic side—was 119 μg/day (range 50 to 360 μg/day). However, 6 patients experienced functional deterioration as ITB weakened their paretic side such that the antigravity pattern they used for ambulation was suppressed. In 2 patients, spasticity-associated pain and spasms subsided and they underwent implantation of a long-term drug delivery system. Conclusions. ITB may reduce spasticity in a dose-dependent manner irrespective of its origin. Although not primarily antinociceptive in humans, ITB may alleviate pain if arising from increased muscle tone. A functional benefit may result if ITB can uncover “subclinical” motor control that had been suppressed by spasticity. However, when a patient uses antigravity patterns for ambulation in the absence of more complex motor control, ITB may cause the loss of residual walking ability, which becomes a major limitation for patients with hemiplegic stroke.
The IL-15 receptor α chain cytoplasmic domain is critical for normal IL-15Rα function but is not required for trans-presentation
Authors: Wu Zheng , Xue Hai-Hui , Bernard Jérôme , Zeng Rong , Issakov Dmitry , Bollenbacher-Reilley Julie , Belyakov Igor M. , Oh SangKon , Berzofsky Jay A. , Leonard Warren J.
Published: September 2008

IL-15 is critical for natural killer (NK)–cell development and function and for memory CD8+ T-cell homeostasis. The IL-15 receptor consists of IL-15Rα, IL-2Rβ, and the common cytokine receptor γ chain (γc). IL-15Rα is known to “trans-present” IL-15 to an IL-2Rβ/γc heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Rα cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Rα and intracellular domain of IL-2Rα (IL-15Rαext/IL-2Rαint) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8+ T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15–induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Rα expression, indicating a signaling role for the IL-15Rα cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Rα and IL-15Rα cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Rαext/IL-2Rαint receptor still supports trans-presentation. These experiments collectively indicate that IL-15Rα can act in cis in addition to acting in trans to present IL-15 to responding cells.
Early chimerism threshold predicts sustained engraftment and NK-cell tolerance in prenatal allogeneic chimeras
Authors: Durkin Emily T. , Jones Kelly A. , Rajesh Deepika , Shaaban Aimen F.
Published: September 2008

The failure of engraftment in human cases of in utero hematopoietic cell transplantation (IUHCT) in which no immunodeficiency exists suggests the presence of an unrecognized fetal immune barrier. A similar barrier in murine IUHCT appears to be dependent on the chimerism level and is poorly explained by a lack of T-cell tolerance induction. Therefore, we studied the effect of the chimerism level on engraftment and host natural killer (NK)–cell education in a murine model of IUHCT. The dose of transplanted cells was found to exhibit a strong correlation with both the engraftment rate and chimerism level. More specifically, a threshold level of initial chimerism (> 1.8%) was identified that predicted durable engraftment for allogeneic IUHCT, whereas low initial chimerism (< 1.8%) predicted a loss of engraftment. NK cells taken from chimeras above the “chimerism threshold” displayed durable calibration of alloresponsive Ly49A receptors and tolerance to donor antigens. Depletion of recipient NK cells stabilized engraftment in low-level chimeras (< 1.8%). These studies illustrate the importance of the early chimerism threshold in predicting long-term engraftment and host NK-cell tolerance after in utero transplantation.
ASB2 targets filamins A and B to proteasomal degradation
Authors: Heuzé Mélina L. , Lamsoul Isabelle , Baldassarre Massimiliano , Lad Yatish , Lévêque Sophie , Razinia Ziba , Moog-Lutz Christel , Calderwood David A. , Lutz Pierre G.
Published: September 2008

The ordered series of proliferation and differentiation from hematopoietic progenitor cells is disrupted in leukemia, resulting in arrest of differentiation at immature proliferative stages. Characterizing the molecular basis of hematopoietic differentiation is therefore important for understanding and treating disease. Retinoic acid induces expression of ankyrin repeat-containing protein with a suppressor of cytokine signaling box 2 (ASB2) in acute promyelocytic leukemia cells, and ASB2 expression inhibits growth and promotes commitment, recapitulating an early step critical for differentiation. ASB2 is the specificity subunit of an E3 ubiquitin ligase complex and is proposed to exert its effects by regulating the turnover of specific proteins; however, no ASB2 substrates had been identified. Here, we report that ASB2 targets the actin-binding proteins filamin A and B for proteasomal degradation. Knockdown of endogenous ASB2 in leukemia cells delays retinoic acid-induced differentiation and filamin degradation; conversely, ASB2 expression in leukemia cells induces filamin degradation. ASB2 expression inhibits cell spreading, and this effect is recapitulated by knocking down both filamin A and filamin B. Thus, we suggest that ASB2 may regulate hematopoietic cell differentiation by modulating cell spreading and actin remodeling through targeting of filamins for degradation.
Etiologic heterogeneity among non-Hodgkin lymphoma subtypes
Authors: Morton Lindsay M. , Wang Sophia S. , Cozen Wendy , Linet Martha S. , Chatterjee Nilanjan , Davis Scott , Severson Richard K. , Colt Joanne S. , Vasef Mohammad A. , Rothman Nathaniel , Blair Aaron , Bernstein Leslie , Cross Amanda J. , De Roos Anneclaire J. , Engels Eric A. , Hein David W. , Hill Deirdre A. , Kelemen Linda E. , Lim Unhee , Lynch Charles F. , Schenk Maryjean , Wacholder Sholom , Ward Mary H. , Hoar Zahm Shelia , Chanock Stephen J. , Cerhan James R. , Hartge Patricia
Published: September 2008

Understanding patterns of etiologic commonality and heterogeneity for non-Hodgkin lymphomas may illuminate lymphomagenesis. We present the first systematic comparison of risks by lymphoma subtype for a broad range of putative risk factors in a population-based case-control study, including diffuse large B-cell (DLBCL; N = 416), follicular (N = 318), and marginal zone lymphomas (N = 106), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL; N = 133). We required at least 2 of 3 analyses to support differences in risk: (1) polytomous logistic regression, (2) homogeneity tests, or (3) dichotomous logistic regression, analyzing all 7 possible pairwise comparisons among the subtypes, corresponding to various groupings by clinical behavior, genetic features, and differentiation. Late birth order and high body mass index (≥ 35) kg/m2) increased risk for DLBCL alone. Autoimmune conditions increased risk for marginal zone lymphoma alone. The tumor necrosis factor G-308A polymorphism (rs1800629) increased risks for both DLBCL and marginal zone lymphoma. Exposure to certain dietary heterocyclic amines from meat consumption increased risk for CLL/SLL alone. We observed no significant risk factors for follicular lymphoma alone. These data clearly support both etiologic commonality and heterogeneity for lymphoma subtypes, suggesting that immune dysfunction is of greater etiologic importance for DLBCL and marginal zone lymphoma than for CLL/SLL and follicular lymphoma.
Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome
Authors: Frémeaux-Bacchi Veronique , Miller Elizabeth C. , Liszewski M. Kathryn , Strain Lisa , Blouin Jacques , Brown Alison L. , Moghal Nadeem , Kaplan Bernard S. , Weiss Robert A. , Lhotta Karl , Kapur Gaurav , Mattoo Tej , Nivet Hubert , Wong William , Gie Sophie , de Ligny Bruno Hurault , Fischbach Michel , Gupta Ritu , Hauhart Richard , Meunier Vincent , Loirat Chantal , Dragon-Durey Marie-Agnès , Fridman Wolf H. , Janssen Bert J. C. , Goodship Timothy H. J. , Atkinson John P.
Published: September 2008

Atypical hemolytic uremic syndrome (aHUS) is a disease of complement dysregulation. In approximately 50% of patients, mutations have been described in the genes encoding the complement regulators factor H, MCP, and factor I or the activator factor B. We report here mutations in the central component of the complement cascade, C3, in association with aHUS. We describe 9 novel C3 mutations in 14 aHUS patients with a persistently low serum C3 level. We have demonstrated that 5 of these mutations are gain-of-function and 2 are inactivating. This establishes C3 as a susceptibility factor for aHUS.
The PHD fingers of MLL block MLL fusion protein–mediated transformation
Authors: Muntean Andrew G. , Giannola Diane , Udager Aaron M. , Hess Jay L.
Published: September 2008

Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3-kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their specific role in transformation has not been explored. Here we show that inclusion of the PHD fingers in the MLL fusion protein MLL-AF9 blocked immortalization of hematopoietic progenitors. Inclusion of 2 or more PHD fingers reduced association with the Hoxa9 locus and suppressed Hoxa9 up-regulation in hematopoietic progenitors. These data provide an explanation for why MLL translocation breakpoints exclude the PHD fingers and suggest a possible role for these domains in regulating the function of wild-type MLL.
Constitutively activated Notch signaling is involved in survival and apoptosis resistance of B-CLL cells
Authors: Rosati Emanuela , Sabatini Rita , Rampino Giuliana , Tabilio Antonio , Di Ianni Mauro , Fettucciari Katia , Bartoli Andrea , Coaccioli Stefano , Screpanti Isabella , Marconi Pierfrancesco
Published: September 2008

Notch signaling is involved in tumorigenesis, but its role in B–chronic lymphocytic leukemia (B-CLL) pathogenesis is not completely defined. This study examined the expression and activation of Notch receptors in B-CLL cells and the role of Notch signaling in sustaining the survival of these cells. Our results show that B-CLL cells but not normal B cells constitutively express Notch1 and Notch2 proteins as well as their ligands Jagged1 and Jagged2. Notch signaling is constitutively activated in B-CLL cells, and its activation is further increased in B-CLL cells, which resist spontaneous apoptosis after 24-hour ex vivo culture. Notch stimulation by a soluble Jagged1 ligand increases B-CLL cell survival and is accompanied by increased nuclear factor–kappa B (NF-κB) activity and cellular inhibitor of apoptosis protein 2 (c-IAP2) and X-linked inhibitor of apoptosis protein (XIAP) expression. In contrast, Notch-signaling inhibition by the γ-secretase inhibitor I (GSI; z-Leu-Leu-Nle-CHO) and the specific Notch2 down-regulation by small-interfering RNA accelerate spontaneous B-CLL cell apoptosis. Apoptotic activity of GSI is accompanied by reduction of NF-κB activity and c-IAP2 and XIAP expression. Overall, our findings show that Notch signaling plays a critical role in B-CLL cell survival and apoptosis resistance and suggest that it could be a novel potential therapeutic target.
Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5
Authors: Schulteis Ryan D. , Chu Haiyan , Dai Xuezhi , Chen Yuhong , Edwards Brandon , Haribhai Dipica , Williams Calvin B. , Malarkannan Subramaniam , Hessner Martin J. , Glisic-Milosavljevic Sanja , Jana Srikanta , Kerschen Edward J. , Ghosh Soumitra , Wang Demin , Kwitek Anne E. , Lernmark Ake , Gorski Jack , Weiler Hartmut
Published: September 2008

The loss of Gimap5 (GTPase of the immune-associated protein 5) gene function is the underlying cause of lymphopenia and autoimmune diabetes in the BioBreeding (BB) rat. The in vivo function of murine gimap5 is largely unknown. We show that selective gene ablation of the mouse gimap5 gene impairs the final intrathymic maturation of CD8 and CD4 T cells and compromises the survival of postthymic CD4 and CD8 cells, replicating findings in the BB rat model. In addition, gimap5 deficiency imposes a block of natural killer (NK)- and NKT-cell differentiation. Development of NK/NKT cells is restored on transfer of gimap5−/− bone marrow into a wild-type environment. Mice lacking gimap5 have a median survival of 15 weeks, exhibit chronic hepatic hematopoiesis, and in later stages show pronounced hepatocyte apoptosis, leading to liver failure. This pathology persists in a Rag2-deficient background in the absence of mature B, T, or NK cells and cannot be adoptively transferred by transplanting gimap5−/− bone marrow into wild-type recipients. We conclude that mouse gimap5 is necessary for the survival of peripheral T cells, NK/NKT-cell development, and the maintenance of normal liver function. These functions involve cell-intrinsic as well as cell-extrinsic mechanisms.
c-Abl kinase inhibitors overcome CD40-mediated drug resistance in CLL: implications for therapeutic targeting of chemoresistant niches
Authors: Hallaert Delfine Y. H. , Jaspers Annelieke , van Noesel Carel J. , van Oers Marinus H. J. , Kater Arnon P. , Eldering Eric
Published: September 2008

In lymph node (LN) proliferation centers in chronic lymphocytic leukemia (CLL), the environment protects from apoptotic and cytotoxic triggers. Here, we aimed to define the molecular basis for the increased drug resistance and searched for novel strategies to circumvent it. The situation in CLL LN could be mimicked by prolonged in vitro CD40 stimulation, which resulted in up-regulation of antiapoptotic Bcl-xL, A1/Bfl-1, and Mcl-1 proteins, and afforded resistance to various classes of drugs (fludarabine, bortezomib, roscovitine). CD40 stimulation also caused ERK-dependent reduction of Bim-EL protein, but ERK inhibition did not prevent drug resistance. Drugs combined with sublethal doses of the BH3-mimetic ABT-737 displayed partial and variable effects per individual CD40-stimulated CLL. The antiapoptotic profile of CD40-triggered CLL resembled BCR-Abl–dependent changes seen in chronic myeloid leukemia (CML), which prompted application of c-Abl inhibitors imatinib or dasatinib. Both compounds, but especially dasatinib, prevented the entire antiapoptotic CD40 program in CLL cells, and restored drug sensitivity. These effects also occurred in CLL samples with dysfunctional p53. Importantly, ex vivo CLL LN samples also displayed strong ERK activation together with high Bcl-xL and Mcl-1 but low Bim levels. These data indicate that CLL cells in chemoresistant niches may be sensitive to therapeutic strategies that include c-Abl inhibitors.
The Glut1 and Glut4 glucose transporters are differentially expressed during perinatal and postnatal erythropoiesis
Authors: Montel-Hagen Amélie , Blanc Lionel , Boyer-Clavel Myriam , Jacquet Chantal , Vidal Michel , Sitbon Marc , Taylor Naomi
Published: September 2008

Glucose is a major source of energy for living organisms, and its transport in vertebrates is a universally conserved property. Of all cell lineages, human erythrocytes express the highest level of the Glut1 glucose transporter with more than 200 000 molecules per cell. However, we recently reported that erythrocyte Glut1 expression is a specific trait of vitamin C–deficient mammalian species, comprising only higher primates, guinea pigs, and fruit bats. Here, we show that in all other tested mammalian species, Glut1 was transiently expressed in erythrocytes during the neonatal period. Glut1 was up-regulated during the erythroblast stage of erythroid differentiation and was present on the vast majority of murine red blood cells (RBCs) at birth. Notably though, Glut1 was not induced in adult mice undergoing anemia-induced erythropoiesis, and under these conditions, the up-regulation of a distinct transporter, Glut4, was responsible for an increased glucose transport. Sp3 and Sp1 transcriptions factors have been proposed to regulate Glut1 transcription, and we find that the concomitant repression of Glut1 and induction of Glut4 was associated with a significantly augmented Sp3/Sp1 ratio. Glucose transporter expression patterns in mice and human erythrocytes are therefore distinct. In mice, there is a postnatal switch from Glut1 to Glut4, with Glut4 further up-regulated under anemic conditions.
Requirement of vasculogenesis and blood circulation in late stages of liver growth in zebrafish
Authors: Korzh Svetlana , Pan Xiufang , Garcia-Lecea Marta , Winata Cecilia Lanny , Pan Xiaotao , Wohland Thorsten , Korzh Vladimir , Gong Zhiyuan
Published: September 2008

Background

Early events in vertebrate liver development have been the major focus in previous studies, however, late events of liver organogenesis remain poorly understood. Liver vasculogenesis in vertebrates occurs through the interaction of endoderm-derived liver epithelium and mesoderm-derived endothelial cells (ECs). In zebrafish, although it has been found that ECs are not required for liver budding, how and when the spatio-temporal pattern of liver growth is coordinated with ECs remains to be elucidated.

Results

To study the process of liver development and vasculogenesis in vivo, a two-color transgenic zebrafish line Tg(lfabf:dsRed; elaA:EGFP) was generated and named LiPan for liver-specific expression of DsRed RFP and exocrine pancreas-specific expression of GFP. Using the LiPan line, we first followed the dynamic development of liver from live embryos to adult and showed the formation of three distinct yet connected liver lobes during development. The LiPan line was then crossed with Tg(fli1:EGFP)y1 and vascular development in the liver was traced in vivo. Liver vasculogenesis started at 55–58 hpf when ECs first surrounded hepatocytes from the liver bud surface and then invaded the liver to form sinusoids and later the vascular network. Using a novel non-invasive and label-free fluorescence correction spectroscopy, we detected blood circulation in the liver starting at ~72 hpf. To analyze the roles of ECs and blood circulation in liver development, both cloche mutants (lacking ECs) and Tnnt2 morphants (no blood circulation) were employed. We found that until 70 hpf liver growth and morphogenesis depended on ECs and nascent sinusoids. After 72 hpf, a functional sinusoidal network was essential for continued liver growth. An absence of blood circulation in Tnnt2 morphants caused defects in liver vasculature and small liver.

Conclusion

There are two phases of liver development in zebrafish, budding and growth. In the growth phase, there are three distinct stages: avascular growth between 50–55 hpf, where ECs are not required; endothelium-dependent growth, where ECs or sinusoids are required for liver growth between 55–72 hpf before blood circulation in liver sinusoids; and circulation-dependent growth, where the circulation is essential to maintain vascular network and to support continued liver growth after 72 hpf.
Somatic mutation analysis of MYH11in breast and prostate cancer
Authors: Alhopuro Pia , Karhu Auli , Winqvist Robert , Waltering Kati , Visakorpi Tapio , Aaltonen Lauri A
Published: September 2008

Background

MYH11 (also known as SMMHC) encodes the smooth-muscle myosin heavy chain, which has a key role in smooth muscle contraction. Inversion at the MYH11 locus is one of the most frequent chromosomal aberrations found in acute myeloid leukemia. We have previously shown that MYH11 mutations occur in human colorectal cancer, and may also be associated with Peutz-Jeghers syndrome. The mutations found in human intestinal neoplasia result in unregulated proteins with constitutive motor activity, similar to the mutant myh11 underlying the zebrafish meltdown phenotype characterized by disrupted intestinal architecture. Recently, MYH1 and MYH9 have been identified as candidate breast cancer genes in a systematic analysis of the breast cancer genome.

Methods

The aim of this study was to investigate the role of somatic MYH11 mutations in two common tumor types; breast and prostate cancers. A total of 155 breast cancer and 71 prostate cancer samples were analyzed for those regions in MYH11 (altogether 8 exons out of 42 coding exons) that harboured mutations in colorectal cancer in our previous study.

Results

In breast cancer samples only germline alterations were observed. One prostate cancer sample harbored a frameshift mutation c.5798delC, which we have previously shown to result in a protein with unregulated motor activity.

Conclusion

Little evidence for a role of somatic MYH11 mutations in the formation of breast or prostate cancers was obtained in this study.
The cancer secretome: a reservoir of biomarkers
Authors: Xue Hua , Lu Bingjian , Lai Maode
Published: September 2008

Biomarkers are pivotal for cancer detection, diagnosis, prognosis and therapeutic monitoring. However, currently available cancer biomarkers have the disadvantage of lacking specificity and/or sensitivity. Developing effective cancer biomarkers becomes a pressing and permanent need. The cancer secretome, the totality of proteins released by cancer cells or tissues, provides useful tools for the discovery of novel biomarkers. The focus of this article is to review the recent advances in cancer secretome analysis. We aim to elaborate the approaches currently employed for cancer secretome studies, as well as its applications in the identification of biomarkers and the clarification of carcinogenesis mechanisms. Challenges encountered in this newly emerging field, including sample preparation, in vivo secretome analysis and biomarker validation, are also discussed. Further improvements on strategies and technologies will continue to drive forward cancer secretome research and enable development of a wealth of clinically valuable cancer biomarkers.