bluuebunny/crossref_metadata_2025 huggingface dataset:
Why Have Lending Programs Targeting Disadvantaged Small Business Borrowers Achieved So Little Success in the United States?
Authors: Bates Timothy , Lofstrom Magnus , Servon Lisa J.
Published: May 2011

Small business lending programs designed to move disadvantaged low-income people into business ownership have been difficult to implement successfully in the U.S. context. Based in part on the premise that financing requirements are an entry barrier limiting the ability of aspiring entrepreneurs to create small businesses, these programs are designed to alleviate such barriers for low net-worth individuals with limited borrowing opportunities. The authors’ analysis tracks through time nationally representative samples of adults to investigate the role of financial constraints and other factors delineating self-employment entrants from nonentrants. Paying particular attention to lines of business most accessible to adults lacking college credentials and substantial personal net worth, the authors’ analysis yields no evidence that financial capital constraints are a significant barrier to small-firm creation.
Accounting at the London School of Economics: Opportunity lost?
Authors: Napier Christopher J.
Published: May 2011

Given the aims of the founders of the London School of Economics, it is not surprising that accounting should have been taught at the School from soon after its establishment. An early focus on teaching practical accounting, with professional practitioners as teachers, was gradually supplanted by approaches informed by the economics of decision-making in conditions of scarce resources. By the 1930s, the Department of Business Administration provided an intellectual basis for thinking about financial reporting and costing that challenged taken-for-granted practices. After World War II, the “LSE Triumvirate” of William Baxter, Harold Edey and David Solomons took forward ideas of opportunity cost and value to the owner as core theoretical concepts, while developing undergraduate and later postgraduate programmes that provided rigorous education for future accountants, administrators, business people and academics. However, the focus on education, and the weak infrastructure for accounting research in the UK had the unintended consequence that, by the early 1970s, the Department of Accounting did not have the opportunity of responding to changes in research focus in North America, which were influenced by developments in financial economics.
Cite and seek: Exploring accounting history through citation analysis of the specialist accounting history journals, 1996 to 2008
Authors: Bisman Jayne Elizabeth
Published: May 2011

Elements of the history of research publications on accounting’s past are examined through an analysis of citations appearing in 546 articles published from 1996 to 2008 in the three specialized, English language, accounting history journals. The purpose was to enlighten understandings of this corpus of literature, particularly through the exploration of the significance, interrelationships and comparative dimensions of this journal network and its scholarly community. There was an observable insularity in citation patterns within the specialist journals, and yet a degree of heterogeneity across these journals. The analysis also defined a group of core, commonly cited articles in these journals, although all such articles were drawn from generalist accounting journals, with the extent of citations to the broader business, economic and management history literatures illustrating minimal engagement with these related disciplines. The findings suggest that while accounting history, as a discipline, can foster excellence in research, there is considerable scope for addressing identified deficiencies in the literature and for expanding the research community to enliven the discipline.
Composite Structural Health Monitoring Through Use of Embedded PZT Sensors
Authors: Tang Hong-Yue , Winkelmann Charles , Lestari Wahyu , La Saponara Valeria
Published: May 2011

The need to understand and monitor the integrity of structural components made of composite materials is becoming critical, due to an increase of the use of composites in aerospace, civil, wind energy, and transportation engineering. Off-the-shelf piezoelectric transducers embedded inside the composites or bonded onto the structure surface are a possible solution for on-line structural health monitoring and non-destructive evaluation: they can be used to generate Lamb waves, which are able to detect damage. This article focuses on the behavior of two sets of woven fiberglass/epoxy specimens, one with embedded, one with surface-mounted piezoelectric wafer transducers (lead zirconate titanate). The specimens are tested under axial tensile fatigue at high stress ratio, and the transducers are interrogated in pitch-catch mode at different stages of the specimens’ life, while they are subjected to the mean test load (the testing machine is paused). A novel signal processing technique based on wavelet thresholding/denoising and Gabor wavelet transform is discussed. This technique identifies changes in boundary conditions, loading/unloading prior to damage and during damage. It appears to correlate the contour area changes with the so-called characteristic damage state observed in the literature in composite laminates under tensile fatigue.
Anticipatory Grief Among Close Relatives of Patients in Hospice and Palliative Wards
Authors: Johansson Åsa K. , Grimby Agneta
Published: May 2011

A Swedish widowhood study revealed that four out of ten widows regarded the pre-loss period more stressful than the post-loss. The present investigation of close relatives to patients dying from cancer (using interviews and the Anticipatory Grief Scale) found that preparatory grief involves much emotional stress, as intense preoccupation with the dying, longing for his/her former personality, loneliness, tearfulness, cognitive dysfunction, irritability, anger and social withdrawal, and a need to talk. Psychological status was bad one by every fifth. However, the relatives mostly stated adjustment and ability to mobilize strength to cope with the situation. The results suggest development of support and guiding programs also for the anticipatory period.
Effect of Damages on Crack-visible of the Cavity Opening Displacement in Burning Solid Fuel
Authors: Mirsalimov V. M. , Rustamov B. E.
Published: May 2011

The problem of the mechanics of fracture of the medium weakened by crack-visible cavity, whose surfaces burns, is considered. It is considered that in the vicinity of technological defect (crack-visible cavity), there are zones with the interparticle bonds in the material. It has been investigated for the quasi-static process of deformation of burning fuel. Determination of the unknown parameters describing crack-visible cavity opening displacement is reduced to the solution of a system of singular integral equations, from the solution of which the tractions in the bonds are found. The sufficient condition of stability of a mode ‘burning-fracture’ is received.
Academic Politics between Democracy and Aristocracy
Authors: Kochin Michael S.
Published: May 2011

The Republic’s account of the relation between talking about politics and doing politics illuminates the nature of political action. Plato’s Socrates argues that those who ought to govern are those who know about politics and who know what politics is about, since political things are images of ideas. Socrates’ alternative to democracy is thus an academic rather than an aristocratic elite—an elite of those who know. Yet the academic elite Plato imagined does not dispute the right of the people to decide between it, the aristocrats, and the men of the people.
Sexuality Counseling: A Professional Specialization Comes of Age
Authors: Southern Stephen , Cade Rochelle
Published: May 2011

For individuals and couples experiencing such distress, sexuality counseling, an emerging specialization in professional counseling, may provide relief, understanding, healing, and intimacy. This review attempts to describe the paradigm shifts and key figures in the field, sexuality counseling as a professional specialization, the process of sexuality counseling including assessment, diagnosis and treatment planning, and various roadblocks to intimacy. It concludes with advocacy of the new specialization as a synthesis of trends in sexual health.
Direct and Mediated Effects of Two Theoretically Based Interventions to Increase Consumption of Fruits and Vegetables in the Healthy Body Healthy Spirit Trial
Authors: Shaikh Abdul R. , Vinokur Amiram D. , Yaroch Amy L. , Williams Geoffrey C. , Resnicow Ken
Published: May 2011

This study tested the effects of two theory-based interventions to increase fruit and vegetable intake. Hypothesized intervention mediators included self-efficacy (SE), social support (SS), autonomous motivation (AM), and controlled motivation (CM). At baseline, 1,021 African American adults were recruited from 16 churches randomized to one comparison and two intervention groups: Group 1 (standard educational materials), Group 2 (culturally targeted materials), and Group 3 (culturally targeted materials and telephone-based motivational interviewing). A well-fitted model based on structural equation modeling—χ2( df = 541, N = 353, 325) = 864.28, p < .001, normed fit index = .96, nonnormed fit index = .98, comparative fit index = .98, root mean square error of approximation = .042—demonstrated that AM was both a significant mediator and moderator. In the subgroup with low baseline AM, AM mediated 17% of the effect of the Group 3 intervention on fruit and vegetable intake. Conversely, SS, SE, and CM were not significant mediators. Implications related to theory and intervention development are discussed.
Reframing criminal victimization: Finding a place for vulnerability and resilience
Authors: Walklate Sandra
Published: May 2011

The purpose of this article is to examine the ways in which studies of criminal victimization have contributed to this presumption of human vulnerability, and to examine the potential in understandings of resilience for overcoming this presumption. In order to do this the argument falls into three parts. In the first part I shall consider the different ways in which victimization and vulnerability have been linked together. In the second I shall examine the concept of resilience and its relationship, if any, with vulnerability and victimization. Throughout this discussion I shall draw on feminist informed work as a way of suggesting a differently oriented approach to both of these concepts: presented here as thinking otherwise. In the final and concluding part of this article the implications of contemporary understandings of these concepts will be situated within the broader policy context characterized by Aradau (2004) as informed by a ‘politics of pity’.
Situation Awareness Catches On: What? So What? Now What?
Authors: Tenney Yvette J. , Pew Richard W.
Published: May 2011

Human factors/ergonomics professionals regularly study the situation awareness (SA) problems of pilots, air traffic controllers, automobile drivers, power plant workers, ambulance dispatchers, urban search and rescue professionals, and unmanned vehicle operators, to mention a few. The challenge has been to define SA operationally and devise measurement strategies that focus on attention and recall on the one hand and relevant actions on the other. Although there have been many successes, challenges remain. This review is organized in three parts. Under “What?” we discuss definitions of SA, their interpretations in terms of human information processing and ecological psychological theories, as well as techniques for measuring SA. Under “So what?” we introduce SA applications'information requirements, technological tools, and training systems'that support the way people work and live. Finally, under “Now what?” we discuss future directions for SA research.
Representation Aiding to Support Performance on Problem-Solving Tasks
Authors: Smith Philip J. , Bennett Kevin B. , Stone R. Brian
Published: May 2011

A substantial literature has been developed that deals with the use of visual displays to support human problem solving. In particular, the cognitive systems engineering literature has emphasized the use of visual displays to improve performance on complex real-world tasks such as process control with the labels direct perception, ecological interface design, representational design, and semantic mapping, focusing on the use of representations that take advantage of powerful perceptual processes to support problem solving. Although the theoretical orientations and details of each approach are slightly different, they all share a fundamental core belief: The effectiveness of a graphical decision aid depends on relationships between the representation, the domain and associated task(s), and the characteristics of the agent (person). This review begins with a discussion of strategies for representation aiding, assuming that the appropriate domain semantics have been determined. It then discusses a core assumption in this literature that, in the design of complex real-world systems, designers cannot anticipate all the possible scenarios that could arise and must therefore design displays that support effective problem solving even when novel or unanticipated scenarios are encountered. Finally, the results of empirical studies of designs based on representation aiding are reviewed.
Usability Assessment Methods
Authors: Dumas Joseph S. , Salzman Marilyn C.
Published: May 2011

Usability assessment methods evolved from traditional human factors/ergonomics techniques beginning in the early 1980s. Following a brief historical introduction, we describe the four major categories of these methods: usability testing; usability inspections; surveys, interviews, and focus groups; and field methods. We describe the basic techniques of these methods, their strengths and weaknesses, their measurement characteristics, their validity and reliability, and how they are being applied to product development and assessment. We discuss the new challenges to usability assessment: (a) using the methods thoughtfully, (b) expanding the scope of assessment beyond usability and productivity to affect end user experience, (c) and emphasizing design solutions to problems in addition to simply finding the problems themselves.
Satisfying Divergent Needs in User-Centered Computing: Accounting for Varied Levels of Visual Function
Authors: Jacko Julie A. , Leonard V. Kathlene
Published: May 2011

The ubiquity of information technologies imposes serious and debilitating limitations on people whose abilities fall outside the range of what is generally considered normal. Those at all ages who experience perceptual, physical, and/or cognitive impairments often have diminished functional abilities, and thus, their technology interaction requirements are often unmet by mainstream technologies. In this chapter, we describe an approach to the advancement of baseline human-centered computing for all users, as well as a summary of advancements championed by research, industry, and government initiatives. These efforts have generated a need for a measured, scientific method to unify accessibility design approaches that can be applied in practice. A user's functional abilities serve as the foundation for this framework on which the design process can evolve. Methods for deriving user needs and establishing thresholds for performance are described in the context of human-computer interactions by users with visual impairment. This framework provides the basis for users who have limited functional abilities to claim or reclaim access to information technologies, sustain or regain independence in their lives, and take full advantage of the opportunities that information technologies afford.
Multidimensional Aspects of Slips and Falls
Authors: Gielo-Perczak Krystyna , Maynard Wayne S. , Di Domenico Angela
Published: May 2011

The study of slips and falls has traditionally focused on body kinematics and tribology. However, this strictly mechanical approach does not allow scientists to assess the importance of each component in relation to the complete system, and thus it lacks integration. The purpose of this chapter is to present and demonstrate the components of a broad analysis for in-depth understanding of slips and falls while walking on level surfaces. In most slip-and-fall studies, balance analysis is simplified and attributed to the point of heel contact. To determine sufficient fall prevention strategies, however, one must analyze balance before the critical moment of lost control. Such an approach requires the sciences of biomechanics, mechanics, anatomy, and neuromuscular control, as well as tribology. Causes of slips and falls are complex, and prevention approaches are often reactive, driven by high-injury trends and lawsuits. Prevention strategies need to be more proactive: Understanding the causes of accidents can help in identifying and correcting hazards before they cause problems. Examples include reporting incidents, selecting the right flooring, selecting footwear, and implementing proper floor-cleaning procedures. A combined effort among all members of the organization, including communication across the entire work system, is critical to the success of slip-and-fall prevention efforts.
Designing Effective Warnings
Authors: Laughery Kenneth R. , Wogalter Michael S.
Published: May 2011

Since the early 1980s there has been an increased interest in research on warnings. This chapter has several objectives. First, we describe the purpose of warnings and where warnings fit with other safety considerations, such as design and guarding. Next, we present a model that incorporates both communication and information-processing concepts, which is characteristic of theoretical orientations that have guided much of the warning research. The research and application issues have generally focused on two themes: design factors and non-design factors that influence warning effectiveness. Third, we review the progress and status of research and application, with an emphasis on identifying those factors that appear to be most important in determining warning effectiveness. Finally, we conclude with a discussion of some of the challenges and opportunities facing warning designers and researchers in the future.
Current approaches to the treatment of paraneoplastic encephalitis
Authors: Grisold Wolfgang , Giometto Bruno , Vitaliani Roberta , Oberndorfer Stefan
Published: May 2011

Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and involve both the central nervous system (CNS) and peripheral nervous system. Paraneoplastic encephalitis comprises several diseases such as paraneoplastic cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in addition to other even less frequently occurring entities. LE was the first historically identified CNS PNS, and similarities between other temporal lobe diseases such as herpes encephalitis have been elucidated. In the past few decades several autoantibodies have been described in association with LE. These encompass the classical ‘onconeuronal’ antibodies (abs) such as Hu, Yo, Ri and others, and now additionally abs towards either ion channels or surface antigens. The clinical core findings in LE are various mental changes such as amnesia or confusion, often associated with seizures. Careful characterization of psychiatric manifestations and/or associated neurological signs can help to characterize the syndrome and type of ab. The treatment options in LE depend on the aetiology. In LE caused by onconeuronal abs, the treatment options are poor. In two types of abs associated with LE, abs against ion channels and surface antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these types of LE treatable conditions. However, LE can also occur without being associated with cancer, in which case only immunomodulation is required. Despite effective treatments, some patients’ residual deficits remain, and recurrences have also been described.
Craving Activity and Losing Objectivity
Authors: Hart William , Albarracin Dolores
Published: May 2011

In light of U.S. society’s ever increasing need for activity, the authors used three experiments to examine how general action concepts, activated by subtle priming methods, influence choices to approach information that confirms a recent decision. Findings from Experiments 1 to 3 revealed that viewing action (vs. control) words prior to information selection increased selective approach to supporting information, but viewing inaction (vs. control) words reduced this bias. Experiment 3 also showed that the effect of the action words on this confirmation bias was smaller when participants were allowed to self-affirm by writing about an important personal value. In addition, the experiments found that viewing the action words caused the selection of more total information than viewing the inaction words. The authors conclude that the growing need for activity in the United States may contribute to a loss of objectivity in the way citizens gather information.
Assessing Trustworthiness of Personal Aides
Authors: Lewis Denise Clark , Cho Won Jee
Published: May 2011

Background: Smaller family size has increased the need for assistance from personal aides. Respite care provided by personal aides reduces depressive symptoms and improves intergenerational relations and overall well-being of family members and patients. Yet, little is known about how family members evaluate personal aides prior to and during the employment period. Methods: Qualitative semistructured interviews were conducted face-to-face with 10 families providing home-based care. Family members’ ages ranged from 43 to 70 years. Patients’ ages ranged from 67 to 86 years. Interviews were audio-recorded and transcribed verbatim. Data were coded and themes were identified. Results: Family members emphasized the importance of personal aides. Other concerns included protection of their loved ones against risks from dishonest, unethical, or incompetent personal aides and unsafe, uncomfortable caregiving contexts. After family members hired a personal aide they presumed to be trustworthy, monitoring was a nearly endless task in seeking assurance that their initial assessment was accurate. Conclusions: Appropriate care, according to family members, went far beyond actions required to competently administer medicines, assist with activities of daily living, or maintain a watchful presence in the home. While positive experiences with personal aides added to the quality of life for both family members and patients when trustworthiness was established, quite the opposite was found when trust was violated. Personal relations, interpersonal communication skills, and affection between the aide and the patient were found to be much more important in determining trustworthiness than were standard caregiving skills.
The anti-fibrinolytic SERPIN, plasminogen activator inhibitor 1 (PAI-1), is targeted to and released from catecholamine storage vesicles
Authors: Jiang Qijiao , Gingles Neill A. , Olivier Marc A. , Miles Lindsey A. , Parmer Robert J.
Published: May 2011

Recent studies suggest a crucial role for plasminogen activator inhibitor-1 (PAI-1) in mediating stress-induced hypercoagulability and thrombosis. However, the mechanisms by which PAI-1 is released by stress are not well-delineated. Here, we examined catecholaminergic neurosecretory cells for expression, trafficking, and release of PAI-1. PAI-1 was prominently expressed in PC12 pheochromocytoma cells and bovine adrenomedullary chromaffin cells as detected by Northern blotting, Western blotting, and specific PAI-1 ELISA. Sucrose gradient fractionation studies and immunoelectron microscopy demonstrated localization of PAI-1 to catecholamine storage vesicles. Secretogogue stimulation resulted in corelease of PAI-1 with catecholamines. Parallel increases in plasma PAI-1 and catecholamines were observed in response to acute sympathoadrenal activation by restraint stress in mice in vivo. Reverse fibrin zymography demonstrated free PAI-1 in cellular releasates. Detection of high molecular weight complexes by Western blotting, consistent with PAI-1 complexed with t-PA, as well as bands consistent with cleaved PAI-1, suggested that active PAI-1 was present. Modulation of PAI-1 levels by incubating PC12 cells with anti–PAI-1 IgG caused a marked decrease in nicotine-mediated catecholamine release. In summary, PAI-1 is expressed in chromaffin cells, sorted into the regulated pathway of secretion (into catecholamine storage vesicles), and coreleased, by exocytosis, with catecholamines in response to secretogogues.
A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia
Authors: Chen Yaoyu , Sullivan Con , Peng Cong , Shan Yi , Hu Yiguo , Li Dongguang , Li Shaoguang
Published: May 2011

We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL–induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to dissect this pathway by comparing the gene expression profiles of wild type and Alox5−/− LSCs. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was upregulated in Alox5−/− LSCs, suggesting that Msr1 suppresses the proliferation of LSCs. Using CML mouse model, we show that Msr1 is downregulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and β-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of the tumor suppressor function of Msr1 may be of significance in the development of novel therapeutic strategies for CML.
Tissue inflammation modulates gene expression of lymphatic endothelial cells and dendritic cell migration in a stimulus-dependent manner
Authors: Vigl Benjamin , Aebischer David , Nitschké Maximilian , Iolyeva Maria , Röthlin Tamara , Antsiferova Olga , Halin Cornelia
Published: May 2011

Chemokines and adhesion molecules up-regulated in lymphatic endothelial cells (LECs) during tissue inflammation are thought to enhance dendritic cell (DC) migration to draining lymph nodes, but the in vivo control of this process is not well understood. We performed a transcriptional profiling analysis of LECs isolated from murine skin and found that inflammation induced by a contact hypersensitivity (CHS) response up-regulated the adhesion molecules ICAM-1 and VCAM-1 and inflammatory chemokines. Importantly, the lymphatic markers Prox-1, VEGFR3, and LYVE-1 were significantly down-regulated during CHS. By contrast, skin inflammation induced by complete Freund adjuvant induced a different pattern of chemokine and lymphatic marker gene expression and almost no ICAM-1 up-regulation in LECs. Fluorescein isothiocyanate painting experiments revealed that DC migration to draining lymph nodes was more strongly increased in complete Freund adjuvant-induced than in CHS-induced inflammation. Surprisingly, DC migration did not correlate with the induction of CCL21 and ICAM-1 protein in LECs. Although the requirement for CCR7 signaling became further pronounced during inflammation, CCR7-independent signals had an additional, albeit moderate, impact on enhancing DC migration. Collectively, these findings indicate that DC migration in response to inflammation is stimulus-specific, mainly CCR7-dependent, and overall only moderately enhanced by LEC-induced genes other than CCL21.
Small vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation–associated thrombotic microangiopathy
Authors: Laskin Benjamin L. , Goebel Jens , Davies Stella M. , Jodele Sonata
Published: May 2011

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a challenging diagnosis after hematopoietic stem cell transplantation. Although endothelial injury represents the final common pathway of disease, the exact pathophysiology of TA-TMA remains unclear. Potential causes include infections, chemotherapy, radiation, and calcineurin inhibitors. Recent literature addresses the roles of cytokines, graft-versus-host disease, the coagulation cascade, and complement in the pathogenesis of TA-TMA. Current diagnostic criteria are unsatisfactory, because patients who have received a transplant can have multiple other reasons for the laboratory abnormalities currently used to diagnose TA-TMA. Moreover, our lack of understanding of the exact mechanism of disease limits the development and evaluation of potential treatments. Short- and long-term renal complications contribute to TA-TMA's overall poor prognosis. In light of these challenges, future research must validate novel markers of disease to aid in early diagnosis, guide current and future treatments, prevent long-term morbidity, and improve outcomes. We focus on TA-TMA as a distinct complication of hematopoietic stem cell transplantation, emphasizing the central role of the kidney in this disease.
Risk stratification of intermediate-risk acute myeloid leukemia: integrative analysis of a multitude of gene mutation and gene expression markers
Authors: Rockova Veronika , Abbas Saman , Wouters Bas J. , Erpelinck Claudia A. J. , Beverloo H. Berna , Delwel Ruud , van Putten Wim L. J. , Löwenberg Bob , Valk Peter J. M.
Published: May 2011

Numerous molecular markers have been recently discovered as potential prognostic factors in acute myeloid leukemia (AML). It has become of critical importance to thoroughly evaluate their interrelationships and relative prognostic importance. Gene expression profiling was conducted in a well-characterized cohort of 439 AML patients (age < 60 years) to determine expression levels of EVI1, WT1, BCL2, ABCB1, BAALC, FLT3, CD34, INDO, ERG and MN1. A variety of AML-specific mutations were evaluated, that is, FLT3, NPM1, N-RAS, K-RAS, IDH1, IDH2, and CEBPADM/SM (double/single). Univariable survival analysis shows that (1) patients with FLT3ITD mutations have inferior overall survival (OS) and event-free survival (EFS), whereas CEBPADM and NPM1 mutations indicate favorable OS and EFS in intermediate-risk AML, and (2) high transcript levels of BAALC, CD34, MN1, EVl1, and ERG predict inferior OS and EFS. In multivariable survival analysis, CD34, ERG, and CEBPADM remain significant. Using survival tree and regression methodologies, we show that CEBPADM, CD34, and IDH2 mutations are capable of separating the intermediate group into 2 AML subgroups with highly distinctive survival characteristics (OS at 60 months: 51.9% vs 14.9%). The integrated statistical approach demonstrates that from the multitude of biomarkers a greatly condensed subset can be selected for improved stratification of intermediate-risk AML.
Lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial
Authors: Jakubowiak Andrzej J. , Griffith Kent A. , Reece Donna E. , Hofmeister Craig C. , Lonial Sagar , Zimmerman Todd M. , Campagnaro Erica L. , Schlossman Robert L. , Laubach Jacob P. , Raje Noopur S. , Anderson Tara , Mietzel Melissa A. , Harvey Colleen K. , Wear Sandra M. , Barrickman Jennifer C. , Tendler Craig L. , Esseltine Dixie-Lee , Kelley Susan L. , Kaminski Mark S. , Anderson Kenneth C. , Richardson Paul G.
Published: May 2011

This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone (RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels, including the maximum tolerated dose (MTD). Patients with a very good partial response or better (≥ VGPR) after cycle 4 proceeded to autologous stem cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4 and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/m2, pegylated liposomal doxorubicin 30 mg/m2, and dexamethasone 20/10 mg, as established with 3-week cycles. The most common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality. Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% ≥ VGPR, and 29% and 35% complete or near-complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The estimated 18-month PFS and OS were 80.8% and 98.6%, respectively. RVDD was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered at www.clinicaltrials.gov as NCT00724568.
Secondary autoimmune diseases occurring after HSCT for an autoimmune disease: a retrospective study of the EBMT Autoimmune Disease Working Party
Authors: Daikeler Thomas , Labopin Myriam , Di Gioia Massimo , Abinun Mario , Alexander Tobias , Miniati Irene , Gualandi Francesca , Fassas Athanasios , Martin Thierry , Schwarze Carl Philipp , Wulffraat Nico , Buch Maya , Sampol Antonia , Carreras Enric , Dubois Benedicte , Gruhn Bernd , Güngör Tayfun , Pohlreich David , Schuerwegh Annemie , Snarski Emilian , Snowden John , Veys Paul , Fasth Anders , Lenhoff Stig , Messina Chiara , Voswinkel Jan , Badoglio Manuela , Henes Jörg , Launay David , Tyndall Alan , Gluckman Eliane , Farge Dominique ,   on behalf of the EBMT Autoimmune Disease Working Party
Published: May 2011

To specify the incidence and risk factors for secondary autoimmune diseases (ADs) after HSCT for a primary AD, we retrospectively analyzed AD patients treated by HSCT reported to EBMT from 1995 to 2009 with at least 1 secondary AD (cases) and those without (controls). After autologous HSCT, 29 of 347 patients developed at least 1 secondary AD within 21.9 (0.6-49) months and after allogeneic HSCT, 3 of 16 patients. The observed secondary ADs included: autoimmune hemolytic anemia (n = 3), acquired hemophilia (n = 3), autoimmune thrombocytopenia (n = 3), antiphospholipid syndrome (n = 2), thyroiditis (n = 12), blocking thyroid-stimulating hormone receptor antibody (n = 1), Graves disease (n = 2), myasthenia gravis (n = 1), rheumatoid arthritis (n = 2), sarcoidosis (n = 2), vasculitis (n = 1), psoriasis (n = 1), and psoriatic arthritis (n = 1). After autologous HSCT for primary AD, the cumulative incidence of secondary AD was 9.8% ± 2% at 5 years. Lupus erythematosus as primary AD, and antithymocyte globulin use plus CD34+ graft selection were important risk factors for secondary AD by multivariate analysis. With a median follow-up of 6.2 (0.54-11) years after autologous HSCT, 26 of 29 patients with secondary AD were alive, 2 died during their secondary AD (antiphospholipid syndrome, hemophilia), and 1 death was HSCT-related. This European multicenter study underlines the need for careful management and follow-up for secondary AD after HSCT.
Multiple Hodgkin lymphoma–associated loci within the HLA region at chromosome 6p21.3
Authors: Moutsianas Loukas , Enciso-Mora Victor , Ma Yussanne P. , Leslie Stephen , Dilthey Alexander , Broderick Peter , Sherborne Amy , Cooke Rosie , Ashworth Alan , Swerdlow Anthony J. , McVean Gilean , Houlston Richard S.
Published: May 2011

Since an association between the human leukocyte antigen (HLA) region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both single nucleotide polymorphism (SNP) and classic HLA allele variation in the major histocompatibility complex. However, population stratification and the extent and complexity of linkage disequilibrium within the major histocompatibility complex have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classic HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4736 controls. We confirm that the strongest signal of association comes from an SNP located in the class II region, rs6903608 (odds ratio [OR] = 1.79, P = 6.63 × 10−19), which is unlikely to be driven by association to HLA-DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR = 1.73, P = 6.31 × 10−13), a SNP that maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR = 0.56, P = 1.51 × 10−7). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL.
Genome-wide RNA-seq analysis of human and mouse platelet transcriptomes
Authors: Rowley Jesse W. , Oler Andrew J. , Tolley Neal D. , Hunter Benjamin N. , Low Elizabeth N. , Nix David A. , Yost Christian C. , Zimmerman Guy A. , Weyrich Andrew S.
Published: May 2011

Inbred mice are a useful tool for studying the in vivo functions of platelets. Nonetheless, the mRNA signature of mouse platelets is not known. Here, we use paired-end next-generation RNA sequencing (RNA-seq) to characterize the polyadenylated transcriptomes of human and mouse platelets. We report that RNA-seq provides unprecedented resolution of mRNAs that are expressed across the entire human and mouse genomes. Transcript expression and abundance are often conserved between the 2 species. Several mRNAs, however, are differentially expressed in human and mouse platelets. Moreover, previously described functional disparities between mouse and human platelets are reflected in differences at the transcript level, including protease activated receptor-1, protease activated receptor-3, platelet activating factor receptor, and factor V. This suggests that RNA-seq is a useful tool for predicting differences in platelet function between mice and humans. Our next-generation sequencing analysis provides new insights into the human and murine platelet transcriptomes. The sequencing dataset will be useful in the design of mouse models of hemostasis and a catalyst for discovery of new functions of platelets. Access to the dataset is found in the “Introduction.”
Cigarette smoke exacerbates mouse allergic asthma through Smad proteins expressed in mast cells
Authors: Kim Dae Yong , Kwon Eun Young , Hong Gwan Ui , Lee Yun Song , Lee Seung-Hyo , Ro Jai Youl
Published: May 2011

Background

Many studies have found that smoking reduces lung function, but the relationship between cigarette smoke and allergic asthma has not been clearly elucidated, particularly the role of mast cells. This study aimed to investigate the effects of smoke exposure on allergic asthma and its association with mast cells.

Methods

BALB/c mice were sensitized and challenged by OVA to induce asthma, and bone marrow-derived mast cells (BMMCs) were stimulated with antigen/antibody reaction. Mice or BMMCs were exposed to cigarette smoke or CSE solution for 1 mo or 6 h, respectively. The recruitment of inflammatory cells into BAL fluid or lung tissues was determined by Diff-Quik or H&E staining, collagen deposition by Sircol assay, penh values by a whole-body plethysmography, co-localization of tryptase and Smad3 by immunohistochemistry, IgE and TGF-β level by ELISA, expressions of Smads proteins, activities of signaling molecules, or TGF-β mRNA by immunoblotting and RT-PCR.

Results

Cigarette smoke enhanced OVA-specific IgE levels, penh values, recruitment of inflammatory cells including mast cells, expressions of smad family, TGF-β mRNA and proteins, and cytokines, phosphorylations of Smad2 and 3, and MAP kinases, co-localization of tryptase and Smad3, and collagen deposition more than those of BAL cells and lung tissues of OVA-induced allergic mice. CSE solution pretreatment enhanced expressions of TGF-β, Smad3, activities of MAP kinases, NF-κB/AP-1 or PAI-1 more than those of activated-BMMCs.

Conclusions

The data suggest that smoke exposure enhances antigen-induced mast cell activation via TGF-β/Smad signaling pathways in mouse allergic asthma, and that it exacerbates airway inflammation and remodeling.
Elucidating the domain architecture and functions of non-core RAG1: The capacity of a non-core zinc-binding domain to function in nuclear import and nucleic acid binding
Authors: Arbuckle Janeen L , Rahman Negar S , Zhao Shuying , Rodgers William , Rodgers Karla K
Published: May 2011

Background

The repertoire of the antigen-binding receptors originates from the rearrangement of immunoglobulin and T-cell receptor genetic loci in a process known as V(D)J recombination. The initial site-specific DNA cleavage steps of this process are catalyzed by the lymphoid specific proteins RAG1 and RAG2. The majority of studies on RAG1 and RAG2 have focused on the minimal, core regions required for catalytic activity. Though not absolutely required, non-core regions of RAG1 and RAG2 have been shown to influence the efficiency and fidelity of the recombination reaction.

Results

Using a partial proteolysis approach in combination with bioinformatics analyses, we identified the domain boundaries of a structural domain that is present in the 380-residue N-terminal non-core region of RAG1. We term this domain the Central Non-core Domain (CND; residues 87-217).

Conclusions

We show how the CND alone, and in combination with other regions of non-core RAG1, functions in nuclear localization, zinc coordination, and interactions with nucleic acid. Together, these results demonstrate the multiple roles that the non-core region can play in the function of the full length protein.
Deep sequencing reveals the complex and coordinated transcriptional regulation of genes related to grain quality in rice cultivars
Authors: Venu R C , Sreerekha M V , Nobuta Kan , Beló André , Ning Yuese , An Gynheung , Meyers Blake C , Wang Guo-Liang
Published: May 2011

Background

Milling yield and eating quality are two important grain quality traits in rice. To identify the genes involved in these two traits, we performed a deep transcriptional analysis of developing seeds using both massively parallel signature sequencing (MPSS) and sequencing-by-synthesis (SBS). Five MPSS and five SBS libraries were constructed from 6-day-old developing seeds of Cypress (high milling yield), LaGrue (low milling yield), Ilpumbyeo (high eating quality), YR15965 (low eating quality), and Nipponbare (control).

Results

The transcriptomes revealed by MPSS and SBS had a high correlation co-efficient (0.81 to 0.90), and about 70% of the transcripts were commonly identified in both types of the libraries. SBS, however, identified 30% more transcripts than MPSS. Among the highly expressed genes in Cypress and Ilpumbyeo, over 100 conserved cis regulatory elements were identified. Numerous specifically expressed transcription factor (TF) genes were identified in Cypress (282), LaGrue (312), Ilpumbyeo (363), YR15965 (260), and Nipponbare (357). Many key grain quality-related genes (i.e., genes involved in starch metabolism, aspartate amino acid metabolism, storage and allergenic protein synthesis, and seed maturation) that were expressed at high levels underwent alternative splicing and produced antisense transcripts either in Cypress or Ilpumbyeo. Further, a time course RT-PCR analysis confirmed a higher expression level of genes involved in starch metabolism such as those encoding ADP glucose pyrophosphorylase (AGPase) and granule bound starch synthase I (GBSS I) in Cypress than that in LaGrue during early seed development.

Conclusion

This study represents the most comprehensive analysis of the developing seed transcriptome of rice available to date. Using two high throughput sequencing methods, we identified many differentially expressed genes that may affect milling yield or eating quality in rice. Many of the identified genes are involved in the biosynthesis of starch, aspartate family amino acids, and storage proteins. Some of the differentially expressed genes could be useful for the development of molecular markers if they are located in a known QTL region for milling yield or eating quality in the rice genome. Therefore, our comprehensive and deep survey of the developing seed transcriptome in five rice cultivars has provided a rich genomic resource for further elucidating the molecular basis of grain quality in rice.
The aspartic proteinase family of three Phytophthora species
Authors: Kay John , Meijer Harold JG , ten Have Arjen , van Kan Jan AL
Published: May 2011

Background

Phytophthora species are oomycete plant pathogens with such major social and economic impact that genome sequences have been determined for Phytophthora infestans, P. sojae and P. ramorum. Pepsin-like aspartic proteinases (APs) are produced in a wide variety of species (from bacteria to humans) and contain conserved motifs and landmark residues. APs fulfil critical roles in infectious organisms and their host cells. Annotation of Phytophthora APs would provide invaluable information for studies into their roles in the physiology of Phytophthora species and interactions with their hosts.

Results

Genomes of Phytophthora infestans, P. sojae and P. ramorum contain 11-12 genes encoding APs. Nine of the original gene models in the P. infestans database and several in P. sojae and P. ramorum (three and four, respectively) were erroneous. Gene models were corrected on the basis of EST data, consistent positioning of introns between orthologues and conservation of hallmark motifs. Phylogenetic analysis resolved the Phytophthora APs into 5 clades. Of the 12 sub-families, several contained an unconventional architecture, as they either lacked a signal peptide or a propart region. Remarkably, almost all APs are predicted to be membrane-bound.

Conclusions

One of the twelve Phytophthora APs is an unprecedented fusion protein with a putative G-protein coupled receptor as the C-terminal partner. The others appear to be related to well-documented enzymes from other species, including a vacuolar enzyme that is encoded in every fungal genome sequenced to date. Unexpectedly, however, the oomycetes were found to have both active and probably-inactive forms of an AP similar to vertebrate BACE, the enzyme responsible for initiating the processing cascade that generates the Aβ peptide central to Alzheimer's Disease. The oomycetes also encode enzymes similar to plasmepsin V, a membrane-bound AP that cleaves effector proteins of the malaria parasite Plasmodium falciparum during their translocation into the host red blood cell. Since the translocation of Phytophthora effector proteins is currently a topic of intense research activity, the identification in Phytophthora of potential functional homologues of plasmepsin V would appear worthy of investigation. Indeed, elucidation of the physiological roles of the APs identified here offers areas for future study. The significant revision of gene models and detailed annotation presented here should significantly facilitate experimental design.