bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of graph theory application research in gears
Authors: Xue Hui-Ling , Liu Geng , Yang Xiao-Hui
Published: April 2015

Graph theory has been applied to gear train analysis and synthesis for many years, and it is an effective and systematic modeling approach in the design process of gear transmission. Based on more than 100 references listed in this paper, a review about the graph-based method for kinematic and static force analysis, power flow, and mechanical efficiency computation is presented. The method is based on the concept of fundamental circuit corresponding to a basic epicyclic gear train. A 1-dof epicyclic gear train and a two-stage planetary gear train are used to illustrate the application of this method. Besides, isomorphism identification in the synthesis process and enumeration of 1-dof epicyclic gear train graphs are surveyed particularly. Also, the computerized methods for detection of redundant gears and degenerate structures in epicyclic gear trains are reviewed, respectively.
Research on the biaxial compound pendulum jaw crusher based on seven-bar mechanism
Authors: Zhangfeng Zhao , Yanbiao Li , Wenhao Li , Xian Zhan , Xingliang Zhu , Jiang Zhong
Published: April 2015

Traditional compound pendulum jaw crushers have many disadvantages such as low efficiency and uneven broken materials. This paper proposes a new biaxial compound pendulum jaw crusher to solve these problems. This paper presents the kinematic and dynamic performance of the new crushers, introduces its structure and layout features, derives the equations involving position, velocity, acceleration and kinetics, describes a workspace of the jaw crusher, analyzes the travel characteristic values and crushing force of movable jaw plates, and optimizes its structural and motion parameters through a multi-objective genetic algorithm. After the optimization process, the novel jaw crusher has little force on each hinge and large force on movable jaw plates. Specifically, the forces in the X-direction are 120,300 N for hinge C, 120,200 N for hinge D, and 195,000 N for hinge N; the forces in the Y-direction are 167,100 N, 162,800 N, and 197,900 N accordingly, while the breaking force of the movable jaw plate is 229,600 N. Experiments have been conducted. The results have clearly shown that the new biaxial compound pendulum jaw crusher has many advantages over conventional ones, such as the high crushing efficiency, even crushing, and large crushing force.
Prevalence and associated factors of HIV infection among men who have sex with men in Hefei, China, 2013–2014: a cross-sectional study
Authors: Liu Yan-Yan , Tao Hai-Dong , Liu Juan , Fan Yin-Guang , Zhang Chao , Li Peng , Li Lian-Ju , Huang Qing , Zhao Wei , Ye Dong-Qing
Published: April 2015

The objective of this study was to investigate the prevalence and influencing factors of HIV infection among men who have sex with men (MSM) in Hefei, China. A total of 578 MSM were recruited, with a mean age of 28.13 ± 6.91; 70.7% were under 30. The awareness rate was 95.4% (560/587) in the cross-sectional study. Of all the respondents, 73 (12.44%) were seropositive for HIV and 56 (9.54%) for syphilis. Multivariate analysis showed that self-reported sexually transmitted infections (STIs) (AOR = 8.02, 95% CI: 2.58–24.98, P < 0.001), received HIV testing in the past year (AOR = 0.33, 95% CI: 0.19–0.60, P < 0.001) and syphilis (AOR = 3.40, 95% CI: 1.69– 6.85, P = 0.001) were independently associated with HIV infection. It is necessary for post-test counselling to address risk among those who engage in sexual risk behaviours. More efforts are needed to enhance HIV/STI testing and treatment services in China.
Correlates of anal sex roles among Malay and Chinese MSM in Kuala Lumpur, Malaysia
Authors: Dangerfield Derek T , Gravitt Patti , Rompalo Anne M , Tai Raymond , Lim Sin How
Published: April 2015

Identifying roles for anal sex is an important issue for populations of MSM. We describe the prevalence of identifying as being ‘top’, ‘bottom’, ‘versatile’, or ‘don’t know/not applicable’ among Malay and Chinese MSM in Kuala Lumpur, Malaysia, and behavioural outcomes according to these labels for sexual role identity. Data analysis was conducted on a survey administered during weekly outreach throughout Kuala Lumpur in 2012. Pearson’s Chi square tests were used to compare demographic and behavioural characteristics of MSM who reported roles for anal sex. Binary logistic regression was used to explore the odds of behavioural outcomes among MSM who identified as ‘bottom’, ‘versatile,’ and ‘don't know' compared to MSM who reported that ‘top' was their sexual role. Labels for anal sex roles were significantly associated with condom use for last anal sex. Among MSM who used labels for anal sex roles, MSM who identified as ‘bottom’ had highest level of not using condoms for last anal sex (24.1%, p = .045). In binary logistic regression model, identifying as ‘top’ was significantly associated with reporting using a condom during last anal sex and reported consistent condom use for anal sex in the past six months ( p = .039 and .017, respectively). With regard to sexual role identity, some MSM may be a part of a special subgroup of at-risk men to be targeted. Future research should evaluate the origins, meanings, and perceptions of these labels, and the developmental process of how these MSM identify with any of these categories. Research should also uncover condom use decision making with regard to these labels for sexual positioning.
When Does the In-Group Like the Out-Group? Bias Among Children as a Function of Group Norms
Authors: Rutland Adam , Hitti Aline , Mulvey Kelly Lynn , Abrams Dominic , Killen Melanie
Published: April 2015

Research indicates that in-group favoritism is prevalent among both adults and children. Although research has documented that individuals do not consistently display an in-group bias, the conditions under which out-group preference exists are not well understood. In this study, participants ( N = 462) aged 9 to 16 years judged in-group deviant acts that were either in line with or counter to a generic norm shared by both groups. The findings demonstrated, for the first time, that children preferred out-group over in-group deviance only when the in-group peer’s deviance was in line with the generic norm and a threat to their group’s identity. Participants justified their disapproval of these deviants by focusing on the need for group cohesion and loyalty, while they signified their approval by spotlighting the need for autonomy. Our findings suggest that children’s intergroup attitudes are influenced by how the behavior of their peers matches different levels of group norms.
Re-designing the everyday: The use and perception of time among cancer patients combining work and treatment
Authors: Hauge Bettina
Published: April 2015

This article describes how time was used dynamically by a group of people at risk of losing their lives. It is shown how these people appeared to experience a change in the relationship between inner and outer time and that time literally was felt in this situation. An empirical investigation of 16 cancer patients performing their jobs while going through demanding treatment programs found time as their main motive for working while being seriously ill. Actions at work point to a time ahead, so by taking part in the time at the workplace they were inscribed in a future presently under pressure by their cancer diagnosis. The article describes how cancer-struck women and men perceived time in their different life-worlds, at work, at home on temporary sick leave, and at the hospital, and it shows how these perceptions changed during the process of recovery. To these people, time appeared in three forms: a time beyond control, realizing that they had cancer; taking control of time, discovering that they could go to work; the time of the future, which was their new perception of time as cured. This new perception of time reflected the incidental discovery of the cancer, realizing life as coincidental. Having their life time threatened made them feel vulnerable and liminal (neither sick nor well, but on the way to recovery). This vulnerability can be seen as the result of a breakdown of our taken-for-granted space–time world. For these people, going to work seemed to reduce the unbearable waiting time towards recovery by re-establishing links to a well-known life-world, the workplace.
The difference homeland security makes: Comparing municipal corporate security in Canada and the United States
Authors: Walby Kevin , Lippert Randy K.
Published: April 2015

We explore what we refer to as municipal corporate security (MCS) units, a new form of security organization that differs significantly from public police and private contract security. Based on 36 interviews with MCS managers in 16 cities across Canada and in the United States, we examine how in-house security practices developed in private corporations are being transferred to municipal governments. We draw from the sociology of security governance to demonstrate how the Department of Homeland Security funding and policy has shaped MCS in the USA since 2001. The absence of similar centralized funding and policy for MCS in Canada has led to more piecemeal policy transfer, fewer links to federal government or national security, and more focus on nuisance policing than anti-terrorism. We also engage with the sociology of security consumption to argue that governments should be conceived as major buyers of security goods.
Future making in farm management accounting: The Australian “Blue Book”
Authors: Jack Lisa
Published: April 2015

In the late 1960s, an attempt was made to implement throughout Australia an innovative scheme to develop and standardise management accounting in the agricultural sector. Despite enthusiastic support for the proposed scheme, it was not implemented, although elements of it can be found in farm consultancy practice today. The story of the “Blue Book” ( Accounting and Planning for Farm Management) and the Australian Committee for the Coding of Rural Accounts (ACCRA) is analysed in the context of diffusion of innovation frameworks. However, as these frameworks do not adequately capture the visions of the future and the related emotional investment in innovations, the concept of future making is introduced from the work of Barbara Adam on future time in social studies, as a further layer of analysis in this case study. In particular, the problems of embedding management accounting innovations in new software in a time when information technology is changing rapidly affected significantly the diffusion of the innovation in Australia.
Establishing Survey Validity and Reliability for American Indians Through “Think Aloud” and Test–Retest Methods
Authors: Hauge Cindy Horst , Jacobs-Knight Jacque , Jensen Jamie L. , Burgess Katherine M. , Puumala Susan E. , Wilton Georgiana , Hanson Jessica D.
Published: April 2015

The purpose of this study was to use a mixed-methods approach to determine the validity and reliability of measurements used within an alcohol-exposed pregnancy prevention program for American Indian women. To develop validity, content experts provided input into the survey measures, and a “think aloud” methodology was conducted with 23 American Indian women. After revising the measurements based on this input, a test–retest was conducted with 79 American Indian women who were randomized to complete either the original measurements or the new, modified measurements. The test–retest revealed that some of the questions performed better for the modified version, whereas others appeared to be more reliable for the original version. The mixed-methods approach was a useful methodology for gathering feedback on survey measurements from American Indian participants and in indicating specific survey questions that needed to be modified for this population.
Dynamic Reflexivity in Action
Authors: Cheek Julianne , Lipschitz David L. , Abrams Elizabeth M. , Vago David R. , Nakamura Yoshio
Published: April 2015

Dynamic reflexivity is central to enabling flexible and emergent qualitatively driven inductive mixed-method and multiple methods research designs. Yet too often, such reflexivity, and how it is used at various points of a study, is absent when we write our research reports. Instead, reports of mixed-method and multiple methods research focus on what was done rather than how it came to be done. This article seeks to redress this absence of emphasis on the reflexive thinking underpinning the way that mixed- and multiple methods, qualitatively driven research approaches are thought about and subsequently used throughout a project. Using Morse’s notion of an armchair walkthrough, we excavate and explore the layers of decisions we made about how, and why, to use qualitatively driven mixed-method and multiple methods research in a study of mindfulness training (MT) in schoolchildren.
Biomarkers for Prediction of Central Venous Catheter Related-Thrombosis in Patients With Hematological Malignancies
Authors: Boersma R. S. , Hamulyak K. , van Oerle R. , Tuinenburg A. , ten Cate-Hoek A. J. , Schouten H. C.
Published: April 2015

Objective:

In a prospective setting, we aimed to find associations between biomarkers of the hemostatic system and the occurrence of central venous catheter (CVC)-related thrombosis in patients with hematological malignancies undergoing intensive chemotherapy.

Methods:

The study was conducted between July 2006 and August 2010 at the University Hospital Maastricht, the Netherlands. Consecutive adult patients with hematological malignancies who were going to receive a CVC for intensive chemotherapy were included. The primary end points were (a) symptomatic CVC-related thrombosis and (b) CVC-related infections. Blood samples were taken directly after catheterization, and easy to determine biomarkers (platelet count, leukocyte count, and hemoglobin level) in combination with blood group, factor VIII (FVIII), plasminogen activator inhibitor 1 (PAI-1), activated protein C (APC) resistance, and free protein S antigen were determined.

Results:

Blood was collected and analyzed from 168 patients. The incidence of symptomatic CVC-related thrombosis was 9%. In univariate analysis, white blood cell count >10.6 × 109/L, mean FVIII activity, and PAI-1 >12.2 IU/mL were found to be associated with the development of symptomatic CVC-related thrombosis.

Conclusion:

Elevated leukocyte count, high PAI-1, and high FVIII were associated with an increased incidence of symptomatic CVC-related thrombosis. We hope in future that simple, easy to determine laboratory tests that reflect the hemostatic and fibrinolytic activity in combination with clinical parameters may help to identify hematological patients at highest risk of CVC-related thrombosis and help to tailor the management of thromboprophylaxis in hematological patients undergoing CVC placement.
Loss of Work Productivity and Quality of Life in Patients With Autoimmune Bullous Dermatoses
Authors: Heelan K. , Hitzig S. L. , Knowles S. , Drucker A. M. , Mittmann N. , Walsh S. , Shear N. H.
Published: April 2015

Background:

Little is known about quality of life and work productivity in autoimmune bullous dermatoses (AIBDs).

Objective:

To determine the impact of AIBDs on quality of life and work productivity.

Methods:

An observational cross-sectional study took place between February and May 2013 at an AIBD tertiary referral centre. Ninety-four patients were included. All participants completed the Dermatology Life Quality Index and the Work Productivity and Activity Impairment–Specific Health Problem questionnaires.

Results:

Responders to treatment had less impairment ( P < .001) than nonresponders. Patients with severe AIBD had significantly more impairment that those with mild ( P < .001) and moderate ( P = .002) AIBD. Greater impairment was associated with higher percentage of work missed. Those with a higher Dermatology Life Quality Index score had greater work impairment and overall activity impairment ( P = .041, P = .024). Nonresponders had increased impairment while working ( P < .001), overall work impairment ( P < .001), and activity impairment ( P < .001). Severely affected patients had worse impairment in all Work Productivity and Activity Impairment Questionnaire domains.

Conclusions:

AIBD has the potential to be a large burden on ability to work and quality of life. Larger studies are needed to clarify how these domains change over time and whether or not they improve with treatment.
Local heat generation and material flow in friction stir welding of mild steel assemblies
Authors: Micallef Daniel , Camilleri Duncan , Toumpis Athanasios , Galloway Alexander , Arbaoui Larbi
Published: April 2015

In friction stir welding, assemblies are joined by means of plasticising, shearing and stirring non-molten material. The heat generation is directly related to the viscous behaviour of plasticised material, through coupled Navier–Stokes thermo-fluid flow stress equations. A significant amount of research has been conducted on aluminium friction stir welding but studies on mild steel assemblies are limited. The aim of this work is to understand the influence of the tool rotational and traverse speed on the resulting material stir zone shape and the heat power generated in friction stir welding of mild steel assemblies. A numerical and experimental approach is adopted in this study. Material visco-plastic properties are primarily established experimentally and are then applied to a computational fluid dynamics model through user-defined material flow stress constitutive laws. The model was further validated through a series of thermocouple and macrograph measurements and later on used to fulfil the aims of this work. This study identifies that the total heat generated for different welding parameters follows a non-linear variation with radial and angular tool position. These results provide a platform for the accurate definition of heat flux inputs and thermal strains to global thermo-elasto-plastic models, replacing more simplified linear specifications currently used in the literature.
General practitioners’ perceptions of the barriers and solutions to good-quality palliative care in dementia
Authors: Carter Gillian , van der Steen Jenny T , Galway Karen , Brazil Kevin
Published: April 2015

The general practitioner (GP) is in a pivotal position to initiate and adapt care for their patients living with dementia. This study aimed to elicit GPs’ perceptions of the potential barriers and solutions to the provision of good-quality palliative care in dementia in their practices. A postal survey of GPs across Northern Ireland was conducted with open-ended items soliciting for barriers in their practices and possible solutions; 40.6% (138/340) were returned completed. Barriers to palliative care in dementia were perceived to be a dementia knowledge deficit for healthcare staff and the public, a resource shortfall within the GP practice and community, poor team coordination alongside inappropriate dementia care provision, and disagreements from and within families. These findings have significant implications for educators and clinicians as enhanced dementia education and training were highlighted as a strong agenda for GPs with the suggestions of dementia awareness programmes for the public.
A feasibility study of translating “Living Well with Dementia” groups into a Primary Care Improving Access to Psychological Therapy service (innovative practice)
Authors: Cheston Richard , Howells Liz
Published: April 2015

This paper describes the use of the “Living Well with Dementia” or LivDem model of group support for people affected by dementia within a Primary Care setting. Five people affected by dementia and their carers joined a 10-week group, although one man withdrew before the start due to illness. Joint sessions were held on the first and the final meetings, with separate parallel group sessions for people affected by dementia and their carers for the remaining eight sessions. One person affected by dementia and their carer withdrew due to illness before the end of the sessions. A self-report measure of Quality of Life suggested improvements for two of the three people affected by dementia who completed all of the sessions. The proxy ratings of carers indicated improvements for all three participants. Qualitative interviews were carried out with participants and carers to assess their experience of the group. Although both people affected by dementia and their carers found the LivDem intervention helpful, concerns remain about the continued need for support by a Dementia specialist.
From gay liberation to marriage equality: A political lesson to be learnt
Authors: Croce Mariano
Published: April 2015

This article deals with the issue of resignification to advance a hypothesis on the way in which social practices are transformed with recourse to the language of institutions. It first discusses the transition from gay liberation to same-sex marriage equality by exploring the trajectory of homosexuals’ rights claims. The article continues by providing a theoretical interpretation of what brought this shift about, that is, what the author calls a movement ‘from the street to the court’: in both civil law and common law jurisdictions, legal means are increasingly being used by individuals and groups to make their claims audible to political institutions and to society at large. Then, an analysis is offered of the shape that social struggles take when socio-political claims are articulated with recourse to the legal language. The conclusion is that reliance on the law as a device to achieve political goals and construct same-sex group identity risks producing but a feeble resignification of the conventional heterosexual matrix. In light of that, a more effective way to defy this matrix is to create awareness of what is gained and what gets lost in becoming legally visible.
Reactive nitrogen species in cellular signaling
Authors: Adams Levi , Franco Maria C , Estevez Alvaro G
Published: April 2015

The transduction of cellular signals occurs through the modification of target molecules. Most of these modifications are transitory, thus the signal transduction pathways can be tightly regulated. Reactive nitrogen species are a group of compounds with different properties and reactivity. Some reactive nitrogen species are highly reactive and their interaction with macromolecules can lead to permanent modifications, which suggested they were lacking the specificity needed to participate in cell signaling events. However, the perception of reactive nitrogen species as oxidizers of macromolecules leading to general oxidative damage has recently evolved. The concept of redox signaling is now well established for a number of reactive oxygen and nitrogen species. In this context, the post-translational modifications introduced by reactive nitrogen species can be very specific and are active participants in signal transduction pathways. This review addresses the role of these oxidative modifications in the regulation of cell signaling events.
The non-canonical role of vascular endothelial growth factor-C axis in cancer progression
Authors: Wang Chu-An , Tsai Shaw-Jenq
Published: April 2015

It has been shown in many clinical studies that the level of vascular endothelial growth factor-C (VEGF-C) positively correlates with lymph node metastasis. Nevertheless, beyond the canonical role of VEGF-C in stimulating lymphangiogenesis and thus promoting lymph node/distant metastasis, emerging evidence indicates that expression of VEGF-C contributes to various aspects of carcinogenicity via autocrine regulation. The newly identified functions of VEGF-C include but are not limited to proliferation, migration, invasion, and chemo-resistance. Besides tumor cell autocrine regulation, VEGF-C can also modulate the immune system such that tumor cells more easily escape immune surveillance. Therefore, understanding the functional roles and regulatory mechanisms related to the VEGF-C axis may lead to alternative strategies for cancer treatment. This mini-review will focus on summarizing recent discoveries regarding the unconventional functions of VEGF-C in cancer progression.
Murder Incorporated
Authors: Ferrucci Patrick
Published: April 2015

Research shows that market orientation affects news content. However, very little research examines how market orientation affects the coverage of a particular story. This is the first to examine news content concerning the same story covered by two different organizations: a strongly market-oriented legacy outlet and a weakly market-oriented digitally native news nonprofit. This study employs textual analysis to examine how the New Haven Register and the New Haven Independent electronically covered the Annie Le murder and investigation. While both organizations covered the same story and concentrated on the same aspects of the story, the results appear very different. The Register highlighted the more salacious aspects and focused on speculation and scoops, while the Independent focused more on why it happened and what it meant to readers. The results of this study are analyzed through the lens of gatekeeping theory.
Mechanical Loading of Cartilage Explants with Compression and Sliding Motion Modulates Gene Expression of Lubricin and Catabolic Enzymes
Authors: Schätti Oliver R. , Marková Michala , Torzilli Peter A. , Gallo Luigi M.
Published: April 2015

Objective

Translation of the contact zone in articulating joints is an important component of joint kinematics, yet rarely investigated in a biological context. This study was designed to investigate how sliding contact areas affect cartilage mechanobiology. We hypothesized that higher sliding speeds would lead to increased extracellular matrix mechanical stress and the expression of catabolic genes.

Design

A cylindrical Teflon indenter was used to apply 50 or 100 N normal forces at 10, 40, or 70 mm/s sliding speed. Mechanical parameters were correlated with gene expressions using a multiple linear regression model.

Results

In both loading groups there was no significant effect of sliding speed on any of the mechanical parameters (strain, stress, modulus, tangential force). However, an increase in vertical force (from 50 to 100 N) led to a significant increase in extracellular matrix strain and stress. For 100 N, significant correlations between gene expression and mechanical parameters were found for TIMP-3 (r2 = 0.89), ADAMTS-5 (r2 = 0.73), and lubricin (r2 = 0.73).

Conclusions

The sliding speeds applied do not have an effect on the mechanical response of the cartilage, this could be explained by a partial attainment of the “elastic limit” at and above a sliding speed of 10 mm/s. Nevertheless, we still found a relationship between sliding speed and gene expression when the tissue was loaded with 100 N normal force. Thus despite the absence of speed-dependent mechanical changes (strain, stress, modulus, tangential force), the sliding speed had an influence on gene expression.
Antiproliferative and Apoptotic Effects of Shemamruthaa, a Herbal Preparation, in 7,12-Dimethylbenz(a)Anthracene-Induced Breast Cancer Rats
Authors: Purushothaman Ayyakkannu , Nandhakumar Elumalai , Shanthi Palanivelu , Sachidanandam Thiruvaiyaru Panchanatham
Published: April 2015

A herbal preparation, Shemamruthaa (SM), was formulated to investigate the molecular mechanism by which it exhibits anticancer effects in mammary carcinoma bearing rats. Female Sprague-Dawley rats were used for the study, and mammary carcinoma was induced by administration of 7,12-dimethylbenz( a)anthracene, intragastrically. After 3 months of induction period, the rats were treated with SM (400 mg/kg body weight) for 14 days. Our study shows that SM-treated mammary carcinoma rats showed regression in tumor volume with concomitant increase in p53, Bax, caspase-3, and caspase-9 mRNA and protein levels compared with mammary carcinoma–induced rats. Proliferating cell nuclear antigen and anti-apoptotic Bcl-2 were markedly increased in mammary carcinoma–induced rats, whereas the SM treatment significantly decreased the expression of these proteins. The expression pattern of apoptotic signaling molecules analyzed in the present study signifies the therapeutic efficacy of SM against breast cancer.
The Sources of Self-Efficacy
Authors: Hendricks Karin S.
Published: April 2015

Music teachers can empower students with control over their own music ability development by helping them foster positive self-efficacy beliefs. This article reviews general education and music research concerning Bandura’s theoretical four sources of self-efficacy (enactive mastery experience, vicarious experience, verbal/social persuasion, and physiological and affective states), in order to guide music teachers in determining effective methods and approaches to help students develop a sense of music self-efficacy and subsequent music achievement. A brief summary of each self-efficacy source category is provided, along with a discussion of the means whereby self-efficacy perceptions can be developed within both general education and music learning environments. Each of these four sections reviews research and simultaneously provides corresponding practical suggestions for educators.
Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor–expressing T cells
Authors: Lynn Rachel C. , Poussin Mathilde , Kalota Anna , Feng Yang , Low Philip S. , Dimitrov Dimiter S. , Powell Daniel J.
Published: April 2015

Key Points

Human FRβ-specific CAR T cells target AML in vitro and in vivo without toxicity against healthy bone marrow HSCs. Combination with ATRA-mediated receptor upregulation may augment FRβ-directed CAR therapy of AML.
Noninvasive monitoring of diffuse large B-cell lymphoma by immunoglobulin high-throughput sequencing
Authors: Kurtz David M. , Green Michael R. , Bratman Scott V. , Scherer Florian , Liu Chih Long , Kunder Christian A. , Takahashi Kazuhiro , Glover Cynthia , Keane Colm , Kihira Shingo , Visser Brendan , Callahan Jason , Kong Katherine A. , Faham Malek , Corbelli Karen S. , Miklos David , Advani Ranjana H. , Levy Ronald , Hicks Rodney J. , Hertzberg Mark , Ohgami Robert S. , Gandhi Maher K. , Diehn Maximilian , Alizadeh Ash A.
Published: April 2015

Key Points

DLBCL can be detected in the blood by immunoglobulin high-throughput sequencing (Ig-HTS) with high specificity. Although DLBCL can be detected in leukocytes or plasma by Ig-HTS, plasma has greater sensitivity and more accurately reflects disease.
Addressing challenges of training a new generation of clinician‐innovators through an interdisciplinary medical technology design program: Bench‐to‐Bedside
Authors: Loftus Patrick D , Elder Craig T , D’Ambrosio Troy , Langell John T
Published: April 2015

Graduate medical education has traditionally focused on training future physicians to be outstanding clinicians with basic and clinical science research skills. This focus has resulted in substantial knowledge gains, but a modest return on investment based on direct improvements in clinical care. In today's shifting healthcare landscape, a number of important challenges must be overcome to not only improve the delivery of healthcare, but to prepare future physicians to think outside the box, focus on and create healthcare innovations, and navigate the complex legal, business and regulatory hurdles of bringing innovation to the bedside. We created an interdisciplinary and experiential medical technology design competition to address these challenges and train medical students interested in moving new and innovative clinical solutions to the forefront of medicine. Medical students were partnered with business, law, design and engineering students to form interdisciplinary teams focused on developing solutions to unmet clinical needs. Over the course of six months teams were provided access to clinical and industry mentors, $500 prototyping funds, development facilities, and non‐mandatory didactic lectures in ideation, design, intellectual property, FDA regulatory requirements, prototyping, market analysis, business plan development and capital acquisition. After four years of implementation, the program has supported 396 participants, seen the development of 91 novel medical devices, and launched the formation of 24 new companies. From our perspective, medical education programs that develop innovation training programs and shift incentives from purely traditional basic and clinical science research to also include high‐risk innovation will see increased student engagement in improving healthcare delivery and an increase in the quality and quantity of innovative solutions to medical problems being brought to market.
Localized SCF and IGF-1 secretion enhances erythropoiesis in the spleen of murine embryos
Authors: Tan Keai Sinn , Inoue Tomoko , Kulkeaw Kasem , Tanaka Yuka , Lai Mei I , Sugiyama Daisuke
Published: April 2015

Fetal spleen is a major hematopoietic site prior to initiation of bone marrow hematopoiesis. Morphologic analysis suggested erythropoietic activity in fetal spleen, but it remained unclear how erythropoiesis was regulated. To address this question, we performed flow cytometric analysis and observed that the number of spleen erythroid cells increased 18.6-fold from 16.5 to 19.5 days post-coitum (dpc). Among erythropoietic cytokines, SCF and IGF-1 were primarily expressed in hematopoietic, endothelial and mesenchymal-like fetal spleen cells. Cultures treated with SCF and/or IGF-1R inhibitors showed significantly decreased CD45−c-Kit−CD71+/−Ter119+ erythroid cells and downregulated Gata1, Klf1 and β-major globin expression. Administration of these inhibitors to pregnant mice significantly decreased the number of CD45−c-Kit−CD71+/−Ter119+ cells and downregulated β-major globin gene expression in embryos derived from these mice. We conclude that fetal spleen is a major erythropoietic site where endothelial and mesenchymal-like cells primarily accelerate erythropoietic activity through SCF and IGF-1 secretion.
Mutant human torsinA, responsible for early-onset dystonia, dominantly suppresses GTPCH expression, dopamine levels and locomotion inDrosophila melanogaster
Authors: Wakabayashi-Ito Noriko , Ajjuri Rami R. , Henderson Benjamin W. , Doherty Olugbenga M. , Breakefield Xandra O. , O'Donnell Janis M. , Ito Naoto
Published: April 2015

Dystonia represents the third most common movement disorder in humans with over 20 genetic loci identified. TOR1A (DYT1), the gene responsible for the most common primary hereditary dystonia, encodes torsinA, an AAA ATPase family protein. Most cases of DYT1 dystonia are caused by a 3 bp (ΔGAG) deletion that results in the loss of a glutamic acid residue (ΔE302/303) in the carboxyl terminal region of torsinA. This torsinAΔE mutant protein has been speculated to act in a dominant-negative manner to decrease activity of wild type torsinA. Drosophila melanogaster has a single torsin-related gene, dtorsin. Null mutants of dtorsin exhibited locomotion defects in third instar larvae. Levels of dopamine and GTP cyclohydrolase (GTPCH) proteins were severely reduced in dtorsin-null brains. Further, the locomotion defect was rescued by the expression of human torsinA or feeding with dopamine.

Here, we demonstrate that human torsinAΔE dominantly inhibited locomotion in larvae and adults when expressed in neurons using a pan-neuronal promoter Elav. Dopamine and tetrahydrobiopterin (BH4) levels were significantly reduced in larval brains and the expression level of GTPCH protein was severely impaired in adult and larval brains. When human torsinA and torsinAΔE were co-expressed in neurons in dtorsin-null larvae and adults, the locomotion rates and the expression levels of GTPCH protein were severely reduced. These results support the hypothesis that torsinAΔE inhibits wild type torsinA activity. Similarly, neuronal expression of a Drosophila DtorsinΔE equivalent mutation dominantly inhibited larval locomotion and GTPCH protein expression. These results indicate that both torsinAΔE and DtorsinΔE act in a dominant-negative manner. We also demonstrate that Dtorsin regulates GTPCH expression at the post-transcriptional level. This Drosophila model of DYT1 dystonia provides an important tool for studying the differences in the molecular function between the wild type and the mutant torsin proteins.
PKA and cAMP/CNG Channels Independently Regulate the Cholinergic Ca2+-Response ofDrosophilaMushroom Body Neurons
Authors: Pavot Pierre , Carbognin Elena , Martin Jean-René
Published: April 2015

The mushroom bodies (MBs), one of the main structures in the adult insect brain, play a critical role in olfactory learning and memory. Though historical genes such asdunceandrutabaga, which regulate the level of cAMP, were identified more than 30 years ago, theirin vivoeffects on cellular and physiological mechanisms and particularly on the Ca2+-responses still remain largely unknown. In this work, performed inDrosophila, we took advantage ofin vivobioluminescence imaging, which allowed real-time monitoring of the entire MBs (both the calyx/cell-bodies and the lobes) simultaneously. We imaged neuronal Ca2+-activity continuously, over a long time period, and characterized the nicotine-evoked Ca2+-response. Using both genetics and pharmacological approaches to interfere with different components of the cAMP signaling pathway, we first show that the Ca2+-response is proportional to the levels of cAMP. Second, we reveal that an acute change in cAMP levels is sufficient to trigger a Ca2+-response. Third, genetic manipulation of protein kinase A (PKA), a direct effector of cAMP, suggests that cAMP also has PKA-independent effects through the cyclic nucleotide-gated Ca2+-channel (CNG). Finally, the disruption of calmodulin, one of the main regulators of therutabagaadenylate cyclase (AC), yields different effects in the calyx/cell-bodies and in the lobes, suggesting a differential and regionalized regulation of AC. Our results provide insights into the complex Ca2+-response in the MBs, leading to the conclusion that cAMP modulates the Ca2+-responses through both PKA-dependent and -independent mechanisms, the latter through CNG-channels.
Inferring causal metabolic signals that regulate the dynamic TORC1‐dependent transcriptome
Authors: Oliveira Ana Paula , Dimopoulos Sotiris , Busetto Alberto Giovanni , Christen Stefan , Dechant Reinhard , Falter Laura , Haghir Chehreghani Morteza , Jozefczuk Szymon , Ludwig Christina , Rudroff Florian , Schulz Juliane Caroline , González Asier , Soulard Alexandre , Stracka Daniele , Aebersold Ruedi , Buhmann Joachim M , Hall Michael N , Peter Matthias , Sauer Uwe , Stelling Jörg
Published: April 2015

Cells react to nutritional cues in changing environments via the integrated action of signaling, transcriptional, and metabolic networks. Mechanistic insight into signaling processes is often complicated because ubiquitous feedback loops obscure causal relationships. Consequently, the endogenous inputs of many nutrient signaling pathways remain unknown. Recent advances for system‐wide experimental data generation have facilitated the quantification of signaling systems, but the integration of multi‐level dynamic data remains challenging. Here, we co‐designed dynamic experiments and a probabilistic, model‐based method to infer causal relationships between metabolism, signaling, and gene regulation. We analyzed the dynamic regulation of nitrogen metabolism by the target of rapamycin complex 1 (TORC1) pathway in budding yeast. Dynamic transcriptomic, proteomic, and metabolomic measurements along shifts in nitrogen quality yielded a consistent dataset that demonstrated extensive re‐wiring of cellular networks during adaptation. Our inference method identified putative downstream targets of TORC1 and putative metabolic inputs of TORC1, including the hypothesized glutamine signal. The work provides a basis for further mechanistic studies of nitrogen metabolism and a general computational framework to study cellular processes.
Differential genetic interactions of yeast stress response MAPK pathways
Authors: Martin Humberto , Shales Michael , Fernandez‐Piñar Pablo , Wei Ping , Molina Maria , Fiedler Dorothea , Shokat Kevan M , Beltrao Pedro , Lim Wendell , Krogan Nevan J
Published: April 2015

Genetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large‐scale genetic interaction analysis in Saccharomyces cerevisiae involving approximately 49 × 1,200 double mutants in the presence of five different stress conditions, including osmotic, oxidative and cell wall‐altering stresses. This resulted in the generation of a differential E‐MAP (or dE‐MAP) comprising over 250,000 measurements of conditional interactions. We found an extensive number of conditional genetic interactions that recapitulate known stress‐specific functional associations. Furthermore, we have also uncovered previously unrecognized roles involving the phosphatase regulator Bud14, the histone methylation complex COMPASS and membrane trafficking complexes in modulating the cell wall integrity pathway. Finally, the osmotic stress differential genetic interactions showed enrichment for genes coding for proteins with conditional changes in phosphorylation but not for genes with conditional changes in gene expression. This suggests that conditional genetic interactions are a powerful tool to dissect the functional importance of the different response mechanisms of the cell.
A Phase Ib Study of Safety and Pharmacokinetics of Ramucirumab in Combination With Paclitaxel in Patients With Advanced Gastric Adenocarcinomas
Authors: Ueda Shinya , Satoh Taroh , Gotoh Masahiro , Gao Ling , Doi Toshihiko
Published: April 2015

Lessons Learned

The pharmacokinetic results of this phase Ib study of ramucirumab combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastro-esophageal junction adenocarcinoma are in line with previous ramucirumab studies. This combination at the doses and schedule given did not result in any dose-limiting toxicities and appeared to be safe and well tolerated.

Background.

This phase Ib study evaluated the tolerability and pharmacokinetics of ramucirumab, an anti-VEGFR-2 antibody, combined with paclitaxel as second-line therapy in Japanese patients with metastatic gastric or gastroesophageal junction adenocarcinoma after first-line therapy with fluoropyrimidines and/or platinum.

Methods.

Patients received ramucirumab 8 mg/kg on days 1 and 15 and paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Safety analyses included all patients (n = 6).

Results.

No dose-limiting toxicities occurred in the first cycle. All patients experienced ≥1 treatment-emergent adverse event (TEAE); 5 patients experienced grade ≥3 TEAEs. There were two deaths caused by disease progression. The best overall responses were stable disease (n = 5) and partial response (n = 1). Patients received ramucirumab and paclitaxel for a median of 12.5 weeks (range: 11.4–42.7 weeks) and 12.2 weeks (range: 11.0–41.0 weeks), respectively. Following a single dose of ramucirumab IV infusion 8 mg/kg, clearance was ∼0.017 L/hour, half-life (t1/2) was 138 to 225 hours, and steady-state volume of distribution (Vss) was ∼3 L.

Conclusion.

The ramucirumab/paclitaxel combination appears to be well-tolerated in Japanese patients with advanced gastric adenocarcinomas. These results are in line with previous ramucirumab pharmacokinetic studies as anticipated.
Balancing control for grid-scale battery energy storage system
Authors: Ooi Chia Ai , Rogers Daniel , Jenkins Nick
Published: April 2015

Lithium (Li)-ion cells are becoming increasingly attractive for use in grid-scale battery energy storage systems (BESSs). A key problem with BESSs is the potential for poor utilisation of mismatched cells and reliability issues resulting from the use of large series strings of cells. This paper investigates the close integration of a full-bridge modular multi-level converter and a large number of lithium-ion cells interfacing with an AC electrical grid. The cells are organised in a hierarchical structure consisting of modules, sub-banks, banks and phases. The control strategy includes five levels of balancing: balancing of cells within a module, balancing of modules within a sub-bank, sub-banks within banks, banks within phases and balancing between phases. The system is validated in simulation for a 380 kWh BESS using 2835 lithium-ion cells. Charge balancing is demonstrated for mismatched cells by varying the parameters such as ampere-hour capacity, internal resistance and initial state of charge. A ‘peak sharing’ concept is implemented so that alternative modules assume a portion of the load when certain modules are not capable of meeting the demand. This work is intended to address the challenges of eventual scaling towards a 100 MWh + BESS, which may be composed of 100 000 individual cells.
Deconstructing the “Power and Control Motive”: Moving Beyond a Unidimensional View of Power in Domestic Violence Theory
Authors: Wagers Shelly M.
Published: April 2015

Despite the increased social recognition, law and policy changes within the criminal justice system, and the widespread use of court mandated batterer intervention programs (BIPs) domestic violence continues to be a persistent problem. The lack of significant decline in incidence rates along with a growing body of empirical evidence that indicates BIPs are, at best, only moderately effective raises serious concern. Effective policies and programs should be based on empirically tested theory. The assertion “the batterer’s motive is power and control” has become fundamental to many of the currently used BIPs and accepted mainstream theoretical explanations regarding domestic violence. However, the domestic violence literature has not yet advanced any specific conceptualizations of power, it has not produced a theoretical model of power that articulates why or how power specifically acts as a motive for a batterer, nor has it empirically tested this fundamental assertion. The main goal of this article is to take a step toward addressing this gap and advance our current understanding of an individual’s sense of power and control as a motive for using violence against an intimate partner. Specifically, it will review the pertinent literature regarding power and domestic violence, propose a new theoretical construct calledinternal power, and discuss internal power’s application to understanding a batterer’s “power motive.”
Working Systemically With the Legacies of Interpersonal Violence: A Case Study of Couples Therapy
Authors: Vetere Arlene
Published: April 2015

This article describes our attachment narrative approach to systemic couples therapy in which we help couples repair their relationship in the aftermath once the physical violence has stopped. Using a case study example from therapeutic practice, this article outlines the complex legacies of interpersonal violence for couple relationships, such as unresolved trauma responses and losses, lingering fears, shame and humiliation, responsibility for safety and harm, forgiveness, apology and reconciliation, the meaning of love, and commitment and hope for the future. Helping couples stop the violence is often the first part of the therapy (Vetere, 2011). If a couple choose to stay together, they need support to confront these complex legacies and the impact on their development and that of their children, as part of a process of healing.