bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive change-point mixed models applied to data on outpatient tetracycline use in Europe
Authors: Minalu Girma , Aerts Marc , Coenen Samuel , Versporten Ann , Muller Arno , Adriaenssens Niels , Beutels Philippe , Molenberghs Geert , Goossens Herman , Hens Niel
Published: June 2013

In this paper, we propose a change-point mixed model to assess the change in the trend of outpatient antibiotic use in a Bayesian framework, where the change-points are unknown parameters of the model. Model selection using DIC indicates that the data supports the model with a country-specific change-point. The location of the change-points may be related to points in time where public health strategies aiming at increasing the awareness of the public to a more rational use of antibiotics or targeting to reduce overconsumption of antibiotics were initiated.
Evaluation of visual analytics environments: The road to the Visual Analytics Science and Technology challenge evaluation methodology
Authors: Scholtz Jean , Plaisant Catherine , Whiting Mark , Grinstein Georges
Published: June 2013

Evaluation of software can take many forms ranging from algorithm correctness and performance to evaluations that focus on the value to the end user. This article presents a discussion of the development of an evaluation methodology for visual analytics environments. The Visual Analytics Science and Technology Challenge was created as a community evaluation resource. This resource is available to researchers and developers of visual analytics environments and allows them to test out their designs and visualization and compare the results with the solution and the entries prepared by others. Sharing results allows the community to learn from each other and to hopefully advance more quickly. In this article, we discuss the original challenge and its evolution during the 7 years since its inception. While the Visual Analytics Science and Technology Challenge is the focus of this article, there are lessons for many involved in setting up a community evaluation program, including the need to understand the purpose of the evaluation, decide upon the right metrics to use, and the appropriate implementation of those metrics including datasets and evaluators. For ongoing evaluations, it is also necessary to track the evolution and to ensure that the evaluation methodologies are keeping pace with the science being evaluated. The discussions on the Visual Analytics Science and Technology Challenge on these topics should be pertinent to many interested in community evaluations.
CBM Progress Monitoring in Foreign Language Learning for Secondary School Students
Authors: Chung Siuman , Espin Christine A.
Published: June 2013

The reliability and validity of three curriculum-based measures as indicators of learning English as a foreign language were examined. Participants were 260 Dutch students in Grades 8 and 9 who were receiving English-language instruction. Predictor measures were maze-selection, Dutch-to-English word translation, and English-to-Dutch word translation. Criterion variables were years of English instruction, school level, course grades, and scores on a standardized reading test. Different scoring procedures and time frames were compared. Alternate-form reliabilities ranged from .44 to .88. Significant differences in maze scores were found between school levels but not between years of English-language instruction. Correlations between predictor and criterion variables ranged from .19 to .79. A regression analysis revealed that a combination of maze and English-to-Dutch translation predicted English course grades better than a single measure alone.
Curriculum-Based Measurement in Science Learning
Authors: Espin Christine A. , Busch Todd W. , Lembke Erica S. , Hampton David D. , Seo Kyounghee , Zukowski Beth A.
Published: June 2013

The technical adequacy of curriculum-based measures in the form of short and simple vocabulary-matching probes to predict students’ performance and progress in science at the secondary level was investigated. Participants were 198 seventh-grade students from 10 science classrooms. Curriculum-based measurements (CBM) were 5-min vocabulary-matching probes administered once weekly over a period of 14 weeks. Criterion measures were knowledge pre- and posttests, the science subtest of the Iowa Test of Basic Skills (ITBS), and course grades. Alternate-form reliability coefficients ranged from r = .64 to .84. Coefficients increased over time and by combining scores across probes. Correlations between scores on the vocabulary-matching and criterion measures ranged from r = .55 to .76. The estimated mean group growth rate on the vocabulary-matching measure was .63 correct matches per week, which was significantly different from zero. The measures produced significant interindividual differences in growth rates, and growth on the measures was related to performance on the ITBS, course grades, and pre–post gains on the knowledge test. Results provide initial support for the technical adequacy of vocabulary-matching as an indicator of performance and progress in science.
Virtual Reality–Augmented Neurorehabilitation Improves Motor Function and Reduces Neuropathic Pain in Patients With Incomplete Spinal Cord Injury
Authors: Villiger Michael , Bohli Dominik , Kiper Daniel , Pyk Pawel , Spillmann Jeremy , Meilick Bruno , Curt Armin , Hepp-Reymond Marie-Claude , Hotz-Boendermaker Sabina , Eng Kynan
Published: June 2013

Background. Neurorehabilitation interventions to improve lower limb function and neuropathic pain have had limited success in people with chronic, incomplete spinal cord injury (iSCI). Objective. We hypothesized that intense virtual reality (VR)–augmented training of observed and executed leg movements would improve limb function and neuropathic pain. Methods. Patients used a VR system with a first-person view of virtual lower limbs, controlled via movement sensors fitted to the patient’s own shoes. Four tasks were used to deliver intensive training of individual muscles (tibialis anterior, quadriceps, leg ad-/abductors). The tasks engaged motivation through feedback of task success. Fourteen chronic iSCI patients were treated over 4 weeks in 16 to 20 sessions of 45 minutes. Outcome measures were 10 Meter Walking Test, Berg Balance Scale, Lower Extremity Motor Score, Spinal Cord Independence Measure, Locomotion and Neuropathic Pain Scale (NPS), obtained at the start and at 4 to 6 weeks before intervention. Results. In addition to positive changes reported by the patients (Patients’ Global Impression of Change), measures of walking capacity, balance, and strength revealed improvements in lower limb function. Intensity and unpleasantness of neuropathic pain in half of the affected participants were reduced on the NPS test. Overall findings remained stable 12 to 16 weeks after termination of the training. Conclusions. In a pretest/posttest, uncontrolled design, VR-augmented training was associated with improvements in motor function and neuropathic pain in persons with chronic iSCI, several of which reached the level of a minimal clinically important change. A controlled trial is needed to compare this intervention to active training alone or in combination.
Restoring Tactile Awareness Through the Rubber Hand Illusion in Cervical Spinal Cord Injury
Authors: Lenggenhager Bigna , Scivoletto Giorgio , Molinari Marco , Pazzaglia Mariella
Published: June 2013

Background. Bodily sensations are an important component of corporeal awareness. Spinal cord injury can leave affected body parts insentient and unmoving, leading to specific disturbances in the mental representation of one’s own body and the sense of self. Objective. Here, we explored how illusions induced by multisensory stimulation influence immediate sensory signals and tactile awareness in patients with spinal cord injuries. Methods. The rubber hand illusion paradigm was applied to 2 patients with chronic and complete spinal cord injury of the sixth cervical spine, with severe somatosensory impairments in 2 of 5 fingers. Results. Both patients experienced a strong illusion of ownership of the rubber hand during synchronous, but not asynchronous, stroking. They also, spontaneously reported basic tactile sensations in their previously numb fingers. Tactile awareness from seeing the rubber hand was enhanced by progressively increasing the stimulation duration. Conclusions. Multisensory illusions directly and specifically modulate the reemergence of sensory memories and enhance tactile sensation, despite (or as a result of) prior deafferentation. When sensory inputs are lost, and are later illusorily regained, the brain updates a coherent body image even several years after the body has become permanently unable to feel. This particular example of neural plasticity represents a significant opportunity to strengthen the sense of the self and the feelings of embodiment in patients with spinal cord injury.
A random graph generation algorithm for the analysis of social networks
Authors: Morris James F. , O’Neal Jerome W. , Deckro Richard F.
Published: June 2013

Social network analysis (SNA) is a rapidly growing field with numerous applications in industry and government. However, the field still lacks means to generate random social networks with certain desired properties, thus inhibiting their ability to test new SNA algorithms and metrics. Available random graph generation algorithms suffer from tendencies to generate disconnected graphs and sometimes induce undesirable network properties. In this paper, we present an algorithm, the prescribed node degree, connected graph (PNDCG) algorithm, designed to generate weakly connected social networks. Extensions to the PNDCG algorithm allow one to create random graphs that control the clustering coefficient and degree correlation within the generated networks. Empirical test results demonstrate the capability of the PNDCG algorithm to produce networks with the desired properties.
Maximum Fractal Dimension of Cerebral Seizure Remains Constant Through the Course of Electroconvulsive Therapy
Authors: Rakesh Gopalkumar , Abhishekh Hulegar A. , Thirthalli Jagadisha , Phutane Vivek H. , Muralidharan Kesavan , Candade Vittal S. , Gangadhar Bangalore N.
Published: June 2013

Electroconvulsive therapy (ECT), in which electrical current is used to induce seizures, is an effective treatment in psychiatry. Different methods of analyzing the electroencephalogram (EEG) changes during ECT have been studied for predicting clinical outcome. Analysis of the fractal dimension (FD) is one such method. Mid-seizure and post-seizure FD has been shown to correlate with antidepressant effect. In this study, we examined whether the highest fractal dimension achieved during each ECT session changed over the course of 6 ECTs. The sample for this study came from a randomized controlled trial, comparing the efficacy of bifrontal and bitemporal electrode placements in schizophrenia. EEG was recorded using bilateral frontal pole leads during all ECT sessions. In 40 of the 114 randomized patients, we could obtain artifact-free EEGs for the first 6 ECT sessions. FD was calculated using standardized algorithms. For each session, the average of 5 highest FDs was calculated. The change in this value over a course of 6 ECTs was analyzed using repeated-measures analysis of variance. The average highest FD remained virtually unchanged across the 6 ECT sessions. Means (standard deviations) average maximum FDs over the 6 sessions were 1.57 (0.075), 1.57 (0.064), 1.56 (0.064), 1.57 (0.062), 1.55 (0.07), and 1.56 (0.067); occasion effect, F = 0.5, P = .75. Group effect ( F = 0.01, P = .92) and group × occasion interaction effect ( F = 1.88, P = .1) were not significant, suggesting no influence of electrode placement on maximum FD. Seizure duration, however, showed significant decline over the course of ECT. Maximum FD of ECT-induced EEG seizure remains fairly constant over frontal poles across the first 6 ECT sessions, which is true irrespective of ECT electrode placements.
Modeling Human–Automation Function Allocation
Authors: Pritchett Amy R. , Kim So Young , Feigh Karen M.
Published: June 2013

The collective taskwork of a team spans the functions required to achieve work goals. Within this context, function allocation is the design decision in which taskwork functions are assigned to all agents in a team, both human and automated. In addition, the allocation of taskwork functions then creates the need for additional teamwork functions to coordinate between agents. In this paper, we identify important requirements for function allocation within teams of human and automated agents. Of note, many important attributes may be observed only within the detailed dynamics of simulation or actual operations, particularly when a function allocation requires tightly coupled interactions. Building on the preceding companion paper’s conceptual review of the requirements of effective function allocation, in this paper we develop a modeling framework that increases the number of aspects of function allocation that can be examined simultaneously through both static analysis and dynamic computational simulations. The taskwork and teamwork of a modern air transport flight deck with a range of function allocations is used as an example throughout, highlighting the range of phenomenon these models can describe. A follow-on companion paper discusses specific metrics of function allocation that can be derived both from such models and from observations in high-fidelity human-in-the-loop simulations or real operations.
Neonatal palliative care in action: moving beyond the rhetoric and influencing policy
Authors: Kain Victoria J. , Wilkinson Dominic J.
Published: June 2013

The purpose of this paper is to move beyond the rhetoric of espousing the importance and timeliness of palliative care for the neonatal population, and to explore how what is known can influence health and social policy. A recent Commonwealth of Australia Senate enquiry into palliative care raised concerns about the current lack of specialist perinatal and neonatal palliative care in Australia. Inherent to the difficulties of moving a neonatal palliative care model forwards are the identified barriers to palliative care practice in the clinical setting, which have been well defined. To inform policy, it is imperative that health professionals in the neonatal discipline are knowledgeable about legislative priorities and the public concerns regarding palliative care for neonates. This paper argues that there are several priorities for moving this model of care forwards, which include legislation that supports access to care such as development and funding support of perinatal hospices, continuity of care, caregiver support, research and in particular education for the health care professionals caring for dying babies and their families. To achieve this, we need to set national research priorities that reflect a truly collaborative partnership. It is time to move beyond the rhetoric.
Mitochondrial damage-associated molecular patterns activate γδ T-cells
Authors: Schwacha Martin G , Rani Meenakshi , Zhang Qiong , Nunez-Cantu Oliver , Cap Andre P
Published: June 2013

Gamma delta T-cells have been shown to be important in the early immunoinflammatory response to injury, which can be independent of infection. This sterile inflammatory response is believed to be, in part, associated with danger-associated molecular patterns (DAMPs). Mitochondrial DAMPs (MTDs) have been shown to be important in trauma-induced neutrophil activation, but it is unknown whether MTDs activate other innate immune cells, such as γδ T-cells. To study this, splenic CD3+ γδ T-cells were isolated from αβ T-cell-deficient C57BL/6 mice and mitochondria isolated from wild type mouse livers. MTDs were isolated from mitochondria by sonication and centrifugation. Gamma delta T-cells were incubated with various concentrations of MTDs (0–500 µg/ml) for 24 h. T-cells were phenotyped for TLR expression by flow cytometry and the supernatants assayed for cytokine and growth factor content. MTDs caused a dose-dependent increase in TLR2 and TLR4 expression by γδ T-cells. Both the percentage of cells positive for TLRs and the degree of expression increased. MTDs also induced the production of IL-1β, IL-6, IL-10, RANTES, fibroblast growth factor-basic and vascular endothelial growth factor by γδ T-cells. These findings support the concept that the MTDs released after tissue/cellular injury are capable of activating γδ T-cells, thus initiating sterile inflammation, as well as subsequent healing processes.
microRNAs as potential regulators of myeloid-derived suppressor cell expansion
Authors: El-Gazzar Mohamed
Published: June 2013

Proper development and activation of cells of the myeloid lineage are critical for supporting innate immunity. This myelopoiesis is orchestrated by interdependent interactions between cytokine receptors, transcription factors and, as recently described, microRNAs (miRNAs). miRNAs contribute to normal and dysregulated myelopoiesis. Alterations in myelopoiesis underlie myeloid-derived suppressor cell (MDSC) expansion, a poorly understood heterogeneous population of immature and suppressive myeloid cells that expand in nearly all diseases where inflammation exists. MDSCs associated with inflammation often have immunosuppressive properties, but molecular mechanisms responsible for MDSC expansion are unclear. Emerging data implicate miRNAs in MDSC expansion. This review focuses on miRNAs that contribute to myeloid lineage differentiation and maturation under physiological conditions, and introduces the concept that altered miRNA expression my underlie expansion and accumulation of MDSCs. We divide our miRNAs into those with potential to promote MDSC expansion and two with known direct links to MDSC expansion, miR-223 and miR-494.
Evidence for the efficacy of enzalutamide in postchemotherapy metastatic castrate-resistant prostate cancer
Authors: Saad Fred
Published: June 2013

The treatment of metastatic castrate-resistant prostate cancer (mCRPC) has evolved rapidly with the recent approval of a number of treatments and agents, including docetaxel, sipuleucel T, abiraterone, cabazitaxel, and enzalutamide. Enzalutamide (previously MDV-3100) is a novel oral androgen receptor inhibitor that targets multiple steps in the androgen receptor signaling pathway. The randomized phase III AFFIRM study demonstrated significant improvements in a number of efficacy endpoints, including the primary endpoint of overall survival and secondary endpoints of progression-free survival, and time to prostate-specific antigen progression in patients with progressive mCRPC who had received prior treatment with docetaxel. Enzalutamide was well tolerated and there were comparable incidences of grade 3 or greater adverse events reported for the enzalutamide and placebo control arms in AFFIRM. Unlike some other treatments for mCRPC, enzalutamide does not require administration with steroids. The ongoing randomized phase III PREVAIL trial will investigate the efficacy and safety of enzalutamide in chemotherapy-naïve patients with mCRPC. Additional trials are investigating the use of enzalutamide in a number of disease settings.
Antinomies of Pluralism: Modulating Conceptions of Politics and Agency in India
Authors: Hegde Sasheej
Published: June 2013

Conceptions of pluralism and identity exert a powerful influence both on the process of politics and on the study of politics. They inform a wide range of ideals and methods and, more importantly, shape influential definitions of politics and political subjectivity and agency across national spaces. The article is an attempt to formulate an approach to pluralism that allows us to enrich accounts of political subjectivity and agency at the same time that it forces us to rethink our relation to political theory and political sociology. The context in question is India—indeed certain broad transitions in the social and historical landscape of modern Indian political thought and practice—which serves to complicate extant versions of the contending models of politics. The argument is certainly not for a new, extra-historical (or post-cultural) foundation for agency and for political claims, but rather to set up a heuristic for contending with the antinomies of pluralism as they articulate in the space of politics and agency in India. The ground traversed is an attempt to meet the constraints as much of historical sociology as of normative theory (or theorising).
Engaging the ‘Long 1980s’: On the Emergence of the Mission Mode of State-fabrication in India
Authors: Routray Sailen
Published: June 2013

This article argues that in India, the key period for locating morphings of the state on the ground is the period between 1977 and 1991, a period it calls ‘the long 1980s’. It then identifies a key aspect of such changes as the emergence of the mission mode of state-fabrication in which work of the government increasingly happens through the various missions as opposed to the traditional way of delivering governmental programmes through the line departments. This has involved a shift towards ‘quotidian logistics’ of state-fabrication as opposed to the ‘symbolic logistics’ operational in the immediate aftermath of decolonisation involving the growing importance of ‘social’ technologies of statecraft. Fabricating the state in the mission mode has seen the governmental apparatus reaching deep into hitherto marginal rural areas and population groups through missions. The arguments offered in the article provide an alternative to the accounts of the processes of change in the governmental system offered by the ‘passive revolution thesis’.
Reordering of Postcolonial Sri Pāda Temple in Sri Lanka: Buddhism, State and Nationalism
Authors: De Silva Premakumara
Published: June 2013

Historically speaking, Sri Pāda temple is a remarkable place of worship for people belonging to all four major religions in Sri Lanka where they share one particular object of worship—the sacred footprint. However, this pilgrimage site, which was previously considered a multi-religious site, or site of plural worship, has now been transformed, constructed or rather reordered into an ethnic majoritarian Buddhist space, concurrent with the rise of Sinhala Buddhist nationalism in post-colonial Sri Lanka. This article explores the most important historical conjuncture where such Buddhicisation began to view or in other words ordering of Sri Pāda temple came to centrally visible in post-colonial Sri Lanka.
Intelligence Failure or Design?: Karkare, Kamte and the Campaign for 26/11 Truth
Authors: Muralidharan Sukumar
Published: June 2013

For an event that traumatised the nation and created a serious crisis of citizen loyalty to the Indian State, the November 2008 terrorist attacks in Mumbai have not been put through a rigorous process of public accountability. Information available in the public domain has frequently been inconsistent and the official responses, often reflexive and formulaic, have evaded serious scrutiny because they have conformed to a predetermined template on terrorism. Though the pressures enforcing conformity have been acute, a number of independent analyses have emerged which point to the need for greater public engagement with the process of unravelling the truth behind the sixty hour siege of Mumbai. Dispassionate examination of all available evidence indicates that terrorism in the current millennium is a more complex phenomenon than ordinarily supposed, with a vastly variegated cast of actors.
Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer
Authors: Zhang Hua , Maric Irena , DiPrima Michael J. , Khan Javed , Orentas Rimas J. , Kaplan Rosandra N. , Mackall Crystal L.
Published: June 2013

Key Points

Myeloid cells in subjects with cancer contain fibrocytes, a cell subset previously implicated in chronic inflammation. Fibrocytes in cancer patients are immunosuppressive and may contribute to immune escape.
cAMP-induced secretion of endothelial von Willebrand factor is regulated by a phosphorylation/dephosphorylation switch in annexin A2
Authors: Brandherm Ines , Disse Jennifer , Zeuschner Dagmar , Gerke Volker
Published: June 2013

Key Points

A calcineurin-like phosphatase dephosphorylates annexin A2 in the course of cAMP-induced Weibel-Palade body exocytosis. Dephosphorylation at serine 11 of annexin A2 triggers complex formation with S100A10 that is required for von Willebrand factor secretion.
Evolution and divergence of the mammalian SAMD9/SAMD9L gene family
Authors: Lemos de Matos Ana , Liu Jia , McFadden Grant , Esteves Pedro J
Published: June 2013

Background

The physiological functions of the human Sterile Alpha Motif Domain-containing 9 (SAMD9) gene and its chromosomally adjacent paralogue,SAMD9-like (SAMD9L), currently remain unknown. However, the direct links between the deleterious mutations or deletions in these two genes and several human disorders, such as inherited inflammatory calcified tumors and acute myeloid leukemia, suggest their biological importance. SAMD9 and SAMD9L have also recently been shown to play key roles in the innate immune responses to stimuli such as viral infection. We were particularly interested in understanding the mammalian evolutionary history of these two genes. The phylogeny ofSAMD9andSAMD9Lgenes was reconstructed using the Maximum Likelihood method. Furthermore, six different methods were applied to detect SAMD9 and SAMD9L codons under selective pressure: the site-specific model M8 implemented in the codeml program in PAML software and five methods available on the Datamonkey web server, including the Single Likelihood Ancestor Counting method, the Fixed Effect Likelihood method, the Random Effect Likelihood method, the Mixed Effects Model of Evolution method and the Fast Unbiased Bayesian AppRoximation method. Additionally, the house mouse (Mus musculus) genome has lost theSAMD9gene,while keepingSAMD9Lintact, prompting us to investigate whether this loss is a unique event during evolution.

Results

Our evolutionary analyses suggest thatSAMD9andSAMD9Larose through an ancestral gene duplication event after the divergence of Marsupialia from Placentalia. Additionally, selection analyses demonstrated that both genes have been subjected to positive evolutionary selection. The absence of eitherSAMD9orSAMD9Lgenes from some mammalian species supports a partial functional redundancy between the two genes.

Conclusions

To the best of our knowledge, this work is the first study on the evolutionary history of mammalianSAMD9andSAMD9Lgenes. We conclude that evolutionary selective pressure has acted on both of these two genes since their divergence, suggesting their importance in multiple cellular processes, such as the immune responses to viral pathogens.
Inference of synergy/antagonism between anticancer drugs from the pooled analysis of clinical trials
Authors: Kang Wenfeng , DiPaola Robert S , Vazquez Alexei
Published: June 2013

Background

Drug interactions can have a significant impact on the response to combinatorial therapy for anticancer treatment. In some instances these interactions can be anticipated based on pre-clinical models. However, the anticipation of drug interactions in the clinical context is in general a challenging task.

Methods

Here we propose the pooled analysis of clinical trials as a mean to investigate drug interactions in anticancer therapy. To this end we collected 1,163 Phase II clinical trials with response data on over 53,745 subjects.

Results

We provide statistical definitions of drugs resulting in clinical synergy and antagonism and identify drug combinations in each group. We also quantify the possibility of inferring interactions between three or more drugs from parameters characterizing the action of single and two-drugs combinations.

Conclusions

Our analysis provides a statistical methodology to track the performance of drug combinations in anticancer therapy and to quantify drug interactions in the clinical context.
Global profiling of prolactin-modulated transcripts in breast cancer in vivo
Authors: Sato Takahiro , Tran Thai H , Peck Amy R , Liu Chengbao , Ertel Adam , Lin Justin , Neilson Lynn M , Rui Hallgeir
Published: June 2013

Background

Prolactin (PRL) is essential for normal mammary gland development. PRL promotes mammary tumor formation in rodents and elevated serum prolactin is associated with increased risk of estrogen-receptor positive breast cancer in women. On the other hand, PRL may also exert pro-differentiation effects and act to suppress invasive features of established breast cancer. Previously published limited global transcript profiling analyses of prolactin-regulated gene expression in human breast cancer cells have exclusively been performed in vitro. The present study aimed to shed new light on how PRL modulates estrogen receptor (ER)-positive breast cancer through global transcript profiling of a human breast cancer xenograft model in vivo.

Methods

The prolactin-responsive human T47D breast cancer cell line was xenotransplanted into nude mice and global transcript profiling was carried out following treatment with or without human PRL for 48 h. A subset of PRL-modulated transcripts was further validated using qRT-PCR and immunohistochemistry.

Results

The in vivo analyses identified 130 PRL-modulated transcripts, 75 upregulated and 55 downregulated, based on fold change >1.6 and P-value <0.05. From this initial panel of transcripts, a subset of 18 transcripts with established breast cancer-relevance were selected and validated by qRT-PCR. Some but not all of the transcripts were also PRL-modulated in vitro. The selected PRL-modulated transcripts were tested for dependence on Stat5, Jak1 or Jak2 activation, and for co-regulation by 17β-estradiol (E2). The protein encoded by one of the PRL-regulated transcripts, PTHrP, was examined in a panel of 92 human breast cancers and found by in situ quantitative immunofluorescence analysis to be highly positively correlated with nuclear localized and tyrosine phosphorylated Stat5. Gene Ontology analysis revealed that PRL-upregulated genes were enriched in pathways involved in differentiation. Finally, a gene signature based on PRL-upregulated genes was associated with prolonged relapse-free and metastasis-free survival in breast cancer patients.

Conclusions

This global analysis identified and validated a panel of PRL-modulated transcripts in an ER-positive human breast cancer xenotransplant model, which may have value as markers of relapse-free and metastasis-free survival. Gene products identified in the present study may facilitate ongoing deciphering of the pleiotropic effects of PRL on human breast cancer.
Nectin-2 is a potential target for antibody therapy of breast and ovarian cancers
Authors: Oshima Tsutomu , Sato Shuji , Kato Junichi , Ito Yuki , Watanabe Takahiro , Tsuji Isamu , Hori Akira , Kurokawa Tomofumi , Kokubo Toshio
Published: June 2013

Background

Nectin-2 is a Ca2+-independent cell-cell adhesion molecule that is one of the plasma membrane components of adherens junctions. However, little has been reported about the involvement of Nectin-2 in cancer.

Methods

To determine the expression of Nectin-2 in cancer tissues and cancer cell lines, we performed gene expression profile analysis, immunohistochemistry studies, and flow cytometry analysis. We also investigated the potential of this molecule as a target for antibody therapeutics to treat cancers by generating and characterizing an anti-Nectin-2 rabbit polyclonal antibody (poAb) and 256 fully human anti-Nectin-2 monoclonal antibodies (mAbs). In addition, we tested anti-Nectin-2 mAbs in several in vivo tumor growth inhibition models to investigate the primary mechanisms of action of the mAbs.

Results

In the present study, we found that Nectin-2 was over-expressed in clinical breast and ovarian cancer tissues by using gene expression profile analysis and immunohistochemistry studies. Nectin-2 was over-expressed in various cancer cell lines as well. Furthermore, the polyclonal antibody specific to Nectin-2 suppressed the in vitro proliferation of OV-90 ovarian cancer cells, which express endogenous Nectin-2 on the cell surface. The anti-Nectin-2 mAbs we generated were classified into 7 epitope bins. The anti-Nectin-2 mAbs demonstrated antibody-dependent cellular cytotoxicity (ADCC) and epitope bin-dependent features such as the inhibition of Nectin-2-Nectin-2 interaction, Nectin-2-Nectin-3 interaction, and in vitro cancer cell proliferation. A representative anti-Nectin-2 mAb in epitope bin VII, Y-443, showed anti-tumor effects against OV-90 cells and MDA-MB-231 breast cancer cells in mouse therapeutic models, and its main mechanism of action appeared to be ADCC.

Conclusions

We observed the over-expression of Nectin-2 in breast and ovarian cancers and anti-tumor activity of anti-Nectin-2 mAbs via strong ADCC. These findings suggest that Nectin-2 is a potential target for antibody therapy against breast and ovarian cancers.
Development of a screening tool to identify female survivors of gender-based violence in a humanitarian setting: qualitative evidence from research among refugees in Ethiopia
Authors: Wirtz Andrea L , Glass Nancy , Pham Kiemanh , Aberra Amsale , Rubenstein Leonard S , Singh Sonal , Vu Alexander
Published: June 2013

Background

High levels of gender-based violence (GBV) persist among conflict-affected populations and within humanitarian settings and are paralleled by under-reporting and low service utilization. Novel and evidence-based approaches are necessary to change the current state of GBV amongst these populations. We present the findings of qualitative research, which were used to inform the development of a screening tool as one potential strategy to identify and respond to GBV for females in humanitarian settings.

Methods

Qualitative research methods were conducted from January-February 2011 to explore the range of experiences of GBV and barriers to reporting GBV among female refugees. Individual interview participants (n=37) included female refugees (≥15 years), who were survivors of GBV, living in urban or one of three camps settings in Ethiopia, and originating from six conflict countries. Focus group discussion participants (11 groups; 77 participants) included health, protection and community service staff working in the urban or camp settings. Interviews and discussions were conducted in the language of preference, with assistance by interpreters when needed, and transcribed for analysis by grounded-theory technique.

Results

Single and multiple counts of GBV were reported and ranged from psychological and social violence; rape, gang rape, sexual coercion, and other sexual violence; abduction; and physical violence. Domestic violence was predominantly reported to occur when participants were living in the host country. Opportunistic violence, often manifested by rape, occurred during transit when women depended on others to reach their destination. Abduction within the host country, and often across borders, highlighted the constant state of vulnerability of refugees. Barriers to reporting included perceived and experienced stigma in health settings and in the wider community, lack of awareness of services, and inability to protect children while mothers sought services.

Conclusions

Findings demonstrate that GBV persists across the span of the refugee experience, though there is a transition in the range of perpetrators and types of GBV that are experienced. Further, survivors experience significant individual and system barriers to disclosure and service utilization. The findings suggest that routine GBV screening by skilled service providers offers a strategy to confidentially identify and refer survivors to needed services within refugee settings, potentially enabling survivors to overcome existing barriers.
Detection of clade types (clades I and II) within Anopheles funestus sensu stricto by the hydrolysis probe analysis (Taqman assay)
Authors: Choi Kwang Shik , Coetzee Maureen , Koekemoer Lizette L
Published: June 2013

Background

Recent studies presented two clades (clades I and II) within the major malaria vector, Anopheles funestus s.s. on the mitochondrial DNA. We describe a hydrolysis probe analysis (Taqman assay) method for the rapid identification of these two clades.

Findings

A total of 53 An. funestus s.s. from Malawi and Mozambique were tested for detection of clade types using the hydrolysis probe analysis. Results were compared to DNA sequence analysis to verify the accuracy of the probes Taqman assay for this vector species. Analysis using the hydrolysis probe revealed that there were 21 individuals from Malawi and 13 individuals from Mozambique for clade I, and 19 individuals from Mozambique for clade II. The results were consistent with the results of DNA sequences. A field sample from northern Zambia revealed the presence of both clade types.

Conclusion

A diagnostic method using the hydrolysis probe analysis was developed to identify clade types within An. funestus s.s. This assay will be useful for screening clade types of field-collected An. funestus specimens accurately and efficiently in malaria vector research and control studies.
Linking cytoarchitecture to metabolism: sarcolemma-associated plectin affects glucose uptake by destabilizing microtubule networks in mdx myofibers
Authors: Raith Marianne , Valencia Rocio G , Fischer Irmgard , Orthofer Michael , Penninger Josef M , Spuler Simone , Rezniczek Günther A , Wiche Gerhard
Published: June 2013

Background

Duchenne muscular dystrophy (DMD) is one of the most frequent forms of muscular disorders. It is caused by the absence of dystrophin, a core component of the sarcolemma-associated junctional complex that links the cytoskeleton to the extracellular matrix. We showed previously that plectin 1f (P1f), one of the major muscle-expressed isoforms of the cytoskeletal linker protein plectin, accumulates at the sarcolemma of DMD patients as well as ofmdxmice, a widely studied animal model for DMD.

Based on plectin’s dual role as structural protein and scaffolding platform for signaling molecules, we speculated that the dystrophic phenotype observed after loss of dystrophin was caused, at least to some extent, by excess plectin. Thus, we hypothesized that elimination of plectin expression inmdxskeletal muscle, while probably resulting in an overall more severe phenotype, may lead to a partial phenotype rescue. In particular, we wanted to assess whether excess sarcolemmal plectin contributes to the dysregulation of sugar metabolism inmdxmyofibers.

Methods

We generated plectin/dystrophin double deficient (dKO) mice by breedingmdxwith conditional striated muscle-restricted plectin knockout (cKO) mice. The phenotype of these mice was comparatively analyzed with that ofmdx, cKO, and wild-type mice, focusing on structural integrity and dysregulation of glucose metabolism.

Results

We show that the accumulation of plectin at the sarcolemma ofmdxmuscle fibers hardly compensated for their loss of structural integrity. Instead, it led to an additional metabolic deficit by impairing glucose uptake. While dKO mice suffered from an overall more severe form of muscular dystrophy compared tomdxor plectin-deficient mice, sarcolemmal integrity as well as glucose uptake of their myofibers were restored to normal levels upon ablation of plectin. Furthermore, microtubule (MT) networks in intact dKO myofibers, including subsarcolemmal areas, were found to be more robust than those inmdxmice. Finally, myotubes differentiated from P1f-overexpressing myoblasts showed an impairment of glucose transporter 4 translocation and a destabilization of MT networks.

Conclusions

Based on these results we propose that sarcolemma-associated plectin acts as an antagonist of MT network formation in myofibers, thereby hindering vesicle-mediated (MT-dependent) transport of glucose transporter 4. This novel role of plectin throws a bridge between extra-sarcomeric cytoarchitecture and metabolism of muscle fibers. Our study thus provides new insights into pathomechanisms of plectinopathies and muscular dystrophies in general.
Spontaneous processes of reproduction of family-based entrepreneurship: an empirical research on the cognitive nature of the spin-offs
Authors: Del Giudice Manlio , Peruta Maria Rosaria Della , Maggioni Vincenzo
Published: June 2013

Spin-offs refer to the creation of new firms by employees breaking off from existing firms to give birth to companies of their own. However, this phenomenon has not been predominantly observed in the context of family businesses. Employment in the family firm creates an expectation that family members will act in a manner supportive to the family business: when an employee leaves to become an entrepreneur, parent companies also have to consider whether a spin-off could eventually become a competitor. In this view, when a spin-off process occurs, the parent company could ‘gain’ a new stakeholder. Cognitive scripts that enable codified knowledge to be transferred to a spin-off may grant the new firm a substantial advantage over the parent company. Therefore, it is assumed that such a stakeholder serves purposes similar to those of the parent company, however assuming a hostile attitude towards the latter. The plausibility of this hypothesis is subsequently tested through multivariate statistical techniques.
Uncertainty-aware visualization and proximity monitoring in urban excavation: a geospatial augmented reality approach
Authors: Su Xing , Talmaki Sanat , Cai Hubo , Kamat Vineet R
Published: June 2013

Background

This research aims to improve the urban excavation safety by creating an uncertainty-aware, geospatial augmented reality (AR) to visualize and monitor the proximity between invisible utilities and digging implements. Excavation is the single largest cause of utility strikes. Utility strikes could be prevented if the excavator operator were able to “see” buried utilities and excavator movement, and judge the proximity between them in real time. Geospatial augmented reality (AR) is an enabling technology for such knowledge-based excavation. It synergizes the geospatial utility locations and the excavator movement into a real-time, three-dimensional (3D) spatial context accessible to excavator operators. The key to its success is the quality of the utility location data.

Methods

This paper describes a dynamic approach to incorporate positional uncertainties of buried utilities into an uncertainty-aware, geospatial-AR system for real time visualization and proximity analysis. Uncertainties are modeled as probability bands (e.g. spatial bands with certain probabilities of enclosing the “true” location of utilities). Positional uncertainties are derived in real time by referring to its determinant, data lineage, the genesis and processes used to collect and interpret data.

Results

A computational framework, and a generic data model and its XML-format implementation are developed and tested. A method is developed to analyze the proximity in the context of positional uncertainties of both the utilities and the excavator movement.

Conclusions

This newly created approach is expected to contribute to the safety in urban excavation via the integration of Geoinformatics and construction informatics into an uncertainty-aware, geospatial-AR, with real time visualization and analytical capabilities.
The Munc18-1 domain 3a loop is essential for neuroexocytosis but not for syntaxin-1A transport to the plasma membrane
Authors: Martin Sally , Tomatis Vanesa M. , Papadopulos Andreas , Christie Michelle P. , Malintan Nancy T. , Gormal Rachel S. , Sugita Shuzo , Martin Jennifer L. , Collins Brett M. , Meunier Frederic A.
Published: June 2013

Munc18-1 plays a dual role in transporting syntaxin-1A (Sx1a) to the plasma membrane and regulating SNARE-mediated membrane fusion. As impairment of either function leads to a common exocytic defect, assigning specific roles for various Munc18-1 domains has proved difficult. Structural analyses predict that a loop region in Munc18-1 domain 3a could catalyse the conversion of Sx1a from a ‘closed’, fusion-incompetent to an ‘open’, fusion-competent conformation. As this conversion occurs at the plasma membrane, mutations in this loop could potentially separate the chaperone and exocytic functions of Munc18-1. Expression of a Munc18-1 deletion mutant lacking 17 residues of the domain 3a loop (Munc18-1Δ317–333) in PC12 cells deficient in endogenous Munc18 (DKD-PC12 cells) fully rescued transport of Sx1a to the plasma membrane, but not exocytic secretory granule fusion. In vitro binding of Munc18-1Δ317–333 to Sx1a was indistinguishable from that of full-length Munc18-1, consistent with the critical role of the closed conformation in Sx1a transport. However, in DKD-PC12 cells, Munc18-1Δ317–333 binding to Sx1a was greatly reduced compared to that of full-length Munc18-1, suggesting that closed conformation binding contributes little to the overall interaction at the cell surface. Furthermore, we found that Munc18-1Δ317–333 could bind SNARE complexes in vitro, suggesting that additional regulatory factors underpin the exocytic function of Munc18-1 in vivo. Together, these results point to a defined role for Munc18-1 in facilitating exocytosis linked to the loop region of domain 3a that is clearly distinct from its function in Sx1a transport.
Perception and coding of envelopes in weakly electric fishes
Authors: Stamper Sarah A. , Fortune Eric S. , Chacron Maurice J.
Published: June 2013

Natural sensory stimuli have a rich spatiotemporal structure and can often be characterized as a high frequency signal that is independently modulated at lower frequencies. This lower frequency modulation is known as the envelope. Envelopes are commonly found in a variety of sensory signals, such as contrast modulations of visual stimuli and amplitude modulations of auditory stimuli. While psychophysical studies have shown that envelopes can carry information that is essential for perception, how envelope information is processed in the brain is poorly understood. Here we review the behavioral salience and neural mechanisms for the processing of envelopes in the electrosensory system of wave-type gymnotiform weakly electric fishes. These fish can generate envelope signals through movement, interactions of their electric fields in social groups or communication signals. The envelopes that result from the first two behavioral contexts differ in their frequency content, with movement envelopes typically being of lower frequency. Recent behavioral evidence has shown that weakly electric fish respond in robust and stereotypical ways to social envelopes to increase the envelope frequency. Finally, neurophysiological results show how envelopes are processed by peripheral and central electrosensory neurons. Peripheral electrosensory neurons respond to both stimulus and envelope signals. Neurons in the primary hindbrain recipient of these afferents, the electrosensory lateral line lobe (ELL), exhibit heterogeneities in their responses to stimulus and envelope signals. Complete segregation of stimulus and envelope information is achieved in neurons in the target of ELL efferents, the midbrain torus semicircularis (Ts).
Neuromodulation of early electrosensory processing in gymnotiform weakly electric fish
Authors: Márquez Brenda Toscano , Krahe Rüdiger , Chacron Maurice J.
Published: June 2013

Sensory neurons continually adapt their processing properties in response to changes in the sensory environment or the brain's internal state. Neuromodulators are thought to mediate such adaptation through a variety of receptors and their action has been implicated in processes such as attention, learning and memory, aggression, reproductive behaviour and state-dependent mechanisms. Here, we review recent work on neuromodulation of electrosensory processing by acetylcholine and serotonin in the weakly electric fish Apteronotus leptorhynchus. Specifically, our review focuses on how experimental application of these neuromodulators alters excitability and responses to sensory input of pyramidal cells within the hindbrain electrosensory lateral line lobe. We then discuss current hypotheses on the functional roles of these two neuromodulatory pathways in regulating electrosensory processing at the organismal level and the need for identifying the natural behavioural conditions that activate these pathways.