Miracle-dz/UniFAR-FTUs huggingface dataset:
Signaling Interplay between Bone Marrow Adipose Tissue and Multiple Myeloma cells

In the year 2000, Hanahan and Weinberg (1) defined the six Hallmarks of Cancer as: self-sufficiency in growth signals, evasion of apoptosis, insensitivity to antigrowth mechanisms, tissue invasion and metastasis, limitless replicative potential, and sustained angiogenesis. Eleven years later, two new Hallmarks were added to the list (avoiding immune destruction and reprograming energy metabolism) and two new tumor characteristics (tumor-promoting inflammation and genome instability and mutation) (2). In multiple myeloma (MM), a destructive cancer of the plasma cell that grows predominantly in the bone marrow (BM), it is clear that all these hallmarks and characteristics are in play, contributing to tumor initiation, drug resistance, disease progression, and relapse. Bone marrow adipose tissue (BMAT) is a newly recognized contributor to MM oncogenesis and disease progression, potentially affecting MM cell metabolism, immune action, inflammation, and influences on angiogenesis. In this review, we discuss the confirmed and hypothetical contributions of BMAT to MM development and disease progression. BMAT has been understudied due to technical challenges and a previous lack of appreciation for the endocrine function of this tissue. In this review, we define the dynamic, responsive, metabolically active BM adipocyte. We then describe how BMAT influences MM in terms of: lipids/metabolism, hypoxia/angiogenesis, paracrine or endocrine signaling, and bone disease. We then discuss the connection between BMAT and systemic inflammation and potential treatments to inhibit the feedback loops between BM adipocytes and MM cells that support MM progression. We aim for researchers to use this review to guide and help prioritize their experiments to develop better treatments or a cure for cancers, such as MM, that associate with and may depend on BMAT.
Dopamine D2 receptor occupancy and cognition in schizophrenia: analysis of the CATIE data.

INTRODUCTION Antipsychotic drugs exert antipsychotic effects by blocking dopamine D2 receptors in the treatment of schizophrenia. However, effects of D2 receptor blockade on neurocognitive function still remain to be elucidated. The objective of this analysis was to evaluate impacts of estimated dopamine D2 receptor occupancy with antipsychotic drugs on several domains of neurocognitive function in patients with schizophrenia in the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE) trial. METHODS The dataset from the CATIE trial was used in the present analysis. Data were extracted from 410 subjects who were treated with risperidone, olanzapine, or ziprasidone, received assessments for neurocognitive functions (verbal memory, vigilance, processing speed, reasoning, and working memory) and psychopathology, and provided plasma samples for the measurement of plasma antipsychotic concentrations. D2 receptor occupancy levels on the day of neurocognitive assessment were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our recently developed model. A multivariate general linear model was used to examine effects of clinical and demographic characteristics, including estimated D2 occupancy levels, on neurocognitive functions. RESULTS D2 occupancy levels showed significant associations with the vigilance and the summary scores. Neurocognitive functions, including vigilance, were especially impaired in subjects who showed D2 receptor occupancy level of >77%. DISCUSSION These findings suggest a nonlinear relationship between prescribed antipsychotic doses and overall neurocognitive function and vigilance. This study shows that D2 occupancy above approximately 80% not only increases the risk for extrapyramidal side effects as consistently reported in the literature but also increases the risk for cognitive impairment.
The influence of test experience and NK1 receptor antagonists on the performance of NK1R-/- and wild type mice in the 5-Choice Serial Reaction-Time Task

Genetically-altered mice, lacking functional NK1 receptors (NK1R-/-), express abnormal behaviours that are prominent in Attention Deficit Hyperactivity Disorder: namely, inattentiveness and impulsivity (indicated by their greater % omissions and premature responses in the 5-Choice Serial Reaction-Time Task (5-CSRTT) and locomotor hyperactivity. We investigated how behaviour in the 5-CSRTT is affected by repeated testing and whether the abnormalities expressed by NK1R-/- mice are mimicked by treating wild type mice with a NK1R antagonist (L 733060 or RP 67580; 5 or 10 mg/kg). Repeated testing with a variable (VITI) or fixed, prolonged (LITI) intertrial interval reduced % omissions. Premature responses also declined, but only in NK1R-/- mice, in the VITI test. By contrast, perseveration increased in both genotypes. RP 67580 (10 mg/kg) increased the % omissions in both genotypes in the VITI, an action which cannot be attributed to NK1R antagonism. Neither drug affected perseveration. However, for premature responses, the response profile suggested that the low and high doses of RP 67580 (VITI) and L 733060 (LITI) had opposing effects on this behaviour. We infer that the effect of NK1R antagonists in the 5-CSRTT is confounded by animals’ test experience and non-specific drug effects at sites other than NK1R, possibly L-type Ca2+v channels.
Follower Behavior and Organizational Performance: The Impact of Transformational Leaders

This study sheds light on the mediating processes by which transformational leadership influences follower performance and innovation, respectively. We hypothesize that transformational leaders boost follower performance by stimulating organizational citizenship behavior, whereas they enhance follower innovation by triggering controversial discussion of task related issues (debate). On the contrary, we do not expect these mediating effects to hold for the relationship between transactional leadership and follower performance and innovation, respectively. Our hypotheses were confirmed in an empirical study of N = 91 leaders from 91 German companies. Conclusions for leadership research are drawn. Key words: debate, innovation, organizational citizenship behavior, transactional leadership, transformational leadership
Cost of foundation failures due to limited site investigations

One of the greatest causes of foundation failure is due to insufficient knowledge of ground conditions. Uncertainty in ground conditions can also cause significant cost overruns and time delays for both client and contractor. Site investigations aim to reduce the uncertainty of ground conditions by various combinations of field and laboratory testing. However, time and cost constraints, as well as the judgement and experience of the consulting geotechnical engineer, have traditionally governed the scope of such site investigations. Analyses have been undertaken to investigate the performance of various site investigation schemes with respect to the cost of the resulting pad foundation system and the probability of failure. Penalty costs are attributed to foundation designs that experience excessive settlement to enable direct comparisons with foundation designs that conform to the design criteria. Designs resulting from the site investigation data are compared to a benchmark design achieved by employing a 3-dimensional finite element analysis within a trial-and-error process. Many realisations are undertaken for varying soil types in a Monte Carlo analysis by generating 3-dimensional simulated soil profiles using random field theory. The results illustrate a decreasing trend of total foundation cost for an increasing site investigation scope. The results also show that the cost of a foundation, excluding the penalty cost of failure, designed using an increased amount of knowledge regarding the site, does not always result in a less expensive foundation. However, all results suggest that a site investigation scheme with limited testing will result in a more expensive foundation, when the cost of possible foundation failure is included.
Influence of the Sea Surface Temperature in the Indian Ocean on the In-Phase Transition between the South Asian and North Australian Summer Monsoons

In this study we investigate the physical processes underlying maintenance of an in-phase transition between the South Asian summer monsoon (SASM) and the succeeding North Australian summer monsoon (NASM). In particular, our attentions were focused on identification of the roles of sea surface temperature anomaly (SSTA) in the Indian Ocean in contrast to that of the El Niño-Southern Oscillation (ENSO). To realize this goal, we partition the in-phase years into two groups, those being ENSO and non-ENSO groupings, and then we conduct a composite study. For the non-ENSO-year composite, the associated SST changes resemble a dipole structure characterized by a SST warming in the western Indian Ocean and a cooling in the southeastern Indian Ocean in the boreal summer and fall. The warm SSTA, along with a stimulated ascent, expands eastward in the boreal fall and arrives in the eastern Indian Ocean around northern Australia, concurrent with a cold SSTA to its north with a descent. Therefore, a strong ascent in northern Australia associated with the regional Hadley circulation occurring in the Philippine Sea-northern Australia region is responsible for a wet NASM. Our study also identifies the enlarged influence of the SSTA in the Indian Ocean being likely associated with change in the background SST state that occurred around 1976 77 over the Indian Ocean.
Enterovirus 71 VP1 Activates Calmodulin-Dependent Protein Kinase II and Results in the Rearrangement of Vimentin in Human Astrocyte Cells

Enterovirus 71 (EV71) is one of the main causative agents of foot, hand and mouth disease. Its infection usually causes severe central nervous system diseases and complications in infected infants and young children. In the present study, we demonstrated that EV71 infection caused the rearrangement of vimentin in human astrocytoma cells. The rearranged vimentin, together with various EV71 components, formed aggresomes-like structures in the perinuclear region. Electron microscopy and viral RNA labeling indicated that the aggresomes were virus replication sites since most of the EV71 particles and the newly synthesized viral RNA were concentrated here. Further analysis revealed that the vimentin in the virus factories was serine-82 phosphorylated. More importantly, EV71 VP1 protein is responsible for the activation of calmodulin-dependent protein kinase II (CaMK-II) which phosphorylated the N-terminal domain of vimentin on serine 82. Phosphorylation of vimentin and the formation of aggresomes were required for the replication of EV71 since the latter was decreased markedly after phosphorylation was blocked by KN93, a CaMK-II inhibitor. Thus, as one of the consequences of CaMK-II activation, vimentin phosphorylation and rearrangement may support virus replication by playing a structural role for the formation of the replication factories. Collectively, this study identified the replication centers of EV71 in human astrocyte cells. This may help us understand the replication mechanism and pathogenesis of EV71 in human.
Transformation and Self-Identity: Student Narratives in Post-Apartheid South Africa.

Organisational change processes are by nature complex and often highly contested. This is particularly true of the transformation South African institutions of higher education have been going through since the end of the apartheid era. Using a narrative approach, this article presents a multi-faceted range of stories by the University of the Free State (UFS) students who took part in a particular leadership programme designed to make a contribution to institutional, and even, societal change. The plurivocality of the identity work the UFS students’ stories display is based on their ethnic, gender and class diversity. It is the context-sensitive ‘tales of the field’ they tell that might help to understand why the transformation concept as well the various transformation-driven practices in higher education are so ambiguous and contested.
Obatoclax Interacts Synergistically with the Irreversible Proteasome Inhibitor Carfilzomib in GC- and ABC-DLBCL Cells In Vitro and In Vivo

Interactions between the irreversible proteasome inhibitor carfilzomib and the pan-BH3 mimetic obatoclax were examined in germinal center (GC)- and activated B-cell–diffuse large B-cell lymphoma (ABC-DLBCL) cells. Cotreatment with minimally toxic concentrations of carfilzomib (i.e., 2–6 nmol/L) and subtoxic concentrations of obatoclax (0.05–2.0 μmol/L) synergistically increased apoptosis in multiple DLBCL cell lines and increased lethality toward primary human DLBCL but not normal CD34+ cells. Synergistic interactions were associated with sharp increases in caspase-3 activation, PARP cleavage, p-JNK induction, upregulation of Noxa, and AKT dephosphorylation. Combined treatment also diminished carfilzomib-mediated Mcl-1 upregulation whereas immunoprecipitation analysis revealed reduced associations between Bak and Mcl-1/Bcl-xL and Bim and Mcl-1. The carfilzomib/obatoclax regimen triggered translocation, conformational change, and dimerization of Bax and activation of Bak. Genetic interruption of c-jun-NH2-kinase (JNK) and Noxa by short hairpin RNA knockdown, ectopic Mcl-1 expression, or enforced activation of AKT significantly attenuated carfilzomib/obatoclax-mediated apoptosis. Notably, coadministration of carfilzomib/obatoclax sharply increased apoptosis in multiple bortezomib-resistant DLBCL models. Finally, in vivo administration of carfilzomib and obatoclax to mice inoculated with SUDHL4 cells substantially suppressed tumor growth, activated JNK, inactivated AKT, and increased survival compared with the effects of single-agent treatment. Together, these findings argue that a strategy combining carfilzomib and obatoclax warrants attention in DLBCL. Mol Cancer Ther; 11(5); 1122–32. ©2012 AACR.
Children and Young People's Developing Concept of Perceived Value

This thesis examines value perception as part of the decision to purchase, from the perspective of the child consumer. To date no academic research has defined the concept of value perception from a child‟s perspective. On the basis of a two stage qualitative investigation with children aged eight to fourteen years, value for children was found to be an important concept in consumer decisions. Even from the age of eight years, evidence emerged that children were quite „canny‟ in their purchasing. While value was found to be comprised of benefits and costs of purchase for children from this young age, the nature of these factors and the way they contributed to value perception varied considerably as they grew older. Six distinct dimensions emerged from diaries and a series of in-depth interviews with children. The benefits which were identified were functional value, emotional value, social value and curiosity/novelty value while the costs included both price and risk related factors. The way in which the dimensions were considered was found to vary with age, changing from separate consideration of benefits and costs to a more adult like trade-off between the two. The emotional value of products was consistently important for children of all ages, sensory response in particular. Several concepts were found to become increasingly complex. Conceptual understanding of quality emerged as children grew older. Branding was found to be central to children‟s value perceptions despite limited conceptual understanding for very young consumers and the way price was considered changed markedly with age and experience. A conceptual model defining perceived value from a child‟s perspective is detailed and a series of propositions relating important conditions to perceived value are advanced. A discussion of the findings as they relate to the extant literature is provided along with directions for future research, building on the results of this work. Finally, a discussion of the implications of this work for the field of Marketing is presented.
Analysing the Visual Dynamics of Spatial Morphology

Recently there has been a revival of interest in visibility analysis of architectural configurations. The new analyses rely heavily on computing power and statistical analysis, two factors which, according to the postpositivist school of geography, should immediately cause us to be wary. The danger, they would suggest, is in the application of a reductionist formal mathematical description in order to ‘explain’ multilayered sociospatial phenomena. The author presents an attempt to rationalise how we can use visibility analysis to explore architecture in this multilayered context by considering the dynamics that lead to the visual experience. In particular, it is recommended that we assess the visual process of inhabitation, rather than assess the visibility in vacuo. In order to investigate the possibilities and limitations of the methodology, an urban environment is analysed by means of an agent-based model of visual actors within the configuration. The results obtained from the model are compared with actual pedestrian movement and other analytic measurements of the area: the agents correlate well both with human movement patterns and with configurational relationship as analysed by space-syntax methods. The application of both methods in combination improves on the correlation with observed movement of either, which in turn implies that an understanding of both the process of inhabitation and the principles of configuration may play a crucial role in determining the social usage of space.
Virtual Adversarial Training: A Regularization Method for Supervised and Semi-Supervised Learning

We propose a new regularization method based on virtual adversarial loss: a new measure of local smoothness of the conditional label distribution given input. Virtual adversarial loss is defined as the robustness of the conditional label distribution around each input data point against local perturbation. Unlike adversarial training, our method defines the adversarial direction without label information and is hence applicable to semi-supervised learning. Because the directions in which we smooth the model are only “virtually” adversarial, we call our method virtual adversarial training (VAT). The computational cost of VAT is relatively low. For neural networks, the approximated gradient of virtual adversarial loss can be computed with no more than two pairs of forward- and back-propagations. In our experiments, we applied VAT to supervised and semi-supervised learning tasks on multiple benchmark datasets. With a simple enhancement of the algorithm based on the entropy minimization principle, our VAT achieves state-of-the-art performance for semi-supervised learning tasks on SVHN and CIFAR-10.
Explorer Interaction between hedgehog signalling and PAX 6 dosage mediates maintenance and regeneration of the corneal epithelium

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Factors affecting uptake of measles, mumps, and rubella immunisation.

OBJECTIVE--To study factors affecting uptake of measles, mumps, and rubella immunisation. DESIGN--Cohort study using data from computerised child health systems. SETTING--10 health districts in North East Thames and North West Thames regions. SUBJECTS--7841 children born in January to March 1990 and resident in the districts up till the end of October 1991. MAIN OUTCOME MEASURES--Overall uptake of measles, mumps, and rubella immunisation, variation of uptake among groups of children, and odds ratio of being vaccinated against measles, mumps, and rubella. RESULTS--The overall uptake rate of measles, mumps, and rubella immunisation for the study cohort in the 10 districts was 82%. Wide variation was identified among children with different demographic characteristics. Lower uptake was associated with absent or incomplete primary immunisation, including omission of pertussis vaccine. Other factors affecting uptake included the type of resident district, birth order, where registered for immunisation (general practitioner or clinic), and one parent family status. CONCLUSIONS--Many districts have difficulties in meeting the 90% target for measles, mumps, and rubella immunisation, mainly because of the characteristics of their local population. To increase overall coverage, the health service should target families with adverse factors, especially those whose children have missed previous immunisations.
Establishing Scientific Discourse in Classroom Interaction Teacher Students’ Orientation to Mundane Versus Technical Talk in the School Subject Norwegian

ABSTRACT This article reports a case study on classroom interaction in teacher education in Norway. It addresses how teacher students in the school subject Norwegian constitute scientific talk in a student-led discussion. First, the analysis reveals tension in the classroom conversation between mundane talk—that is, where students make claims with reference to their personal epistemic domain—and scientific talk—that is, where students make claims with reference to a shared scientific epistemic domain. Then, the analysis identifies specific interactional resources (reproach, embedded correction, formulation, and recontextualization) that the students use to regulate and bridge the 2 levels of discourse. Finally, the article provides insights into how scientific discourse is collaboratively established through conversational turns and considers how teacher education might use these findings for communication-skill training.