Miracle-dz/UniFAR-FTUs huggingface dataset:
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors

γ-secretase inhibitors (GSIs) can block NOTCH receptor signaling in vitro and therefore offer an attractive targeted therapy for tumors dependent on deregulated NOTCH activity. To clarify the basis for GSI resistance in T cell acute lymphoblastic leukemia (T-ALL), we studied T-ALL cell lines with constitutive expression of the NOTCH intracellular domain (NICD), but that lacked C-terminal truncating mutations in NOTCH1. Each of the seven cell lines examined and 7 of 81 (8.6%) primary T-ALL samples harbored either a mutation or homozygous deletion of the gene FBW7, a ubiquitin ligase implicated in NICD turnover. Indeed, we show that FBW7 mutants cannot bind to the NICD and define the phosphodegron region of the NICD required for FBW7 binding. Although the mutant forms of FBW7 were still able to bind to MYC, they do not target it for degradation, suggesting that stabilization of both NICD and its principle downstream target, MYC, may contribute to transformation in leukemias with FBW7 mutations. In addition, we show that all seven leukemic cell lines with FBW7 mutations were resistant to the MRK-003 GSI. Most of these resistant lines also failed to down-regulate the mRNA levels of the NOTCH targets MYC and DELTEX1 after treatment with MRK-003, implying that residual NOTCH signaling in T-ALLs with FBW7 mutations contributes to GSI resistance.
Risk factors and management of white spot lesions in orthodontics

The formation of white spot lesions or enamel demineralization around fixed orthodontic attachments is a common complication during and following fixed orthodontic treatment, which mars the result of a successfully completed case. This article is a contemporary review of the risk factors, preventive methods and fate of these orthodontics scars. The importance of excellent oral hygiene practice during fixed orthodontic treatment must be explained. Preventive programs must be emphasized to all orthodontic patients. Suggestions are offered in the literature for ways to prevent this condition from manifesting itself.
Modeling and computational framework for the specification and simulation of large-scale spiking neural networks

MODELING AND COMPUTATIONAL FRAMEWORK FOR THE SPECIFICATION AND SIMULATION OF LARGE-SCALE SPIKING NEURAL NETWORKS David J. Herzfeld, B.S. Marquette University, 2011 Recurrently connected neural networks, in which synaptic connections between neurons can form directed cycles, have been used extensively in the literature to describe various neurophysiological phenomena, such as coordinate transformations during sensorimotor integration. Due to the directed cycles that can exist in recurrent networks, there is no well-known way to a priori specify synaptic weights to elicit neuron spiking responses to stimuli based on neurophysiology. Using a common mean field assumption, that synaptic inputs are uncorrelated for sufficiently large populations of neurons, we show that the connection topology and a neuron’s response characteristics can be decoupled. This assumption allows specification of neuron steady-state responses independent of the connection topology. Specification of neuron responses necessitates the creation of a novel computational framework which allows modeling of large populations of connected spiking neurons. We describe the implementation of a spike-based computational framework, designed to take advantage of high performance computing architectures when available. We show that performance of the computational framework is improved using multiple message passing processes for large populations of neurons, resulting in a worst-case linear relationship between the number of neurons and the time required to complete a simulation. Using the computational framework and the ability to specify neuron response characteristics independent of synaptic weights, we systematically investigate the effects of Hebbian-style learning on the hemodynamic response. Changes in the magnitude of the hemodynamic responses of neural populations are assessed using a forward model that relates population synaptic currents to the blood oxygen level dependant (BOLD) response via local field potentials. We show that the magnitude of the hemodynamic response is not a accurate indicator of underlying spiking activity for all network topologies. Instead, we note that large changes in the aggregate response of the population may occur with a decrease in the overall magnitude of the BOLD signal. We hypothesize that the BOLD magnitude changed due to fluctuations in the balance of excitatory and inhibitory inputs in neural subpopulations. These results have important implications for mean-field models, suggesting that the underlying excitatory/inhibitory neural dynamics within a population may need to be incorporated to accurately predict BOLD signals.
How marketers can use celebrities to sell more effectively

The first part of this paper summarises the key points about the use of celebrities in advertising, sets this particular creative technique in context and demonstrates how significant its return on investment can be. In the second part the paper goes on to report a more detailed analysis of the ‘celebrity’ case histories among the winners in the IPA Effectiveness Awards, and how practitioners have applied celebrity use to brands to make exceptional impacts on profitability.
Variogram based Robust Extraction of Process Variation Model

Aggressive device scaling has made it imperative to account for process variations in the design flow. A robust model of process variations is an essential requirement for any meaningful variation aware design analysis and optimization. Unfortunately the previous approaches on extracting spatial correlation function assume ergodicity and isotropy while estimating the inter-die(global) component of variation and spatial correlation function, respectively. We find that making such simplifying assumptions may result in significant estimation error. In this work to address these issues, we propose an alternative approach to extract spatial variation models based on the theory of spatial statistics. The proposed approach uses the concept of variogram function that represents how parameters can covary as a function of spatial distance. The variogram function provides us with a representation that is independent of the global component of variation. This allows us to directly estimate the within die component of variations and thus circumvents the need for making ergodicity assumption. We further show that using two dimensional variogram functions allows us to model geometrically anisotropic process variation data. Additionally, for extracting process variation models in the presence of significant measurement noise, we employ weighted least squares regression technique, which is known to be statistically more robust technique than the previously used ordinary least square technique. Our experimental results on extracting the process variation model model from a Monte-Carlo generated data-set corrupted with significant random noise validates the robustness of the proposed approach.
Serological memory and long-term protection to novel H1N1 influenza virus after skin vaccination.

BACKGROUND A major goal in influenza vaccine development is induction of serological memory and cellular responses to confer long-term protection and limit virus spread after infection. Here, we investigate induction of long-lived immunity against the 2009 H1N1 virus after skin vaccination. METHODS BALB/c mice received a single dose of 5 μg inactivated A/California/04/09 virus via coated metal microneedles (MN) applied to skin or via subcutaneous injection. RESULTS MN or subcutaneous vaccination elicited similar serum IgG and hemagglutination inhibition titers and 100% protection against lethal viral challenge 6 weeks after vaccination. Six months after vaccination, the subcutaneous group exhibited a 60% decrease in functional antibody titers and extensive lung inflammation after challenge with 10 × LD(50) of homologous virus. In contrast, the MN group maintained high functional antibody titers and IFN-γ levels, inhibition of viral replication, and no signs of lung inflammation after challenge. MN vaccination conferred complete protection against lethal challenge, whereas subcutaneous vaccination induced only partial protection. These findings were further supported by high numbers of bone marrow plasma cells and spleen antibody-secreting cells detected in the MN group. CONCLUSIONS A single skin vaccination with MN induced potent long-lived immunity and improved protection against the 2009 H1N1 influenza virus, compared with subcutaneous injection.
The microbiome‐gut‐brain axis: from bowel to behavior

The ability of gut microbiota to communicate with the brain and thus modulate behavior is emerging as an exciting concept in health and disease. The enteric microbiota interacts with the host to form essential relationships that govern homeostasis. Despite the unique enteric bacterial fingerprint of each individual, there appears to be a certain balance that confers health benefits. It is, therefore, reasonable to note that a decrease in the desirable gastrointestinal bacteria will lead to deterioration in gastrointestinal, neuroendocrine or immune relationships and ultimately disease. Therefore, studies focusing on the impact of enteric microbiota on the host and in particular on the central nervous system are essential to our understanding of the influence of this system. Recent studies published in this Journal demonstrate that germ‐free mice display alterations in stress‐responsivity, central neurochemistry and behavior indicative of a reduction in anxiety in comparison to conventional mice. Such data offer the enticing proposition that specific modulation of the enteric microbiota may be a useful strategy for stress‐related disorders and for modulating the co‐morbid aspects of gastrointestinal disorders such as irritable bowel syndrome and inflammatory bowel disease.
Mechanisms of Amygdala Modulation of Hippocampal Plasticity

Basolateral amygdala (BLA) activation by emotional arousal modulates memory-related processes in the hippocampus. We have shown (Akirav and Richter-Levin, 1999b) that activating the BLA before perforant path (PP) tetanization has a biphasic effect on hippocampal plasticity; priming the BLA immediately before PP tetanization results in the enhancement of dentate gyrus (DG) long-term potentiation (LTP) (an “emotional tag”), whereas stimulation in a spaced interval results in the suppression of DG-LTP. Here, we aimed to elucidate the mechanisms underlying BLA modulation of DG-LTP and specifically to examine whether the stress hormones norepinephrine (NE) and corticosterone (CORT) are main mediators of the BLA biphasic effects. We found that the BLA affects hippocampal plasticity in a complex manner; BLA priming enhanced DG-LTP, and both NE and CORT mediated this effect. Furthermore, we found that ipsilateral BLA spaced activation (2 hr before PP tetanization) suppressed DG-LTP and that this suppressive effect was also mediated by NE and CORT. Priming the contralateral BLA enhanced DG-LTP similarly to the ipsilateral enhancement, but neither NE nor CORT mediated this effect. The spaced activation of the contralateral BLA did not suppress DG-LTP. Taken together, these results suggest that differential mechanisms underlie the ipsilateral and contralateral BLA effects on hippocampal plasticity. Hence, the BLA modulates hippocampal memory processes, presumably via the mediation of the stress hormones NE and CORT, to establish a diverse memory of the experience. Possibly, at the onset of an emotional event the stress hormones permissively mediate plasticity. However, their prolonged presence in the system may suppress the cognitive response to stress.
Governance in Dark Times: Practical Philosophy for Public Service

AcknowledgementsIntroduction PART I: Thinking, Reason, and Truth: Philosophy for Public Service 1. Rethinking Reason after September 11 2. Public Administration and the Question of Torture 3. Thinking, Judging, and Public Life PART II: Two Models of Governance 4. There's No Place Like Homeland: Security in Dark Times 5. The Social Reality of Public Space 6. Governance from Ground Up PART III: Philosophy for Practice 7. Pragmatism in Public Service 8. Public Service Ethics in Dark Times Index
Multi-Objective Multiagent Credit Assignment in NSGA-II Using Difference Evaluations

Determining the contribution of an agent to a system-level objective function (credit assignment) is a key area of research in cooperative multiagent systems. Multi-objective optimization is a growing area of research, though mostly focused on single agent settings. Many real-world problems are multiagent and multi-objective, (e.g., air traffic management, scheduling observations across multiple exploration robots) yet there is little work on their intersection. In this work, we leverage recent advances in single-objective multiagent learning to address multi-objective domains. We focus on the impact of difference evaluation functions (which extracts an agent's contribution to the team objective) on the Non-dominated Sorting Genetic Algorithm-II (NSGA-II), a state-of-the-art multi-objective evolutionary algorithm. We derive multiple methods for incorporating difference evaluations into the NSGA-II framework, and test each in a multiagent rover exploration domain, which is a good surrogate for a wide variety of distributed scheduling and resource gathering problems. We show that how and where difference evaluations are incorporated in the NSGA-II algorithm is critical, and can either provide significant benefits or destroy system performance, depending on how it is used. Median performance of the correctly used difference evaluations dominates best-case performance of NSGA-II in a multiagent multi-objective problem.
A super low power MICS band receiver front-end down converter on 65 nm CMOS

This paper presents a super low power MICS band receiver front-end down converter on 65 nm CMOS for implantable biomedical devices. This down converter, including a LNA and a quadrature mixer, only consumes 500 µA DC current under 1 V supply. With a small LO swing of 300 mV, it provides a voltage conversion gain of 35 dB and a noise figure of 7.4 dB, while a −20 dBm IIP3 is obtained. In order to achieve super low power, current-reuse structure is adopted and all transistors are operated in deep sub-threshold region. Circuits level issues and techniques are also discussed.
Comparative antioxidant activity of cultivated and wild Vaccinium species investigated by EPR, human neutrophil burst and COMET assay.

OBJECTIVES The Vaccinium (V.) spp. berries are considered a source of antioxidants, mainly belonging to polyphenols, specifically flavonoids and anthocyanins. Wild genotypes generally contain more antioxidants than cultivated counterparts. So, seven different antioxidants assays on extracts from cultivated and wild Vaccinium berries were performed, to evaluate their difference in terms of bioactivity on oxidative protection and minimum dosage to have a significant action. MATERIALS AND METHODS Four cell-free antioxidant assays (ABTS radical scavenging and electronic paramagnetic resonance using Fremy's salt, superoxide anion and hydroxyl radical), and three assays on human cells (two luminol amplified chemiluminescence, LACL, one on DNA damage, COMET) were used to measure the effects of cultivated blueberry (V. corymbosum) and wild bilberry (V. myrtillus) on the differently induced oxidative stress. Concentrations vs activity patterns were obtained by successive dilutions of extracts in order to identify both EC50 and minimum significant activity (MSA). RESULTS All the assays (except for the hydroxyl radical scavenging) showed a good relationship mainly with anthocyanin and polyphenol content and the significant greater activity of wild Vaccinium extracts. In fact, LACL data gave an EC50 of 11.8 and an MSA of 5.2 g were calculated as fresh weight dosage in cultivated berries, compared with lower doses in wild berries, EC50 of 5.7 g and MSA of 3.4 g. CONCLUSIONS Wild Vaccinium extracts averaged 3.04 and 2.40 fold more activity than cultivated extracts by EC50 and MSA, respectively. COMET assay confirmed the stronger action on DNA protection in wild samples.
Quantitative ultrasound imaging of the uterus for improved embryo implantation: Preliminary study

Enhanced by the modern trend in postponing conception, infertility problems touch nowadays an increasing number of women. Many couples are therefore referred for in vitro fertilization procedures. Despite representing the most advanced option, in vitro fertilization still counts for a low success rate of about 30%. There is evidence that uterine movement may play an important role influencing the procedure outcome. Until now, no objective means of measuring uterine movement is available. Therefore, in this work we present the first method for quantitative analysis of the uterine movement. Given its widespread availability and relatively low cost, ultrasound imaging is employed for the analysis. In particular, a speckle-tracking algorithm has been implemented that is based on block matching by normalized cross correlation. Wiener deconvolution is used to regularize the image resolution prior to speckle tracking. The method feasibility was tested for its ability to distinguish between active and non-active phase of a natural menstrual cycle in eight women. Two pairs of sites were manually defined on the uterine muscle and automatically tracked over time. Variance and mean frequency of the strain and distance between these sites were the features extracted and evaluated for classification. The results are promising, showing significant class separation by Student t-test (p <; 0.05), and sensitivity and specificity both equal to 75% for the strain variance and distance mean frequency. Extensive validation is however required to confirm this result, also involving the evaluation of additional features. Once fully validated, this method will be tested for quantitative evaluation of uterine movement in the context of in vitro fertilization.
Study on meaningful and verified Thresholds for minimizing the consequences of human-robot collisions

In order to define meaningful limit values for human-robot collisions, we have come to the conclusion that only comprehensive collision tests with live test subjects will successfully lead to verified limit values. A literature survey about current approaches for limiting the consequences of hazardous contacts between humans and moving machines (including robots) showed that limit values are often specified without an appropriate injury severity or without considering the variety of the human body. In this article, we show why the injury onset is appropriate to limit the consequences of human-robot collisions, and how this onset can be quantified through collision tests with live test subjects. With our work we would like to present a promising method that can remedy the current lack of consensus regarding an appropriate injury severity and verified limit values.
Calcification intensity in planktonic Foraminifera reflects ambient conditions irrespective of environmental stress

Planktonic Foraminifera are important marine calcifiers, and the ongoing change in the oceanic carbon system makes it essential to understand the influence of environmental factors on the biomineralization of their shells. The amount of calcite deposited by planktonic Foraminifera during calcification has been hypothesized to reflect a range of environmental factors. However, it has never been assessed whether their calcification only passively responds to the conditions of the ambient seawater or whether it reflects changes in resource allocation due to physiological stress. To disentangle these two end-member scenarios, an experiment is required where the two processes are separated. A natural analogue to such an experiment occurred during the deposition of the Mediterranean sapropels, where large changes in surface water composition and stratification at the onset of the sapropel deposition were decoupled from local extinctions of planktonic Foraminifera species. We took advantage of this natural experiment and investigated the reaction of calcification intensity, expressed as mean area density (MAD), of four species of planktonic Foraminifera to changing conditions during the onset of Sapropel S5 (126–121 ka) in a sediment core from the Levantine Basin. We observed a significant relationship between MAD and surface water properties, as reflected by stable isotopes in the calcite of Foraminifera shells, but we failed to observe any reaction of calcification intensity on ecological stress during times of decreasing abundance culminating in local extinction. The reaction of calcification intensity to surface water perturbation at the onset of the sapropel was observed only in surface-dwelling species, but all species calcified more strongly prior to the sapropel deposition and less strongly within the sapropel than at similar conditions during the present-day. These results indicate that the high-salinity environment of the glacial Mediterranean Sea prior to sapropel deposition induced a~more intense calcification, whereas the freshwater injection to the surface waters associated with sapropel deposition inhibited calcification. The results are robust to changes in carbonate preservation and collectively imply that changes in normalized shell weight in planktonic Foraminifera should reflect mainly abiotic forcing.
ToF‐SIMS analysis of a polymer microarray composed of poly(meth)acrylates with C6 derivative pendant groups

Surface analysis plays a key role in understanding the function of materials, particularly in biological environments. Time‐of‐flight secondary ion mass spectrometry (ToF‐SIMS) provides highly surface sensitive chemical information that can readily be acquired over large areas and has, thus, become an important surface analysis tool. However, the information‐rich nature of ToF‐SIMS complicates the interpretation and comparison of spectra, particularly in cases where multicomponent samples are being assessed. In this study, a method is presented to assess the chemical variance across 16 poly(meth)acrylates. Materials are selected to contain C6 pendant groups, and ten replicates of each are printed as a polymer microarray. SIMS spectra are acquired for each material with the most intense and unique ions assessed for each material to identify the predominant and distinctive fragmentation pathways within the materials studied. Differentiating acrylate/methacrylate pairs is readily achieved using secondary ions derived from both the polymer backbone and pendant groups. Principal component analysis (PCA) is performed on the SIMS spectra of the 16 polymers, whereby the resulting principal components are able to distinguish phenyl from benzyl groups, mono‐functional from multi‐functional monomers and acrylates from methacrylates. The principal components are applied to copolymer series to assess the predictive capabilities of the PCA. Beyond being able to predict the copolymer ratio, in some cases, the SIMS analysis is able to provide insight into the molecular sequence of a copolymer. The insight gained in this study will be beneficial for developing structure–function relationships based upon ToF‐SIMS data of polymer libraries. © 2016 The Authors Surface and Interface Analysis Published by John Wiley & Sons Ltd.