956 resultados para dynamic response optimization


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We describe the use of dynamic combinatorial chemistry (DCC) to identify ligands for the stem-loop structure located at the exon 10-5'-intron junction of Tau pre-mRNA, which is involved in the onset of several tauopathies including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). A series of ligands that combine the small aminoglycoside neamine and heteroaromatic moieties (azaquinolone and two acridines) have been identified by using DCC. These compounds effectively bind the stem-loop RNA target (the concentration required for 50% RNA response (EC(50)): 2-58 μM), as determined by fluorescence titration experiments. Importantly, most of them are able to stabilize both the wild-type and the +3 and +14 mutated sequences associated with the development of FTDP-17 without producing a significant change in the overall structure of the RNA (as analyzed by circular dichroism (CD) spectroscopy), which is a key factor for recognition by the splicing regulatory machinery. A good correlation has been found between the affinity of the ligands for the target and their ability to stabilize the RNA secondary structure.

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The goal of this work is to develop a method to objectively compare the performance of a digital and a screen-film mammography system in terms of image quality. The method takes into account the dynamic range of the image detector, the detection of high and low contrast structures, the visualisation of the images and the observer response. A test object, designed to represent a compressed breast, was constructed from various tissue equivalent materials ranging from purely adipose to purely glandular composition. Different areas within the test object permitted the evaluation of low and high contrast detection, spatial resolution and image noise. All the images (digital and conventional) were captured using a CCD camera to include the visualisation process in the image quality assessment. A mathematical model observer (non-prewhitening matched filter), that calculates the detectability of high and low contrast structures using spatial resolution, noise and contrast, was used to compare the two technologies. Our results show that for a given patient dose, the detection of high and low contrast structures is significantly better for the digital system than for the conventional screen-film system studied. The method of using a test object with a large tissue composition range combined with a camera to compare conventional and digital imaging modalities can be applied to other radiological imaging techniques. In particular it could be used to optimise the process of radiographic reading of soft copy images.

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Using rice (Oryza sativa) as a model crop species, we performed an in-depth temporal transcriptome analysis, covering the early and late stages of Pi deprivation as well as Pi recovery in roots and shoots, using next-generation sequencing. Analyses of 126 paired-end RNA sequencing libraries, spanning nine time points, provided a comprehensive overview of the dynamic responses of rice to Pi stress. Differentially expressed genes were grouped into eight sets based on their responses to Pi starvation and recovery, enabling the complex signaling pathways involved in Pi homeostasis to be untangled. A reference annotation-based transcript assembly was also generated, identifying 438 unannotated loci that were differentially expressed under Pi starvation. Several genes also showed induction of unannotated splice isoforms under Pi starvation. Among these, PHOSPHATE2 (PHO2), a key regulator of Pi homeostasis, displayed a Pi starvation-induced isoform, which was associated with increased translation activity. In addition, microRNA (miRNA) expression profiles after long-term Pi starvation in roots and shoots were assessed, identifying 20 miRNA families that were not previously associated with Pi starvation, such as miR6250. In this article, we present a comprehensive spatio-temporal transcriptome analysis of plant responses to Pi stress, revealing a large number of potential key regulators of Pi homeostasis in plants.

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BACKGROUND: In a simulation based on a pharmacokinetic model we demonstrated that increasing the erythropoiesis stimulating agents (ESAs) half-life or shortening their administration interval decreases hemoglobin variability. The benefit of reducing the administration interval was however lessened by the variability induced by more frequent dosage adjustments. The purpose of this study was to analyze the reticulocyte and hemoglobin kinetics and variability under different ESAs and administration intervals in a collective of chronic hemodialysis patients. METHODS: The study was designed as an open-label, randomized, four-period cross-over investigation, including 30 patients under chronic hemodialysis at the regional hospital of Locarno (Switzerland) in February 2010 and lasting 2 years. Four subcutaneous treatment strategies (C.E.R.A. every 4 weeks Q4W and every 2 weeks Q2W, Darbepoetin alfa Q4W and Q2W) were compared with each other. The mean square successive difference of hemoglobin, reticulocyte count and ESAs dose was used to quantify variability. We distinguished a short- and a long-term variability based respectively on the weekly and monthly successive difference. RESULTS: No difference was found in the mean values of biological parameters (hemoglobin, reticulocytes, and ferritin) between the 4 strategies. ESAs type did not affect hemoglobin and reticulocyte variability, but C.E.R.A induced a more sustained reticulocytes response over time and increased the risk of hemoglobin overshooting (OR 2.7, p = 0.01). Shortening the administration interval lessened the amplitude of reticulocyte count fluctuations but resulted in more frequent ESAs dose adjustments and in amplified reticulocyte and hemoglobin variability. Q2W administration interval was however more favorable in terms of ESAs dose, allowing a 38% C.E.R.A. dose reduction, and no increase of Darbepoetin alfa. CONCLUSIONS: The reticulocyte dynamic was a more sensitive marker of time instability of the hemoglobin response under ESAs therapy. The ESAs administration interval had a greater impact on hemoglobin variability than the ESAs type. The more protracted reticulocyte response induced by C.E.R.A. could explain both, the observed higher risk of overshoot and the significant increase in efficacy when shortening its administration interval.Trial registrationClinicalTrials.gov NCT01666301.

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The objective of this work was to evaluate the water flow computer model, WATABLE, using experimental field observations on water table management plots from a site located near Hastings, FL, USA. The experimental field had scale drainage systems with provisions for subirrigation with buried microirrigation and conventional seepage irrigation systems. Potato (Solanum tuberosum L.) growing seasons from years 1996 and 1997 were used to simulate the hydrology of the area. Water table levels, precipitation, irrigation and runoff volumes were continuously monitored. The model simulated the water movement from a buried microirrigation line source and the response of the water table to irrigation, precipitation, evapotranspiration, and deep percolation. The model was calibrated and verified by comparing simulated results with experimental field observations. The model performed very well in simulating seasonal runoff, irrigation volumes, and water table levels during crop growth. The two-dimensional model can be used to investigate different irrigation strategies involving water table management control. Applications of the model include optimization of the water table depth for each growth stage, and duration, frequency, and rate of irrigation.

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Large Dynamic Message Signs (DMSs) have been increasingly used on freeways, expressways and major arterials to better manage the traffic flow by providing accurate and timely information to drivers. Overhead truss structures are typically employed to support those DMSs allowing them to provide wider display to more lanes. In recent years, there is increasing evidence that the truss structures supporting these large and heavy signs are subjected to much more complex loadings than are typically accounted for in the codified design procedures. Consequently, some of these structures have required frequent inspections, retrofitting, and even premature replacement. Two manufacturing processes are primarily utilized on truss structures - welding and bolting. Recently, cracks at welding toes were reported for the structures employed in some states. Extremely large loads (e.g., due to high winds) could cause brittle fractures, and cyclic vibration (e.g., due to diurnal variation in temperature or due to oscillations in the wind force induced by vortex shedding behind the DMS) may lead to fatigue damage, as these are two major failures for the metallic material. Wind and strain resulting from temperature changes are the main loads that affect the structures during their lifetime. The American Association of State Highway and Transportation Officials (AASHTO) Specification defines the limit loads in dead load, wind load, ice load, and fatigue design for natural wind gust and truck-induced gust. The objectives of this study are to investigate wind and thermal effects in the bridge type overhead DMS truss structures and improve the current design specifications (e.g., for thermal design). In order to accomplish the objective, it is necessary to study structural behavior and detailed strain-stress of the truss structures caused by wind load on the DMS cabinet and thermal load on the truss supporting the DMS cabinet. The study is divided into two parts. The Computational Fluid Dynamics (CFD) component and part of the structural analysis component of the study were conducted at the University of Iowa while the field study and related structural analysis computations were conducted at the Iowa State University. The CFD simulations were used to determine the air-induced forces (wind loads) on the DMS cabinets and the finite element analysis was used to determine the response of the supporting trusses to these pressure forces. The field observation portion consisted of short-term monitoring of several DMS Cabinet/Trusses and long-term monitoring of one DMS Cabinet/Truss. The short-term monitoring was a single (or two) day event in which several message sign panel/trusses were tested. The long-term monitoring field study extended over several months. Analysis of the data focused on trying to identify important behaviors under both ambient and truck induced winds and the effect of daily temperature changes. Results of the CFD investigation, field experiments and structural analysis of the wind induced forces on the DMS cabinets and their effect on the supporting trusses showed that the passage of trucks cannot be responsible for the problems observed to develop at trusses supporting DMS cabinets. Rather the data pointed toward the important effect of the thermal load induced by cyclic (diurnal) variations of the temperature. Thermal influence is not discussed in the specification, either in limit load or fatigue design. Although the frequency of the thermal load is low, results showed that when temperature range is large the restress range would be significant to the structure, especially near welding areas where stress concentrations may occur. Moreover stress amplitude and range are the primary parameters for brittle fracture and fatigue life estimation. Long-term field monitoring of one of the overhead truss structures in Iowa was used as the research baseline to estimate the effects of diurnal temperature changes to fatigue damage. The evaluation of the collected data is an important approach for understanding the structural behavior and for the advancement of future code provisions. Finite element modeling was developed to estimate the strain and stress magnitudes, which were compared with the field monitoring data. Fatigue life of the truss structures was also estimated based on AASHTO specifications and the numerical modeling. The main conclusion of the study is that thermal induced fatigue damage of the truss structures supporting DMS cabinets is likely a significant contributing cause for the cracks observed to develop at such structures. Other probable causes for fatigue damage not investigated in this study are the cyclic oscillations of the total wind load associated with the vortex shedding behind the DMS cabinet at high wind conditions and fabrication tolerances and induced stresses due to fitting of tube to tube connections.

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The silicon photomultiplier (SiPM) is a novel detector technology that has undergone a fast development in the last few years, owing to its single-photon resolution and ultra-fast response time. However, the typical high dark count rates of the sensor may prevent the detection of low intensity radiation fluxes. In this article, the time-gated operation with short active periods in the nanosecond range is proposed as a solution to reduce the number of cells fired due to noise and thus increase the dynamic range. The technique is aimed at application fields that function under a trigger command, such as gated fluorescence lifetime imaging microscopy.

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An experiment was carried out to examine the impact on electrodermal activity of people when approached by groups of one or four virtual characters at varying distances. It was premised on the basis of proxemics theory that the closer the approach of the virtual characters to the participant, the greater the level of physiological arousal. Physiological arousal was measured by the number of skin conductance responses within a short time period after the approach, and the maximum change in skin conductance level 5 s after the approach. The virtual characters were each either female or a cylinder of human size, and one or four characters approached each subject a total of 12 times. Twelve male subjects were recruited for the experiment. The results suggest that the number of skin conductance responses after the approach and the change in skin conductance level increased the closer the virtual characters approached toward the participants. Moreover, these response variables were inversely correlated with the number of visits, showing a typical adaptation effect. There was some evidence to suggest that the number of characters who simultaneously approached (one or four) was positively associated with the responses. Surprisingly there was no evidence of a difference in response between the humanoid characters and cylinders on the basis of this physiological data. It is suggested that the similarity in this quantitative arousal response to virtual characters and virtual objects might mask a profound difference in qualitative response, an interpretation supported by questionnaire and interview results. Overall the experiment supported the premise that people exhibit heightened physiological arousal the closer they are approached by virtual characters.

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An experiment was carried out to examine the impact on electrodermal activity of people when approached by groups of one or four virtual characters at varying distances. It was premised on the basis of proxemics theory that the closer the approach of the virtual characters to the participant, the greater the level of physiological arousal. Physiological arousal was measured by the number of skin conductance responses within a short time period after the approach, and the maximum change in skin conductance level 5 s after the approach. The virtual characters were each either female or a cylinder of human size, and one or four characters approached each subject a total of 12 times. Twelve male subjects were recruited for the experiment. The results suggest that the number of skin conductance responses after the approach and the change in skin conductance level increased the closer the virtual characters approached toward the participants. Moreover, these response variables were inversely correlated with the number of visits, showing a typical adaptation effect. There was some evidence to suggest that the number of characters who simultaneously approached (one or four) was positively associated with the responses. Surprisingly there was no evidence of a difference in response between the humanoid characters and cylinders on the basis of this physiological data. It is suggested that the similarity in this quantitative arousal response to virtual characters and virtual objects might mask a profound difference in qualitative response, an interpretation supported by questionnaire and interview results. Overall the experiment supported the premise that people exhibit heightened physiological arousal the closer they are approached by virtual characters.

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Sphingomonas paucimobilis B90A is able to degrade the alpha-, beta-, gamma-, and delta-isomers of hexachlorocyclohexane (HCH). It contains the genes linA, linB, linC, linD, linE, and linR, which have been implicated in HCH degradation. In this study, dynamic expression of the lin genes was measured in chemostat-grown S. paucimobilis B90A by RNA dot blot hybridization and real-time reverse transcriptase PCR upon exposure to a pulse of different HCH isomers. Irrespective of the addition of HCH, linA, linB, and linC were all expressed constitutively. In contrast, linD and linE were induced with alpha-HCH (2 mg/liter) and gamma-HCH (7 mg/liter). A sharp increase in mRNA levels for linD and linE was observed from 10 to 45 min after the addition of alpha- or gamma-HCH. Induction of linD and linE was not detectable upon the addition of 0.7 mg of gamma-HCH per liter, although the compound was degraded by the cells. The addition of beta-HCH (5 mg/liter) or delta-HCH (20 mg/liter) did not lead to linE and linD induction, despite the fact that 50% of the compounds were degraded. This suggests that degradation of beta- and delta-HCH proceeds by a different pathway than that of alpha- and gamma-HCH.

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An experiment was carried out to examine the impact on electrodermal activity of people when approached by groups of one or four virtual characters at varying distances. It was premised on the basis of proxemics theory that the closer the approach of the virtual characters to the participant, the greater the level of physiological arousal. Physiological arousal was measured by the number of skin conductance responses within a short time period after the approach, and the maximum change in skin conductance level 5 s after the approach. The virtual characters were each either female or a cylinder of human size, and one or four characters approached each subject a total of 12 times. Twelve male subjects were recruited for the experiment. The results suggest that the number of skin conductance responses after the approach and the change in skin conductance level increased the closer the virtual characters approached toward the participants. Moreover, these response variables were inversely correlated with the number of visits, showing a typical adaptation effect. There was some evidence to suggest that the number of characters who simultaneously approached (one or four) was positively associated with the responses. Surprisingly there was no evidence of a difference in response between the humanoid characters and cylinders on the basis of this physiological data. It is suggested that the similarity in this quantitative arousal response to virtual characters and virtual objects might mask a profound difference in qualitative response, an interpretation supported by questionnaire and interview results. Overall the experiment supported the premise that people exhibit heightened physiological arousal the closer they are approached by virtual characters.

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Left rostral dorsal premotor cortex (rPMd) and supramarginal gyrus (SMG) have been implicated in the dynamic control of actions. In 12 right-handed healthy individuals, we applied 30 min of low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) over left rPMd to investigate the involvement of left rPMd and SMG in the rapid adjustment of actions guided by visuospatial cues. After rTMS, subjects underwent functional magnetic resonance imaging while making spatially congruent button presses with the right or left index finger in response to a left- or right-sided target. Subjects were asked to covertly prepare motor responses as indicated by a directional cue presented 1 s before the target. On 20% of trials, the cue was invalid, requiring subjects to readjust their motor plan according to the target location. Compared with sham rTMS, real rTMS increased the number of correct responses in invalidly cued trials. After real rTMS, task-related activity of the stimulated left rPMd showed increased task-related coupling with activity in ipsilateral SMG and the adjacent anterior intraparietal area (AIP). Individuals who showed a stronger increase in left-hemispheric premotor-parietal connectivity also made fewer errors on invalidly cued trials after rTMS. The results suggest that rTMS over left rPMd improved the ability to dynamically adjust visuospatial response mapping by strengthening left-hemispheric connectivity between rPMd and the SMG-AIP region. These results support the notion that left rPMd and SMG-AIP contribute toward dynamic control of actions and demonstrate that low-frequency rTMS can enhance functional coupling between task-relevant brain regions and improve some aspects of motor performance.

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Firms operating in a changing environment have a need for structures and practices that provide flexibility and enable rapid response to changes. Given the challenges they face in attempts to keep up with market needs, they have to continuously improve their processes and products, and develop new products to match market requirements. Success in changing markets depends on the firm's ability to convert knowledge into innovations, and consequently their internal structures and capabilities have an important role in innovation activities. According 10 the dynamic capability view of the firm, firms thus need dynamic capabilities in (he form ofassets, processes and structures that enable strategic flexibility and support entrepreneurial opportunity sensing and exploitation. Dynamic capabilities are also needed in conditions of rapid change in the operating environment, and in activities such as new product development and expansion to new markets. Despite the growing interest in these issues and the theoretical developments in the field of strategy research, there are still only very few empirical studies, and large-scale empirical studies in particular, that provide evidence that firms'dynamic capabilities are reflected in performance differences. This thesis represents an attempt to advance the research by providing empirical evidence of thelinkages between the firm's dynamic capabilities and performance in intenationalization and innovation activities. The aim is thus to increase knowledge and enhance understanding of the organizational factors that explain interfirm performance differences. The study is in two parts. The first part is the introduction and the second part comprises five research publications covering the theoretical foundations of the dynamic capability view and subsequent empirical analyses. Quantitative research methodology is used throughout. The thesis contributes to the literature in several ways. While a lot of prior research on dynamic capabilities is conceptual in nature, or conducted through case studies, this thesis introduces empirical measures for assessing the different aspects, and uses large-scale sampling to investigate the relationships between them and performance indicators. The dynamic capability view is further developed by integrating theoretical frameworks and research traditions from several disciplines. The results of the study provide support for the basic tenets of the dynamic capability view. The empirical findings demonstrate that the firm's ability to renew its knowledge base and other intangible assets, its proactive, entrepreneurial behavior, and the structures and practices that support operational flexibility arepositively related to performance indicators.

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BACKGROUND: Mitogen activated protein kinases (MAPK) play an essential role in integrating extra-cellular signals and intra-cellular cues to allow cells to grow, adapt to stresses, or undergo apoptosis. Budding yeast serves as a powerful system to understand the fundamental regulatory mechanisms that allow these pathways to combine multiple signals and deliver an appropriate response. To fully comprehend the variability and dynamics of these signaling cascades, dynamic and quantitative single cell measurements are required. Microscopy is an ideal technique to obtain these data; however, novel assays have to be developed to measure the activity of these cascades. RESULTS: We have generated fluorescent biosensors that allow the real-time measurement of kinase activity at the single cell level. Here, synthetic MAPK substrates were engineered to undergo nuclear-to-cytoplasmic relocation upon phosphorylation of a nuclear localization sequence. Combination of fluorescence microscopy and automated image analysis allows the quantification of the dynamics of kinase activity in hundreds of single cells. A large heterogeneity in the dynamics of MAPK activity between individual cells was measured. The variability in the mating pathway can be accounted for by differences in cell cycle stage, while, in the cell wall integrity pathway, the response to cell wall stress is independent of cell cycle stage. CONCLUSIONS: These synthetic kinase activity relocation sensors allow the quantification of kinase activity in live single cells. The modularity of the architecture of these reporters will allow their application in many other signaling cascades. These measurements will allow to uncover new dynamic behaviour that previously could not be observed in population level measurements.

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Does realistic lighting in an immersive virtual reality application enhance presence, where participants feel that they are in the scene and behave correspondingly? Our previous study indicated that presence is more likely with real-time ray tracing compared with ray casting, but we could not separate the effects of overall quality of illumination from the dynamic effects of real-time shadows and reflections. Here we describe an experiment where 20 people experienced a scene rendered with global or local illumination. However, in both conditions there were dynamically changing shadows and reflections. We found that the quality of illumination did not impact presence, so that the earlier result must have been due to dynamic shadows and reflections. However, global illumination resulted in greater plausibility - participants were more likely to respond as if the virtual events were real. We conclude that global illumination does impact the responses of participants and is worth the effort.