Enhanced Atlantic subpolar gyre variability through baroclinic threshold in a coarse resolution model

Direct observations, satellite measurements and paleo records reveal strong variability in the Atlantic subpolar gyre on various time scales. Here we show that variations of comparable amplitude can only be simulated in a coupled climate model in the proximity of a dynamical threshold. The threshold and the associated dynamic response is due to a positive feedback involving increased salt transport in the subpolar gyre and enhanced deep convection in its centre. A series of sensitivity experiments is performed with a coarse resolution ocean general circulation model coupled to a statistical-dynamical atmosphere model which in itself does not produce atmospheric variability. To simulate the impact of atmospheric variability, the model system is perturbed with freshwater forcing of varying, but small amplitude and multi-decadal to centennial periodicities and observational variations in wind stress. While both freshwater and wind-stress-forcing have a small direct effect on the strength of the subpolar gyre, the magnitude of the gyre's response is strongly increased in the vicinity of the threshold. Our results indicate that baroclinic self-amplification in the North Atlantic ocean can play an important role in presently observed SPG variability and thereby North Atlantic climate variability on multi-decadal scales.

Northern hemispheric winter warming pattern after tropical volcanic eruptions: Sensitivity to the ozone climatology

An important key for the understanding of the dynamic response to large tropical volcanic eruptions is the warming of the tropical lower stratosphere and the concomitant intensification of the polar vortices. Although this mechanism is reproduced by most general circulation models today, most models still fail in producing an appropriate winter warming pattern in the Northern Hemisphere. In this study ensemble sensitivity experiments were carried out with a coupled atmosphere-ocean model to assess the influence of different ozone climatologies on the atmospheric dynamics and in particular on the northern hemispheric winter warming. The ensemble experiments were perturbed by a single Tambora-like eruption. Larger meridional gradients in the lower stratospheric ozone favor the coupling of zonal wind anomalies between the stratosphere and the troposphere after the eruption. The associated sea level pressure, temperature, and precipitation patterns are more pronounced and the northern hemispheric winter warming is highly significant. Conversely, weaker meridional ozone gradients lead to a weaker response of the winter warming and the associated patterns. The differences in the number of stratosphere-troposphere coupling events between the ensembles experiments indicate a nonlinear response behavior of the dynamics with respect to the ozone and the volcanic forcing.

Dynamic Optimization of SLA-Based Services Scaling Rules

Current advanced cloud infrastructure management solutions allow scheduling actions for dynamically changing the number of running virtual machines (VMs). This approach, however, does not guarantee that the scheduled number of VMs will properly handle the actual user generated workload, especially if the user utilization patterns will change. We propose using a dynamically generated scaling model for the VMs containing the services of the distributed applications, which is able to react to the variations in the number of application users. We answer the following question: How to dynamically decide how many services of each type are needed in order to handle a larger workload within the same time constraints? We describe a mechanism for dynamically composing the SLAs for controlling the scaling of distributed services by combining data analysis mechanisms with application benchmarking using multiple VM configurations. Based on processing of multiple application benchmarks generated data sets we discover a set of service monitoring metrics able to predict critical Service Level Agreement (SLA) parameters. By combining this set of predictor metrics with a heuristic for selecting the appropriate scaling-out paths for the services of distributed applications, we show how SLA scaling rules can be inferred and then used for controlling the runtime scale-in and scale-out of distributed services. We validate our architecture and models by performing scaling experiments with a distributed application representative for the enterprise class of information systems. We show how dynamically generated SLAs can be successfully used for controlling the management of distributed services scaling.

Region Specific Response of Intervertebral Disc Cells to Complex Dynamic Loading: An Organ Culture Study Using a Dynamic Torsion-Compression Bioreactor

The spine is routinely subjected to repetitive complex loading consisting of axial compression, torsion, flexion and extension. Mechanical loading is one of the important causes of spinal diseases, including disc herniation and disc degeneration. It is known that static and dynamic compression can lead to progressive disc degeneration, but little is known about the mechanobiology of the disc subjected to combined dynamic compression and torsion. Therefore, the purpose of this study was to compare the mechanobiology of the intervertebral disc when subjected to combined dynamic compression and axial torsion or pure dynamic compression or axial torsion using organ culture. We applied four different loading modalities 1. control: no loading (NL), 2. cyclic compression (CC), 3. cyclic torsion (CT), and 4. combined cyclic compression and torsion (CCT) on bovine caudal disc explants using our custom made dynamic loading bioreactor for disc organ culture. Loads were applied for 8 h/day and continued for 14 days, all at a physiological magnitude and frequency. Our results provided strong evidence that complex loading induced a stronger degree of disc degeneration compared to one degree of freedom loading. In the CCT group, less than 10\% nucleus pulposus (NP) cells survived the 14 days of loading, while cell viabilities were maintained above 70\% in the NP of all the other three groups and in the annulus fibrosus (AF) of all the groups. Gene expression analysis revealed a strong up-regulation in matrix genes and matrix remodeling genes in the AF of the CCT group. Cell apoptotic activity and glycosaminoglycan content were also quantified but there were no statistically significant differences found. Cell morphology in the NP of the CCT was changed, as shown by histological evaluation. Our results stress the importance of complex loading on the initiation and progression of disc degeneration.

Dynamic SLA management with forecasting using multi-objective optimization

Cost-efficient operation while satisfying performance and availability guarantees in Service Level Agreements (SLAs) is a challenge for Cloud Computing, as these are potentially conflicting objectives. We present a framework for SLA management based on multi-objective optimization. The framework features a forecasting model for determining the best virtual machine-to-host allocation given the need to minimize SLA violations, energy consumption and resource wasting. A comprehensive SLA management solution is proposed that uses event processing for monitoring and enables dynamic provisioning of virtual machines onto the physical infrastructure. We validated our implementation against serveral standard heuristics and were able to show that our approach is significantly better.

The effects of dynamic loading on the intervertebral disc

Loading is important to maintain the balance of matrix turnover in the intervertebral disc (IVD). Daily cyclic diurnal assists in the transport of large soluble factors across the IVD and its surrounding circulation and applies direct and indirect stimulus to disc cells. Acute mechanical injury and accumulated overloading, however, could induce disc degeneration. Recently, there is more information available on how cyclic loading, especially axial compression and hydrostatic pressure, affects IVD cell biology. This review summarises recent studies on the response of the IVD and stem cells to applied cyclic compression and hydrostatic pressure. These studies investigate the possible role of loading in the initiation and progression of disc degeneration as well as quantifying a physiological loading condition for the study of disc degeneration biological therapy. Subsequently, a possible physiological/beneficial loading range is proposed. This physiological/beneficial loading could provide insight into how to design loading regimes in specific system for the testing of various biological therapies such as cell therapy, chemical therapy or tissue engineering constructs to achieve a better final outcome. In addition, the parameter space of 'physiological' loading may also be an important factor for the differentiation of stem cells towards most ideally 'discogenic' cells for tissue engineering purpose.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with 1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with 35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with 1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.

Multiple time scales of temporal response in pyramidal and fast spiking cortical neurons

Neural dynamic processes correlated over several time scales are found in vivo, in stimulus-evoked as well as spontaneous activity, and are thought to affect the way sensory stimulation is processed. Despite their potential computational consequences, a systematic description of the presence of multiple time scales in single cortical neurons is lacking. In this study, we injected fast spiking and pyramidal (PYR) neurons in vitro with long-lasting episodes of step-like and noisy, in-vivo-like current. Several processes shaped the time course of the instantaneous spike frequency, which could be reduced to a small number (1-4) of phenomenological mechanisms, either reducing (adapting) or increasing (facilitating) the neuron's firing rate over time. The different adaptation/facilitation processes cover a wide range of time scales, ranging from initial adaptation (<10 ms, PYR neurons only), to fast adaptation (<300 ms), early facilitation (0.5-1 s, PYR only), and slow (or late) adaptation (order of seconds). These processes are characterized by broad distributions of their magnitudes and time constants across cells, showing that multiple time scales are at play in cortical neurons, even in response to stationary stimuli and in the presence of input fluctuations. These processes might be part of a cascade of processes responsible for the power-law behavior of adaptation observed in several preparations, and may have far-reaching computational consequences that have been recently described.

Optimization of corticosteroid induced osteoporosis in ovariectomized sheep. A bone histomorphometric study

During osteoporosis induction in sheep, side effects of the steroids were observed in previous studies. The aim of this study was to improve the induction regimen consisting of ovariectomy, calcium/vitamin D- restricted diet and methylprednisolone (-MP)- medication with respect to the bone metabolism and to reduce the adverse side effects. Thirty-six ewes (age 6.5 +/- 0.6 years) were divided into four MP-administration groups (n = 9) with a total dose of 1800 mg MP: group 1: 20 mg/day, group 2: 60 mg/every third day, group 3: 3 x 500 mg and 1 x 300 mg at intervals of three weeks, group 4: weekly administration, starting at 70 mg and weekly reduction by 10 mg. After double-labelling with Calcein Green and Xylenol Orange, bone biopsy specimens were taken from the iliac crest (IC) at the beginning and four weeks after the last MP injection, and additionally from the vertebral body (VB) at the end of the experiment. Bone samples were processed into stained and fluorescent sections, static and dynamic measurements were performed. There were no significant differences for static parameters between the groups initially. The bone perimeter and the bone area values were significantly higher in the VB than in the IC (Pm: 26%, p < 0.0001, Ar: 11%, p < 0.0166). A significant decrease (20%) of the bone area was observed after corticosteroid-induced osteoporosis (p < 0.0004). For the dynamic parameters, no significant difference between the groups was found. Presence of Calcein Green and Xylenol Orange labels were noted in 50% of the biopsies in the IC, 100% in the VB. Group 3 showed the lowest prevalence of adverse side effects. The bone metabolism changes were observed in all four groups, and the VB bone metabolism was higher when compared to the IC. In conclusion, when using equal amounts of steroids adverse side effects can be reduced by decreasing the number of administrations without reducing the effect regarding corticosteroid-induced osteoporosis. This information is useful to reduce the discomfort of the animals in this sheep model of corticosteroid-induced osteoporosis.

Oxidative stress precedes peak systemic inflammatory response in pediatric patients undergoing cardiopulmonary bypass operation

Oxidative stress seems to contribute to cardiopulmonary bypass (CPB)-related postoperative complications. Pediatric patients are particularly prone to these complications. With this in mind, we measured oxidative stress markers in blood plasma of 20 children undergoing elective heart surgery before, during, and up to 48 h after cessation of CPB, along with inflammatory parameters and full analysis of iron status. Ascorbate levels were decreased by approximately 50% (P < 0.001) at the time of aorta cross-clamp removal (or pump switch-off in 4 patients with partial CPB), and associated with corresponding increases in dehydroascorbate (P < 0.001, r = -0.80) and malondialdehyde (P < 0.01, r = -0.59). In contrast to the immediate oxidative response, peak levels of IL-6 and IL-8 were not observed until 3-12 h after CPB cessation. The early loss of ascorbate correlated with duration of CPB (P < 0.002, r = 0.72), plasma hemoglobin after cross-clamp removal (P < 0.001, r = 0.70), and IL-6 and IL-8 levels at 24 and 48 h after CPB (P < 0.01), but not with postoperative lactate levels, strongly suggesting that hemolysis, and not inflammation or ischemia, was the main cause of early oxidative stress. The correlation of ventilation time with early changes in ascorbate (P < 0.02, r = 0.55), plasma hemoglobin (P < 0.01, r = 0.60), and malondialdehyde (P < 0.02, r = 0.54) suggests that hemolysis-induced oxidative stress may be an underlying cause of CPB-associated pulmonary dysfunction. Optimization of surgical procedures or therapeutic intervention that minimize hemolysis (e.g., off-pump surgery) or the resultant oxidative stress (e.g., antioxidant treatment) should be considered as possible strategies to lower the rate of postoperative complications in pediatric CPB.

Leaf transmission reduction using moving jaws for dynamic MLC IMRT

The aim of this work is to investigate to what extent it is possible to use the secondary collimator jaws to reduce the transmitted radiation through the multileaf collimator (MLC) during an intensity modulated radiation therapy (IMRT). A method is developed and introduced where the jaws follow the open window of the MLC dynamically (dJAW method). With the aid of three academic cases (Closed MLC, Sliding-gap, and Chair) and two clinical cases (prostate and head and neck) the feasibility of the dJAW method and the influence of this method on the applied dose distributions are investigated. For this purpose the treatment planning system Eclipse and the Research-Toolbox were used as well as measurements within a solid water phantom were performed. The transmitted radiation through the closed MLC leads to an inhomogeneous dose distribution. In this case, the measured dose within a plane perpendicular to the central axis differs up to 40% (referring to the maximum dose within this plane) for 6 and 15 MV. The calculated dose with Eclipse is clearly more homogeneous. For the Sliding-gap case this difference is still up to 9%. Among other things, these differences depend on the depth of the measurement within the solid water phantom and on the application method. In the Chair case, the dose in regions where no dose is desired is locally reduced by up to 50% using the dJAW method instead of the conventional method. The dose inside the chair-shaped region decreased up to 4% if the same number of monitor units (MU) as for the conventional method was applied. The undesired dose in the volume body minus the planning target volume in the clinical cases prostate and head and neck decreased up to 1.8% and 1.5%, while the number of the applied MU increased up to 3.1% and 2.8%, respectively. The new dJAW method has the potential to enhance the optimization of the conventional IMRT to a further step.

Dosimetric impact of geometric errors due to respiratory motion prediction on dynamic multileaf collimator-based four-dimensional radiation delivery

The synchronization of dynamic multileaf collimator (DMLC) response with respiratory motion is critical to ensure the accuracy of DMLC-based four dimensional (4D) radiation delivery. In practice, however, a finite time delay (response time) between the acquisition of tumor position and multileaf collimator response necessitates predictive models of respiratory tumor motion to synchronize radiation delivery. Predicting a complex process such as respiratory motion introduces geometric errors, which have been reported in several publications. However, the dosimetric effect of such errors on 4D radiation delivery has not yet been investigated. Thus, our aim in this work was to quantify the dosimetric effects of geometric error due to prediction under several different conditions. Conformal and intensity modulated radiation therapy (IMRT) plans for a lung patient were generated for anterior-posterior/posterior-anterior (AP/PA) beam arrangements at 6 and 18 MV energies to provide planned dose distributions. Respiratory motion data was obtained from 60 diaphragm-motion fluoroscopy recordings from five patients. A linear adaptive filter was employed to predict the tumor position. The geometric error of prediction was defined as the absolute difference between predicted and actual positions at each diaphragm position. Distributions of geometric error of prediction were obtained for all of the respiratory motion data. Planned dose distributions were then convolved with distributions for the geometric error of prediction to obtain convolved dose distributions. The dosimetric effect of such geometric errors was determined as a function of several variables: response time (0-0.6 s), beam energy (6/18 MV), treatment delivery (3D/4D), treatment type (conformal/IMRT), beam direction (AP/PA), and breathing training type (free breathing/audio instruction/visual feedback). Dose difference and distance-to-agreement analysis was employed to quantify results. Based on our data, the dosimetric impact of prediction (a) increased with response time, (b) was larger for 3D radiation therapy as compared with 4D radiation therapy, (c) was relatively insensitive to change in beam energy and beam direction, (d) was greater for IMRT distributions as compared with conformal distributions, (e) was smaller than the dosimetric impact of latency, and (f) was greatest for respiration motion with audio instructions, followed by visual feedback and free breathing. Geometric errors of prediction that occur during 4D radiation delivery introduce dosimetric errors that are dependent on several factors, such as response time, treatment-delivery type, and beam energy. Even for relatively small response times of 0.6 s into the future, dosimetric errors due to prediction could approach delivery errors when respiratory motion is not accounted for at all. To reduce the dosimetric impact, better predictive models and/or shorter response times are required.

UPLC-ESI-TOFMS-based metabolomics and gene expression dynamics inspector self-organizing metabolomic maps as tools for understanding the cellular response to ionizing radiation

Global transcriptomic and proteomic profiling platforms have yielded important insights into the complex response to ionizing radiation (IR). Nonetheless, little is known about the ways in which small cellular metabolite concentrations change in response to IR. Here, a metabolomics approach using ultraperformance liquid chromatography coupled with electrospray time-of-flight mass spectrometry was used to profile, over time, the hydrophilic metabolome of TK6 cells exposed to IR doses ranging from 0.5 to 8.0 Gy. Multivariate data analysis of the positive ions revealed dose- and time-dependent clustering of the irradiated cells and identified certain constituents of the water-soluble metabolome as being significantly depleted as early as 1 h after IR. Tandem mass spectrometry was used to confirm metabolite identity. Many of the depleted metabolites are associated with oxidative stress and DNA repair pathways. Included are reduced glutathione, adenosine monophosphate, nicotinamide adenine dinucleotide, and spermine. Similar measurements were performed with a transformed fibroblast cell line, BJ, and it was found that a subset of the identified TK6 metabolites were effective in IR dose discrimination. The GEDI (Gene Expression Dynamics Inspector) algorithm, which is based on self-organizing maps, was used to visualize dynamic global changes in the TK6 metabolome that resulted from IR. It revealed dose-dependent clustering of ions sharing the same trends in concentration change across radiation doses. "Radiation metabolomics," the application of metabolomic analysis to the field of radiobiology, promises to increase our understanding of cellular responses to stressors such as radiation.

Quantile-Based Optimization of Noisy Computer Experiments with Tunable Precision

This article addresses the issue of kriging-based optimization of stochastic simulators. Many of these simulators depend on factors that tune the level of precision of the response, the gain in accuracy being at a price of computational time. The contribution of this work is two-fold: first, we propose a quantile-based criterion for the sequential design of experiments, in the fashion of the classical expected improvement criterion, which allows an elegant treatment of heterogeneous response precisions. Second, we present a procedure for the allocation of the computational time given to each measurement, allowing a better distribution of the computational effort and increased efficiency. Finally, the optimization method is applied to an original application in nuclear criticality safety. This article has supplementary material available online. The proposed criterion is available in the R package DiceOptim.

Solar wind dynamic pressure effect on planetary wave propagation and synoptic-scale Rossby wave breaking

We provide statistical evidence of the effect of the solar wind dynamic pressure (Psw) on the northern winter and spring circulations. We find that the vertical structure of the Northern Annular Mode (NAM), the zonal mean circulation, and Eliassen-Palm (EP)-flux anomalies show a dynamically consistent pattern of downward propagation over a period of ~45 days in response to positive Psw anomalies. When the solar irradiance is high, the signature of Psw is marked by a positive NAM anomaly descending from the stratosphere to the surface during winter. When the solar irradiance is low, the Psw signal has the opposite sign, occurs in spring, and is confined to the stratosphere. The negative Psw signal in the NAM under low solar irradiance conditions is primarily governed by enhanced vertical EP-flux divergence and a warmer polar region. The winter Psw signal under high solar irradiance conditions is associated with positive anomalies of the horizontal EP-flux divergence at 55°N–75°N and negative anomalies at 25°N–45°N, which corresponds to the positive NAM anomaly. The EP-flux divergence anomalies occur ~15 days ahead of the mean-flow changes. A significant equatorward shift of synoptic-scale Rossby wave breaking (RWB) near the tropopause is detected during January–March, corresponding to increased anticyclonic RWB and a decrease in cyclonic RWB. We suggest that the barotropic instability associated with asymmetric ozone in the upper stratosphere and the baroclinic instability associated with the polar vortex in the middle and lower stratosphere play a critical role for the winter signal and its downward propagation.