The roles of costimulatory molecules in the cooperative effects of combination epinephrine and dexamethasone on type-1/type-2 cytokine production in tetanus-toxoid specific stimulated human peripheral blood mononuclear cells

A growing number of studies show strong associations between stress and altered immune function. In vivo studies of chronic and acute stress have demonstrated that cognitive stressors are strongly correlated with high circulating levels of catecholamines (CT) and corticosteroids (CS) that are associated with changes in type-1/type-2 cytokine expression. Although individual pharmacologic doses of CS and CT can inhibit the expression of T-helper 1 (Th1, type-1 like) and promote the production of T-helper 2 (Th2, type-2 like) cytokines in antigen-specific and mitogen stimulated human leukocyte cultures in vitro, little attention has been focused on the effects of combination physiologic-stress doses of CT and CS that may be more physiologically relevant. In addition, both in-vivo and in-vitro studies suggest that the differential expression of the B7 family of costimulatory molecules CD80 and CD86 may promote the expression of type-1 or type-2 cytokines, respectively. Furthermore, corticosteroids can influence the expression of β2-adrenergic receptors in various human tissues. We therefore investigated the combined effects of physiologic-stress doses of in vitro CT and CS upon the type-1/type-2 cytokine balance and expression of B7 costimulatory molecules of human peripheral blood mononuclear cells (PBMC) as a model to study the immunomodulatory effects of physiologic stress. Results demonstrated a significant decrease in type-1 cytokine expression and a significant increase in type-2 cytokine production in our CS+CT incubated cultures when compared to either CT or CS agents alone. In addition, we demonstrated the differential expression of CD80/CD86 in favor of CD86 at the cellular and population level as determined by flow cytometry in lipopolysaccharide stimulated human Monocytes. Furthermore, we developed flow cytometry based assays to detect total β2AR in human CD4+ T-lymphocytes that demonstrated decreased expression of β2AR in mitogen stimulated CD4+ T-lymphocytes in the presence of physiologic stress levels of CS and CT as single in vitro agents, however, when both CS and CT were combined, significantly higher expression of β2AR was observed. In summary, our in vitro data suggest that both CS and CT work cooperatively to shift immunity towards type-2 responses. ^

Perchlorate remediation technologies: A systematic review of solely biodegradation versus a combination of ion-exchange and biodegradation technologies

A systematic review was performed in order to evaluate perchlorate remediation technologies. The two included technologies were ion-exchange concerted with biodegradation and solely biodegradation. A meta-analysis was completed and subsequently, a regression model was formed to conduct a degradation rate analysis and to depict the association between rate and various dependent variables (salinity/sali, nitrate concentration/nitc and carbon source concentration/csou). The outcome of the model analysis suggested that salt concentration did have an effect on the degradation rate in the ion-exchange process and that with a salt concentration greater than or equal to 18.6 g/L, the biodegradation process will produce a greater reduction of perchlorate than ion-exchange concerted with biodegradation. However, when a t-test examined the difference in perchlorate degradation rate between the two cleanup methods, there was no significant difference seen (p=0.7351, α = 0.05).^

Identifying and Targeting Molecular Deregulations in Uterine Leiomyosarcoma: A Role for mTOR Inhibition-Based Combination Therapies

Uterine leiomyosarcoma (ULMS) is an aggressive malignancy characterized by marked chemoresistance, frequent relapses, and poor outcome. Despite efforts to improve survival over the past several decades, only minimal advances have been made. Hence, there is an urgent and unmet need for better understanding of the molecular deregulations that underlay ULMS and development of more effective therapeutic strategies. This work identified several common deregulations in a large (n=208) tissue microarray of ULMS compared to GI smooth muscle, myometrium, and leiomyoma controls. Our results suggest that significant loss of smooth muscle and gynecological differentiation markers is common in ULMS, a finding that could help render improved ULMS diagnosis, especially for advanced disease. Similarly to reports in other malignancies, we found that several cancer-related proteins were differentially expressed; these could be useful together as biomarkers for ULMS. Notably, we identified significant upregulation and overexpression of the mTOR pathway in ULMS, examined the possible contribution of tyrosine kinase receptor deregulation promoting mTOR activation, and unraveled a role for pS6RP and p4EBP1 as molecular disease prognosticators. The significance of mTOR activation in ULMS and its potential as a therapeutic target were further investigated. Rapamycin abrogated ULMS cell growth and cell cycle progression in vitro but induced only sight growth delay in vivo. Given that effective mTOR therapies likely require combination mTOR blockade with inhibition of other targets, coupled with recent observations suggesting that Aurora A kinase (Aurk A) deregulations commonly occur in ULMS, the preclinical impact of dually targeting both pathways was evaluated. Combined therapy with rapamycin (an mTORC1 inhibitor) and MLN8237 (an investigational Aurk A inhibitor) profoundly and synergistically abrogated ULMS growth in vitro. Interestingly, the superior effects were noted only when MLN8237 was pre-administered. This novel therapeutic combination and scheduling regimen resulted in marked tumor growth inhibition in vivo. Together, these data support further exploration of dual mTOR and Aurk A blockade for the treatment of human ULMS.

PIM KINASE INHIBITION: SINGLE AGENT AND COMBINATION APPROACHES IN B-CELL LYMPHOMA

Proviral integration site for Moloney murine leukemia virus (Pim) kinases are Ser/Thr/Tyr kinases. They modulate B-cell development but become oncoproteins and promote cancer development once overexpressed. Containing three isoforms, Pim-1, -2 and -3 are known to phosphorylate various substrates that regulate transcription, translation, cell cycle, and survival pathways in both hematological and solid tumors. Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma. Elevated Pim kinase levels are common in MCL, and it negatively correlates with patient outcome. SGI-1776 is a small molecule inhibitor selective for Pim-1/-3. We hypothesize that SGI-1776 treatment in MCL will inhibit Pim kinase function, and inhibition of downstream substrates phosphorylation will disrupt transcriptional, translational, and cell cycle processes while promoting apoptosis. SGI-1776 treatment induced moderate to high levels of apoptosis in four MCL cell lines (JeKo-1, Mino, SP-53 and Granta-519) and peripheral blood mononuclear cells (PBMCs) from MCL patients. Phosphorylation of transcription and translation regulators, c-Myc and 4E-BP1 declined in both model systems. Additionally, levels of short-lived Mcl-1 mRNA and protein also decreased and correlated with decline of global RNA synthesis. Collectively, our investigations highlight Pim kinases as viable drug targets in MCL and emphasize their roles in transcriptional and translational regulation. We further investigated a combination strategy using SGI-1776 with bendamustine, an FDA-approved DNA-damaging alkylating agent for treating non-Hodgkin’s lymphoma. We hypothesized this combination will enhance SGI-1776-induced transcription and translation inhibition, while promoting bendamustine-triggered DNA damage and inducing additive to synergistic cytotoxicity in B-cell lymphoma. Bendamustine alone resulted in moderate levels of apoptosis induction in MCL cell lines (JeKo-1 and Mino), and in MCL and splenic marginal zone lymphoma (a type of B-cell lymphoma) primary cells. An additive effect in cell killing was observed when combined with SGI-1776. Expectedly, SGI-1776 effectively decreased global RNA and protein synthesis levels, while bendamustine significantly inhibited DNA synthesis and generated DNA damage response. In combination, intensified inhibitory effects in DNA, RNA and protein syntheses were observed. Together, these data suggested feasibility of using Pim kinase inhibitor in combination with chemotherapeutic agents such as bendamustine in B-cell lymphoma, and provided foundation of their mechanism of actions in lymphoma cells.

Atmospheric, oceanic and hydrological polar motion excitation mechanisms based on a combination of geometric and gravimetric space observations

The goal of our study is to determine accurate time series of geophysical Earth rotation excitations to learn more about global dynamic processes in the Earth system. For this purpose, we developed an adjustment model which allows to combine precise observations from space geodetic observation systems, such as Satellite Laser Ranging (SLR), Global Navigation Satellite Systems (GNSS), Very Long Baseline Interferometry (VLBI), Doppler Orbit determination and Radiopositioning Integrated on Satellite (DORIS), satellite altimetry and satellite gravimetry in order to separate geophysical excitation mechanisms of Earth rotation. Three polar motion time series are applied to derive the polar motion excitation functions (integral effect). Furthermore we use five time variable gravity field solutions from Gravity Recovery and Climate Experiment (GRACE) to determine not only the integral mass effect but also the oceanic and hydrological mass effects by applying suitable filter techniques and a land-ocean mask. For comparison the integral mass effect is also derived from degree 2 potential coefficients that are estimated from SLR observations. The oceanic mass effect is also determined from sea level anomalies observed by satellite altimetry by reducing the steric sea level anomalies derived from temperature and salinity fields of the oceans. Due to the combination of all geodetic estimated excitations the weaknesses of the individual processing strategies can be reduced and the technique-specific strengths can be accounted for. The formal errors of the adjusted geodetic solutions are smaller than the RMS differences of the geophysical model solutions. The improved excitation time series can be used to improve the geophysical modeling.

Combination of optical and on-destructivemechanicaltechniques for the measurement of maturity in peach

Increasing consumer dissatisfaction related with lack of ripeness in peach has been repeatedly reported since 1990 to the present day. There is thus, a great interest in improving the assessment of peach maturity, currently based on Magness Taylor firmness (destructive, highly variable, and time consuming) and colour (not reliable for highly coloured varieties). The present research studies as an alternative several non-destructive (ND) measurements, based on multispectral imaging, visible spectra, and low mass impact response. Their relationship with maturity, as well as the potential of their combination was studied. As a result, two rather independent (R2 = 0.3) groups of non-destructive measurements, chlorophyll related optical indexes and low mass impact (LMI) measurements, were identified. Optical measurements showed the best behaviour for assessing maturity at harvest, while LMI measurements reflected handling incidences, showing a promising potential to be used to control transport and postharvest handling.

Series combination of a switched dc-dc converter and a linear regulator for high frequency RF envelope amplifier

Classical linear amplifiers such as A, AB and B offer very good linearity suitable for RF power amplifiers. However, its inherent low efficiency limits its use especially in base-stations that manage tens or hundreds of Watts. The use of linearization techniques such as Envelope Elimination and Restoration (EER) allow an increase of efficiency keeping good linearity. This technique requires a very fast dc-dc power converter to provide variable voltage supply to the power amplifier. In this paper, several alternatives are analyzed to implement the envelope amplifier based on a cascade association of a switched dc-dc converter and a linear regulator. A simplified version of this approach is also suitable to operate with Envelope Tracking technique.

PSO and neural networks: Optimal combination to solve non linear complex problems

Swarm colonies reproduce social habits. Working together in a group to reach a predefined goal is a social behaviour occurring in nature. Linear optimization problems have been approached by different techniques based on natural models. In particular, Particles Swarm optimization is a meta-heuristic search technique that has proven to be effective when dealing with complex optimization problems. This paper presents and develops a new method based on different penalties strategies to solve complex problems. It focuses on the training process of the neural networks, the constraints and the election of the parameters to ensure successful results and to avoid the most common obstacles when searching optimal solutions.

The Optimal combination: Grammatical Swarm, Particle Swarm Optimization and Neural Networks.

Social behaviour is mainly based on swarm colonies, in which each individual shares its knowledge about the environment with other individuals to get optimal solutions. Such co-operative model differs from competitive models in the way that individuals die and are born by combining information of alive ones. This paper presents the particle swarm optimization with differential evolution algorithm in order to train a neural network instead the classic back propagation algorithm. The performance of a neural network for particular problems is critically dependant on the choice of the processing elements, the net architecture and the learning algorithm. This work is focused in the development of methods for the evolutionary design of artificial neural networks. This paper focuses in optimizing the topology and structure of connectivity for these networks.

Brain structural and functional recovery following initiation of combination antiretroviral therapy

NeuroAIDS persists in the era of combination antiretroviral therapies. We describe here the recovery of brain structure and function following 6 months of therapy in a treatment-naive patient presenting with HIV-associated dementia. The patient’s neuropsychological test performance improved and his total brain volume increased by more than 5 %. Neuronal functional connectivity measured by magnetoencephalography changed from a pattern identical to that observed in other HIV-infected individuals to one that was indistinguishable from that of uninfected control subjects. These data suggest that at least some of the effects of HIV on the brain can be fully reversed with treatment.

Phytostabilization of metals in mine soils using Brassica juncea in combination with organic amendments

Background and aims The high metal bioavailability and the poor conditions of mine soils yield a low plant biomass, limiting the application of phytoremediation techniques. A greenhouse experiment was performed to evaluate the effects of organic amendments on metal stabilization and the potential of Brassica juncea L. for phytostabilization in mine soils. Methods Plants were grown in pots filled with soils collected from two mine sites located in Central Spain mixed with 0, 30 and 60 tha?1 of pine bark compost and horse- and sheep-manure compost. Plant biomass and metal concentrations in roots and shoots were measured. Metal bioavailability was assessed using a rhizosphere-based method (rhizo), which consists of a mixture of low-molecular-weight organic acids to simulate root exudates. Results Manure reduced metal concentrations in shoots (10?50 % reduction of Cu and 40?80 % of Zn in comparison with non-amended soils), bioconcentration factor (10?50 % of Cu and 40?80 % of Zn) and metal bioavailability in soil (40?50 % of Cu and 10?30 % of Zn) due to the high pH and the contribution of organic matter. Manure improved soil fertility and was also able to increase plant biomass (5?20 times in shoots and 3?30 times in roots), which resulted in a greater amount of metals removed from soil and accumulated in roots (increase of 2?7 times of Cu and Zn). Plants grown in pine bark treatments and in non-amended soils showed a limited biomass and high metal concentrations in shoots. Conclusions The addition of manure could be effective for the stabilization of metals and for enhancing the phytostabilization ability of B. juncea in mine soils. In this study, this species resulted to be a potential candidate for phytostabilization in combination with manure, differing from previous results, in which B. juncea had been recognized as a phytoextraction plant.

Advanced background modeling with RGB-D sensors through classifiers combination and inter-frame foreground prediction

An innovative background modeling technique that is able to accurately segment foreground regions in RGB-D imagery (RGB plus depth) has been presented in this paper. The technique is based on a Bayesian framework that efficiently fuses different sources of information to segment the foreground. In particular, the final segmentation is obtained by considering a prediction of the foreground regions, carried out by a novel Bayesian Network with a depth-based dynamic model, and, by considering two independent depth and color-based mixture of Gaussians background models. The efficient Bayesian combination of all these data reduces the noise and uncertainties introduced by the color and depth features and the corresponding models. As a result, more compact segmentations, and refined foreground object silhouettes are obtained. Experimental results with different databases suggest that the proposed technique outperforms existing state-of-the-art algorithms.

Scalable UWB photonic generator based on the combination of doublet pulses

We propose and experimentally demonstrate a scalable and reconfigurable optical scheme to generate high order UWB pulses. Firstly, various ultra wideband doublets are created through a process of phase-tointensity conversion by means of a phase modulation and a dispersive media. In a second stage, doublets are combined in an optical processing unit that allows the reconfiguration of UWB high order pulses. Experimental results both in time and frequency domains are presented showing good performance related to the fractional bandwidth and spectral efficiency parameters.