bluuebunny/crossref_metadata_2025 huggingface dataset:
The Current Knowledge of the Role of PPAR in Hepatic Ischemia-Reperfusion Injury
Authors: Elias-Miró M. , Jiménez-Castro M. B. , Mendes-Braz M. , Casillas-Ramírez A. , Peralta C.
Published: May 2012

Strategies to improve the viability of steatotic livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid metabolism and inflammation. In this paper, we review the PPAR signaling pathways and present some of their lesser-known functions in liver regeneration. Potential therapies based on PPAR regulation will be discussed. The data suggest that further investigations are required to elucidate whether PPAR could be a potential therapeutic target in liver surgery and to determine the most effective therapies that selectively regulate PPAR with minor side effects.
New Results in Optical Modelling of Quantum Well Solar Cells
Authors: Fara Silvian , Sterian Paul , Fara Laurentiu , Iancu Mihai , Sterian Andreea
Published: May 2012

This project brought further advancements to the quantum well solar cell concept proposed by Keith Barnham. In this paper, the optical modelling of MQW solar cells was analyzed and we focussed on the following topics: (i) simulation of the refraction index and the reflectance, (ii) simulation of the absorption coefficient, (iii) simulation of the quantum efficiency for the absorption process, (iv) discussion and modelling of the quantum confinement effect, and (v) evaluation of datasheet parameters of the MQW cell.
Heat and Mass Transfer during Hydrogen Generation in an Array of Fuel Bars of a BWR Using a Periodic Unit Cell
Authors: Romero-Paredes H. , Valdés-Parada F. J. , Espinosa-Paredes G.
Published: May 2012

This paper presents, the numerical analysis of heat and mass transfer during hydrogen generation in an array of fuel cylinder bars, each coated with a cladding and a steam current flowing outside the cylinders. The analysis considers the fuel element without mitigation effects. The system consists of a representative periodic unit cell where the initial and boundary-value problems for heat and mass transfer were solved. In this unit cell, we considered that a fuel element is coated by a cladding with steam surrounding it as a coolant. The numerical simulations allow describing the evolution of the temperature and concentration profiles inside the nuclear reactor and could be used as a basis for hybrid upscaling simulations.
Online Health Management for Complex Nonlinear Systems Based on Hidden Semi‐Markov Model Using Sequential Monte Carlo Methods
Authors: Liu Qinming , Dong Ming
Published: May 2012

Health management for a complex nonlinear system is becoming more important for condition‐based maintenance and minimizing the related risks and costs over its entire life. However, a complex nonlinear system often operates under dynamically operational and environmental conditions, and it subjects to high levels of uncertainty and unpredictability so that effective methods for online health management are still few now. This paper combines hidden semi‐Markov model (HSMM) with sequential Monte Carlo (SMC) methods. HSMM is used to obtain the transition probabilities among health states and health state durations of a complex nonlinear system, while the SMC method is adopted to decrease the computational and space complexity, and describe the probability relationships between multiple health states and monitored observations of a complex nonlinear system. This paper proposes a novel method of multisteps ahead health recognition based on joint probability distribution for health management of a complex nonlinear system. Moreover, a new online health prognostic method is developed. A real case study is used to demonstrate the implementation and potential applications of the proposed methods for online health management of complex nonlinear systems.
Awareness and Perception of Plastic Surgery among Healthcare Professionals in Pune, India: Do They Really Know What We Do?
Authors: Panse Nikhil , Panse Smita , Kulkarni Priya , Dhongde Rajendra , Sahasrabudhe Parag
Published: May 2012

Purpose. The aim of this study is to understand the level of awareness and knowledge of plastic surgery in healthcare professionals in a tertiary health care facility in Pune, India. This study also aims to highlight the perception of the medical professionals about plastic surgery and what they think a plastic surgeon does. Materials and Methods. A questionnaire-based survey was done at B.J Medical College and Sassoon Hospital, Pune in 2011. Feedback evaluation forms from hundred resident doctors and faculty were evaluated and analyzed. Results. There is not much awareness about plastic surgery as a specialty amongst health care providers. Plastic surgery is mostly perceived as cosmetic surgery, and the other spectrum of the patients we cater to goes largely unnoticed. Of all the clinical conditions given to the participants, there was not a single clinical condition where the respondents favored unanimously for plastic surgeons. Conclusion. Plastic surgery as a specialty is poorly understood by our medical colleagues, and the onus of creating and improving the awareness and perception of our specialty lies on us. Herculean unified efforts at individual as well as global level will help us achieve this goal.
Differential Expression of 2′,3′-Cyclic-Nucleotide 3′-Phosphodiesterase and Neural Lineage Markers Correlate with Glioblastoma Xenograft Infiltration and Patient Survival
Authors: Zorniak Michael , Clark Paul A. , Leeper Heather E. , Tipping Matthew D. , Francis David M. , Kozak Kevin R. , Salamat M. Shahriar , Kuo John S.
Published: May 2012

Purpose: Glioblastoma multiforme (GBM) is a poorly treated human brain cancer with few established clinically useful molecular prognostic markers. We characterized glioblastoma stem–like cells (GSC) according to developmental neural lineage markers and correlated their expression with patient survival.

Experimental Design: Immunoblot array of neural lineage markers classified five independently isolated human GSC lines into three classes exhibiting differential expression of oligodendrocyte progenitor cells (OPC), astrocyte progenitor cells (APC), and neural progenitor cells (NPC) markers. Immunodeficient mice were orthotopically implanted with each cell line to evaluate tumor infiltration and recipient survival. 2′,3′-Cyclic-nucleotide 3′-phosphodiesterase (CNP) antigenic expression was used to evaluate a clinically annotated GBM tissue microarray with 115 specimens.

Results: We report that molecular classification of patient-derived GSCs using neural lineage markers show association with differential xenograft invasiveness, and also show significant correlation to survival in both the mouse model and human patients. Orthotopic implantation into immunodeficient mice showed Ki-67 proliferative index independent xenograft infiltration: class I GSCs (OPC and NPC positive) established focal lesions, class II GSCs (NPC positive) formed minimally invasive lesions, and class III GSCs (APC positive) established highly infiltrative lesions. The OPC marker, CNP also exhibited high expression in focal xenografts versus low expression in invasive xenografts. Differential CNP expression correlated with mouse model survival, and CNP immunoassay of a large GBM tissue microarray also showed significant differential patient survival.

Conclusions: GSC classification with developmental neural lineage markers revealed CNP as a novel and potentially useful clinical prognosis marker, and suggests clinical importance for patient-specific GSC analysis. Clin Cancer Res; 18(13); 3628–36. ©2012 AACR.
FES Kinase Promotes Mast Cell Recruitment to Mammary Tumors via the Stem Cell Factor/KIT Receptor Signaling Axis
Authors: Kwok Ester , Everingham Stephanie , Zhang Shengnan , Greer Peter A. , Allingham John S. , Craig Andrew W.B.
Published: May 2012

KIT receptor is required for mast cell development, survival, and migration toward its ligand stem cell factor (SCF). Many solid tumors express SCF and this leads to mast cell recruitment to tumors and release of mediators linked to tumor angiogenesis, growth, and metastasis. Here, we investigate whether FES protein-tyrosine kinase, a downstream effector of KIT signaling in mast cells, is required for migration of mast cells toward SCF-expressing mammary tumors. Using a novel agarose drop assay for chemotaxis of bone marrow–derived mast cells (BMMC) toward SCF, we found that defects in chemotaxis of fes-null BMMCs correlated with disorganized microtubule networks in polarized cells. FES displayed partial colocalization with microtubules in polarized BMMCs and has at least two direct microtubule binding sites within its N-terminal F-BAR and SH2 domains. An oligomerization-disrupting mutation within the Fer/CIP4 homology-Bin/Amphiphysin/Rvs (F-BAR) domain had no effect on microtubule binding, whereas microtubule binding to the SH2 domain was dependent on the phosphotyrosine-binding pocket. FES involvement in mast cell recruitment to tumors was tested using the AC2M2 mouse mammary carcinoma model. These tumor cells expressed SCF and promoted BMMC recruitment in a KIT- and FES-dependent manner. Engraftment of AC2M2 orthotopic and subcutaneous tumors in control or fes-null mice, revealed a key role for FES in recruitment of mast cells to the tumor periphery. This may contribute to the reduced tumor growth and metastases observed in fes-null mice compared with control mice. Taken together, FES is a potential therapeutic target to limit the progression of tumors with stromal mast cell involvement. Mol Cancer Res; 10(7); 881–91. ©2012 AACR.
Dietary Energy Balance Modulates Epithelial-to-Mesenchymal Transition and Tumor Progression in Murine Claudin-Low and Basal-like Mammary Tumor Models
Authors: Dunlap Sarah M. , Chiao Lucia J. , Nogueira Leticia , Usary Jerry , Perou Charles M. , Varticovski Lyuba , Hursting Stephen D.
Published: May 2012

Using novel murine models of claudin-low and basal-like breast cancer, we tested the hypothesis that diet-induced obesity (DIO) and calorie restriction (CR) differentially modulate progression of these aggressive breast cancer subtypes. For model development, we characterized two cell lines, “mesenchymal (M)-Wnt” and “epithelial (E)-Wnt,” derived from MMTV-Wnt-1 transgenic mouse mammary tumors. M-Wnt, relative to E-Wnt, cells were tumor-initiating cell (TIC)-enriched (62% vs. 2.4% CD44high/CD24low) and displayed enhanced ALDEFLUOR positivity, epithelial-to-mesenchymal transition (EMT) marker expression, mammosphere-forming ability, migration, invasion, and tumorigenicity (P < 0.001; each parameter). M-Wnt and E-Wnt cells clustered with claudin-low and basal-like breast tumors, respectively, in gene expression profiles and recapitulated these tumors when orthotopically transplanted into ovariectomized C57BL/6 mice. To assess the effects of energy balance interventions on tumor progression and EMT, mice were administered DIO, control, or CR diets for 8 weeks before orthotopic transplantation of M-Wnt or E-Wnt cells (for each cell line, n = 20 mice per diet) and continued on their diets for 6 weeks while tumor growth was monitored. Relative to control, DIO enhanced M-Wnt (P = 0.01), but not E-Wnt, tumor progression; upregulated EMT- and TIC-associated markers including N-cadherin,fibronectin, TGFβ, Snail, FOXC2, and Oct4 (P < 0.05, each); and increased intratumoral adipocytes. Conversely, CR suppressed M-Wnt and E-Wnt tumor progression (P < 0.02, each) and inhibited EMT and intratumoral adipocyte accumulation. Thus, dietary energy balance interventions differentially modulate EMT and progression of claudin-low and basal-like tumors. EMT pathway components may represent targets for breaking the obesity–breast cancer link, particularly for preventing and/or controlling TIC-enriched subtypes such as claudin-low breast cancer. Cancer Prev Res; 5(7); 930–42. ©2012 AACR.
Limitations of Ranking Lists Based on Cardiac Surgery Mortality Rates
Authors: Siregar Sabrina , Groenwold Rolf H.H. , Jansen Evert K. , Bots Michiel L. , van der Graaf Yolanda , van Herwerden Lex A.
Published: May 2012

Background—

Ranking lists are a common way of reporting performance in cardiac surgery; however, rankings have shown to be imprecise, yet the extent of this imprecision is unknown. We aimed to determine the precision of, and fluctuations in, ranking lists in the comparison of cardiac surgery mortality rates.

Methods and Results—

Information on all adult cardiac surgery patients in all 16 cardiothoracic centers in The Netherlands from January 1, 2007, until December 31, 2009, was extracted from the database of the Netherlands Association for Cardio-Thoracic Surgery (n=46883). Ranks were assessed using crude and adjusted mortality rates, using a random effects logistic regression model. Risk adjustment was performed using the logistic EuroSCORE. Statistical precision of ranks was assessed with 95% confidence intervals. Additional analyses were performed for patients with isolated coronary artery bypass grafting. The ranking lists, based on mortality rates in 3 consecutive years, showed considerable reshuffling. When all data were pooled, the mean width of the 95% confidence intervals was 10 ranks using crude and 8 ranks using adjusted mortality rates. The large overlap of the confidence intervals across hospitals indicates that rank statistics were not materially different. Results were similar in the isolated coronary artery bypass grafting subgroup.

Conclusions—

Rankings are an imprecise statistical method to report cardiac surgery mortality rates and prone to (random) fluctuation. Hence, reshuffling of ranks can be expected solely due to chance. Therefore, we strongly discourage the use of ranking lists in the comparison of mortality rates.
Hebbian Learning of Recurrent Connections: A Geometrical Perspective
Authors: Galtier Mathieu N. , Faugeras Olivier D. , Bressloff Paul C.
Published: May 2012

We show how a Hopfield network with modifiable recurrent connections undergoing slow Hebbian learning can extract the underlying geometry of an input space. First, we use a slow and fast analysis to derive an averaged system whose dynamics derives from an energy function and therefore always converges to equilibrium points. The equilibria reflect the correlation structure of the inputs, a global object extracted through local recurrent interactions only. Second, we use numerical methods to illustrate how learning extracts the hidden geometrical structure of the inputs. Indeed, multidimensional scaling methods make it possible to project the final connectivity matrix onto a Euclidean distance matrix in a high-dimensional space, with the neurons labeled by spatial position within this space. The resulting network structure turns out to be roughly convolutional. The residual of the projection defines the nonconvolutional part of the connectivity, which is minimized in the process. Finally, we show how restricting the dimension of the space where the neurons live gives rise to patterns similar to cortical maps. We motivate this using an energy efficiency argument based on wire length minimization. Finally, we show how this approach leads to the emergence of ocular dominance or orientation columns in primary visual cortex via the self-organization of recurrent rather than feedforward connections. In addition, we establish that the nonconvolutional (or long-range) connectivity is patchy and is co-aligned in the case of orientation learning.
Learning the Dynamics of Objects by Optimal Functional Interpolation
Authors: Ahn Jong-Hoon , Kim In Young
Published: May 2012

Many areas of science and engineering rely on functional data and their numerical analysis. The need to analyze time-varying functional data raises the general problem of interpolation, that is, how to learn a smooth time evolution from a finite number of observations. Here, we introduce optimal functional interpolation (OFI), a numerical algorithm that interpolates functional data over time. Unlike the usual interpolation or learning algorithms, the OFI algorithm obeys the continuity equation, which describes the transport of some types of conserved quantities, and its implementation shows smooth, continuous flows of quantities. Without the need to take into account equations of motion such as the Navier-Stokes equation or the diffusion equation, OFI is capable of learning the dynamics of objects such as those represented by mass, image intensity, particle concentration, heat, spectral density, and probability density.
Sensitivity of Cloud Liquid Water Content Estimates to the Temperature-Dependent Thermodynamic Phase: A Global Study Using CloudSat Data
Authors: Devasthale Abhay , Thomas Manu Anna
Published: May 2012

The main purpose of this study is to underline the sensitivity of cloud liquid water content (LWC) estimates purely to 1) the shape of computationally simplified temperature-dependent thermodynamic phase and 2) the range of subzero temperatures covered to partition total cloud condensate into liquid and ice fractions. Linear, quadratic, or sigmoid-shaped functions for subfreezing temperatures (down to −20° or −40°C) are often used in climate models and reanalysis datasets for partitioning total condensate. The global vertical profiles of clouds obtained from CloudSat for the 4-yr period June 2006–May 2010 are used for sensitivity analysis and the quantitative estimates of sensitivities based on these realistic cloud profiles are provided. It is found that three cloud regimes in particular—convective clouds in the tropics, low-level clouds in the northern high latitudes, and middle-level clouds over the midlatitudes and Southern Ocean—are most sensitive to assumptions on thermodynamic phase. In these clouds, the LWC estimates based purely on quadratic or sigmoid-shaped functions with a temperature range down to −20°C can differ by up to 20%–40% over the tropics (in seasonal means), 10%–30% over the midlatitudes, and up to 50% over high latitudes compared to a linear assumption. When the temperature range is extended down to −40°C, LWC estimates in the sigmoid case can be much higher than the above values over high-latitude regions compared to the commonly used case with quadratic dependency down to −20°C. This sensitivity study emphasizes the need to critically investigate radiative impacts of cloud thermodynamic phase assumptions in simplified climate models and reanalysis datasets.
Improving HF Radar Estimates of Surface Currents Using Signal Quality Metrics, with Application to the MVCO High-Resolution Radar System
Authors: Kirincich Anthony R. , de Paolo Tony , Terrill Eric
Published: May 2012

Estimates of surface currents over the continental shelf are now regularly made using high-frequency radar (HFR) systems along much of the U.S. coastline. The recently deployed HFR system at the Martha’s Vineyard Coastal Observatory (MVCO) is a unique addition to these systems, focusing on high spatial resolution over a relatively small coastal ocean domain with high accuracy. However, initial results from the system showed sizable errors and biased estimates of M2 tidal currents, prompting an examination of new methods to improve the quality of radar-based velocity data. The analysis described here utilizes the radial metric output of CODAR Ocean Systems’ version 7 release of the SeaSonde Radial Site Software Suite to examine both the characteristics of the received signal and the output of the direction-finding algorithm to provide data quality controls on the estimated radial currents that are independent of the estimated velocity. Additionally, the effect of weighting spatial averages of radials falling within the same range and azimuthal bin is examined to account for differences in signal quality. Applied to two month-long datasets from the MVCO high-resolution system, these new methods are found to improve the rms difference comparisons with in situ current measurements by up to 2 cm s−1, as well as reduce or eliminate observed biases of tidal ellipses estimated using standard methods.
Comparisons of Single- and Double-Moment Microphysics Schemes in the Simulation of a Synoptic-Scale Snowfall Event
Authors: Molthan Andrew L. , Colle Brian A.
Published: May 2012

The Canadian CloudSat/Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) Validation Project (C3VP) provided aircraft, surface, and remotely sensed observations of cloud and precipitation characteristics to support improved simulation of cold-season precipitation within weather forecast models and new developments in satellite and radar precipitation retrievals. On 22 January 2007, the C3VP campaign executed an intensive observation period to sample widespread snowfall that occurred as a midlatitude cyclone tracked along the U.S.–Canadian border. Surface air temperature and precipitation measurements, combined with aircraft measurement of hydrometeor content and size distribution, are used to examine various assumptions and parameterizations included within four bulk water microphysics schemes available within the Weather Research and Forecasting Model (WRF).

In a simulation of the 22 January 2007 event, WRF forecasts reproduced the overall precipitation pattern observed during aircraft sampling, allowing for a comparison between C3VP measurements and microphysics scheme assumptions. Single-moment schemes that provide flexibility in size distribution parameters as functions of temperature can represent much of the vertical variability observed in aircraft data, but variability is reduced in an environment where the simulated temperature profile is nearly isothermal. Double-moment prediction of total number concentration may improve the representation of ice crystal aggregation. Inclusion of both temperature dependence on distribution parameters and variability in mass–diameter or diameter–fall speed relationships suggest a means of improving upon single-moment predictions.
Two Overlooked Biases of the Advanced Research WRF (ARW) Model in Geopotential Height and Temperature
Authors: Wee Tae-Kwon , Kuo Ying-Hwa , Lee Dong-Kyou , Liu Zhiquan , Wang Wei , Chen Shu-Ya
Published: May 2012

The authors have discovered two sizeable biases in the Weather Research and Forecasting (WRF) model: a negative bias in geopotential and a warm bias in temperature, appearing both in the initial condition and the forecast. The biases increase with height and thus manifest themselves at the upper part of the model domain. Both biases stem from a common root, which is that vertical structures of specific volume and potential temperature are convex functions. The geopotential bias is caused by the particular discrete hydrostatic equation used in WRF and is proportional to the square of the thickness of model layers. For the vertical levels used in this study, the bias far exceeds the gross 1-day forecast bias combining all other sources. The bias is fixed by revising the discrete hydrostatic equation. WRF interpolates potential temperature from the grids of an external dataset to the WRF grids in generating the initial condition. Associated with the Exner function, this leads to the marked bias in temperature. By interpolating temperature to the WRF grids and then computing potential temperature, the bias is removed. The bias corrections developed in this study are expected to reduce the disparity between the forecast and observations, and eventually to improve the quality of analysis and forecast in the subsequent data assimilation. The bias corrections might be especially beneficial to assimilating height-based observations (e.g., radio occultation data).
Celebrating Thirty Years of the JLSP
Authors: Gasiorek Jessica , Giles Howard , Holtgraves Thomas , Robbins Stephanie
Published: May 2012

The Journal of Language and Social Psychology has been publishing articles for 30 years. In this article, three different kinds of analyses (viz., content codings, word clouds, and a textual procedure) examining trends over and between the three decades are reported. Drawing on these, future directions for the journal and the field in general are anticipated and proposed.
Hemodynamic Monitoring in the Intensive Care Unit
Authors: Muller Joseph C. , Kennard Jason W. , Browne Jeffrey S. , Fecher Alison M. , Hayward Thomas Z.
Published: May 2012

Patients in the intensive care unit are often critically ill with inadequate tissue perfusion and oxygenation. This inadequate delivery of substrates at the cellular level is a common definition of shock. Hemodynamic monitoring is the observation of cardiovascular physiology. The purpose of hemodynamic monitoring is to identify abnormal physiology and intervene before complications, including organ failure and death, occur. The most common types of invasive hemodynamic monitors are central venous catheters, pulmonary artery catheters, and arterial pulse‐wave analysis. Ultrasonography is a noninvasive alternative being used in intensive care units for hemodynamic measurements and assessments.
Kinetic stability of all-in-one parenteral nutrition admixtures in the presence of high dose Ca2+ additive under clinical application circumstances
Authors: Télessy István G , Balogh Judith , Szabó Barnabás , Csempesz Ferenc , Zelkó Romána
Published: May 2012

Background

TPN infusions are usually administered during a treatment period of 10–24 hours per day due to the metabolic capacity of the liver. During this time interval physicochemically stable TPN solution (emulsion) is needed for the treatment. The purpose of the present study was to examine how the kinetic stability features of ready-made total parenteral nutrition admixtures containing olive oil and soybean oil will change under the usage-modeling 24-hour application with and without overdose Ca2+.

Methods

Particle size analysis and zeta potential measurements were carried out to evaluate the possible changes in the kinetic stability of the emulsions.

Results

Our results indicate that in two of the four mixtures bimodal droplet-size distribution figures were detected and appearance of fat particles over 5 μm can not be disclosed. The tendency for separation of large diameter droplets in the two types of oil-based emulsion systems was different. In case of soybean containing emulsion second peak of droplets appeared in the bottom of the container in contrast to the olive oil containing emulsions where the second peak appeared in the surface layer. Interestingly this phenomenon is independent of calcium-content.

Conclusions

From therapeutic point the emulsions of the bigger droplets containing upper layer are safer because the potentially dangerous big droplets could remain in the infusion bag after the administration.
Effects of combined antiretroviral therapy on B- and T-cell release from production sites in long-term treated HIV-1+ patients
Authors: Quiros-Roldan Eugenia , Serana Federico , Chiarini Marco , Zanotti Cinzia , Sottini Alessandra , Gotti Daria , Torti Carlo , Caimi Luigi , Imberti Luisa
Published: May 2012

Background

The immune system reconstitution in HIV-1- infected patients undergoing combined antiretroviral therapy is routinely evaluated by T-cell phenotyping, even though the infection also impairs the B-cell mediated immunity. To find new laboratory markers of therapy effectiveness, both B- and T- immune recovery were evaluated by means of a follow-up study of long-term treated HIV-1- infected patients, with a special focus on the measure of new B- and T-lymphocyte production.

Methods

A longitudinal analysis was performed in samples obtained from HIV-1-infected patients before therapy beginning and after 6, 12, and 72 months with a duplex real-time PCR allowing the detection of K-deleting recombination excision circles (KRECs) and T-cell receptor excision circles (TRECs), as measures of bone-marrow and thymic output, respectively. A cross sectional analysis was performed to detect B- and T-cell subsets by flow cytometry in samples obtained at the end of the follow-up, which were compared to those of untreated HIV-1-infected patients and uninfected controls.

Results

The kinetics and the timings of B- and T-cell release from the bone marrow and thymus during antiretroviral therapy were substantially different, with a decreased B-cell release and an increased thymic output after the prolonged therapy. The multivariable regression analysis showed that a longer pre-therapy infection duration predicts a minor TREC increase and a major KREC reduction.

Conclusions

The quantification of KRECs and TRECs represents an improved method to monitor the effects of therapies capable of influencing the immune cell pool composition in HIV-1-infected patients.
Rational design of 13C-labeling experiments for metabolic flux analysis in mammalian cells
Authors: Crown Scott B , Ahn Woo Suk , Antoniewicz Maciek R
Published: May 2012

Background

13C-Metabolic flux analysis (13C-MFA) is a standard technique to probe cellular metabolism and elucidate in vivo metabolic fluxes. 13C-Tracer selection is an important step in conducting 13C-MFA, however, current methods are restricted to trial-and-error approaches, which commonly focus on an arbitrary subset of the tracer design space. To systematically probe the complete tracer design space, especially for complex systems such as mammalian cells, there is a pressing need for new rational approaches to identify optimal tracers.

Results

Recently, we introduced a new framework for optimal 13C-tracer design based on elementary metabolite units (EMU) decomposition, in which a measured metabolite is decomposed into a linear combination of so-called EMU basis vectors. In this contribution, we applied the EMU method to a realistic network model of mammalian metabolism with lactate as the measured metabolite. The method was used to select optimal tracers for two free fluxes in the system, the oxidative pentose phosphate pathway (oxPPP) flux and anaplerosis by pyruvate carboxylase (PC). Our approach was based on sensitivity analysis of EMU basis vector coefficients with respect to free fluxes. Through efficient grouping of coefficient sensitivities, simple tracer selection rules were derived for high-resolution quantification of the fluxes in the mammalian network model. The approach resulted in a significant reduction of the number of possible tracers and the feasible tracers were evaluated using numerical simulations. Two optimal, novel tracers were identified that have not been previously considered for 13C-MFA of mammalian cells, specifically [2,3,4,5,6-13C]glucose for elucidating oxPPP flux and [3,4-13C]glucose for elucidating PC flux. We demonstrate that 13C-glutamine tracers perform poorly in this system in comparison to the optimal glucose tracers.

Conclusions

In this work, we have demonstrated that optimal tracer design does not need to be a pure simulation-based trial-and-error process; rather, rational insights into tracer design can be gained through the application of the EMU basis vector methodology. Using this approach, rational labeling rules can be established a priori to guide the selection of optimal 13C-tracers for high-resolution flux elucidation in complex metabolic network models.
Development and myogenesis of the vermiform Buddenbrockia (Myxozoa) and implications for cnidarian body plan evolution
Authors: Gruhl Alexander , Okamura Beth
Published: May 2012

Background

The enigmatic wormlike parasite Buddenbrockia plumatellae has recently been shown to belong to the Myxozoa, which are now supported as a clade within Cnidaria. Most myxozoans are morphologically extremely simplified, lacking major metazoan features such as epithelial tissue layers, gut, nervous system, body axes and gonads. This hinders comparisons to free-living cnidarians and thus an understanding of myxozoan evolution and identification of their cnidarian sister group. However, B. plumatellae is less simplified than other myxozoans and therefore is of specific significance for such evolutionary considerations.

Methods

We analyse and describe the development of major body plan features in Buddenbrockia worms using a combination of histology, electron microscopy and confocal microscopy.

Results

Early developmental stages develop a primary body axis that shows a polarity, which is manifested as a gradient of tissue development, enabling distinction between the two worm tips. This polarity is maintained in adult worms, which, in addition, often develop a pore at the distal tip. The musculature comprises tetraradially arranged longitudinal muscle blocks consisting of independent myocytes embedded in the extracellular matrix between inner and outer epithelial tissue layers. The muscle fibres are obliquely oriented and in fully grown worms consistently form an angle of 12° with respect to the longitudinal axis of the worm in each muscle block and hence confer chirality. Connecting cells form a link between each muscle block and constitute four rows of cells that run in single file along the length of the worm. These connecting cells are remnants of the inner epithelial tissue layer and are anchored to the extracellular matrix. They are likely to have a biomechanical function.

Conclusions

The polarised primary body axis represents an ancient feature present in the last common ancestor of Cnidaria and Bilateria. The tetraradial arrangement of musculature is consistent with a medusozoan affinity for Myxozoa. However, the chiral pattern of muscle fibre orientation is apparently novel within Cnidaria and could thus be a specific adaptation. The presence of independent myocytes instead of Cnidaria-like epitheliomuscular cells can be interpreted as further support for the presence of mesoderm in cnidarians, or it may represent convergent evolution to a bilaterian condition.
Heritable differences in chemosensory ability among humans
Authors: Newcomb Richard D , Xia Mary B , Reed Danielle R
Published: May 2012

The combined senses of taste, smell and the common chemical sense merge to form what we call ‘flavor.’ People show marked differences in their ability to detect many flavors, and in this paper, we review the role of genetics underlying these differences in perception. Most of the genes identified to date encode receptors responsible for detecting tastes or odorants. We list these genes and describe their characteristics, beginning with the best-studied case, that of differences in phenylthiocarbamide (PTC) detection, encoded by variants of the bitter taste receptor gene TAS2R38. We then outline examples of genes involved in differences in sweet and umami taste, and discuss what is known about other taste qualities, including sour and salty, fat (termed pinguis), calcium, and the ‘burn’ of peppers. Although the repertoire of receptors involved in taste perception is relatively small, with 25 bitter and only a few sweet and umami receptors, the number of odorant receptors is much larger, with about 400 functional receptors and another 600 potential odorant receptors predicted to be non-functional. Despite this, to date, there are only a few cases of odorant receptor variants that encode differences in the perception of odors: receptors for androstenone (musky), isovaleric acid (cheesy), cis-3-hexen-1-ol (grassy), and the urinary metabolites of asparagus. A genome-wide study also implicates genes other than olfactory receptors for some individual differences in perception. Although there are only a small number of examples reported to date, there may be many more genetic variants in odor and taste genes yet to be discovered.
Poultry fat decreased fatty acid transporter protein mRNA expression and affected fatty acid composition in chickens
Authors: Yuan Jianmin , Zhang Bingkun , Guo Yuming
Published: May 2012

Background

A study was undertaken to examine the effects of poultry fat (PF) compared with those of soybean oil (SBO) on intestinal development, fatty acid transporter protein (FATP) mRNA expression, and fatty acid composition in broiler chickens. A total of 144 day-old male commercial broilers were randomly allocated to 2 treatment groups (6 replicates of 12 chicks for each treatment) and fed isocaloric diets containing 3.0% PF or 2.7% SBO at 0 to 3 wk and 3.8% PF or 3.5% SBO at 4 to 6 wk, respectively.

Results

PF had no influence on intestinal morphology, weight, or DNA, RNA, or protein concentrations at 2, 4, and 6 wk of age. However, compared with SBO, PF significantly decreased FATP mRNA abundance at 4 wk (P = 0.009) and 6 wk of age (P < 0.001); decreased liver fatty acid-binding protein (L-FABP) mRNA abundance at 6 wk of age (P = 0.039); and decreased C18:2 (P = 0.015), C18:3 (P < 0.001), C20:2 (P = 0.018), Σ-polyunsaturated fatty acids ( Σ-PUFA) (P = 0.020), and the proportion of PUFA (P < 0.001) in the intestinal mucosa and decreased C18:2 (P = 0.010), C18:3 (P < 0.001), C20:2 (P < 0.001), Σ-PUFA (P = 0.005), and the proportion of PUFA (P < 0.001) in breast muscle at 6 wk of age.

Conclusions

PF decreases FATP and L-FABP mRNA expression and decreased the proportion of PUFA in the intestinal mucosa and breast muscle.
The role of inflammation and cardiovascular disease risk on microvascular and macrovascular endothelial function in patients with rheumatoid arthritis: a cross-sectional and longitudinal study
Authors: Sandoo Aamer , Kitas George D , Carroll Douglas , Veldhuijzen van Zanten Jet JCS
Published: May 2012

Introduction

Rheumatoid arthritis (RA) is associated with an increased risk for cardiovascular disease (CVD), and it has been postulated that RA disease-related inflammation contributes to endothelial dysfunction. The aim of the present work was to examine predictors (RA-related and CVD risk factors) and anti-tumor necrosis factor-alpha (anti-TNF-α) treatment effects on endothelial function in different vascular beds.

Methods

Microvascular endothelial function (laser Doppler imaging with iontophoresis of acetylcholine and sodium-nitroprusside), and macrovascular endothelial function (flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation) were analyzed in parallel with disease activity. Individual CVD risk factors and global CVD risk were assessed cross-sectionally in 99 unselected RA patients and longitudinally (baseline, 2 weeks, and 3 months) in 23 RA patients commencing anti-TNF-α therapy.

Results

In this cross-sectional study, regression analyses revealed that markers of RA disease-related inflammation were not associated with microvascular or macrovascular endothelium-dependent function (P > 0.05); global CVD risk inversely correlated with microvascular endothelium-dependent function (P < 0.01) and with macrovascular endothelium-independent function (P < 0.01). In the longitudinal study, only microvascular endothelium-dependent function showed an improvement after 2 weeks of anti-TNF-α treatment when compared with baseline (437% ± 247% versus 319% ± 217%; P = 0.001), but no association was evident between change in endothelial function and change in inflammatory markers.

Conclusions

Classical CVD risk may influence endothelial function more than disease-related markers of inflammation in RA. Classical CVD risk factors and anti-TNF-α medication have different effects on microvascular and macrovascular endothelial function, suggesting that combined CVD-prevention approaches may be necessary. Prospective studies examining whether assessments of vascular function are predictive of long-term CV outcomes in RA are required.
The intravascular volume effect of Ringer's lactate is below 20%: a prospective study in humans
Authors: Jacob Matthias , Chappell Daniel , Hofmann-Kiefer Klaus , Helfen Tobias , Schuelke Anna , Jacob Barbara , Burges Alexander , Conzen Peter , Rehm Markus
Published: May 2012

Introduction

Isotonic crystalloids play a central role in perioperative fluid management. Isooncotic preparations of colloids (for example, human albumin or hydroxyethyl starch) remain nearly completely intravascular when infused to compensate for acute blood losses. Recent data were interpreted to indicate a comparable intravascular volume effect for crystalloids, challenging the occasionally suggested advantage of using colloids to treat hypovolemia. General physiological knowledge and clinical experience, however, suggest otherwise.

Methods

In a prospective study, double-tracer blood volume measurements were performed before and after intended normovolemic hemodilution in ten female adults, simultaneously substituting the three-fold amount of withdrawn blood with Ringer's lactate. Any originated deficits were substituted with half the volume of 20% human albumin, followed by a further assessment of blood volume. To assess significance between the measurements, repeated measures analysis of variance (ANOVA) according to Fisher were performed. If significant results were shown, paired t tests (according to Student) for the singular measurements were taken. P < 0.05 was considered to be significant.

Results

A total of 1,097 ± 285 ml of whole blood were withdrawn (641 ± 155 ml/m2 body surface area) and simultaneously replaced by 3,430 ± 806 ml of Ringer's lactate. All patients showed a significant decrease in blood volume after hemodilution (-459 ± 185 ml; P < 0.05) that did not involve relevant hemodynamical changes, and a significant increase in interstitial water content (+2,157 ± 606 ml; P < 0.05). The volume effect of Ringer's lactate was 17 ± 10%. The infusion of 245 ± 64 ml of 20% human albumin in this situation restored blood volume back to baseline values, the volume effect being 184 ± 63%.

Conclusions

Substitution of isolated intravascular deficits in cardiopulmonary healthy adults with the three-fold amount of Ringer's lactate impedes maintenance of intravascular normovolemia. The main side effect was an impressive interstitial fluid accumulation, which was partly restored by the intravenous infusion of 20% human albumin. We recommend to substitute the five-fold amount of crystalloids or to use an isooncotic preparation in the face of acute bleeding in patients where edema prevention might be advantageous.
CD56+ T cells inhibit HIV-1 infection of macrophages
Authors: Hou Wei , Ye Li , Ho Wen-Zhe
Published: May 2012

CD56+ T cells, through the secretion of IFN-γ, enhance the expression of IRFs and STATs, resulting in the induction of intracellular IFN-α/β and APOBEC3G/3F.

CD56+ T cells, the crucial component of the host innate immune system, play an important role in defense against viral infections. We investigated the noncytolytic anti-HIV-1 activity of primary CD56+ T cells. SNs collected from CD56+ T cell cultures inhibited HIV-1 infection and replication. This CD56+ T SN-mediated anti-HIV-1 activity was broad-spectrum, as CD56+ T SNs could inhibit infections by laboratory-adapted and clinical strains of HIV-1. The antibody to IFN-γ could partially block the CD56+ T SN-mediated anti-HIV effect. Investigation of mechanism(s) of the CD56+ T cell action on HIV-1 showed that although CD56+ T SN had little effect on HIV-1 entry coreceptor CCR5 expression, CD56+ T SN induced the expression of CC-chemokines, the ligands for CCR5. The antibodies to CC-chemokines also significantly blocked CD56+ T SN-mediated anti-HIV activity. Furthermore, CD56+ T SN up-regulated the expression of STAT-1/-2 and enhanced the expression of IRF1, -3, -7, and -9, resulting in the induction of endogenous IFN-α/β expression in macrophages. Moreover, CD56+ T SN up-regulated intracellular expression of APOBEC3G/3F, the recently identified HIV-1 restriction factors. These findings provide compelling evidence that CD56+ T cells may have a critical role in innate immunity against HIV-1 infection.
CCR7 ligands up-regulate IL-23 through PI3-kinase and NF-κB pathway in dendritic cells
Authors: Kuwabara Taku , Tanaka Yuriko , Ishikawa Fumio , Kondo Motonari , Sekiya Hideki , Kakiuchi Terutaka
Published: May 2012

CCR7 ligands activate PI3-kinase and NF-κB pathways in DC to induce the expression of IL-23p19.

We reported previously that the production of IL-23 is impaired in DCs from mice that lack expression of the chemokines CCL19 and CCL21, which share the receptor CCR7, suggesting that these chemokines are required for IL-23 expression. However, the molecular mechanism of CCR7-mediated IL-23 production in DCs is unknown. We found that CCL19 and CCL21 stimulated DCs through CCR7 and induced transcription of IL-23p19 mRNA and IL-23 production in splenic and BMDC. Stimulation of DCs with CCR7 ligands induced phosphorylation of MAPK family members and of Akt, but only a specific PI3K inhibitor, LY294002, not inhibitors of ERK, JNK, or p38, decreased IL-23p19 transcription and IL-23 production. In DCs stimulated with CCL19 or CCL21, IκBα was degraded, and NF-κB was translocated into the nucleus. Prevention of NF-κB activation blocked chemokine-mediated IL-23p19 transcription. A PI3K inhibitor abolished NF-κB activation and IL-23 production. Based on these findings, we concluded that PI3K and NF-κB signaling pathways play a critical role in CCR7-mediated IL-23 production in murine DCs. As IL-23 contributes to Th17 cell generation, and Th17 cells are pathogenic in autoimmune diseases, precise elucidation of these mechanisms would contribute to the development of strategies to control autoimmune diseases.
Full-waveform inversion of seismic data with the Neighborhood Algorithm
Authors: Fliedner Moritz M. , Treitel Sven , MacGregor Lucy
Published: May 2012

Stochastic (Monte Carlo) optimization methods like the Genetic Algorithm (GA) and Simulated Annealing (SA) have become increasingly popular for the inversion of geophysical data. In contrast to deterministic gradient-descent methods that search for the local minimum of the misfit function near a given starting guess, stochastic methods search for the global minimum of the misfit function even in the absence of a good starting model. Stochastic methods do not require the calculation of gradients of error surfaces. Only forward modeling is needed to evaluate the objective function. In addition to a single “best” model, some stochastic methods yield statistical information about the range of acceptable models for a given error tolerance by estimating Bayesian integrals of the posterior probability density distribution (PPD).
Induction of Gastrin Expression in Gastrointestinal Cells by Hypoxia or Cobalt Is Independent of Hypoxia-Inducible Factor (HIF)
Authors: Xiao Lin , Kovac Suzana , Chang Mike , Shulkes Arthur , Baldwin Graham S. , Patel Oneel
Published: May 2012

Gastrin and its precursors have been shown to promote mitogenesis and angiogenesis in gastrointestinal tumors. Hypoxia stimulates tumor growth, but its effect on gastrin gene regulation has not been examined in detail. Here we have investigated the effect of hypoxia on the transcription of the gastrin gene in human gastric cancer (AGS) cells. Gastrin mRNA was measured by real-time PCR, gastrin peptides were measured by RIA, and gastrin promoter activity was measured by dual-luciferase reporter assay. Exposure to a low oxygen concentration (1%) increased gastrin mRNA concentrations in wild-type AGS cells (AGS) and in AGS cells overexpressing the gastrin receptor (AGS-cholecystokinin receptor 2) by 2.1 ± 0.4- and 4.1 ± 0.3-fold (P < 0.05), respectively. The hypoxia mimetic, cobalt chloride (300 μM), increased gastrin promoter activity in AGS cells by 2.4 ± 0.3-fold (P < 0.05), and in AGS-cholecystokinin receptor 2 cells by 4.0 ± 0.3-fold (P < 0.05), respectively. The observations that either deletion from the gastrin promoter of the putative binding sites for the transcription factor hypoxia-inducible factor 1 (HIF-1) or knockdown of either the HIF-1α or HIF-1β subunit did not affect gastrin promoter inducibility under hypoxia indicated that the hypoxic activation of the gastrin gene is likely HIF independent. Mutational analysis of previously identified Sp1 regulatory elements in the gastrin promoter also failed to abrogate the induction of promoter activity by hypoxia. The observations that hypoxia up-regulates the gastrin gene in AGS cells by HIF-independent mechanisms, and that this effect is enhanced by the presence of gastrin receptors, provide potential targets for gastrointestinal cancer therapy.