Systems approaches to modelling pathways and networks.

Peer reviewedPreprin

Construction, Concentration, and (Dis)Continuities in Social Valuations

I review and integrate recent sociological research that makes progress on three interrelated questions pertaining to social valuation: (a) the degree of social construction relative to objective constraints; (b) the degree of concentration in social valuations at a single point in time; and (c) the conditions that govern two broad forms of temporal discontinuity—(i) fashion cycles, especially in cultural expression and in managerial practices, and (ii) bubble/crash dynamics, as witnessed in such domains as authoritarian regimes and financial markets. In the course of the review, I argue for the importance of identifying how objective conditions constrain social construction and suggest two contrarian mechanisms by which this is accomplished—valuation opportunism and valuation entrepreneurship—and the conditions under which they are more or less effective

Factors Associated with Influenza Vaccination of Hospitalized Elderly Patients in Spain

Vaccination of the elderly is an important factor in limiting the impact of influenza in the community. The aim of this study was to investigate the factors associated with influenza vaccination coverage in hospitalized patients aged ≥ 65 years hospitalized due to causes unrelated to influenza in Spain. We carried out a cross-sectional study. Bivariate analysis was performed comparing vaccinated and unvaccinated patients, taking in to account sociodemographic variables and medical risk conditions. Multivariate analysis was performed using multilevel regression models. We included 1038 patients: 602 (58%) had received the influenza vaccine in the 2013-14 season. Three or more general practitioner visits (OR = 1.61; 95% CI 1.19-2.18); influenza vaccination in any of the 3 previous seasons (OR = 13.57; 95% CI 9.45-19.48); and 23-valent pneumococcal polysaccharide vaccination (OR = 1.97; 95% CI 1.38-2.80) were associated with receiving the influenza vaccine. Vaccination coverage of hospitalized elderly people is low in Spain and some predisposing characteristics influence vaccination coverage. Healthcare workers should take these characteristics into account and be encouraged to proactively propose influenza vaccination to all patients aged ≥ 65 year

Study on the Decomposition of the Amadori Compound N-( l-Deoxy-D-fructos-l-yl)-glycine in Model Systems : Quantification by Fast Atom Bombardment Tandem Mass Spectrometry

A new method for the quantification of N-(ldeoxy-D-huctas-l-yl)-glycine (DFG) was developed based on isotope dilution fast atom bombardment tandem mass spectrometry using '3C-laheUed DFG as an internal standard. This method, which requires neither derivatization nor clean-up of the samples, was used to study the degradation of DFG under different conditions (time and pH). It was found that the decomposition of DFG at 90°C was favoured at pH 7 compared to pH 6. The higher stability of DFG at pH 6 was due to 1,2-enolization leading to the relatively stable 3deoxglucoson

A transient third cranial nerve palsy as presenting sign of spontaneous intracranial hypotension

Spontaneous intracranial hypotension is an uncommon cause of sudden and persistent headache: associated symptoms are common, among which there are cranial nerve palsies, especially of the abducens nerve. We report a case of a 21-year-old man with a transient and isolated third nerve palsy due to spontaneous intracranial hypotension. To our knowledge, there are only few reports in the literature of such association

C–O–H–S fluids and granitic magma : how S partitions and modifies CO2 concentrations of fluid-saturated felsic melt at 200 MPa

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Contributions to Mineralogy and Petrology 162 (2011): 849-865, doi:10.1007/s00410-011-0628-1.Hydrothermal volatile-solubility and partitioning experiments were conducted with fluid-saturated haplogranitic melt, H2O, CO2, and S in an internally heated pressure vessel at 900°C and 200 MPa; three additional experiments were conducted with iron-bearing melt. The run-product glasses were analyzed by electron microprobe, FTIR, and SIMS; and they contain ≤ 0.12 wt% S, ≤ 0.097 wt.% CO2, and ≤ 6.4 wt.% H2O. Apparent values of log ƒO2 for the experiments at run conditions were computed from the [(S6+)/(S6++S2-)] ratio of the glasses, and they range from NNO-0.4 to NNO+1.4. The C-O-H-S fluid compositions at run conditions were computed by mass balance, and they contained 22-99 mol% H2O, 0-78 mol% CO2, 0-12 mol% S, and < 3 wt% alkalis. Eight S-free experiments were conducted to determine the H2O and CO2 concentrations of melt and fluid compositions and to compare them with prior experimental results for C-O-H fluid-saturated rhyolite melt, and the agreement is excellent. Sulfur partitions very strongly in favor of fluid in all experiments, and the presence of S modifies the fluid compositions, and hence, the CO2 solubilities in coexisting felsic melt. The square of the mole fraction of H2O in melt increases in a linear fashion, from 0.05-0.25, with the H2O concentration of the fluid. The mole fraction of CO2 in melt increases linearly, from 0.0003-0.0045, with the CO2 concentration of C-O-H-S fluids. Interestingly, the CO2 concentration in melts, involving relatively reduced runs (log ƒO2 ≤ NNO+0.3) that contain 2.5-7 mol% S in the fluid, decreases significantly with increasing S in the system. This response to the changing fluid composition causes the H2O and CO2 solubility curve for C-O-H-S fluid-saturated haplogranitic melts at 200 MPa to shift to values near that modeled for C-O-H fluid-saturated, S-free rhyolite melt at 150 MPa. The concentration of S in haplogranitic melt increases in a linear fashion with increasing S in C-O-H-S fluids, but these data show significant dispersion that likely reflects the strong influence of ƒO2 on S speciation in melt and fluid. Importantly, the partitioning of S between fluid and melt does not vary with the (H2O/H2O+CO2) ratio of the fluid. The fluid-melt partition coefficients for H2O, CO2, and S and the atomic (C/S) ratios of the run-product fluids are virtually identical to thermodynamic constraints on volatile partitioning and the H, S, and C contents of pre-eruptive magmatic fluids and volcanic gases for subduction-related magmatic systems thus confirming our experiments are relevant to natural eruptive systems.This research was supported in part by National Science Foundation awards EAR 0308866 and EAR-0836741 to J.D.W

The Intermediate Filament Network in Cultured Human Keratinocytes Is Remarkably Extensible and Resilient

The prevailing model of the mechanical function of intermediate filaments in cells assumes that these 10 nm diameter filaments make up networks that behave as entropic gels, with individual intermediate filaments never experiencing direct loading in tension. However, recent work has shown that single intermediate filaments and bundles are remarkably extensible and elastic in vitro, and therefore well-suited to bearing tensional loads. Here we tested the hypothesis that the intermediate filament network in keratinocytes is extensible and elastic as predicted by the available in vitro data. To do this, we monitored the morphology of fluorescently-tagged intermediate filament networks in cultured human keratinocytes as they were subjected to uniaxial cell strains as high as 133%. We found that keratinocytes not only survived these high strains, but their intermediate filament networks sustained only minor damage at cell strains as high as 100%. Electron microscopy of stretched cells suggests that intermediate filaments are straightened at high cell strains, and therefore likely to be loaded in tension. Furthermore, the buckling behavior of intermediate filament bundles in cells after stretching is consistent with the emerging view that intermediate filaments are far less stiff than the two other major cytoskeletal components F-actin and microtubules. These insights into the mechanical behavior of keratinocytes and the cytokeratin network provide important baseline information for current attempts to understand the biophysical basis of genetic diseases caused by mutations in intermediate filament genes

Understanding the Adaptive Growth Strategy of Lactobacillus plantarum by In Silico Optimisation

In the study of metabolic networks, optimization techniques are often used to predict flux distributions, and hence, metabolic phenotype. Flux balance analysis in particular has been successful in predicting metabolic phenotypes. However, an inherent limitation of a stoichiometric approach such as flux balance analysis is that it can predict only flux distributions that result in maximal yields. Hence, previous attempts to use FBA to predict metabolic fluxes in Lactobacillus plantarum failed, as this lactic acid bacterium produces lactate, even under glucose-limited chemostat conditions, where FBA predicted mixed acid fermentation as an alternative pathway leading to a higher yield. In this study we tested, however, whether long-term adaptation on an unusual and poor carbon source (for this bacterium) would select for mutants with optimal biomass yields. We have therefore adapted Lactobacillus plantarum to grow well on glycerol as its main growth substrate. After prolonged serial dilutions, the growth yield and corresponding fluxes were compared to in silico predictions. Surprisingly, the organism still produced mainly lactate, which was corroborated by FBA to indeed be optimal. To understand these results, constraint-based elementary flux mode analysis was developed that predicted 3 out of 2669 possible flux modes to be optimal under the experimental conditions. These optimal pathways corresponded very closely to the experimentally observed fluxes and explained lactate formation as the result of competition for oxygen by the other flux modes. Hence, these results provide thorough understanding of adaptive evolution, allowing in silico predictions of the resulting flux states, provided that the selective growth conditions favor yield optimization as the winning strategy

PTHrP Induces Autocrine/Paracrine Proliferation of Bone Tumor Cells through Inhibition of Apoptosis

Giant Cell Tumor of Bone (GCT) is an aggressive skeletal tumor characterized by local bone destruction, high recurrence rates and metastatic potential. Previous work in our lab has shown that the neoplastic cell of GCT is a proliferating pre-osteoblastic stromal cell in which the transcription factor Runx2 plays a role in regulating protein expression. One of the proteins expressed by these cells is parathryroid hormone-related protein (PTHrP). The objectives of this study were to determine the role played by PTHrP in GCT of bone with a focus on cell proliferation and apoptosis. Primary stromal cell cultures from 5 patients with GCT of bone and one lung metastsis were used for cell-based experiments. Control cell lines included a renal cell carcinoma (RCC) cell line and a human fetal osteoblast cell line. Cells were exposed to optimized concentrations of a PTHrP neutralizing antibody and were analyzed with the use of cell proliferation and apoptosis assays including mitochondrial dehydrogenase assays, crystal violet assays, APO-1 ELISAs, caspase activity assays, flow cytometry and immunofluorescent immunohistochemistry. Neutralization of PTHrP in the cell environment inhibited cell proliferation in a consistent manner and induced apoptosis in the GCT stromal cells, with the exception of those obtained from a lung metastasis. Cell cycle progression was not significantly affected by PTHrP neutralization. These findings indicate that PTHrP plays an autocrine/paracrine neoplastic role in GCT by allowing the proliferating stromal cells to evade apoptosis, possibly through non-traditional caspase-independent pathways. Thus PTHrP neutralizing immunotherapy is an intriguing potential therapeutic strategy for this tumor

Adult zebrafish as a model organism for behavioural genetics

Recent research has demonstrated the suitability of adult zebrafish to model some aspects of complex behaviour. Studies of reward behaviour, learning and memory, aggression, anxiety and sleep strongly suggest that conserved regulatory processes underlie behaviour in zebrafish and mammals. The isolation and molecular analysis of zebrafish behavioural mutants is now starting, allowing the identification of novel behavioural control genes. As a result of this, studies of adult zebrafish are now helping to uncover the genetic pathways and neural circuits that control vertebrate behaviour