bluuebunny/crossref_metadata_2025 huggingface dataset:
A random kinetic energy model for rock avalanches: Eight case studies
Authors: Preuth T. , Bartelt P. , Korup O. , McArdell B. W.
Published: September 2010

We apply a numerical avalanche dynamics model to predict runout, velocity, and spatial distribution of deposit thickness of eight rock avalanches. The model solves depth‐averaged mass and momentum conservation equations for avalanche flow in general three‐dimensional terrain using a second‐order finite‐volume method. In this paper, these standard mass and momentum equations are supplemented with an additional relation describing the production and decay of the kinetic energy associated with the random motion of rock fragments within the avalanche flow. Using results from full‐scale experiments with granular snow avalanches, we show that the random energy cannot perform mechanical work. Therefore, fundamental thermodynamic constraints exist between frictional shearing and the production of random energy that explain the reduction of flow friction as a function of the random kinetic energy fluxes. We utilize this result to extend the Voellmy avalanche rheology and simulate the eight case studies using one parameter set to avoid site‐specific parameter tuning. This procedure allows us to evaluate and compare simulation results of the case studies and gauge model performance. Our results support the hypothesis that the production of random kinetic energy within the flow is of relevance in the runout of rock avalanches. Although this random kinetic energy description is capable of reproducing a wide range of avalanche behavior, including extreme runout, more work is required to relate material properties of different rock types to the coefficients governing the production and decay processes. Furthermore, the fragmentation process itself must be included in the model to limit production rates.
Biomass collapse and carbon emissions from forest fragmentation in the Brazilian Amazon
Authors: Numata Izaya , Cochrane Mark A. , Roberts Dar A. , Soares João V. , Souza Carlos M. , Sales Marcio H.
Published: September 2010

Forest fragmentation due to deforestation is one of the major causes of forest degradation in the Amazon. Biomass collapse near forest edges, especially within 100 m, alters aboveground biomass and has potentially important implications for carbon emissions in the region. This phenomenon is tightly linked to spatial and temporal dynamics of forest edges in a landscape. However, the potential biomass loss and carbon emissions from forest edges and these spatiotemporal changes have never been estimated for actual landscapes in the Amazon. We conducted a deep temporal analysis of Rondônia, southwestern Brazilian Amazonia, using six Landsat path‐row scenes covering the 1985–2008 time period to estimate annual biomass loss and associated carbon emissions within 100 m of forest edges. Annual edge biomass loss averaged 9.1% of the biomass loss from deforestation during the study period, whereas average annual edge‐related carbon emissions from biomass loss were 6.0% of deforestation‐derived carbon emissions. However, because many edges were subsequently deforested during the 24 year study period, actual unaccounted for edge‐related carbon emissions during the 1985–2008 period, calculated from edges of all ages extant on the landscape in 2008, amounted to 3.6% of that attributed to all deforestation‐derived carbon fluxes for this time interval. Biomass loss and carbon emissions are highly influenced by the extent and age of edge‐affected forests. Large annual contributions of biomass loss and carbon emissions were found from active deforestation regions with young edges, whereas regions dominated by older edges had lower biomass loss and carbon emissions from edges.
Effects of acid leaching on the Sr‐Nd‐Hf isotopic compositions of ocean island basalts
Authors: Nobre Silva Inês G. , Weis Dominique , Scoates James S.
Published: September 2010

The ability to conduct multi‐isotopic analyses (e.g., Sr‐Nd‐Hf‐Pb) on the same sample is critical for studies that evaluate the mantle source components of oceanic basalts. The isotopic compositions of relatively immobile elements, such as Nd (and other REE) and Hf, are considered to be relatively resistant to alteration, however, accurate Sr and Pb isotopic analyses of oceanic basalts require thorough acid leaching prior to dissolution. A detailed study of the Sr, Nd and Hf isotopic systematics of acid‐leached oceanic basalts from Hawaii and Kerguelen was undertaken to assess how acid leaching affects their isotopic compositions. Most of the Sr, Nd and Hf was removed in the first acid leaching steps. Hawaiian basalts lose up to 35% and 40% of their total Sr and Hf contents, respectively, whereas for Kerguelen basalts the corresponding losses are 63% and ∼70%. Acid leaching leads to significant loss of the original Nd content (up to 90%), which cannot be solely explained by the elimination of alteration phases and is likely related to preferential removal of the REE in the constituent silicate minerals (e.g., plagioclase, clinopyroxene). The leached residues yield Sr isotopic ratios significantly less radiogenic than their respective unleached powders and Nd‐Hf isotopic compositions that are within analytical uncertainty of the respective unleached powders. This study shows that multi‐isotopic analyses on the same acid‐leached sample aliquot can produce reliable results for use in the discrimination of mantle source components of oceanic basalts.
The Matsuno‐Gill model and equatorial superrotation
Authors: Showman Adam P. , Polvani Lorenzo M.
Published: September 2010

Equatorial superrotation can be generated in global general circulation models (GCMs) when forced with longitudinally varying heating, similar to that postulated in the Matsuno‐Gill model. However, the implications of the classical Matsuno‐Gill theory for equatorial superrotation have not, to date, been addressed. Here, we show that the classic, shallow‐water Matsuno‐Gill solutions do not exhibit equatorial superrotation: although the flow converges westerly momentum from high latitudes to the equator—promoting superrotation—they also contain an artificial source of easterly momentum at the equator that cancels the latitudinal momentum convergence and prevents superrotation from emerging. This artificial momentum source results from a physically inconsistent representation of vertical momentum transport in the model. We show that if the Matsuno‐Gill model is modified to properly account for momentum exchange with an underlying quiescent layer, the solutions naturally exhibit equatorial superrotation, at any forcing amplitude.
Midlatitude nighttime D region ionosphere variability on hourly to monthly time scales
Authors: Han Feng , Cummer Steven A.
Published: September 2010

Significant temporal variability of the nighttime D region is well known, but its inaccessibility means that the time scales, magnitudes, and sources for that variability are not well understood. We probed the ionospheric D region by measuring the high‐power broadband very low frequency (VLF) signals launched by lightning and propagating in the Earth‐ionosphere waveguide. We analyzed broadband sferic data of July and August 2005 recorded by our sensors located near Duke University by comparing measured sferic spectra to model results and extracted the height of an assumed exponential electron density profile for each measurement. The measured nighttime D region electron density profile heights showed large temporal variations of several kilometers on some nights and relatively stable behaviors on others. The measured hourly average heights in 260 h ranged between 82.0 and 87.2 km, with a mean value of 84.9 km and a standard deviation of 1.1 km. The maximum variation in the 5 h period was around just above 4.0 km and the maximum variation in the 1 h period was around 1.3 km, with sharper gradients observed over shorter time periods. We also observed spatial variability as large as 2.0 km over 5° latitudes on some nights and no spatial variability on others. On some nights, the temporal variability exhibited a close correlation with the occurrence rate of lightning discharges under the probed region. This suggests that the direct energy coupling between lightning discharges and lower ionosphere can be a significant source of the D region variability. However, on other nights, the measured height temporal variability showed weak to no correlation with local lightning, displaced lightning (as would be expected for lightning‐induced electron precipitation), or geomagnetic activities. These measurements suggest that nighttime D region variability may be driven by many sources.
Effects of causally driven cusp O+ outflow on the storm time magnetosphere‐ionosphere system using a multifluid global simulation
Authors: Brambles O. J. , Lotko W. , Damiano P. A. , Zhang B. , Wiltberger M. , Lyon J.
Published: September 2010

It is widely accepted that the ionosphere is an important source of ions in the magnetosphere and until recently this population has largely been neglected from many global simulations. In this study, a causally regulated cusp O+ outflow is added to the multifluid version of the Lyon‐Fedder‐Mobarry (LFM) global simulation. The cusp outflow algorithm uses empirical relationships to regulate the outflow flux with further conditioning to isolate the outflow spatially to a dynamic cusp. The impact cusp O+ outflow has on the magnetosphere‐ionosphere (MI) system is investigated for a moderate storm on 31 August 2005. It is found the MI system response depends upon the specification of the outflow velocity and temperature. More energetic outflow tends to flow downtail whilst colder, slower outflow fills the inner magnetosphere. High O+ densities in the inner magnetosphere can increase the strength of the ring current, reducing Dst and inflating the magnetosphere. This effect is mostly found for the less energetic outflow specification. O+ outflow is found to reduce the access of solar wind ions to the inner magnetosphere, which, through the MI coupling in LFM reduces the precipitating electron power, conductance and field‐aligned currents. The effect outflow has on the cross polar cap potential (CPCP) depends upon two competing factors. The reduction in Region I currents when outflow is present appears to increase the CPCP whilst the inflation of the magnetosphere due to an enhanced ring current decreases the CPCP.
Chorus wave generation near the dawnside magnetopause due to drift shell splitting of substorm‐injected electrons
Authors: Min Kyungguk , Lee Jeongwoo , Keika Kunihiro
Published: September 2010

We study the relationship between the electron injection and the chorus waves during a substorm event on 23 March 2007. The chorus waves were detected at high geomagnetic latitude (∼70°S) Antarctic observatories in the range of 0600–0900 h in magnetic local time (MLT). Electrons drifting from the injection event were measured by two LANL spacecraft at 0300 and 0900 MLT. The mapping of auroral brightening areas to the magnetic equator shows that the injection occurred in an MLT range of 2200–2400. This estimate is consistent with observations by the THEMIS A, B, and D spacecraft (which were located at 2100 MLT and did not observe electron injections). Our backward model tracing from the magnetic equator near the dawnside magnetopause (which magnetically connects to the Antarctic observatories) also supports the deduced injection region. Since chorus waves are believed to be generated through the electron cyclotron instability by an anisotropic temperature distribution, we examine, by performing forward model tracing, whether the electrons injected during this substorm form a pancake‐like pitch angle distribution when they arrive near the dawn‐side magnetopause. We find that the onset time of the modeled pitch angle anisotropy is consistent with that of the observed chorus waves. We conclude that the development of the anisotropy is due to particle drift shell splitting.
Accelerated ions ahead of earthward propagating dipolarization fronts
Authors: Zhou X.‐Z. , Angelopoulos V. , Sergeev V. A. , Runov A.
Published: September 2010

We report on the evolving ion distributions associated with the arrival of an earthward propagating dipolarization front in the near‐Earth magnetotail using Time History of Events and Macroscale Interactions during Substorms (THEMIS). Ion distributions exhibit steady duskward anisotropy well before the front arrival, suggesting thin current sheet formation at ∼11 RE, during the growth phase of a moderate geomagnetic substorm. As the dipolarization front moves closer, an additional, earthward streaming ion population appears, resulting in an earthward velocity moment. This population eventually overwhelms the preexisting duskward anisotropy and merges with the earthward convecting bulk flow once the dipolarization front arrives. Test‐particle simulations show that the observed ion evolution is consistent with a picture of ions reflected and accelerated by the approaching front and moving ahead of it.
Improving the shuffled complex evolution scheme for optimization of complex nonlinear hydrological systems: Application to the calibration of the Sacramento soil‐moisture accounting model
Authors: Chu Wei , Gao Xiaogang , Sorooshian Soroosh
Published: September 2010

An innovative algorithm, shuffled complexes with principal components analysis (SP‐UCI), is developed to overcome a critical deficiency of the shuffled complex evolution scheme: population degeneration. Population degeneration means that, during the evolutionary search process, the population of search particles may degenerate into a subspace of the full parameter space, thereby missing the capacity of fully exploring the parameter space. Being confined in a subspace may even lead the particle population to converge to nonstationary points, which is a fatal malfunction. To overcome this problem, SP‐UCI employs the principal components analysis to detect the occurrence of population degeneration and remedy the adverse effects. The ensemble of calibrations of the Sacramento soil moisture accounting model with the SP‐UCI method over the Leaf River basin, Mississippi, retrieves the optimal parameter values with the lowest recorded root‐mean‐squared error of simulated daily runoff against the observation. Moreover, the result also provides consistent (narrow ranges) model parameter distribution, which results in a better understanding of the model's behavior, given the watershed's hydrologic features.
Human platelets express and are activated by galectin-8
Authors: Romaniuk Maria Albertina , Tribulatti Maria Virginia , Cattaneo Valentina , Lapponi Maria Jose , Molinas Felisa Concepcion , Campetella Oscar , Schattner Mirta
Published: September 2010

Gals (galectins) are proteins with glycan affinity that are emerging as mediators of atherosclerosis. Despite the similarities in structure and sequence, different Gals exert distinct effects on their target cells. We have shown that Gal-1 triggers platelet activation, suggesting a role for Gals in thrombus formation. Since Gal-8 is expressed upon endothelial activation and also contributes to inflammation, to understand further the role of these lectins in haemostasis, we evaluated the effect of Gal-8 on human platelets. Gal-8 bound specific glycans in the platelet membrane and triggered spreading, calcium mobilization and fibrinogen binding. It also promoted aggregation, thromboxane generation, P-selectin expression and granule secretion. GP (glycoprotein) αIIb and Ib-V were identified as putative Gal-8 counter-receptors by MS. Studies performed using platelets from Glanzmann's thromboasthenia and Bernard–Soulier syndrome patients confirmed that GPIb is essential for transducing Gal-8 signalling. Accordingly, Src, PLC2γ (phospholipase C2γ), ERK (extracellular-signal-regulated kinase) and PI3K (phosphoinositide 3-kinase)/Akt downstream molecules were involved in the Gal-8 signalling pathway. Gal-8 fragments containing either the N- or C-terminal carbohydrate-recognition domains showed that activation is exerted through the N-terminus. Western blotting and cytometry showed that platelets not only contain Gal-8, but also expose Gal-8 after thrombin activation. These findings reveal Gal-8 as a potent platelet activator, supporting a role for this lectin in thrombosis and inflammation.
Unfolded protein response (UPR) gene expression during antibody-dependent enhanced infection of cultured monocytes correlates with dengue disease severity
Authors: Paradkar Prasad N. , Ooi Eng Eong , Hanson Brendon J. , Gubler Duane J. , Vasudevan Subhash G.
Published: September 2010

DENV (dengue virus) induces UPR (unfolded protein response) in the host cell, which strikes a balance between pro-survival and pro-apoptotic signals. We previously showed that Salubrinal, a drug that targets the UPR, inhibits DENV replication. Here, we examine the impact on UPR after direct or ADE (antibody-dependent enhanced) infection of cells with DENV clinical isolates. THP-1 cells in the presence of subneutralizing concentration of humanized antibody 4G2 (cross-reactive with flavivirus envelope protein) or HEK-293 cells (human embryonic kidney 293 cells) were infected with DENV-1–4 serotypes. UPR gene expression was monitored under these infection conditions using real-time RT–PCR (reverse transcription–PCR) and Western blots to analyse serotype-dependent variations. Subsequently, in a blinded study, strain-specific differences were compared between DENV-2 clinical isolates obtained from a single epidemic. Results showed that THP-1 cells were infected efficiently and equally by DENV-1–4 in the ADE mode. At 48 hpi (h post infection), DENV-1 and -3 showed a higher replication rate and induced higher expression of several UPR genes such as BiP (immunoglobulin heavy-chain-binding protein), GADD34 (growth arrest DNA damage-inducible protein 34) and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein]. The ADE infection of THP-1 cells with epidemic DENV-2 high-UPR-gene-expressing strains appears to correlate with severe disease; however, no such correlation could be made when the same viruses were used to infect HEK-293 cells. Our finding that UPR gene expression in THP-1 cells during ADE infection correlates with dengue disease severity is consistent with a previous study [Morens, Marchette, Chu and Halstead (1991) Am. J. Trop. Med. Hyg. 45, 644–651] that showed that the growth of DENV 2 isolates in human peripheral blood leucocytes correlated with severe and mild dengue diseases.
Structure, evolution and dynamics of transcriptional regulatory networks
Authors: Babu M. Madan
Published: September 2010

The availability of entire genome sequences and the wealth of literature on gene regulation have enabled researchers to model an organism's transcriptional regulation system in the form of a network. In such a network, TFs (transcription factors) and TGs (target genes) are represented as nodes and regulatory interactions between TFs and TGs are represented as directed links. In the present review, I address the following topics pertaining to transcriptional regulatory networks. (i) Structure and organization: first, I introduce the concept of networks and discuss our understanding of the structure and organization of transcriptional networks. (ii) Evolution: I then describe the different mechanisms and forces that influence network evolution and shape network structure. (iii) Dynamics: I discuss studies that have integrated information on dynamics such as mRNA abundance or half-life, with data on transcriptional network in order to elucidate general principles of regulatory network dynamics. In particular, I discuss how cell-to-cell variability in the expression level of TFs could permit differential utilization of the same underlying network by distinct members of a genetically identical cell population. Finally, I conclude by discussing open questions for future research and highlighting the implications for evolution, development, disease and applications such as genetic engineering.
Systems biochemistry in practice: experimenting with modelling and understanding, with regulation and control
Authors: Westerhoff Hans V. , Verma Malkhey , Nardelli Maria , Adamczyk Malgorzata , van Eunen Karen , Simeonidis Evangelos , Bakker Barbara M.
Published: September 2010

Biology and medicine have become ‘big science’, even though we may not always like this: genomics and the subsequent analysis of what the genomes encode has shown that interesting living organisms require many more than 300 gene products to interact. We once thought that somewhere in this jungle of interacting macromolecules was hidden the molecule that constitutes the secret of Life, and therewith of health and disease. Now we know that, somehow, the secret of Life is the jungle of interactions. Consequently, we need to find the Rosetta Stones, i.e. interpretations of this jungle of systems biology. We need to find, perhaps convoluted, paths of understanding and intervention. Systems biochemistry is a good place to start, as it has the foothold that what goes in must come out. In the present paper, we review two strategies, which look at control and regulation. We discuss the difference between control and regulation and prove a relationship between them.
Imaging tumour cell metabolism using hyperpolarized 13C magnetic resonance spectroscopy
Authors: Witney Timothy H. , Brindle Kevin M.
Published: September 2010

Patients with similar tumour types frequently show different responses to the same therapy. The development of new treatments would benefit, therefore, from imaging methods that allow an early assessment of treatment response in individual patients, allowing rapid selection of the most effective treatment. We have been using 13C MRSI (magnetic resonance spectroscopic imaging) of tumour cell metabolism, using hyperpolarized 13C-labelled cellular metabolites, to detect treatment response. Nuclear spin hyperpolarization can increase sensitivity in the magnetic resonance experiment >10000 times, allowing us to image labelled cell substrates in vivo and their subsequent metabolism. We showed that exchange of hyperpolarized 13C label between lactate and pyruvate, catalysed by lactate dehydrogenase, was decreased in treated tumours undergoing drug-induced cell death, and that tissue pH could be imaged from the ratio of the signal intensities of hyperpolarized H13CO3− and 13CO2 following intravenous injection of hyperpolarized H13CO3. Tumour cell glutaminase activity, a potential measure of cell proliferation, can be determined using hyperpolarized [5-13C]glutamine, and treatment-induced tumour cell necrosis can be imaged in vivo from measurements of the conversion of hyperpolarized [1,4-13C2]fumarate into malate. Since these substrates are endogenous and, in some cases, have already been safely infused into patients, these techniques have the potential to translate to the clinic.
Why does yeast ferment? A flux balance analysis study
Authors: Simeonidis Evangelos , Murabito Ettore , Smallbone Kieran , Westerhoff Hans V.
Published: September 2010

Advances in biological techniques have led to the availability of genome-scale metabolic reconstructions for yeast. The size and complexity of such networks impose limits on what types of analyses one can perform. Constraint-based modelling overcomes some of these restrictions by using physicochemical constraints to describe the potential behaviour of an organism. FBA (flux balance analysis) highlights flux patterns through a network that serves to achieve a particular objective and requires a minimal amount of data to make quantitative inferences about network behaviour. Even though FBA is a powerful tool for system predictions, its general formulation sometimes results in unrealistic flux patterns. A typical example is fermentation in yeast: ethanol is produced during aerobic growth in excess glucose, but this pattern is not present in a typical FBA solution. In the present paper, we examine the issue of yeast fermentation against respiration during growth. We have studied a number of hypotheses from the modelling perspective, and novel formulations of the FBA approach have been tested. By making the observation that more respiration requires the synthesis of more mitochondria, an energy cost related to mitochondrial synthesis is added to the FBA formulation. Results, although still approximate, are closer to experimental observations than earlier FBA analyses, at least on the issue of fermentation.
Modelling the peroxisomal carbon leak during lipid mobilization in Arabidopsis
Authors: Hooks Mark A. , Allen Elizabeth , Wattis Jonathan A.D.
Published: September 2010

Mutation of the ACN1 (acetate non-utilizing 1) locus of Arabidopsis results in altered acetate assimilation into gluconeogenic sugars and anapleurotic amino acids and leads to an overall depression in primary metabolite levels by approx. 50% during seedling development. Levels of acetyl-CoA were higher in acn1 compared with wild-type, which is counterintuitive to the activity of ACN1 as a peroxisomal acetyl-CoA synthetase. We hypothesize that ACN1 recycles free acetate to acetyl-CoA within peroxisomes in order that carbon remains fed into the glyoxylate cycle. When ACN1 is not present, carbon in the form of acetate can leak out of peroxisomes and is reactivated to acetyl-CoA within the cytosol. Kinetic models incorporating estimates of carbon input and pathway dynamics from a variety of literature sources have proven useful in explaining how ACN1 may prevent the carbon leak and even contribute to the control of peroxisomal carbon metabolism.
Systems-level feedback in cell-cycle control
Authors: Novák Béla , Vinod P.K. , Freire Paula , Kapuy Orsolya
Published: September 2010

Alternation of chromosome replication and segregation is essential for successful completion of the cell cycle and it requires an oscillation of Cdk1 (cyclin-dependent kinase 1)–CycB (cyclin B) activity. In the present review, we illustrate the essential features of checkpoint controlled and uncontrolled cell-cycle oscillations by using mechanical metaphors. Despite variations in the molecular details of the oscillatory mechanism, the underlying network motifs responsible for the oscillations are always well-conserved. The checkpoint-controlled cell cycles are always driven by a negative-feedback loop amplified by double-negative feedbacks (antagonism).
Tuning sperm chemotaxis
Authors: Guerrero Adán , Wood Christopher D. , Nishigaki Takuya , Carneiro Jorge , Darszon Alberto
Published: September 2010

Sperm chemotaxis is a long-term puzzle and most of our knowledge comes from studying marine animals that are external fertilizers. Sperm are attracted by diffusible chemical factors (chemoattractants) released from the egg which redirect their swimming paths towards their source. This redirection is driven by increases in flagellar curvature that correlate with transient flagellar Ca2+ increases. Recent experimental and modelling results provide insights into the signal flow underlying the translation of an external chemical gradient into an intracellular molecular and motor response. A fundamental element of sea-urchin sperm chemotaxis lies in the ability of these cells to suppress Ca2+-mediated increases in flagellar curvature while experiencing an increasing chemoattractant gradient. The article considers this new evidence and summarizes the known underlying cellular mechanisms and behavioural strategies that sperm use to locate and fertilize the oocyte.
Systems biochemistry approaches to vertebrate phototransduction: towards a molecular understanding of disease
Authors: Dell'Orco Daniele , Koch Karl-Wilhelm
Published: September 2010

Phototransduction in vertebrates represents a paradigm of signalling pathways, in particular those mediated by G-protein-coupled receptors. The variety of protein–protein, protein–ion and protein–nucleotide interactions makes up an intricate network which is finely regulated by activating–deactivating molecules and chemical modifications. The holistic systems properties of the network allow for typical adaptation mechanisms, which ultimately result in fine adjustments of sensitivity and electrical response of the photoreceptor cells to the broad range of light stimuli. In the present article, we discuss a novel bottom-up strategy to study the phototransduction cascade in rod cells starting from the underlying biochemistry. The resulting network model can be simulated and the predicted dynamic behaviour directly compared with data from electrophysiological experiments performed on a wide range of illumination conditions. The advantage of applying procedures typical of systems theory to a well-studied signalling pathway is also discussed. Finally, the potential application to the study of the molecular basis of retinal diseases is highlighted through a practical example, namely the simulation of conditions related to Leber congenital amaurosis.
Mathematical modelling of Wnt/β-catenin signalling
Authors: Kofahl Bente , Wolf Jana
Published: September 2010

The Wnt/β-catenin pathway plays an important role in development and disease. Theoretical approaches have been used to describe this pathway and have provided intriguing insights into its signalling characteristics. In the present paper, we review mathematical models of the pathway. We focus on a quantitative kinetic model for canonical Wnt/β-catenin signalling describing the reactions of the pathway's core compounds [Lee, Salic, Krüger, Heinrich and Kirschner (2003) PLoS Biol. 1, 116–132]. Numerous modifications and further analyses with respect to signalling characteristics, transcriptional feedback and cross-talk were performed. In addition, the role of β-catenin in gene expression and cell–cell adhesion as well as spatial aspects of signalling are investigated in various theoretical models.
Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models
Authors: Bakker Barbara M. , van Eunen Karen , Jeneson Jeroen A.L. , van Riel Natal A.W. , Bruggeman Frank J. , Teusink Bas
Published: September 2010

Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these ‘lessons from glycolysis’, we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.
Metabolic network adaptations in cancer as targets for novel therapies
Authors: Cascante Marta , Benito Adrian , Zanuy Miriam , Vizán Pedro , Marín Silvia , de Atauri Pedro
Published: September 2010

Metabolite concentrations and fluxes are the system variables that characterize metabolism. The systematic study of metabolite profiles is known as metabolomics; however, knowledge of the complete set of metabolites may not be enough to predict distinct phenotypes. A complete understanding of metabolic processes requires detailed knowledge of enzyme-controlled intracellular fluxes. These can be estimated through quantitative measurements of metabolites at different times or by analysing the stable isotope patterns obtained after incubation with labelled substrates. We have identified distinct intracellular fluxes associated with metabolic adaptations accompanying cancer. The maintenance of an imbalance between fluxes for the oxidative and non-oxidative PPP (pentose phosphate pathway) has been shown to be critical for angiogenesis and cancer cell survival. Mouse NIH 3T3 cells transformed by different mutated K-ras oncogenes have differential routing of glucose to anaerobic glycolysis, the PPP and the Krebs cycle. These results indicate that knowledge of metabolic fingerprints associated with an altered genetic profile could be exploited in the rational design of new therapies. We conclude that the understanding of the multifactorial nature of metabolic adaptations in cancer may open new ways to develop novel multi-hit antitumoral therapies.
Glycoproteomics: a powerful tool for characterizing the diverse glycoforms of bacterial pilins and flagellins
Authors: Hitchen Paul G. , Twigger Katie , Valiente Esmeralda , Langdon Rebecca H. , Wren Brendan W. , Dell Anne
Published: September 2010

With glycosylation now firmly established across both Archaeal and bacterial proteins, a wide array of glycan diversity has become evident from structural analysis and genomic data. These discoveries have been built in part on the development and application of mass spectrometric technologies to the bacterial glycoproteome. This review highlights recent findings using high sensitivity MS of the large variation of glycans that have been reported on flagellin and pilin proteins of bacteria, using both ‘top down’ and ‘bottom up’ approaches to the characterization of these glycoproteins. We summarize current knowledge of the sugar modifications that have been observed on flagellins and pilins, in terms of both the diverse repertoire of monosaccharides observed, and the assemblage of moieties that decorate many of these sugars.
System analysis of the effect of various drugs on cardiac contraction energetics
Authors: Deschodt-Arsac Véronique , Calmettes Guillaume , Gouspillou Gilles , Rouland Richard , Thiaudiere Eric , Miraux Sylvain , Franconi Jean-Michel , Diolez Philippe
Published: September 2010

We used MoCA (Modular Control and Regulation Analysis) to demonstrate in intact beating rat heart that physiological activation of contraction by adrenaline involves the almost perfect parallel activation of both mitochondria and myofibrils by intracellular Ca2+. This explains the perfect homoeostasis of the energetic intermediate PCr (phosphocreatine) in heart. When using drugs specifically stimulating either supply or demand activities, MoCA helped reveal the very specific mode of regulation of heart contraction energetics. Only activation of myofibrils activity (demand), either by increasing intracellular Ca2+ concentration or myofibrils sensitivity to Ca2+, triggers activation of contractile activity. In contrast, the activation of mitochondrial activity (supply) has strictly no effect on contraction, either directly or through PCr changes (intermediate).
Structural Glycobiology and Human Health
Authors: Mulloy Barbara , Corfield Anthony P.
Published: September 2010

The glycans (carbonhydrates) form a diverse group of biomolecules which play active parts in most physiological processes. The field of structural glycobiology concerns the structures of the glycans themselves, the proteins which interact with them and the nature of the interactions between the two. The resulting information is important for our understainding of human health and disease, and for development of new therapeutic strategies. A series of articles is introduced based on the topics covered at the Structural Glycobiology and Human Health Biochemical Society Focused Meeting. Their subjects range from in-depth determinations of three-dimensional protein structure to broad screening techniques for glycan–protein interactions relevant to disease processes, including bacterial, parasitic and viral infections, inflammatory processes, cancer and diabetes.
Complement factor H and age-related macular degeneration: the role of glycosaminoglycan recognition in disease pathology
Authors: Clark Simon J. , Bishop Paul N. , Day Anthony J.
Published: September 2010

AMD (age-related macular degeneration) is the major cause of blindness in the western world, associated with the formation of extracellular deposits called drusen in the macula, i.e. the central region of the retina. These drusen contain cellular debris and proteins, including components of the complement system such as the regulator CFH (complement factor H); dysregulation of complement is thought to play a major role in the development of AMD. CFH acts through its capacity to recognize polyanionic structures [e.g. sulfated GAGs (glycosaminoglycans)] found on host tissues, and thereby inactivates any C3b that becomes deposited. Importantly, a common polymorphism in CFH (Y402H) has been strongly associated with an increased risk of AMD. This polymorphism, which causes a tyrosine to histidine coding change, has been shown to alter the binding of CFH to sulfated GAGs, as well as to other ligands including C-reactive protein, necrotic cells and bacterial coat proteins. Of these, the change in the GAG-recognition properties of CFH is likely to be of most significance to AMD. Recent research has revealed that the disease-associated 402H allotype interacts less well (compared with 402Y) with binding sites within the macula (e.g. Bruch's membrane), where the GAGs heparan sulfate and dermatan sulfate play a major role in mediating the interaction with CFH. Reduced binding of the 402H allotype could result in impaired regulation of complement leading to chronic local inflammation that may contribute to the accumulation of drusen and thus the initiation, development and progression of AMD.
Shared paramyxoviral glycoprotein architecture is adapted for diverse attachment strategies
Authors: Bowden Thomas A. , Crispin Max , Jones E. Yvonne , Stuart David I.
Published: September 2010

Members within the paramyxovirus subfamily Paramyxovirinae constitute a large number of highly virulent human and animal pathogens. The glycoproteins present on these viruses are responsible for mediating host cell attachment and fusion and are key targets for the design of antiviral entry inhibitors. In the present review, we discuss recent structural studies which have led to a better understanding of the various mechanisms by which different paramyxoviruses use their attachment glycoproteins to hijack specific protein and glycan cell-surface receptors to facilitate viral entry. It is observed that the paramyxovirus attachment glycoprotein consists of a conserved overall structure which includes an N-terminal six-bladed β-propeller domain which is responsible for cell receptor binding. Crystal structures of this domain from different biomedically important paramyxoviruses, including measles, Nipah, Hendra, Newcastle disease and parainfluenza viruses, alone and in complex with their functional cell-surface receptors, demonstrate three contrasting mechanisms of receptor engagement that paramyxoviruses have evolved to confer discreet protein- and glycan-receptor specificity. This structural information highlights the adaptability of the paramyxovirus attachment glycoprotein surface and the potential for the emergence of new and potentially harmful viruses in human hosts.
Heparan sulfate glycomics: towards systems biology strategies
Authors: Turnbull Jeremy E.
Published: September 2010

HSs (heparan sulfates) are a complex family of cell-surface and matrix polysaccharides that have diverse biological functions, underpinned by structurally diverse patterns of backbone chain modification, especially by sulfate groups. These variant structures represent a molecular code, the ‘heparanome’, that confers the ability to interact selectively with a wide interactome of proteins, the ‘heparactome’, and thereby influence a network of cellular events. It is becoming increasingly apparent that understanding the structure–activity relationships of these enigmatic molecules requires the development of a holistic systems biology view of their structure and interactions. In the present paper, I describe some of the new tools available to realize this strategy, and discuss the future potential for the combined application of glycomics and other ‘-omics’ approaches to define the molecular code of the heparanome.
Neoglycolipid (NGL)-based oligosaccharide microarrays and highlights of their recent applications in studies of the molecular basis of pathogen–host interactions
Authors: Liu Yan
Published: September 2010

Carbohydrate microarray technologies are new developments at the frontier of glycomics that are showing great promise as tools for high-throughput analysis of carbohydrate-mediated interactions and the elucidation of carbohydrate ligands involved not only in endogenous receptor systems, but also pathogen–host interactions. The main advantage of microarray analysis is that a broad range of glycan sequences can be immobilized on solid matrices as minute spots and simultaneously interrogated. Different methodologies have emerged for constructing carbohydrate microarrays. The NGL (neoglycolipid)-based oligosaccharide microarray platform is among the relatively few systems that are beyond proof-of-concept and have provided new biological information. In the present article, I dwell, in some detail, on the NGL-based microarray. Highlights are the recent applications of NGL-based microarrays that have contributed to knowledge on the molecular basis of pathogen–host interactions, namely the assignments of the carbohydrate-binding specificities of several key surface-adhesive proteins of Toxoplasma gondii and other apicomplexan parasites, and the elucidation of receptor-binding specificities of the pandemic influenza A (H1N1) 2009 (H1N1pdm) virus compared with seasonal H1N1 virus.
Carbohydrate binding of Salmonella phage P22 tailspike protein and its role during host cell infection
Authors: Andres Dorothee , Baxa Ulrich , Hanke Christin , Seckler Robert , Barbirz Stefanie
Published: September 2010

TSPs (tailspike proteins) are essential infection organelles of bacteriophage P22. Upon infection, P22TSP binds to and cleaves the O-antigen moiety of the LPS (lipopolysaccharide) of its Salmonella host. To elucidate the role of TSP during infection, we have studied binding to oligosaccharides and polysaccharides of Salmonella enterica Typhimurium and Enteritidis in vitro. P22TSP is a trimeric β-helical protein with a carbohydrate-binding site on each subunit. Octasaccharide O-antigen fragments bind to P22TSP with micromolar dissociation constants. Moreover, P22TSP is an endorhamnosidase and cleaves the host O-antigen. Catalytic residues lie at the periphery of the high-affinity binding site, which enables unproductive binding modes, resulting in slow hydrolysis. However, the role of this hydrolysis function during infection remains unclear. Binding of polysaccharide to P22TSP is of high avidity with slow dissociation rates when compared with oligosaccharides. In vivo, the infection of Salmonella with phage P22 can be completely inhibited by the addition of LPS, indicating that binding of phage to its host via TSP is an essential step for infection.
Discrepant effects of mammalian factors on molluscan cell motility, chemotaxis and phagocytosis: Divergent evolution or finely tuned contingency?
Authors: Malagoli Davide , Ottaviani Enzo
Published: September 2010

Cell motility, cell migration and phagocytosis are distinct, though frequently sequential, processes. They are fundamental for the maintenance of homoeostasis in single cells as well as in pluricellular organisms. Like vertebrates, invertebrate immune functions are strictly dependent on cell motility, chemotaxis and phagocytosis. Several comparative immunobiology experiments have tested the effects of mammalian factors on cell migration and phagocytic activity in invertebrate immune‐competent cells. The discrepancies that were found suggest various hypotheses, e.g. species‐specific reactions to heterologous factors. Here, we reconsider data concerning the effects of POMC (proopiomelanocortin)‐derived peptides, cytokines and growth factors on molluscan immunocytes in the light of recent findings that also encompass the effects of experimental conditions.
Switching from bone marrow‐derived neurons to epithelial cells through dedifferentiation and translineage redifferentiation
Authors: Liu Yang , Jiang Xiaohua , Yu Kuen Mei , Dong Jianda , Zhang Xiaohu , Tsang Ling Lai , Chung Wa Yiu , Li Tingyu , Chan Chang Hsiao
Published: September 2010

While the ability of stem cells to switch lineages has been suggested, the route(s) through which this may happen is unclear. To date, the best characterized adult stem cell population considered to possess transdifferentiation capacity is BM‐MSCs (bone marrow mesenchymal stem cells). We investigated whether BM‐MSCs that had terminally differentiated into the neural or epithelial lineage could be induced to transdifferentiate into the other phenotype in vitro. Our results reveal that neuronal phenotypic cells derived from adult rat bone marrow cells can be switched to epithelial phenotypic cells, or vice versa, by culture manipulation allowing the differentiated cells to go through, first, dedifferentiation and then redifferentiation to another phenotype. Direct transdifferentiation from differentiated neuronal or epithelial phenotype to the other differentiated phenotype cannot be observed even when appropriate culture conditions are provided. Thus, dedifferentiation appears to be a prerequisite for changing fate and differentiating into a different lineage from a differentiated cell population.
Erythropoietin and the heart: facts and perspectives
Authors: Mastromarino Vittoria , Volpe Massimo , Musumeci Maria B. , Autore Camillo , Conti Elena
Published: September 2010

EPO (erythropoietin) has long been identified as a primary regulator of erythropoiesis. Subsequently, EPO has been recognized as playing a role in a broad variety of processes in cardiovascular pathophysiology. In particular, the tight interactions of EPO with the nitric oxide pathway, apoptosis, ischaemia, cell proliferation and platelet activation appear of great interest. Although enhanced EPO synthesis is viewed as an appropriate compensatory mechanism in the cardio–renal syndrome, which features CHF (congestive heart failure) and CRF (chronic renal failure), maladaptative excessive EPO synthesis in the advanced stages of these diseases appears to be predictive of higher mortality. Clinical trials based on the use of EPO in both heart and renal failure have so far produced contradictory results, whereas treatment targeted to restore low Hb levels appears rational and is supported by regulatory authorities. New areas for therapeutic use of EPO, such as acute coronary syndromes, are under investigation, and they are discussed in the present review together with other clinical applications in cardiovascular diseases. The revisited concept of a potential use of endogenous EPO levels as a predictor of CHF severity, as well as in the monitoring of responses to treatment, deserves appropriate investigation, as this may identify EPO as a useful biomarker in the clinical management of cardiovascular diseases.