bluuebunny/crossref_metadata_2025 huggingface dataset:
Observations of nucleation of new particles in a volcanic plume
Authors: Boulon Julien , Sellegri Karine , Hervo Maxime , Laj Paolo
Published: July 2011

Volcanic eruptions caused major weather and climatic changes on timescales ranging from hours to centuries in the past. Volcanic particles are injected in the atmosphere both as primary particles rapidly deposited due to their large sizes on time scales of minutes to a few weeks in the troposphere, and secondary particles mainly derived from the oxidation of sulfur dioxide. These particles are responsible for the atmospheric cooling observed at both regional and global scales following large volcanic eruptions. However, large condensational sinks due to preexisting particles within the plume, and unknown nucleation mechanisms under these circumstances make the assumption of new secondary particle formation still uncertain because the phenomenon has never been observed in a volcanic plume. In this work, we report the first observation of nucleation and new secondary particle formation events in a volcanic plume. These measurements were performed at the puy de Dôme atmospheric research station in central France during the Eyjafjallajokull volcano eruption in Spring 2010. We show that the nucleation is indeed linked to exceptionally high concentrations of sulfuric acid and present an unusual high particle formation rate. In addition we demonstrate that the binary H2SO4 - H2O nucleation scheme, as it is usually considered in modeling studies, underestimates by 7 to 8 orders of magnitude the observed particle formation rate and, therefore, should not be applied in tropospheric conditions. These results may help to revisit all past simulations of the impact of volcanic eruptions on climate.
Nonresonant femtosecond laser vaporization of aqueous protein preserves folded structure
Authors: Brady John J. , Judge Elizabeth J. , Levis Robert J.
Published: July 2011

Femtosecond laser vaporization-based mass spectrometry can be used to measure protein conformation in vitro at atmospheric pressure. Cytochrome c and lysozyme are vaporized from the condensed phase into the gas phase intact when exposed to an intense (10
13
 W/cm
2
), nonresonant (800 nm), ultrafast (75 fs) laser pulse. Electrospray postionization time-of-flight mass spectrometry reveals that the vaporized protein maintains the solution-phase conformation through measurement of the charge-state distribution and the collision-induced dissociation channels.
Identification of markers that distinguish IgE- from IgG-mediated anaphylaxis
Authors: Khodoun Marat V. , Strait Richard , Armstrong Laura , Yanase Noriko , Finkelman Fred D.
Published: July 2011

IgG-mediated anaphylaxis occurs in mice and may contribute to human reactions to infused drugs. To distinguish IgE- from putative IgG-mediated human anaphylaxis, we developed blood markers for murine anaphylaxis and evaluated their human relevance. Both IgG- and IgE-mediated anaphylaxis were characterized by decreased basophil and monocyte percentages and an increased neutrophil percentage in mouse blood. IgE- but not IgG-mediated murine anaphylaxis was accompanied by large increases in IL-4 secretion, plasma soluble IL-4 receptor-α (IL-4Rα) concentration, and T-cell membrane IL-4Rα expression. T-cell IL-4Rα expression also increased when mice that express human Fcε receptor Iα were sensitized with IgG-depleted serum from a peanut-allergic individual and challenged with peanut extract. Increased T-cell IL-4Rα expression is likely to also be a marker for human IgE-mediated anaphylaxis, because IgE-activated human basophils secrete IL-4, and IL-4 increases human T-cell IL-4Rα expression in vitro. Murine IgG- but not IgE-mediated anaphylaxis was characterized by decreased neutrophil Fcγ receptor III (FcγRIII) expression that was observed even when the antigen dose was insufficient to induce shock. Human neutrophils cultured with IgG immune complexes also lost FcγRIII. These observations suggest that decreased blood neutrophil FcγRIII expression without increased IL-4Rα expression can be used to determine whether and when IgG-mediated anaphylaxis occurs in man.
Related pituitary cell lineages develop into interdigitated 3D cell networks
Authors: Budry Lionel , Lafont Chrystel , El Yandouzi Taoufik , Chauvet Norbert , Conéjero Geneviève , Drouin Jacques , Mollard Patrice
Published: July 2011

The pituitary gland has long been considered to be a random patchwork of hormone-producing cells. By using pituitary-scale tridimensional imaging for two of the least abundant cell lineages, the corticotropes and gonadotropes, we have now uncovered highly organized and interdigitated cell networks that reflect homotypic and heterotypic interactions between cells. Although newly differentiated corticotrope cells appear on the ventral surface of the gland, they rapidly form homotypic strands of cells that extend from the lateral tips of the anterior pituitary along its ventral surface and into the medial gland. As the corticotrope network is established away from the microvasculature, cell morphology changes from rounded, to polygonal, and finally to cells with long cytoplasmic processes or cytonemes that connect corticotropes to the perivascular space. Gonadotropes differentiate later and are positioned in close proximity to corticotropes and capillaries. Blockade of corticotrope terminal differentiation produced by knockout of the gene encoding the transcription factor Tpit results in smaller gonadotropes within an expanded cell network, particularly in the lateral gland. Thus, pituitary-scale tridimensional imaging reveals highly structured cell networks of unique topology for each pituitary lineage. The sequential development of interdigitated cell networks during organogenesis indicate that extensive cell:cell interactions lead to a highly ordered cell positioning rather than random patchwork.
Controversies in clinical cancer dormancy
Authors: Uhr Jonathan W. , Pantel Klaus
Published: July 2011

Clinical cancer dormancy is defined as an unusually long time between removal of the primary tumor and subsequent relapse in a patient who has been clinically disease-free. The condition is frequently observed in certain carcinomas (e.g., breast cancer), B-cell lymphoma, and melanoma, with relapse occurring 5–25 y later. Clinical data suggest that a majority of breast cancer survivors have cancer cells for decades but can remain clinically cancer-free for their lifetime. Thus, there is a major effort to characterize the molecular mechanisms responsible for inducing tumor cell dormancy using experimental models or studying the early phases of cancer growth in humans. Many molecules and signaling pathways have been characterized and have led to concepts that dominate the field, such as the possible role of innate and adaptive immunity in immune surveillance and initiation and maintenance of dormancy. However, recent clinical data do not support many of these concepts. Several areas need further study to determine their relevance to clinical cancer dormancy. We suggest hypotheses that may contribute to elucidation of the mechanisms underlying the dormant state.
Tumor-associated macrophages regulate tumorigenicity and anticancer drug responses of cancer stem/initiating cells
Authors: Jinushi Masahisa , Chiba Shigeki , Yoshiyama Hironori , Masutomi Kenkichi , Kinoshita Ichiro , Dosaka-Akita Hirotoshi , Yagita Hideo , Takaoka Akinori , Tahara Hideaki
Published: July 2011

Recent evidence has unveiled the critical role of tumor cells with stem cell activities in tumorigenicity and drug resistance, but how tumor microenvironments regulate cancer stem/initiating cells (CSCs) remains unknown. We clarified the role of tumor-associated macrophages (TAMs) and their downstream factor milk-fat globule-epidermal growth factor-VIII (MFG-E8) in the regulation of CSC activities. Bone marrow chimeric systems and adoptive cell transfers elucidated the importance of MFG-E8 from TAMs in conferring to CSCs with the ability to promote tumorigenicity and anticancer drug resistance. MFG-E8 mainly activates signal transducer and activator of transcription-3 (Stat3) and Sonic Hedgehog pathways in CSCs and further amplifies their anticancer drug resistance in cooperation with IL-6. Thus, the pharmacological targeting of key factors derived from tumor-associated inflammation provides a unique strategy to eradicate therapy-resistant tumors by manipulating CSC activities.
NMR basis for interprotein electron transfer gating between cytochrome
c
and cytochrome
c
oxidase
Authors: Sakamoto Koichi , Kamiya Masakatsu , Imai Mizue , Shinzawa-Itoh Kyoko , Uchida Takeshi , Kawano Keiichi , Yoshikawa Shinya , Ishimori Koichiro
Published: July 2011

The final interprotein electron transfer (ET) in the mammalian respiratory chain, from cytochrome
c
(Cyt
c
) to cytochrome
c
oxidase (C
c
O) is investigated by
1
H-
15
N heteronuclear single quantum coherence spectral analysis. The chemical shift perturbation in isotope-labeled Cyt
c
induced by addition of unlabeled C
c
O indicates that the hydrophobic heme periphery and adjacent hydrophobic amino acid residues of Cyt
c
dominantly contribute to the complex formation, whereas charged residues near the hydrophobic core refine the orientation of Cyt
c
to provide well controlled ET. Upon oxidation of Cyt
c
, the specific line broadening of N-H signals disappeared and high field
1
H chemical shifts of the N-terminal helix were observed, suggesting that the interactions of the N-terminal helix with C
c
O are reduced by steric constraint in oxidized Cyt
c
, while the chemical shift perturbations in the C-terminal helix indicate notable interactions of oxidized Cyt
c
with C
c
O. These results suggest that the overall affinity of oxidized Cyt
c
for C
c
O is significantly, but not very much weaker than that of reduced Cyt
c
. Thus, electron transfer is gated by dissociation of oxidized Cyt
c
from C
c
O, the rate of which is controlled by the affinity of oxidized Cyt
c
to C
c
O for providing an appropriate electron transfer rate for the most effective energy coupling. The conformational changes in Lys13 upon C
c
O binding to oxidized Cyt
c
, shown by
1
H- and
1
H,
15
N-chemical shifts, are also expected to gate intraprotein ET by a polarity control of heme
c
environment.
Exoplasmic cysteine Cys384 of the HDL receptor SR-BI is critical for its sensitivity to a small-molecule inhibitor and normal lipid transport activity
Authors: Yu Miao , Romer Katherine A. , Nieland Thomas J. F. , Xu Shangzhe , Saenz-Vash Veronica , Penman Marsha , Yesilaltay Ayce , Carr Steven A. , Krieger Monty
Published: July 2011

The HDL receptor, scavenger receptor, class B, type I (SR-BI), is a homooligomeric cell surface glycoprotein that controls HDL structure and metabolism by mediating the cellular selective uptake of lipids, mainly cholesteryl esters, from HDL. The mechanism underlying SR-BI-mediated lipid transfer, which differs from classic receptor-mediated endocytosis, involves a two-step process (binding followed by lipid transport) that is poorly understood. Our previous structure/activity analysis of the small-molecule inhibitor blocker of lipid transport 1 (BLT-1), which potently (IC
50
 ∼ 50 nM) blocks SR-BI-mediated lipid transport, established that the sulfur in BLT-1’s thiosemicarbazone moiety was essential for activity. Here we show that BLT-1 is an irreversible inhibitor of SR-BI, raising the possibility that cysteine(s) in SR-BI interact with BLT-1. Mass spectrometric analysis of purified SR-BI showed two of its six exoplasmic cysteines have free thiol groups (Cys251 and Cys384). Converting Cys384 (but not Cys251) to serine resulted in complete BLT-1 insensitivity, establishing that the unique molecular target of BLT-1 inhibition of cellular SR-BI dependent lipid transport is SR-BI itself. The C384S substitution reduced the receptor’s intrinsic lipid uptake activity by approximately 60% without dramatically altering its surface expression, homooligomerization, or HDL binding. Thus, a small-molecule screening approach identified a key residue in SR-BI involved in lipid transport, providing a powerful springboard into the analyses of the structure and mechanism of SR-BI, and highlighting the power of this approach for such analyses.
Government-NGO Networks & Nature Conservation in Belize: Examining the Theory of the Hollow State in a Developing Country Context
Authors: Brechin Steven R. , Salas Osmany
Published: July 2011

We use the Theory of the Hollow State to explore public-private-partnerships in Belize, Central America. Networks of contracted relationships between Belizean governments and domestic non-government organizations (NGOs) were created to manage a significant portion of Belize's extensive system of protected areas. Because of limited resources, the Belizean state, however, has been a weak network hub, leading to the rise of a separate network among the NGOs themselves. Instead of hollowing out the state, we argued that the NGO network has helped to fill one in by providing a state-like presence that otherwise would be absent. This article adds to our understanding of nature conservation in weak states while attempting to internationalize public administration theory.
Implementation and Resistance: Networking to Create and Renegotiate Natura 2000
Authors: Welch-Devine Meredith
Published: July 2011

The implementation of the European Union's flagship conservation initiative— Natura 2000—has been particularly drawn out and difficult in the French Basque province of Soule. Local actors have vigorously resisted the creation of Natura 2000 sites and the design of management plans for these sites. This article examines the network of actors and organizations that sprung up to resist Natura 2000 alongside the network designed for its implementation. It explores the role of ethnography in network analysis and discusses the implications of this analysis for conservation policy.
B cells enhance early innate immune responses during bacterial sepsis
Authors: Kelly-Scumpia Kindra M. , Scumpia Philip O. , Weinstein Jason S. , Delano Matthew J. , Cuenca Alex G. , Nacionales Dina C. , Wynn James L. , Lee Pui Y. , Kumagai Yutaro , Efron Philip A. , Akira Shizuo , Wasserfall Clive , Atkinson Mark A. , Moldawer Lyle L.
Published: July 2011

Microbes activate pattern recognition receptors to initiate adaptive immunity. T cells affect early innate inflammatory responses to viral infection, but both activation and suppression have been demonstrated. We identify a novel role for B cells in the early innate immune response during bacterial sepsis. We demonstrate that Rag1−/− mice display deficient early inflammatory responses and reduced survival during sepsis. Interestingly, B cell–deficient or anti-CD20 B cell–depleted mice, but not α/β T cell–deficient mice, display decreased inflammatory cytokine and chemokine production and reduced survival after sepsis. Both treatment of B cell–deficient mice with serum from wild-type (WT) mice and repletion of Rag1−/− mice with B cells improves sepsis survival, suggesting antibody-independent and antibody-dependent roles for B cells in the outcome to sepsis. During sepsis, marginal zone and follicular B cells are activated through type I interferon (IFN-I) receptor (IFN-α/β receptor [IFNAR]), and repleting Rag1−/− mice with WT, but not IFNAR−/−, B cells improves IFN-I–dependent and –independent early cytokine responses. Repleting B cell–deficient mice with the IFN-I–dependent chemokine, CXCL10 was also sufficient to improve sepsis survival. This study identifies a novel role for IFN-I–activated B cells in protective early innate immune responses during bacterial sepsis.
Alignment of transmembrane regions in the cystic fibrosis transmembrane conductance regulator chloride channel pore
Authors: Wang Wuyang , El Hiani Yassine , Linsdell Paul
Published: July 2011

Different transmembrane (TM) α helices are known to line the pore of the cystic fibrosis TM conductance regulator (CFTR) Cl− channel. However, the relative alignment of these TMs in the three-dimensional structure of the pore is not known. We have used patch-clamp recording to investigate the accessibility of cytoplasmically applied cysteine-reactive reagents to cysteines introduced along the length of the pore-lining first TM (TM1) of a cysteine-less variant of CFTR. We find that methanethiosulfonate (MTS) reagents irreversibly modify cysteines substituted for TM1 residues K95, Q98, P99, and L102 when applied to the cytoplasmic side of open channels. Residues closer to the intracellular end of TM1 (Y84–T94) were not apparently modified by MTS reagents, suggesting that this part of TM1 does not line the pore. None of the internal MTS reagent-reactive cysteines was modified by extracellular [2-(trimethylammonium)ethyl] MTS. Only K95C, closest to the putative intracellular end of TM1, was apparently modified by intracellular [2-sulfonatoethyl] MTS before channel activation. Comparison of these results with recent work on CFTR-TM6 suggests a relative alignment of these two important TMs along the axis of the pore. This alignment was tested experimentally by formation of disulfide bridges between pairs of cysteines introduced into these two TMs. Currents carried by the double mutants K95C/I344C and Q98C/I344C, but not by the corresponding single-site mutants, were inhibited by the oxidizing agent copper(II)-o-phenanthroline. This inhibition was irreversible on washing but could be reversed by the reducing agent dithiothreitol, suggesting disulfide bond formation between the introduced cysteine side chains. These results allow us to develop a model of the relative positions, functional contributions, and alignment of two important TMs lining the CFTR pore. Such functional information is necessary to understand and interpret the three-dimensional structure of the pore.
Local constraints in either the GluN1 or GluN2 subunit equally impair NMDA receptor pore opening
Authors: Talukder Iehab , Wollmuth Lonnie P.
Published: July 2011

The defining functional feature of N-methyl-d-aspartate (NMDA) receptors is activation gating, the energetic coupling of ligand binding into opening of the associated ion channel pore. NMDA receptors are obligate heterotetramers typically composed of glycine-binding GluN1 and glutamate-binding GluN2 subunits that gate in a concerted fashion, requiring all four ligands to bind for subsequent opening of the channel pore. In an individual subunit, the extracellular ligand-binding domain, composed of discontinuous polypeptide segments S1 and S2, and the transmembrane channel–forming domain, composed of M1–M4 segments, are connected by three linkers: S1–M1, M3–S2, and S2–M4. To study subunit-specific events during pore opening in NMDA receptors, we impaired activation gating via intrasubunit disulfide bonds connecting the M3–S2 and S2–M4 in either the GluN1 or GluN2A subunit, thereby interfering with the movement of the M3 segment, the major pore-lining and channel-gating element. NMDA receptors with gating impairments in either the GluN1 or GluN2A subunit were dramatically resistant to channel opening, but when they did open, they showed only a single-conductance level indistinguishable from wild type. Importantly, the late gating steps comprising pore opening to its main long-duration open state were equivalently affected regardless of which subunit was constrained. Thus, the NMDA receptor ion channel undergoes a pore-opening mechanism in which the intrasubunit conformational dynamics at the level of the ligand-binding/transmembrane domain (TMD) linkers are tightly coupled across the four subunits. Our results further indicate that conformational freedom of the linkers between the ligand-binding and TMDs is critical to the activation gating process.
Charge substitution for a deep-pore residue reveals structural dynamics during BK channel gating
Authors: Chen Xixi , Aldrich Richard W.
Published: July 2011

The pore-lining amino acids of ion channel proteins reside on the interface between a polar (the pore) and a nonpolar environment (the rest of the protein). The structural dynamics of this region, which physically controls ionic flow, are essential components of channel gating. Using large-conductance, Ca2+-dependent K+ (BK) channels, we devised a systematic charge–substitution method to probe conformational changes in the pore region during channel gating. We identified a deep-pore residue (314 in hSlo1) as a marker of structural dynamics. We manipulated the charge states of this residue by substituting amino acids with different valence and pKa, and by adjusting intracellular pH. We found that the charged states of the 314 residues stabilized an open state of the BK channel. With models based on known structures of related channels, we postulate a dynamic rearrangement of the deep-pore region during BK channel opening/closing, which involves a change of the degree of pore exposure for 314.
From the Myth to the Margins: The Patriarch’s Piazza at San Pietro di Castello in Venice*
Authors: Marina Areli
Published: July 2011

This study analyzes thecampoof San Pietro di Castello from its mythologized origins to the Renaissance, paying particular attention to the architectural and political forces that shaped it. Although San Pietro was Venice’s cathedral from the ninth to the nineteenth centuries, civic leaders marginalized the site, which incarnated the contentious relationship between the Roman Church and the Venetian republic. The essay places thecampoat the center of inquiry because the episcopal complex’s significance is best discerned through diachronic analysis of the urban landscape. The building activities of its medieval and Quattrocento patrons generated a heterogeneouscampothat incorporated morphological elements from two Venetian urbanistic types: the parishcampoand the monastic island. Its sixteenth-century patriarchs created a new architectural vision of thecampo, contesting its slippage from the center of Venetian life and forging a distinctive ensemble that differs markedly from the better-known piazzas at San Marco and Rialto.
Remembering the Death of Turnus: Spenser'sFaerie Queeneand the Ending of theAeneid*
Authors: Svensson Lars-Håkan
Published: July 2011

Most of the key episodes in book 1 of Edmund Spenser's Faerie Queene (1590) replay famous passages in Virgil's Aeneid. However, the concluding canto, describing the Redcrosse knight's betrothal to Una, is based on Maffeo Vegio's fifteenth-century Supplementum to the Aeneid, while, surprisingly, the Aeneid's much-disputed ending appears in triplicate in early sections of book 1. This article examines the place and function of book 1’s three imitations of the Aeneid's ending, while also relating them to Spenser's appropriations of the ending in later books of The Faerie Queene. It argues that, in making Redcrosse assume the position of Aeneas in largely negative contexts, book 1 opposes standard sixteenth-century interpretations of Aeneas's pietas, whereas later books of The Faerie Queene usually conform to prevalent early modern interpretations of the moral import of this powerful cultural memory.
Sofic representations of amenable groups
Authors: Elek Gábor , Szabó Endre
Published: July 2011

Using probabilistic methods, Collins and Dykema proved that the free product of two sofic groups amalgamated over a monotileabe amenable subgroup is sofic as well. We show that the restriction is unnecessary; the free product of two sofic groups amalgamated over an arbitrary amenable subgroup is sofic. We also prove a group-theoretical analogue of a result of Kenley Jung. A finitely generated group is amenable if and only if it has only one sofic representation up to conjugacy equivalence.
Random maximal isotropic subspaces and Selmer groups
Authors: Poonen Bjorn , Rains Eric
Published: July 2011

Under suitable hypotheses, we construct a probability measure on the set of closed maximal isotropic subspaces of a locally compact quadratic space over

F

p

\mathbb {F}_p

. A random subspace chosen with respect to this measure is discrete with probability

1
1

, and the dimension of its intersection with a fixed compact open maximal isotropic subspace is a certain nonnegative-integer-valued random variable.

We then prove that the

p
p

-Selmer group of an elliptic curve is naturally the intersection of a discrete maximal isotropic subspace with a compact open maximal isotropic subspace in a locally compact quadratic space over

F

p

\mathbb {F}_p

. By modeling the first subspace as being random, we can explain the known phenomena regarding distribution of Selmer ranks, such as the theorems of Heath-Brown, Swinnerton-Dyer, and Kane for

2
2

-Selmer groups in certain families of quadratic twists, and the average size of

2
2

- and

3
3

-Selmer groups as computed by Bhargava and Shankar. Our model is compatible with Delaunay’s heuristics for

p
p

-torsion in Shafarevich-Tate groups, and predicts that the average rank of elliptic curves over a fixed number field is at most

1

/

2

1/2

. Many of our results generalize to abelian varieties over global fields.
Closures of 𝐾-orbits in the flag variety for 𝑆𝑈*(2𝑛)
Authors: McGovern William
Published: July 2011

We characterize the

S

p

2
n

Sp_{2n}

-orbits in the flag variety for

S

L

2
n

SL_{2n}

with rationally smooth closure via a pattern avoidance criterion, also showing that the singular and rationally singular loci of such orbit closures coincide.
Birds flee en mass from New Year’s Eve fireworks
Authors: Shamoun-Baranes Judy , Dokter Adriaan M. , van Gasteren Hans , van Loon E. Emiel , Leijnse Hidde , Bouten Willem
Published: July 2011

Anthropogenic disturbances of wildlife, such as noise, human presence, hunting activity, and motor vehicles, are becoming an increasing concern in conservation biology. Fireworks are an important part of celebrations worldwide, and although humans often find fireworks spectacular, fireworks are probably perceived quite differently by wild animals. Behavioral responses to fireworks are difficult to study at night, and little is known about the negative effects fireworks may have on wildlife. Every year, thousands of tons of fireworks are lit by civilians on New Year’s Eve in the Netherlands. Using an operational weather radar, we quantified the reaction of birds to fireworks in 3 consecutive years. Thousands of birds took flight shortly after midnight, with high aerial movements lasting at least 45 min and peak densities measured at 500 m altitude. The highest densities were observed over grasslands and wetlands, including nature conservation sites, where thousands of waterfowl rest and feed. The Netherlands is the most important winter staging area for several species of waterfowl in Europe. We estimate that hundreds of thousands of birds in the Netherlands take flight due to fireworks. The spatial and temporal extent of disturbance is substantial, and potential consequences are discussed. Weather radar provides a unique opportunity to study the reaction of birds to fireworks, which has otherwise remained elusive.
Circadian desynchronization
Authors: Granada Adrián E. , Cambras Trinitat , Díez-Noguera Antoni , Herzel Hanspeter
Published: July 2011

The suprachiasmatic nucleus (SCN) coordinates via multiple outputs physiological and behavioural circadian rhythms. The SCN is composed of a heterogeneous network of coupled oscillators that entrain to the daily light–dark cycles. Outside the physiological entrainment range, rich locomotor patterns of desynchronized rhythms are observed. Previous studies interpreted these results as the output of different SCN neural subpopulations. We find, however, that even a single periodically driven oscillator can induce such complex desynchronized locomotor patterns. Using signal analysis, we show how the observed patterns can be consistently clustered into two generic oscillatory interaction groups: modulation and superposition. In seven of 17 rats undergoing forced desynchronization, we find a theoretically predicted third spectral component. Combining signal analysis with the theory of coupled oscillators, we provide a framework for the study of circadian desynchronization.
C-type period-doubling transition in nephron autoregulation
Authors: Laugesen Jakob L. , Mosekilde Erik , Holstein-Rathlou Niels-Henrik
Published: July 2011

The functional units of the kidney, called nephrons, utilize mechanisms that allow the individual nephron to regulate the incoming blood flow in response to fluctuations in the arterial pressure. This regulation tends to be unstable and to generate self-sustained oscillations, period-doubling bifurcations, mode-locking and other nonlinear dynamic phenomena in the tubular pressures and flows. Using a simplified nephron model, the paper examines how the regulatory mechanisms react to an external periodic variation in arterial pressure near a region of resonance with one of the internally generated mode-locked cycles. We show how the stable and unstable resonance cycles generated in this response undergo interconnected cascades of period-doubling bifurcations and how each period doubling leads to the formation of a new pair of saddle-node bifurcation curves along the edges of the resonance zone. We also show how period doubling of the resonance cycles is accompanied by a torus-doubling process in the quasiperiodic regime that exists outside of the resonance zone.
Construction and validation of anisotropic and orthotropic ventricular geometries for quantitative predictive cardiac electrophysiology
Authors: Benson Alan P. , Bernus Olivier , Dierckx Hans , Gilbert Stephen H. , Greenwood John P. , Holden Arun V. , Mohee Kevin , Plein Sven , Radjenovic Aleksandra , Ries Michael E. , Smith Godfrey L. , Sourbron Steven , Walton Richard D.
Published: July 2011

Reaction–diffusion computational models of cardiac electrophysiology require both dynamic excitation models that reconstruct the action potentials of myocytes as well as datasets of cardiac geometry and architecture that provide the electrical diffusion tensor
D
, which determines how excitation spreads through the tissue. We illustrate an experimental pipeline we have developed in our laboratories for constructing and validating such datasets. The tensor
D
changes with location in the myocardium, and is determined by tissue architecture. Diffusion tensor magnetic resonance imaging (DT-MRI) provides three eigenvectors
e

i

and eigenvalues
λ

i

at each voxel throughout the tissue that can be used to reconstruct this architecture. The primary eigenvector
e
1
is a histologically validated measure of myocyte orientation (responsible for anisotropic propagation). The secondary and tertiary eigenvectors (
e
2
and
e
3
) specify the directions of any orthotropic structure if
λ
2
is significantly greater than
λ
3
—this orthotropy has been identified with sheets or cleavage planes. For simulations, the components of
D
are scaled in the fibre and cross-fibre directions for anisotropic simulations (or fibre, sheet and sheet normal directions for orthotropic tissues) so that simulated conduction velocities match values from optical imaging or plunge electrode experiments. The simulated pattern of propagation of action potentials in the models is partially validated by optical recordings of spatio-temporal activity on the surfaces of hearts. We also describe several techniques that enhance components of the pipeline, or that allow the pipeline to be applied to different areas of research: Q ball imaging provides evidence for multi-modal orientation distributions within a fraction of voxels, infarcts can be identified by changes in the anisotropic structure—irregularity in myocyte orientation and a decrease in fractional anisotropy, clinical imaging provides human ventricular geometry and can identify ischaemic and infarcted regions, and simulations in human geometries examine the roles of anisotropic and orthotropic architecture in the initiation of arrhythmias.
Exocytosis from pancreatic β-cells: mathematical modelling of the exit of low-molecular-weight granule content
Authors: Galvanovskis Juris , Braun Matthias , Rorsman Patrik
Published: July 2011

Pancreatic β-cells use Ca
2+
-dependent exocytosis of large dense core vesicles to release insulin. Exocytosis in β-cells has been studied biochemically, biophysically and optically. We have previously developed a biophysical method to monitor release of endogenous intragranular constituents that are co-released with insulin. This technique involves the expression of ionotropic membrane receptors in the β-cell plasma membrane and enables measurements of exocytosis of individual vesicles with sub-millisecond resolution. Like carbon fibre amperometry, this method allows fine details of the release process, like the expansion of the fusion pore (the narrow connection between the granule lumen and the extracellular space), to be monitored. Here, we discuss experimental data obtained with this method within the framework of a simple mathematical model that describes the release of low-molecular constituents during exocytosis of the insulin granules. Our findings suggest that the fusion pore functions as a molecular sieve, allowing differential release of low- and high-molecular-weight granule constituents.
Can biofuels be a solution to climate change? The implications of land use change-related emissions for policy
Authors: Khanna Madhu , Crago Christine L. , Black Mairi
Published: July 2011

Biofuels have gained increasing attention as an alternative to fossil fuels for several reasons, one of which is their potential to reduce the greenhouse gas (GHG) emissions from the transportation sector. Recent studies have questioned the validity of claims about the potential of biofuels to reduce GHG emissions relative to the liquid fossil fuels they are replacing when emissions owing to direct (DLUC) and indirect land use changes (ILUC) that accompany biofuels are included in the life cycle GHG intensity of biofuels. Studies estimate that the GHG emissions released from ILUC could more than offset the direct GHG savings by producing biofuels and replacing liquid fossil fuels and create a ‘carbon debt’ with a long payback period. The estimates of this payback period, however, vary widely across biofuels from different feedstocks and even for a single biofuel across different modelling assumptions. In the case of corn ethanol, this payback period is found to range from 15 to 200 years. We discuss the challenges in estimating the ILUC effect of a biofuel and differences across biofuels, and its sensitivity to the assumptions and policy scenarios considered by different economic models. We also discuss the implications of ILUC for designing policies that promote biofuels and seek to reduce GHG emissions. In a first-best setting, a global carbon tax is needed to set both DLUC and ILUC emissions to their optimal levels. However, it is unclear whether unilateral GHG mitigation policies, even if they penalize the ILUC-related emissions, would increase social welfare and lead to optimal emission levels. In the absence of a global carbon tax, incentivizing sustainable land use practices through certification standards, government regulations and market-based pressures may be a viable option for reducing ILUC.
Modelling of pH dynamics in brain cells after stroke
Authors: Orlowski Piotr , Chappell Michael , Park Chang Sub , Grau Vicente , Payne Stephen
Published: July 2011

The identification of salvageable brain tissue is a major challenge at stroke presentation. Standard techniques used in this context, such as theperfusion–diffusion mismatch, remain controversial. There is thus a need for new methods to help guide treatment. The potential role of pH imaging in this context is currently being investigated. Intracellular pH varies as a function of local perfusion, intracellular energy stores and time. Low pH triggers the production of free radicals and affects the calcium balance of the cells, which may lead to apoptosis and cell death. Thus, the characterization of pH dynamics may have predictive value for cell death after stroke, particularly when combined with novel imaging techniques. Therefore, we have extended an existing model of brain cellular metabolism to simulate the pH response of cells to ischaemia. Simulation results for conditions of reduced cerebral blood flow show good agreement for the evolution of intracellular pH with previously reported measurements and encourage the development of quantitative pH imaging to validate the predictive value of pH.
A tool for multi-scale modelling of the renal nephron
Authors: Nickerson David P. , Terkildsen Jonna R. , Hamilton Kirk L. , Hunter Peter J.
Published: July 2011

We present the development of a tool, which provides users with the ability to visualize and interact with a comprehensive description of a multi-scale model of the renal nephron. A one-dimensional anatomical model of the nephron has been created and is used for visualization and modelling of tubule transport in various nephron anatomical segments. Mathematical models of nephron segments are embedded in the one-dimensional model. At the cellular level, these segment models use models encoded in CellML to describe cellular and subcellular transport kinetics. A web-based presentation environment has been developed that allows the user to visualize and navigate through the multi-scale nephron model, including simulation results, at the different spatial scales encompassed by the model description. The Zinc extension to Firefox is used to provide an interactive three-dimensional view of the tubule model and the native Firefox rendering of scalable vector graphics is used to present schematic diagrams for cellular and subcellular scale models. The model viewer is embedded in a web page that dynamically presents content based on user input. For example, when viewing the whole nephron model, the user might be presented with information on the various embedded segment models as they select them in the three-dimensional model view. Alternatively, the user chooses to focus the model viewer on a cellular model located in a particular nephron segment in order to view the various membrane transport proteins. Selecting a specific protein may then present the user with a description of the mathematical model governing the behaviour of that protein—including the mathematical model itself and various simulation experiments used to validate the model against the literature.
Patient-specific modelling of whole heart anatomy, dynamics and haemodynamics from four-dimensional cardiac CT images
Authors: Mihalef Viorel , Ionasec Razvan Ioan , Sharma Puneet , Georgescu Bogdan , Voigt Ingmar , Suehling Michael , Comaniciu Dorin
Published: July 2011

There is a growing need for patient-specific and holistic modelling of the heart to support comprehensive disease assessment and intervention planning as well as prediction of therapeutic outcomes. We propose a patient-specific model of the whole human heart, which integrates morphology, dynamics and haemodynamic parameters at the organ level. The modelled cardiac structures are robustly estimated from four-dimensional cardiac computed tomography (CT), including all four chambers and valves as well as the ascending aorta and pulmonary artery. The patient-specific geometry serves as an input to a three-dimensional Navier–Stokes solver that derives realistic haemodynamics, constrained by the local anatomy, along the entire heart cycle. We evaluated our framework with various heart pathologies and the results correlate with relevant literature reports.
Clinically driven design of multi-scale cancer models: the ContraCancrum project paradigm
Authors: Marias K. , Dionysiou D. , Sakkalis V. , Graf N. , Bohle R. M. , Coveney P. V. , Wan S. , Folarin A. , Büchler P. , Reyes M. , Clapworthy G. , Liu E. , Sabczynski J. , Bily T. , Roniotis A. , Tsiknakis M. , Kolokotroni E. , Giatili S. , Veith C. , Messe E. , Stenzhorn H. , Kim Yoo-Jin , Zasada S. , Haidar A. N. , May C. , Bauer S. , Wang T. , Zhao Y. , Karasek M. , Grewer R. , Franz A. , Stamatakos G.
Published: July 2011

The challenge of modelling cancer presents a major opportunity to improve our ability to reduce mortality from malignant neoplasms, improve treatments and meet the demands associated with the individualization of care needs. This is the central motivation behind the ContraCancrum project. By developing integrated multi-scale cancer models, ContraCancrum is expected to contribute to the advancement of
in silico
oncology through the optimization of cancer treatment in the patient-individualized context by simulating the response to various therapeutic regimens. The aim of the present paper is to describe a novel paradigm for designing clinically driven multi-scale cancer modelling by bringing together basic science and information technology modules. In addition, the integration of the multi-scale tumour modelling components has led to novel concepts of personalized clinical decision support in the context of predictive oncology, as is also discussed in the paper. Since clinical adaptation is an inelastic prerequisite, a long-term clinical adaptation procedure of the models has been initiated for two tumour types, namely non-small cell lung cancer and glioblastoma multiforme; its current status is briefly summarized.
A global conversation about energy from biomass: the continental conventions of the global sustainable bioenergy project
Authors: Lynd Lee Rybeck , Aziz Ramlan Abdul , de Brito Cruz Carlos Henrique , Chimphango Annie Fabian Abel , Cortez Luis Augusto Barbosa , Faaij Andre , Greene Nathanael , Keller Martin , Osseweijer Patricia , Richard Tom L. , Sheehan John , Chugh Archana , van der Wielen Luuk , Woods Jeremy , van Zyl Willem Heber
Published: July 2011

The global sustainable bioenergy (GSB) project was formed in 2009 with the goal of providing guidance with respect to the feasibility and desirability of sustainable, bioenergy-intensive futures. Stage 1 of this project held conventions with a largely common format on each of the world's continents, was completed in 2010, and is described in this paper. Attended by over 400 persons, the five continental conventions featured presentations, breakout sessions, and drafting of resolutions that were unanimously passed by attendees. The resolutions highlight the potential of bioenergy to make a large energy supply contribution while honouring other priorities, acknowledge the breadth and complexity of bioenergy applications as well as the need to take a systemic approach, and attest to substantial intra- and inter-continental diversity with respect to needs, opportunities, constraints and current practice relevant to bioenergy. The following interim recommendations based on stage 1 GSB activities are offered:

— Realize that it may be more productive, and also more correct, to view the seemingly divergent assessments of bioenergy as answers to two different questions rather than the same question. Viewed in this light, there is considerably more scope for reconciliation than might first be apparent, and it is possible to be informed rather than paralysed by divergent assessments.

— Develop established and advanced bioenergy technologies such that each contributes to the other's success. That is, support and deploy in the near-term meritorious, established technologies in ways that enhance rather than impede deployment of advanced technologies, and support and deploy advanced technologies in ways that expand rather than contract opportunities for early adopters and investors.

— Be clear in formulating policies what mix of objectives are being targeted, measure the results of these policies against these objectives and beware of unintended consequences.

— Undertake further exploration of land efficiency levers and visions for multiply-beneficial bioenergy deployment. This should be unconstrained by current practices, since we cannot hope to achieve a sustainable and a secure future by continuing the practices that have led to the unsustainable and insecure present. It should also be approached from a global perspective, based on the best science available, and consider the diverse realities, constraints, needs and opportunities extant in different regions of the world.

The future trajectory of the GSB project is also briefly considered.
Differential and integral views of genetics in computational systems biology
Authors: Noble Denis
Published: July 2011

This article uses an integrative systems biological view of the relationship between genotypes and phenotypes to clarify some conceptual problems in biological debates about causality. The differential (gene-centric) view is incomplete in a sense analogous to using differentiation without integration in mathematics. Differences in genotype are frequently not reflected in significant differences in phenotype as they are buffered by networks of molecular interactions capable of substituting an alternative pathway to achieve a given phenotype characteristic when one pathway is removed. Those networks integrate the influences of many genes on each phenotype so that the effect of a modification in DNA depends on the context in which it occurs. Mathematical modelling of these interactions can help to understand the mechanisms of buffering and the contextual-dependence of phenotypic outcome, and so to represent correctly and quantitatively the relations between genomes and phenotypes. By incorporating all the causal factors in generating a phenotype, this approach also highlights the role of non-DNA forms of inheritance, and of the interactions at multiple levels.
Thermal strain imaging: a review
Authors: Seo Chi Hyung , Shi Yan , Huang Sheng-Wen , Kim Kang , O'Donnell Matthew
Published: July 2011

Thermal strain imaging (TSI) or temporal strain imaging is an ultrasound application that exploits the temperature dependence of sound speed to create thermal (temporal) strain images. This article provides an overview of the field of TSI for biomedical applications that have appeared in the literature over the past several years. Basic theory in thermal strain is introduced. Two major energy sources appropriate for clinical applications are discussed. Promising biomedical applications are presented throughout the paper, including non-invasive thermometry and tissue characterization. We present some of the limitations and complications of the method. The paper concludes with a discussion of competing technologies.