bluuebunny/crossref_metadata_2025 huggingface dataset:
IMAGING DIAGNOSIS—EXTRAHEPATIC BILIARY TRACT OBSTRUCTION SECONDARY TO A BILIARY FOREIGN BODY IN A CAT
Authors: Brioschi Valentina , Rousset Nicolas , Ladlow Jane F.
Published: August 2013

An 11‐year‐old, neutered female British Shorthair cat was referred with a 4‐week history of abdominal pain and vomiting. Abdominal ultrasonography revealed a dilated common bile duct containing a spindle‐shaped structure with several reflecting interfaces. Differentials that were considered included an intraluminal foreign body, or helminth parasites within the common bile duct. Surgical exploration of the abdominal cavity demonstrated the presence of two grass awns obstructing the common bile duct. Anomalies of the portal vasculature were noted during surgery and were considered an incidental finding. The clinical signs resolved following surgical removal of the grass awns.
On the Number ofp-Regular Elements in Finite Simple Groups
Authors: Babai László , Pálfy Péter P. , Saxl Jan
Published: August 2013

Ap-regular element in a finite group is an element of order not divisible by the prime numberp. We show that for every primepand every finite simple groupS, a fair proportion of elements ofSisp-regular. In particular, we show that the proportion ofp-regular elements in a finite classical simple group (not necessarily of characteristicp) is greater than 1/(2n), wheren– 1 is the dimension of the projective space on whichSacts naturally. Furthermore, in an exceptional group of Lie type this proportion is greater than 1/15. For the alternating group An, this proportion is at least 26/(27√n), and for sporadic simple groups, at least 2/29.

We also show that for an arbitrary fieldF, if the simple groupSis a quotient of a finite subgroup ofGLn(F) then for any primep, the proportion ofp-regular elements inSis at least min{1/31, 1/(2n)}.

Along the way we obtain estimates for the proportion of elements of certain primitive prime divisor orders in exceptional groups, complementing work by Niemeyer and Praeger (1998).Our result shows that in finite simple groups,p-regular elements can be found efficiently by random sampling. This is a key ingredient to recent polynomial-time Monte Carlo algorithms for matrix groups.

Finally we complement our lower bound results with the following upper bound: for alln≥ 2 there exist infinitely many prime powersqsuch that the proportion of elements of odd order inPSL(n,q) is less than 3/√n.
Reduction of Binary Cubic and Quartic Forms
Authors: Cremona J. E.
Published: August 2013

A reduction theory is developed for binary forms (homogeneous polynomials) of degrees three and four with integer coefficients. The resulting coefficient bounds simplify and improve on those in the literature, particularly in the case of negative discriminant. Applications include systematic enumeration of cubic number fields, and 2-descent on elliptic curves defined over the set of rational numbers. Remarks are given concerning the extension of these results to forms defined over number fields.
Symbolic Collection using Deep Thought
Authors: Leedham-Green C. R. , Soicher Leonard H.
Published: August 2013

We describe the “Deep Thought” algorithm, which can, among other things, take a commutator presentation for a finitely generated torsion-free nilpotent group G, and produce explicit polynomials for the multiplication of elements of G. These polynomials were first shown to exist by Philip Hall, and allow for “symbolic collection” in finitely generated nilpotent groups. We discuss various practicalissues in calculations in such groups, including the construction of a hybrid collector, making use of both the polynomials and ordinary collection from the left.
A Mechanically Checked Proof of IEEE Compliance of the Floating Point Multiplication, Division and Square Root Algorithms of the AMD-K7™ Processor
Authors: Russinoff David M.
Published: August 2013

We describe a mechanically verified proof of correctness of the floating point multiplication, division, and square root instructions of the AMD-K7 microprocessor. The instructions are implemented in hardware and represented here by register-transfer level specifications, the primitives of which are logical operations on bit vectors. On the other hand, the statements of correctness, derived from IEEE Standard 754, are arithmetic in nature and considerably more abstract. Therefore, we begin by developing a theory of bit vectors and their role in floating point representations and rounding. We then present the hardware model and a rigorous proof of its correctness. All of our definitions, lemmas and theorems have been formally encoded in the ACL2 logic, and every step in the proof has been mechanically checked with the ACL2 prover.
Using Program Schemes to Capture Polynomial-Time Logically on Certain Classes of Structures
Authors: Stewart Iain A.
Published: August 2013

In this paper, the study of the expressive power of certain classes of program schemes on finite structures is continued, in relation to more mainstream logics studied in finite model theory and to computational complexity. The author shows that there exists a program scheme – whose constructs are assignments and while-loops with quantifier-free tests and which has access to a stack – that can accept a P-complete problem, the deterministic path system problem, even in the absence of non-determinism, so long as problem instances are presented in a functional style. (The proof given here leans heavily on Cook's proof that the classes of formal languages accepted by deterministic and non-deterministic logspace auxiliary pushdown machines coincide.) However, whilst this result is of independent interest, in that it leads to a deterministic model of computation capturing P, whose non-deterministic variant also captures P, the program scheme can also be used to build a successor relation in certain classes of structures (namely: the class of strongly connected locally ordered digraphs, the class of connected planar embeddings, and the class of triangulations), with the consequence that on these classes of graphs, (a fragment of) path system logic (with no built-in relations) captures exactly the polynomial-time solvable problems.
Numerical Evidence for a Conjectural Generalization of Hilbert's Theorem 132
Authors: Bley W.
Published: August 2013

This paper presents an algorithm for computing numerical evidence for a conjecture whose validity is predicted by the requirement that the equivariant Tamagawa number conjectures for Tate motives as formulated by Burns and Flach are compatible with the functional equation of the Artin L-series. The algorithm includes methods for the computation of Fitting ideals and projective lattices over the integral group ring.
Exponential Mean-Square Stability of Numerical Solutions to Stochastic Differential Equations
Authors: Higham Desmond J. , Mao Xuerong , Stuart Andrew M.
Published: August 2013

Positive results are proved here about the ability of numerical simulations to reproduce the exponential mean-square stability of stochastic differential equations (SDEs). The first set of results applies under finite-time convergence conditions on the numerical method. Under these conditions, the exponential mean-square stability of the SDE and that of the method (for sufficiently small step sizes) are shown to be equivalent, and the corresponding second-moment Lyapunov exponent bounds can be taken to be arbitrarily close. The required finite-time convergence conditions hold for the class of stochastic theta methods on globally Lipschitz problems. It is then shown that exponential mean-square stability for non-globally Lipschitz SDEs is not inherited, in general, by numerical methods. However, for a class of SDEs that satisfy a one-sided Lipschitz condition, positive results are obtained for two implicit methods. These results highlight the fact that for long-time simulation on nonlinear SDEs, the choice of numerical method can be crucial.
Polynomials with Restricted Coefficients and Prescribed Noncyclotomic Factors
Authors: Mossinghoff Michael J.
Published: August 2013

The algorithms described in this paper were developed to investigate three problems regarding polynomials with restricted coefficients: (i) determining whether there exist polynomials with {0, 1} coefficients and repeated noncyclotomic factors, (ii) searching for polynomials with {−1, 1} coefficients and small Mahler measure, and (iii) finding polynomials with {−1, 0, 1} coefficients with a root of high multiplicity off the unit circle. The results in the first problem presented here answer a question of Odlyzko and Poonen.
Corrigenda: Low-dimensional Representations of Quasi-simple Groups
Authors: Hiss Gerhard , Malle Gunter
Published: August 2013

This paper contains corrections to the tables of low-dimensional representations of quasi-simple groups published in the paper, ‘Low-dimensional representations of quasi-simple groups’, LMS Journal of Computation and Mathematics 4 (2001) 22–63.
On Deciding Finiteness for Matrix Groups over Fields of Positive Characteristic
Authors: Detinko A.
Published: August 2013

The author considers the development of algorithms for deciding whether a finitely generated matrix group over a field of positive characteristic is finite. A deterministic algorithm for deciding the finiteness is presented for the case of a field of transcendence degree one over a finite field.
Small Degree Representations of Finite Chevalley Groups in Defining Characteristic
Authors: Lübeck Frank
Published: August 2013

The author has determined, for all simple simply connected reductive linear algebraic groups defined over a finite field, all the irreducible representations in their defining characteristic of degree below some bound. These also give the small degree projective representations in defining characteristic for the corresponding finite simple groups. For large rank l, this bound is proportional to l3, and for rank less than or equal to 11 much higher. The small rank cases are based on extensive computer calculations.
Constructing Maximal Subgroups of Classical Groups
Authors: Holt Derek F. , Roney-Dougal Colva M.
Published: August 2013

The maximal subgroups of the finite classical groups are divided by a theorem of Aschbacher into nine classes. In this paper, the authors show how to construct those maximal subgroups of the finite classical groups of linear, symplectic or unitary type that lie in the first eight of these classes. The ninth class consists roughly of absolutely irreducible groups that are almost simple modulo scalars, other than classical groups over the same field in their natural representation. All of these constructions can be carried out in low-degree polynomial time.
Spider Diagrams
Authors: Howse John , Stapleton Gem , Taylor John
Published: August 2013

The use of diagrams in mathematics has traditionally been restricted to guiding intuition and communication. With rare exceptions such as Peirce's alpha and beta systems, purely diagrammatic formal reasoning has not been in the mathematician's or logician's toolkit. This paper develops a purely diagrammatic reasoning system of “spider diagrams” that builds on Euler, Venn and Peirce diagrams. The system is known to be expressively equivalent to first-order monadic logic with equality. Two levels of diagrammatic syntax have been developed: an ‘abstract’ syntax that captures the structure of diagrams, and a ‘concrete’ syntax that captures topological properties of drawn diagrams. A number of simple diagrammatic transformation rules are given, and the resulting reasoning system is shown to be sound and complete.
Stable Model of X0(125)
Authors: McMurdy Ken
Published: August 2013

In this paper, the components in the stable model of X0(125) over C5 are determined by constructing (in the language of R. Coleman's ‘Stable maps of curves’, to appear in the Kato Volume of Doc. Math.) an explicit semi-stable covering. Empirical data is then offered regarding the placement of certain CM j-invariants in the supersingular disk of X(1) over C5, which suggests a moduli-theoretic interpretation for the components of the stable model. The paper then concludes with a conjecture regarding the stable model of X0(p3) for p > 3, which is as yet unknown.
Automating Symmetry-Breaking Calculations
Authors: Matthews P. C.
Published: August 2013

The process of classifying possible symmetry-breaking bifurcations requires a computation involving the subgroups and irreducible representations of the original symmetry group. It is shown how this calculation can be automated using a group theory package such as GAP. This enables a number of new results to be obtained for larger symmetry groups, where manual computation is impractical. Examples of symmetric and alternating groups are given, and the method is also applied to the spatial symmetry-breaking of periodic patterns observed in experiments.
Hurwitz Groups of Intermediate Rank
Authors: Vsemirnov M.
Published: August 2013

This paper is concerned with (2, 3, 7)-generated linear groups of ranks less than 287. In particular, sixty new values of n are found, such that the groups SLn(q) are Hurwitz for any prime powerq. This result provides the next step in deciding which classical groups are Hurwitz.
Improved Mixing Bounds for the Anti-Ferromagnetic Potts Model on Z2
Authors: Goldberg Leslie Ann , Jalsenius Markus , Martin Russell , Paterson Mike
Published: August 2013

The authors of this paper consider the anti-ferromagnetic Potts model on the the integer lattice Z2. The model has two parameters: q, the number of spins, and λ = exp(−β), where β 4 is ‘inverse temperature’. It is known that the model has strong spatial mixing if q > 7, or if q = 7 and λ = 0 or λ > 1/8, or if q = 6 and λ = 0 or λ > 1/4. The λ = 0 case corresponds to the model in which configurations are proper q-colourings of Z2. It is shown that the system has strong spatial mixing for q ≥ 6 and any λ. This implies that Glauber dynamics is rapidly mixing (so there is a fully-polynomial randomised approximation scheme for the partition function), and also that there is a unique infinite-volume Gibbs state. We also show that strong spatial mixing occurs for a larger range of λ than was previously known for q = 3, q = 4 and q = 5.
On Small Characteristic Algebraic Tori in Pairing-Based Cryptography
Authors: Granger R. , Page D. , Stam M.
Published: August 2013

The value ot the late pairing on an elliptic curve over a finite field may be viewed as an element of an algebraic torus. Using this simple observation, we transfer techniques recently developed for torus-based cryptography to pairing-based cryptography, resulting in more efficient computations, and lower bandwidth requirements. To illustrate the efficacy of this approach, we apply the method to pairings on supersingular elliptic curves in characteristic three.
A Covariance Matrix Inversion Problem arising from the Construction of Phylogenetic Trees
Authors: Nye Tom M. W. , Baxter Brad J. C. , Gilks Walter R.
Published: August 2013

We describe an efficient algorithm for the inversion of covariance matrices that arise in the context of phylogenetic tree construction. Phylogenetic trees describe the evolutionary relationships between species, and their construction is computationally demanding. Many approaches involve the symmetric matrix of evolutionary distances between species. Regarding these distances as random variables, the corresponding set of variances and covariances form a rank-4 tensor, and the inner-product defined by its inverse can be used to assign statistical scores to candidate trees. We describe a natural set of assumptions for the phylogenetic tree under construction, and show how under these assumptions the covariance tensor for a tree with n leaves can be inverted inO(n2) operations. In addition to presenting the inversion algorithm, we hope this article will open algebraic and computational problems from the field of phylogeny to a wider audience.
An Indefinite Convection-Diffusion Operator
Authors: Davies E.B.
Published: August 2013

We give a mathematically rigorous analysis which confirms the surprising results in a recent paper of Benilov, O‘Brien and Sazonov [J. Fluid Mech. 497 (2003) 201-224] about the spectrum of a highly singular non-self-adjoint operator that arises in a problem in fluid mechanics. We also show that the set of eigenvectors does not form a basis for the operator.
On 4-Engel Groups
Authors: Vaughan-Lee Michael
Published: August 2013

In this note, the author proves that a group G is a 4-Engel group if and only if the normal closure of every element g ∈ G is a 3-Engel group
Arithmetic E8 Lattices with Maximal Galois Action
Authors: Várilly-Alvarado Anthony , Zywina David
Published: August 2013

We construct explicit examples of E8 lattices occurring in arithmetic for which the natural Galois action is equal to the full group of automorphisms of the lattice, i.e., the Weyl group of E8. In particular, we give explicit elliptic curves over Q(t) whose Mordell-Weil lattices are isomorphic to E8 and have maximal Galois action.

Our main objects of study are del Pezzo surfaces of degree 1 over number fields. The geometric Picard group, considered as a lattice via the negative of the intersection pairing, contains a sublattice isomorphic to E8. We construct examples of such surfaces for which the action of Galois on the geometric Picard group is maximal.
Computations in Relative Algebraic K-Groups
Authors: Bley Werner , Wilson Stephen M. J.
Published: August 2013

Let G be finite group and K a number field or a p-adic field with ring of integers OK. In the first part of the manuscript we present an algorithm that computes the relative algebraic K-group K0(OK[G], K) as an abstract abelian group. We also give algorithms to solve the discrete logarithm problems in K0(OK[G], K) and in the locally free class group cl(OK[G]). All algorithms have been implemented in Magma for the case K = Q.

In the second part of the manuscript we prove formulae for the torsion subgroup of K0(Z[G], Q) for large classes of dihedral and quaternion groups.
Strong Spatial Mixing and Rapid Mixing with Five Colours for the Kagome Lattice
Authors: Jalsenius Markus
Published: August 2013

We consider proper 5-colourings of the kagome lattice. Proper q-colourings correspond to configurations in the zero-temperature q-state anti-ferromagnetic Potts model. Salas and Sokal have given a computer assisted proof of strong spatial mixing on the kagome lattice for q ≥ 6 under any temperature, including zero temperature. It is believed that there is strong spatial mixing for q ≥ 4. Here we give a computer assisted proof of strong spatial mixing for q = 5 and zero temperature. It is commonly known that strong spatial mixing implies that there is a unique infinite-volume Gibbs measure and that the Glauber dynamics is rapidly mixing. We give a proof of rapid mixing of the Glauber dynamics on any finite subset of the vertices of the kagome lattice, provided that the boundary is free (not coloured). The Glauber dynamics is not necessarily irreducible if the boundary is chosen arbitrarily for q = 5 colours. The Glauber dynamics can be used to uniformly sample proper 5-colourings. Thus, a consequence of rapidly mixing Glauber dynamics is that there is fully polynomial randomised approximation scheme for counting the number of proper 5-colourings.
On level one cuspidal Bianchi modular forms
Authors: Rahm Alexander D. , Şengün Mehmet Haluk
Published: August 2013

In this paper, we present the outcome of vast computer calculations, locating several of the very rare instances of level one cuspidal Bianchi modular forms that are not lifts of elliptic modular forms.
Interlimb communication to the knee flexors during walking in humans
Authors: Stevenson Andrew J. T. , Geertsen Svend S. , Andersen Jacob B. , Sinkjær Thomas , Nielsen Jens B. , Mrachacz‐Kersting Natalie
Published: August 2013

Key points

Following unexpected ipsilateral knee extension joint rotations applied during the late stance phase of the gait cycle in humans, a crossed reflex response was observed in the contralateral biceps femoris (cBF) muscle with a mean onset latency of 76 ms.

Transcranial magnetic and electrical stimulation applied to the primary motor cortex revealed that a transcortical pathway probably contributes to the cBF response.

We hypothesize that the cBF response signifies a preparation of the contralateral leg for early load bearing, helping the body to maintain dynamic stability during walking.

This is the first study to show that a transcortical pathway contributes to an interlimb reflex in upper leg muscles. The transcortical nature of the response may allow for more adaptable responses than purely spinally mediated reflexes due to integration with other sensory information.

Abstract  A strong coordination between the two legs is important for maintaining a symmetric gait pattern and adapting to changes in the external environment. In humans as well as animals, receptors arising from the quadriceps muscle group influence the activation of ipsilateral muscles. Moreover, strong contralateral spinal connections arising from quadriceps and hamstring afferents have been shown in animal models. Therefore, the aims of the present study were to assess if such connections also exist in humans and to elucidate on the possible pathways. Contralateral reflex responses were investigated in the right leg following unexpected unilateral knee joint rotations during locomotion in either the flexion or extension direction. Strong reflex responses in the contralateral biceps femoris (cBF) muscle with a mean onset latency of 76 ± 6 ms were evoked only from ipsilateral knee extension joint rotations in the late stance phase. To investigate the contribution of a transcortical pathway to this response, transcranial magnetic and electrical stimulation were applied. Motor evoked potentials elicited by transcranial magnetic stimulation, but not transcranial electrical stimulation, were facilitated when elicited at the time of the cBF response to a greater extent than the algebraic sum of the cBF reflex and motor evoked potentials elicited separately, indicating that a transcortical pathway probably contributes to this interlimb reflex. The cBF reflex response may therefore be integrated with other sensory input, allowing for responses that are more flexible. We hypothesize that the cBF reflex response may be a preparation of the contralateral leg for early load bearing, slowing the forward progression of the body to maintain dynamic equilibrium during walking.
Exposure to cocaine regulates inhibitory synaptic transmission from the ventral tegmental area to the nucleus accumbens
Authors: Ishikawa Masago , Otaka Mami , Neumann Peter A. , Wang Zhijian , Cook James M. , Schlüter Oliver M. , Dong Yan , Huang Yanhua H.
Published: August 2013

Key points

Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway; in addition to the well‐known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, but the cellular nature of VTA‐to‐NAc fast synaptic transmission and its roles in drug‐induced adaptations are not well understood.

Using optogenetic approaches, the present study profiled fast excitatory synaptic projection from dopaminergic neurons and inhibitory synaptic projection from GABAergic neurons in the VTA to NAc core (NAcCo) medium spiny neurons.

We further identified that, following repeated non‐contingent exposure to cocaine, VTA‐to‐NAcCo inhibitory synaptic transmission appears to be enhanced by an increase in the presynaptic release probability.

No postsynaptic alterations were detected at either excitatory or inhibitory synapses within the VTA‐to‐NAcCo projection.

Abstract  Synaptic projections from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) make up the backbone of the brain reward pathway, a neural circuit that mediates behavioural responses elicited by natural rewards as well as by cocaine and other drugs of abuse. In addition to the well‐known modulatory dopaminergic projection, the VTA also provides fast excitatory and inhibitory synaptic input to the NAc, directly regulating NAc medium spiny neurons (MSNs). However, the cellular nature of VTA‐to‐NAc fast synaptic transmission and its roles in drug‐induced adaptations are not well understood. Using viral‐mediated in vivo expression of channelrhodopsin 2, the present study dissected fast excitatory and inhibitory synaptic transmission from the VTA to NAc MSNs in rats. Our results suggest that, following repeated exposure to cocaine (15 mg kg−1 day−1× 5 days, i.p., 1 or 21 day withdrawal), a presynaptic enhancement of excitatory transmission and suppression of inhibitory transmission occurred at different withdrawal time points at VTA‐to‐NAc core synapses. In contrast, no postsynaptic alterations were detected at either type of synapse. These results suggest that changes in VTA‐to‐NAc fast excitatory and inhibitory synaptic transmissions may contribute to cocaine‐induced alteration of the brain reward circuitry.
Wind Tunnel Experiment of Bluff Body Aerodynamic Models Using a New Type of Magnetic Suspension and Balance System
Authors: Kawamura Y. , Mizota T.
Published: August 2013

We have measured drag coefficients of a sphere and a circular cylindrical aerodynamic model using a five axes and a six axes control magnetic suspension and balance system (MSBS) developed by us. This MSBS has the characteristics of large aperture relative to the weight, light weight, and small electric power consumption in comparison with the conventional ones. We had good agreements between the measured values of the drag coefficient and the values appearing in the common aerodynamic handbook or textbook. We also succeeded in measuring the aerodynamic influence of a supporting rod of the aerodynamic models making use of the characteristics of the MSBS. Conventionally, the MSBS can be used only in large scale laboratories because the size, weight, and electric power consumption are large. We think that successful measurements of various aerodynamic characteristics using this type of MSBS will stimulate the introduction of it into the wind tunnel experiments in small scale laboratories.
A Computational Investigation of the Steady State Vibrations of Unbalanced Flexibly Supported Rigid Rotors Damped by Short Magnetorheological Squeeze Film Dampers
Authors: Zapoměl Jaroslav , Ferfecki Petr , Forte Paola
Published: August 2013

Unbalance is the principal cause of excitation of lateral vibrations of rotors and generation of the forces transmitted through the rotor supports to the foundations. These effects can be significantly reduced if damping devices are added to the constraint elements. To achieve their optimum performance, their damping effect must be controllable. The possibility of controlling the damping force is offered by magnetorheological squeeze film dampers. This article presents an original investigation of the dynamical behavior of a rigid flexibly supported rotor loaded by its unbalance and equipped with two short magnetorheological squeeze film dampers. In the computational model, the rotor is considered as absolutely rigid and the dampers are represented by force couplings. The pressure distribution in the lubricating layer is governed by a modified Reynolds equation adapted for Bingham material, which is used to model the magnetorheological fluid. To obtain the steady state solution of the equations of motion, a collocation method is employed. Stability of the periodic vibrations is evaluated by means of the Floquet theory. The proposed approach to study the behavior of rigid rotors damped by semi-active squeeze film magnetorheological dampers and the developed efficient computational methods to calculate the system steady state response and to evaluate its stability represent new contributions of this article.
Simulations using patient data to evaluate systematic errors that may occur in 4D treatment planning: A proof of concept study
Authors: James Sara St. , Seco Joao , Mishra Pankaj , Lewis John H.
Published: August 2013

Purpose:

The purpose of this work is to present a framework to evaluate the accuracy of four‐dimensional treatment planning in external beam radiation therapy using measured patient data and digital phantoms.

Methods:

To accomplish this, 4D digital phantoms of two model patients were created using measured patient lung tumor positions. These phantoms were used to simulate a four‐dimensional computed tomography image set, which in turn was used to create a 4D Monte Carlo (4DMC) treatment plan. The 4DMC plan was evaluated by simulating the delivery of the treatment plan over approximately 5 min of tumor motion measured from the same patient on a different day. Unique phantoms accounting for the patient position (tumor position and thorax position) at 2 s intervals were used to represent the model patients on the day of treatment delivery and the delivered dose to the tumor was determined using Monte Carlo simulations.

Results:

For Patient 1, the tumor was adequately covered with 95.2% of the tumor receiving the prescribed dose. For Patient 2, the tumor was not adequately covered and only 74.3% of the tumor received the prescribed dose.

Conclusions:

This study presents a framework to evaluate 4D treatment planning methods and demonstrates a potential limitation of 4D treatment planning methods. When systematic errors are present, including when the imaging study used for treatment planning does not represent all potential tumor locations during therapy, the treatment planning methods may not adequately predict the dose to the tumor. This is the first example of a simulation study based on patient tumor trajectories where systematic errors that occur due to an inaccurate estimate of tumor motion are evaluated.
Response to Comment on “The Placental Mammal Ancestor and the Post–K-Pg Radiation of Placentals”
Authors: O’Leary Maureen A. , Bloch Jonathan I. , Flynn John J. , Gaudin Timothy J. , Giallombardo Andres , Giannini Norberto P. , Goldberg Suzann L. , Kraatz Brian P. , Luo Zhe-Xi , Meng Jin , Ni Xijun , Novacek Michael J. , Perini Fernando A. , Randall Zachary , Rougier Guillermo W. , Sargis Eric J. , Silcox Mary T. , Simmons Nancy B. , Spaulding Michelle , Velazco Paúl M. , Weksler Marcelo , Wible John R. , Cirranello Andrea L.
Published: August 2013

Tree-building with diverse data maximizes explanatory power. Application of molecular clock models to ancient speciation events risks a bias against detection of fast radiations subsequent to the Cretaceous-Paleogene (K-Pg) event. Contrary to Springer
et al
., post–K-Pg placental diversification does not require “virus-like” substitution rates. Even constraining clade ages to their model, the explosive model best explains placental evolution.
Flashing a Light on the Spatial Organization of Transcription
Authors: Rickman Colin , Bickmore Wendy A.
Published: August 2013

Transient and highly dynamic clusters of RNA polymerase II form during the initiation phase of transcription.

[Also see Report by

Cisse
et al.

]
Computing a Better Fire Forecast
Authors: Kintisch Eli
Published: August 2013

Scientists and firefighters ponder new ways to predict the spread of wildfire as the U.S. West faces ever more potent blazes.
Simultaneous Profiling of 194 Distinct Receptor Transcripts in Human Cells
Authors: Kang Byong H. , Jensen Karin J. , Hatch Jaime A. , Janes Kevin A.
Published: August 2013

Receptor transcript profiling defines context-specific signaling signatures.
The Receptor AXL Diversifies EGFR Signaling and Limits the Response to EGFR-Targeted Inhibitors in Triple-Negative Breast Cancer Cells
Authors: Meyer Aaron S. , Miller Miles A. , Gertler Frank B. , Lauffenburger Douglas A.
Published: August 2013

Amplification of downstream signaling by AXL receptor tyrosine kinase alters the migratory response of breast cancer cells.
Protecting the Guts
Authors: Mueller Kristen
Published: August 2013

Bacterial fermentation products regulate the number and function of regulatory T cells in the mouse colon.
Vancomycin-Rifampin Combination Therapy Has Enhanced Efficacy against an Experimental Staphylococcus aureus Prosthetic Joint Infection
Authors: Niska Jared A. , Shahbazian Jonathan H. , Ramos Romela Irene , Francis Kevin P. , Bernthal Nicholas M. , Miller Lloyd S.
Published: August 2013

Treatment of prosthetic joint infections often involves a two-stage exchange, with implant removal and antibiotic spacer placement followed by systemic antibiotic therapy and delayed reimplantation. However, if antibiotic therapy can be improved, one-stage exchange or implant retention may be more feasible, thereby decreasing morbidity and preserving function. In this study, a mouse model of prosthetic joint infection was used in which
Staphylococcus aureus
was inoculated into a knee joint containing a surgically placed metallic implant extending from the femur. This model was used to evaluate whether combination therapy of vancomycin plus rifampin has increased efficacy compared with vancomycin alone against these infections. On postoperative day 7, vancomycin with or without rifampin was administered for 6 weeks with implant retention.
In vivo
bioluminescence imaging,
ex vivo
CFU enumeration, X-ray imaging, and histologic analysis were carried out. We found that there was a marked therapeutic benefit when vancomycin was combined with rifampin compared with vancomycin alone. Taken together, our results suggest that the mouse model used could serve as a valuable
in vivo
preclinical model system to evaluate and compare efficacies of antibiotics and combinatory therapy for prosthetic joint infections before more extensive studies are carried out in human subjects.
Systematic Review and Meta-Analysis of
In Vitro
Synergy of Polymyxins and Carbapenems
Authors: Zusman Oren , Avni Tomer , Leibovici Leonard , Adler Amos , Friberg Lena , Stergiopoulou Theodouli , Carmeli Yehuda , Paul Mical
Published: August 2013

Our objective was to examine the evidence of
in vitro
synergy of polymyxin-carbapenem combination therapy against Gram-negative bacteria (GNB). A systematic review and meta-analysis were performed. All studies examining
in vitro
interactions of antibiotic combinations consisting of any carbapenem with colistin or polymyxin B against any GNB were used. A broad search was conducted with no language, date, or publication status restrictions. Synergy rates, defined as a fractional inhibitory concentration index of ≤0.5 or a >2-log reduction in CFU, were pooled separately for time-kill, checkerboard, and Etest methods in a mixed-effect meta-analysis of rates. We examined whether the synergy rate depended on the testing method, type of antibiotic, bacteria, and resistance to carbapenems. Pooled rates with 95% confidence intervals (CI) are shown. Thirty-nine published studies and 15 conference proceeding were included, reporting on 246 different tests on 1,054 bacterial isolates. In time-kill studies, combination therapy showed synergy rates of 77% (95% CI, 64 to 87%) for
Acinetobacter baumannii
, 44% (95% CI, 30 to 59%) for
Klebsiella pneumoniae
, and 50% (95% CI, 30 to 69%) for
Pseudomonas aeruginosa
, with low antagonism rates for all. Doripenem showed high synergy rates for all three bacteria. For
A. baumannii
, meropenem was more synergistic than imipenem, whereas for
P. aeruginosa
the opposite was true. Checkerboard and Etest studies generally reported lower synergy rates than time-kill studies. The use of combination therapy led to less resistance development
in vitro
. The combination of a carbapenem with a polymyxin against GNB, especially
A. baumannii
, is supported
in vitro
by high synergy rates, with low antagonism and less resistance development. These findings should be examined in clinical studies.
Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy
Authors: Pan Xiaolei , Wang Li , Gründemann Dirk , Sweet Douglas H.
Published: August 2013

According to the 2012 WHO global tuberculosis (TB) report (http://apps.who.int/iris/bitstream/10665/75938/1/9789241564502_eng.pdf), the death rate for tuberculosis was over 1.4 million patients in 2011, with ∼9 million new cases diagnosed. Moreover, the frequency of comorbidity with human immunodeficiency virus (HIV) and with diabetes is on the rise, increasing the risk of these patients for experiencing drug-drug interactions (DDIs) due to polypharmacy. Ethambutol is considered a first-line antituberculosis drug. Ethambutol is an organic cation at physiological pH, and its major metabolite, 2,2′-(ethylenediimino)dibutyric acid (EDA), is zwitterionic. Therefore, we assessed the effects of ethambutol and EDA on the function of human organic cation transporter 1 (hOCT1), hOCT2, and hOCT3 and that of EDA on organic anion transporter 1 (hOAT1) and hOAT3. Potent inhibition of hOCT1- and hOCT2-mediated transport by ethambutol (50% inhibitory concentration [IC50] = 92.6 ± 10.9 and 253.8 ± 90.8 μM, respectively) was observed. Ethambutol exhibited much weaker inhibition of hOCT3 (IC50= 4.1 ± 1.6 mM); however, significant inhibition (>80%) was observed at physiologically relevant concentrations in the gastrointestinal (GI) tract after oral dosing. EDA failed to exhibit any inhibitory effects that warranted further investigation. DDI analysis indicated a strong potential for ethambutol interaction on hOCT1 expressed in enterocytes and hepatocytes and on hOCT3 in enterocytes, which would alter absorption, distribution, and excretion of coadministered cationic drugs, suggesting thatin vivopharmacokinetic studies are necessary to confirm drug safety and efficacy. In particular, TB patients with coexisting HIV or diabetes might experience significant DDIs in situations of coadministration of ethambutol and clinical therapeutics known to be hOCT1/hOCT3 substrates (e.g., lamivudine or metformin).
New Role for DCR-1/Dicer in Caenorhabditis elegans Innate Immunity against the Highly Virulent Bacterium Bacillus thuringiensis DB27
Authors: Iatsenko Igor , Sinha Amit , Rödelsperger Christian , Sommer Ralf J.
Published: August 2013

Bacillus thuringiensisproduces toxins that target invertebrates, includingCaenorhabditis elegans. Virulence ofBacillusstrains is often highly specific, such thatB. thuringiensisstrain DB27 is highly pathogenic toC. elegansbut shows no virulence for another model nematode,Pristionchus pacificus. To uncover the underlying mechanisms of the differential responses of the two nematodes toB. thuringiensisDB27 and to reveal theC. elegansdefense mechanisms against this pathogen, we conducted a genetic screen forC. elegansmutants resistant toB. thuringiensisDB27. Here, we describe aB. thuringiensisDB27-resistantC. elegansmutant that is identical tonasp-1, which encodes theC. eleganshomolog of the nuclear-autoantigenic-sperm protein. Gene expression analysis indicated a substantial overlap between the genes downregulated in thenasp-1mutant and targets ofC. elegansdcr-1/Dicer, suggesting thatdcr-1is repressed innasp-1mutants, which was confirmed by quantitative PCR. Consistent with this, thenasp-1mutant exhibits RNA interference (RNAi) deficiency and reduced longevity similar to those of adcr-1mutant. Building on these surprising findings, we further explored a potential role fordcr-1inC. elegansinnate immunity. We show thatdcr-1mutant alleles deficient in microRNA (miRNA) processing, but not those deficient only in RNAi, are resistant toB. thuringiensisDB27. Furthermore,dcr-1overexpression rescues thenasp-1mutant's resistance, suggesting that repression ofdcr-1determines thenasp-1mutant's resistance. Additionally, we identified the collagen-encoding genecol-92as one of the downstream effectors ofnasp-1that play an important role in resistance to DB27. Taken together, these results uncover a previously unknown role for DCR-1/Dicer inC. elegansantibacterial immunity that is largely associated with miRNA processing.
Reduced Virulence of the Vibrio cholerae
fadD
Mutant Is Due to Induction of the Extracytoplasmic Stress Response
Authors: Chatterjee Epshita , Chowdhury Rukhsana
Published: August 2013

Vibrio cholerae
, an important human intestinal pathogen, is responsible for the diarrheal disease cholera. The pathogenesis of
V. cholerae
is a highly coordinated process that involves diverse regulatory factors. It has recently been demonstrated that disruption of the
V. cholerae
fadD
gene, encoding a long-chain fatty acyl coenzyme A (acyl-CoA) ligase, drastically reduces expression of the major virulence genes and
in vivo
lethality of this important human pathogen. This effect was due to reduced membrane localization of the central virulence regulator TcpP. In this study, the reason for the impaired membrane localization of TcpP in the
fadD
mutant was investigated. We demonstrate that extracytoplasmic stress is induced in the
V. cholerae
Δ
fadD
strain. In response to the extracytoplasmic stress, the integral membrane protease RseP is activated and degrades the membrane-localized TcpP in the
fadD
mutant strain. Indeed, disruption of the
rseP
gene in a
fadD
mutant background restored membrane localization of TcpP and expression of the downstream virulence genes
toxT
,
ctxA
, and
tcpA
. Increased expression of the σ
E
regulon genes in ethanol-treated wild-type
V. cholerae
indicated that ethanol exposure could induce an extracytoplasmic stress response in
V. cholerae
. Ethanol treatment also led to activation of the RseP protease activity and resulted in degradation of membrane-localized TcpP and subsequent reduction in expression of the virulence genes. Taken together, these results suggest that extracytoplasmic stress response
per se
reduces virulence of
V. cholerae
by impairing membrane localization of TcpP.
Leishmania amazonensis Amastigotes Trigger Neutrophil Activation but Resist Neutrophil Microbicidal Mechanisms
Authors: Carlsen Eric D. , Hay Christie , Henard Calvin A. , Popov Vsevolod , Garg Nisha Jain , Soong Lynn
Published: August 2013

Neutrophils are the first cells to infiltrate to the site of
Leishmania
promastigote infection, and these cells help to reduce parasite burden shortly after infection is initiated. Several clinical reports indicate that neutrophil recruitment is sustained over the course of leishmaniasis, and amastigote-laden neutrophils have been isolated from chronically infected patients and experimentally infected animals. The goal of this study was to compare how thioglycolate-elicited murine neutrophils respond to
L. amazonensis
metacyclic promastigotes and amastigotes derived from axenic cultures or from the lesions of infected mice. Neutrophils efficiently internalized both amastigote and promastigote forms of the parasite, and phagocytosis was enhanced in lipopolysaccharide (LPS)-activated neutrophils or when parasites were opsonized in serum from infected mice. Parasite uptake resulted in neutrophil activation, oxidative burst, and accelerated neutrophil death. While promastigotes triggered the release of tumor necrosis factor alpha (TNF-α), uptake of amastigotes preferentially resulted in the secretion of interleukin-10 (IL-10) from neutrophils. Finally, the majority of promastigotes were killed by neutrophils, while axenic culture- and lesion-derived amastigotes were highly resistant to neutrophil microbicidal mechanisms. This study indicates that neutrophils exhibit distinct responses to promastigote and amastigote infection. Our findings have important implications for determining the impact of sustained neutrophil recruitment and amastigote-neutrophil interactions during the late phase of cutaneous leishmaniasis.
CD30 Is Required for Activation of a Unique Subset of Interleukin-17A-Producing γδ T Cells in Innate Immunity against Mycobacterium bovis Bacillus Calmette-Guérin Infection
Authors: Guo Ying , Sun Xun , Shibata Kensuke , Yamada Hisakata , Muta Hiromi , Podack Eckhard R. , Yoshikai Yasunobu
Published: August 2013

Interleukin-17A (IL-17A)-producing γδ T cells are known to be activated followingMycobacterium bovisbacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1−Vγ4−γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1−Vγ4−γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling byin vivoadministration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1−Vγ4−γδ T cells in WT mice, while stimulating CD30L/CD30 signaling byin vivoadministration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1−Vγ4−γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 at an early stage of BCG infection.
Contribution of Secretory Antibodies to Intestinal Mucosal Immunity against Helicobacter pylori
Authors: Gorrell Rebecca J. , Wijburg Odilia L. C. , Pedersen John S. , Walduck Anna K. , Kwok Terry , Strugnell Richard A. , Robins-Browne Roy M.
Published: August 2013

The natural immune response toHelicobacter pylorineither clears infection nor prevents reinfection. However, the ability of secretory antibodies to influence the course ofH. pyloriinfection has not been determined. We compared the natural progression ofH. pyloriinfection in wild-type C57BL/6 mice with that in mice lacking the polymeric immunoglobulin receptor (pIgR) that is essential for the secretion of polymeric antibody across mucosal surfaces.H. pyloriSS1-infected wild-type and pIgR knockout (KO) mice were sampled longitudinally for gastrointestinal bacterial load, antibody response, and histological changes. The gastric bacterial loads of wild-type and pIgR KO mice remained constant and comparable at up to 3 months postinfection (mpi) despite SS1-reactive secretory IgA in the intestinal contents of wild-type mice at that time. Conversely, abundant duodenal colonization of pIgR KO animals contrasted with the near-total eradication ofH. pylorifrom the intestine of wild-type animals by 3 mpi.H. pyloriwas cultured only from the duodenum of those animals in which colonization in the distal gastric antrum was of sufficient density for immunohistological detection. By 6 mpi, the gastric load ofH. pyloriin wild-type mice was significantly lower than in pIgR KO animals. While there was no corresponding difference between the two mouse strains in gastric pathology results at 6 mpi, reductions in gastric bacterial load correlated with increased gastric inflammation together with an intestinal secretory antibody response in wild-type mice. Together, these results suggest that naturally produced secretory antibodies can modulate the progress ofH. pyloriinfection, particularly in the duodenum.