bluuebunny/crossref_metadata_2025 huggingface dataset:
A note regarding ‘On the power-law distribution of language family sizes’
Authors: ARNOLD RICHARD , BAUER LAURIE
Published: June 2006

Wichmann (2005) discusses the power-law distribution n=ar−b as a description of the relationship between the number of languages n in a language family, and the rank r of that family in a list ordered by decreasing n. Two datasets are used by Wichmann, one from Ethnologue (Grimes 2000), which lists 130 language families, and one from Ruhlen (1987), listing 21 families. We have reanalysed these data and find that the method of fitting a power-law used in the paper is not optimal because it does not allow for a sensible maximum value for the family size n.
Biology and language: a response to Everett (2005)
Authors: ANDERSON STEPHEN R. , LIGHTFOOT DAVID W.
Published: June 2006

In a recent review article in this journal, Everett (2005) finds our book Anderson & Lightfoot (2002) (as well as Givón 2002) seriously lacking and unpersuasive in the case it attempts to make for the importance of an understanding of the human language faculty as an aspect of our species' biology. Negative reviews are of course a feature of academic life, but Everett's piece exhibits enough misconceptions and misrepresentations, both of our work and of the nature of biology, to warrant a response.
Biology and language: response to Anderson & Lightfoot
Authors: EVERETT DANIEL L.
Published: June 2006

‘Sometimes nothin’ can be a real cool hand.’

Cool Hand Luke
Implications of reproductive technologies for birth and developmental outcomes: imprinting defects and beyond
Authors: Paoloni-Giacobino Ariane
Published: June 2006

Assisted reproductive techniques (ARTs) have been widely used over the past two decades to help infertile couples conceive. Recent studies on the ART-conceived population have raised concern about the possible risks of these techniques, in particular with regard to increased incidence of growth and developmental disorders. Some of these effects might be linked to genomic imprinting defects, although current evidence does not allow definite conclusions to be drawn. This review summarises studies that have examined effects of gamete and embryo manipulations on imprinted genes, and discusses the evidence for and against effects of ARTs on offspring health, and in particular imprinting-related conditions.
The Anaesthetic Nurses' Perception of Their Role
Authors: Oakley Melanie
Published: June 2006

ABSTRACT

Much has been written about the role of the nurse within the operating department but much less has been uncovered about the role of the anaesthetic nurse within this area. By detailing research undertaken by the author, anaesthetic nurses' perception of their role is recounted and how they interact with other disciplines within the operating department – Operating Department Practitioners (ODPs). These two groups appear to work in relative harmony but there is need for examination and change to the training of both nurses and ODPs, and maybe looking at core training for perioperative staff, which could be accessed at differing levels and can be re-entered at a higher level for further qualifications.
First observations of detached equatorial ionospheric plasma depletions using OI 630.0 nm and OI 777.4 nm emissions nightglow imaging
Authors: Sahai Y. , Abalde J. R. , Fagundes P. R. , Pillat V. G. , Bittencourt J. A.
Published: June 2006

Near‐simultaneous all‐sky (180° field of view) observations of the OI 630.0 nm and OI 777.4 nm nightglow emissions are being carried out on a routine basis at “Laboratorio Nacional de Astrofisica (LNA)”, Brazópolis (22.5° S, 45.6° W; dip latitude 17.5° S; altitude 1860 m), Brazil, since September 2002. The all‐sky imaging observations of the OI 630.0 nm and OI 777.4 nm emissions, which arise from the dissociative recombination of O2+ ions and radiative recombination of O+ ions (mainly), respectively, are used to monitor the morphology and dynamics of the equatorial F‐region at the respective emission heights. In this paper we present and discuss the first observations showing detached equatorial F‐region plasma depletions or bubbles. Three cases are presented from observations during the years 2002 and 2003. We suggest a possible mechanism for their generation.
Equatorial ionospheric responses to high‐intensity long‐duration auroral electrojet activity (HILDCAA)
Authors: Sobral José Humberto A. , Abdu Mangalathayil A. , Gonzalez Walter D. , Gonzalez Alicia C. , Tsurutani Bruce T. , da Silva Renato R. L. , Barbosa Isabela G. , Arruda Daniela C. S. , Denardini Clezio M. , Zamlutti Carlos J. , Guarnieri Fernando
Published: June 2006

The knowledge of the coupling processes between the magnetosphere and the equatorial ionosphere is of basic importance to the understanding of the near‐Earth space weather. This study focuses on observational results of such coupling processes based on data collected during the phenomenon defined as high‐intensity long‐duration continuous AE activity (HILDCAA) which occurs outside the main phase of geomagnetic storms. The fact that the responses of the equatorial/low‐latitude ionosphere to HILDCAA events have not been specifically focused so far is one of the motivations for this study. Ionosonde data on hmF2, h′F, and foF2 from three locations in Brazil (magnetic equatorial station São Luis (SL), subequatorial station Fortaleza (FZ), and low‐latitude station Cachoeira Paulista (CP)) are analyzed together with ACE satellite data on solar wind and interplanetary magnetic and electric fields during three HILDCAA events that occurred in the years 2000 and 2001. The results did not indicate any presence of penetrating electric field disturbance during these events. However, they provided clear evidence of disturbance dynamo electric field and disturbance thermospheric winds, through F layer height changes that were similar but generally less intense than those observed during a typical storm event. The foF2 presented no particular disturbances that can be clearly attributed to the HILDCAA event. Previous extensive studies carried out by the authors on ionospheric storm effects for these same three stations clearly illustrate the much more intense F layer storm disturbances compared with HILDCAA events disturbances.
Ion emission spectra in the Jovian X‐ray aurora
Authors: Kharchenko V. , Dalgarno A. , Schultz D. R. , Stancil P. C.
Published: June 2006

X‐ray and Extreme Ultraviolet emission spectra resulting from energetic sulfur and oxygen ions precipitating into the Jovian atmosphere are calculated. Monte Carlo simulations of the energy and charge relaxation of downward ion fluxes are carried out, using updated collision cross sections for stripping, electron capture, and target ionization. Energy and charge distributions of precipitating sulfur ions are presented for the first time and the equilibrium charge model is shown to be inadequate. X‐ray emission spectra are calculated for different sulfur and oxygen mixtures and for different initial entry energies. Satisfactory agreement with both Chandra and XMM‐Newton observations is obtained by an equal population of sulfur and oxygen ions with energies between 1 and 2 MeV/amu. The agreement provides a reconciliation of the two spectral data sets and the inferred initial energies are consistent with the view that the ions are magnetospheric in origin and have been accelerated to MeV/amu energies.
Presynaptic opioid receptors on noradrenergic and serotonergic neurons in the human as compared to the rat neocortex
Authors: Berger Benjamin , Rothmaier Anna Katharina , Wedekind Franziska , Zentner Josef , Feuerstein Thomas J , Jackisch Rolf
Published: June 2006

Electrically evoked release of [3H]‐noradrenaline ([3H]‐NA) or [3H]‐5‐hydroxytryptamine ([3H]‐5‐HT) in slices of human and the rat neocortex was used to characterize presynaptic opioid receptors.

Release of [3H]‐NA in rat neocortical slices was reduced only by the μ‐receptor agonist DAMGO (pIC50: 7.27, CI95: [7.22, 7.32]; Imax: 77.6±1.6%; antagonized by naloxone: pA2: 8.88, CI95: [8.78, 8.98]).

Release of [3H]‐NA in human neocortical slices was unaffected by DAMGO, but inhibited by the δ‐receptor agonist DPDPE (Imax: 25.7±2.2%) and the κ‐receptor agonist U‐50,488H (19.7±2.7% inhibition at 1 μM). Both effects were antagonized by naltrindole (1 μM).

Release of [3H]‐5‐HT in rat neocortical slices, was inhibited by DAMGO (10 μM) and U‐50,488H (1 and 10 μM) only in the presence of the 5‐HT receptor antagonist methiotepin (1 μM).

Release of [3H]‐5‐HT in human neocortical slices was unaffected by DPDPE, but U‐50,488H (Imax: 40.8±8.3%; antagonized by 0.1 μM norbinaltorphimine) and DAMGO (16.4±3.9% inhibition at 1 μM; antagonized by 0.1 μM naloxone) acted inhibitory.

Release of [3H]‐5‐HT in human neocortical slices was reduced by nociceptin/orphanin (0.1 and 1 μM). These effects were antagonized by the ORL1 antagonist J‐113397 (1‐[(3R,4R)‐1‐cyclo‐octylmethyl‐3‐hydroxymethyl‐4‐piperidyl]‐3‐ethyl‐1,3‐dihydro‐2H‐benzimidazol‐2‐one; 0.1 μM).

This study provides evidence for significant species differences in opioid receptor‐mediated modulation of NA and 5‐HT‐release in human vs rat neocortex. In rats, μ‐opioid receptors modulate NA release, but 5‐HT release is only weakly affected by μ‐ and κ‐opioids. In contrast, NA release in human neocortex is modulated via δ‐opioid receptors, but 5‐HT release mainly via κ‐opioid receptors. In addition also the ORL1 receptor seems to be involved in 5‐HT release modulation.

British Journal of Pharmacology (2006) 148, 795–806. doi:10.1038/sj.bjp.0706782
Profiling of functional phosphodiesterase in mesangial cells using a CRE‐SEAP‐based reporting system
Authors: Zhu Ying , Yao Jian , Meng Yiman , Kasai Ayumi , Hiramatsu Nobuhiko , Hayakawa Kunihiro , Miida Takashi , Takeda Masayuki , Okada Masahiko , Kitamura Masanori
Published: June 2006

Phosphodiesterases (PDEs) are critically implicated in the regulation of mesangial cell function, but profile of functional PDEs in mesangial cells is still unclear. In this study, we investigated roles of individual PDEs in the regulation of mesangial cell behavior by the cAMP pathway.

Reporter mesangial cells that express secreted alkaline phosphatase (SEAP) under the control of the cAMP response element (CRE) were exposed to selective PDE inhibitors in the presence or absence of cAMP, and activity of CRE, expression of CRE‐regulated protein, mitogenesis and cell survival were examined.

Exposure of reporter cells to cAMP‐elevating agents resulted in time‐ and concentration‐dependent activation of CRE. Treatment of the cells with any PDE inhibitors alone did not induce CRE activation. Under stimulation with 8‐bromo‐cAMP or 8‐bromo‐cGMP, however, inhibitors of PDE2, PDE3, PDE4 and PDE5 enhanced activation of CRE. Inhibition of PDE1 or PDE6 did not affect the CRE activation.

Among different combinations tested, only inhibitors of PDE3 and PDE4 cooperatively increased the level of intracellular cAMP, activity of protein kinase A, activation of CRE, and CRE‐regulated protein, connexin43.

Concomitant inhibition of PDE3 and PDE4 attenuated mitogen‐induced activation of extracellular signal‐regulated kinases and cell proliferation. Under serum deprivation, combinational inhibition of PDE3 and PDE4 exclusively caused activation of caspase‐3 and apoptosis.

The present data elucidated that PDE3 and PDE4 play critical roles in the regulation of mesangial cell function. PDE3 and PDE4 were identified as the novel, antiapoptotic machinery that supports survival of mesangial cells.

British Journal of Pharmacology (2006) 148, 833–844. doi:10.1038/sj.bjp.0706785
Counteracting effect of glycyrrhizin on the hemostatic abnormalities induced by Bothrops jararaca snake venom
Authors: Assafim Mariane , Ferreira Marcos S , Frattani Flávia S , Guimarães Jorge A , Monteiro Robson Q , Zingali Russolina B
Published: June 2006

Envenomation by the snake Bothrops jararaca is typically associated with hemostatic abnormalities including pro‐ and anticoagulant disturbances. Glycyrrhizin (GL) is a plant‐derived thrombin inhibitor that also exhibits in vivo antithrombotic properties. Here, we evaluated the ability of GL to counteract the hemostatic abnormalities promoted by B. jararaca venom.

GL inhibited the human fibrinogen clotting (IC50=∼1.0 mg ml−1; 1.2 mM), H‐D‐phenylalanyl‐L‐pipecolyl‐L‐arginine‐p‐nitroanilide dihydrochloride hydrolysis (IC50=∼0.4 mg ml−1; 0.47 mM) and platelet aggregation (IC50=∼0.28 mg ml−1; 0.33 mM) induced by B. jararaca venom, in vitro.

The in vivo effect of GL was tested in rats using a model of venous thrombosis in which intravenous (i.v.) administration of B. jararaca venom (100 μg kg−1) produced in all animals a thrombus with a mean weight of 10.6±1.7 mg.

Prior administration of GL (180 mg kg−1) or antibothropic serum (27 μl kg−1) inhibited thrombus formation by 86 and 67%, respectively. Remarkably, co‐administration of ineffective doses of GL and antibothropic serum markedly decreased thrombus weight, suggesting a synergistic effect.

Co‐administration of GL with antibothropic serum abolished venom‐induced bleeding. Ex vivo clotting times showed that rat plasma was non‐clotting after i.v. administration of B. jararaca venom. Treatment with GL, antibothropic serum or both before venom administration efficiently prevented this abnormality.

Altogether, we demonstrate here that GL prevents both in vitro and in vivo venom‐induced changes in hemostasis, suggesting a potential antiophidic activity.

British Journal of Pharmacology (2006) 148, 807–813. doi:10.1038/sj.bjp.0706786
Exact expressions of mean first-passage times and splitting probabilities for random walks in bounded rectangular domains
Authors: Condamin S. , Bénichou O.
Published: June 2006

We give exact and explicit expressions of mean first-passage times for random walks in a rectangular domain in both cases of reflecting boundary conditions and periodic boundary conditions. The situations with one or two absorbing targets are considered.
Atoms-in-molecules in momentum space: A Hirshfeld partitioning of electron momentum densities
Authors: Balanarayan P. , Gadre Shridhar R.
Published: June 2006

A direct application of the Hirshfeld atomic partitioning (HAP) scheme is implemented for molecular electron momentum densities (EMDs). The momentum density contributions of individual atoms in diverse molecular systems are analyzed along with their topographical features and the kinetic energies of the atomic partitions. The proposed p-space HAP-based charge scheme does seem to possess the desirable attributes expected of any atoms in molecules partitioning. In addition to this, the main strength of the p-space HAP is the exact knowledge of the kinetic energy functional and the inherent ease in computing the kinetic energy. The charges derived from HAP in momentum space are found to match chemical intuition and the generally known chemical characteristics such as electronegativity, etc.
Tungsten nanotip fabrication by spatially controlled field-assisted reaction with nitrogen
Authors: Rezeq Moh’d , Pitters Jason , Wolkow Robert
Published: June 2006

In this report we present a straightforward new technique for fabricating nanotips. This approach is based on spatially controlling the reaction of nitrogen gas with the surface atoms of a tungsten tip in a field ion microscope (FIM). Confining this field-assisted etching reaction to the shank has enabled us to produce single-atom tips with an apex radius far sharper than the nominal 10nm radius of curvature tips we start with. Tip sharpening is evidenced in several ways. The FIM imaging voltage drops dramatically from, typically, 4.4to1.6kV. Nanotip formation is also evident from the increase in the FIM magnification and the decrease in the apex area, which are monitored throughout the experiment. A subsequent field evaporation allows the nanotip to be sequentially deconstructed to further describe the extraordinary sharp tip that was formed. We also demonstrate the utility of these nanotips for the scanning tunneling microscope.
Nuclear magnetic resonance structural investigations of ammonia-doped fullerides
Authors: Shiroka T. , Fumera G. , Ligabue O. , Riccò M. , Antonioli G. C.
Published: June 2006

The dynamic and structural properties of the ammonia-doped superconducting fulleride (NH3)xNaK2C60 (0.5⩽x⩽1), well known for its anomalous decrease of transition temperature with doping, have been investigated using sodium and deuterium solid-state NMR techniques. The independence of Na23 quadrupole splitting from the ammonia content x, which, at the same time, substantially affects Tc, suggests a marginal role of the cation position in the superconducting mechanism. On the other hand, a strong reduction of the deuterium quadrupole coupling with respect to the free ammonia value denotes the presence of weak hydrogen bonds between the deuterium atoms and fullerene π orbitals. Despite the bond weakness, as evinced by the lively ammonia rotational dynamics even at very low temperatures, the resulting electron localization could explain the observed Tc anomaly. The motion of the ND3–Na group (located in the compound’s octahedral voids), as well as the evolution of the ammonia dynamics as a function of temperature, were determined from deuterium NMR line shape analysis and from detailed numerical simulations. While at the lowest measured temperatures only the ammonia rotation around its own C3 axis takes place, above ∼25 and 70K, respectively, also the wobbling of the C3 axis and the ND3 relocation become active, successfully modeled by a strongly correlated motion involving two different time scales.
Molecular dynamics simulation of the density and surface tension of water by particle-particle particle-mesh method
Authors: Shi Bo , Sinha Shashank , Dhir Vijay K.
Published: June 2006

In this work, molecular dynamics simulation is performed to study the density and surface tension of water for a range of temperatures from 300to600K. The extended simple point charge interaction potential for water is used. The particle-particle particle-mesh method, which automatically includes untruncated long-range terms, is used for the Lennard-Jones and the Coulombic terms. The results show that the long-range correction for the Lennard-Jones term is very important for the calculation of surface tension. It is found that the calculated density and surface tension of water fit well with experimental data for temperatures less than 500K. Near the critical temperature, the simulation results are off from the experimental data.
Herman-Kluk semiclassical dynamics in action-angle representation: New approaches to mapping quantum degrees of freedom
Authors: Saha Rajdeep , Ovchinnikov M.
Published: June 2006

A general approach to mapping a discrete quantum mechanical problem by a continuous Hamiltonian is presented. The method is based on the representation of the quantum number by a continuous action variable that extends from −∞ to ∞. The projection of this Hilbert space onto the set of integer quantum numbers reduces the Hamiltonian to a discrete matrix of interest. The theory allows the application of the semiclassical methods to discrete quantum mechanical problems and, in particular, to problems where quantum Hamiltonians are coupled to continuous degrees of freedom. The Herman Kluk semiclassical propagation is used to calculate the nonadiabatic dynamics for a model avoided crossing system. The results demonstrate several advantages of the new theory compared to the existing mapping approaches.
Multiple structural transformations in Lennard-Jones clusters: Generic versus size-specific behavior
Authors: Mandelshtam Vladimir A. , Frantsuzov Pavel A.
Published: June 2006

The size-temperature “phase diagram” for Lennard-Jones clusters LJn with sizes up to n=147 is constructed based on the analysis of the heat capacities and orientational bond order parameter distributions computed by the exchange Monte Carlo method. Two distinct types of “phase transitions” accompanied by peaks in the heat capacities are proven to be generic. Clusters with Mackay atom packing in the overlayer undergo a lower-temperature melting (or Mackay–anti-Mackay) transition that occurs within the overlayer. All clusters undergo a higher-temperature transition, which for the three-layer clusters is proven to be the 55-atom-core-melting transition. For the two-layer clusters, the core/overlayer subdivision is ambiguous, so the higher-temperature transition is better characterized as the breaking of the local icosahedral coordination symmetry. A pronounced size-specific behavior can typically be observed at low temperatures and often occurs in clusters with highly symmetric global minima. An example of such behavior is LJ135, which undergoes a low-temperature solid-solid transition, besides the two generic transitions, i.e., the overlayer reconstruction and the core melting.
Microfibrillar structure of type I collagen
in situ
Authors: Orgel Joseph P. R. O. , Irving Thomas C. , Miller Andrew , Wess Tim J.
Published: June 2006

The fibrous collagens are ubiquitous in animals and form the structural basis of all mammalian connective tissues, including those of the heart, vasculature, skin, cornea, bones, and tendons. However, in comparison with what is known of their production, turnover and physiological structure, very little is understood regarding the three-dimensional arrangement of collagen molecules in naturally occurring fibrils. This knowledge may provide insight into key biological processes such as fibrillo-genesis and tissue remodeling and into diseases such as heart disease and cancer. Here we present a crystallographic determination of the collagen type I supermolecular structure, where the molecular conformation of each collagen segment found within the naturally occurring crystallographic unit cell has been defined (P1,
a
≈ 40.0 Å,
b
≈ 27.0 Å,
c
≈ 678 Å, α ≈ 89.2°, β ≈ 94.6°, γ ≈ 105.6°; reflections: 414, overlapping, 232, and nonoverlapping, 182; resolution, 5.16 Å axial and 11.1 Å equatorial). This structure shows that the molecular packing topology of the collagen molecule is such that packing neighbors are arranged to form a supertwisted (discontinuous) right-handed microfibril that interdigitates with neighboring microfibrils. This interdigitation establishes the crystallographic superlattice, which is formed of quasihexagonally packed collagen molecules. In addition, the molecular packing structure of collagen shown here provides information concerning the potential modes of action of two prominent molecules involved in human health and disease: decorin and the Matrix Metallo-Proteinase (MMP) collagenase.
The role of NF-κB-1 and NF-κB-2-mediated resistance to apoptosis in lymphomas
Authors: Bernal-Mizrachi Leon , Lovly Christine M. , Ratner Lee
Published: June 2006

The NF-κB pathways have been implicated in tumorigenesis in several lymphoid malignancies, including non-Hodgkin's and Hodgkin's lymphomas. However, the antiapoptotic functions and the mechanism responsible for signaling through each NF-κB pathway remain to be elucidated. In the current study, lymphoma cell lines with constitutively active NF-κB were found to be resistant to inducers of the extrinsic and intrinsic apoptosis pathways. Resistance to cell death resulted from blocks early and late in the apoptosis cascade. Several NF-κB target genes were overexpressed in these cell lines, including Bcl-xL, Fas-associated death domain-like IL-1β-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. Inhibition of the canonical or noncanonical NF-κB pathways with small interfering RNAs or adenovirus expressing a stable form of inhibitor of NF-κB (IκB) enhanced sensitivity to apoptosis inducers and resulted in lower levels of Bcl-xL or Fas-associated death domain-like IL-1β-converting enzyme inhibitor protein, cellular inhibitor of apoptosis, and X inhibitor of apoptosis. These findings demonstrate an important role of both NF-κB pathways in mediating resistance to apoptosis and distinctive antiapoptotic downstream target gene profiles responsible for this effect.
A unique lymphotoxin αβ-dependent pathway regulates thymic emigration of Vα14 invariant natural killer T cells
Authors: Franki Ann Sophie , Van Beneden Katrien , Dewint Pieter , Hammond Kirsten J. L. , Lambrecht Stijn , Leclercq Georges , Kronenberg Mitchell , Deforce Dieter , Elewaut Dirk
Published: June 2006

Natural killer (NK) T cells using an invariant Vα14 (Vα14i) T cell receptor rearrangement form a distinct immunoregulatory T cell lineage. Several studies indicated that a NK1.1−Vα14iNKT precursor cell differentiates and expands within the thymus before export to the peripheral tissues occurs. However, little is known about the signals that cause the emigration of Vα14iNKT cells from the thymus to the periphery. Here we show that signaling of lymphotoxin (LT) αβ through the LTβ receptor (LTβR) is indispensable for regulating peripheral but not thymic Vα14iNKT cell numbers. Homing to and homeostatic proliferation of thymic Vα14iNKT cells in peripheral organs, however, was not dependent on LTβR. Instead, our data indicate that a LTβR-expressing thymic stromal cell regulates the thymic emigration of Vα14iNKT cells but not conventional T cell receptor αβ cells.
The critical mutagenic translesion DNA polymerase Rev1 is highly expressed during G
2
/M phase rather than S phase
Authors: Waters Lauren S. , Walker Graham C.
Published: June 2006

The Rev1 protein lies at the root of mutagenesis in eukaryotes. Together with DNA polymerase ζ (Rev3/7), Rev1 function is required for the active introduction of the majority of mutations into the genomes of eukaryotes from yeast to humans. Rev1 and polymerase ζ are error-prone translesion DNA polymerases, but Rev1's DNA polymerase catalytic activity is not essential for mutagenesis. Rather, Rev1 is thought to contribute to mutagenesis principally by engaging in crucial protein–protein interactions that regulate the access of translesion DNA polymerases to the primer terminus. This inference is based on the requirement of the N-terminal BRCT (BRCA1 C-terminal) domain of
Saccharomyces cerevisiae
Rev1 for mutagenesis and the interaction of the C-terminal region of mammalian Rev1 with several other translesion DNA polymerases. Here, we report that
S. cerevisiae
Rev1 is subject to pronounced cell cycle control in which the levels of Rev1 protein are ≈50-fold higher in G
2
and throughout mitosis than during G
1
and much of S phase. Differential survival of a
rev1
Δ strain after UV irradiation at various points in the cell cycle indicates that this unanticipated regulation is physiologically relevant. This unexpected finding has important implications for the regulation of mutagenesis and challenges current models of error-prone lesion bypass as a process involving polymerase switching that operates mainly during S phase to rescue stalled replication forks.
The group covariance effect and fitness trade-offs during evolutionary transitions in individuality
Authors: Michod Richard E.
Published: June 2006

Transforming our understanding of life is the realization that evolution occurs not only among individuals within populations but also through the integration of groups of preexisting individuals into a new higher-level individual, that is, through evolutionary transitions in individuality. During evolutionary transitions (such as during the origin of gene networks, bacteria-like cells, eukaryotic cells, multicellular organisms, and societies), fitness must be reorganized; specifically, it must be transferred from the lower- to the higher-level units and partitioned among the lower-level units that specialize in the fitness components of the new higher-level individual. This paper studies the role of fitness trade-offs in fitness reorganization, the evolution of cooperation, and the conversion of a group into a new individual during the origin of multicellular life. Specifically, this study shows that the fitness of the group is augmented over the average fitness of its members according to a covariance effect. This covariance effect appears to be one of the first emergent properties of the group and a general aspect of groups with multiplicative properties that are themselves averages of properties of lower-level units. The covariance effect allows groups to break through the constraints that govern their members, and this effect likely applies to group dynamics in other fields.
Ultrasensitive and absolute quantification of the phosphoinositide 3-kinase/Akt signal transduction pathway by mass spectrometry
Authors: Cutillas Pedro R. , Khwaja Asim , Graupera Mariona , Pearce Wayne , Gharbi Severine , Waterfield Mike , Vanhaesebroeck Bart
Published: June 2006

The phosphoinositide 3-kinase (PI3K)/Akt pathway controls a vast array of normal physiological processes and is frequently aberrantly activated in cancer, thus identifying PI3K/Akt-signaling components as promising drug targets in oncology. However, implementation of rational cancer therapies for this pathway needs robust and simple tools to stratify patients according to PI3K pathway activation and to validate and measure the impact of targeted inhibition on primary cancer tissues. Herein we present a technique for the quantification of the PI3K/Akt-signaling pathway based on the mass spectrometric measurement of PI3K-dependent protein kinase activity in cell lysates. The concept of this application of MS is to exploit enzymatic activity to amplify the signal of the enzyme under study analogous to the PCR used to amplify nucleic acid sequences. We show that this approach allows quantitative analysis of a cell-signaling pathway with high sensitivity, precision of quantification, and specificity. Due to its special analytical capabilities and potential for multiplexing, this approach could contribute significantly to cell-signaling studies and to the development and implementation of personalized cancer therapies.
Conformational suppression of inter-receptor signaling defects
Authors: Ames Peter , Parkinson John S.
Published: June 2006

Motile bacteria follow gradients of attractant and repellent chemicals with high sensitivity. Their chemoreceptors are physically clustered, which may enable them to function as a cooperative array. Although native chemoreceptor molecules are typically transmembrane homodimers, they appear to associate through their cytoplasmic tips to form trimers of dimers, which may be an important architectural element in the assembly and operation of receptor clusters. The five receptors of
Escherichia coli
that mediate most of its chemotactic and aerotactic behaviors have identical trimer contact residues and have been shown by
in vivo
crosslinking methods to form mixed trimers of dimers. Mutations at the trimer contact sites of Tsr, the serine chemoreceptor, invariably abrogate Tsr function, but some of those lesions (designated Tsr*) are epistatic and block the function of heterologous chemoreceptors. We isolated and characterized mutations (designated Tar
⋀
) in the aspartate chemoreceptor that restored function to Tsr* receptors. The suppressors arose at or near the Tar trimer contact sites and acted in an allele-specific fashion on Tsr* partners. Alone, many Tar
⋀
receptors were unable to mediate chemotactic responses to aspartate, but all formed clusters with varying efficiencies. Most of those Tar
⋀
receptors were epistatic to WT Tsr, but some regained Tar function in combination with a suppressible Tsr* partner. Tar
⋀
–Tsr* suppression most likely occurs through compensatory changes in the conformation or dynamics of a mixed receptor signaling complex, presumably based on trimer-of-dimer interactions. These collaborative teams may be responsible for the high-gain signaling properties of bacterial chemoreceptors.
Observation of fragile-to-strong dynamic crossover in protein hydration water
Authors: Chen S.-H. , Liu L. , Fratini E. , Baglioni P. , Faraone A. , Mamontov E.
Published: June 2006

At low temperatures, proteins exist in a glassy state, a state that has no conformational flexibility and shows no biological functions. In a hydrated protein, at temperatures ≳220 K, this flexibility is restored, and the protein is able to sample more conformational substates, thus becoming biologically functional. This “dynamical” transition of protein is believed to be triggered by its strong coupling with the hydration water, which also shows a similar dynamic transition. Here we demonstrate experimentally that this sudden switch in dynamic behavior of the hydration water on lysozyme occurs precisely at 220 K and can be described as a fragile-to-strong dynamic crossover. At the fragile-to-strong dynamic crossover, the structure of hydration water makes a transition from predominantly high-density (more fluid state) to low-density (less fluid state) forms derived from the existence of the second critical point at an elevated pressure.
Item memory, source memory, and the medial temporal lobe: Concordant findings from fMRI and memory-impaired patients
Authors: Gold Jeffrey J. , Smith Christine N. , Bayley Peter J. , Shrager Yael , Brewer James B. , Stark Craig E. L. , Hopkins Ramona O. , Squire Larry R.
Published: June 2006

We studied item and source memory with fMRI in healthy volunteers and carried out a parallel study in memory-impaired patients. In experiment 1, volunteers studied a list of words in the scanner and later took an item memory test and a source memory test. Brain activity in the hippocampal region, perirhinal cortex, and parahippocampal cortex was associated with words that would later be remembered (item memory). The activity in these regions that predicted subsequent success at item memory predicted subsequent source memory to a similar degree. In experiment 2, memory-impaired patients with damage thought to be limited to the hippocampal region were given an item memory test and a source memory test, as in experiment 1. The patients were similarly impaired on the item memory test and the source memory test. Together, the findings suggest that medial temporal lobe structures broadly support recognition memory function and that item memory and source memory similarly depend on these structures.
Experimental and computational probes of the space in a self-assembled capsule
Authors: Ajami Dariush , Iwasawa Tetsuo , Rebek Julius
Published: June 2006

Self-assembled capsules are hosts that recognize and surround smaller molecule guests of appropriate size, shape, and chemical surfaces. The space available inside is a cage of fixed solvent molecules, many of which are aromatic. These aromatics provide anisotropic shielding to guests, and a map of induced magnetic shielding for the inner space can be obtained through nucleus-independent chemical shift calculations. Experimental values of the magnetic environment can be determined by NMR spectra of the guests inside. We describe here the environment in a cylindrical capsule with tapered ends. A series of terminal acetylenes—the narrowest of organic structures—was synthesized and used to probe the magnetic shielding of the capsule’s ends. Their NMR spectra showed that the acetylenic hydrogen experiences deshielding as it is forced deeper into the tapered end of the capsule where four benzene rings converge. Modeling and density functional theory calculations provided excellent agreement with the experimental values and established a molecular ruler to explore steric and magnetic environments inside the capsule.
Tests of parallel molecular evolution in a long-term experiment withEscherichia coli
Authors: Woods Robert , Schneider Dominique , Winkworth Cynthia L. , Riley Margaret A. , Lenski Richard E.
Published: June 2006

The repeatability of evolutionary change is difficult to quantify because only a single outcome can usually be observed for any precise set of circumstances. In this study, however, we have quantified the frequency of parallel and divergent genetic changes in 12 initially identical populations ofEscherichia colithat evolved in identical environments for 20,000 cell generations. Unlike previous analyses in which candidate genes were identified based on parallel phenotypic changes, here we sequenced four loci (pykF,nadR,pbpA-rodA, andhokB/sokB) in which mutations of unknown effect had been discovered in one population, and then we compared the substitution pattern in these “blind” candidate genes with the pattern found in 36 randomly chosen genes. Two candidate genes,pykFandnadR, had substitutions in all 11 other populations, and the other 2 in several populations. There were very few cases, however, in which the exact same mutations were substituted, in contrast to the findings from conceptually related work performed with evolving virus populations. No random genes had any substitutions except in four populations that evolved defects in DNA repair. Tests of four different statistical aspects of the pattern of molecular evolution all indicate that adaptation by natural selection drove the parallel changes in these candidate genes.
Genome-wide RNAi screen of Ca
2+
influx identifies genes that regulate Ca
2+
release-activated Ca
2+
channel activity
Authors: Zhang Shenyuan L. , Yeromin Andriy V. , Zhang Xiang H.-F. , Yu Ying , Safrina Olga , Penna Aubin , Roos Jack , Stauderman Kenneth A. , Cahalan Michael D.
Published: June 2006

Recent studies by our group and others demonstrated a required and conserved role of
Stim
in store-operated Ca
2+
influx and Ca
2+
release-activated Ca
2+
(CRAC) channel activity. By using an unbiased genome-wide RNA interference screen in
Drosophila
S2 cells, we now identify 75 hits that strongly inhibited Ca
2+
influx upon store emptying by thapsigargin. Among these hits are 11 predicted transmembrane proteins, including
Stim
, and one,
olf186-F
, that upon RNA interference-mediated knockdown exhibited a profound reduction of thapsigargin-evoked Ca
2+
entry and CRAC current, and upon overexpression a 3-fold augmentation of CRAC current. CRAC currents were further increased to 8-fold higher than control and developed more rapidly when
olf186-F
was cotransfected with
Stim
.
olf186-F
is a member of a highly conserved family of four-transmembrane spanning proteins with homologs from
Caenorhabditis elegans
to human. The endoplasmic reticulum (ER) Ca
2+
pump sarco-/ER calcium ATPase (SERCA) and the single transmembrane-soluble
N
-ethylmaleimide-sensitive (NSF) attachment receptor (SNARE) protein Syntaxin5 also were required for CRAC channel activity, consistent with a signaling pathway in which
Stim
senses Ca
2+
depletion within the ER, translocates to the plasma membrane, and interacts with
olf186-F
to trigger CRAC channel activity.
Neuroanatomical evidence for segregation of nerve fibers conveying light touch and pain sensation in Eimer’s organ of the mole
Authors: Marasco Paul D. , Tsuruda Pamela R. , Bautista Diana M. , Julius David , Catania Kenneth C.
Published: June 2006

Talpid moles are small insectivores that live in dark underground tunnels. They depend heavily on touch to navigate and find food. Most species have an array of complex epidermal sensory structures called Eimer’s organs that cover the tip of the nose. In this study, the anatomy of Eimer’s organ was examined in the coast mole and star-nosed mole by using the fluorescent styryl pyridinium dye AM1-43 and immunocytochemical staining for neurofilament 200 and substance P. In addition, DiI was used to label neural components of Eimer’s organ. AM1-43 labeled all of the Eimer’s organ receptors after systemic injection, suggesting a role in mechanotransduction. Immunostaining with neurofilament 200 and substance P labeled distinct subtypes of sensory fibers. Substance P labeled a group of free nerve endings along the outer edge of Eimer’s organ, indicating a nociceptive role for these fibers. In contrast, neurofilament 200 labeled a more central set of nerve endings, suggesting that these fibers function as low-threshold mechanoreceptors. By labeling subsets of trigeminal afferents distant from the receptor array with DiI, we revealed innervation patterns indicating that one afferent supplies the outer, substance P-positive set of free nerve endings, whereas several afferents differentially innervate the central free nerve endings. Our results suggest that the free nerve endings innervating Eimer’s organ are largely mechanosensitive and may play an important role in the rapid sensory discrimination observed in these species.
Tyrosyl-DNA phosphodiesterase (Tdp1) participates in the repair of Top2-mediated DNA damage
Authors: Nitiss Karin C. , Malik Mobeen , He Xiaoping , White Stephen W. , Nitiss John L.
Published: June 2006

Agents targeting topoisomerases are active against a wide range of human tumors. Stabilization of covalent complexes, converting topoisomerases into DNA-damaging agents, is an essential aspect of cell killing by these drugs. A unique aspect of the repair of topoisomerase-mediated DNA damage is the requirement for pathways that can remove protein covalently bound to DNA. Tyrosyl-DNA phosphodiesterase (Tdp1) is an enzyme that removes phosphotyrosyl moieties bound to the 3′ end of DNA. Cells lacking Tdp1 are hypersensitive to camptothecin, consistent with a role for Tdp1 in processing 3′ phosphotyrosyl protein–DNA covalent complexes. Because Top2p forms a 5′ phosphotyrosyl linkage with DNA, previous work predicted that Tdp1p would not be active against lesions involving Top2p. We found that deletion of the
TDP1
gene in yeast confers hypersensitivity to Top2 targeting agents. Combining
tdp1
mutations with deletions of genes involved in nonhomologous end joining, excision repair, or postreplication repair enhanced sensitivity to Top2 targeting drugs over the level seen with single mutants, suggesting that Tdp1 may function in collaboration with multiple pathways involved in strand break repair.
tdp1
mutations can sensitize yeast cells to drugs targeting Top2 even when
TOP1
is deleted. Finally, bacterially expressed yeast Tdp1p is able to remove a peptide derived from yTop2 that is covalently bound to DNA by a 5′ phosphotyrosyl linkage. Our results show that Tdp1 plays more general roles in DNA repair than repair of Top1 mediated DNA damage, and may participate in repairing many types of base damage to DNA.
Getting NATO's Success in Kosovo Right: The Theory and Logic of Counter-Coercion
Authors: Harvey Frank P.
Published: June 2006

The overwhelming consensus in the literature on Slobodan Milosevic's decision to pull Serb troops out of Kosovo in June, 1999, is very clear—his concession after 78 days of bombing was a direct product of both air strikes and NATO's preparations for a ground war. Most analysts believe it was the combination of these two pressures that established a sufficiently clear, resolute and capable threat to force Milosevic to comply. This paper directly challenges standard interpretations of `successful' coercion in Kosovo on empirical, theoretical and logical grounds, and offers a resounding disconfirmation of conventional wisdom: (1) the ground war threat failed to satisfy even the most basic prerequisites for effective coercion; (2) Milosevic had no reason to interpret the threat as credible, given the very clear signals from NATO confirming the `refusal' to mobilize and deploy ground troops; (3) the assertion that Milosevic viewed the threat as credible would require an assumption of procedural non-rationality derived from misperception theory (an assumption that lies outside the boundaries of rational coercion); (4) to the extent that Milosevic may have misperceived the evidence, he would rationally have preferred to fight the kind of ground war NATO appeared to be planning as a way of maximizing counter-coercion leverage (Milosevic's only hope for success); and (5) given the identical nature of the outcomes, it would have made more strategic sense for Milosevic to risk losing Kosovo after a ground war (in the hopes of significantly increasing NATO's costs) rather than be forced to hand over the territory to NATO after an essentially cost-free, `virtual' war. In direct contrast to accepted wisdom, the air strike and ground war threats were mutually exclusive and contradictory. To the extent that a ground war threat was credible, the impact on successful coercion would have been negative, not positive. Stated in terms of necessary and sufficient conditions, theabsence of a credible ground war threat (both in terms of the `threat' and the actual `deployment' of troops) was a necessary condition for NATO'ssuccess , and, in combination with an escalation in air strikes in the final two weeks of May, constituted sufficient conditions for NATO's victory. This interpretation of the Kosovo case constitutes a more balanced and complete explanation for Milosevic's decision that is empirically valid, logically consistent and theoretically sound—conventional wisdom fails on all three grounds.
Self‐reported headache in schoolchildren: Parents underestimate their children's headaches
Authors: Lundqvist Christofer , Clench‐Aas Jocelyne , Hofoss Dag , Bartonova Alena
Published: June 2006

Background: Most previous studies of childhood headache have used indirect parental/physician reports to estimate the prevalence of headache in children. Aim: To use direct information from children and to compare the results with data collected from parents. Study design/methods: A cross‐sectional questionnaire was sent to parents of 7–12‐y‐olds in Oslo, Norway. The questionnaire included retrospective reports by the parents of the presence of headache among their children during the past 6 mo. A panel study was subsequently done with daily diaries completed by the children over 6 wk. This was done at school. Results: For 2126 children, both diary reports and parental reports were available. We found a 1‐mo prevalence of self‐reported headache of 57.6%. Parents, particularly fathers, reported lower headache prevalence than the children. The difference between parental reports and those of the children was larger when the child was a girl. There was a clear difference for the youngest children and parental underreporting for children with the most frequent headaches.

Conclusion: Since indirect parental reports of child headache underestimated headache frequency compared to direct diary‐based self‐reports, we suggest more widespread use of diary registration of headaches in studies of child headache.
Reventilation with room air or 100% oxygen after asphyxia differentially affects cerebral neuropathology in newborn pigs
Authors: Domoki Ferenc , Zimmermann Aliz , Cserni Gabor , Bori Rita , Temesvári Peter , Bari Ferenc
Published: June 2006

Aim: To test if reventilation with room air (RA) or 100% oxygen (O2) after asphyxia would differentially affect neuronal damage in different brain areas of newborn pigs. Methods: Anaesthetized piglets were subjected to 10 min asphyxia (n= 27) or served as time controls (n= 7). Reventilation started with either RA or O2 for 1 h, and was continued with RA for an additional 1 – 3 h. Cortical or cerebellar blood flow was assessed with laser‐Doppler flowmetry (LDF). Haematoxylin/eosin‐stained sections from six brain regions were prepared for blinded neuropathological examination and scoring. Results: Asphyxia resulted in significant neuronal damage compared to time controls in all areas examined except the pons. O2 ventilation elicited greater neuronal lesions in the hippocampus and the cerebellum but smaller damage in the basal ganglia compared to RA. The assessed physiological parameters including the LDF signals were similar in both ventilation groups, except for PaO2 in the first hour of reventilation (RA 75±5 mmHg, O2 348±57 mmHg; p <0.05). Interestingly, however, reactive hyperaemia was much higher in the O2‐sensitive cerebellum as compared with the cortex (1101±227 vs 571±73; p <0.05, area under the curve).

Conclusion: O2 toxicity after asphyxia was demonstrated in the piglet hippocampus and cerebellum but not in the cerebral cortex or basal ganglia. The observed regional differences may be associated with local haemodynamic factors.