bluuebunny/crossref_metadata_2025 huggingface dataset:
Logic in Grammar
Authors: Chierchia Gennaro
Published: October 2013

This book explores the relation between language and logic through an analysis of polarity sensitivity and free choice effects. A wide variety of items are considered, with the intent of identifying the common core of the Polarity System as well as the choices that determine the stunningly diverse array of its manifestations. Sensitivity to polarity and freedom of choice are analyzed as a form of grammaticized Scalar Implicature. This requires a reassessment of how the different components of language (i.e. syntax, semantics and pragmatics) interact. But perhaps the most surprising outcome of t Logical Syntax of Language his book concers the relation of syntax to logic. In his classic, Carnap defines syntax as a lexicon and a set of formation rule and logic proper as a set of inference rules. Modern linguistics in the generative tradition has maintained a similar modular set up: a combinatorial apparatus generates structures over which semantic/pragmatic relations (like entailment, presuppositions and implicatures) are defined. This book argues that a wide array of structures that are typically perceived and analyzed as syntactically deviant owe in fact their status to their logical properties, i.e. whether they are contradictory/analytically true in specific ways (‘G-trivial’). This alters the Carnapian view, as the characterization of ‘grammatical structure’ now requires a more direct role of logical inferences. The functional lexicon of grammar comes with a set of inference rules that crucially and directly determine grammaticality patterns. Logic in Grammar presents the results of a decade’s work on semantics, pragmatics and syntax. It extends the author’s long-term project on how humans categorize the world and how they reason. It is, in sum, a mind-opening contribution to the understanding of the fundamental operations of language and thought, a book that will interest linguists, philosophers, and cognitive scientists alike.
EvenNegative Polarity Items andOnlyNegative Polarity Items
Authors: Chierchia Gennaro
Published: October 2013

Chapter 3 presents the main thesis of the book: Negative Polarity Items (NPIs) activate obligatorily the alternatives that ordinary indefinites activate optionally (i.e. subject to relevance). Two classes of NPIs are discussed: emphatic (minimizers, even-one/some NPIs) and non emphatic (ever, NP-any, Italian alcun). Emphatic NPIs activate linearly ordered scales and are exhaustified via a covert counterpart of even, thank to a principle of ‘Optimal Fit’ (an extension of ‘Maximize Presupposition’). Non emphatic NPIs are counterparts of plain indefinites that do not admit the value ‘-‘ (‘inactive’) for their scalar and domain alternatives. Their distribution is derived from these assumptions. It is proposed that the reason why NPIs have to be weakest element on a scale is because non weakest elements in DE contexts generate positive implicatures that make exhaustification contradictory (i.e. G-trivial). Apparent counterexamples to this claim - e.g. NPIs like much (non end of scale) or at all (strongest element of a scale) are analyzed in terms of independently observable scalar principles (scale truncation, and scale reversal respectively).
Where We Stand
Authors: Chierchia Gennaro
Published: October 2013

This chapter synthesizes and discusses the main results of the book, namely (i) the treatment of ordinary scalar terms and their implicatures, (ii) pure NPIs (emphatic, weak, strong) (iii) NPIs that double up as FCIs (existential and universal), and (iv) intervention effects of various sorts. The data seem to bear out the claim that Polarity Sensitive Items (PSIs) are indefinites whose alternatives have become obligatorily active (a case of ‘grammaticization’). The behavior of PSIs follows under these assumptions from a general view of how alternatives are factored into meaning via a process of exhaustification. A tightly regulated system of parameters paves the way to understanding both historical and typological variation in the Polarity System. Minimality effects constitute a key piece of evidence in favor of this view and a unique window on how the Polarity System works. The crucial role that logical triviality plays in this account is also discussed along with consequences of such role on the relation between syntax and logic, on the generative paradigm, and on our understanding of human cognition.
The Ethics of Fighting, Refraining from Fighting, and Peacemaking
Authors: Afsaruddin Asma
Published: October 2013

In addition to verses discussed in Chapter Two which have to do primarily with legitimate reasons for engaging in fighting, this chapter discusses the exegeses of verses which prescribe specific conduct during warfare, the manner of terminating hostilities, and making peace with enemies. Some of the most frequently cited verses in connection with the ethics of war and peace are discussed under the following rubrics: a) obligation to fight under justified circumstances; b) abstention from and termination of hostilities; and c) peacemaking. The survey of exegetical works undertaken in this chapter reveal that when and exactly upon whom the commandment to fight was binding and how this duty should be discharged remained subjects of lively debate through the centuries.
Modern and Contemporary Debates on Jihād and Martyrdom I
Authors: Afsaruddin Asma
Published: October 2013

Chapter Eight discusses how late medieval discourses on jihād in particular have been appropriated and selectively adapted for new political and ideological ends by political ideologues and radical Islamists in the contemporary period. In the first group are included Hasan al-Bannā, Abū’l-’Alā’ Mawdūdi, Sayyid Qutb, Ayatullah Khomeini, and Muhammad ’Abd al-Salām Faraj from the twentieth century. From the post-September 11 period the views of Abū Yahyāal-Lībī; Yūsuf al-Qaradāwī, and Abū Baṣīr al-Tartūsī are discussed among others. The Islamicizing rhetoric of these ideologues and radicals are subjected to a close analysis and how they use and misuse the classical and later sources to grant religious legitimacy to their various enterprises is scrutinized in detail. Attention is also paid to the views of the last three on particularly suicide bombings.
The Matrix of American Catholicism
Authors: McDonough Peter
Published: October 2013

This chapter and the next highlight four changes that have shaped American Catholicism since the sixties: the separation of church and state ratified by Vatican II, the revolution in sexual norms and gender roles, the Hispanicization of the Catholic population, and the attenuation of clerical control over church's outreach ministries in health, education, and welfare. Against this background, the chapter shows how issues tend to be differentially conflictual in Catholicism. Sexual matters lie at the nonnegotiable core, in large part because of their link with traditional lines of authority. The church's teachings on economic policy, and its stance on church-state matters since Vatican II, are generally less incendiary. Reform groups choose their battles in light of this escalating gradient of touchiness. They also take into account their own financial and membership resources, as well as the legal environment that may provide openings for pressuring the church.
The Dynamics of Tradition
Authors: McDonough Peter
Published: October 2013

This chapter lays out the options adopted by proponents of change and tradition. The groups include neoconservative Catholics aligned with the periodical First Things, advocates such as Survivors Networks of those Abused by Priests (SNAP), moderate progressives joined with Voice of the Faithful (VOTF), business leaders and philanthropists associated with the National Leadership Roundtable for Church Management, and FutureChurch, a group that promotes women's ordination to the priesthood. Lay interests have usually followed one of two strategies since John Courtney Murray, the Jesuit theologian, succeeded in expanding tolerance for religious freedom and political pluralism at Vatican II. One path is doctrinally confrontational, pitting traditionalists against reformers favoring women's rights. Another is legalistic-combative or administrative-collaborative. SNAP focuses on curbing the church's “immunity” from civil and criminal prosecution in cases of sexual abuse. The Roundtable counts on administrative reform from within to upgrade the ministries of the church.
Welfare Reform, American Values, and the Triumph of Catholic Neoconservatism
Authors: McDonough Peter
Published: October 2013

This chapter wraps up the analysis of Catholic neoconservatism with the ratification of the Welfare Reform Act of 1996 under Bill Clinton. The bill, ending “welfare as we know it,” reflected a convergence between Protestant evangelicals, Catholic conservatives, business interests, and political managers who tried to undo what they saw as the harmful effects of welfare dependency on family life and economic progress. The chapter compares the views of the liberal Catholic Mary Jo Bane, who quit the Clinton administration over her boss's signing of the bill, and Larry Mead, a Protestant who provided much of the rationale behind the reform. The chapter concludes with an evaluation of the triumphs and limitations of Catholic neoconservatism, inside and outside the church, as well as an assessment of the plight of Catholic progressivism.
Conciliarism and Other Dormant Traditions
Authors: McDonough Peter
Published: October 2013

This chapter reviews the development of lesser-known traditions in Catholicism. One is conciliarism, a movement promoting collegiality between the papacy and bishops, that virtually disappeared with the Counter-Reformation. Another goes under the label “corporatism” or “trusteeism.” This is a system of low-key collaboration between laity and priests in the management of the finances and other “temporalities.” In modern times the practice shows up prominently in the administration and fund-raising operations for the church's ministries in health care and higher education. Still another tradition, common though all but nameless, is a culture that prizes discretion, deception, and behind-the-scenes wheeling-and-dealing in the everyday activities of the church. This practice, crystallized by the seventeenth-century Spanish Jesuit Baltasar Gracián, has bequeathed a legacy of surreptitious individualism that discourages collective action in the internal politics of the church.
The Safety and Strength of a Novel Medial, Partial Nonthreaded Pedicle Screw
Authors: Kwan Mun Keong , Chan Chris Yin Wei , Saw Lim Beng , Rukmanikanthan Shanmugam , Lenke Lawrence G.
Published: October 2013

Study Design:

Cadaveric and biomechanical study.

Objective:

The aim of this study was to assess the safety and pullout strength of medial, partial nonthreaded thoracic pedicle screws compared with conventional screws.

Summary of Background Data:

The perforation rate of the pedicle screws has been reported as high as 41%. Nerve injury and irritation can result from the compression of malpositioned screw on neural structures.

Methods:

Ten fresh cadavers were studied. Screws, 5.0 and 6.0 mm, were inserted from T1 to T6 and T7 to T12, respectively. Pedicle perforations and fractures were recorded upon screw insertion and final positioning (nonthreaded portion facing medially) after a wide laminectomy. Pullout strength of novel and conventional screws were then tested using an Instron machine in an artificial bone substitute.

Results:

A total of 240 thoracic pedicle screws were inserted. Of them, 88.8% (213 screws) were fully contained during screw insertion. There were 5.0% (12 screws) grade 1 medial perforations and 6.2% (15 screws) grade 1 lateral perforations during screw insertion. Upon final positioning, 93.8% (225 screws) were fully contained. All grade 1 medial perforations, which occurred during insertion, were converted to grade 0. No dural or nerve root injuries occurred. Pedicle split fractures were noted in 6.7% (16 screws). The use of medial, partial nonthreaded screws reduced the overall perforation rate from 11.2% to 6.2%. The mean pullout load for the 5 mm fully threaded screw versus medial, partial nonthreaded was 1419.3±106.1 N (1275.8–1538.8 N) and 1336.6±44.2 N (1293.0–1405.1 N) respectively, whereas 6 mm pullout load averaged 2126.0±134.8 N (1986.3–2338.3 N) and 2036.5±210.0 N (1818.4–2355.9 N). The difference was not statistically significant.

Conclusions:

The use of medial, partial nonthreaded pedicle screws reduced the medial perforation rate from 5.0% to 0%; however, the pullout strength was not significantly reduced. The use of this novel screw can potentially reduce the incidence of nerve injury or irritation after medial pedicle perforations.
Managing hydroclimatic risks in federal rivers: a diagnostic assessment
Authors: Garrick Dustin , De Stefano Lucia , Fung Fai , Pittock Jamie , Schlager Edella , New Mark , Connell Daniel
Published: October 2013

Hydroclimatic risks and adaptive capacity are not distributed evenly in large river basins of federal countries, where authority is divided across national and territorial governments. Transboundary river basins are a major test of federal systems of governance because key management roles exist at all levels. This paper examines the evolution and design of interstate water allocation institutions in semi-arid federal rivers prone to drought extremes, climatic variability and intensified competition for scarce water. We conceptualize, categorize and compare federal rivers as social–ecological systems to analyse the relationship between governance arrangements and hydroclimatic risks. A diagnostic approach is used to map over 300 federal rivers and classify the hydroclimatic risks of three semi-arid federal rivers with a long history of interstate allocation tensions: the Colorado River (USA/Mexico), Ebro River (Spain) and Murray–Darling River (Australia). Case studies review the evolution and design of water allocation institutions. Three institutional design trends have emerged: adoption of proportional interstate allocation rules; emergence of multi-layered river basin governance arrangements for planning, conflict resolution and joint monitoring; and new flexibility to adjust historic allocation patterns. Proportional allocation rules apportion water between states based on a share of available water, not a fixed volume or priority. Interstate allocation reform efforts in the Colorado and Murray–Darling rivers indicate that proportional allocation rules are prevalent for upstream states, while downstream states seek reliable deliveries of fixed volumes to increase water security. River basin governance arrangements establish new venues for multilayered planning, monitoring and conflict resolution to balance self governance by users and states with basin-wide coordination. Flexibility to adjust historic allocation agreements, without risk of defection or costly court action, also provides adaptive capacity to manage climatic variability and shifting values. Future research should develop evidence about pathways to adaptive capacity in different classes of federal rivers, while acknowledging limits to transferability and the need for context-sensitive design.
Risks and responses to universal drinking water security
Authors: Hope Robert , Rouse Michael
Published: October 2013

Risks to universal drinking water security are accelerating due to rapid demographic, climate and economic change. Policy responses are slow, uneven and largely inadequate to address the nature and scale of the global challenges. The challenges relate both to maintaining water security in increasingly fragile supply systems and to accelerating reliable access to the hundreds of millions who remain water-insecure. A conceptual framework illustrates the relationship between institutional, operational and financial risks and drinking water security outcomes. We apply the framework to nine case studies from rural and urban contexts in South Asia and sub-Saharan Africa. Case studies are purposively selected based on established and emerging examples of political, technological or institutional reforms that address water security risks. We find broad evidence that improved information flows reduce institutional costs and promote stronger and more transparent operational performance to increase financial sustainability. However, political barriers need to be overcome in all cases through internal or external interventions that require often decadal time frames and catalytic investments. No single model exists, though there is sufficient evidence to demonstrate that risks to drinking water security can be reduced even in the most difficult and challenging contexts.
Multicolor Flow Cytometric Analysis of Immune Cell Subsets in Tumor-Bearing Mice
Authors: Bayne Lauren J. , Vonderheide Robert H.
Published: October 2013

This protocol describes a procedure for obtaining a single-cell suspension from mouse spleen or solid tissue. Once a single-cell suspension is prepared, multicolor flow cytometry is used to identify subsets of immune cells in the samples of interest. This protocol can be used to evaluate the following immune cell populations, defined by the expression of certain cell surface molecules: total leukocytes, T lymphocytes and CD4+ and CD8+ T-cell subsets, B lymphocytes, natural killer cells, dendritic cells, and immature myeloid cells.
Analysis of Splicing In Vitro Using Extracts of Saccharomyces cerevisiae
Authors: Ares Manuel
Published: October 2013

In vitro splicing studies are a powerful means of investigating the requirements and mechanisms of action of the many components of the splicing apparatus. The ability to add and subtract components, purify activities, and reconstitute activity, as well as to expose the apparatus to chemical probes of various types, allows a far more mechanistically detailed view of the process to emerge than is available from genetic or in vivo studies alone. Two kinds of activities are assayed during in vitro splicing. The first concerns the chemical conversion of the substrate pre-mRNA into splicing intermediates and products and is usually visualized using a labeled substrate followed by separation on a denaturing gel. The second concerns the assembly of noncovalent complexes between the substrate and the myriad components of the splicing apparatus. This is also visualized using a labeled substrate, but the separation of complexes is achieved using native gel electrophoresis or gradient sedimentation. In this protocol, we describe the splicing reaction and its preparation for analysis by denaturing gels and native splicing complex gels. We also provide conditions for depletion of ATP, a critical cofactor that is hydrolyzed during numerous key steps in spliceosome assembly and splicing progression.
Analysis of Splicing Complexes on Native Gels
Authors: Ares Manuel
Published: October 2013

Splicing requires a complex set of ATP-dependent macromolecular associations that lead to the rearrangement of just a few covalent bonds in the pre-mRNA substrate. Seeing only the covalent bonds breaking and forming is seeing only a very small part of the process. Analysis of native splicing complexes into which the radiolabeled substrate has been assembled, but not necessarily completely reacted, has provided a good understanding of the process. This protocol describes a gel method for detecting and analyzing yeast splicing complexes formed in vitro on a radiolabeled pre-mRNA substrate. Complexes formed during the splicing reaction are quenched by dilution and addition of an excess of RNA, which is thought to strip nonspecifically bound proteins from the labeled substrate RNA. After loading on a low-percentage, low-cross-linking ratio composite agarose–acrylamide gel (in 10% glycerol), labeled bands are detected. These can be extracted and shown to contain small nuclear RNAs (snRNAs) and partly reacted pre-mRNA.
Measurement of Calibration Constants for Quantitative Calcium Fluorimetry
Authors: Neher Erwin
Published: October 2013

A careful calibration of the fluorescence setup is essential when using Fura-2 for quantitative fluorimetry. The calibration procedure described here is used for experiments in which the indicator dye is introduced into the cell through a patch-clamp pipette. The fluorescence ratio is determined in whole-cell recordings for three different calibration parameters that reflect different [Ca2+]: very high (R1), intermediate (Keff), and zero (R0).
Poly[bis(ethanol)(μ4-2,3,5,6-tetrafluorobenzene-1,4-dicarboxylato)cadmium]
Authors: Ko Nakeun , Kim Jaheon
Published: October 2013

In the title compound, [Cd(C8F4O4)(C2H5OH)2]n, the CdIIcation sits on an inversion centre and is coordinated by six O atoms from four tetrafluorobenzene-1,4-dicarboxylate anions and two ethanol molecules in a distorted octahedral geometry. The anionic ligand is also located on an inversion centre, and connects four CdIIcations, generating a two-dimensional polymeric layer parallel to theabplane. Within the layer, the ethanol molecule links F and O atoms of the nearest anionic ligandsviaO—H...O and O—H...F hydrogen bonds. The ethyl group of the ethanol molecule is disordered over two positions with an occupancy ratio of 0.567 (10):0.433 (10).
N-(4-Fluorophenyl)-2,6-dimethyl-1,3-dioxan-4-amine
Authors: Rambabu Gottimukkala , Fatima Zeenat , Reddy Bandapalli Palakshi , Vijayakumar Vijayaparthasarathi , Velmurugan Devadasan
Published: October 2013

In the title compound, C12H16FNO2, the dioxane ring adopts a chair conformation with the methyl substituents and the C—N bond in equatorial orientations. Its mean plane subtends a dihedral angle of 40.17 (6)° with the benzene ring. In the crystal, weak N—H...F hydrogen bonds link the molecules intoC(7) chains propagating in [100].
Seeing the trees for the wood – beech (Fagus sylvatica) decay fungal volatiles influence the structure of saproxylic beetle communities
Authors: Leather Simon R. , Baumgart Eligiusz A. , Evans Hugh F. , Quicke Donald L. J.
Published: October 2013

Two experiments were conducted to investigate the role of basidiomycetes and volatiles in the ecology of saproxylic Coleoptera. Volatile organic compounds (VOCs) were sampled from beech (Fagus sylvatica) logs experimentally inoculated with the basidiomycetes Stereum hirsutum, Coriolus versicolor, Phanerochaete velutina, Hypholoma fasiculare, Bjerkandera adusta both singly and in various combinations. Volatile emissions were found to be in accordance with amounts detectable to insects suggesting that in a natural decay situation, saproxylic volatiles are readily available as insect semiochemicals.

Furthermore, fungal community structure was found to significantly affect the volatile profile of decaying wood, with specific VOCs associated with particular fungal treatments. Thus, volatiles of fungal origin are a strong potential source of semiochemicals for those insects utilising the saproxylic habitat and their natural enemies.

Beetles were reared from logs inoculated with the same basidiomycete treatments as described earlier and a total of 604 individuals comprising 84 species were obtained. Eleven species (Cis boleti, C. micans, Dacne bipustulata, Latridius consimilis, Mycetophagus atomarius, M. quadripustulatus, Octotemnus glabriculus, Platystomus albinos, Ptilinus pectinicornis, Stictoleptura scutellata, Tomoxia bucephala) exhibited significant associations with one or more fungal treatments.

Explanations are provided for the various beetle–fungus associations observed. The data set is notable for the presence of various wood boring species that tend to be absent in experiments where volatiles from fungi are presented in isolation.

Coarse woody debris (CWD) and its interaction with fungi CWD, are shown to give off VOCs of varying degrees of specificity. These VOCs are potential semiochemicals for saproxylic insects and may mediate fungus/CWD‐specific interactions. We conclude that future work in this direction would be profitable.
Mini Nutritional Assessment as a Useful Method of Predicting the Development of Pressure Ulcers in Elderly Inpatients
Authors: Yatabe Midori S. , Taguchi Fumie , Ishida Izumi , Sato Atsuko , Kameda Toshio , Ueno Shuichi , Takano Kozue , Watanabe Tsuyoshi , Sanada Hironobu , Yatabe Junichi
Published: October 2013

Objectives

To determine the usefulness of the Mini Nutritional Assessment (MNA) and plasma amino acid analysis in predicting the formation of pressure ulcers (PUs) in inpatients.

Design

Prospective, observational cohort study with a mean observation period of 62.2 ± 86.4 days.

Setting

Intermediate and acute care wards of a hospital in rural Japan.

Participants

Inpatients with an average age of 85.0 ± 7.6 (N = 422).

Measurements

Mini Nutritional Assessment, Subjective Global Assessment (SGA), Braden Scale (PU prognostic score), PU formation, and biochemical analysis including plasma amino acid concentrations.

Results

PUs developed in 7.1% of participants. A MNA score of less than 8 was more sensitive than a rating of moderate or severe malnourishment on the SGA combined with a Braden Scale score of less than 15 in predicting future PUs. The area under the receiver operating characteristic curve (AUC) of the MNA was superior to that of the Braden Scale. The Braden Scale nutrition subscore had the lowest AUC of the six Braden Scale subscores. Individuals who developed PUs had significantly lower plasma arginine concentrations than those who did not.

Conclusion

Mini Nutritional Assessment was able to predict the development of PUs. A MNA score of less than 8 performed better than the SGA, Braden Scale, and plasma arginine levels in predicting PU development. Although lower plasma arginine concentration at time of admission was associated with PU development, the AUC for arginine was not significantly different from 0.50. The findings from this prospective study support the use of nutritional assessment in inpatients to predict PU risk and target appropriate interventions.
Corticospinal modulation induced by sounds depends on action preparedness
Authors: Marinovic Welber , Tresilian James R. , de Rugy Aymar , Sidhu Simranjit , Riek Stephan
Published: October 2013

Key points

Unexpected loud auditory stimuli can trigger the involuntary release of motor actions during preparation to move.

Because acoustic stimulation can suppress motor cortex excitability during action, this early release could be independent of the motor cortex, and interpreted as pre‐planned action stored and triggered from subcortical areas.

In contrast, we show that corticospinal excitability in response to the loud auditory stimuli was increased when people were highly prepared to move, and reduced otherwise.

Our results also indicate that auditory stimuli can affect intracortical excitability by increasing intracortical facilitation and reducing short‐interval intracortical inhibition.

Together, our findings demonstrate that the early release of motor responses by auditory stimuli involves the motor cortex.

Abstract A loud acoustic stimulus (LAS) presented during movement preparation can induce an early release of the prepared action. Because loud sound has been found to have an inhibitory effect on motor cortex excitability, it is possible that the motor cortex plays little role in the early release of prepared responses. We sought to shed new light on this suggestion by probing changes in corticospinal excitability after LAS presentation during preparation for an anticipatory action. Unexpectedly, we show that the changes in corticospinal excitability after LAS presentation are not fixed. Based on the magnitude of motor‐evoked potentials elicited by transcranial magnetic and electric stimulation of the motor cortex, we demonstrate that the effects of auditory stimuli on corticospinal excitability depend on the level of readiness for action: inhibition in early preparation and facilitation close to movement onset. We also show that auditory stimuli can regulate intracortical excitability by increasing intracortical facilitation and reducing short‐interval intracortical inhibition. Together, these findings indicate that, at least in part, the early release of motor responses by auditory stimuli involves the motor cortex.
Calcineurin inhibitor induces pain hypersensitivity by potentiating pre‐ and postsynaptic NMDA receptor activity in spinal cords
Authors: Chen Shao‐Rui , Hu Yi‐Min , Chen Hong , Pan Hui‐Lin
Published: October 2013

Key points

We developed an animal model to study the mechanisms underlying the pain syndrome commonly seen in organ transplant patients receiving calcineurin inhibitors.

Systemic treatment with the calcineurin inhibitor induces long‐lasting pain hypersensitivity and increases glutamate receptor activity in the spinal cord.

Blocking glutamate receptor activity at the spinal cord level effectively reduces pain hypersensitivity induced by the calcineurin inhibitor.

This information advances our understanding of the molecular basis of pain caused by calcineurin inhibitors and identifies new strategies for treating such pain syndrome in transplant patients.

Abstract  Calcineurin inhibitors, such as cyclosporin A and tacrolimus (FK506), have played a pivotal role in the preservation of allograft function. However, these drugs can cause unexplained severe pain in patients, often referred to as calcineurin inhibitor‐induced pain syndrome (CIPS). Although calcineurin can regulate NMDA receptor (NMDAR) activity, the causal relationship between spinal synaptic plasticity and CIPS remains unknown. In this study, we showed that systemic administration of FK506 (1.5 mg kg−1 day−1) for 7 days in rats led to long‐lasting nociceptive and mechanical hypersensitivity. Whole‐cell patch‐clamp recordings in spinal cord slices revealed that FK506 treatment caused a large increase in the amplitude of NMDAR‐mediated excitatory postsynaptic currents (EPSCs) of dorsal horn neurons evoked by dorsal root stimulation. The amplitude of NMDAR currents elicited by puff NMDA application to dorsal horn neurons was also significantly greater in FK506‐treated than in vehicle‐treated rats. The frequency of spontaneous and miniature EPSCs in most dorsal horn neurons was profoundly increased in FK506‐treated rats and was reduced by blocking NMDARs. Furthermore, blocking GluN2A or GluN2B subunits similarly reduced the amplitude of evoked EPSCs and the frequency of miniature EPSCs in dorsal horn neurons of FK506‐treated rats. In addition, intrathecal injection of an NMDAR antagonist or systemic administration of memantine effectively reversed nociceptive and mechanical hypersensitivity in FK506‐treated rats. Our findings indicate that calcineurin inhibition increases glutamate‐mediated nociceptive input by potentiating presynaptic and postsynaptic NMDAR activity in spinal cords. NMDAR antagonists may represent a new therapeutic option for the treatment of CIPS.
Raising Accuracy in Physically Based Simulations Through Scaling Equations
Authors: Hofmann Daniel , Reinhart Gunther
Published: October 2013

In the recent years, the physically based simulation has been developed and applied to various engineering processes. So far the use of this simulation method was limited to calculate the behavior of objects with large dimensions, as the calculation of small objects leads to severe inaccuracies. Thus, simulation results for small objects cannot be used in the engineering process. However, technical systems often consist of a variety of small functional components and workpieces. This paper proposes a new method to significantly improve the accuracy of physically based simulations of small objects by scaling. First, a set of scaling equations is introduced, which allow physically correct scaling of dynamic rigid body systems. Second, the equations are validated by simulating a cube with an edge length of only 20 μm. In this simulation scenario, the new method is compared to the conventional, nonscaling physically based simulation and the improvements of the simulation results are examined. With the scaling equations, technical systems of small components and workpieces can virtually be tested and optimized. This affects a significant reduction of hardware based time and cost consuming experiments.
A Comparative Analysis of the Kinetic Experiments in Polyethylene Pyrolysis
Authors: Kannan Pravin , Ibrahim Salisu , Suresh Kumar Reddy K. , Al Shoaibi Ahmed , Srinivasakannan C.
Published: October 2013

A review of literature has been conducted to survey the kinetic data of low-density polyethylene (LDPE) pyrolysis. The review reveals large variations in the reported global kinetic parameters. The cause of variation has been identified to be the difference in the experimental techniques, including thermogravimetric analysis (TGA) and non-TGA methods. Even within the nonisothermal TGA data, large variations have been observed at heating rate of 20 K/min, while the variations are insignificant at lower heating rate regimes (2–10 K/min), indicating the influence of heat/mass transfer resistance controlling the kinetics. Detailed analysis revealed that most of the current techniques are unable to capture all the relevant data necessary for estimating the kinetic parameters of the aforementioned process. The outcome of this review work thrusts the need for a better experimental technique to estimate the kinetic parameters of complex reactions, such as polymer pyrolysis.
Sustained High-Frequency Dynamic Instability of a Nonlinear System of Coupled Oscillators Forced by Single or Repeated Impulses: Theoretical and Experimental Results
Authors: Remick Kevin , Vakakis Alexander , Bergman Lawrence , McFarland D. Michael , Quinn D. Dane , Sapsis Themistoklis P.
Published: October 2013

This report describes the impulsive dynamics of a system of two coupled oscillators with essential (nonlinearizable) stiffness nonlinearity. The system considered consists of a grounded weakly damped linear oscillator coupled to a lightweight weakly damped oscillating attachment with essential cubic stiffness nonlinearity arising purely from geometry and kinematics. It has been found that under specific impulse excitations the transient damped dynamics of this system tracks a high-frequency impulsive orbit manifold (IOM) in the frequency-energy plane. The IOM extends over finite frequency and energy ranges, consisting of a countable infinity of periodic orbits and an uncountable infinity of quasi-periodic orbits of the underlying Hamiltonian system and being initially at rest and subjected to an impulsive force on the linear oscillator. The damped nonresonant dynamics tracking the IOM then resembles continuous resonance scattering; in effect, quickly transitioning between multiple resonance captures over finite frequency and energy ranges. Dynamic instability arises at bifurcation points along this damped transition, causing bursts in the response of the nonlinear light oscillator, which resemble self-excited resonances. It is shown that for an appropriate parameter design the system remains in a state of sustained high-frequency dynamic instability under the action of repeated impulses. In turn, this sustained instability results in strong energy transfers from the directly excited oscillator to the lightweight nonlinear attachment; a feature that can be employed in energy harvesting applications. The theoretical predictions are confirmed by experimental results.
Dictating the Route
Authors: Gough Nancy R.
Published: October 2013

Phosphorylation of a specific tyrosine residue on the receptor controls whether a fibroblast growth factor receptor is recycled or degraded.
Safety, Tolerability, and Pharmacokinetics of Ribavirin in Hepatitis C Virus-Infected Patients with Various Degrees of Renal Impairment
Authors: Brennan B. J. , Wang K. , Blotner S. , Magnusson M. O. , Wilkins J. J. , Martin P. , Solsky J. , Nieforth K. , Wat C. , Grippo J. F.
Published: October 2013

Ribavirin (RBV) is an integral part of standard-of-care hepatitis C virus (HCV) treatments and many future regimens under investigation. The pharmacokinetics (PK), safety, and tolerability of RBV in chronically HCV-infected patients with renal impairment are not well defined and were the focus of an open-label PK study in HCV-infected patients receiving RBV plus pegylated interferon. Serial RBV plasma samples were collected over 12 h on day 1 of weeks 1 and 12 from patients with moderate renal impairment (creatinine clearance [CL
CR
], 30 to 50 ml/min; RBV, 600 mg daily), severe renal impairment (CL
CR
, <30 ml/min; RBV, 400 mg daily), end-stage renal disease (ESRD) (RBV, 200 mg daily), or normal renal function (CL
CR
, >80 ml/min; RBV, 800 to 1,200 mg daily). Of the 44 patients, 9 had moderately impaired renal function, 10 had severely impaired renal function, 13 had ESRD, and 12 had normal renal function. The RBV dose was reduced because of adverse events (AEs) in 71% and 53% of severe and moderate renal impairment groups, respectively. Despite this modification, patients with moderate and severe impairment had 12-hour (area under the concentration-time curve from 0 to 12 h [AUC
0–12
]) values 36% (38,452 ng · h/ml) and 25% (35,101 ng · h/ml) higher, respectively, than those with normal renal function (28,192 ng · h/ml). Patients with ESRD tolerated a 200-mg daily dose, and AUC
0–12
was 20% lower (22,629 ng · h/ml) than in patients with normal renal function. PK modeling and simulation (M&S) indicated that doses of 200 mg or 400 mg alternating daily for patients with moderate renal impairment and 200 mg daily for patients with severe renal impairment were the most appropriate dose regimens in these patients.
Antibiotic Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae: Systematic Evaluation of the Available Evidence
Authors: Falagas Matthew E. , Lourida Panagiota , Poulikakos Panagiotis , Rafailidis Petros I. , Tansarli Giannoula S.
Published: October 2013

We sought to evaluate the effectiveness of the antibiotic treatment administered for infections caused by carbapenemase-producing
Enterobacteriaceae
. The PubMed and Scopus databases were systematically searched. Articles reporting the clinical outcomes of patients infected with carbapenemase-producing
Enterobacteriaceae
according to the antibiotic treatment administered were eligible. Twenty nonrandomized studies comprising 692 patients who received definitive treatment were included. Almost all studies reported on
Klebsiella
spp. In 8 studies, the majority of infections were bacteremia, while pneumonia and urinary tract infections were the most common infections in 12 studies. In 10 studies, the majority of patients were critically ill. There are methodological issues, including clinical heterogeneity, that preclude the synthesis of the available evidence using statistical analyses, including meta-analysis. From the descriptive point of view, among patients who received combination treatment, mortality was up to 50% for the tigecycline-gentamicin combination, up to 64% for tigecycline-colistin, and up to 67% for carbapenem-colistin. Among the monotherapy-treated patients, mortality was up to 57% for colistin and up to 80% for tigecycline. Certain regimens were administered to a small number of patients in certain studies. Three studies reporting on 194 critically ill patients with bacteremia showed individually significantly lower mortality in the combination arm than in the monotherapy arm. In the other studies, no significant difference in mortality was recorded between the compared groups. Combination antibiotic treatment may be considered the optimal option for severely ill patients with severe infections. However, well-designed randomized studies of specific patient populations are needed to further clarify this issue.
A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults
Authors: Robbie Gabriel J. , Criste Ryan , Dall'Acqua William F. , Jensen Kathryn , Patel Nita K. , Losonsky Genevieve A. , Griffin M. Pamela
Published: October 2013

The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (
n
= 31) were randomized to receive a single intravenous (i.v.) dose of motavizumab-YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (
t
1/2
) was 2- to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. (This study has been registered at ClinicalTrials.gov under registration no. NCT00578682.)
Cell Culture-Selected Substitutions in Influenza A(H3N2) Neuraminidase Affect Drug Susceptibility Assessment
Authors: Tamura Daisuke , Nguyen Ha T. , Sleeman Katrina , Levine Marnie , Mishin Vasiliy P. , Yang Hua , Guo Zhu , Okomo-Adhiambo Margaret , Xu Xiyan , Stevens James , Gubareva Larisa V.
Published: October 2013

Assessment of drug susceptibility has become an integral part of influenza virus surveillance. In this study, we describe the drug resistance profile of influenza A(H3N2) virus, A/Mississippi/05/2011, collected from a patient treated with oseltamivir and detected via surveillance. An MDCK cell-grown isolate of this virus exhibited highly reduced inhibition by the neuraminidase (NA) inhibitors (NAIs) oseltamivir (8,005-fold), zanamivir (813-fold), peramivir (116-fold), and laninamivir (257-fold) in the NA inhibition assay. Sequence analysis of its NA gene revealed a known oseltamivir-resistance marker, the glutamic acid-to-valine substitution at position 119 (E119V), and an additional change, threonine to isoleucine at position 148 (T148I). Unlike E119V, T148I was not detected in the clinical sample but acquired during viral propagation in MDCK cells. Using recombinant proteins, T148I by itself was shown to cause only a 6-fold increase in the zanamivir 50% inhibitory concentration (IC
50
) and had no effect on inhibition by other drugs. The T148I substitution reduced NA activity by 50%, most likely by affecting the positioning of the 150 loop at the NA catalytic site. Using pyrosequencing, changes at T148 were detected in 35 (23%) of 150 MDCK cell-grown A(H3N2) viruses tested, which was lower than the frequency of changes at D151 (85%), an NA residue previously implicated in cell selection. We demonstrate that culturing of the A(H3N2) viruses (
n
= 11) at a low multiplicity of infection delayed the emergence of the NA variants with changes at position 148 and/or 151, especially when conducted in MDCK-SIAT1 cells. Our findings highlight the current challenges in monitoring susceptibility of influenza A(H3N2) viruses to the NAI class of antiviral drugs.
Repeat Polymorphisms in the Low-Complexity Regions of Plasmodium falciparum ABC Transporters and Associations with
In Vitro
Antimalarial Responses
Authors: Okombo John , Abdi Abdirahman I. , Kiara Steven M. , Mwai Leah , Pole Lewa , Sutherland Colin J. , Nzila Alexis , Ochola-Oyier Lynette Isabella
Published: October 2013

The
Plasmodium falciparum
genome is rich in regions of low amino acid complexity which evolve with few constraints on size. To explore the extent of diversity in these loci, we sequenced repeat regions in
pfmdr1
,
pfmdr5
,
pfmdr6
,
pfmrp2
, and the antigenic locus
pfmsp8
in laboratory and cultured-adapted clinical isolates. We further assessed associations between the repeats and parasite
in vitro
responses to 7 antimalarials to determine possible adaptive roles of these repeats in drug tolerance. Our results show extensive repeat variations in the reference and clinical isolates in all loci. We also observed a modest increase in dihydroartemisinin activity in parasites harboring the
pfmdr1
sequence profile 7-2-10 (reflecting the number of asparagine repeats, number of aspartate repeats, and number of asparagine repeats in the final series of the gene product) (
P
= 0.0321) and reduced sensitivity to chloroquine, mefloquine, quinine, and dihydroartemisinin in those with the 7-2-11 profile (
P
= 0.0051, 0.0068, 0.0011, and 0.0052, respectively). Interestingly, we noted an inverse association between two drugs whereby isolates with 6 asparagine repeats encoded by
pfmdr6
were significantly more susceptible to piperaquine than those with 8 (
P
= 0.0057). Against lumefantrine, those with 8 repeats were, however, more sensitive (
P
= 0.0144). In
pfmrp2
, the 7-
D
NNNTS/
N
NNNTS (number of DNNNTS or NNNNTS motifs; underlining indicates dimorphism) repeat group was significantly associated with a higher lumefantrine 50% inhibitory concentration (IC
50
) (
P
= 0.008) than in those without. No associations were observed with
pfmsp8
. These results hint at the probable utility of some repeat conformations as markers of
in vitro
antimalarial response; hence, biochemical functional studies to ascertain their role in
P. falciparum
are required.
Within-Host Selection Is Limited by an Effective Population of Streptococcus pneumoniae during Nasopharyngeal Colonization
Authors: Li Yuan , Thompson Claudette M. , Trzciński Krzysztof , Lipsitch Marc
Published: October 2013

Streptococcus pneumoniae
(pneumococcus) is a significant pathogen that frequently colonizes the human nasopharynx. Environmental factors, including antimicrobial use and host immunity, exert selection on members of the nasopharyngeal population, and the dynamics of selection are influenced by the effective population size of the selected population, about which little is known. We measured here the variance effective population size (N
e
) of pneumococcus in a mouse colonization model by monitoring the frequency change of two cocolonizing, competitively neutral pneumococcal strains over time. The point estimate of N
e
during nasal carriage in 16 BALB/c mice was 133 (95% confidence interval [CI] = 11 to 203). In contrast, the lower-bound census population exhibited a mean of 5768 (95% CI = 2,515 to 9,021). Therefore, pneumococcal N
e
during nasal carriage is substantially smaller than the census population. The N
e
during day 1 to day 4 of colonization was comparable to the N
e
during day 4 to day 8. Similarly, a low N
e
was also evident for the colonization of pneumococcus in BALB/c mice exposed to cholera toxin 4 weeks prior to challenge and in another mouse strain (DO11.10 RAG
−/−
). We developed a mathematical model of pneumococcal colonization composed of two subpopulations with differential contribution to future generations. By stochastic simulation, this model can reproduce the pattern of observed pneumococcal N
e
and predicts that the selection coefficients may be difficult to measure
in vivo
. We hypothesized that such a small N
e
may reduce the effectiveness of within host selection for pneumococcus.