bluuebunny/crossref_metadata_2025 huggingface dataset:
The Chronicle of Seert
Authors: Wood Philip
Published: October 2013

This book is a study of the cultural and political history of Christian Iraq, the Church of the East, the so–called ‘Nestorians’. This history is seen through the Chronicle of Seert, a medieval Arabic Chronicle that reuses sources written several centuries earlier. This monograph aims to isolate different layers of composition and looks for trends in the choice of material and the agenda of their historians. Each layer of the text provides insight into the social construction of ‘orthodox belief’ in Iraq and the church as an institution. A central narrative is the growing power of the bishops (catholicoi) of the Sasanian capital of Ctesiphon, their apostolic heritage, and their alliance with the Persian shahs. The monograph also considers the relationship of the catholicoi with monastic and scholarly centres and with Christian communities of the West. In each of these cases, the material that the Chronicle includes shows us how independent historical traditions were annexed by a narrative focused on Ctesiphon and its bishops. The monograph begins in the fifth century, when a series of abortive alliances between church and shah generated small-scale persecutions. It continues this story into the sixth and early seventh, when the church witnessed considerable growth in numbers and prestige. At each stage, we can see Christians rewriting the past to accommodate a new political and social situation, turning a murky past into a glorious golden age. The book concludes with a final chapter on the church under Muslim rule, when the Chronicle was compiled.
The Solution
Authors: Insole Christopher J.
Published: October 2013

The previous chapter demonstrated that Kant begins to have a problem from the 1760s onwards in relating human freedom and divine creative action. This chapter sets out the solution that Kant moves towards in the late 1770s, and sets out extensively in the 1780s: we can be said to be free to the extent that we regard ourselves as intelligible beings, capable of noumenal first causation. ‘Noumenal first causation’ involves being ultimately responsible for the series of (determined) spatio-temporal empirical events that appear in the phenomenal realm, in such a way that we are able to do otherwise. Kant’s solution belongs in the context of the strand of his mature philosophy known as ‘transcendental idealism’. Drawing on primary texts and an extensive secondary literature, the chapter aligns itself with a metaphysical interpretation of transcendental idealism (Ameriks, Adams, Hogan), paying particular attention to the categories of pure and phenomenal substance (Wuerth).
Belief
Authors: Insole Christopher J.
Published: October 2013

The book argues that Kant has a ‘theological problem’ than runs into his critical period. This is not feasible if Kant no longer believes in God in a significant sense in this mature thought. This chapter defends the position that Kant continues to believe in God in the critical period, albeit that our warrant for this belief arises from practical rather than theoretical reason. The chapter argues against deflationary readings of these commitments (Allison), which hold that Kant merely intends us to proceed ‘as if’ certain claims were true, whilst bracketing out any fundamental commitment to their being so. The chapter explores the epistemic status of faith (Glaube), and the practical postulates, drawing upon medieval accounts of the voluntary dimension to faith, and recent epistemological debates concerning the distinction between acceptance and belief. The epistemological discussion draws upon Stevenson, Chignell, Ullman-Margalit, Margalit, and Aquinas.
On the Topology and Future Stability of the Universe
Authors: Ringström Hans
Published: October 2013

The subject of the book is the topology and future stability of models of the universe. In standard cosmology, the universe is assumed to be spatially homogeneous and isotropic. However, it is of interest to know whether perturbations of the corresponding initial data lead to similar solutions or not. This is the question of stability. It is also of interest to know what the limitations on the global topology imposed by observational constraints are. These are the topics addressed in the book. The theory underlying the discussion is the general theory of relativity. Moreover, in the book, matter is modelled using kinetic theory. As background material, the general theory of the Cauchy problem for the Einstein–Vlasov equations is therefore developed.
Fighting in the Path of God
Authors: Afsaruddin Asma
Published: October 2013

Chapter Two discusses the introduction of fighting (qitāl) in the Qur’ān as an important component of jihād in specific circumstances when believers are under attack by hostile forces, ending the prohibition against armed combat during the Meccan and early Medinan periods. The Qur’ān adopts trenchant language to impress upon the faithful that in response to certain conditions, believers should not shrink from carrying out this religious and moral obligation when commanded to do so by God and His prophet. The taking of human life that armed combat entails in such specific situations is acknowledged in the Qur’ān as an act of enormity. Several verses enumerate the conditions under which qitāl becomes necessary – primarily in self-defense -- and outline the limits of justified military combat which should not be contravened by the faithful.
Dying in the Path of God
Authors: Afsaruddin Asma
Published: October 2013

Chapter Four discusses the concept of martyrdom in the Qur’ān as primarily adumbrated in the ambiguous and multivalent phrase man qutila fī sabīl allāh (“those who are slain in the path of God”) and its exegeses through time. The focus of attention is on six frequently-cited verses -- all deemed to be early Medinan revelations from roughly before the fifth year of the hijra -- which are usually interpreted in the context of martyrdom. The chapter also discusses the various meanings of the Arabic term shahīd and its plural shuhadā’, tracing its semantic transformation from its meaning in the Qur’ān as “a legal or eye-witness” to a “martyr” in extra-Qur’anic literature. Another less-commonly occurring concept of selling or bartering (yashrā/yashrūn) one’s self or the life of this world for the hereafter is also discussed as being connected to the notion of martyrdom.
Jihād and Martyrdom Compared in Early and Later Hadı̄th Literature
Authors: Afsaruddin Asma
Published: October 2013

Chapter Five compares early (from before the late third/ninth century) and late hadīth works and brings to the fore a range of competing interpretations on how best to strive in the path of God, engendered by the polyvalence of the term jihād in the Qur’ān. Similarly, early hadīth works, in contrast to later ones, also preserve a broad range of meanings for the terms shahīd and shuhadā’ that are often not replicated in later works. The preservation of the broader semantic content of these terms in diverse early works in comparison with later sources allows for reasoned speculation on the probable historical and socio-political reasons for the subsequent circumscription of their meanings. The chapter discusses in great detail the contents of the fadā’il al-jihād sections in al-Musannaf of ’Abd al-Razzāq, al-Muṣannaf of Ibn Abī Shayba (d. 235/849) and in the six authoritative Sunnī hadīth compilations.
Jihād and Martyrdom in Early and Late Treatises on the Merits of Jihād
Authors: Afsaruddin Asma
Published: October 2013

Chapter Six deals extensively with the contents of independent fadā’il al-jihād works, which include the Kitāb al-Jihād of ’Abd Allāh Ibn al-Mubārak (d. 181/797), Kitāb al-jihād by Ibn Abī ’āṣim (d. 287/900); the Ahkām al-jihād wa-fadā’ilih by ’Abd al-’Azīz b. ’Abd al-Salām al-Sulamī (d. 660/1262) and the Mashāri’ al-ashwāq ilāmaṣāri’ al-ushshāq of Ibn al-Nahhas (d. 814/1411). The extensive comparison of the contents of these works allows for the mapping of the changing semantic landscape, as reflected in this primarily hadith-based discourse, and permits the establishment of a repertoire of meanings assigned to the termjihad and its socio-political function in different historical contexts. In both chapters Five and Six, the chains of transmission of a number of these reports are scrutinized in order to single out their most prolific narrators and discern the probable motivations for the propagation of these reports.
Conclusion
Authors: Afsaruddin Asma
Published: October 2013

The Conclusion weighs the evidence and assess when, how, and why scholars in the classical and medieval periods — exegetes,hadīth specialists and historians — increasingly chose to privilege a monovalent, belligerent interpretation of jihād roughly from the late second/eighth century on, which in turn instigated counter-narratives which foregrounded and praised its non-militant aspects. The historical and political motivations propelling these developments are reconstructed and the extent to which this broadens and nuances current perspectives on jihād are indicated. This chapter concludes by observing that the literatures extolling the excellences (fadā’il) of military combat and of patient forbearance in particular often encode a number of these concerns in a consciously vaunting manner, creating competing paradigms of piety while invoking, co-opting, and reworking the common idioms -- Qur’anic and otherwise -- of jihād and martyrdom broadly construed.
The Catholic Labyrinth
Authors: McDonough Peter
Published: October 2013

In the wake of revelations about sexual abuse that scandalized the Catholic church, several groups came to prominence in the United States, some as advocates of reform, others as defenders of clerical governance. Three considerations have shaped their strategies. One is the connection between the sexual teaching of the church and its hierarchical structure of authority. Catholic neoconservatives succeeded in wedding traditional concerns about sexuality and gender roles, heightened in reaction to the upheavals of the 1960s, with support for family values and a turn away from progressive economic and social policies. Such polarization and retrenchment have encouraged some reformers to explore a second venue, putting their efforts into less contentious areas like the schools, social services, and health care programs affiliated with the church. A significant constraint on this generally popular strategy is that efforts to secure funding for the good works of Catholicism can run up against constitutional principles regarding the separation of church and state. Third, while Catholic opinion increasingly favors changes like the abolition of the celibacy requirement for priests, a legacy of deference, indifference, and selective adherence, together with the conservative leanings of recent immigrants, have slowed the dynamics of modernization. Managerial improvements show greater promise of advancing change than challenges to doctrine. Yet it is doubtful whether reforms stressing administrative performance over fairness—notably, with regard to to the status of women—can reverse the exodus and dimming of commitment among ordinary Catholics.
Curve Characteristics and Foraminal Dimensions in Patients With Adult Scoliosis and Radiculopathy
Authors: Pugely Andrew J. , Ries Zachary , Gnanapragasam Gnanapradeep , Gao Yubo , Nash Rachel , Mendoza-Lattes Sergio A.
Published: October 2013

Study Design:

Retrospective cohort study.

Objective:

To demonstrate a correlation between radiculopathy symptoms, foraminal morphology, and curve types.

Summary of Background Data:

Patients with degenerative scoliosis frequently present with foraminal stenosis and radiculopathy, the origin of which is not well understood.

Methods:

A total of 48 patients (384 foraminas) were included: 14 with low back pain (B); 16 with femoral nerve pain (F); and 18 with sciatic nerve pain (S). The symptomatic foramen of groups F and S were compared with asymptomatic foramina. Alignment was measured from standardized radiographs; 3D-CT reconstructions were used to measure foraminal height and area. Data are presented as mean±SD. The χ2, t test, and Pearson coefficients were calculated; as well as interobserver and intraobserver reproducibility (Cohen κ).

Results:

Seventeen of the 18 patients with sciatic nerve pain (S) presented foraminal stenosis (<40 mm2) at the concavity of the fractional curve distal to the main lumbar structural curve. The symptomatic foramina were significantly smaller in height (7.8±2.5 vs. 12.1±3.1 mm, P<0.0001) and area (30.1±14.3 vs. 57.6±28.7 mm2, P<0.0001) compared with asymptomatic foramen; 7/7 patients with femoral nerve pain (F) and lumbar structural curves (apex L3 or lower) had foraminal stenosis at the concavity of the fractional curve. Eight of the 9 patients with femoral nerve pain (F) and thoracic, thoracolumbar, or lumbar (apex L2 or higher) curves, presented foraminal stenosis in the concavity of the caudal fractional curve. The symptomatic foraminal spaces were significantly smaller in height (9.2±3.2 vs. 12.1±3.1 mm, P<0.0001) and area (30.1±15.2 vs. 57.6±28.7 mm2, P<0.0001). Foraminal height correlated with foraminal area (r=0.68–0.85; P<0.0001). Interobserver agreement was between 0.6092 and 0.8679.

Conclusions:

A correlation between curve types and symptomatic foraminal stenosis exists. Adult scoliosis patients with sciatic nerve pain typically present with foraminal stenosis at the concavity of the caudal fractional curve. Similarly, patients with femoral nerve pain present with foraminal stenosis at the concavity of the caudal fractional curve when the main structural curve is thoracic, thoracolumbar, or lumbar (apex L2 or higher).
Water security in one blue planet: twenty-first century policy challenges for science
Authors: Grey D. , Garrick D. , Blackmore D. , Kelman J. , Muller M. , Sadoff C.
Published: October 2013

Water-related risks threaten society at the local, national and global scales in our inter-connected and rapidly changing world. Most of the world's poor are deeply water insecure and face intolerable water-related risks associated with complex hydrology. Most of the world's wealthy face lower water-related risks and less complex hydrology. This inverse relationship between hydrological complexity and wealth contributes to a divided world. This must be addressed if global water security is to be achieved. Using a risk-based framework provides the potential to link the current policy-oriented discourse on water security to a new and rigorous science-based approach to the description, measurement, analysis and management of water security. To provide the basis for this science-based approach, we propose an encompassing definition rooted in risk science:
water security is a tolerable level of water-related risk to society
. Water security policy questions need to be framed so that science can marshal interdisciplinary data and evidence to identify solutions. We join a growing group of scientists in asserting a bold vision for science leadership, calling for a new and comprehensive understanding of the planet's water system and society's water needs.
Risk-based principles for defining and managing water security
Authors: Hall Jim , Borgomeo Edoardo
Published: October 2013

The concept of water security implies concern about potentially harmful states of coupled human and natural water systems. Those harmful states may be associated with water scarcity (for humans and/or the environment), floods or harmful water quality. The theories and practices of risk analysis and risk management have been developed and elaborated to deal with the uncertain occurrence of harmful events. Yet despite their widespread application in public policy, theories and practices of risk management have well-known limitations, particularly in the context of severe uncertainties and contested values. Here, we seek to explore the boundaries of applicability of risk-based principles as a means of formalizing discussion of water security. Not only do risk concepts have normative appeal, but they also provide an explicit means of addressing the variability that is intrinsic to hydrological, ecological and socio-economic systems. We illustrate the nature of these interconnections with a simulation study, which demonstrates how water resources planning could take more explicit account of epistemic uncertainties, tolerability of risk and the trade-offs in risk among different actors.
The politics of African energy development: Ethiopia’s hydro-agricultural state-building strategy and clashing paradigms of water security
Authors: Verhoeven Harry
Published: October 2013

As key economic, ecological and demographic trends converge to reshape Africa and its relationship with the outside world, a new politics is emerging in the twenty-first century around the water–food–energy nexus, which is central to the continent's relevance in the global economy. On the one hand, Malthusian anxieties are proliferating; pessimists link population growth and growing water scarcity to state failure and ‘water wars’. On the other hand, entrepreneurs, sovereign wealth funds and speculators consider Africa's potential in water resources, energy production and food output as one of the last great untapped opportunities for the global economy: Africa is on the brink of an agro-industrial transformation. This article examines how African actors are not merely responding to economic and environmental changes but also thinking politically about water, food and energy security. Many of them are seizing the new opportunities to redefine their national politics, their relationship with local communities and their ties with external players, regionally and globally. Ethiopia's project of hydro-agricultural state-building helps to identify the most important fault lines of this new politics at the national, local and international level. The politics of water security and energy development simultaneously puts African states and their populations on the defensive, as they grapple with huge challenges, but also provides them with unique opportunities to take advantage of a more favourable global configuration of forces.
The governance dimensions of water security: a review
Authors: Bakker Karen , Morinville Cynthia
Published: October 2013

Water governance is critical to water security, and to the long-term sustainability of the Earth's freshwater systems. This review examines recent debates regarding the governance dimensions of water security, including adaptive governance, polycentric governance, social learning and multi-level governance. The analysis emphasizes the political and institutional dimensions of water governance, and explores the relevance of social power—an overlooked yet important aspect of the water security debate. In addition, the review explores the intersection and potential synergies between water governance perspectives and risk-based approaches to water security, and offers critiques and suggestions for further research questions and agendas.
Analyses of Ca2+ Accumulation and Dynamics in the Endoplasmic Reticulum of Arabidopsis Root Cells Using a Genetically Encoded Cameleon Sensor
Authors: Bonza Maria Cristina , Loro Giovanna , Behera Smrutisanjita , Wong Andrea , Kudla Jörg , Costa Alex
Published: October 2013

In planta, very limited information is available about how the endoplasmic reticulum (ER) contributes to cellular Ca2+ dynamics and homeostasis. Here, we report the generation of an ER-targeted Cameleon reporter protein suitable for analysis of Ca2+ accumulation and dynamics in the lumen of the ER in plant cells. Using stably transformed Arabidopsis (Arabidopsis thaliana) plants expressing this reporter protein, we observed a transiently enhanced accumulation of Ca2+ in the ER in response to stimuli inducing cytosolic Ca2+ rises in root tip cells. In all experimental conditions, ER Ca2+ dynamics were substantially different from those monitored in the cytosol. A pharmacological approach enabled us to evaluate the contribution of the different ER-resident Ca2+-ATPase classes in the regulation of the ER Ca2+ homeostasis. Taken together, our results do not provide evidence for a role of the ER as a major source that releases Ca2+ for stimulus-induced increases in cytosolic Ca2+ concentration. Instead, our results show that the luminal ER Ca2+ elevations typically follow cytosolic ones, but with distinct dynamics. These findings suggest fundamental differences for the function of the ER in cellular Ca2+ homeostasis in plants and animals.
(1S,1′S,2′R,4a'S,9a'S,9b'R)-1′-Acetyloxy-2,4′-dioxo-2′,4′,4a',7′,8′,9′,9a',9b'-octahydro-1′H,2H-spiro[acenaphthylene-1,5′-pyrano[4,3-a]pyrrolizin]-2′-ylmethyl acetate
Authors: Santhiya S. , Naga Siva Rao J. , Raghunathan R. , Latha N. , Lakshmi S.
Published: October 2013

In the title compound C26H25NO7, the mean plane through the lactone-substituted ring of the pyrrolizidine moiety forms dihedral angles of 78.46 (6) and 58.28 (8)° with the acenaphthylene moiety and the sugar based-lactone ring, respectively. The sum of the angles at the the N atom of the pyrrolizidine ring (335.0°) is in accordance withsp3hybridization. Some atoms of the acetate group are disordered and were refined using a split model [occupancy ratio 0.673 (10):0.327 (10)].
Anthracene-1,4,9,10-tetraone
Authors: Kitamura Chitoshi , Kawase Takeshi
Published: October 2013

The asymmetric unit of the title compound, C14H6O4, contains three independent molecules (A,BandC). In moleculeC, there are two disordered sets of two carbonyl O atoms [occupancies = 0.643 (11) and 0.357 (11)]. All three molecules are non-planar due to repulsion between two O atoms inperipositions on the anthracene ring, showing a slight difference in deviation of the carbonyl O atoms. The intramolecular distances between the two nearest O atoms are in the range of 2.685 (10)–2.766 (10) Å. In the crystal, molecules are linked by C—H...O and π–π [centroid–centroid distances = 3.615 (2), 3.844 (2) and 3.921 (2) Å] interactions, which lead to the formation of a herringbone-like arrangement.
2-(2,4-Difluorophenyl)-4,5-dimethyl-1-(4-methylphenyl)-1H-imidazole monohydrate
Authors: Srinivasan Natesan , Rizwana Begum Syed Rafee Ahamed , Hema Ramu , Sridhar Balasubramanian , Anitha Azhagan Ganapathi
Published: October 2013

The asymmetric unit of the title compound, C18H16F2N2·H2O, contains two independent molecules (AandB), and two independent water molecules of crystallization. In moleculeA, the imidazole ring makes dihedral angles of 47.46 (7) and 60.98 (6)° with the 2,4-difluorophenyl and methylphenyl rings, respectively. The corresponding angles in moleculeBare 45.85 (7) and 62.78 (7)°, respectively. The dihedral angle between the two benzene rings is 64.98 (7)° in moleculeAand 65.53 (7)° in moleculeB. In the crystal, the two independent molecules are linked by O—H...N and O—H...O hydrogen bonds, forming chains propagating along [100]. These chains are linkedviaC—H...F hydrogen bonds, forming slab-like two-dimensional networks lying parallel to (001).
Bis[μ-N-(pyridin-2-ylmethyl)pyridin-3-amine-κ2N:N′]disilver(I) bis(perchlorate) dimethyl sulfoxide disolvate
Authors: Moon Suk-Hee , Park Ki-Min
Published: October 2013

In the binuclear title compound, [Ag2(C11H11N3)2](ClO4)2·2C2H6SO, the complex cation is centrosymmetric, with the unique AgIcation coordinated by two pyridine N atoms from two symmetry-relatedN-(pyridine-2-ylmethyl)pyridine-3-amine ligands in a geometry slightly distorted from linear [N—Ag—N = 170.78 (9)°], resulting in the formation of a 16-membered cyclic dimer. The two pyridine rings coordinating to the AgIatom are almost perpendicular to each other [dihedral angle = 87.73 (10)°]. Intermolecular Ag...O interactions [3.149 (3) and 2.686 (3) Å], N—H...O and C—H...O hydrogen bonds and C—H...π interactions between the cyclic dimers and the anions or the solvent molecules lead to the formation of a three-dimensional supramolecular network.
Flow Fields in an Axial Flow Compressor During Four-Quadrant Operation
Authors: Gill Andrew , Von Backström Theodor W. , Harms Thomas M.
Published: October 2013

It has been shown in previous investigations that when all combinations of both positive and negative direction of rotation and flow direction are allowed in operating a multistage axial flow compressor, the operating point may be in any of the four quadrants of the pressure rise versus flow characteristic. The present paper is the first discussion of the flow field of all possible modes of operation of an axial flow compressor. During the present study interstage time dependent hot film velocity measurements and five hole pneumatic probe measurements were combined with steady and time dependent CFD solutions to investigate the flow fields in the three-stage axial compressor. Results are presented in terms of mean-line velocity triangles, mean stream surface plots, midspan radial velocity contours right through the compressor, rotor-downstream radial distributions of axial and tangential velocity, stator-downstream axial velocity contours and midspan entropy contours through the compressor. Main flow features are pointed out and discussed. The study was instigated in an effort to understand possible accident scenarios in a three-shaft closed cycle nuclear powered helium gas turbine.
Elastic-Plastic Contact Conditions for Frictionally Constrained Bodies Under Cyclic Tangential Loading
Authors: Chaudhry V. , Kailas Satish V.
Published: October 2013

A Frictionally constrained condition implies dependence of friction force on tangential displacement amplitude. The condition may occur due to chemical, physical, and/or mechanical interaction between the contacting surfaces. The condition, sometimes also referred to as the presliding condition or partial slip condition, is characterized under fretting. Under such conditions, various experimental studies indicate the existence of two distinguishable regions, that is, stick region and slip region. In the present study, frictionally constrained conditions are identified and the evolutions of stick-slip regions are investigated in detail. Investigations have been performed on self-mated stainless steel and chromium carbide coated surfaces mated against stainless steel, under both vacuum and ambient conditions. Contact conditions prevailing at the contact interface were identified based on the mechanical responses and were correlated with the surface damage observed. Surface degradation has been observed in the form of microcracks and material transfer. Detailed numerical analysis has also been performed in order to understand the energy dissipation and the damage mode involved in the surface or subsurface damage. It has been observed that under frictionally constrained conditions, the occurrence of annular slip features are mainly due to the junction growth, resulting from elastic-plastic deformation at the contact interface. Ratcheting has been observed as the governing damage mode under cyclic tangential loading condition.
Synthesis and Characterization of Al/Al3Fe Nanocomposite for Tribological Applications
Authors: Agarwal Rahul , Mohan Anita , Mohan Sunil , Gautam Rakesh Kr.
Published: October 2013

Aluminum based composites find diverse applications due to their superior mechanical and physical properties. Aluminum matrix nanocomposites have been synthesized with Al3Fe nanocrystalline intermetallics reinforcement using the powder metallurgy route. The prepared composites have been characterized for various physical and mechanical properties such as density measurement, bulk hardness, compressive strength, and tribological properties. The theoretical coefficient of the linear thermal expansion has also been predicted. The composite shows a high strength to weight ratio and excellent wear resistance, along with a low coefficient of friction. The observed wear rate is superior to other composites irrespective of the load and sliding velocity chosen for the study and it continuously decreases withan increasing amount of dispersoid.
The TNF Family Member 4-1BBL Sustains Inflammation by Interacting with TLR Signaling Components During Late-Phase Activation
Authors: Ma Jianhui , Bang Bo-Ram , Lu Jiawei , Eun So-Young , Otsuka Motoyuki , Croft Michael , Tobias Peter , Han Jiahuai , Takeuchi Osamu , Akira Shizuo , Karin Michael , Yagita Hideo , Kang Young Jun
Published: October 2013

Limiting the late phase of the macrophage response to microbial products can prevent lethal sepsis in mice.
Science Signaling
Podcast: 1 October 2013
Authors: Gorbea Carlos , VanHook Annalisa M.
Published: October 2013

A subset of 26
S
proteasomes attenuates TLR3-mediated antiviral signaling.
Strong Bones for a Strong Mind
Authors: VanHook Annalisa M.
Published: October 2013

A hormone secreted by osteoblasts protects mice from depression and anxiety and promotes learning.
Cycling to Live Differently
Authors: Berndt Jason D.
Published: October 2013

The cell cycle determines the cell fate of embryonic stem cells.
Diurnal Immunology
Authors: Mueller Kristen L.
Published: October 2013

The clock protein Bmal1 regulates daily changes in white blood cell trafficking and susceptibility to inflammation in mice.
Drugs, Dopamine, and Disinhibition
Authors: Stern Peter R.
Published: October 2013

Changes in specific neuronal circuits suggest that drug-evoked synaptic plasticity facilitates drug-adaptive behavior.
Impact of Lipopolysaccharide-Induced Inflammation on the Disposition of the Aminocephalosporin Cefadroxil
Authors: Huh Yeamin , Keep Richard F. , Smith David E.
Published: October 2013

The purpose of this study was to determine if the disposition of cefadroxil, an α-amino-containing β-lactam antibiotic, changes during lipopolysaccharide (LPS)-induced acute inflammation. Six hours after LPS or saline treatment, mice received 1 nmol/g cefadroxil intravenously along with inulin for glomerular filtration rate (GFR) determination. Serial blood samples, along with tissue and urine samples, were collected at predetermined time points. In order to determine inflammation-induced changes in GFR, renal tubular secretion, and reabsorption, it was necessary to coadminister 70 mg/kg probenecid. Changes in the expression of the mRNA of transporters involved in cefadroxil disposition in the kidneys and choroid plexus were also investigated 6 h after LPS treatment. The results demonstrated marked increases in blood, cerebrospinal fluid, and tissue cefadroxil concentrations with LPS treatment. Tissue-to-blood concentration ratios were decreased by 4.6-fold in the choroid plexus and by 2.5-fold in the kidneys during LPS-induced inflammation. Renal, but not choroid plexus, mRNA expression of peptide transporter 2, organic-anion transporter 1 (OAT1), OAT3, and multidrug resistance-associated protein 4 was mildly reduced in LPS-treated mice. The renal clearance of cefadroxil was substantially decreased by LPS treatment (3-fold). GFR was also reduced by 3-fold in LPS-treated mice, but no significant differences in the fractional reabsorption of cefadroxil and renal secretion once normalized by GFR were observed. These findings demonstrated that LPS-induced inflammation has a dramatic effect on the renal excretion of cefadroxil. It appears that changes in transporter expression played a minor role during LPS treatment but that renal dysfunction, associated with GFR reduction, was responsible for the substantial increase in plasma cefadroxil concentration-time profiles.
In Vitro
Activity of Ozenoxacin against Quinolone-Susceptible and Quinolone-Resistant Gram-Positive Bacteria
Authors: López Y. , Tato M. , Espinal P. , Garcia-Alonso F. , Gargallo-Viola D. , Cantón R. , Vila J.
Published: October 2013

In vitro
activity of ozenoxacin, a novel nonfluorinated topical (L. D. Saravolatz and J. Leggett, Clin. Infect. Dis.
37:
1210–1215, 2003) quinolone, was compared with the activities of other quinolones against well-characterized quinolone-susceptible and quinolone-resistant Gram-positive bacteria. Ozenoxacin was 3-fold to 321-fold more active than other quinolones. Ozenoxacin could represent a first-in-class nonfluorinated quinolone for the topical treatment of a broad range of dermatological infections.
Daptomycin Activity against Uncommonly Isolated Streptococcal and Other Gram-Positive Species Groups
Authors: Sader Helio S. , Flamm Robert K. , Farrell David J. , Jones Ronald N.
Published: October 2013

A total of 1,356 clinical isolates were tested against daptomycin by broth microdilution methods. Daptomycin was active against seven groups of viridans group streptococci (MIC
50
and MIC
90
values ranging from ≤0.06 and ≤0.06 μg/ml [
Streptococcus bovis
and
Streptococcus dysgalactiae
] to 0.5 and 1 μg/ml [
Streptococcus mitis
,
Streptococcus oralis
, and
Streptococcus parasanguinis
], respectively), beta-hemolytic streptococci serogroups C, F, and G (MIC
50
and MIC
90
, ≤0.06 to 0.25 and 0.12 to 0.25 μg/ml, respectively),
Corynebacterium
spp. (MIC
50
and MIC
90
, ≤0.06 and 0.12 μg/ml, respectively), and
Micrococcus
spp. (MIC
50
and MIC
90
, ≤0.06 and 0.25 μg/ml, respectively).
Listeria monocytogenes
exhibited higher daptomycin MICs (MIC
50
and MIC
90
, 2 and 4 μg/ml, respectively) than other tested organisms.
Pharmacokinetics of Hydroxymethylnitrofurazone, a Promising New Prodrug for Chagas' Disease Treatment
Authors: Serafim Eliana Ometto Pavan , Silva Antonio Távora de Albuquerque e , Moreno Andréia de Haro , Vizioli Ednir de Oliveira , Ferreira Elizabeth Igne , Peccinini Rosângela Gonçalves , Ribeiro Maria Lucia , Chung Man Chin
Published: October 2013

Hydroxymethylnitrofurazone (NFOH) is a trypanocidal prodrug of nitrofurazone (NF), devoid of mutagenic toxicity. The purpose of this work was to study the chemical conversion of NFOH into NF in sodium acetate buffer (pH 1.2 and 7.4) and in human plasma and to determine preclinical pharmacokinetic parameters in rats. At pH 1.2, the NFOH was totally transformed into NF, the parent drug, after 48 h, while at pH 7.4, after the same period, the hydrolysis rate was 20%. In human plasma, 50% of NFOH was hydrolyzed after 24 h. In the investigation of kinetic disposition, the concentration of drug in serum
versus
time curve was used to calculate the pharmacokinetic parameters after a single-dose regimen. NFOH showed a time to maximum concentration of drug in serum (
T
max
) as 1 h, suggesting faster absorption than NF (4 h). The most important results observed were the volume of distribution (
V
) of NFOH through the tissues, which showed a rate that is 20-fold higher (337.5 liters/kg of body weight) than that of NF (17.64 liters/kg), and the concentration of NF obtained by
in vivo
metabolism of NFOH, which was about four times lower (maximum concentration of drug in serum [
C
max]
= 0.83 μg/ml; area under the concentration-time curve from 0 to 12 h [AUC
0–12]
= 5.683 μg/ml · h) than observed for administered NF (
C
max
= 2.78 μg/ml; AUC
0–12
= 54.49 μg/ml · h). These findings can explain the superior activity and lower toxicity of the prodrug NFOH in relation to its parent drug and confirm NFOH as a promising anti-Chagas' disease drug candidate.
Significance of the
d
-Serine-Deaminase and
d
-Serine Metabolism of Staphylococcus saprophyticus for Virulence
Authors: Korte-Berwanger Miriam , Sakinc Türkan , Kline Kimberly , Nielsen Hailyn V. , Hultgren Scott , Gatermann Sören G.
Published: October 2013

Staphylococcus saprophyticus
is the only species of
Staphylococcus
that is typically uropathogenic and possesses a gene coding for a
d
-serine-deaminase (DsdA). As
d
-serine is prevalent in urine and toxic or bacteriostatic to many bacteria, it is not surprising that the
d
-serine-deaminase gene is found in the genome of uropathogens. It has been suggested that
d
-serine-deaminase or the ability to respond to or to metabolize
d
-serine is important for virulence. For uropathogenic
Escherichia coli
(UPEC), a high intracellular
d
-serine concentration affects expression of virulence factors.
S. saprophyticus
is able to grow in the presence of high
d
-serine concentrations; however, its
d
-serine metabolism has not been described. The activity of the
d
-serine-deaminase was verified by analyzing the formation of pyruvate from
d
-serine in different strains with and without
d
-serine-deaminase. Cocultivation experiments were performed to show that
d
-serine-deaminase confers a growth advantage to
S. saprophyticus
in the presence of
d
-serine. Furthermore,
in vivo
coinfection experiments showed a disadvantage for the Δ
dsdA
mutant during urinary tract infection. Expression analysis of known virulence factors by reverse transcription-quantitative PCR (RT-qPCR) showed that the surface-associated lipase Ssp is upregulated in the presence of
d
-serine. In addition, we show that
S. saprophyticus
is able to use
d
-serine as the sole carbon source, but interestingly,
d
-serine had a negative effect on growth when glucose was also present. Taken together,
d
-serine metabolism is associated with virulence in
S. saprophyticus
, as at least one known virulence factor is upregulated in the presence of
d
-serine and a Δ
dsdA
mutant was attenuated in virulence murine model of urinary tract infection.
Differences in Purinergic Amplification of Osmotic Cell Lysis by the Pore-Forming RTX Toxins Bordetella pertussis CyaA and Actinobacillus pleuropneumoniae ApxIA: the Role of Pore Size
Authors: Masin Jiri , Fiser Radovan , Linhartova Irena , Osicka Radim , Bumba Ladislav , Hewlett Erik L. , Benz Roland , Sebo Peter
Published: October 2013

A large subgroup of the
r
epeat in
t
o
x
in (RTX) family of leukotoxins of Gram-negative pathogens consists of pore-forming hemolysins. These can permeabilize mammalian erythrocytes (RBCs) and provoke their colloid osmotic lysis (hemolytic activity). Recently, ATP leakage through pannexin channels and P2X receptor-mediated opening of cellular calcium and potassium channels were implicated in cell permeabilization by pore-forming toxins. In the study described here, we examined the role played by purinergic signaling in the cytolytic action of two RTX toxins that form pores of different sizes. The cytolytic potency of ApxIA hemolysin of
Actinobacillus pleuropneumoniae
, which forms pores about 2.4 nm wide, was clearly reduced in the presence of P2X
7
receptor antagonists or an ATP scavenger, such as pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), Brilliant Blue G, ATP oxidized sodium salt, or hexokinase. In contrast, antagonists of purinergic signaling had no impact on the hemolytic potency of the adenylate cyclase toxin-hemolysin (CyaA) of
Bordetella pertussis
, which forms pores of 0.6 to 0.8 nm in diameter. Moreover, the conductance of pores formed by ApxIA increased with the toxin concentration, while the conductance of the CyaA single pore units was constant at various toxin concentrations. However, the P2X
7
receptor antagonist PPADS inhibited in a concentration-dependent manner the exacerbated hemolytic activity of a CyaA-ΔN489 construct (lacking 489 N-terminal residues of CyaA), which exhibited a strongly enhanced pore-forming propensity (>20-fold) and also formed severalfold larger conductance units in planar lipid bilayers than intact CyaA. These results point to a pore size threshold of purinergic amplification involvement in cell permeabilization by pore-forming RTX toxins.
Nlrp-3-Driven Interleukin 17 Production by γδT Cells Controls Infection Outcomes during Staphylococcus aureus Surgical Site Infection
Authors: Maher Belinda M. , Mulcahy Michelle E. , Murphy Alison G. , Wilk Mieszko , O'Keeffe Kate M. , Geoghegan Joan A. , Lavelle Ed C. , McLoughlin Rachel M.
Published: October 2013

Recent work has identified T cells and the cytokines they produce as important correlates of immune protection during
Staphylococcus aureus
infections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for γδT cells in controlling
S. aureus
surgical site infection (SSI). γδT cells are recruited to the wound site following
S. aureus
challenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-γδT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor-deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during
S. aureus
SSI. However, we demonstrate a strain-dependent requirement for γδT cells in this process due to the differential abilities of individual strains to activate IL-1β production. IL-1β processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control
S. aureus
SSI due to reduced production of IL-17 by γδT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during
S. aureus
infection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during
S. aureus
SSI, the relative contribution of γδT cells to these protective effects may be strain dependent.
The Pseudomonas aeruginosa Periplasmic Protease CtpA Can Affect Systems That Impact Its Ability To Mount Both Acute and Chronic Infections
Authors: Seo Jin , Darwin Andrew J.
Published: October 2013

Proteases play important roles in the virulence of
Pseudomonas aeruginosa
. Some are exported to act on host targets and facilitate tissue destruction and bacterial dissemination. Others work within the bacterial cell to process virulence factors and regulate virulence gene expression. Relatively little is known about the role of one class of bacterial serine proteases known as the carboxyl-terminal processing proteases (CTPs). The
P. aeruginosa
genome encodes two CTPs annotated as PA3257/Prc and PA5134/CtpA in strain PAO1. Prc degrades mutant forms of the anti-sigma factor MucA to promote mucoidy in some cystic fibrosis lung isolates. However, nothing is known about the role or importance of CtpA. We have now found that endogenous CtpA is a soluble periplasmic protein and that a
ctpA
null mutant has specific phenotypes consistent with an altered cell envelope. Although a
ctpA
null mutation has no major effect on bacterial growth in the laboratory, CtpA is essential for the normal function of the type 3 secretion system (T3SS), for cytotoxicity toward host cells, and for virulence in a mouse model of acute pneumonia. Conversely, increasing the amount of CtpA above its endogenous level induces an uncharacterized extracytoplasmic function sigma factor regulon, an event that has been reported to attenuate
P. aeruginosa
in a rat model of chronic lung infection. Therefore, a normal level of CtpA activity is critical for T3SS function and acute virulence, whereas too much activity can trigger an apparent stress response that is detrimental to chronic virulence.
Chlamydia pneumoniae Infection Promotes Vascular Smooth Muscle Cell Migration through a Toll-Like Receptor 2-Related Signaling Pathway
Authors: Wang Beibei , Zhang Lijun , Zhang Tengteng , Wang Haiwei , Zhang Junxia , Wei Junyan , Shen Bingling , Liu Xin , Xu Zhelong , Zhang Lijun
Published: October 2013

The migration of vascular smooth muscle cells (VSMCs) from the media to the intima is proposed to be a key event in the development of atherosclerosis. Recently, we reported that
Chlamydia pneumoniae
infection is involved in VSMC migration. However, the exact mechanisms for
C. pneumoniae
infection-induced VSMC migration are not yet well elucidated. In this study, we examined the role of the Toll-like receptor 2 (TLR2) activation-related signaling pathway in VSMC migration induced by
C. pneumoniae
infection. An Affymetrix-based gene expression array was conducted to identify the changes of gene expression in rat primary VSMCs (rVSMCs) infected with
C. pneumoniae
. Both the microarray analysis and quantitative real-time reverse transcription (RT)-PCR revealed that TLR2 mRNA expression was strongly upregulated 12 h after
C. pneumoniae
infection. RT-PCR and Western blot analysis further showed that the expression levels of TLR2 mRNA and protein significantly increased at the different time points after infection. Immunocytochemical analysis suggested a TLR2 recruitment to the vicinity of
C. pneumoniae
inclusions. Cell migration assays showed that the TLR2-neutralizing antibody could significantly inhibit
C. pneumoniae
infection-induced rVSMC migration. In addition,
C. pneumoniae
infection stimulated Akt phosphorylation at Ser 473, which was obviously suppressed by the PI3K inhibitor LY294002, thereby inhibiting rVSMC migration caused by
C. pneumoniae
infection. Furthermore, both the infection-induced Akt phosphorylation and rVSMC migration were suppressed by the TLR2-neutralizing antibody. Taken together, these data suggest that
C. pneumoniae
infection can promote VSMC migration possibly through the TLR2-related signaling pathway.
Proinsulin C-peptide potentiates the inhibitory action of insulin on glucose synthesis in primary cultured rabbit kidney-cortex tubules: Metabolic studies
Authors: Usarek Michal , Jagielski Adam Konrad , Krempa Paulina , Dylewska Anna , Kiersztan Anna , Drozak Jakub , Girstun Agnieszka , Derlacz Rafal Andrzej , Bryla Jadwiga
Published: October 2013

Effects of equimolar concentrations of proinsulin C-peptide and insulin on glucose synthesis were studied in primary cultures of rabbit kidney-cortex tubules grown in the presence of alanine, glycerol, and octanoate. The rhodamine-labeled C-peptide entered renal tubular cells and localized in nuclei, both in the presence and absence of insulin; preincubations with the unlabeled compound inhibited internalization. C-peptide did not affect glucose formation when added alone but potentiated the inhibitory action of insulin by about 20% due to a decrease in flux through glucose-6-phosphate isomerase (GPI) and (or) glucose-6-phosphatase (G6Pase). GPI inhibition was caused by: (i) increased intracellular contents of fructose-1,6-bisphosphate and fructose-1-phosphate, inhibitors of the enzyme and (ii) reduced level of the phosphorylated GPI, which exhibits higher enzymatic activity in the presence of casein kinase 2. A decrease in flux through G6Pase, due to diminished import of G6P by G6P-transporter from the cytoplasm into endoplasmic reticulum lumen, is also suggested. The data show for the first time that in the presence of insulin and C-peptide, both GPI and G6P-ase may act as regulatory enzymes of renal gluconeogenic pathway.
Reevaluating the self-thinning boundary line for ponderosa pine (Pinus ponderosa) forests
Authors: Zhang Jianwei , Oliver William W. , Powers Robert F.
Published: October 2013

The self-thinning rule has been used extensively to predict population dynamics under intraspecific and interspecific competition. In forestry, it is an important silvicultural concept for maintaining stand health in the face of climate change and biotic stress, but uncertainty exists because traditional self-thinning limits were set subjectively without regard to site quality. We addressed this by analyzing ponderosa pine (Pinus ponderosa Lawson & C. Lawson) data from 109 research plots measured repeatedly and 59 inventory plots measured once across California. Self-thinning boundaries were fitted to the data with quantile regression and stochastic frontier function (SFF) techniques with and without site index (SI) as a covariate. The models from both methods fitted the data well with either research plots or all plots. Slopes for size-density trajectories were –0.45 with the 0.99 quantile and –0.47 for SFF. Maximum stand density indices (SDI) were 1250 trees per hectare (TPH) with the 0.99 quantile and 1050–1060 TPH with SFF. Mortality occurred when site occupancy from SFF reached 0.75, suggesting a zone of imminent mortality. Curvilinear trends in maximum SDI across SI for both methods indicate that self-thinning varies with site quality. Any management regimes that increase site quality and productivity will increase the self-thinning boundary.