bluuebunny/crossref_metadata_2025 huggingface dataset:
Context-dependent clustering for dynamic cellular state modeling of microarray gene expression
Authors: Yuan Shinsheng , Li Ker-Chau
Published: September 2007

Motivation: High-throughput expression profiling allows researchers to study gene activities globally. Genes with similar expression profiles are likely to encode proteins that may participate in a common structural complex, metabolic pathway or biological process. Many clustering, classification and dimension reduction approaches, powerful in elucidating the expression data, are based on this rationale. However, the converse of this common perception can be misleading. In fact, many biologically related genes turn out uncorrelated in expression.

Results: In this article, we present a novel method for investigating gene co-expression patterns. We assume the correlation between functionally related genes can be strengthened or weakened according to changes in some relevant, yet unknown, cellular states. We develop a context-dependent clustering (CDC) method to model the cellular state variable. We apply it to the transcription regulatory study for Saccharomyces cerevisiae, using the Stanford cell-cycle gene expression data. We investigate the co-expression patterns between transcription factors (TFs) and their target genes (TGs) predicted by the genome-wide location analysis of Harbison et al. Since TF regulates the expression of its TGs, correlation between TFs and TGs expression profiles can be expected. But as many authors have observed, the expression of transcription factors do not correlate well with the expression of their target genes. Instead of attributing the main reason to the lack of correlation between the transcript abundance and TF activity, we search for cellular conditions that would facilitate the TF-TG correlation. The results for sulfur amino acid pathway regulation by MET4, respiratory genes regulation by HAP4, and mitotic cell cycle regulation by ACE2/SWI5 are discussed in detail. Our method suggests a new way to understand the complex biological system from microarray data.

Availability: The program is written in ANSI C. The source code could be downloaded from http://kiefer.stat.sinica.edu.tw/CDC/index.php

Contact:  kcli@stat.ucla.edu

Supplementary information: Supplementary data are available at Bioinformatics online.
Testing the Predictions of the Multidimensional Spatial Voting Model with Roll Call Data
Authors: Jeong Gyung-Ho
Published: September 2007

This paper develops a procedure for locating proposals and legislators in a multidimensional policy space by applying agenda-constrained ideal point estimation. Placing proposals and legislators on the same scale allows an empirical test of the predictions of the spatial voting model. I illustrate this procedure by testing the predictive power of the uncovered set—a solution concept of the multidimensional spatial voting model—using roll call data from the U.S. Senate. Since empirical tests of the predictive power of the uncovered set have been limited to experimental data, this is the first empirical test of the concept's predictive power using real-world data.
Mixed valence and superconductivity
Authors: Larsson Sven
Published: September 2007

Mixed-valence (MV) systems are referred to here as MV-2 and MV-3 depending on whether two or three consecutive valence states are involved. MV-3 systems range from systems with Hubbard
U
≫0, corresponding to a single stable, intermediate valence state, and
U
≪0, corresponding to stable alternating valences differing by two units. Experiments using inelastic neutron scattering or inelastic X-ray scattering show softening of breathing phonon modes in MV systems compared with related systems with a single valence. It is hypothesized that softening is due to coupling between potential energy surfaces, corresponding to differing localizations of the electron. As predicted, softening is larger in the delocalized case. A mechanism for superconductivity is suggested.
Electronic phase separation and other novel phenomena and properties exhibited by mixed-valent rare-earth manganites and related materials
Authors: Shenoy Vijay B , Rao C.N.R
Published: September 2007

Transition metal oxides, such as the mixed-valent rare-earth manganites Ln

(1−
x
)

A

x

MnO
3
(Ln, rare-earth ion, and A, alkaline-earth ion), show a variety of electronic orders with spatially correlated charge, spin and orbital arrangements, which in turn give rise to many fascinating phenomena and properties. These materials are also electronically inhomogeneous, i.e. they contain disjoint spatial regions with different electronic orders. Not only do we observe signatures of such electronic phase separation in a variety of properties, but we can also observe the different ‘phases’ visually through different types of imaging. We discuss various experiments pertaining to electronic orders and electronic inhomogeneities in the manganites and present a discussion of theoretical approaches to their understanding. It is noteworthy that the mixed-valent rare-earth cobaltates of the type Ln

(1−
x
)

A

x

CoO
3
also exhibit electronic inhomogeneities just as the manganites.
Solitons, polarons and their dynamics in mixed-valence halogen-bridged MX-chains
Authors: Takaishi Shinya , Yamashita Masahiro
Published: September 2007

This article describes the photo-generation processes of elementary excitations such as solitons and polarons, and their dynamics in the one-dimensional (1D) halogen-bridged Pt compound [Pt(en)
2
Br](ClO
4
)
2
. Spin-solitons were photo-generated via relaxation processes of CT excitons and self-trapped excitons, made evident by photo-induced absorption and photo-induced electron spin resonance spectra. Polarons were not generated from CT excitons. Diffusion of spin-solitons on the 1D chain was studied quantitatively by analysing
1
H NMR spin-lattice relaxation times (
T
1
).
Mixed valency in organic charge transfer complexes
Authors: Saito Gunzi , Murata Tsuyoshi
Published: September 2007

Mixed-valence (partial charge transfer state) and segregated stacking are the key factors for constructing organic metals. Here, we discuss the ionicity phase diagrams for a variety of charge transfer systems to provide a strategy for the development of functional organic materials (Mott insulator, semiconductor, superconductor, metal, complex isomer, neutral–ionic system, etc.).
Basic auditory processes involved in the analysis of speech sounds
Authors: Moore Brian C.J
Published: September 2007

This paper reviews the basic aspects of auditory processing that play a role in the perception of speech. The frequency selectivity of the auditory system, as measured using masking experiments, is described and used to derive the internal representation of the spectrum (the excitation pattern) of speech sounds. The perception of timbre and distinctions in quality between vowels are related to both static and dynamic aspects of the spectra of sounds. The perception of pitch and its role in speech perception are described. Measures of the temporal resolution of the auditory system are described and a model of temporal resolution based on a sliding temporal integrator is outlined. The combined effects of frequency and temporal resolution can be modelled by calculation of the spectro-temporal excitation pattern, which gives good insight into the internal representation of speech sounds. For speech presented in quiet, the resolution of the auditory system in frequency and time usually markedly exceeds the resolution necessary for the identification or discrimination of speech sounds, which partly accounts for the robust nature of speech perception. However, for people with impaired hearing, speech perception is often much less robust.
Phonetic learning as a pathway to language: new data and native language magnet theory expanded (NLM-e)
Authors: Kuhl Patricia K , Conboy Barbara T , Coffey-Corina Sharon , Padden Denise , Rivera-Gaxiola Maritza , Nelson Tobey
Published: September 2007

Infants' speech perception skills show a dual change towards the end of the first year of life. Not only does non-native speech perception decline, as often shown, but native language speech perception skills show improvement, reflecting a facilitative effect of experience with native language. The mechanism underlying change at this point in development, and the relationship between the change in native and non-native speech perception, is of theoretical interest. As shown in new data presented here, at the cusp of this developmental change, infants' native and non-native phonetic perception skills predict later language ability, but in opposite directions. Betternativelanguage skill at 7.5 months of age predicts faster language advancement, whereas betternon-nativelanguage skill predicts slower advancement. We suggest that native language phonetic performance is indicative ofneural commitmentto the native language, while non-native phonetic performance revealsuncommitted neural circuitry. This paper has three goals: (i) to review existing models of phonetic perception development, (ii) to present new event-related potential data showing that native and non-native phonetic perception at 7.5 months of age predicts language growth over the next 2 years, and (iii) to describe a revised version of our previous model, the native language magnet model, expanded (NLM-e). NLM-e incorporates five new principles. Specific testable predictions for future research programmes are described.
New insights into crystallographic correlations between ferrite and cementite in lamellar eutectoid structures, obtained by SEM–FEG/EBSD and an indirect two-trace method
Authors: Zhang Y. D. , Esling C. , Calcagnotto M. , Zhao X. , Zuo L.
Published: September 2007

Four different ferrite/cementite orientation relationships (ORs) in near-eutectoid steel are derived using SEM–FEG/EBSD (scanning electron microscopy–field emission gun/electron back-scatter diffraction) and an indirect two-trace method. They show a common feature of close-packed plane parallelism between ferrite and cementite. Their crystallographic compatibility with habit planes shows a variety of possible habit planes and excludes the existence of the exact conventional Bagaryatsky and Pitsch–Petch ORs. Each of these new ferrite/cementite ORs is correlated with a different edge-to-edge matching condition between austenite and pearlitic ferrite, and between austenite and pearlitic cementite, and possesses specific morphological features. The present results may give deep insight into the crystallography of pearlitic transformation and provide useful information for materials design through interface tailoring in steels.
Ewald construction and resolution function for rocking-curve small-angle neutron scattering experiments
Authors: Daniilidis Nikolaos , Dimitrov Ivo , Ling Xinsheng Sean
Published: September 2007

A geometrical Ewald construction for small-angle neutron scattering experiments from line-like objects with a preferential orientation of the lines, such as flux-line lattices in type-II superconductors, is described. The Ewald construction offers a straightforward way to interpret rocking-curve experiments. It allows calculation of the resolution function in rocking-curve measurements. The resolution function for a given instrumental geometry can be readily computed by performing two numerical integrations.
Advances in thefree lunchmethod
Authors: Caliandro Rocco , Carrozzini Benedetta , Cascarano Giovanni Luca , De Caro Liberato , Giacovazzo Carmelo , Siliqi Dritan
Published: September 2007

The most critical limit of macromolecular crystallography, the experimental data resolution, is partially `tricked' by the `free lunchmethod' (non-measured reflection extrapolation). The best electron density map available when only observed data are used may be employed to extrapolate moduli and phases of unobserved reflections behind and beyond the experimental resolution limit. The method is able to reduce the mean phase error of the observed reflections and to produce a more interpretable (in terms of a molecular model) electron density map. The main features of thefree lunchmethod have been studied and its performance has been enhanced; it is beneficial even if data resolution is about 2 Å. Furthermore, the technique has been parameterized so that it may be routinely used by other phasing programs.
CLEARER: a new tool for the analysis of X-ray fibre diffraction patterns and diffraction simulation from atomic structural models
Authors: Sumner Makin O. , Sikorski Pawel , Serpell Louise C.
Published: September 2007

Fibre diffraction can provide structural information about polymers and biopolymers that is unobtainable using other methods. This method has been used to elucidate the structures of many polymers, biopolymers and protein assemblies. Extracting structural information from fibre diffraction patterns is a major challenge. A computer program calledCLEARERhas been developed that aids the detailed analysis of polycrystalline fibre diffraction patterns. It offers an easy-to-use interface that enables diffraction data processing, analysis and simulation of diffraction patterns. It is likely to be applicable to structural determination for a wide range of polymeric fibrous materials.CLEARERsimplifies and speeds up the data analysis process and helps to utilize all of the structural information present in the analysed X-ray and electron diffraction patterns.
A double-supermirror monochromator for neutron instrumentation at Laboratoire Léon Brillouin
Authors: Désert S. , Thévenot V. , Gabriel A. , Permingeat P. , Oberdisse J. , Brûlet A.
Published: September 2007

The design and characteristics of a double-supermirror monochromator for neutron instrumentation at the Laboratoire Léon Brillouin are described. The aim of this monochromator is to reduce the intense γ radiation produced by conventional velocity selectors and to avoid a direct view of the guide while keeping a comparable neutron transmission (70%). The monochromator offers a continuous choice of wavelength selection in the range 0.5–2 nm.
The impact of later trading hours for hotels (public houses) on breath alcohol levels of apprehended impaired drivers
Authors: Chikritzhs Tanya , Stockwell Tim
Published: September 2007

Aim To examine the impact of extended trading permits (ETPs) for licensed hotels in Perth, Western Australia on impaired driver breath alcohol levels (BALs) between July 1993 and June 1997.

Design Forty‐three hotels obtained ETPs allowing later closing hours and 130 maintained standard closing time (controls). Impaired driver BALs were linked to ‘last place of drinking’ hotels. Before and after period BALs of drivers who last drank at ETP or non‐ETP hotels were compared by time of day of apprehension and sex, controlling for age.

Findings Impaired female drivers apprehended between 10.01 p.m. and 12 midnight (before closing time) had significantly lower BALs after drinking at ETP hotels. Male drivers aged 18–25 years and apprehended between 12.01 and 2.00 a.m. after drinking at ETP hotels had significantly higher BALs than drivers who drank at non‐ETP hotels.

Conclusions At peak times for alcohol‐related offences, late trading is associated with higher BALs among those drinkers most at risk of alcohol‐related harm.
PERMANENT GENETIC RESOURCES: Isolation and characterization of microsatellite loci in the North Island brown kiwi, Apteryx mantelli
Authors: JENSEN THOMAS , NUTT KAREN J. , SEAL BRUCE S. , FERNANDES LUIZA B. , DURRANT BARBARA
Published: September 2007

We report the isolation and characterization of eight polymorphic and five monomorphic microsatellites in North Island brown kiwi (NIBK, Apteryx mantelli), using two polymerase chain reaction (PCR) techniques employing either short‐tandem repeat primers (STR method) or random PCR‐based isolation of microsatellite arrays (PIMA method). Microsatellite polymorphism was subsequently determined using 65 individuals. There were two to seven alleles for each polymorphic locus with heterozygozity ranging between 0.04 and 0.86. These primers will be used in future studies to determine the level of extra‐pair copulation, dispersal patterns, and genetic diversity within and between wild populations of NIBK.
PERMANENT GENETIC RESOURCES: Microsatellite markers for the threatened Bliss Rapids snail (Taylorconcha serpenticola) and cross‐amplification in its congener, T. insperata
Authors: LIU H. ‐P. , HERSHLER R.
Published: September 2007

We developed and tested microsatellite markers to investigate population structure of a threatened North American freshwater gastropod, Taylorconcha serpenticola. Of the 21 primer pairs that were evaluated, 11 were readily optimized and scored, providing amplification of 12 loci that were screened for 820 specimens from 29 populations. The number of alleles across 11 of these polymorphic loci ranged from three to 20 and the observed heterozygosity varied from 0.0061 to 0.7561. All loci yielded suitable amplification products in the second species of Taylorconcha (T. insperata) and three proved to be diagnostic for these congeners, demonstrating that these markers are also useful for species identification studies.
Receptor‐ and calcium‐dependent induced inositol 1,4,5‐trisphosphate increases in PC12h cells as shown by fluorescence resonance energy transfer imaging
Authors: Morita Mitsuhiro , Yoshiki Fumito , Nakane Akira , Okubo Yoshiumi , Kudo Yoshihisa
Published: September 2007

The production and further metabolism of inositol 1,4,5‐trisphosphate [Ins(1,4,5)P3] require several calcium‐dependent enzymes, but little is known about subsequent calcium‐dependent changes in cellular Ins(1,4,5)P3. To study the calcium dependence of muscarinic acetylcholine receptor‐induced Ins(1,4,5)P3 increases in PC12h cells, we utilized an Ins(1,4,5)P3 imaging system based on fluorescence resonance energy transfer and using green fluorescent protein variants fused with the pleckstrin homology domain of phospholipase C‐δ1. The intracellular calcium concentration, monitored by calcium imaging, was adjusted by thapsigargin pretreatment or alterations in extracellular calcium concentration, enabling rapid receptor‐independent changes in calcium concentration via store‐operated calcium influx. We found that Ins(1,4,5)P3 production was increased by a combination of receptor‐ and calcium‐dependent components, rather than by calcium alone. The level of Ins(1,4,5)P3 induced by the receptor was found to be half that induced by the combined receptor and calcium components. Increases in calcium levels prior to receptor activation did not affect the subsequent receptor‐induced Ins(1,4,5)P3 increase, indicating that calcium does not influence Ins(1,4,5)P3 production without receptor activation. Removal of both the receptor agonists and calcium rapidly restored calcium and Ins(1,4,5)P3 levels, whereas removal of calcium alone restored calcium to its basal concentration. Similar calcium‐dependent increases in Ins(1,4,5)P3 were also observed in Chinese hamster ovary cells expressing m1 muscarinic acetylcholine receptor, indicating that the observed calcium dependence is common to Ins(1,4,5)P3 production. To our knowledge, our results are the first showing receptor‐ and calcium‐dependent components within cellular Ins(1,4,5)P3.
The heat shock protein 70 molecular chaperone network in the pancreatic endoplasmic reticulum − a quantitative approach
Authors: Weitzmann Andreas , Baldes Christiane , Dudek Johanna , Zimmermann Richard
Published: September 2007

Traditionally, the canine pancreatic endoplasmic reticulum (ER) has been the workhorse for cell‐free studies on protein transport into the mammalian ER. These studies have revealed multiple roles for the major ER‐luminal heat shock protein (Hsp) 70, IgG heavy chain‐binding protein (BiP), at least one of which also involves the second ER‐luminal Hsp70, glucose‐regulated protein (Grp) 170. In addition, at least one of these BiP activities depends on Hsp40. Up to now, five Hsp40s and two nucleotide exchange factors, Sil1 and Grp170, have been identified in the ER of different mammalian cell types. Here we quantified the various proteins of this chaperone network in canine pancreatic rough microsomes. We also characterized the various purified proteins with respect to their affinities for BiP and their effect on the ATPase activity of BiP. The results identify Grp170 as the major nucleotide exchange factor for BiP, and the resident ER‐membrane proteins ER‐resident J‐domain protein 1 plus ER‐resident J‐domain protein 2/Sec63 as prime candidates for cochaperones of BiP in protein transport in the pancreatic ER. Thus, these data represent a comprehensive analysis of the BiP chaperone network that was recently linked to two human inherited diseases, polycystic liver disease and Marinesco–Sjögren syndrome.
First report of canine African trypanosomosis in the UK
Authors: Gow A. G. , Simpson J. W. , Picozzi K.
Published: September 2007

A six‐year‐old neutered male Jack Russell terrier was presented two years after importation into the UK from southern Africa with severe anaemia and abdominal distension. Abdominal ultrasonography revealed the presence of hepato‐splenomegaly and ascites. A diagnosis of trypanosomosis was made by blood smear examination. Shortly after admission the dog collapsed and died. PCR analysis revealed a single infection with Trypanosoma congolense savannah type. This is the first reported case of canine African trypanosomosis in Europe and suggests that chronic trypanosomosis may allow importation of the disease in apparently asymptomatic animals, even with extended quarantine periods.
Ureteral spindle cell sarcoma in a dog
Authors: Guilherme S. , Polton G. , Bray J. , Blunden A. , Corzo N.
Published: September 2007

A five‐year‐old, female spayed Labrador retriever was presented for further investigation of an intra‐abdominal mass. Abdominal exploration showed a large mass arising from the right ureter and a ureteronephrectomy was performed. Histopathology of the ureteral mass was consistent with a spindle cell sarcoma. The patient recovered well, but five months later was diagnosed with another tumour, this time in her left abdominal wall. The owners decided not to pursue further treatment and euthanasia was performed a month later.
Negation – An Overview of Typological Research
Authors: Miestamo Matti
Published: September 2007

This article is an overview of the current state of typological research on negation. Structures expressing standard negation – the negation of declarative verbal main clauses – can be classified on the basis of the status of the negative marker, or on the basis of the structure of the negative clause as a whole. Structural similarities and differences (symmetry and asymmetry) between negatives and affirmatives can be observed and classified into different types which can then be offered functional explanations. Negative strategies used in imperatives, existentials and nonverbal clauses often differ from standard negation; these differences are exemplified and discussed. The interaction between negative indefinite pronouns and standard negation shows interesting cross‐linguistic variation in terms of whether the latter co‐occurs with the indefinite and whether the indefinite is inherently negative. Some cross‐linguistic observations on diachronic developments and on the interaction between negation and modality and negation and focus are also briefly discussed.
Video‐Based Studies of Work Practice
Authors: Hindmarsh Jon , Heath Christian
Published: September 2007

The use of the visual, let alone video, is surprisingly rare within social scientific studies of work and organisations. Nevertheless there is an emerging corpus of research that use video recordings, augmented by field work, as their principal data; recordings that provide access to the fine details of work as it is accomplished within everyday organisational settings. They include studies of work in a broad range of domains, including call centres, mobile offices, operating theatres, construction sites and control centres. This paper outlines the nature of these video‐based studies of work and organisation and highlights some of their major contributions to our understanding of issues such as the nature of skill and expertise, the use of technology and the organisation of teamwork. It also reflects on the impact that these studies, and this approach, are having within the practical fields of industrial and market research.
Linear strain tensor and differential geometry
Authors: de Prunelé E.
Published: September 2007

The components of the linear strain tensor in spherical coordinates are calculated using three methods. The first is a change of basis method and does not require elaborate concepts. The second requires the concept of covariant derivative, and the third requires the concept of a Lie derivative. The calculation provides an opportunity to become familiar with both tensorial methods and associated computational tools in the context of an elementary physical situation. The components of the linear strain tensor in an arbitrary curvilinear orthonormal basis are interpreted geometrically as half the sum of two scalar products.
Reciprocal transmittances and reflectances: An elementary proof
Authors: Iwanaga Masanobu , Vengurlekar A. S. , Hatano Takafumi , Ishihara Teruya
Published: September 2007

We present an elementary proof concerning reciprocal transmittances and reflectances. The proof is direct, simple, and valid for the diverse objects that can be absorptive and induce diffraction and scattering, as long as the objects respond linearly and locally to electromagnetic waves. The proof enables students who understand the basics of classical electromagnetics to grasp the physical basis of reciprocal optical responses. We show an example to demonstrate reciprocal response numerically and experimentally.
Evaporation in atomic traps: A simple approach
Authors: Henn E. A. L. , Seman J. A. , Ramos E. R. F. , Iavaronni A. H. , Amthor T. , Bagnato V. S.
Published: September 2007

We present a simple model to describe evaporative cooling of ultracold trapped atoms. The cooling is used to achieve low temperatures of the gaseous sample by removing the most energetic atoms and subsequently rethermalizing the remaining atoms at a lower temperature. The model assumes a Maxwell-Boltzmann distribution of energies and allows the calculation of the temperature and the number of remaining atoms after the most energetic atoms have been removed and rethermalization has taken place.
How to detect level crossings without looking at the spectrum
Authors: Bhattacharya M.
Published: September 2007

It is possible to tell if two or more eigenvalues of a matrix are equal without calculating the eigenvalues. We use this property to detect (avoided) crossings in the spectra of Hamiltonians representable by matrices. This approach provides a pedagogical introduction to (avoided) crossings, is capable of handling realistic Hamiltonians analytically, and offers a way to visualize crossings that is sometimes superior to that provided by the spectrum directly. We illustrate the method using the Breit-Rabi Hamiltonian to describe the hyperfine-Zeeman structure of the ground-state hydrogen atom in a uniform magnetic field.
Resource Letter STMN-1: Spin transport in magnetic nanostructures
Authors: Hathaway Kristl , Dahlberg E. Dan
Published: September 2007

This Resource Letter provides a guide to the literature in the still rapidly developing area of spin-dependent transport phenomena, which forms the basis for applications in magnetoelectronics. Citations to original papers and review articles are provided for the major topics of giant magnetoresistance, spin-dependent tunneling, exchange coupling between magnetic layers, and micromagnetics of the nanostructures in which these occur. Related phenomena, such as exchange coupling in magnetic multilayers, exchange biasing, and the various experimental techniques developed to observe these effects are covered more briefly, with citations only to historically significant papers and selected review articles.
A heuristic approach to the weakly interacting Bose gas
Authors: Nattermann Thomas
Published: September 2007

Some of the thermodynamic properties of weakly interacting Bose systems are derived from dimensional and heuristic arguments and thermodynamic relations, without resorting to statistical mechanics. Our approach assumes only the existence of a branch of acoustic phonons in the interacting system.
Evaluation of Tigecycline Penetration into Colon Wall Tissue and Epithelial Lining Fluid Using a Population Pharmacokinetic Model and Monte Carlo Simulation
Authors: Rubino Christopher M. , Ma Lei , Bhavnani Sujata M. , Korth-Bradley Joan , Speth John , Ellis-Grosse Evelyn , Rodvold Keith R. , Ambrose Paul G. , Drusano George L.
Published: September 2007

The objective of these analyses was to assess the penetration of tigecycline into colon wall tissue and epithelial lining fluid (ELF). The analyses included data from subjects without infection (phase 1) and patients with intra-abdominal infections (phase 2/3). Steady-state serum samples were collected from all subjects/patients (
n
= 577), while colon wall specimens (
n
= 23) and ELF specimens (
n
= 30) were obtained from subjects without infection. Tissue and serum data were simultaneously comodeled by using the BigNPAG program, and a four-compartment, open model with zero-order intravenous input and first-order elimination was employed. To examine the full range of tissue penetration and the associated probabilities of occurrence, a 9,999-subject Monte Carlo simulation was performed with two outputs, one for ELF penetration and one for colon wall tissue penetration. Data were well fit using models described above, with all
r
2
values above 0.95. For subjects without infection, the median (5th and 95th percentiles) colon wall and ELF penetration ratios were 1.73 (0.160 and 199) and 1.15 (0.561 and 5.23), respectively. Simulation results predict that tissue penetration varies considerably and likely explain unexpected clinical outcomes for those patients infected with strains at margins of the MIC distribution.
Effect of Oral Treatment with Hexadecyloxypropyl-[(
S
)-9-(3-Hydroxy-2- Phosphonylmethoxypropyl)Adenine] [(
S
)-HPMPA] or Octadecyloxyethyl-(
S
)-HPMPA on Cowpox or Vaccinia Virus Infections in Mice
Authors: Quenelle Debra C. , Collins Deborah J. , Herrod Bridgett P. , Keith Kathy A. , Trahan Julissa , Beadle James R. , Hostetler Karl Y. , Kern Earl R.
Published: September 2007

We have previously reported that (
S
)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, or (
S
)-HPMPA, is active in vitro against cowpox virus (CV) and vaccinia virus (VV) but is not active orally in animals. However, the ether lipid esters of (
S
)-HPMPA, hexadecyloxypropyl-[(
S
)-HPMPA] [HDP-(
S
)-HPMPA] and octadecyloxyethyl-[(
S
)-HPMPA] [ODE-(
S
)-HPMPA], had significantly enhanced activity in vitro and are orally bioavailable in mice. In the current study, HDP-(
S
)-HPMPA and ODE-(
S
)-HPMPA were prepared in water and administered once daily by oral gavage to mice at doses of 30, 10, and 3 mg/kg of body weight for 5 days beginning 24, 48, or 72 h after inoculation with CV or VV. Oral HDP-(
S
)-HPMPA and ODE-(
S
)-HPMPA were both highly effective (
P
< 0.001) at preventing mortality due to CV at 30 mg/kg, even when treatments were delayed until up to 72 h postinfection. ODE-(
S
)-HPMPA or HDP-(
S
)-HPMPA were also highly effective (
P
< 0.001) at preventing mortality in mice infected with VV at 30 mg/kg when treatments were delayed until to 48 or 72 h postinfection, respectively. Protection against both viruses was associated with a significant reduction of virus replication in the liver, spleen, and kidney but not in the lung. These data indicate that HDP-(
S
)-HPMPA and ODE-(
S
)-HPMPA are active when given orally against lethal CV and VV infections in mice, and further evaluation is warranted to provide additional information on the potential of these orally active compounds for treatment of human orthopoxvirus infection.
Small-Molecule Scaffolds for CYP51 Inhibitors Identified by High-Throughput Screening and Defined by X-Ray Crystallography
Authors: Podust Larissa M. , von Kries Jens P. , Eddine Ali Nasser , Kim Youngchang , Yermalitskaya Liudmila V. , Kuehne Ronald , Ouellet Hugues , Warrier Thulasi , Alteköster Markus , Lee Jong-Seok , Rademann Jörg , Oschkinat Hartmut , Kaufmann Stefan H. E. , Waterman Michael R.
Published: September 2007

Sterol 14α-demethylase (CYP51), a major checkpoint in membrane sterol biosynthesis, is a key target for fungal antibiotic therapy. We sought small organic molecules for lead candidate CYP51 inhibitors. The changes in CYP51 spectral properties following ligand binding make CYP51 a convenient target for high-throughput screening technologies. These changes are characteristic of either substrate binding (type I) or inhibitor binding (type II) in the active site. We screened a library of 20,000 organic molecules against
Mycobacterium tuberculosis
CYP51 (CYP51
Mt
), examined the top type I and type II binding hits for their inhibitory effects on
M. tuberculosis
in broth culture, and analyzed them spectrally for their ability to discriminate between CYP51
Mt
and two reference
M. tuberculosis
CYP proteins, CYP130 and CYP125. We determined the binding mode for one of the top type II hits, α-ethyl-
N
-4-pyridinyl-benzeneacetamide (EPBA), by solving the X-ray structure of the CYP51
Mt
-EPBA complex to a resolution of 1.53 Å. EPBA binds coordinately to the heme iron in the CYP51
Mt
active site through a lone pair of nitrogen electrons and also through hydrogen bonds with residues H259 and Y76, which are invariable in the CYP51 family, and hydrophobic interactions in a phylum- and/or substrate-specific cavity of CYP51. We also identified a second compound with structural and binding properties similar to those of EPBA, 2-(benzo[d]-2,1,3-thiadiazole-4-sulfonyl)-2-amino-2-phenyl-
N
-(pyridinyl-4)-acetamide (BSPPA). The congruence between the geometries of EPBA and BSPPA and the CYP51 binding site singles out EPBA and BSPPA as lead candidate CYP51 inhibitors with optimization potential for efficient discrimination between host and pathogen enzymes.
Randomized, Double-Blind, Placebo-Controlled Trial of Cephalexin for Treatment of Uncomplicated Skin Abscesses in a Population at Risk for Community-Acquired Methicillin-Resistant
Staphylococcus aureus
Infection
Authors: Rajendran Priya M. , Young David , Maurer Toby , Chambers Henry , Perdreau-Remington Francoise , Ro Peter , Harris Hobart
Published: September 2007

Empirical use of beta-lactam antibiotics, the preferred agents for treating uncomplicated skin and soft tissue infections, may no longer be appropriate for these infections because of the increasing prevalence of community strains of methicillin-resistant
Staphylococcus aureus
(MRSA). Retrospective studies, however, suggest that outcomes are good even when beta-lactams are used. We conducted a randomized, double-blind trial of 166 outpatient subjects comparing placebo to cephalexin at 500 mg orally four times for 7 days after incision and drainage of skin and soft tissue abscesses. The primary outcome was clinical cure or failure 7 days after incision and drainage.
S. aureus
was isolated from 70.4% of abscess cultures. Of the isolates tested 87.8% were MRSA, 93% of which were positive for Panton-Valentine leucocidin genes. Clinical cure rates were 90.5% (95% confidence interval, 0.82 to 0.96) in the 84 placebo recipients and 84.1% (95% confidence interval, 0.74 to 0.91) in the 82 cephalexin recipients (difference in the two proportions, 0.0006; 95% confidence interval, −0.0461 to 0.0472;
P
= 0.25). The 90.5% cure rate observed in the placebo arm and 84.1% cure rate observed in the cephalexin arm provide strong evidence that antibiotics may be unnecessary after surgical drainage of uncomplicated skin and soft tissue abscesses caused by community strains of MRSA.
Tn
6001
, a Transposon-Like Element Containing the
bla
VIM-3
-Harboring Integron In450
Authors: Tseng Sung-Pin , Hsueh Po-Ren , Tsai Jui-Chang , Teng Lee-Jene
Published: September 2007

We describe the structure of a transposon-like element named Tn
6001
, which contains a
bla
VIM-3
-harboring integron In450, which was derived from a multidrug-resistant
Pseudomonas aeruginosa
clinical isolate in Taiwan. The transposon backbone structure is most closely related to those of Tn
1404
* and Tn
1403
. Tn
6001
was inserted into the chromosome of the clinical isolate.
Antibiotic Resistance and Single-Nucleotide Polymorphism Cluster Grouping Type in a Multinational Sample of Resistant
Mycobacterium tuberculosis
Isolates
Authors: Brimacombe M. , Hazbon M. , Motiwala A. S. , Alland D.
Published: September 2007

A single-nucleotide polymorphism-based cluster grouping (SCG) classification system for
Mycobacterium tuberculosis
was used to examine antibiotic resistance type and resistance mutations in relationship to specific evolutionary lineages. Drug resistance and resistance mutations were seen across all SCGs. SCG-2 had higher proportions of
katG
codon 315 mutations and resistance to four drugs.
Design, Synthesis, and Evaluation of 10-N-Substituted Acridones as Novel Chemosensitizers inPlasmodium falciparum
Authors: Kelly Jane X. , Smilkstein Martin J. , Cooper Roland A. , Lane Kristin D. , Johnson Robert A. , Janowsky Aaron , Dodean Rozalia A. , Hinrichs David J. , Winter Rolf , Riscoe Michael
Published: September 2007

A series of novel 10-N-substituted acridones, bearing alkyl side chains with tertiary amine groups at the terminal position, were designed, synthesized, and evaluated for the ability to enhance the potency of quinoline drugs against multidrug-resistant (MDR)Plasmodium falciparummalaria parasites. A number of acridone derivatives, with side chains bridged three or more carbon atoms apart between the ring nitrogen and terminal nitrogen, demonstrated chloroquine (CQ)-chemosensitizing activity against the MDR strain ofP. falciparum(Dd2). Isobologram analysis revealed that selected candidates demonstrated significant synergy with CQ in the CQ-resistant (CQR) parasite Dd2 but only additive (or indifferent) interaction in the CQ-sensitive (CQS) D6. These acridone derivatives also enhanced the sensitivity of other quinoline antimalarials, such as desethylchloroquine (DCQ) and quinine (QN), in Dd2. The patterns of chemosensitizing effects of selected acridones on CQ and QN were similar to those of verapamil against various parasite lines with mutations encoding amino acid 76 of theP. falciparumCQ resistance transporter (PfCRT). Unlike other known chemosensitizers with recognized psychotropic effects (e.g., desipramine, imipramine, and chlorpheniramine), these novel acridone derivatives exhibited no demonstrable effect on the uptake or binding of important biogenic amine neurotransmitters. The combined results indicate that 10-N-substituted acridones present novel pharmacophores for the development of chemosensitizers againstP. falciparum.
Global Phenotype Screening and Transcript Analysis Outlines the Inhibitory Mode(s) of Action of Two Amphibian-Derived, α-Helical, Cationic Peptides on
Saccharomyces cerevisiae
Authors: Morton C. Oliver , Hayes Andrew , Wilson Michael , Rash Bharat M. , Oliver Stephen G. , Coote Peter
Published: September 2007

Dermaseptin S3(1-16) [DsS3(1-16)] and magainin 2 (Mag 2) are two unrelated, amphibian-derived cationic peptides that adopt an α-helical structure within microbial membranes and have been proposed to kill target organisms via membrane disruption. Using a combination of global deletion mutant library phenotypic screening, expression profiling, and physical techniques, we have carried out a comprehensive in vitro analysis of the inhibitory action of these two peptides on the model fungus
Saccharomyces cerevisiae
. Gene ontology profiling (of biological processes) was used to identify both common and unique effects of each peptide. Resistance to both peptides was conferred by genes involved in telomere maintenance, chromosome organization, and double-strand break repair, implicating a common inhibitory action of DNA damage. Crucially, each peptide also required unique genes for maintaining resistance; for example, DsS3(1-16) required genes involved in protein targeting to the vacuole, and Mag 2 required genes involved in DNA-dependent DNA replication and DNA repair. Thus, DsS3(1-16) and Mag 2 have both common and unique antifungal actions that are not simply due to membrane disruption. Physical techniques revealed that both peptides interacted with DNA in vitro but in subtly different ways, and this observation was supported by the functional genomics experiments that provided evidence that both peptides also interfered with DNA integrity differently in vivo. This implies that both peptides are able to pass through the cytoplasmic membrane of yeast cells and damage DNA, an inhibitory action that has not been previously attributed to either of these peptides.
Interaction Study of the Combined Use of Paroxetine and Fosamprenavir-Ritonavir in Healthy Subjects
Authors: van der Lee Manon J. , Blenke Audrey A. M. , Rongen Gerard A. , Verwey-van Wissen Corrien P. W. G. M. , Koopmans Peter P. , Pharo Cristina , Burger David M.
Published: September 2007

Human immunodeficiency virus-infected patients have an increased risk for depression. Despite the high potential for drug-drug interactions, limited data on the combined use of antidepressants and antiretrovirals are available. Theoretically, ritonavir-boosted protease inhibitors may inhibit CYP2D6-mediated metabolism of paroxetine. We wanted to determine the effect of fosamprenavir-ritonavir on paroxetine pharmacokinetics and vice versa and to evaluate the safety of the combination. Group A started with 20 mg paroxetine every day for 10 days; after a wash-out period of 16 days, subjects received paroxetine (20 mg every day) plus fosamprenavir-ritonavir (700/100 mg twice a day) from days 28 to 37. Group B received the regimens in reverse order. On days 10 and 37, pharmacokinetic curves were recorded. Twenty-six healthy subjects (18 females, 8 males) were included. Median (range) age and weight were 44.4 (18.2 to 64.3) years and 68.8 (51.0 to 89.4) kg. Three subjects were excluded (two because of adverse events; one for nonadherence). Addition of fosamprenavir-ritonavir to paroxetine resulted in a significant decrease in paroxetine exposure: the geometric mean ratios (90% confidence intervals) of paroxetine plus fosamprenavir-ritonavir to paroxetine alone were 0.45 (0.41 to 0.49) for the area under the concentration-time curve from 0 to 24 h (AUC
0-24
), 0.49 (0.45 to 0.53) for the maximum concentration of the drug in plasma (
C
max
), and 0.75 (0.71 to 0.80) for the apparent elimination half-life (
t
1/2
). The free fraction of paroxetine showed a median (interquartile range) increase of 30% (18 to 42%) after the addition of fosamprenavir-ritonavir. The AUC
0-12
,
C
max
,
C
min
, and
t
1/2
of amprenavir and ritonavir were similar to those of historical controls. No serious adverse events occurred. Fosamprenavir-ritonavir reduced total paroxetine exposure by 55%. This is partly explained by protein displacement of paroxetine. We think that this interaction is clinically relevant and that titration to a higher dose of paroxetine may be necessary to accomplish the needed antidepressant effect.
Molecular Epidemiology of Clinical Isolates of Carbapenem-Resistant
Acinetobacter
spp. from Chinese Hospitals
Authors: Wang Hui , Guo Ping , Sun Hongli , Wang He , Yang Qiwen , Chen Minjun , Xu Yingchun , Zhu Yuanjue
Published: September 2007

Carbapenem resistance in
Acinetobacter
spp. is an emerging problem in China. We investigated the molecular epidemiology and carbapenemase genes of 221 nonrepetitive imipenem-resistant clinical isolates of
Acinetobacter
spp. collected from 1999 to 2005 at 11 teaching hospitals in China. Genotyping by pulsed-field gel electrophoresis (PFGE) found 15 PFGE patterns. Of these, one (clone P) was identified at four hospitals in Beijing and another (clone A) at four geographically disparate cities. Most imipenem-resistant isolates exhibited high-level resistance to all β-lactams and were only susceptible to colistin.
bla
OXA-23
-like genes were found in 97.7% of isolates. Sequencing performed on 60 representative isolates confirmed the presence of the
bla
OXA-23
carbapenemase gene. Analysis of the genetic context of
bla
OXA-23
showed the presence of IS
Aba1
upstream of
bla
OXA-23
. All of the 187
A. baumannii
isolates identified by amplified RNA gene restriction analysis carried a
bla
OXA-51
-like oxacillinase gene, while this gene was absent from isolates of other species. Sequencing indicated the presence of
bla
OXA-66
for 18 representative isolates. Seven isolates of one clone (clone T) carried the plasmid-mediated
bla
OXA-58
carbapenemase gene, while one isolate of another clone (clone L) carried the
bla
OXA-72
carbapenemase gene. Only 1 isolate of clone Q carried the
bla
IMP-8
metallo-β-lactamase gene, located in a class 1 integron. Of 221 isolates, 77.8% carried
bla
PER-1
-like genes. Eleven different structures of class 1 integrons were detected, and most integrons carried genes mediating resistance to aminoglycosides, rifampin, and chloramphenicol. These findings indicated clonal spread of imipenem-resistant
Acinetobacter
spp. and wide dissemination of the OXA-23 carbapenemase in China.
Delineation of Species-Specific Binding Properties of the CspZ Protein (BBH06) of Lyme Disease Spirochetes: Evidence for New Contributions to the Pathogenesis of
Borrelia
spp
Authors: Rogers Elizabeth A. , Marconi Richard T.
Published: September 2007

Borrelia burgdorferi
CspZ (TIGR open reading frame designation, BBH06) is part of a functionally related group of proteins that bind one or more members of the factor H (FH) protein family. In this report we assess the conservation, distribution, properties, and ligand binding abilities of CspZ from the three main
Borrelia
species associated with Lyme disease infections in humans. CspZ (also referred to as BbCRASP-2 in the literature) was found to be highly conserved at the intraspecies level but divergent at the interspecies level. All CspZ orthologs that originated from
B. burgdorferi
isolates bound FH from a diverse group of mammals. In contrast, CspZ derived from
B. garinii
and
B. afzelii
did not. Regardless of the
Borrelia
species of origin, all CspZ proteins tested bound to unknown ∼60-kDa serum proteins produced by different mammals. To further define the molecular basis for the differential binding of CspZ orthologs to host proteins, DNA sequence, truncation, and site-directed mutagenesis analyses were performed. DNA sequence analyses revealed that
B. garinii
and
B. afzelii
CspZ orthologs possess a 64-amino-acid N-terminal domain that is absent from
B. burgdorferi
CspZ. However, binding analyses of recombinant proteins revealed that this domain does not in and of itself influence ligand binding properties. Truncation and mutagenesis analyses further revealed that the key determinants required for ligand binding are discontinuous and that the presentation of the ligand binding pocket is dependent on alpha helices with high coiled-coil formation probability. The data presented here provide insight into the molecular basis of CspZ-ligand interactions and suggest that CspZ orthologs from diverse
Borrelia
species can contribute to the host-pathogen interaction through their interaction with serum proteins.
Polarographic Behavior and Determination of 1,1-Dimethyl-3-phenyltriazene
Authors: Ignjatović Ljubiša M. , Barek Jiří , Zima Jiří , Marković Dragan A.
Published: September 2007

Polarographic behavior of the genotoxic substance 1,1-dimethyl-3-phenyltriazene was investigated and optimum conditions were found for its determination by sampled direct current polarography and differential pulse polarography at a static mercury drop electrode in the concentration range from 1 × 10-4 to 1 × 10-7 mol l-1. It was established that for reduction of the triazene group four electrons are required resulting in the formation of amino and hydrazo compound. The resulting products were identified, and the reduction pathway was proposed.
SOME REMARKS ON THE HERRERA-HOJMAN SYSTEM
Authors: PUTA MIRCEA , TUDORAN RAMONA , TUDORAN RĂZVAN MICU , BOLEANTU MIHAI
Published: September 2007

We present some new properties of the Herrera-Hojman system from the Poisson geometry point of view.