bluuebunny/crossref_metadata_2025 huggingface dataset:
Extended spectral scaling laws for shear-Alfvén wave turbulence
Authors: Galtier S. , Chandran B. D. G.
Published: November 2006

In this paper, resonant interactions among three shear-Alfvén waves is investigated in weak incompressible magnetohydrodynamics (MHD) turbulence, neglecting interactions involving the pseudo-Alfvén waves. It is found that these interactions lead to a wave kinetic equation that has the same compact form as the full nonlinear MHD system in the highly anisotropic limit (k⊥⪢k‖). These results have important implications for interpreting the effects of resonant three-wave interactions among shear-Alfvén waves throughout k space. In particular, it shows that resonant three-wave interactions involving only shear-Alfvén waves attempt to set up a k⊥nsf(k‖) 3D shear-Alfvén-wave spectrum (with −4<ns<−2, and f an arbitrary function depending on the initial conditions). The results also provide a framework for estimating the time scale on which the three shear-Alfvén-wave interactions transfer energy to larger k⊥ everywhere in the k⊥-k‖ plane. The compatibility of the results with previous predictions and the possible astrophysical implications of these extended spectral solutions for anisotropic plasmas is discussed.
DNA confined in nanochannels: Hairpin tightening by entropic depletion
Authors: Odijk Theo
Published: November 2006

A theory is presented of the elongation of double-stranded DNA confined in a nanochannel based on a study of the formation of hairpins. A hairpin becomes constrained as it approaches the wall of a channel which leads to an entropic force causing the hairpin to tighten. The DNA in the hairpin remains double-stranded. The free energy of the hairpin is significantly larger than what one would expect if this entropic effect were unimportant. As a result, the distance between hairpins or the global persistence length is often tens of micrometer long and may even reach millimeter sizes for 10nm thin channels. The hairpin shape and size and the DNA elongation are computed for nanoslits and circular and square nanochannels. A comparison with experiment is given.
Internal rotation in some organic molecules containing methyl, amino, hydroxyl, and formyl groups
Authors: Radom L , Lathan WA , Hehre WJ , Pople JA
Published: November 2006

Ab initio molecular orbital theory is used to study internal rotation in 20
organic molecules of the types X-Y, X-CH2-Y, X-SH-Y, X-O-Y, and
X-CO-Y-where X and Y are methyl, amino, hydroxy, or formyl
groups. In some of these molecules, internal rotation about two bonds is
possible. The theoretical results are generally in moderate agreement with
available experimental data and, in addition, lead to a number of predictions
for molecules for which experimental information is lacking.
Genetic modification of somatic cells for producing animal models and for cellular transplantation
Authors: Norgren Robert B.
Published: November 2006

Great progress has been made in two technologies related to biomedical research: (1) manipulating the genomes of cells; and (2) inducing stem cells in culture to differentiate into potentially useful cell types. These technologies can be used to create animal models of human disease and to provide cells for transplantation to ameliorate human disease. Both embryonic stem cells and adult stem cells have been studied for these purposes. Genetically modified somatic cells provide another source of cells for creating animal models and for cellular transplantation.
Derivation of human embryonic stem cell lines, towards clinical quality
Authors: Hovatta Outi
Published: November 2006

Human embryonic stem (hES) cells offer an excellent source of cells for transplantation in the treatment of severe diseases. To be clinically safe, the lines have to be derived using strict quality criteria and good manufacturing practice. Animal proteins are immunogenic and may contain microbes, and they should not be used in establishing or propagating hES cells. Derivation systems have been improved towards clinical quality by establishing all 25 hES cell lines using human skin fibroblasts as feeder cells instead of mouse fibroblasts. A further 21 cell lines have been established using synthetic serum instead of fetal calf serum in the medium. In the five latest derivations, the inner cell mass was isolated mechanically instead of by immunosurgery (animal antibodies). Feeder-free derivation would be optimal, but it is not yet considered safe. Clinical-quality lines can be derived by establishing the skin fibroblast feeders in the good manufacturing practice laboratory with human serum in the medium, and by establishing the hES cells on such feeders. In this process, a serum replacement that contains only human protein can be used, the inner cell mass has to be isolated mechanically, and the colonies have to be split mechanically for passaging. Somatic cell nuclear transfer would help to overcome rejection of transplanted cells.
Genomic imprinting in primate embryos and embryonic stem cells
Authors: Mitalipov Shoukhrat M.
Published: November 2006

Embryonic stem (ES) cells hold promise for cell and tissue replacement approaches to treating human diseases. However, long-term in vitro culture and manipulations of ES cells may adversely affect their epigenetic integrity including imprinting. Disruption or inappropriate expression of imprinted genes is associated with several clinically significant syndromes and tumorigenesis in humans. We demonstrated aberrant biallelic expression of IGF2 and H19 in several rhesus monkey ES cell lines while SNRPN and NDN were normally imprinted and expressed from the paternal allele. In contrast, expanded blastocyst-stage embryos, from which these ES cells were derived, exhibited normal paternal expression of IGF2 and maternal expression of H19. To test the possibility that aberrant methylation at an imprinting centre (IC) upstream of H19 accounts for the relaxed imprinting of IGF2 and H19, we performed comprehensive methylation analysis by investigating methylation profiles of CpG sites within the IGF2/H19 IC. Our results demonstrate abnormal hypermethylation within the IGF2/H19 IC in all analysed ES cell lines consistent with biallelic expression of these genes. Cellular overproliferation and tumour formation resulting from tissue or cell transplantation are potential problems that must be addressed before clinical trials of ES cell-based therapy are initiated.
Relative blindsight in normal observers and the neural correlate of visual consciousness
Authors: Lau Hakwan C. , Passingham Richard E.
Published: November 2006

By using a paradigm based on metacontrast masking, we created experimental conditions in which the subjective report of consciousness differs but the objectively measured ability to discriminate visual targets does not. This approach allowed us to study the neural correlate of consciousness while having performance levels carefully matched in healthy human subjects. A comparison of the neural activity associated with these conditions as measured by functional MRI showed that conscious perception is associated with spatially specific activity in the mid-dorsolateral prefrontal cortex (area 46). Further analysis confirms that this activation is not only free from any performance confound, but is also not driven by differences in the timing of the physical stimuli. Our results suggest that the prefrontal cortex is important for the essentially subjective aspects of conscious perception.
A different function for a member of an ancient and highly conserved cytochrome P450 family: From essential sterols to plant defense
Authors: Qi Xiaoquan , Bakht Saleha , Qin Bo , Leggett Mike , Hemmings Andrew , Mellon Fred , Eagles John , Werck-Reichhart Daniele , Schaller Hubert , Lesot Agnes , Melton Rachel , Osbourn Anne
Published: November 2006

CYP51 sterol demethylases are the only cytochrome P450 enzymes with a conserved function across the animal, fungal, and plant kingdoms (in the synthesis of essential sterols). These highly conserved enzymes, which are important targets for cholesterol-lowering drugs, antifungal agents, and herbicides, are regarded as the most ancient member cytochrome P450 family. Here we present a report of a CYP51 enzyme that has acquired a different function. We show that the plant enzyme AsCYP51H10 is dispensable for synthesis of essential sterols and has been recruited for the production of antimicrobial compounds (avenacins) that confer disease resistance in oats. The
AsCyp51H10
gene is synonymous with
Sad2
, a gene that we previously had defined by mutation as being required for avenacin synthesis. In earlier work, we showed that
Sad1
, the gene encoding the first committed enzyme in the avenacin pathway (β-amyrin synthase), had arisen by duplication and divergence of a cycloartenol synthase-like gene. Together these data indicate an intimate evolutionary connection between the sterol and avenacin pathways.
Sad1
and
Sad2
lie within 70 kb of each other and are expressed specifically in the epidermal cells of the root tip, the site of accumulation of avenacins. These findings raise intriguing questions about the recruitment, coevolution, and regulation of the components of this specialized defense-related metabolic pathway.
NTP Workshop: Animal Models for the NTP Rodent Cancer Bioassay: Stocks and Strains—Should We Switch?
Authors: King-Herbert Angela , Thayer Kristina
Published: November 2006

The National Toxicology Program (NTP) hosted a workshop, “Animal Models for the NTP Rodent Cancer Bioassay: Strains and Stocks—Should We Switch?” on June 16–17, 2005, at the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. The workshop’s objectives were to determine (1) whether the currently used models, the F344/N rat and B6C3F1/N mouse, continue to be appropriate to identify substances that may pose a carcinogenic hazard for humans and (2) whether the NTP should consider conducting cancer bioassays using multiple strains of rats and/or mice to better capture the range of genetic variability. Workshop participants advised the NTP to discontinue using the current F344/N strain due to the recent issues with fertility, seizure activity, and chylothorax and provided several options on how the program should approach identifying and selecting a new rat model. Participants believed that the B6C3F1/N mouse is still appropriate for use by the NTP, but suggested the NTP take steps to better understand and address increases in background rates of liver tumors in this strain. Finally, the participants supported the NTP exploring the use of the multiple strain approach, although they raised many questions concerning data interpretation and feasibility. This article also outlines the NTP’s next steps in pursuing the workshop recommendations.
WHAP: haplotype-based association analysis
Authors: Purcell Shaun , Daly Mark J. , Sham Pak C.
Published: November 2006

Summary: We describe a software tool to perform haplotype-based association analysis, for quantitative and qualitative traits, in population and family samples, using single nucleotide polymorphism or multiallelic marker data. A range of tests is offered: omnibus and haplotype-specific tests; prospective and retrospective likelihoods; covariates and moderators; sliding window analyses; permutation P-values. We focus on the ability to flexibly impose constraints on haplotype effects, which allows for a range of conditional haplotype-based likelihood ratio tests: for example, whether an allele has an effect independent of its haplotypic background, or whether a single variant can explain the overall association at a locus. We illustrate using these tests to dissect a multi-locus association.

Availability: WHAP is a C/C++ program, freely available from the author's website:

Contact:  shaun@pngu.mgh.harvard.edu
The impact of high‐altitude ski‐runs on alpine grassland bird communities
Authors: ROLANDO ANTONIO , CAPRIO ENRICO , RINALDI ENRICO , ELLENA IVAN
Published: November 2006

Treeless mountainous areas at high altitudes have increased in value as wildlife habitat, but they are affected and increasingly threatened by ski‐resort developments, in particular by the construction and enlargement of ski‐pistes. To assess the extent of this threat, we compared bird diversity and community composition in circular plots centred on (i) ski‐runs of recent construction, (ii) grassland habitats adjacent to ski‐runs and (iii) natural grassland habitats far from the ski‐runs.

Plots located in natural grasslands supported the greatest bird species richness and diversity and the greatest grassland species density, whereas those set in ski‐pistes presented the lowest values. Plots located beside ski‐runs did not support smaller numbers of bird species and diversity than plots of natural areas, but they supported a significantly lower bird density. This suggests that ski‐pistes, besides exerting a negative direct effect on the structure of local bird communities, may also exert an indirect, detrimental effect on bird density in nearby patches.

Generalized linear models showed that species richness and diversity, and abundance of grassland species were best modelled by combinations of factors, including habitat type (the three categories defined above) and altitude. The category ski‐run, in particular, was negatively correlated with species richness, diversity and abundance, and altitude was negatively associated with richness and diversity.

Richness and abundance of arthropods were significantly lower in ski‐pistes than in the other plot types. Given that many invertebrates were preyed upon by birds, low food availability on ski‐runs may be one of the factors reducing the attractiveness of these patches to birds.

Synthesis and applications. Retaining the avifauna around ski‐resorts is likely to involve developing new, environmentally friendly ways of constructing pistes, such as only removing rocks and/or levelling the roughest ground surfaces, to preserve as much soil and natural vegetation as possible. Restoration of ski‐pistes should promote the recovery and maintenance of local vegetation to enhance invertebrate and bird assemblages. In order to not compromise the safety of the ski‐runs, it may be necessary to control encroaching shrubs through pruning and/or cattle grazing.
Selection for increased allocation to offspring number under environmental unpredictability
Authors: SIMONS A. M.
Published: November 2006

According to life‐history theory, the evolution of offspring size is constrained by the trade‐off between allocation of resources to individual offspring and the number of offspring produced. Existing models explore the ecological consequences of offspring size, whereas number is invariably treated simply as an outcome of the trade‐off with size. Here I ask whether there is a direct evolutionary advantage of increased allocation to offspring number under environmental unpredictability. Variable environments are expected to select for diversification in the timing of egg hatch and seed germination, yet the dependence of the expression of diversification strategies, and thus parental fitness, on offspring number has not previously been recognized. I begin by showing that well‐established sampling theory predicts that a target bet‐hedging diversification strategy is more reliably achieved as offspring number increases. I then use a simulation model to demonstrate that higher offspring number leads to greater geometric mean fitness under environmental uncertainty. Natural selection is thus expected to act directly to increase offspring number under assumptions of environmental unpredictability in season quality.
Respiratory inhibition after crying in infants
Authors: MINOWA HIDEKI , KUBO SATOMI , YOSHIZAWA HIROYUKI , HAYASHI YUKIKO , HAYASHI TAMAKI , YOSHIDA KOICHI , EBISU REIKO , UCHIDA YUMIKO , OHGITANI AYAKO
Published: November 2006

Background: Among full‐term neonates, the authors discovered infants who showed respiratory inhibition after crying which involved a marked decrease in SpO2. The infants were found to present increased echogenicity or a cyst in a cranial region termed the ganglionic eminence, or to have a subependymal cyst. The authors prospectively examined the relationship between respiratory inhibition after crying and these changes to examine the prevention and treatment of the episode.

Methods: The authors conducted cranial ultrasonography to screen 381 full‐term neonates who showed no abnormalities at birth and whose parents requested ultrasonographic screening of the head, followed by polygraphy of infants who showed increased echogenicity or a cyst in ganglionic eminence, or had a subependymal cyst. The authors similarly conducted polygraphy for 50 neonates without cranial ultrasound abnormalities; the former constituted the control group. Respiratory inhibition was defined to be central apnea immediately after crying with a decrease in SpO2 to <60%.

Results: Among 381 neonates examined, 104 showed cranial ultrasound abnormalities; 60 of the 104 neonates indicated respiratory inhibition after crying. Oxygenation failed to improve the episode in 17 neonates with severe respiratory inhibition. However, theophylline alleviated the episode, and SpO2 no longer decreased to <60%. Theophylline was discontinued successfully by 6 months after birth, while 50 neonates in the control group showed no respiratory inhibition after crying.

Conclusion: Respiratory inhibition after crying which involved a marked decrease in SpO2 was observed in full‐term neonates who showed no abnormalities after birth. These neonates could be screened by cranial ultrasonography.
Congenital malaria in Thailand, an appraisal of previous cases
Authors: WIWANITKIT VIROJ
Published: November 2006

Background: Malaria is an important vector‐borne infectious disease. Many tropical countries are the endemic area of malaria. Thailand, a tropical country in Southeast Asia, is the well‐known endemic area for malaria. Although Thailand has a high prevalence of malaria, few cases of congenital malaria were reported in the past.

Methods: Here, the author performed a literature review of the reports of congenital malaria in Thailand in order to summarize the characteristics of this infection among Thai patients.

Results: According to this study, there have been at least six reports in the literature of 27 cases of congenital malaria infection in the Thai population, of which no case was lethal. There were 22 vivax (81.5%) and five falciparum (18.5%) malarial cases. The details on clinical presentations of these cases are presented and discussed.

Conclusion: According to this study, it can be seen that congenital malaria may occur in the absence of clinical symptoms in mothers as well as their children. Concerning the species of malaria, the vivax malaria is more common in this case series.
Formation of the indigo precursor indican in genetically engineered tobacco plants and cell cultures
Authors: Warzecha Heribert , Frank Andreas , Peer Markus , Gillam Elizabeth M.J. , Guengerich F. Peter , Unger Matthias
Published: November 2006

The production of the blue dye indigo in plants has been assumed to be a possible route to the introduction of novel coloration into flowers or fibres. As the human cytochrome P450 mono‐oxygenase 2A6 (CYP2A6) can form indigo in bacterial cultures, we investigated whether the expression of the corresponding cDNA in transgenic plants could lead to indigo formation. In a first attempt, we generated tobacco cell suspension cultures expressing the cDNA encoding human CYP2A6. Supplementation of the medium with indole led to the generation of indican (3‐hydroxyindole‐β‐d‐glucoside), a metabolite usually exclusively present in indigoferous dye plants. Hence, the recombinant CYP2A6 converted indole to the reactive metabolite 3‐hydroxyindole (indoxyl), whereas rapid glucosylation is obviously conducted by ubiquitous plant glucosyl transferases (GTs). Interestingly, of nine additionally tested plant cell suspension cultures from various plant families, five were also capable of the formation of indican after indole supplementation, although this metabolism was more pronounced in transgenic tobacco cell suspension cultures expressing CYP2A6 cDNA. To evaluate whether indican or even indigo could be produced in whole plants, we generated transgenic tobacco plants harbouring active CYP2A6 together with an indole synthase (BX1) from maize. The genetically engineered tobacco plants accumulated indican, but did not develop a blue coloration. Although the de novo formation of indican in transgenic tobacco plants hampered indigo formation, it supports the contention that biosynthetic pathways can be efficiently mimicked by metabolic engineering.
Point Cloud to CAD Model Registration Methods in Manufacturing Inspection
Authors: Tucker Thomas M. , Kurfess Thomas R.
Published: November 2006

Modern computer vision and coordinate metrology systems provide an ever-increasing flow of information from the physical world we live in to the virtual world inside computer systems. Often the coordinate system of the metrology device has a different coordinate frame from that of the existing objects in the virtual world. To rectify these differences, a process called registration is often applied. This paper uses a case study to highlight the differences between various registration techniques.
Reverse Engineering Methods for Digital Restoration
Applications
Authors: Boier-Martin Ioana , Rushmeier Holly
Published: November 2006

In this paper we discuss the challenges of processing and converting 3D scanned data to representations suitable for interactive manipulation in the context of virtual restoration applications. We present a constrained parametrization approach that allows us to represent 3D scanned models as parametric surfaces defined over polyhedral domains. A combination of normal- and spatial-based clustering techniques is used to generate a partition of the model into regions suitable for parametrization. Constraints can be optionally imposed to enforce a strict correspondence between input and output features. We consider two types of virtual restoration methods: (a) a paint restoration method that takes advantage of the normal-based coarse partition to identify large regions of reduced metric distortion suitable for texture mapping and (b) a shape restoration approach that relies on a refined partition used to convert the input model to a multiresolution subdivision representation suitable for intuitive interactive manipulation during digital studies of historical artifacts.
Digital Photogrammetry for Facial Recognition
Authors: Galantucci L. M. , Ferrandes R. , Percoco G.
Published: November 2006

In this paper, the authors present a biometric low-cost 3D acquisition system, based on a digital photogrammetry technique. The aim of the work is to analyze the suitability of this system for facial recognition purposes. The facial data of a set of 20 people were acquired with the photogrammetric system developed by the authors, and different CAD 3D models were reconstructed for each person. The results are quantified by aligning the models and calculating mean distances and standard deviations between them using two different methods. The former considers the entire face; the latter is based on a few fiducial points of the face.
Nanosized particles in bone and dissolution insensitivity of bone mineral
Authors: Wang Lijun , Nancollas George H. , Henneman Zachary J. , Klein Eugenia , Weiner Steve
Published: November 2006

Most of the mineral crystals in bone are platelets of carbonated apatite with thicknesses of a few nanometers embedded in a collagen matrix.We report that spherical to cylindrical shaped nanosized particles are also an integral part of bone structure observed by high resolution scanning electron microscopy. High resolution back scattered electron imaging reveals that the spherical particles have a contrast similar to the crystal platelets, suggesting that they are thus likely to have similar mineral properties. By means of constant composition (CC) dissolution of bone, similar sized nanoparticles are shown to be insensitive to demineralization and are thought to be dynamically stabilized due to the absence of active pits/defects on the crystallite surfaces. Similar reproducible self-inhibited dissolution was observed with these nanoparticles during CC dissolution of synthetic carbonated apatite. This result rules out the possible influence of complicating biological factors such as the possible presence of organic matrix components and other impurities. This phenomenon can be explained by a unique dissolution model involving size considerations at the nanoscale. The unexpected presence of nanoparticles in mature bone may also be due to the stabilization of some nanosized particles during the formation process in a fluctuating biological milieux.
Understanding stable levitation of superconductors from intermediate electromagnetics
Authors: Badía-Majós A.
Published: November 2006

Levitation experiments with superconductors in the Meissner state are hindered by low stability except for specifically designed configurations. In contrast, magnetic force experiments with strongly pinned superconductors and permanent magnets display high stability, allowing the demonstration of striking effects, such as lateral or inverted levitation. These facts are explained by using a variational theory. Illustrations based on calculated magnetic field lines for various configurations are presented. They provide a qualitative physical understanding of the stability features.
Molecular Mechanism of a Thumb Domain Hepatitis C Virus Nonnucleoside RNA-Dependent RNA Polymerase Inhibitor
Authors: Howe Anita Y. M. , Cheng Huiming , Thompson Ian , Chunduru Srinivas K. , Herrmann Steve , O'Connell John , Agarwal Atul , Chopra Rajiv , Del Vecchio Alfred M.
Published: November 2006

A new pyranoindole class of small-molecule inhibitors was studied to understand viral resistance and elucidate the mechanism of inhibition in hepatitis C virus (HCV) replication. HCV replicon variants less susceptible to inhibition by the pyranoindoles were selected in Huh-7 hepatoma cells. Variant replicons contained clusters of mutations in the NS5B polymerase gene corresponding to the drug-binding pocket on the surface of the thumb domain identified by X-ray crystallography. An additional cluster of mutations present in part of a unique β-hairpin loop was also identified. The mutations were characterized by using recombinant replicon variants engineered with the corresponding amino acid substitutions. A single mutation (L419M or M423V), located at the pyranoindole-binding site, resulted in an 8- to 10-fold more resistant replicon, while a combination mutant (T19P, M71V, A338V, M423V, A442T) showed a 17-fold increase in drug resistance. The results of a competition experiment with purified NS5B enzyme with GTP showed that the inhibitory activity of the pyranoindole inhibitor was not affected by GTP at concentrations up to 250 μM. Following de novo initiation, the presence of a pyranoindole inhibitor resulted in the accumulation of a five-nucleotide oligomer, with a concomitant decrease in higher-molecular-weight products. The results of these studies have confirmed that pyranoindoles target the NS5B polymerase through interactions at the thumb domain. This inhibition is independent of GTP concentrations and is likely mediated by an allosteric blockade introduced by the inhibitor during the transition to RNA elongation after the formation of an initiation complex.
General Catalytic Deficiency of Hepatitis C Virus RNA Polymerase with an S282T Mutation and Mutually Exclusive Resistance towards 2′-Modified Nucleotide Analogues
Authors: Dutartre Hélène , Bussetta Cécile , Boretto Joëlle , Canard Bruno
Published: November 2006

The hepatitis C virus (HCV) RNA-dependent RNA polymerase NS5B is an important target for antiviral therapies. NS5B is able to initiate viral RNA synthesis de novo and then switch to a fast and processive RNA elongation synthesis mode. The nucleotide analogue 2′-
C
-methyl CTP (2′-
C
-Me-CTP) is the active metabolite of NM283, a drug currently in clinical phase II trials. The resistance mutation S282T can be selected in HCV replicon studies. Likewise, 2′-
O
-Me nucleotides are active both against the purified polymerase and in replicon studies. We have determined the molecular mechanism by which the S282T mutation confers resistance to 2′-modified nucleotide analogues. 2′-
C
-Me-CTP is no longer incorporated during the initiation step of RNA synthesis and is discriminated 21-fold during RNA elongation by the NS5B S282T mutant. Strikingly, 2′-
O
-methyl CTP sensitivity does not change during initiation, but the analogue is no longer incorporated during elongation. This mutually exclusive resistance mechanism suggests not only that “2′-conformer” analogues target distinct steps in RNA synthesis but also that these analogues have interesting potential in combination therapies. In addition, the presence of the S282T mutation induces a general cost in terms of polymerase efficiency that may translate to decreased viral fitness: natural nucleotides become 5- to 20-fold less efficiently incorporated into RNA by the NS5B S282T mutant. As in the case for human immunodeficiency virus, our results might provide a mechanistic basis for the rational combination of drugs for low-fitness viruses.
Biocompatibility of Solid-Dosage Forms of Anti-Human Immunodeficiency Virus Type 1 Microbicides with the Human Cervicovaginal Mucosa Modeled Ex Vivo
Authors: Trifonova Radiana T. , Pasicznyk Jenna-Malia , Fichorova Raina N.
Published: November 2006

Topical anti-human immunodeficiency virus (HIV) microbicides are being sought to reduce the spread of HIV type 1 (HIV-1) during sexual intercourse. The success of this strategy depends upon the selection of formulations compatible with the natural vaginal mucosal barrier. This study applied ex vivo-modeled human cervicovaginal epithelium to evaluate experimental solid-dosage forms of the anti-HIV-1 microbicide cellulose acetate 1,2-benzenedicarboxylate (CAP) and over-the-counter (OTC) vaginal products for their impact on inflammatory mediators regarded as potential HIV-1-enhancing risk factors. We assessed product-induced imbalances between interleukin-1α (IL-1α) and IL-1β and the natural IL-1 receptor antagonist (IL-1RA) and changes in levels of IL-6, tumor necrosis factor alpha, IL-8, gamma interferon inducible protein 10 (IP-10), and macrophage inflammatory protein 3α (MIP-3α), known to recruit and activate monocytes, dendritic cells, and T cells to the inflamed mucosa. CAP film and gel formulation, similarly to the hydroxyethylcellulose universal vaginal placebo gel and the OTC K-Y moisturizing gel, were nontoxic and caused no significant changes in any inflammatory biomarker. In contrast, OTC vaginal cleansing and contraceptive films containing octoxynol-9 or nonoxynol-9 (N-9) demonstrated similar levels of toxicity but distinct immunoinflammatory profiles. IL-1α, IL-1β, IL-8, and IP-10 were increased after treatment with both OTC vaginal cleansing and contraceptive films; however, MIP-3α was significantly elevated by the N-9-based film only (P< 0.01). Although both films increased extracellular IL-1RA, the cleansing film only significantly elevated the IL-1RA/IL-1 ratio (P< 0.001). The N-9-based film decreased intracellular IL-1RA (P< 0.05), which has anti-inflammatory intracrine functions. This study identifies immunoinflammatory biomarkers that can discriminate between formulations better than toxicity assays and should be clinically validated in relevance to the risk of HIV-1 acquisition.
Prevalence of
Trichomonas vaginalis
Isolates with Resistance to Metronidazole and Tinidazole
Authors: Schwebke Jane R. , Barrientes Frank J.
Published: November 2006

Clinical isolates of
Trichomonas vaginalis
were obtained from women consecutively enrolled in a study of partner notification. Testing of susceptibility to metronidazole and tinidazole was performed. Resistance to metronidazole and tinidazole was present in 17/178 (9.6%) and 1/178 (0.56%) strains, respectively. In vitro resistance was poorly correlated with clinical response to treatment.
Functional Analysis of DNA Gyrase Mutant Enzymes Carrying Mutations at Position 88 in the A Subunit Found in Clinical Strains of
Mycobacterium tuberculosis
Resistant to Fluoroquinolones
Authors: Matrat Stéphanie , Veziris Nicolas , Mayer Claudine , Jarlier Vincent , Truffot-Pernot Chantal , Camuset Juliette , Bouvet Elisabeth , Cambau Emmanuelle , Aubry Alexandra
Published: November 2006

We investigated the enzymatic efficiency and inhibition by quinolones of
Mycobacterium tuberculosis
DNA gyrases carrying the previously described GyrA G88C mutation and the novel GyrA G88A mutation harbored by two multidrug-resistant clinical strains and reproduced by site-directed mutagenesis. Fluoroquinolone MICs and 50% inhibitory concentrations for both mutants were 2- to 43-fold higher than for the wild type, demonstrating that these mutations confer fluoroquinolone resistance in
M. tuberculosis
.
Activity of DX-619 Compared to Other Agents against Viridans Group Streptococci,
Streptococcus bovis
, and
Cardiobacterium hominis
Authors: Kosowska-Shick Klaudia , Smith Kathy , Bogdanovich Tatiana , Ednie Lois M. , Jones Ronald N. , Appelbaum Peter C.
Published: November 2006

Against 198 viridans group streptococci, 25
Streptococcus bovis
strains, and 5
Cardiobacterium hominis
strains, MICs of DX-619, a des-F(6)-quinolone, were between 0.004 and 0.25 μg/ml. These MICs were lower than those of other quinolones (≤0.008 to >32 μg/ml). β-Lactam MICs were between ≤0.008 and 16 μg/ml. Azithromycin resistance was found in most species, while most were telithromycin susceptible. Glycopeptides and linezolid were active against viridans group strains but inactive against
C. hominis
.
Diversity of
Archaea
in Marine Sediments from Skan Bay, Alaska, Including Cultivated Methanogens, and Description of
Methanogenium boonei
sp. nov
Authors: Kendall Melissa M. , Wardlaw George D. , Tang Chin F. , Bonin Adam S. , Liu Yitai , Valentine David L.
Published: November 2006

Methanogenesis in cold marine sediments is a globally important process leading to methane hydrate deposits, cold seeps, physical instability of sediment, and atmospheric methane emissions. We employed a multidisciplinary approach that combined culture-dependent and -independent analyses with geochemical measurements in the sediments of Skan Bay, Alaska (53°N, 167°W), to investigate methanogenesis there. Cultivation-independent analyses of the archaeal community revealed that uncultivated microbes of the kingdoms
Euryarchaeota
and
Crenarchaeota
are present at Skan Bay and that methanogens constituted a small proportion of the archaeal community. Methanogens were cultivated from depths of 0 to 60 cm in the sediments, and several strains related to the orders
Methanomicrobiales
and
Methanosarcinales
were isolated. Isolates were psychrotolerant marine-adapted strains and included an aceticlastic methanogen, strain AK-6, as well as three strains of CO
2
-reducing methanogens: AK-3, AK7, and AK-8. The phylogenetic positions and physiological characteristics of these strains are described. We propose a new species,
Methanogenium boonei
, with strain AK-7 as the type strain.
A Genomic Island of the Pathogen
Leptospira interrogans
Serovar Lai Can Excise from Its Chromosome
Authors: Bourhy Pascale , Salaün Laurence , Lajus Aurélie , Médigue Claudine , Boursaux-Eude Caroline , Picardeau Mathieu
Published: November 2006

An examination of the two
Leptospira interrogans
genomes sequenced so far reveals few genetic differences, including an extra DNA region, 54 kb in length, in
L. interrogans
serovar Lai. This locus contains 103 predicted coding sequences that are absent from the genome of
L. interrogans
serovar Copenhageni, of which only 20% had significant BLASTP hits in GenBank. By analyzing the
L. interrogans
serovar Lai genome by pulsed-field gel electrophoresis, we also found that this 54-kb DNA fragment exists as a circular plasmid. This was confirmed by amplification of a DNA fragment corresponding to that of the predicted fragment if this region excised from the chromosome and its left and right ends joined together. In addition, cloning of the putative
rep
gene of this DNA region was responsible for autonomous replication in
Leptospira
spp., therefore generating a new
Escherichia coli-Leptospira
sp. shuttle vector. Taken together, our results show that this genomic island can excise from the chromosome and form a replicative plasmid. Analysis of the distribution of this genomic island revealed that highly related sequences exist in other
L. interrogans
virulent strains. This genomic island, containing a high proportion of novel genes, may have an important role in spreading genes, including virulence factors, among bacterial populations.
Intranasal Vaccination with a Secreted Chlamydial Protein Enhances Resolution of GenitalChlamydia muridarumInfection, Protects against Oviduct Pathology, and Is Highly Dependent upon Endogenous Gamma Interferon Production
Authors: Murthy Ashlesh K. , Chambers James P. , Meier Patricia A. , Zhong Guangming , Arulanandam Bernard P.
Published: November 2006

There is currently no licensed vaccine againstChlamydia trachomatis, the leading cause of sexually transmitted bacterial disease worldwide. Conventional vaccination attempts using surface-exposed chlamydial antigens have achieved only partial success. We have employed a novel vaccination strategy using a secreted protein, chlamydial protease-like activity factor (CPAF), which has been shown to degrade host major histocompatibility complex transcription factors and keratin-8 and therefore may allow immune evasion and establishment of a productive infection. Intranasal immunization using recombinant CPAF (rCPAF) plus interleukin-12 (IL-12) (rCPAF+IL-12 immunization) was used to assess the protective immunity against genitalChlamydia muridaruminfection in BALB/c mice. rCPAF+IL-12 immunization induced robust gamma interferon (IFN-γ) production and minimal IL-4 production by splenocytes upon in vitro recall with rCPAF. The total and immunoglobulin G2a (IgG2a) anti-rCPAF antibody levels in serum were significantly elevated after rCPAF+IL-12 vaccination, as were the total antibody, IgG2a, and IgA levels in bronchoalveolar lavage and vaginal fluids when the animals were compared to animals that received rCPAF alone. rCPAF+IL-12-vaccinated mice displayed significantly reduced bacterial shedding upon chlamydial challenge and accelerated resolution of infection compared to mock-immunized (phosphate-buffered saline) animals. Moreover, rCPAF+IL-12-immunized animals exhibited protection against pathological consequences of chlamydial infection, including the development of hydrosalpinx and oviduct dilatation. This vaccination regimen also reduced the development of fibrosis and the influx of neutrophils into the upper genital tract when the animals were compared to mock-immunized (phosphate-buffered saline) animals after bacterial challenge. rCPAF+IL-12-mediated resolution of the bacterial infection and protection againstChlamydia-induced inflammatory disease were highly dependent on endogenous IFN-γ production. Together, these results demonstrate that secreted chlamydial antigens may be novel vaccine candidates to induce protective immunity.
Mechanisms of blood pressure and heart rate variability: an insight from low-level paraplegia
Authors: Castiglioni Paolo , Di Rienzo Marco , Veicsteinas Arsenio , Parati Gianfranco , Merati Giampiero
Published: November 2006

It is still unclear whether the low-frequency oscillation in heart rate is generated by an endogenous neural oscillator or by a baroreflex resonance. Our aim was to investigate this issue by analyzing blood pressure and heart rate variability and the baroreflex function in paraplegic subjects with spinal cord injury below the fourth thoracic vertebra. These subjects were selected because they represent a model of intact central neural drive to the heart, with a partially impaired autonomic control of the vessels. In our study, arterial blood pressure and ECG were recorded in 33 able-bodied controls and in 33 subjects with spinal cord lesions between the fifth thoracic and the fourth lumbar vertebra 1) during supine rest (lowest sympathetic activation), 2) sitting on a wheelchair (light sympathetic activation), and 3) during exercise (moderate sympathetic activation). Blood pressure and heart rate spectra, coherence, and baroreflex function (sequence technique) were estimated in each condition. Compared with controls, paraplegic subjects showed a reduction of the low-frequency power of blood pressure and heart rate, and, unlike controls, a 0.1-Hz peak did not appear in their spectra. Sympathetic activation increased the 0.1-Hz peak of blood pressure and heart rate and the coherence at 0.1 Hz in controls only. Paraplegic subjects also had significantly lower baroreflex effectiveness and greater blood pressure variability. In conclusion, the disappearance of the 10-s oscillation of heart rate and blood pressure in subjects with spinal cord lesion supports the hypothesis of the baroreflex nature of this phenomenon.
Altered Cardiac Myocyte Ca Regulation In Heart Failure
Authors: Bers Donald M.
Published: November 2006

Ca is critical in both the electrical and mechanical properties of cardiac myocytes, and much is known about ionic currents and the normal excitation-contraction coupling process. In heart failure, there are significant alterations in how myocyte Ca is regulated, and these alterations are critical in dictating both contractile dysfunction and certain cardiac arrhythmias that are characteristic of heart failure.
SIRT1: Linking Adaptive Cellular Responses to Aging-Associated Changes in Organismal Physiology
Authors: Anastasiou Dimitrios , Krek Wilhelm
Published: November 2006

Sirtuins comprise a family of enzymes implicated in the determination of organismal life span in yeast and the nematode. The mammalian sirtuin SIRT1 has been shown to deacetylate several proteins in an NAD+-dependent manner. SIRT1 substrates are involved in the regulation of apoptosis/cell survival, endocrine signaling, differentiation, chromatin remodeling, and transcription. Thus SIRT1 provides a molecular link between nutrient availability and adaptive transcriptional responses. This review presents current evidence as to how SIRT1 functions are relevant to changes in tissue physiology that occur with ageing and its implications for future pharmacological intervention to alleviate such degenerative processes.
Lipid Rafts, Detergent-Resistant Membranes, and Raft Targeting Signals
Authors: Brown Deborah A.
Published: November 2006

Lipid rafts are liquid-ordered (lo) phase microdomains proposed to exist in biological membranes. Rafts have been widely studied by isolating lo-phase detergent-resistant membranes (DRMs) from cells. Recent findings have shown that DRMs are not the same as preexisting rafts, prompting a major revision of the raft model. Nevertheless, raft-targeting signals identified by DRM analysis are often required for protein function, implicating rafts in a variety of cell processes.
Combined Transcriptional and Translational Targeting of EWS/FLI-1 in Ewing's Sarcoma
Authors: Mateo-Lozano Silvia , Gokhale Prafulla C. , Soldatenkov Viatcheslav A. , Dritschilo Anatoly , Tirado Oscar M. , Notario Vicente
Published: November 2006

Purpose: To show the efficacy of targeting EWS/FLI-1 expression with a combination of specific antisense oligonucleotides and rapamycin for the control of Ewing's sarcoma (EWS) cell proliferation in vitro and the treatment of mouse tumor xenografts in vivo.

Experimental Design: EWS cells were simultaneously exposed to EWS/FLI-1–specific antisense oligonucleotides and rapamycin for various time periods. After treatment, the following end points were monitored and evaluated: expression levels of the EWS/FLI-1 protein, cell proliferation, cell cycle distribution, apoptotic cell death, caspase activation, and tumor growth in EWS xenografts implanted in nude mice.

Results: Simultaneous exposure of EWS cells in culture to an EWS/FLI-1–targeted suppression therapy using specific antisense oligonucleotides and rapamycin resulted in the activation of a caspase-dependent apoptotic process that involved the restoration of the transforming growth factor-β–induced proapoptotic pathway. In vivo, individual administration of either antisense oligonucleotides or rapamycin significantly delayed tumor development, and the combined treatment with antisense oligonucleotides and rapamycin caused a considerably stronger inhibition of tumor growth.

Conclusions: Concurrent administration of EWS/FLI-1 antisense oligonucleotides and rapamycin efficiently induced the apoptotic death of EWS cells in culture through a process involving transforming growth factor-β. In vivo experiments conclusively showed that the combined treatment with antisense oligonucleotides and rapamycin caused a significant inhibition of tumor growth in mice. These results provide proof of principle for further exploration of the potential of this combined therapeutic modality as a novel strategy for the treatment of tumors of the Ewing's sarcoma family.
Loss of Breast Cancer Metastasis Suppressor 1 Protein Expression Predicts Reduced Disease-Free Survival in Subsets of Breast Cancer Patients
Authors: Hicks David G. , Yoder Brian J. , Short Sarah , Tarr Shannon , Prescott Nichole , Crowe Joseph P. , Dawson Andrea E. , Budd G. Thomas , Sizemore Steven , Cicek Muzaffer , Choueiri Toni K. , Tubbs Raymond R. , Gaile Daniel , Nowak Norma , Accavitti-Loper Mary Ann , Frost Andra R. , Welch Danny R. , Casey Graham
Published: November 2006

Purpose: This study aims to determine the effect of loss of breast cancer metastasis suppressor 1 (BRMS1) protein expression on disease-free survival in breast cancer patients stratified by estrogen receptor (ER), progesterone receptor (PR), or HER2 status, and to determine whether loss of BRMS1 protein expression correlated with genomic copy number changes.

Experimental Design: A tissue microarray immunohistochemical analysis was done on tumors of 238 newly diagnosed breast cancer patients who underwent surgery at the Cleveland Clinic between January 1, 1995 and December 31, 1996, and a comparison was made with 5-year clinical follow-up data. Genomic copy number changes were determined by array-based comparative genomic hybridization in 47 breast cancer cases from this population and compared with BRMS1 staining.

Results: BRMS1 protein expression was lost in nearly 25% of cases. Patients with tumors that were PR negative (P = 0.006) or HER2 positive (P = 0.039) and <50 years old at diagnosis (P = 0.02) were more likely to be BRMS1 negative. No overall correlation between BRMS1 staining and disease-free survival was observed. A significant correlation, however, was seen between loss of BRMS1 protein expression and reduced disease-free survival when stratified by either loss of ER (P = 0.008) or PR (P = 0.029) or HER2 overexpression (P = 0.026). Overall, there was poor correlation between BRMS1 protein staining and copy number status.

Conclusions: These data suggest a mechanistic relationship between BRMS1 expression, hormone receptor status, and HER2 growth factor. BRMS1 staining could potentially be used in patient stratification in conjunction with other prognostic markers. Further, mechanisms other than genomic deletion account for loss of BRMS1 gene expression in breast tumors.