bluuebunny/crossref_metadata_2025 huggingface dataset:
Metabolic basis for the differential susceptibility of Gram-positive pathogens to fatty acid synthesis inhibitors
Authors: Parsons Joshua B. , Frank Matthew W. , Subramanian Chitra , Saenkham Panatda , Rock Charles O.
Published: August 2011

The rationale for the pursuit of bacterial type 2 fatty acid synthesis (FASII) as a target for antibacterial drug discovery in Gram-positive organisms is being debated vigorously based on their ability to incorporate extracellular fatty acids. The regulation of FASII by extracellular fatty acids was examined in
Staphylococcus aureus
and
Streptococcus pneumoniae
, representing two important groups of pathogens. Both bacteria use the same enzymatic tool kit for the conversion of extracellular fatty acids to acyl-acyl carrier protein, elongation, and incorporation into phospholipids. Exogenous fatty acids completely replace the endogenous fatty acids in
S. pneumoniae
but support only 50% of phospholipid synthesis in
S. aureus
. Fatty acids overcame FASII inhibition in
S. pneumoniae
but not in
S. aureus
. Extracellular fatty acids strongly suppress malonyl-CoA levels in
S. pneumoniae
but not in
S. aureus
, showing a feedback regulatory system in
S. pneumoniae
that is absent in
S. aureus
. Fatty acids overcame either a biochemical or a genetic block at acetyl-CoA carboxylase (ACC) in
S. aureus
, confirming that regulation at the ACC step is the key difference between these two species. Bacteria that possess a stringent biochemical feedback inhibition of ACC and malonyl-CoA formation triggered by environmental fatty acids are able to circumvent FASII inhibition. However, if exogenous fatty acids do not suppress malonyl-CoA formation, FASII inhibitors remain effective in the presence of fatty acid supplements.
Large collective motions regulate the functional properties of glutamate transporter trimers
Authors: Jiang Jie , Shrivastava Indira H. , Watts Spencer D. , Bahar Ivet , Amara Susan G.
Published: August 2011

Glutamate transporters clear synaptically released glutamate to maintain precise communication between neurons and limit glutamate neurotoxicity. Although much progress has been made on the topology, structure, and function of these carriers, few studies have addressed large-scale structural motions collectively associated with substrate transport. Here we show that a series of single cysteine substitutions in the helical hairpin HP2 of excitatory amino acid transporter 1 form intersubunit disulfide cross-links within the trimer. After cross-linking, substrate uptake, but not substrate-activated anion conductance, is completely inhibited in these mutants. These disulfide bridges link residue pairs > 40 
Å
apart in the outward-facing crystal structure, and can be explained by concerted subunit movements predicted by the anisotropic network model (ANM). The existence of these global motions is further supported by the observation that single cysteine substitutions at the extracellular part of the transmembrane domain 8 can also be cross-linked by copper phenanthroline as predicted by the ANM. Interestingly, the transport domain in the un-cross-linked subunit of the trimer assumes an inward-facing orientation, suggesting that individual subunits potentially undergo separate transitions between outward- and inward-facing forms, rather than an all-or-none transition of the three subunits, a mechanism also supported by ANM-predicted intrinsic dynamics. These results shed light on how large collective motions contribute to the functional dynamics of glutamate transporters.
Differentiation-dependent functional and epigenetic landscapes for cytokine genes in virus-specific CD8+T cells
Authors: Denton Alice E. , Russ Brendan E. , Doherty Peter C. , Rao Sudha , Turner Stephen J.
Published: August 2011

Although the simultaneous engagement of multiple effector mechanisms is thought to characterize optimal CD8+T-cell immunity and facilitate pathogen clearance, the differentiation pathways leading to the acquisition and maintenance of such polyfunctional activity are not well understood. Division-dependent profiles of effector molecule expression for virus-specific T cells are analyzed here by using a combination of carboxyfluorescein succinimidyl ester dilution and intracellular cytokine staining subsequent to T-cell receptor ligation. The experiments show that, although the majority of naive CD8+T-cell precursors are preprogrammed to produce TNF-α soon after stimulation and a proportion make both TNF-α and IL-2, the progressive acquisition of IFN-γ expression depends on continued lymphocyte proliferation. Furthermore, the extensive division characteristic of differentiation to peak effector activity is associated with the progressive dominance of IFN-γ and the concomitant loss of polyfunctional cytokine production, although this is not apparent for long-term CD8+T-cell memory. Such proliferation-dependent variation in cytokine production appears tied to the epigenetic signatures within theifnGandtnfAproximal promoters. Specifically, those cytokine gene loci that are rapidly expressed following antigen stimulation at different stages of T-cell differentiation can be shown (by ChIP) to have permissive epigenetic and RNA polymerase II docking signatures. Thus, the dynamic changes in cytokine profiles for naive, effector, and memory T cells are underpinned by specific epigenetic landscapes that regulate responsiveness following T-cell receptor ligation.
Quantitative lipid composition of cell envelopes of
Corynebacterium glutamicum
elucidated through reverse micelle extraction
Authors: Bansal-Mutalik Ritu , Nikaido Hiroshi
Published: August 2011

Cells of the
Corynebacterium-Nocardia-Mycobacterium
group of bacteria are surrounded by an outer membrane (OM) containing mycolic acids that are covalently linked to the underlying arabinogalactan-peptidoglycan complex. This OM presumably acts as a permeability barrier that imparts high levels of intrinsic drug resistance to some members of this group, such as
Mycobacterium tuberculosis
, and its component lipids have been studied intensively in a qualitative manner over the years. However, the quantitative lipid composition of this membrane has remained obscure, mainly because of difficulties in isolating it without contamination from the inner cytoplasmic membrane. Here we use the extraction, with reverse surfactant micelles, of intact cells of
Corynebacterium glutamicum
and show that this method extracts the free OM lipids quantitatively with no contamination from lipids of the cytoplasmic membrane, such as phosphatidylglycerol. Although only small amounts of corynomycolate were esterified to arabinogalactan, a large amount of cardiolipin was present in a nonextractable form, tightly associated, possibly covalently, with the peptidoglycan-arabinogalactan complex. Furthermore, we show that the OM contains just enough lipid hydrocarbons to produce a bilayer covering the cell surface, with its inner leaflet composed mainly of the aforementioned nonextractable cardiolipin and its outer leaflet composed of trehalose dimycolates, phosphatidylinositol mannosides, and highly apolar lipids, similar to the Minnikin model of 1982. The reverse micelle extraction method is also useful for extracting proteins associated with the OM, such as porins.
Budding yeast star in their own biofilm
Authors: Short Ben
Published: August 2011

Study describes the multicellular, differentiated structures formed by wild strains of S. cerevisiae.
Epigenetic displacement of HP1 from heterochromatin by HIV-1 Vpr causes premature sister chromatid separation
Authors: Shimura Mari , Toyoda Yusuke , Iijima Kenta , Kinomoto Masanobu , Tokunaga Kenzo , Yoda Kinya , Yanagida Mitsuhiro , Sata Tetsutaro , Ishizaka Yukihito
Published: August 2011

Although pericentromeric heterochromatin is essential for chromosome segregation, its role in humans remains controversial. Dissecting the function of HIV-1–encoded Vpr, we unraveled important properties of heterochromatin during chromosome segregation. In Vpr-expressing cells, hRad21, hSgo1, and hMis12, which are crucial for proper chromosome segregation, were displaced from the centromeres of mitotic chromosomes, resulting in premature chromatid separation (PCS). Interestingly, Vpr displaced heterochromatin protein 1-α (HP1-α) and HP1-γ from chromatin. RNA interference (RNAi) experiments revealed that down-regulation of HP1-α and/or HP1-γ induced PCS, concomitant with the displacement of hRad21. Notably, Vpr stimulated the acetylation of histone H3, whereas p300 RNAi attenuated the Vpr-induced displacement of HP1-α and PCS. Furthermore, Vpr bound to p300 that was present in insoluble regions of the nucleus, suggesting that Vpr aberrantly recruits the histone acetyltransferase activity of p300 to chromatin, displaces HP1-α, and causes chromatid cohesion defects. Our study reveals for the first time centromere cohesion impairment resulting from epigenetic disruption of higher-order structures of heterochromatin by a viral pathogen.
Flo11p, drug efflux pumps, and the extracellular matrix cooperate to form biofilm yeast colonies
Authors: Váchová Libuše , Šťovíček Vratislav , Hlaváček Otakar , Chernyavskiy Oleksandr , Štěpánek Luděk , Kubínová Lucie , Palková Zdena
Published: August 2011

Much like other microorganisms, wild yeasts preferentially form surface-associated communities, such as biofilms and colonies, that are well protected against hostile environments and, when growing as pathogens, against the host immune system. However, the molecular mechanisms underlying the spatiotemporal development and environmental resistance of biofilms and colonies remain largely unknown. In this paper, we show that a biofilm yeast colony is a finely tuned, complex multicellular organism in which specialized cells jointly execute multiple protection strategies. These include a Pdr1p-regulated mechanism whereby multidrug resistance transporters Pdr5p and Snq2p expel external compounds solely within the surface cell layers as well as developmentally regulated production by internal cells of a selectively permeable extracellular matrix. The two mechanisms act in concert during colony development, allowing growth of new cell generations in a well-protected internal cavity of the colony. Colony architecture is strengthened by intercellular fiber connections.
Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway
Authors: Viatour Patrick , Ehmer Ursula , Saddic Louis A. , Dorrell Craig , Andersen Jesper B. , Lin Chenwei , Zmoos Anne-Flore , Mazur Pawel K. , Schaffer Bethany E. , Ostermeier Austin , Vogel Hannes , Sylvester Karl G. , Thorgeirsson Snorri S. , Grompe Markus , Sage Julien
Published: August 2011

Hepatocellular carcinoma (HCC) is the third cancer killer worldwide with >600,000 deaths every year. Although the major risk factors are known, therapeutic options in patients remain limited in part because of our incomplete understanding of the cellular and molecular mechanisms influencing HCC development. Evidence indicates that the retinoblastoma (RB) pathway is functionally inactivated in most cases of HCC by genetic, epigenetic, and/or viral mechanisms. To investigate the functional relevance of this observation, we inactivated the RB pathway in the liver of adult mice by deleting the three members of the Rb (Rb1) gene family: Rb, p107, and p130. Rb family triple knockout mice develop liver tumors with histopathological features and gene expression profiles similar to human HCC. In this mouse model, cancer initiation is associated with the specific expansion of populations of liver stem/progenitor cells, indicating that the RB pathway may prevent HCC development by maintaining the quiescence of adult liver progenitor cells. In addition, we show that during tumor progression, activation of the Notch pathway via E2F transcription factors serves as a negative feedback mechanism to slow HCC growth. The level of Notch activity is also able to predict survival of HCC patients, suggesting novel means to diagnose and treat HCC.
RNA PROCESSING FACTOR3 Is Crucial for the Accumulation of MatureccmCTranscripts in Mitochondria of Arabidopsis Accession Columbia
Authors: Jonietz Christian , Forner Joachim , Hildebrandt Tatjana , Binder Stefan
Published: August 2011

RNA PROCESSING FACTOR1 (RPF1) and RPF2 are pentatricopeptide repeat (PPR) proteins involved in 5′ processing of different mitochondrial mRNAs in Arabidopsis (Arabidopsis thaliana). Both factors are highly similar to RESTORERS OF FERTILITY (RF), which are part of cytoplasmic male sterility/restoration systems in various plant species. These findings suggest a predominant role of RF-like PPR proteins in posttranscriptional 5′ processing. To further explore the functions of this group of proteins, we examined a number of T-DNA lines carrying insertions in the corresponding PPR genes. This screening identified a nearly complete absence of mature ccmC transcripts in an At1g62930 T-DNA insertion line, a phenotype that could be restored by the introduction of the intact At1g62930 gene into the mutant. The insertion in this nuclear gene, which we now call RPF3, also leads to a severe reduction of the CcmC protein in mitochondria. The analysis of C24/rpf3-1 F2 hybrids lacking functional RPF3 genes revealed that this gene has less influence on the generation of the mature ccmC 5′ transcript end derived from a distinct ccmC 5′ upstream configuration found in mitochondrial DNAs from C24 and other accessions. These data show that a particular function of an RF-like protein is required only in connection with a distinct mtDNA configuration. Our new results further substantiate the fundamental role of RF-like PPR proteins in the posttranscriptional generation of plant mitochondrial 5′ transcript termini.
Dispersed Benzoxazinone Gene Cluster: Molecular Characterization and Chromosomal Localization of Glucosyltransferase and Glucosidase Genes in Wheat and Rye
Authors: Sue Masayuki , Nakamura Chihiro , Nomura Taiji
Published: August 2011

Benzoxazinones (Bxs) are major defensive secondary metabolites in wheat (Triticum aestivum), rye (Secale cereale), and maize (Zea mays). Here, we identified full sets of homeologous and paralogous genes encoding Bx glucosyltransferase (GT) and Bx-glucoside glucosidase (Glu) in hexaploid wheat (2n = 6x = 42; AABBDD). Four GT loci (TaGTa–TaGTd) were mapped on chromosomes 7A, 7B (two loci), and 7D, whereas four glu1 loci (Taglu1a–Taglu1d) were on chromosomes 2A, 2B (two loci), and 2D. Transcript levels differed greatly among the four loci; B-genome loci of both TaGT and Taglu1 genes were preferentially transcribed. Catalytic properties of the enzyme encoded by each homeolog/paralog also differed despite high levels of identity among amino acid sequences. The predominant contribution of the B genome to GT and Glu reactions was revealed, as observed previously for the five Bx biosynthetic genes, TaBx1 to TaBx5, which are separately located on homeologous groups 4 and 5 chromosomes. In rye, where the ScBx1 to ScBx5 genes are dispersed to chromosomes 7R and 5R, ScGT and Scglu were located separately on chromosomes 4R and 2R, respectively. The dispersal of Bx-pathway loci to four distinct chromosomes in hexaploid wheat and rye suggests that the clustering of Bx-pathway genes, as found in maize, is not essential for coordinated transcription. On the other hand, barley (Hordeum vulgare) was found to lack the orthologous GT and glu loci like the Bx1 to Bx5 loci despite its close phylogenetic relationship with wheat and rye. These results contribute to our understanding of the evolutionary processes that the Bx-pathway loci have undergone in grasses.
Modular compactifications of the space of pointed elliptic curves II
Authors: Smyth David Ishii
Published: August 2011

We prove that the moduli spaces of n-pointed m-stable curves introduced in our previous paper have projective coarse moduli. We use the resulting spaces to run an analogue of Hassett’s log minimal model program for $\overline {M}_{1,n}$.
Some unlikely intersections beyond André–Oort
Authors: Habegger P. , Pila J.
Published: August 2011

According to the André–Oort conjecture, an algebraic curve in Y (1)n that is not equal to a special subvariety contains only finitely many points which correspond to ann-tuple of elliptic curves with complex multiplication. Pink’s conjecture generalizes the André–Oort conjecture to the extent that if the curve is not contained in a special subvariety of positive codimension, then it is expected to meet the union of all special subvarieties of codimension two in only finitely many points. We prove this for a large class of curves in Y (1)n. When restricting to special subvarieties of codimension two that are not strongly special we obtain finiteness for all curves defined over $\overline {\mathbb Q}$. Finally, we formulate and prove a variant of the Mordell–Lang conjecture for subvarieties of Y (1)n.
Evolution of a Novel Intraductal Patent Ductus Arteriosus Occlusion Device
Authors: Agrawal Megha , Sonetha Vaibhavi A. , Sharma Smriti , Parakh Satyajeet , Dalvi Bharat , Bellare Jayesh R.
Published: August 2011

Persistence of the ductus arteriosus (DA) after birth leads to the congenital heart disease known as patent ductus arteriosus (PDA). The objective of this study is to develop an evaluation protocol and to propose a new and innovative intraductal design for a PDA occluder in order to conform to the varied morphology of the DA and to overcome the problems associated with devices relying on the anchorage mechanism. The new design, an assembly of 36 planar thermally treated Nitinol wires called Novel Device 36 (ND36), is in the shape of a frustum of a cone with a larger diameter of 12 mm, smaller diameter of 6 mm, and length of 11 mm. In-vitro biomimetic evaluations, namely, hemolysis tests and platelet adhesion studies, were conducted to ascertain the biocompatibility of the thermally treated Nitinol wires. These tests were also conducted on two different dimensions of Dacron fibers, which were to be sutured onto the device to induce thrombogenesis while in the duct, thereby facilitating better occlusion. Flow dynamics tests, which help simulate the dynamic conditions prevalent in the duct, were carried out on the ND36 and a commercially used PDA occlusion device. An analysis of the scanning electronic microscopy images showed no platelet adhesion on the Nitinol wires. The tested wires also showed nearly 0% hemolysis. Dacron fibers 0.2 mm thick and having an area density of 77 GSM proved to be best suited. Comparative analysis carried out with the commercially available Amplatzer duct occluder during the flow dynamics tests showed that the ND36 was capable of effectively occluding the duct as well as remaining stable under the dynamic conditions encountered in the duct. The ND36 has the potential to efficiently serve as a simplistic and cost effective alternative for PDA occlusion.
Study of Process-Induced Cell Membrane Stability in Cell Direct Writing
Authors: Yin Jun , Huang Yong
Published: August 2011

Process-induced damage to cells is of significant importance and must be mitigated for safe and reproducible cell direct writing. The objective of this study is to investigate the cell membrane stability under the external normal pressure. This investigation is performed by studying the dipalmitoylphosphatidylcholine bilayer behavior under different normal pressures using molecular dynamics. As the normal pressure increases, the force necessary to rupture the bilayer structure decreases, which indicates cell membrane instability under high normal pressure. This phenomenon can also be explained by the change of free energy difference before and after rupture under different normal pressures. The effect of the pulling speed on the rupture force is also investigated, showing that the rupture force increases almost linearly with the pulling speed.
Impact of External Magnetic Field on Weld Quality of Resistance Spot Welding
Authors: Shen Qi , Li YongBing , Lin ZhongQin , Chen GuanLong
Published: August 2011

Electromagnetic stirring (EMS) has been demonstrated to have significant effect on molten metal in terms of crystal orientation, grain refinement and macro appearance of solidified structures by making use of Lorentz force. In the present study, resistance spot welding (RSW) process of 1.25 mm thick dual-phase steel DP780 with and without the external magnetic field applied has been experimentally investigated. Impacts of the EMS method on nugget appearance, quasi-static performance, fatigue life, and fracture morphology have been systematically discussed. Results of the metallographic tests showed that, compared with the traditional resistance spot weld (RSW weld), the weld under the EMS effect (EMS-RSW weld) was wider and thinner with an obvious increase in nugget diameter. Besides, within the EMS-RSW weld, crystal orientation along the faying surface of workpieces was less directional and the grains were refined. Slightly higher uniformity in the fusion zone and more notable softening in the heat affected zone of the EMS-RSW weld were observed by microhardness tests. With regard to the mechanical properties, both tensile-shear and cross-tension samples of the EMS-RSW welds exhibited higher ultimate failure loads and longer elongations at the failure points than that of the traditional RSW welds. The EMS-RSW welds also showed longer fatigue life under dynamic tensile-shear loads, especially in high cycle conditions. Furthermore, the EMS-RSW welds exhibited a higher frequency of button-pullout fractures under the welding current close to the minimum current that the traditional RSW welds required to prevent weld interfacial fractures under quasi-static tensile-shear loads. Even if both types of the welds exhibited interfacial fractures under a relatively weak welding current, more dimples were found in the fracture surfaces of the EMS-RSW welds than that of the traditional RSW welds. It can be concluded that the external magnetic field during RSW process could improve weld performance of DP780 by enhancing weld strength and plasticity. EMS could be an effective method to improve the weldability in RSW of advanced high strength steel, ultra high strength steel, and even light metals.
A virtual source model for Kilo‐voltage cone beam CT: Source characteristics and model validation
Authors: Spezi E. , Volken W. , Frei D. , Fix M. K.
Published: August 2011

Purpose:

The purpose of this investigation was to study the source characteristics of a clinical kilo‐voltage cone beam CT unit and to develop and validate a virtual source model that could be used for treatment planning purposes.

Methods:

We used a previously commissioned full Monte Carlo model and new bespoke software to study the source characteristics of a clinical kilo‐voltage cone beam CT (CBCT) unit. We identified the main particle sources, their spatial, energy and angular distribution for all the image acquisition presets currently used in our clinical practice. This includes a combination of two energies (100 and 120 kVp), two filters (neutral and bowtie), and eight different x‐ray beam apertures. We subsequently built a virtual source model which we validated against full Monte Carlo calculations.

Results:

We found that the radiation output of the clinical kilo‐voltage cone beam CT unit investigated in this study could be reproduced with a virtual model comprising of two sources (target and filtration cone) or three sources (target, filtration cone and bowtie filter) when additional filtration was used. With this model, we accounted for more than 97% of the photons exiting the unit. Each source in our model was characterised by a origin distribution in both X and Y directions, a fluence map, a single energy spectrum for unfiltered beams and a two dimensional energy spectrum for bowtie filtered beams. The percentage dose difference between full Monte Carlo and virtual source model based dose distributions was well within the statistical uncertainty associated with the calculations ( ± 2%, one standard deviation) in all cases studied.

Conclusions:

The virtual source that we developed is accurate in calculating the dose delivered from a commercial kilo‐voltage cone beam CT unit operating with routine clinical image acquisition settings. Our data have also shown that target, filtration cone, and bowtie filter sources needed to be all included in the model in order to accurately replicate the dose distribution from the clinical radiation beam.
Inositol Pyrophosphates as Mammalian Cell Signals
Authors: Chakraborty Anutosh , Kim Seyun , Snyder Solomon H.
Published: August 2011

Identification and knockout of their biosynthetic enzymes has shed light on the diverse functions of the inositol pyrophosphates.
Merlin/NF2 Functions Upstream of the Nuclear E3 Ubiquitin Ligase CRL4
DCAF1
to Suppress Oncogenic Gene ExpressionA presentation from the 50th Annual Meeting of the American Society for Cell Biology in Philadelphia, Pennsylvania, 11 to 15 December 2010.
Authors: Cooper Jonathan , Li Wei , You Liru , Schiavon Gaia , Pepe-Caprio Angela , Zhou Lu , Ishii Ryohei , Giovannini Marco , Hanemann C. Oliver , Long Stephen B. , Erdjument-Bromage Hediye , Zhou Pengbo , Tempst Paul , Giancotti Filippo G.
Published: August 2011

The closed conformer of Merlin inhibits tumorigenesis by inhibiting a ubiquitin ligase implicated in promoting cell cycle progression and inhibiting growth arrest, apoptosis, and adhesion.
The Downside of Diversity
Authors: Kiberstis Paula A.
Published: August 2011

The mutational profile of head and neck cancer is complex and may pose challenges to the development of targeted therapies.
A New Role for SODD with SKIP and PIP
3
Authors: Thompson Heather M.
Published: August 2011

SODD interacts with SKIP and represses its inositol polyphosphate 5-phosphatase activity.
Ctriporin, a New Anti-Methicillin-Resistant Staphylococcus aureus Peptide from the Venom of the Scorpion Chaerilus tricostatus
Authors: Fan Zheng , Cao Luyang , He Yawen , Hu Jun , Di Zhiyong , Wu Yingliang , Li Wenxin , Cao Zhijian
Published: August 2011

Antibiotic-resistant microbes, such as methicillin-resistant
Staphylococcus aureus
, seriously threaten human health. The outbreak of “superbugs” in recent years emphasizes once again the need for the development of new antimicrobial agents or resources. Antimicrobial peptides have an evident bactericidal effect against multidrug-resistant pathogens. In the present study, a new antimicrobial peptide, ctriporin, was cloned and characterized from the venom of the scorpion
Chaerilus tricostatus
, an animal which has not yet been explored for toxic peptide resources. The MICs of ctriporin against
Staphylococcus aureus
,
Bacillus thuringiensis
,
Bacillus subtilis
,
Micrococcus luteus
, and
Candida albicans
are 5 to 20 μg/ml. Meanwhile, it MIC against clinical antibiotic-resistant bacterial strains is 10 μg/ml. Furthermore, the potential for ctriporin to be used as a topical antibiotic for treating staphylococcal skin infections was investigated. External use of the peptide ctriporin dramatically decreased the bacterial counts and cured skin infections in mice. In addition, ctriporin demonstrates antimicrobial efficacy via the bactericidal mechanism of rapid cell lysis. Together, these results suggest the potential of developing ctriporin as a new topical antibiotic.
Pharmacokinetics of Voriconazole Administered Concomitantly with Fluconazole and Population-Based Simulation for Sequential Use
Authors: Damle Bharat , Varma Manthena V. , Wood Nolan
Published: August 2011

In clinical practice, antifungal therapy may be switched from fluconazole to voriconazole; such sequential use poses the potential for drug interaction due to cytochrome P450 2C19 (CYP2C19)-mediated inhibition of voriconazole metabolism. This open-label, randomized, two-way crossover study investigated the effect of concomitant fluconazole on voriconazole pharmacokinetics in 10 subjects: 8 extensive metabolizers and 2 poor metabolizers of CYP2C19. The study consisted of 4-day voriconazole-only and 5-day voriconazole-plus-fluconazole treatments, separated by a 14-day washout. Voriconazole pharmacokinetics were determined by noncompartmental analyses. A physiologically based pharmacokinetic model was developed in Simcyp (Simcyp Ltd., Sheffield, United Kingdom) to predict the magnitude of drug interaction should antifungal therapy be switched from fluconazole to voriconazole, following various simulated lag times for the switch. In CYP2C19 extensive metabolizers, fluconazole increased the maximum plasma concentration and the area under the plasma concentration-time curve (AUC) of voriconazole by 57% and 178%, respectively. In poor metabolizers, however, voriconazole pharmacokinetics were unaffected by fluconazole. The simulations based on pharmacokinetic modeling predicted that if voriconazole was started 6, 12, 24, or 36 h after the last dose of fluconazole, the voriconazole AUC ratios (sequential therapy versus voriconazole only) after the first dose would be 1.51, 1.41, 1.28, and 1.14, respectively. This suggests that the remaining systemic fluconazole would result in a marked drug interaction with voriconazole for ≥24 h. Although no safety issues were observed during coadministration, concomitant use of fluconazole and voriconazole is not recommended. Frequent monitoring for voriconazole-related adverse events is advisable if voriconazole is used sequentially after fluconazole.
Interrogation of Related Clinical Pan-Azole-Resistant Aspergillus fumigatus Strains: G138C, Y431C, and G434C Single Nucleotide Polymorphisms in
cyp51A
, Upregulation of
cyp51A
, and Integration and Activation of Transposon
Atf1
in the
cyp51A
Promoter
Authors: Albarrag Ahmed M. , Anderson Michael J. , Howard Susan J. , Robson Geoff D. , Warn Peter A. , Sanglard Dominique , Denning David W.
Published: August 2011

Multiple
Aspergillus fumigatus
isolates from a patient with two aspergillomas complicating chronic pulmonary aspergillosis were pan-azole resistant. Microsatellite typing was identical for all isolates despite major phenotypic and some growth rate differences. Three different
cyp51A
mutations were found (G138C, Y431C, and G434C), of which the first two were demonstrated by heterologous expression in a hypersusceptible
Saccharomyces cerevisiae
strain to be at least partly responsible for elevated MICs.
cyp51A
and
cyp51B
gene duplication was excluded, but increased expression of
cyp51A
was demonstrated in three isolates selected for additional study (7-to 13-fold increases). In the isolate with the greatest
cyp51A
expression, an
Aft1
transposon was found inserted 370 bp upstream of the start codon of the
cyp51A
gene, an integration location never previously demonstrated in
Aspergillus
. Two transcription start sites were identified at 49 and 136 bp upstream of the start codon. The role of the
Aft1
transposon, if any, in modulating
cyp51A
expression remains to be established. Increased mRNA expression of the transporters
AfuMDR1
and
AfuMDR4
also was demonstrated in some isolates, which could contribute to azole resistance or simply represent a stress response. The diversity of confirmed and possible azole resistance mechanisms demonstrated in a single series of isogenic isolates is remarkable, indicating the ability of
A. fumigatus
to adapt in the clinical setting.
Mortality in Hematologic Malignancy and Hematopoietic Stem Cell Transplant Patients with Mucormycosis, 2001 to 2009
Authors: Hammond Sarah P. , Baden Lindsey R. , Marty Francisco M.
Published: August 2011

Mortality due to mucormycosis is high. We assessed clinical characteristics and mortality among stem cell transplant and hematologic malignancy patients diagnosed with mucormycosis from 2001 to 2009. Thirty patients were diagnosed with probable or proven mucormycosis during the study. Twenty-six were diagnosed premortem, and most were treated with liposomal amphotericin B single-agent antifungal therapy initially. While the initial antifungal and surgical treatment approach remained stable throughout the study period, 6-week mortality significantly declined over time (67% in 2001 to 2003 versus 45% in 2004 to 2006 versus 20% in 2007 to 2009 [
P
= 0.04]), as did 12-week mortality (78% in 2001 to 2003 versus 55% in 2004 to 2006 versus 20% in 2007 to 2009 [
P
= 0.01]).
Nelfinavir and Its Active Metabolite, Hydroxy-
t
-Butylamidenelfinavir (M8), Are Transferred in Small Quantities to Breast Milk and Do Not Reach Biologically Significant Concentrations in Breast-Feeding Infants Whose Mothers Are Taking Nelfinavir
Authors: Weidle Paul J. , Zeh Clement , Martin Amy , Lando Richard , Angira Frank , Osoga Joseph , Ogindo Paul , Girde Sonali , Minniear Timothy D. , Thomas Timothy K.
Published: August 2011

Antiretroviral drugs cross from maternal plasma to breast milk and from breast milk to the infant in different concentrations. We measured concentrations of nelfinavir and its active metabolite (M8) in maternal plasma and breast milk from women and in dried blood spots collected from their infants at delivery and postnatal weeks 2, 6, 14, and 24 in the Kisumu Breastfeeding Study, Kisumu, Kenya. Nelfinavir-based antiretroviral regimens given to mothers as prevention of mother-to-child HIV transmission (PMTCT) do not expose the breast-feeding infant to biologically significant concentrations of nelfinavir or M8.
Filarial Lymphatic Pathology Reflects Augmented Toll-Like Receptor-Mediated, Mitogen-Activated Protein Kinase-Mediated Proinflammatory Cytokine Production
Authors: Babu Subash , Anuradha R. , Kumar N. Pavan , George P. Jovvian , Kumaraswami V. , Nutman Thomas B.
Published: August 2011

Lymphatic filariasis can be associated with the development of serious pathology in the form of lymphedema, hydrocele, and elephantiasis in a subset of infected patients. Toll-like receptors (TLRs) are thought to play a major role in the development of filarial pathology. To elucidate the role of TLRs in the development of lymphatic pathology, we examined cytokine responses to different Toll ligands in patients with chronic lymphatic pathology (CP), infected patients with subclinical pathology (INF), and uninfected, endemic-normal (EN) individuals. TLR2, -7, and -9 ligands induced significantly elevated production of Th1 and other proinflammatory cytokines in CP patients in comparison to both INF and EN patients. TLR adaptor expression was not significantly different among the groups; however, both TLR2 and TLR9 ligands induced significantly higher levels of phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein (MAP) kinases (MAPK) as well as increased activation of NF-κB in CP individuals. Pharmacologic inhibition of both ERK1/2 and p38 MAP kinase pathways resulted in significantly diminished production of proinflammatory cytokines in CP individuals. Our data, therefore, strongly suggest an important role for TLR2- and TLR9-mediated proinflammatory cytokine induction and activation of both the MAPK and NF-κB pathways in the development of pathology in human lymphatic filariasis.
LuxS Mediates Iron-Dependent Biofilm Formation, Competence, and Fratricide in Streptococcus pneumoniae
Authors: Trappetti Claudia , Potter Adam J. , Paton Adrienne W. , Oggioni Marco R. , Paton James C.
Published: August 2011

During infection,
Streptococcus pneumoniae
exists mainly in sessile biofilms rather than in planktonic form, except during sepsis. The capacity to form biofilms is believed to be important for nasopharyngeal colonization as well as disease pathogenesis, but relatively little is known about the regulation of this process. Here, we investigated the effect of exogenous iron [Fe(III)] as well as the role of
luxS
(encoding S-ribosylhomocysteine lyase) on biofilm formation by
S. pneumoniae
D39. Fe(III) strongly enhanced biofilm formation at concentrations of ≥50 μM, while Fe(III) chelation with deferoxamine was inhibitory. Importantly, Fe(III) also upregulated the expression of
luxS
in wild-type D39. A
luxS
-deficient mutant (D39
luxS
) failed to form a biofilm, even with Fe(III) supplementation, whereas a derivative overexpressing
luxS
(D39
luxS
+) exhibited enhanced biofilm formation capacity and could form a biofilm without added Fe(III). D39
luxS
exhibited reduced expression of the major Fe(III) transporter PiuA, and the cellular [Fe(III)] was significantly lower than that in D39; in contrast, D39
luxS
+ had a significantly higher cellular [Fe(III)] than the wild type. The release of extracellular DNA, which is an important component of the biofilm matrix, also was directly related to
luxS
expression. Similarly, genetic competence, as measured by transformation frequency as well as the expression of competence genes
comD
,
comX
,
comW
,
cglA
, and
dltA
and the murein hydrolase
cbpD
, which is associated with fratricide-dependent DNA release, all were directly related to
luxS
expression levels and were further upregulated by Fe(III). Moreover, mutagenesis of
cbpD
blocked biofilm formation. We propose that competence, fratricide, and biofilm formation are closely linked in pneumococci, and that
luxS
is a central regulator of these processes. We also propose that the stimulatory effects of Fe(III) on all of these parameters are due to the upregulation of
luxS
expression, and that LuxS provides for a positive Fe(III)-dependent amplification loop by increasing iron uptake.
Sediment transport processes in an ancient mud-dominated succession: a comparison of processes operating in marine offshore settings and anoxic basinal environments
Authors: Ghadeer Samer G. , Macquaker Joe H.S.
Published: August 2011

Few studies describe and compare the transport mechanisms operating to disperse mud in different parts of basins. Instead, the physical processes operating to disperse mud in offshore environments, where storm and tidal processes are interpreted to dominate, are generally considered in isolation from those occurring in basinal settings where changes in bottom-water anoxia and suspension settling from buoyant plumes are mostly interpreted to dominate. Using microtextural, mineralogical and geochemical data derived from the analyses of 151 thin sections obtained from the Lower Jurassic mudstone-dominated succession exposed on the coast of NE England, we investigate how varying sediment dispersal mechanisms, bioturbation and early diagenesis operated to produce the lithofacies variability observed. In particular, we consider the processes of sediment delivery while bottom waters were interpreted to be euxinic. Analyses of these samples reveal that the succession is highly variable at millimetre to centimetre scales. Six main lithofacies were observed: (1) sand- and clay-bearing, silt-rich mudstones; (2) silt-bearing, clay-rich mudstones; (3) clay-rich mudstones; (4) clay-, calcareous nannoplankton-, and organic carbon-bearing mudstones; (5) fine-grained muddy sandstones; (6) cement-rich mudstones. These units are organized typically into stacked successions of sharp-based, normally graded, thin (<10 mm) beds. Single beds exhibit a variety of sedimentary structures. Specifically tempestites, wave-enhanced sediment gravity flows of fluid mud, ripples and gutter casts are common in the coarser-grained mudstone facies. In contrast, thin siltstone lags, compacted ripples and organo-mineralic aggregates are common in the finer grained mudstone facies and those with significant primary production-derived components. Bioturbation is common throughout. These data indicate that sediment was transported by density flows and traction currents operating at the sediment–water interface in all parts of the studied succession. Bioturbation has overprinted depositional fabrics in the majority of samples. The extent to which persistent bottom-water anoxia and low-energy suspension settling influenced lithofacies variability in the basinal parts of the succession has been overstated; these environments were more dynamic than most researchers have previously concluded.
Geochemical evolution of Dalradian metavolcanic rocks: implications for the break-up of the Rodinia supercontinent
Authors: Fettes D.J. , Macdonald R. , Fitton J.G. , Stephenson D. , Cooper M.R.
Published: August 2011

Neoproterozoic basaltic magmatism in the Dalradian Supergroup of Scotland and Ireland was associated with the break-up of the Rodinia supercontinent. Magmas were erupted in rift-related basins along a strike length of at least 700 km and during a time period of
c
. 80 Ma. New major and trace element analyses of metabasalts from several formations are presented to trace the variations in magma compositions in time and space. The primary magmas resulted from variable degrees of mixing of melts derived from mantle sources similar to those of normal and enriched mid-ocean ridge basalts; some younger lavas also show evidence of contamination with continental crust. In contrast to speculations about magmatism elsewhere in Rodinia, the evidence here suggests that there was no involvement of a mantle plume in basalt generation. For example, the Scottish promontory of Laurentia drifted rapidly southwards through
c
. 25° over the duration of the magmatism, with no evidence of significant elevation above sea level, as might be expected from involvement of a plume. Generation of the primary magmas might have taken place predominantly through decompression melting in depleted upper mantle containing enriched streaks and blobs. Both the Dalradian lithostratigraphy and the metabasaltic compositions are consistent with extreme lithospheric stretching and possibly rupture during the earliest phase of magmatism, whereas generation of later magmatism appears to have been associated with major fault systems, possibly on a foundering continental margin.

Supplementary material:

Chemical analyses of Dalradian metavolcanic rocks (major elements recalculated to 100%, anhydrous) are available at
www.geolsoc.org.uk/SUP18468
.
A record of continental collision and regional sediment flux for the Cretaceous and Palaeogene core of SE Asia: implications for early Cenozoic palaeogeography
Authors: Clements Benjamin , Hall Robert
Published: August 2011

Palaeogene sedimentary rocks exposed in West Java were derived from local volcanic sources and central Sundaland, the continental core of SE Asia. Detrital zircons from seven sandstone samples contain U–Pb age populations with ages of 50–80 Ma, 74–145 Ma, 202–298 Ma, 480–653 Ma and 723–1290 Ma. Late Cretaceous and Palaeogene zircons in Middle Eocene forearc sandstones are interpreted as derived from two spatially and temporally discrete volcanic arcs located in Java and Sulawesi respectively. In contrast, all other populations have a Sundaland provenance. Most Permian–Triassic zircons were derived from granites of this age in the SE Asian Tin Belt. Mid-Cretaceous zircons in all Upper Eocene and Lower Oligocene formations were derived from the Schwaner Mountains of SW Borneo. The differences in zircon populations reflect changing Sundaland sources with time. In the Middle Eocene, sediment was derived mainly from the Tin Belt. From the Late Eocene onwards a Borneo source became more important. Older zircon ages are from SE Asia basement that once formed part of Gondwana. Zircons also record the timing of microcontinental collision at the Java margin (
c
. 80 Ma) that halted Cretaceous subduction and probably resulted in the elevation of large parts of continental SE Asia.

Supplementary material:

Methods, sample locality list, tables for U–Pb zircon age measurements, point count data and heavy mineral assemblages, sandstone petrographic descriptions and palaeocurrent data are available at
www.geolsoc.org.uk/SUP18489
.
Path Planning of Data Mules in Sensor Networks
Authors: Sugihara Ryo , Gupta Rajesh K.
Published: August 2011

We study the problem of planning the motion of “data mules” for collecting the data from stationary sensor nodes in wireless sensor networks. Use of data mules significantly reduces energy consumption at sensor nodes compared to commonly used multihop forwarding approaches, but has a drawback in that it increases the latency of data delivery. Optimizing the motion of data mules, including path and speed, is critical for improving the data delivery latency and making the data mule approach more useful in practice. In this article, we focus on the path selection problem: finding the optimal path of data mules so that the data delivery latency can be minimized. We formulate the path selection problem as a graph problem that is capable of expressing the benefit from larger communication range. The problem is NP-hard and we present approximation algorithms for both single-data mule case and multiple-data mules case. We further consider the case in which we have only partial knowledge of communication range, where we design semionline algorithms that improve the offline plan using online knowledge at runtime. Simulation experiments on Matlab and ns2 demonstrate that our offline and semionline algorithms produce significantly shorter path lengths and data delivery latency compared to previously proposed methods, suggesting that controlled mobility can be exploited much more effectively.
MCRT
Authors: Wang Xiaorui , Wang Xiaodong , Fu Xing , Xing Guoliang
Published: August 2011

As many radio chips used in today’s sensor mote hardware can work at different frequencies, several multichannel communication protocols have recently been proposed to improve network throughput and reduce packet loss for wireless sensor networks. However, existing work cannot utilize multiple channels to provide explicit guarantees for application-specified end-to-end communication delays, which are critical to many real-time applications such as surveillance and disaster response. In this article, we propose MCRT, a multichannel real-time communication protocol that features a flow-based channel allocation strategy. Because of the small number of orthogonal channels available in current mote hardware, MCRT allocates channels to network partitions formed based on many-to-one data flows. To achieve bounded end-to-end communication delay for every data flow, the channel allocation problem has been formulated as a constrained optimization problem and proven to be NP-complete. We then present the design of MCRT, which includes a channel allocation algorithm and a real-time packet forwarding strategy. Extensive simulation results based on a realistic radio model and empirical results on a real hardware testbed of Tmote nodes both demonstrate that MCRT can effectively utilize multiple channels to reduce the number of deadlines missed in end-to-end communications. Our results also show that MCRT outperforms a state-of-the-art real-time protocol and two baseline multichannel communication schemes.
Hierarchical Spatial Gossip for Multiresolution Representations in Sensor Networks
Authors: Sarkar Rik , Zhu Xianjin , Gao Jie
Published: August 2011

In this article we propose a lightweight algorithm for constructing multiresolution data representations for sensor networks. At each sensor node
u
, we compute
O
(log
n
) aggregates about exponentially enlarging neighborhoods centered at
u
. The
i
th aggregate is the aggregated data from nodes approximately within 2
i
hops of
u
. We present a scheme, named the
hierarchical spatial gossip algorithm
, to extract and construct these aggregates, for
all
sensors simultaneously, with a total communication cost of
O
(
n
polylog
n
). The hierarchical gossip algorithm adopts atomic communication steps with each node choosing to exchange information with a node distance
d
away with probability ∼ 1/
d
3
. The attractiveness of the algorithm can be attributed to its simplicity, low communication cost, distributed nature, and robustness to node failures and link failures. We show in addition that computing multiresolution aggregates precisely (i.e., each aggregate uses all and only the nodes within 2
i
hops) requires a communication cost of Ω(
n
√
n
), which does not scale well with network size. An approximate range in aggregate computation like that introduced by the gossip mechanism is therefore necessary in a scalable efficient algorithm. Besides the natural applications of multiresolution data summaries in data validation and information mining, we also demonstrate the application of the precomputed multiresolution data summaries in answering range queries efficiently.