bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two types of extracellular action potentials recorded with narrow‐tipped pipettes in skeletal muscle of frog, Rana temporaria
Authors: Kubasov Igor V. , Dobretsov Maxim 
Published: April 2012

Key points
Two types of extracellular action potentials, bi‐ and tri‐phasic, were recorded within the same fibre of skeletal muscle of frog.
Unlike bi‐phasic, tri‐phasic action potentials were very sensitive to the potassium channel blocker barium, and to a frequency of stimulation of muscle preparation.
It is suggested that currents generated in a specialized t‐tubular compartment of a muscle fibre form the third phase of these action potentials and studies of tri‐phasic action potentials may provide a new tool for evaluating the role of t‐tubules in skeletal muscle contractility.
Susceptibility of Herpes Simplex Virus Isolated from Genital Herpes Lesions to ASP2151, a Novel Helicase-Primase Inhibitor
Authors: Katsumata Kiyomitsu , Weinberg Adriana , Chono Koji , Takakura Shoji , Kontani Toru , Suzuki Hiroshi 
Published: April 2012

ABSTRACT

ASP2151 (amenamevir) is a helicase-primase inhibitor against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus. To evaluate the anti-HSV activity of ASP2151, susceptibility testing was performed on viruses isolated from patients participating in a placebo- and valacyclovir-controlled proof-of-concept phase II study for recurrent genital herpes. A total of 156 HSV strains were isolated prior to the dosing of patients, and no preexisting variants with less susceptibility to ASP2151 or acyclovir (ACV) were detected. ASP2151 inhibited HSV-1 and HSV-2 replication with mean 50% effective concentrations (EC
50
s) of 0.043 and 0.069 μM, whereas ACV exhibited mean EC
50
s of 2.1 and 3.2 μM, respectively. Notably, the susceptibilities of HSV isolates to ASP2151 and ACV were not altered after dosing with the antiviral agents. Taken together, these results demonstrate that ASP2151 inhibits the replication of HSV clinical isolates more potently than ACV, and HSV resistant to this novel helicase-primase inhibitor as well as ACV may not easily emerge in short-term treatment for recurrent genital herpes patients.
Metabolic Activation of the Anti-Hepatitis C Virus Nucleotide Prodrug PSI-352938
Authors: Niu Congrong , Tolstykh Tatiana , Bao Haiying , Park Yeojin , Babusis Darius , Lam Angela M. , Bansal Shalini , Du Jinfa , Chang Wonsuk , Reddy P. Ganapati , Zhang Hai-Ren , Woolley Joseph , Wang Li-Quan , Chao Piyun B. , Ray Adrian S. , Otto Michael J. , Sofia Michael J. , Furman Phillip A. , Murakami Eisuke 
Published: April 2012

ABSTRACT

PSI-352938 is a novel cyclic phosphate prodrug of β-
d
-2′-deoxy-2′-α-fluoro-2′-β-
C
-methylguanosine-5′-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, PSI-352938 must be metabolized to the active triphosphate form, PSI-352666. During
in vitro
incubations with PSI-352938, significantly larger amounts of PSI-352666 were formed in primary hepatocytes than in clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays were performed to define the molecular mechanism of PSI-352938 activation. The first step, removal of the isopropyl group on the 3′,5′-cyclic phosphate moiety, was found to be cytochrome P450 (CYP) 3A4 dependent, with other CYP isoforms unable to catalyze the reaction. The second step, opening of the cyclic phosphate ring, was catalyzed by phosphodiesterases (PDEs) 2A1, 5A, 9A, and 11A4, all known to be expressed in the liver. The role of these enzymes in the activation of PSI-352938 was confirmed in primary human hepatocytes, where prodrug activation was reduced by inhibitors of CYP3A4 and PDEs. The third step, removal of the
O
6
-ethyl group on the nucleobase, was shown to be catalyzed by adenosine deaminase-like protein 1. The resulting monophosphate was consecutively phosphorylated to the diphosphate and to the triphosphate PSI-352666 by guanylate kinase 1 and nucleoside diphosphate kinase, respectively. In addition, formation of nucleoside metabolites was observed in primary hepatocytes, and ecto-5′-nucleotidase was able to dephosphorylate the monophosphate metabolites. Since CYP3A4 is highly expressed in the liver, the CYP3A4-dependent metabolism of PSI-352938 makes it an effective liver-targeted prodrug, in part accounting for the potent antiviral activity observed clinically.
Development of Novel PCR Assays To Detect Azole Resistance-Mediating Mutations of theAspergillus fumigatus cyp51AGene in Primary Clinical Samples from Neutropenic Patients
Authors: Spiess Birgit , Seifarth Wolfgang , Merker Natalia , Howard Susan J. , Reinwald Mark , Dietz Anne , Hofmann Wolf-Karsten , Buchheidt Dieter 
Published: April 2012

ABSTRACTThe increasing incidence of azole resistance inAspergillus fumigatuscausing invasive aspergillosis (IA) in immunocompromised/hematological patients emphasizes the need to improve the detection of resistance-mediatingcyp51Agene mutations from primary clinical samples, particularly as the diagnosis of invasive aspergillosis is rarely based on a positive culture yield in this group of patients. We generated primers from the unique sequence of theAspergillus fumigatus cyp51Agene to establish PCR assays with consecutive DNA sequence analysis to detect and identify theA. fumigatus cyp51Atandem repeat (TR) mutation in the promoter region and the L98H and M220 alterations directly in clinical samples. After testing of the sensitivity and specificity of the assays using serially dilutedA. fumigatusand human DNA,A. fumigatus cyp51Agene fragments of about 150 bp potentially carrying the mutations were amplified directly from primary clinical samples and subsequently DNA sequenced. The determined sensitivities of the PCR assays were 600 fg, 6 pg, and 4 pg ofA. fumigatusDNA for the TR, L98H, and M220 mutations, respectively. There was no cross-reactivity with human genomic DNA detectable. Sequencing of the PCR amplicons forA. fumigatuswild-type DNA confirmed thecyp51Awild-type sequence, and PCR products from one azole-resistantA. fumigatusisolate showed the L98H and TR mutations. The second azole-resistant isolate revealed an M220T alteration. We consider our assay to be of high epidemiological and clinical relevance to detect azole resistance and to optimize antifungal therapy in patients with IA.
In Vitro
Activity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria
Authors: Hirsch Elizabeth B. , Ledesma Kimberly R. , Chang Kai-Tai , Schwartz Michael S. , Motyl Mary R. , Tam Vincent H. 
Published: April 2012

ABSTRACT

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing
Klebsiella pneumoniae
isolate (KP6339) as well as 3
Pseudomonas aeruginosa
isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.
Contribution of Phe-7 to Tat-Dependent Export of β-Lactamase in Xanthomonas campestris
Authors: Lee Chen-Wei , Tseng Yi-Hsuan , Deng Fu-Seng , Lin Juey-Wen , Tseng Yi-Hsiung , Weng Shu-Fen 
Published: April 2012

ABSTRACT

Strains of
Xanthomonas campestris
pv. campestris isolated in Taiwan are commonly resistant to ampicillin owing to the constitutive expression of a chromosomally encoded β-lactamase that is secreted into the periplasm. In this study, we found that levels of β-lactamase vary among
X. campestris
pv. campestris strains, a difference that can be attributed to amino acid substitutions at least at positions 7 and 206, with the former having the major impact. Bioinformatic and PCR analyses indicated that
X. campestris
pv. campestris possesses
tatABC
genes and that the signal peptide of
X. campestris
pv. campestris pre-Bla contains the typical twin-arginine motif (N-R-R-Q-F-L at amino acid residues 3 to 8 in strain
X. campestris
pv. campestris strain 11), suggesting that Bla is secreted via the Tat pathway. To assess the importance of Phe
7
in the efficient export of
X. campestris
pv. campestris Bla, we prepared mutant constructs containing amino acid substitutions and monitored their expression by measuring enzyme activity and detecting Bla protein by Western blotting. The results indicate that replacement of Phe
7
with Leu severely inhibited Bla export whereas replacement with Pro almost abolished it. Although a change to Arg caused moderate inhibition of export, replacement with Tyr had no effect. These results suggest that for efficient export of Bla by
X. campestris
pv. campestris, the aromatic-aromatic interactions and stability of protein structure around the twin-arginine motif are important, since only proteins that can attain a folded state in the cytoplasm are competent for export via the Tat pathway.
The Genome Sequence of Bluetongue Virus Type 10 from India: Evidence for Circulation of a Western Topotype Vaccine Strain
Authors: Maan Sushila , Maan Narender S. , Pullinger Gillian , Nomikou Kyriaki , Morecroft Elizabeth , Guimera Marc , Belaganahalli Manjunatha N. , Mertens Peter P. C. 
Published: April 2012

ABSTRACT

Bluetongue virus
is the type species of the genus
Orbivirus
in the family
Reoviridae
. We report the first complete genome sequence of an isolate (IND2004/01) of bluetongue virus serotype 10 (BTV-10) from Andhra Pradesh, India. This isolate, which is stored in the Orbivirus Reference Collection (ORC) at IAH Pirbright, shows >99% nucleotide identity in all 10 genome segments with a vaccine strain of BTV-10 from the United States.
Flower and seed production as affected by axis category and shoot size in two Patagonian Nothofagus species
Authors: Torres Cristian D. , Puntieri Javier G. , Stecconi Marina 
Published: April 2012

Flower distribution within the tree crown may affect both pollination dynamics and the costs of flowering on tree growth. For Nothofagus obliqua (Mirb.) Oerst. and Nothofagus nervosa (Phil.) Krasser, the production of flowers and viable seeds were compared among axes of contrasting size and category in the tree crown. For annual shoots arising from three axis categories (main branches, secondary branches, and twigs), the numbers of nodes, staminate flowers, pistillate flowers and axillary buds, and seed viability were evaluated. Most flowering shoots produced both staminate and pistillate flowers. The number of flowers of each type was related positively with the number of nodes of the shoot. Longer shoots had proportionally more pistillate flowers than short shoots. The three axis categories produced both flower types in direct proportion to the size of their shoots, but main branches presented more axillary vegetative buds than secondary branches and twigs. For N. obliqua, the percentage of viable seeds was lower in secondary branches than in main branches and twigs, perhaps owing to a lower probability of cross-pollination in secondary branches. The coexistence of vegetative and reproductive functions may cause interference between them. Massive allocation of meristems to flowering reduces meristem availability for growth and, especially, flowering in the following growing season.
Cortinarius parkeri, a new species from the Pacific Northwest of North America
Authors: Ammirati Joseph F. , Barlow Tess E. , Seidl Michelle T. , Ceska Oldriska , Berbee Mary , Harrower Emma , Liimatainen Kare 
Published: April 2012

Cortinarius parkeri , a new vernal species in subgenus Cortinarius , section Veneti , is described from the Pacific Northwest of North America. Within its subgenus, C. parkeri is unique in that its membranous universal veil is attached to the pileus edge of young mushrooms and extends as a covering over the pileus surface. At maturity, the universal veil forms a sheathing membranous volva-like structure that flares out above the stipe base. Sequences of the nuclear ribosomal DNA internal transcribed spacer region (ITS1-5.8s-ITS2) determined for 13 collections of C. parkeri were all identical, except for a polymorphic two base pair indel. In a phylogeny including other related species from North America and Europe, C. parkeri is monophyletic. In contrast to intraspecific distances, the interspecific genetic distance between C. parkeri and other Veneti species sequences was large. Being dikaryotic, mushrooms of C. parkeri contain genomes from two parents. As expected in a dikaryon in an interbreeding population, the polymorphic indel was homozygous in some collections but heterozygous in three collections, with conflicting sequences resulting from mixed parental types. Taken together, morphological and molecular results strongly support C. parkeri as a new and distinctive species.
Tectonic subsidence history and source-rock maturation in the Campos Basin, Brazil
Authors: Beglinger Suzanne E. , van Wees Jan-Diederik , Cloetingh Sierd , Doust Harry 
Published: April 2012

The Campos Basin is a petroleum-productive, marginal sag basin along the Brazilian margin. It contains a stratigraphic sequence recording lithospheric extension and rift tectonics developing to a fully evolved post-break-up setting. We present a combined approach using subsidence analysis and basin history inversion models to make predictions on source-rock maturation. The classical uniform stretching model does not account for the
observed tectonic subsidence
, and so we consider the thermal and subsidence implications of incorporating different events of magmatic underplating. The post-rift is characterized by one major phase of post-rift thermal subsidence: changes in sediment supply and load, as well as halokinetic movements, cause deviations from normal thermal subsidence and relaxation. The dimensions of these events have been examined and quantified.

Our best-fit forward model is tested against measured borehole temperature (BHT) data. Results show a systematic overestimation of present-day temperatures in the shallow-water wells. Including the effects of hydrothermal convection by raising the conductivity of the top part of the stratigraphic sequence results in an almost perfect fit between predicted and measured BHTs in the shallow-water wells.
Based on these forward models, we predict that the lacustrine shales of the syn-rift Lagoa Feia Fm. could be mature to generate oil and/or gas over a larger area than previously expected. Furthermore, our results suggest that the early post-rift Macaé Fm. is locally mature to generate oil, and that the middle/late post-rift Carapebus/Ubatuba Fm. shales are likely to generate oil as well, if organic-rich facies are indeed present. In light of the most recent pre- and post-salt discoveries made near established oil fields in the Campos Basin, our results support the idea that many more such accumulations may be found.
Likert-type scales, statistical methods, and effect sizes
Authors: Robertson Judy 
Published: April 2012

The
Communications
Web site, http://cacm.acm.org, features more than a dozen bloggers in the BLOG@CACM community. In each issue of
Communications
, we'll publish selected posts or excerpts.

twitter

Follow us on Twitter at http://twitter.com/blogCACM
http://cacm.acm.org/blogs/blog-cacm
Judy Robertson writes about researchers' use of the wrong statistical techniques to analyze attitude questionnaires.
SMCSolver and Q-MAM
Authors: Bini D. , Meini B. , Steffé S. , Pérez J. F. , Van Houdt B. 
Published: April 2012

Matrix-analytic methods have advanced considerably since the pioneering work of Marcel Neuts [6, 5] on Quasi-Birth-Death (QBD), GI/M/1- and M/G/1- type Markov chains (MCs). Especially the algorithms involved to (iteratively) solve these structured Markov chains have matured a lot, which has resulted in more efficient, but also more complex algorithms [4, 1]. While the first algorithms were straightforward to implement---as they were based on simple functional iterations---more advanced algorithms/features like cyclic-reduction, the Newton iteration or the shift technique (to accelerate convergence), require more effort; in particular for GI/M/1- and M/G/1-type Markov chains. This has motivated us to develop the Structured Markov Chain Solver (SMCSolver) tool [2], which implements a large number of basic and more advanced algorithms for solving QBD, GI/M/1- and M/G/1-type MCs1 (as well as the more general Non-Skip-Free M/G/1-type MCs). The MATLAB version of the tool consists of a collection of MATLAB functions, while the Fortran version is accompanied by a graphical user-interface (GUI).
Apart from making these more advanced algorithms accessible to non-specialists, the tool is also useful as a platform for the development and study of new algorithms and acceleration techniques. Since its initial release in 2006, various extensions have been made. In [3] different transformation techniques and shift strategies are incorporated in order to speed up and optimize the algorithms, while even more recently an efficient Newton iteration for GI/M/1- and M/G/1-type Markov chains was included [8].
Matrix-analytic methods have also been very effective in the analysis of many queueing systems in both discrete- and continuous-time. The Q-MAM tool [7] is a collection of MATLAB functions that allows one to compute the queue length, waiting time and delay distribution of various queueing systems of infinite size. It includes amongst others implementations of the PH/PH/1, MAP/MAP/1, MAP/M/c, MAP/D/c, RAP/RAP/1, MMAP[K]/PH[K]/1, MMAP[K]/SM[K]/1, SM[K]/PH[K]/1 (many in both discrete- and continuous-time), where state-of-the-art solution techniques are used to solve these models efficiently.
The Matlab version of the SMCSolver and Q-MAM tool is available at http://win.ua.ac.be/?vanhoudt/ while the Fortran 90 version of the SMCSolver tool with the GUI can be downloaded from http://bezout.dm.unipi.it/SMCSolver.
Architecture support for disciplined approximate programming
Authors: Esmaeilzadeh Hadi , Sampson Adrian , Ceze Luis , Burger Doug 
Published: April 2012

Disciplined approximate programming lets programmers declare which parts of a program can be computed approximately and consequently at a lower energy cost. The compiler proves statically that all approximate computation is properly isolated from precise computation. The hardware is then free to selectively apply approximate storage and approximate computation with no need to perform dynamic correctness checks.
In this paper, we propose an efficient mapping of disciplined approximate programming onto hardware. We describe an ISA extension that provides approximate operations and storage, which give the hardware freedom to save energy at the cost of accuracy. We then propose Truffle, a microarchitecture design that efficiently supports the ISA extensions. The basis of our design is dual-voltage operation, with a high voltage for precise operations and a low voltage for approximate operations. The key aspect of the microarchitecture is its dependence on the instruction stream to determine when to use the low voltage. We evaluate the power savings potential of in-order and out-of-order Truffle configurations and explore the resulting quality of service degradation. We evaluate several applications and demonstrate energy savings up to 43%.
DreamWeaver
Authors: Meisner David , Wenisch Thomas F. 
Published: April 2012

Numerous data center services exhibit low average utilization leading to poor energy efficiency. Although CPU voltage and frequency scaling historically has been an effective means to scale down power with utilization, transistor scaling trends are limiting its effectiveness and the CPU is accounting for a shrinking fraction of system power. Recent research advocates the use of full-system idle low-power modes to combat energy losses, as such modes provide the deepest power savings with bounded response time impact. However, the trend towards increasing cores per die is undermining the effectiveness of these sleep modes, particularly for request-parallel data center applications, because the independent idle periods across individual cores are unlikely to align by happenstance.
We propose DreamWeaver, architectural support to facilitate deep sleep for request-parallel applications on multicore servers. DreamWeaver comprises two elements: Weave Scheduling, a scheduling policy to coalesce idle and busy periods across cores to create opportunities for system-wide deep sleep; and the Dream Processor, a light-weight co-processor that monitors incoming network traffic and suspended work during sleep to determine when the system must wake. DreamWeaver is based on two key concepts: (1) stall execution and sleep anytime any core is unoccupied, but (2) constrain the maximum time any request may be stalled. Unlike prior scheduling approaches, DreamWeaver will preempt execution to sleep, maximizing time spent at the systems' most efficient operating point. We demonstrate that DreamWeaver can smoothly trade-off bounded, predictable increases in 99th-percentile response time for increasing power savings, and strictly dominates the savings available with voltage and frequency scaling and timeout-based request batching schemes.
Emerging Epigenetic Targets and Therapies in Cancer Medicine
Authors: Popovic Relja , Licht Jonathan D. 
Published: April 2012

Abstract
Abnormalities in the epigenetic regulation of chromatin structure and function can lead to aberrant gene expression and cancer development. Consequently, epigenetic therapies aim to restore normal chromatin modification patterns through the inhibition of various components of the epigenetic machinery. Histone deacetylase and DNA methyltransferase inhibitors represent the first putative epigenetic therapies; however, these agents have pleiotropic effects and it remains unclear how they lead to therapeutic responses. More recently, drugs that inhibit histone methyltransferases were developed, perhaps representing more specific agents. We review emerging epigenetic targets in cancer and present recent models of promising epigenetic therapies.
Significance: The use of DNA methyltransferase and histone deacetylase inhibitors in patients has validated the use of drugs targeted to epigenetic enzymes and strengthened the need for development of additional therapies. In this review, we summarize recently discovered epigenetic abnormalities, their implications for cancer, and the approaches taken for discovering small-molecule inhibitors targeting various properties of the epigenetic machinery. Cancer Discov; 2(5); 405–13. ©2012 AACR.