bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of Novel Antigiardiasis Drug Candidates
Authors: Kulakova Liudmila , Galkin Andrey , Chen Catherine Z. , Southall Noel , Marugan Juan J. , Zheng Wei , Herzberg Osnat 
Published: September 2014

ABSTRACT

Giardiasis is a severe intestinal parasitic disease caused by
Giardia lamblia
, which inflicts many people in poor regions and is the most common parasitic infection in the United States. Current standard care drugs are associated with undesirable side effects, treatment failures, and an increasing incidence of drug resistance. As follow-up to a high-throughput screening of an approved drug library, which identified compounds lethal to
G. lamblia
trophozoites, we have determined the minimum lethal concentrations of 28 drugs and advanced 10 of them to
in vivo
studies in mice. The results were compared to treatment with the standard care drug, metronidazole, in order to identify drugs with equal or better anti-
Giardia
activities. Three drugs, fumagillin, carbadox, and tioxidazole, were identified. These compounds were also potent against metronidazole-resistant human
G. lamblia
isolates (assemblages A and B), as determined in
in vitro
assays. Of these three compounds, fumagillin is currently an orphan drug used within the European Union to treat microsporidiosis in immunocompromised individuals, whereas carbadox and tioxidazole are used in veterinary medicine. A dose-dependent study of fumagillin in a giardiasis mouse model revealed that the effective dose of fumagillin was ∼100-fold lower than the metronidazole dose. Therefore, fumagillin may be advanced to further studies as an alternative treatment for giardiasis when metronidazole fails.
Potency and Resistance Analysis of Hepatitis C Virus NS5B Polymerase Inhibitor BMS-791325 on All Major Genotypes
Authors: Liu Mengping , Tuttle Maria , Gao Min , Lemm Julie A. 
Published: September 2014

ABSTRACT

BMS-791325 is a hepatitis C virus (HCV) inhibitor binding to the thumb domain of the NS5B RNA-dependent RNA polymerase. BMS-791325 is well characterized in genotype 1 (GT1) and exhibits good inhibitory activity (50% effective concentration [EC
50
], <10 nM) against hybrid replicons containing patient NS5B sequences from GT3a, -4a, and -5a while potency against GT2 is significantly reduced (J. A. Lemm et al., Antimicrob. Agents Chemother. 58:3485–3495, 2014, doi:
http://dx.doi.org/10.1128/AAC.02495-13
). BMS-791325 potency against GT6a hybrid replicons is more variable, with two of three hybrid clones having EC
50
s similar to that for GT1 while a third patient clone was ∼10 times less susceptible to BMS-791325. To characterize the resistance profile of BMS-791325 beyond GT1, curing studies were performed across GT1a and -3a to -6a and demonstrated that GT1a has the highest resistance barrier versus BMS-791325 while GT6a has the lowest. Selection of GT3 to -6 NS5B chimeric replicon cells at different concentrations of BMS-791325 revealed substitutions in the thumb domain of NS5B at residues 494 and 495 that conferred different levels of resistance to BMS-791325 but remained susceptible to NS5A or NS3 protease inhibitors. In addition, we demonstrate that the reduced potency of BMS-791325 against one GT6a patient is due to an A494 polymorphism present in ∼21% of sequences in the European HCV database. The results from this report suggest that BMS-791325 is a candidate for combination treatment of HCV GT3 to -6 chronic infections, and the resistance profiles identified will provide useful information for future clinical development.
Evaluation of Clonality and Carbapenem Resistance Mechanisms among Acinetobacter baumannii-Acinetobacter calcoaceticus Complex and Enterobacteriaceae Isolates Collected in European and Mediterranean Countries and Detection of Two Novel β-Lactamases, GES-22 and VIM-35
Authors: Castanheira Mariana , Costello Sarah E. , Woosley Leah N. , Deshpande Lalitagauri M. , Davies Todd A. , Jones Ronald N. 
Published: September 2014

ABSTRACT

We evaluated doripenem-resistant
Acinetobacter baumannii
-
Acinetobacter calcoaceticus
complex (ACB;
n
= 411) and
Enterobacteriaceae
(
n
= 92) isolates collected from patients from 14 European and Mediterranean countries during 2009 to 2011 for the presence of carbapenemase-encoding genes and clonality. Following susceptibility testing, carbapenem-resistant (doripenem MIC, >2 μg/ml) isolates were screened for carbapenemases. New β-lactamase genes were expressed in a common background and susceptibility was tested. Class 1 integrons were sequenced. Clonality was evaluated by pulsed-field gel electrophoresis and multilocus sequence typing (Pasteur scheme). Relative expression of β-lactam intrinsic resistance mechanisms was determined for carbapenemase-negative
Enterobacteriaceae
. ACB and
Enterobacteriaceae
displayed 58.9 and 0.9% doripenem resistance, respectively.
bla
OXA-23
,
bla
OXA-58
, and
bla
OXA-24/OXA-40
were detected among 277, 77, and 29 ACB, respectively (in 8, 6, and 5 countries). Ten Turkish isolates carried
bla
GES-11
or
bla
GES-22
. GES-22 (G243A and M169L mutations in GES-1) had an extended-spectrum β-lactamase profile. A total of 33 clusters of ≥2 ACB isolates were observed, and 227 isolates belonged to sequence type 2/international clone II. Other international clones were limited to Turkey and Israel. Doripenem-resistant
Enterobacteriaceae
increased significantly (0.7 to 1.6%), and 15
bla
KPC-2
- and 22
bla
KPC-3
-carrying isolates, mostly belonging to clonal complexes 11 and 258, were observed.
Enterobacteriaceae
isolates producing OXA-48 (
n
= 16; in Turkey and Italy), VIM-1 (
n
= 10; in Greece, Poland, and Spain), VIM-26 (
n
= 1; in Greece), and IMP-19, VIM-4, and the novel VIM-35 (
n
= 1 each from Poland) were detected. VIM-35 had one substitution compared to VIM-1 (A235T) and a similar susceptibility profile. One or more resistance mechanisms were identified in 4/6 carbapenemase-negative
Enterobacteriaceae
. This broad evaluation confirms results from country-specific surveys and shows a highly diverse population of carbapenemase-producing ACB and
Enterobacteriaceae
in Europe and Mediterranean countries.
The Endothelin System Has a Significant Role in the Pathogenesis and Progression of Mycobacterium tuberculosis Infection
Authors: Correa Andre F. , Bailão Alexandre M. , Bastos Izabela M. D. , Orme Ian M. , Soares Célia M. A. , Kipnis Andre , Santana Jaime M. , Junqueira-Kipnis Ana Paula 
Published: September 2014

ABSTRACTTuberculosis (TB) remains a major global health problem, and although multiple studies have addressed the relationship betweenMycobacterium tuberculosisand the host on an immunological level, few studies have addressed the impact of host physiological responses. Proteases produced by bacteria have been associated with important alterations in the host tissues, and a limited number of these enzymes have been characterized in mycobacterial species.M. tuberculosisproduces a protease called Zmp1, which appears to be associated with virulence and has a putative action as an endothelin-converting enzyme. Endothelins are a family of vasoactive peptides, of which 3 distinct isoforms exist, and endothelin 1 (ET-1) is the most abundant and the best-characterized isoform. The aim of this work was to characterize the Zmp1 protease and evaluate its role in pathogenicity. Here, we have shown thatM. tuberculosisproduces and secretes an enzyme with ET-1 cleavage activity. These data demonstrate a possible role of Zmp1 for mycobacterium-host interactions and highlights its potential as a drug target. Moreover, the results suggest that endothelin pathways have a role in the pathogenesis ofM. tuberculosisinfections, and ETA or ETB receptor signaling can modulate the host response to the infection. We hypothesize that a balance between Zmp1 control of ET-1 levels and ETA/ETB signaling can allowM. tuberculosisadaptation and survival in the lung tissues.
Global Transcriptional Start Site Mapping Using Differential RNA Sequencing Reveals Novel Antisense RNAs in Escherichia coli
Authors: Thomason Maureen K. , Bischler Thorsten , Eisenbart Sara K. , Förstner Konrad U. , Zhang Aixia , Herbig Alexander , Nieselt Kay , Sharma Cynthia M. , Storz Gisela 
Published: September 2014

ABSTRACT

While the model organism
Escherichia coli
has been the subject of intense study for decades, the full complement of its RNAs is only now being examined. Here we describe a survey of the
E. coli
transcriptome carried out using a differential RNA sequencing (dRNA-seq) approach, which can distinguish between primary and processed transcripts, and an automated prediction algorithm for transcriptional start sites (TSS). With the criterion of expression under at least one of three growth conditions examined, we predicted 14,868 TSS candidates, including 5,574 internal to annotated genes (iTSS) and 5,495 TSS corresponding to potential antisense RNAs (asRNAs). We examined expression of 14 candidate asRNAs by Northern analysis using RNA from wild-type
E. coli
and from strains defective for RNases III and E, two RNases reported to be involved in asRNA processing. Interestingly, nine asRNAs detected as distinct bands by Northern analysis were differentially affected by the
rnc
and
rne
mutations. We also compared our asRNA candidates with previously published asRNA annotations from RNA-seq data and discuss the challenges associated with these cross-comparisons. Our global transcriptional start site map represents a valuable resource for identification of transcription start sites, promoters, and novel transcripts in
E. coli
and is easily accessible, together with the cDNA coverage plots, in an online genome browser.
A Genetic Screen in Myxococcus xanthus Identifies Mutants That Uncouple Outer Membrane Exchange from a Downstream Cellular Response
Authors: Dey Arup , Wall Daniel 
Published: September 2014

ABSTRACT

Upon physical contact with sibling cells, myxobacteria transiently fuse their outer membranes (OMs) and exchange OM proteins and lipids. From previous work, TraA and TraB were identified to be essential factors for OM exchange (OME) in donor and recipient cells. To define the genetic complexity of OME, we carried out a comprehensive forward genetic screen. The screen was based on the observation that
Myxococcus xanthus
nonmotile cells, by a Tra-dependent mechanism, block swarm expansion of motile cells when mixed. Thus, mutants defective in OME or a downstream responsive pathway were readily identified as escape flares from mixed inocula seeded on agar. This screen was surprisingly powerful, as we found >50 mutants defective in OME. Importantly, all of the mutations mapped to the
traAB
operon, suggesting that there may be few, if any, proteins besides TraA and TraB directly required for OME. We also found a second and phenotypically different class of mutants that exhibited wild-type OME but were defective in a responsive pathway. This pathway is postulated to control inner membrane homeostasis by covalently attaching amino acids to phospholipids. The identified proteins are homologous to the
Staphylococcus aureus
MprF protein, which is involved in membrane adaptation and antibiotic resistance. Interestingly, we also found that a small number of nonmotile cells were sufficient to block the swarming behavior of a large gliding-proficient population. This result suggests that an OME-derived signal could be amplified from a few nonmotile producers to act on many responder cells.
The Relation Between Diamond Tiling and Hexagonal Tiling
Authors: Grosser Tobias , Verdoolaege Sven , Cohen Albert , Sadayappan P. 
Published: September 2014

Iterative stencil computations are important in scientific computing and more also in the embedded and mobile domain. Recent publications have shown that tiling schemes that ensure concurrent start provide efficient ways to execute these kernels. Diamond tiling and hybrid-hexagonal tiling are two tiling schemes that enable concurrent start. Both have different advantages: diamond tiling has been integrated in a general purpose optimization framework and uses a cost function to choose among tiling hyperplanes, whereas the greater flexibility with tile sizes for hybrid-hexagonal tiling has been exploited for effective generation of GPU code. In this paper we undertake a comparative study of these two tiling approaches and propose a hybrid approach that combines them. We analyze the effects of tile size and wavefront choices on tile-level parallelism, and formulate constraints for optimal diamond tile shapes. We then extend, for the case of two dimensions, the diamond tiling formulation into a hexagonal tiling one, which offers both the flexibility of hexagonal tiling and the generality of the original diamond tiling implementation. We also show how to compute tile sizes that maximize the compute-to-communication ratio, and apply this result to compare the best achievable ratio and the associated synchronization overhead for diamond and hexagonal tiling.
Code Refinement of Stencil Codes
Authors: Köster Marcel , Leißa Roland , Hack Sebastian , Membarth Richard , Slusallek Philipp 
Published: September 2014

A straightforward implementation of an algorithm in a general-purpose programming language does usually not deliver peak performance: Compilers often fail to automatically tune the code for certain hardware peculiarities like memory hierarchy or vector execution units. Manually tuning the code is firstly error-prone as well as time-consuming and secondly taints the code by exposing those peculiarities to the implementation. A popular method to avoid these problems is to implement the algorithm in a Domain-Specific Language (DSL). A DSL compiler can then automatically tune the code for the target platform. In this article we show how to embed a DSL for stencil codes in another language. In contrast to prior approaches we only use a single language for this task which offers explicit control over code refinement. This is used to specialize stencils for particular scenarios. Our results show that our specialized programs achieve competitive performance compared to hand-tuned CUDA programs while maintaining a convenient coding experience.
Olfaction Modulates Early Neural Responses to Matching Visual Objects
Authors: Robinson Amanda K. , Reinhard Judith , Mattingley Jason B. 
Published: September 2014

Abstract
Sensory information is initially registered within anatomically and functionally segregated brain networks but is also integrated across modalities in higher cortical areas. Although considerable research has focused on uncovering the neural correlates of multisensory integration for the modalities of vision, audition, and touch, much less attention has been devoted to understanding interactions between vision and olfaction in humans. In this study, we asked how odors affect neural activity evoked by images of familiar visual objects associated with characteristic smells. We employed scalp-recorded EEG to measure visual ERPs evoked by briefly presented pictures of familiar objects, such as an orange, mint leaves, or a rose. During presentation of each visual stimulus, participants inhaled either a matching odor, a nonmatching odor, or plain air. The N1 component of the visual ERP was significantly enhanced for matching odors in women, but not in men. This is consistent with evidence that women are superior in detecting, discriminating, and identifying odors and that they have a higher gray matter concentration in olfactory areas of the OFC. We conclude that early visual processing is influenced by olfactory cues because of associations between odors and the objects that emit them, and that these associations are stronger in women than in men.
Selective Attention Modulates Early Human Evoked Potentials during Emotional Face–Voice Processing
Authors: Ho Hao Tam , Schröger Erich , Kotz Sonja A. 
Published: September 2014

Abstract
Recent findings on multisensory integration suggest that selective attention influences cross-sensory interactions from an early processing stage. Yet, in the field of emotional face–voice integration, the hypothesis prevails that facial and vocal emotional information interacts preattentively. Using ERPs, we investigated the influence of selective attention on the perception of congruent versus incongruent combinations of neutral and angry facial and vocal expressions. Attention was manipulated via four tasks that directed participants to (i) the facial expression, (ii) the vocal expression, (iii) the emotional congruence between the face and the voice, and (iv) the synchrony between lip movement and speech onset. Our results revealed early interactions between facial and vocal emotional expressions, manifested as modulations of the auditory N1 and P2 amplitude by incongruent emotional face–voice combinations. Although audiovisual emotional interactions within the N1 time window were affected by the attentional manipulations, interactions within the P2 modulation showed no such attentional influence. Thus, we propose that the N1 and P2 are functionally dissociated in terms of emotional face–voice processing and discuss evidence in support of the notion that the N1 is associated with cross-sensory prediction, whereas the P2 relates to the derivation of an emotional percept. Essentially, our findings put the integration of facial and vocal emotional expressions into a new perspective—one that regards the integration process as a composite of multiple, possibly independent subprocesses, some of which are susceptible to attentional modulation, whereas others may be influenced by additional factors.
A Hippocampal Signature of Perceptual Learning in Object Recognition
Authors: Guggenmos Matthias , Rothkirch Marcus , Obermayer Klaus , Haynes John-Dylan , Sterzer Philipp 
Published: September 2014

Abstract
Perceptual learning is the improvement in perceptual performance through training or exposure. Here, we used fMRI before and after extensive behavioral training to investigate the effects of perceptual learning on the recognition of objects under challenging viewing conditions. Objects belonged either to trained or untrained categories. Trained categories were further subdivided into trained and untrained exemplars and were coupled with high or low monetary rewards during training. After a 3-day training, object recognition was markedly improved. Although there was a considerable transfer of learning to untrained exemplars within categories, an enhancing effect of reward reinforcement was specific to trained exemplars. fMRI showed that hippocampus responses to both trained and untrained exemplars of trained categories were enhanced by perceptual learning and correlated with the effect of reward reinforcement. Our results suggest a key role of hippocampus in object recognition after perceptual learning.
Effects of interspecific competition on food hoarding and pilferage in two sympatric rodents
Authors: Zhang Hongmao , Gao Haiyang , Yang Zheng , Wang Zhenzhen , Luo Yang , Zhang Zhibin 
Published: September 2014

Food hoarding and pilferage in rodents may be regulated by intense competition between sympatric species that have similar habitats, diets and activity, but studies exploring this remain rare. Here, we used semi-natural enclosures to investigate food-hoarding and cache pilferage interactions between sympatric Korean field mice (KFM) (Apodemus peninsulae) and Chinese white-bellied rats (CWR) (Niviventer confucianus). KFM and CWR have similar diets, habitat and nocturnal activity, but the smaller KFM larder and scatter hoards and larger CWR larder hoard only. We found that KFM harvest, larder-hoard and eat seeds at a greater intensity when CWR are present as an audience (present but cannot pilfer). KFM ate 11.5%, re-larder-hoarded 17.9% and re-scatter-hoarded 1.3% of their scatter-hoarded seeds, and ate 29.3% of their larder-hoarded seeds when CWR were present as pilferers. A total of 12.8% of the seeds scatter-hoarded and 50% of seeds directly put on the ground by KFM were pilfered by CWR. CWR did not alter hoarding intensity in the presence of KFM and their stores cannot be pilfered by KFM. These results indicate that large-sized rodent species (more dominant) significantly increase the hoarding intensity of small-sized species and show a unidirectional pilferage of seeds cached by small-sized species. The behavioural differences between these two species may reduce competition for resources and promote coexistence between sympatric rodents.
Multivariate—Intervariable, Spatial, and Temporal—Bias Correction*
Authors: Vrac Mathieu , Friederichs Petra 
Published: September 2014

Abstract
Statistical methods to bias correct global or regional climate model output are now common to get data closer to observations in distribution. However, most bias correction (BC) methods work for one variable and one location at a time and basically reproduce the temporal structure of the models. The intervariable, spatial, and temporal dependencies of the corrected data are usually poor compared to observations. Here, the authors propose a novel method for multivariate BC. The empirical copula–bias correction (EC–BC) combines a one-dimensional BC with a shuffling technique that restores an empirical multidimensional copula. Several BC methods are investigated and compared to high-resolution reference data over the French Mediterranean basin: notably, (i) a 1D BC method applied independently to precipitation and temperature fields, (ii) a recent conditional correction approach developed for producing correct two-dimensional intervariable structures, and (iii) the EC–BC method.
Assessments are realized in terms of intervariable, spatial, and temporal dependencies, and an objective evaluation using the integrated quadratic distance (IQD) is presented. As expected, the 1D methods cannot produce correct multidimensional properties. The conditional technique appears efficient for intervariable properties but not for spatial and temporal dependencies. EC–BC provides realistic dependencies in all respects: intervariable, spatial, and temporal. The IQD results are clearly in favor of EC–BC. As many BC methods, EC–BC relies on a stationarity assumption and is only able to reproduce patterns inherited from historical data. However, because of its ease of coding, its speed of application, and the quality of its results, the EC–BC method is a very good candidate for all needs in multivariate bias correction.