bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Novel, Broad-Spectrum Inhibitor of Enterovirus Replication That Targets Host Cell Factor Phosphatidylinositol 4-Kinase IIIβ
Authors: van der Schaar Hilde M. , Leyssen Pieter , Thibaut Hendrik J. , de Palma Armando , van der Linden Lonneke , Lanke Kjerstin H. W. , Lacroix Céline , Verbeken Erik , Conrath Katja , MacLeod Angus M. , Mitchell Dale R. , Palmer Nicholas J. , van de Poël Hervé , Andrews Martin , Neyts Johan , van Kuppeveld Frank J. M. 
Published: July 2013

ABSTRACT

Despite their high clinical and socioeconomic impacts, there is currently no approved antiviral therapy for the prophylaxis or treatment of enterovirus infections. Here we report on a novel inhibitor of enterovirus replication, compound 1, 2-fluoro-4-(2-methyl-8-(3-(methylsulfonyl)benzylamino)imidazo[1,2-
a
]pyrazin-3-yl)phenol. This compound exhibited a broad spectrum of antiviral activity, as it inhibited all tested species of enteroviruses and rhinoviruses, with 50% effective concentrations ranging between 4 and 71 nM. After a lengthy resistance selection process, coxsackievirus mutants resistant to compound 1 were isolated that carried substitutions in their 3A protein. Remarkably, the same substitutions were recently shown to provide resistance to inhibitors of phosphatidylinositol 4-kinase IIIβ (PI4KIIIβ), a lipid kinase that is essential for enterovirus replication, suggesting that compound 1 may also target this host factor. Accordingly, compound 1 directly inhibited PI4KIIIβ in an
in vitro
kinase activity assay. Furthermore, the compound strongly reduced the PI 4-phosphate levels of the Golgi complex in cells. Rescue of coxsackievirus replication in the presence of compound 1 by a mutant PI4KIIIβ carrying a substitution in its ATP-binding pocket revealed that the compound directly binds the kinase at this site. Finally, we determined that an analogue of compound 1, 3-(3-fluoro-4-methoxyphenyl)-2-methyl-
N
-(pyridin-4-ylmethyl)imidazo[1,2-
a
]pyrazin-8-amine, is well tolerated in mice and has a dose-dependent protective activity in a coxsackievirus serotype B4-induced pancreatitis model.
Complete Nucleotide Sequence of a
bla
KPC
-Harboring IncI2 Plasmid and Its Dissemination in New Jersey and New York Hospitals
Authors: Chen Liang , Chavda Kalyan D. , Al Laham Nahed , Melano Roberto G. , Jacobs Michael R. , Bonomo Robert A. , Kreiswirth Barry N. 
Published: July 2013

ABSTRACT

Klebsiella pneumoniae
carbapenemase (KPC)-producing
K. pneumoniae
strains have spread worldwide and become a significant public health threat.
bla
KPC
, the plasmid-borne KPC gene, was frequently identified on numerous transferable plasmids in different incompatibility replicon groups. Here we report the complete nucleotide sequence of a novel
bla
KPC-3
-harboring IncI2 plasmid, pBK15692, isolated from a multidrug-resistant
K. pneumoniae
ST258 strain isolated from a New Jersey hospital in 2005. pBK15692 is 78 kb in length and carries a backbone that is similar to those of other IncI2 plasmids (pR721, pChi7122-3, pHN1122-1, and pSH146-65), including the genes encoding type IV pili and shufflon regions. Comparative genomics analysis of IncI2 plasmids reveals that they possess a conserved plasmid backbone but are divergent with respect to the integration sites of resistance genes. In pBK15692, the
bla
KPC-3
-harboring Tn
4401
was inserted into a Tn
1331
element and formed a nested transposon. A PCR scheme was designed to detect the prevalence of IncI2 and pBK15692-like plasmids from a collection of clinical strains from six New Jersey and New York hospitals isolated between 2007 and 2011. IncI2 plasmids were found in 46.2% isolates from 318 clinical
K. pneumoniae
strains. Notably, 59 pBK15692-like plasmids (23%) have been identified in 256 KPC-bearing
K. pneumoniae
strains, and all carried KPC-3 and belong to the epidemic ST258 clone. Our study revealed that the prevalence of IncI2 plasmids has been considerably underestimated. Further studies are needed to understand the distribution of this plasmid group in other health care regions and decipher the association between IncI2 plasmids and
bla
KPC-3
-bearing ST258 strains.
Analysis of Antibodies to Newly Described Plasmodium falciparum Merozoite Antigens Supports MSPDBL2 as a Predicted Target of Naturally Acquired Immunity
Authors: Tetteh Kevin K. A. , Osier Faith H. A. , Salanti Ali , Kamuyu Gathoni , Drought Laura , Failly Marilyne , Martin Christophe , Marsh Kevin , Conway David J. 
Published: July 2013

ABSTRACT

Prospective studies continue to identify malaria parasite genes with particular patterns of polymorphism which indicate they may be under immune selection, and the encoded proteins require investigation. Sixteen new recombinant protein reagents were designed to characterize three such polymorphic proteins expressed in
Plasmodium falciparum
schizonts and merozoites: MSPDBL1 (also termed MSP3.4) and MSPDBL2 (MSP3.8), which possess Duffy binding-like (DBL) domains, and SURFIN4.2, encoded by a member of the surface-associated interspersed (
surf
) multigene family. After testing the antigenicities of these reagents by murine immunization and parasite immunofluorescence, we analyzed naturally acquired antibody responses to the antigens in two cohorts in coastal Kenya in which the parasite was endemic (Chonyi [
n
= 497] and Ngerenya [
n
= 461]). As expected, the prevalence and levels of serum antibodies increased with age. We then investigated correlations with subsequent risk of clinical malaria among children <11 years of age during 6 months follow-up surveillance. Antibodies to the polymorphic central region of MSPDBL2 were associated with reduced risk of malaria in both cohorts, with statistical significance remaining for the 3D7 allelic type after adjustment for individuals' ages in years and antibody reactivity to whole-schizont extract (Chonyi, risk ratio, 0.51, and 95% confidence interval [CI], 0.28 to 0.93; Ngerenya, risk ratio, 0.38, and 95% CI, 0.18 to 0.82). For the MSPDBL1 Palo Alto allelic-type antigen, there was a protective association in one cohort (Ngerenya, risk ratio, 0.53, and 95% CI, 0.32 to 0.89), whereas the other antigens showed no protective associations after adjustment. These findings support the prediction that antibodies to the polymorphic region of MSPDBL2 contribute to protective immunity.
LuxR Homologue SmcR Is Essential for Vibrio vulnificus Pathogenesis and Biofilm Detachment, and Its Expression is Induced by Host Cells
Authors: Kim Seung Min , Park Jin Hwan , Lee Hyun Sung , Kim Won Bin , Ryu Jung Min , Han Ho Jae , Choi Sang Ho 
Published: July 2013

ABSTRACT

Quorum sensing is a cell-to-cell communication system known to control many bacterial processes. In the present study, the functions of quorum sensing in the pathogenesis of
Vibrio vulnificus
, a food-borne pathogen, were assessed by evaluating the virulence of a mutant deficient in SmcR, a quorum-sensing regulator and homologue of LuxR. When biofilms were used as an inoculum, the
smcR
mutant was impaired in virulence and colonization capacity in the infection of mice. The lack of SmcR also resulted in decreased histopathological damage in mouse jejunum tissue. These results indicated that SmcR is essential for
V. vulnificus
pathogenesis. Moreover, the
smcR
mutant exhibited significantly reduced biofilm detachment. Upon exposure to INT-407 host cells, the wild type, but not the
smcR
mutant, revealed accelerated biofilm detachment. The INT-407 cells increased
smcR
expression by activating the expression of LuxS, an autoinducer-2 synthase, indicating that host cells manipulate the cellular level of SmcR through the quorum-sensing signaling of
V. vulnificus
. A whole-genome microarray analysis revealed that the genes primarily involved in biofilm detachment and formation are up- and downregulated by SmcR, respectively. Among the SmcR-regulated genes,
vvpE
encoding an elastolytic protease was the most upregulated, and the purified VvpE appeared to dissolve established biofilms directly in a concentration-dependent manner
in vitro
. These results suggest that the host cell-induced SmcR enhances the detachment of
V. vulnificus
biofilms entering the host intestine and thereby may promote the dispersal of the pathogen to new colonization loci, which is crucial for pathogenesis.
CD8+T Cells Specific for a Malaria Cytoplasmic Antigen Form Clusters around Infected Hepatocytes and Are Protective at the Liver Stage of Infection
Authors: Kimura Kazumi , Kimura Daisuke , Matsushima Yoshifumi , Miyakoda Mana , Honma Kiri , Yuda Masao , Yui Katsuyuki 
Published: July 2013

ABSTRACTFollowingAnophelesmosquito-mediated introduction into a human host,Plasmodiumparasites infect hepatocytes and undergo intensive replication. Accumulating evidence indicates that CD8+T cells induced by immunization with attenuatedPlasmodiumsporozoites can confer sterile immunity at the liver stage of infection; however, the mechanisms underlying this protection are not clearly understood. To address this, we generated recombinantPlasmodium bergheiANKA expressing a fusion protein of an ovalbumin epitope and green fluorescent protein in the cytoplasm of the parasite. We have shown that the ovalbumin epitope is presented by infected liver cells in a manner dependent on a transporter associated with antigen processing and becomes a target of specific CD8+T cells from the T cell receptor transgenic mouse line OT-I, leading to protection at the liver stage ofPlasmodiuminfection. We visualized the interaction between OT-I cells and infected hepatocytes by intravital imaging using two-photon microscopy. OT-I cells formed clusters around infected hepatocytes, leading to the elimination of the intrahepatic parasites and subsequent formation of large clusters of OT-I cells in the liver. Gamma interferon expressed in CD8+T cells was dispensable for this protective response. Additionally, we found that polyclonal ovalbumin-specific memory CD8+T cells induced byde novoimmunization were able to confer sterile protection, although the threshold frequency of the protection was relatively high. These studies revealed a novel mechanism of specific CD8+T cell-mediated protective immunity and demonstrated that proteins expressed in the cytoplasm ofPlasmodiumparasites can become targets of specific CD8+T cells during liver-stage infection.
Dissection of the Role of Pili and Type 2 and 3 Secretion Systems in Adherence and Biofilm Formation of an Atypical Enteropathogenic Escherichia coli Strain
Authors: Hernandes Rodrigo T. , De la Cruz Miguel A. , Yamamoto Denise , Girón Jorge A. , Gomes Tânia A. T. 
Published: July 2013

ABSTRACT

Atypical enteropathogenic
Escherichia coli
(aEPEC) strains are diarrheal pathogens that lack bundle-forming pilus production but possess the virulence-associated locus of enterocyte effacement. aEPEC strain 1551-2 produces localized adherence (LA) on HeLa cells; however, its isogenic intimin (
eae
) mutant produces a diffuse-adherence (DA) pattern. In this study, we aimed to identify the DA-associated adhesin of the 1551-2
eae
mutant. Electron microscopy of 1551-2 identified rigid rod-like pili composed of an 18-kDa protein, which was identified as the major pilin subunit of type 1 pilus (T1P) by mass spectrometry analysis. Deletion of
fimA
in 1551-2 affected biofilm formation but had no effect on adherence properties. Analysis of secreted proteins in supernatants of this strain identified a 150-kDa protein corresponding to SslE, a type 2 secreted protein that was recently reported to be involved in biofilm formation of rabbit and human EPEC strains. However, neither adherence nor biofilm formation was affected in a 1551-2
sslE
mutant. We then investigated the role of the EspA filament associated with the type 3 secretion system (T3SS) in DA by generating a double
eae espA
mutant. This strain was no longer adherent, strongly suggesting that the T3SS translocon is the DA adhesin. In agreement with these results, specific anti-EspA antibodies blocked adherence of the 1551-2
eae
mutant. Our data support a role for intimin in LA, for the T3SS translocon in DA, and for T1P in biofilm formation, all of which may act in concert to facilitate host intestinal colonization by aEPEC strains.
Helicobacter pylori Infection in a Pig Model Is Dominated by Th1 and Cytotoxic CD8+T Cell Responses
Authors: Kronsteiner Barbara , Bassaganya-Riera Josep , Philipson Casandra , Viladomiu Monica , Carbo Adria , Pedragosa Mireia , Vento Salvador , Hontecillas Raquel 
Published: July 2013

ABSTRACTHelicobacter pyloriinfection is the leading cause for peptic ulcer disease and gastric adenocarcinoma. Mucosal T cell responses play an important role in mediatingH. pylori-related gastric immunopathology. While induced regulatory T (iTreg) cells are required for chronic colonization without disease, T helper 1 (Th1) effector responses are associated with lower bacterial loads at the expense of gastric pathology. Pigs were inoculated with eitherH. pyloristrain SS1 or J99. Phenotypic and functional changes in peripheral blood mononuclear cell (PBMC) populations were monitored weekly, and mucosal immune responses and bacterial loads were assessed up to 2 months postinfection. BothH. pyloristrains elicited a Th1 response characterized by increased percentages of CD4+Tbet+cells and elevated gamma interferon (IFN-γ) mRNA in PBMCs. A subset of CD8+T cells expressing Tbet and CD16 increased following infection. Moreover, a significant increase in perforin and granzyme mRNA expression was observed in PBMCs of infected pigs, indicating a predominant cytotoxic immune response. Infiltration of B cells, myeloid cells, T cells expressing Treg- and Th17-associated transcription factors, and cytotoxic T cells was found in the gastric lamina propria of both infected groups. Interestingly, based on bacterial reisolation data, strain SS1 showed greater capacity to colonize and/or persist in the gastric mucosa than did strain J99. This novel pig model of infection closely mimics human gastric pathology and presents a suitable avenue for studying effector and regulatory responses towardH. pyloridescribed in humans.
Development of Severe Pathology in Immunized Pregnant Mice Challenged with Lethal Malaria Parasites
Authors: Mineo Shoichiro , Niikura Mamoru , Inoue Shin-Ichi , Kuroda Masahiko , Kobayashi Fumie 
Published: July 2013

ABSTRACTPregnant women are highly susceptible to malaria infection because of their low immunity and are at increased risk of maternal illness or death, in addition to spontaneous abortion, stillbirth, premature delivery, and low birth weight. However, the detailed pathogenesis of maternal malaria remains unclear. In this study, we evaluated a mouse model that shows similar severe pathological features of pregnant women duringPlasmodium falciparuminfection and investigated the pathogenesis of maternal malaria. Pregnant mice immunized by infection with an attenuated parasite,Plasmodium bergheiXAT, were more susceptible to virulentP. bergheiNK65 challenge/infection than were nonpregnant mice and showed high levels of parasitemia and a poor pregnancy outcome associated with placental pathology, such as accumulation of parasitized red blood cells, in the late phase of pregnancy. Notably, the pregnant immune mice challenged/infected withP. bergheiNK65 developed liver injury associated with microvesicular fatty infiltration in late pregnancy. The pathological features were similar to acute fatty liver of pregnancy. Higher levels of gamma interferon and nitric oxide (NO) were found in plasma from pregnant immune mice infected withP. bergheiNK65 than in plasma from nonpregnant mice. These findings suggest that development of liver injury and placental pathology in pregnant immune mice challenged/infected withP. bergheiNK65 is accompanied by enhanced production of proinflammatory cytokines.
The sad truth about the SADPERSONS Scale: an evaluation of its clinical utility in self-harm patients
Authors: Saunders Kate , Brand Fiona , Lascelles Karen , Hawton Keith 
Published: July 2013

BackgroundThe SADPERSONS Scale is commonly used as a screening tool for suicide risk in those who have self-harmed. It is also used to determine psychiatric treatment needs in those presenting to emergency departments. To date, there have been relatively few studies exploring the utility of SADPERSONS in this context.ObjectivesTo determine whether the SADPERSONS Scale accurately predicts psychiatric hospital admission, psychiatric aftercare and repetition of self-harm at presentation to the emergency department following self-harm.MethodsSADPERSONS scores were recorded for 126 consecutive admissions to a general hospital emergency department. Clinical management outcomes following assessment were recorded, including psychiatric hospital admission, community psychiatric aftercare and repetition of self-harm in the following 6 months.ResultsPsychiatric hospital admission was required in five cases (4.0%) and community psychiatric aftercare in 70 (55.5%). 31 patients (24.6%) repeated self-harm. While the specificity of the SADPERSONS scores was greater than 90% for all outcomes, sensitivity for admission was only 2.0%, for community aftercare was 5.8% and for repetition of self-harm in the following 6 months was just 6.6%.ConclusionsFor the purposes of suicide prevention, a low false negative rate is essential. SADPERSONS failed to identify the majority of those either requiring psychiatric admission or community psychiatric aftercare, or to predict repetition of self-harm. The scale should not be used to screen self-harm patients presenting to general hospitals. Greater emphasis should be placed on clinical assessment which takes account of the individual and dynamic nature of risk assessment.
A methodology to characterize fractured reservoirs constrained by statistical geological analysis and production: a real field case study
Authors: Delorme Matthieu , Oliveira Mota Rosane , Khvoenkova Nina , Fourno André , Nœtinger Benoit 
Published: July 2013

Abstract
In the oil industry, complex workflow is used to match or predict fluid production. The large uncertainty of the data can lead to large variability of the simulation results, notably because of the strongly heterogeneous nature of fluid flows. The particular case of naturally fractured reservoirs is well known to be especially difficult to match.
This paper presents a method to improve an initial geological analysis, carried out in 2008, through the integration of hydrodynamic data in the fractured reservoir model. Dynamic data such as production information, production logging tools and well tests are used to determine fractures properties by calibrating the fluid flow or reservoir pressure measured at wells. The approach, applied to a real field case, respects both the statistical geological analysis and the dynamic analysis of the production history. Using this methodology the geological structural model based on static characterization are preserved and available.
In the study we analysed uncertainties and, in respecting the initial geological model, we prove the presence of compartmentalization in the reservoir by matching 1 year of production and three well tests. Both analytical and numerical flow simulations were used at different scales for time and space: near the well and on the whole reservoir.
Detailed mapping, three-dimensional modelling and upscaling of a mixed-influence delta system, Mitchell River delta, Gulf of Carpentaria, Australia
Authors: Massey T. A. , Fernie A. J. , Ainsworth R. B. , Nanson R. A. , Vakarelov B. K. 
Published: July 2013

Abstract
Data from satellite imagery, field measurements and analogues were used to construct a three-dimensional (3D) geocellular facies model of the Mitchell River Delta, Australia; a modern mixed-influence delta system. Detailed mapping identified 16 different facies elements and classified the delta as tide dominated, fluvially influenced and wave affected. The 3D model was subjected to varying degrees of upscaling of the horizontal and vertical dimensions and allowed comparison of volume and connectivity changes throughout. The upscaling process, to coarser grid cells up to 100 m horizontally and 4 m vertically, created false compartmentalization of facies bodies and significant changes in facies bulk volumes. The vertically upscaled models produced greater changes when compared to the horizontally upscaled models. Key changes in reservoir facies connectivity and bulk volume due to upscaling are associated with the facies architecture, including the elongate and thin morphology of beach ridge and channel facies in this mixed-influence delta system. Recognition of the defining reservoir features and incorporation into reservoir modelling methodology can improve volumetric estimation and allow for better predictions of reservoir connectivity in ancient delta systems.
Dependent Type Theory for Verification of Information Flow and Access Control Policies
Authors: Nanevski Aleksandar , Banerjee Anindya , Garg Deepak 
Published: July 2013

Dedicated to the memory of John C. Reynolds (1935--2013).
We present Relational Hoare Type Theory (RHTT), a novel language and verification system capable of expressing and verifying rich information flow and access control policies via dependent types. We show that a number of security policies which have been formalized separately in the literature can all be expressed in RHTT using only standard type-theoretic constructions such as monads, higher-order functions, abstract types, abstract predicates, and modules. Example security policies include conditional declassification, information erasure, and state-dependent information flow and access control. RHTT can reason about such policies in the presence of dynamic memory allocation, deallocation, pointer aliasing and arithmetic.
Quantum rotations
Authors: Kudrow Daniel , Bier Kenneth , Deng Zhaoxia , Franklin Diana , Tomita Yu , Brown Kenneth R. , Chong Frederic T. 
Published: July 2013

Work in quantum computer architecture has focused on communication, layout and fault tolerance, largely driven by Shor's factorization algorithm. For the first time, we study a larger range of benchmarks and find that another critical issue is the generation of code sequences for quantum rotation operations. Specifically, quantum algorithms require arbitrary rotation angles, while quantum technologies and error correction codes provide only for discrete angles and operators. A sequence of quantum machine instructions must be generated to approximate the arbitrary rotation to the required precision.
While previous work has focused exclusively on static compilation, we find that some applications require dynamic code generation and explore the advantages and disadvantages of static and dynamic approaches. We find that static code generation can, in some cases, lead to a terabyte of machine code to support required rotations. We also find that some rotation angles are unknown until run time, requiring dynamic code generation. Dynamic code generation, however, exhibits significant trade-offs in terms of time overhead versus code size. Furthermore, dynamic code generation will be performed on classical (non-quantum) computing resources, which may or may not have a clock speed advantage over the target quantum technology. For example, operations on trapped ions run at kilohertz speeds, but superconducting qubits run at gigahertz speeds.
We introduce a new method for compiling arbitrary rotations dynamically, designed to minimize compilation time. The new method reduces compilation time by up to five orders of magnitude while increasing code size by one order of magnitude.
We explore the design space formed by these trade-offs of dynamic versus static code generation, code quality, and quantum technology. We introduce several techniques to provide smoother trade-offs for dynamic code generation and evaluate the viability of options in the design space.