bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ceftaroline Increases Membrane Binding and Enhances the Activity of Daptomycin against Daptomycin-Nonsusceptible Vancomycin-Intermediate Staphylococcus aureus in a Pharmacokinetic/Pharmacodynamic Model
Authors: Werth Brian J. , Sakoulas George , Rose Warren E. , Pogliano Joseph , Tewhey Ryan , Rybak Michael J. 
Published: October 2012

ABSTRACT

New antimicrobial agents and novel combination therapies are needed to treat serious infections caused by methicillin-resistant
Staphylococcus aureus
(MRSA) with reduced susceptibility to daptomycin and vancomycin. The purpose of this study was to evaluate the combination of ceftaroline plus daptomycin or vancomycin in an
in vitro
pharmacokinetic/pharmacodynamic model. Simulations of ceftaroline-fosamil at 600 mg per kg of body weight every 8 h (q8h) (maximum free-drug concentration in serum [
fC
max
], 15.2 mg/liter; half-life [
t
1/2
], 2.3 h), daptomycin at 10 mg/kg/day (
f
C
max
, 11.3 mg/liter;
t
1/2
, 8 h), vancomycin at 2 g q12h (
fC
max
, 30 mg/liter;
t
1/2
, 6 h), ceftaroline plus daptomycin, and ceftaroline plus vancomycin were evaluated against a clinical, isogenic MRSA strain pair: D592 (daptomycin susceptible and heterogeneous vancomycin intermediate) and D712 (daptomycin nonsusceptible and vancomycin intermediate) in a one-compartment
in vitro
pharmacokinetic/pharmacodynamic model over 96 h. Therapeutic enhancement of combinations was defined as ≥2 log
10
CFU/ml reduction over the most active single agent. The effect of ceftaroline on the membrane charge, cell wall thickness, susceptibility to killing by the human cathelicidin LL37, and daptomycin binding were evaluated. Therapeutic enhancement was observed with daptomycin plus ceftaroline in both strains and vancomycin plus ceftaroline against D592. Ceftaroline exposure enhanced daptomycin-induced depolarization (81.7% versus 72.3%;
P
= 0.03) and killing by cathelicidin LL37 (
P
< 0.01) and reduced cell wall thickness (
P
< 0.001). Fluorescence-labeled daptomycin was bound over 7-fold more in ceftaroline-exposed cells. Whole-genome sequencing and mutation analysis of these strains indicated that change in daptomycin susceptibility is related to an
fmtC
(
mprF
) mutation. The combination of daptomycin plus ceftaroline appears to be potent, with rapid and sustained bactericidal activity against both daptomycin-susceptible and -nonsusceptible strains of MRSA.
Transferable Multiresistance Plasmids Carrying
cfr
in Enterococcus spp. from Swine and Farm Environment
Authors: Liu Yang , Wang Yang , Schwarz Stefan , Li Yun , Shen Zhangqi , Zhang Qijing , Wu Congming , Shen Jianzhong 
Published: October 2012

ABSTRACT

Seventy-seven porcine
Enterococcus
isolates with florfenicol MICs of ≥16 μg of were/ml screened for the presence of the multiresistance gene
cfr
, its location on plasmids, and its genetic environment. Three isolates—
Enterococcus thailandicus
3-38 (from a porcine rectal swab collected at a pig farm),
Enterococcus thailandicus
W3, and
Enterococcus faecalis
W9-2 (the latter two from sewage at a different farm), carried the
cfr
gene. The SmaI pulsed-field gel electrophoresis patterns of the three isolates differed distinctly. In addition,
E. faecalis
W9-2 was assigned to a new multilocus sequence type ST469. Mating experiments and Southern blot analysis indicated that
cfr
is located on conjugative plasmids pW3 (∼75 kb) from
E. thailandicus
W3, p3-38 (∼72 kb) from
E. thailandicus
3-38, and pW9-2 (∼55 kb) from
E. faecalis
W9-2; these plasmids differed in their sizes, additional resistance genes, and the analysis of the segments encompassing the
cfr
gene. Sequence analysis revealed that all plasmids harbored a 4,447-bp central region, in which
cfr
was bracketed by two copies of the novel insertion sequence IS
Enfa4
located in the same orientation. The sequences flanking the central regions of these plasmids, including the partial
tra
gene regions and a ω-ε-ζ toxin-antitoxin module, exhibited >95% nucleotide sequence identity to the conjugative plasmid pAMβ1 from
E. faecalis
. Conjugative plasmids carrying
cfr
appear to play an important role in the dissemination and maintenance of the multiresistance gene
cfr
among enterococcal isolates and possibly other species of Gram-positive bacteria.
VraT/YvqF Is Required for Methicillin Resistance and Activation of the VraSR Regulon in Staphylococcus aureus
Authors: Boyle-Vavra Susan , Yin Shouhui , Jo Dae Sun , Montgomery Christopher P. , Daum Robert S. 
Published: October 2012

ABSTRACT

Staphylococcus aureus
infections caused by strains that are resistant to all forms of penicillin, so-called methicillin-resistant
S. aureus
(MRSA) strains, have become common. One strategy to counter MRSA infections is to use compounds that resensitize MRSA to methicillin.
S. aureus
responds to diverse classes of cell wall-inhibitory antibiotics, like methicillin, using the two-component regulatory system VraSR (
vra
) to up- or downregulate a set of genes (the cell wall stimulon) that presumably facilitates resistance to these antibiotics. Accordingly, VraS and VraR mutations decrease resistance to methicillin, vancomycin, and daptomycin cell wall antimicrobials.
vraS
and
vraR
are encoded together on a transcript downstream of two other genes, which we call
vraU
and
vraT
(previously called
yvqF
). By producing nonpolar deletions in
vraU
and
vraT
in a USA300 MRSA clinical isolate, we demonstrate that
vraT
is essential for optimal expression of methicillin resistance
in vitro
, whereas
vraU
is not required for this phenotype. The deletion of
vraT
also improved the outcomes of oxacillin therapy in mouse models of lung and skin infection. Since
vraT
expressed in
trans
did not complement a
vra
operon deletion, we conclude that VraT does not inactivate the antimicrobial. Genome-wide transcriptional microarray experiments reveal that VraT facilitates resistance by playing a necessary regulatory role in the VraSR-mediated cell wall stimulon. Our data prove that VraTSR comprise a novel three-component regulatory system required to facilitate resistance to cell wall agents in
S. aureus
. We also provide the first
in vivo
proof of principle for using VraT as a sole target to resensitize MRSA to β-lactams.
Childhood adversities and adult-onset asthma: a cohort study
Authors: Korkeila Jyrki , Lietzen Raija , Sillanmäki Lauri H , Rautava Päivi , Korkeila Katariina , Kivimäki Mika , Koskenvuo Markku , Vahtera Jussi 
Published: October 2012

ObjectivesChildhood adversities may be important determinants of later illnesses and poor health behaviour. However, large-scale prospective studies on the associations between childhood adversities and the onset of asthma in adulthood are lacking.DesignProspective cohort study with 7-year follow-up.SettingNationally representative study. Data were collected from the Health and Social Support (HeSSup) survey and national registers.ParticipantsThe participants represent the Finnish population from the following age groups: 20–24, 30–34, 40–44, and 50–54 years at baseline in 1998 (24 057 survey participants formed the final cohort of this study). The occurrence of childhood adversities was assessed at baseline with a six-item survey scale. The analyses were adjusted for sociodemographic characteristics, behavioural health risks and common mental disorders.Primary and secondary outcomesThe survey data were linked to data from national health registers on incident asthma during a 7-year follow-up to define new-onset asthma cases with verified diagnoses.ResultsA total of 12 126 (59%) participants reported that they encountered a childhood adversity. Of them 3677 (18% of all) endured three to six adversities. During a follow-up of 7 years, 593 (2.9%) participants were diagnosed with incident asthma. Those who reported three or more childhood adversities had a 1.6-fold (95% CI 1.31 to 2.01) greater risk of asthma compared to those without childhood adversities. This hazard attenuated but remained statistically significant after adjustment for conventional risk factors (HR 1.33; 95% CI 1.06 to 1.67).ConclusionsAdults who report having encountered adversities in childhood may have an increased risk of developing asthma.
OPTIMAL BINARY SPACE PARTITIONS FOR SEGMENTS IN THE PLANE
Authors: DE BERG MARK , KHOSRAVI AMIRALI 
Published: October 2012

An optimal BSP for a set S of disjoint line segments in the plane is a BSP for S that produces the minimum number of cuts. We study optimal BSPs for three classes of BSPs, which differ in the splitting lines that can be used when partitioning a set of fragments in the recursive partitioning process: free BSPs can use any splitting line, restricted BSPs can only use splitting lines through pairs of fragment endpoints, and auto-partitions can only use splitting lines containing a fragment. We obtain the following two results: • It is NP-hard to decide whether a given set of segments admits an auto-partition that does not make any cuts. • An optimal restricted BSP makes at most 2 times as many cuts as an optimal free BSP for the same set of segments.
Scheduling of stream-based real-time applications for heterogeneous systems
Authors: Virlet Bruno , Zhou Xing , Giacalone Jean Pierre , Kuhn Bob , Garzaran Maria J. , Padua David 
Published: October 2012

Designers of mobile devices face the challenge of providing the user with more processing power while increasing battery life. Heterogeneous systems offer some opportunities to solve this challenge. In an heterogeneous system, multiple classes of processors with dynamic voltage and frequency scaling functionality are embedded in the mobile device. With such a system it is possible to maximize performance while minimizing power consumption if tasks are mapped to the class of processors where they execute the most efficiently.
In this paper, we study the scheduling of tasks in a real-time context on a heterogeneous system-on-chip that has dynamic voltage and frequency scaling functionality. We develop a heuristic scheduling algorithm which minimizes the energy while still meeting the deadline. We introduce the concept of cross-platform task heterogeneity and model sets of tasks to conduct extensive experiments. The experimental results show that our heuristic has a much higher success rate than existing state of the art heuristics and derives a solution whose energy requirements are close to those of the optimal solution.
Precise and efficient parametric path analysis
Authors: Althaus Ernst , Altmeyer Sebastian , Naujoks Rouven 
Published: October 2012

Hard real-time systems require tasks to finish in time. To guarantee the timeliness of such a system, static timing analyses derive upper bounds on the worst-case execution time (WCET) of tasks. There are two types of timing analyses: numeric and parametric. A numeric analysis derives a numeric timing bound and, to this end, assumes all information such as loop bounds to be given a priori. If these bounds are unknown during analysis time, a parametric analysis can compute a timing formula parametric in these variables. A performance bottleneck of timing analyses, numeric and especially parametric, is the so-called path analysis, which determines the path in the analyzed task with the longest execution time bound.
In this paper, we present a new approach to path analysis. This approach exploits the often rather regular structure of software for hard real-time and safety-critical systems. As we show in the evaluation of this paper, we strongly improve upon former techniques in terms of precision and runtime in the parametric case. Even in the numeric case, the approach competes with state-of-the-art techniques and may be an alternative to commercial tools employed for path analysis.
Global productiveness propagation
Authors: Bhagat Indu , Gibert Enric , Sánchez Jesús , González Antonio 
Published: October 2012

This paper proposes a unique hardware-software collaborative strategy to remove useless work at 16-bit data-width granularity. The underlying motivation is to design a low power execution platform by exploiting 'narrow' computations. The proposal uses a strictly narrow bit-wide microarchitecture (16-bit integer datapath), which realizes the goal of a low cost, low hardware complexity, low power execution engine. Software dynamically maps the 64-bit computations by translating them into an equivalent 16-bit instruction stream and optimizing them.
In this paper, we propose an optimization technique, called Global Productiveness Propagation (GPP), which is a dynamic, profile-based optimization technique that infers the minimum required dataflow by pruning narrow computations that are most-probably useless (non-productive). More precisely, GPP speculatively prunes the static backward slices of selected narrow computations: computations that result in the same value (in their respective storage location) as that at the input of the region. This speculative optimization technique is formulated around the concept of 'narrow' computations because the same allow a finer granularity to distinguish between useful (productive) and useless (non-productive) work. GPP has been evaluated on an in-order narrow bit-wide execution core, achieving an average dynamic instruction stream reduction of 6.6%, while improving overall performance by 4.2%.
Underspecified harnesses and interleaved bugs
Authors: Joshi Saurabh , Lahiri Shuvendu K. , Lal Akash 
Published: October 2012

Static assertion checking of open programs requires setting up a precise harness to capture the environment assumptions. For instance, a library may require a file handle to be properly initialized before it is passed into it. A harness is used to set up or specify the appropriate preconditions before invoking methods from the program. In the absence of a precise harness, even the most precise automated static checkers are bound to report numerous false alarms. This often limits the adoption of static assertion checking in the hands of a user.
In this work, we explore the possibility of automatically filtering away (or prioritizing) warnings that result from imprecision in the harness. We limit our attention to the scenario when one is interested in finding bugs due to concurrency. We define a warning to be an interleaved bug when it manifests on an input for which no sequential interleaving produces a warning. As we argue in the paper, limiting a static analysis to only consider interleaved bugs greatly reduces false positives during static concurrency analysis in the presence of an imprecise harness.
We formalize interleaved bugs as a differential analysis between the original program and its sequential version and provide various techniques for finding them. Our implementation CBugs demonstrates that the scheme of finding interleaved bugs can alleviate the need to construct precise harnesses while checking real-life concurrent programs.
Higher-order functional reactive programming in bounded space
Authors: Krishnaswami Neelakantan R. , Benton Nick , Hoffmann Jan 
Published: October 2012

Functional reactive programming (FRP) is an elegant and successful approach to programming reactive systems declaratively. The high levels of abstraction and expressivity that make FRP attractive as a programming model do, however, often lead to programs whose resource usage is excessive and hard to predict. In this paper, we address the problem of space leaks in discrete-time functional reactive programs. We present a functional reactive programming language that statically bounds the size of the dataflow graph a reactive program creates, while still permitting use of higher-order functions and higher-type streams such as streams of streams. We achieve this with a novel linear type theory that both controls allocation and ensures that all recursive definitions are well-founded.
We also give a denotational semantics for our language by combining recent work on metric spaces for the interpretation of higher-order causal functions with length-space models of space-bounded computation. The resulting category is doubly closed and hence forms a model of the logic of bunched implications.
Constraints as control
Authors: Köksal Ali Sinan , Kuncak Viktor , Suter Philippe 
Published: October 2012

We present an extension of Scala that supports constraint programming over bounded and unbounded domains. The resulting language, Kaplan, provides the benefits of constraint programming while preserving the existing features of Scala. Kaplan integrates constraint and imperative programming by using constraints as an advanced control structure; the developers use the monadic 'for' construct to iterate over the solutions of constraints or branch on the existence of a solution. The constructs we introduce have simple semantics that can be understood as explicit enumeration of values, but are implemented more efficiently using symbolic reasoning. Kaplan programs can manipulate constraints at run-time, with the combined benefits of type-safe syntax trees and first-class functions. The language of constraints is a functional subset of Scala, supporting arbitrary recursive function definitions over algebraic data types, sets, maps, and integers.
Our implementation runs on a platform combining a constraint solver with a standard virtual machine. For constraint solving we use an algorithm that handles recursive function definitions through fair function unrolling and builds upon the state-of-the art SMT solver Z3. We evaluate Kaplan on examples ranging from enumeration of data structures to execution of declarative specifications. We found Kaplan promising because it is expressive, supporting a range of problem domains, while enabling full-speed execution of programs that do not rely on constraint programming.
Playing in the grey area of proofs
Authors: Hoder Krystof , Kovacs Laura , Voronkov Andrei 
Published: October 2012

Interpolation is an important technique in verification and static analysis of programs. In particular, interpolants extracted from proofs of various properties are used in invariant generation and bounded model checking. A number of recent papers studies interpolation in various theories and also extraction of smaller interpolants from proofs. In particular, there are several algorithms for extracting of interpolants from so-called local proofs. The main contribution of this paper is a technique of minimising interpolants based on transformations of what we call the "grey area" of local proofs. Another contribution is a technique of transforming, under certain common conditions, arbitrary proofs into local ones.
Unlike many other interpolation techniques, our technique is very general and applies to arbitrary theories. Our approach is implemented in the theorem prover Vampire and evaluated on a large number of benchmarks coming from first-order theorem proving and bounded model checking using logic with equality, uninterpreted functions and linear integer arithmetic. Our experiments demonstrate the power of the new techniques: for example, it is not unusual that our proof transformation gives more than a tenfold reduction in the size of interpolants.
Formalizing the LLVM intermediate representation for verified program transformations
Authors: Zhao Jianzhou , Nagarakatte Santosh , Martin Milo M.K. , Zdancewic Steve 
Published: October 2012

This paper presents Vellvm (verified LLVM), a framework for reasoning about programs expressed in LLVM's intermediate representation and transformations that operate on it. Vellvm provides a mechanized formal semantics of LLVM's intermediate representation, its type system, and properties of its SSA form. The framework is built using the Coq interactive theorem prover. It includes multiple operational semantics and proves relations among them to facilitate different reasoning styles and proof techniques.
To validate Vellvm's design, we extract an interpreter from the Coq formal semantics that can execute programs from LLVM test suite and thus be compared against LLVM reference implementations. To demonstrate Vellvm's practicality, we formalize and verify a previously proposed transformation that hardens C programs against spatial memory safety violations. Vellvm's tools allow us to extract a new, verified implementation of the transformation pass that plugs into the real LLVM infrastructure; its performance is competitive with the non-verified, ad-hoc original.
The ins and outs of gradual type inference
Authors: Rastogi Aseem , Chaudhuri Avik , Hosmer Basil 
Published: October 2012

Gradual typing lets programmers evolve their dynamically typed programs by gradually adding explicit type annotations, which confer benefits like improved performance and fewer run-time failures.
However, we argue that such evolution often requires a giant leap, and that type inference can offer a crucial missing step. If omitted type annotations are interpreted as unknown types, rather than the dynamic type, then static types can often be inferred, thereby removing unnecessary assumptions of the dynamic type. The remaining assumptions of the dynamic type may then be removed by either reasoning outside the static type system, or restructuring the code.
We present a type inference algorithm that can improve the performance of existing gradually typed programs without introducing any new run-time failures. To account for dynamic typing, types that flow in to an unknown type are treated in a fundamentally different manner than types that flow out. Furthermore, in the interests of backward-compatibility, an escape analysis is conducted to decide which types are safe to infer. We have implemented our algorithm for ActionScript, and evaluated it on the SunSpider and V8 benchmark suites. We demonstrate that our algorithm can improve the performance of unannotated programs as well as recover most of the type annotations in annotated programs.
StreamKM++
Authors: Ackermann Marcel R. , Märtens Marcus , Raupach Christoph , Swierkot Kamil , Lammersen Christiane , Sohler Christian 
Published: October 2012

We develop a new <it>k</it>-means clustering algorithm for data streams of points from a Euclidean space. We call this algorithm StreamKM++. Our algorithm computes a small weighted sample of the data stream and solves the problem on the sample using the <it>k</it>-means++ algorithm of Arthur and Vassilvitskii (SODA '07). To compute the small sample, we propose two new techniques. First, we use an adaptive, nonuniform sampling approach similar to the <it>k</it>-means++ seeding procedure to obtain small coresets from the data stream. This construction is rather easy to implement and, unlike other coreset constructions, its running time has only a small dependency on the dimensionality of the data. Second, we propose a new data structure, which we call coreset tree. The use of these coreset trees significantly speeds up the time necessary for the adaptive, nonuniform sampling during our coreset construction.
We compare our algorithm experimentally with two well-known streaming implementations: BIRCH [Zhang et al. 1997] and StreamLS [Guha et al. 2003]. In terms of quality (sum of squared errors), our algorithm is comparable with StreamLS and significantly better than BIRCH (up to a factor of 2). Besides, BIRCH requires significant effort to tune its parameters. In terms of running time, our algorithm is slower than BIRCH. Comparing the running time with StreamLS, it turns out that our algorithm scalesmuch better with increasing number of centers. We conclude that, if the first priority is the quality of the clustering, then our algorithm provides a good alternative to BIRCH and StreamLS, in particular, if the number of cluster centers is large. We also give a theoretical justification of our approach by proving that our sample set is a small coreset in low-dimensional spaces.