bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic and Biochemical Comparison of the Carbapenem-Hydrolyzing Activities of Five Plasmid-Borne AmpC β-Lactamases
Authors: Mammeri Hedi , Guillon Hélène , Eb François , Nordmann Patrice 
Published: August 2010

ABSTRACT

The CMY-2, ACT-1, DHA-1, ACC-1, and FOX-1 enzymes are representative of five plasmid-mediated AmpC (pAmpC) β-lactamase clusters. Resistance to imipenem has been reported in
Enterobacteriaceae
as a result of pAmpC expression combined with decreased outer membrane permeability. The aim of this study was to determine the role of different pAmpCs in carbapenem resistance and to define the structure/activity relationship supporting carbapenemase activity. The
ampC
genes encoding the five pAmpCs and the chromosomal AmpC of
Escherichia coli
EC6, which was used as a reference cephalosporinase, were cloned and introduced into wild-type
E. coli
TOP10 and OmpC/OmpF porin-deficient
E. coli
HB4 strains. The MICs of β-lactams for the recombinant strains revealed that CMY-2, ACT-1, and DHA-1 β-lactamases conferred a high level of resistance to ceftazidime and cefotaxime once expressed in
E. coli
TOP10 and reduced significantly the susceptibility to imipenem once expressed in
E. coli
HB4. In contrast, FOX-1 and ACC-1 enzymes did not confer resistance to imipenem. Biochemical analysis showed that CMY-2 β-lactamase and, to a lesser extent, ACT-1 exhibited the highest catalytic efficiency toward imipenem and showed low

K
m

values. A modeling study revealed that the large R2 binding site of these two enzymes may support the carbapenemase activity. Therefore, CMY-2-type, ACT-1-type, and DHA-1-type β-lactamases may promote the emergence of carbapenem resistance in porin-deficient clinical isolates.
Specific Resistance to
Pseudomonas aeruginosa
Infection in Zebrafish Is Mediated by the Cystic Fibrosis Transmembrane Conductance Regulator
Authors: Phennicie Ryan T. , Sullivan Matthew J. , Singer John T. , Yoder Jeffrey A. , Kim Carol H. 
Published: August 2010

ABSTRACT

Cystic fibrosis (CF) is a genetic disease caused by recessive mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is associated with prevalent and chronic
Pseudomonas aeruginosa
lung infections. Despite numerous studies that have sought to elucidate the role of CFTR in the innate immune response, the links between CFTR, innate immunity, and
P. aeruginosa
infection remain unclear. The present work highlights the zebrafish as a powerful model organism for human infectious disease, particularly infection by
P. aeruginosa
. Zebrafish embryos with reduced expression of the
cftr
gene (Cftr morphants) exhibited reduced respiratory burst response and directed neutrophil migration, supporting a connection between
cftr
and the innate immune response. Cftr morphants were infected with
P. aeruginosa
or other bacterial species that are commonly associated with infections in CF patients, including
Burkholderia cenocepacia
,
Haemophilus influenzae
, and
Staphylococcus aureus
. Intriguingly, the bacterial burden of
P. aeruginosa
was found to be significantly higher in zebrafish Cftr morphants than in controls, but this phenomenon was not observed with the other bacterial species. Bacterial burden in Cftr morphants infected with a
P. aeruginosa
ΔLasR mutant, a quorum sensing-deficient strain, was comparable to that in control fish, indicating that the regulation of virulence factors through LasR is required for enhancement of infection in the absence of Cftr. The zebrafish system provides a multitude of advantages for studying the pathogenesis of
P. aeruginosa
and for understanding the role that innate immune cells, such as neutrophils, play in the host response to acute bacterial infections commonly associated with cystic fibrosis.
Human Intestinal Tissue and Cultured Colonic Cells Contain Globotriaosylceramide Synthase mRNA and the Alternate Shiga Toxin Receptor Globotetraosylceramide
Authors: Zumbrun Steven D. , Hanson Leanne , Sinclair James F. , Freedy James , Melton-Celsa Angela R. , Rodriguez-Canales Jaime , Hanson Jeffrey C. , O'Brien Alison D. 
Published: August 2010

ABSTRACT

Escherichia coli
O157:H7 and other Shiga toxin (Stx)-producing
E. coli
(STEC) bacteria are not enteroinvasive but can cause hemorrhagic colitis. In some STEC-infected individuals, a life-threatening sequela of infection called the hemolytic uremic syndrome may develop that can lead to kidney failure. This syndrome is linked to the production of Stx by the infecting organism. For Stx to reach the kidney, the toxin must first penetrate the colonic epithelial barrier. However, the Stx receptor, globotriaosylceramide (Gb3), has been thought to be absent from human intestinal epithelial cells. Thus, the mechanisms by which the toxin associates with and traverses through the intestine en route to the kidneys have been puzzling aspects of STEC pathogenesis. In this study, we initially determined that both types of Stx made by STEC, Stx1 and Stx2, do in fact bind to colonic epithelia in fresh tissue sections and to a colonic epithelial cell line (HCT-8). We also discovered that globotetraosylceramide (Gb4), a lower-affinity toxin receptor derived from Gb3, is readily detectable on the surfaces of human colonic tissue sections and HCT-8 cells. Furthermore, we found that Gb3 is present on a fraction of HCT-8 cells, where it presumably functions to bind and internalize Stx1 and Stx2. In addition, we established by quantitative real-time PCR (qRT-PCR) that both fresh colonic epithelial sections and HCT-8 cells express Gb3 synthase mRNA. Taken together, our data suggest that Gb3 may be present in small quantities in human colonic epithelia, where it may compete for Stx binding with the more abundantly expressed glycosphingolipid Gb4.
Tolerating byzantine faults in transaction processing systems using commit barrier scheduling
Authors: Vandiver Ben , Balakrishnan Hari , Liskov Barbara , Madden Sam 
Published: August 2010

This paper describes the design, implementation, and evaluation of areplication scheme to handle Byzantine faults in transaction processing database systems. The scheme compares answers from queries and updates on multiple replicas which are unmodified, off-the-shelf systems, to provide a single database that is Byzantine fault tolerant. The scheme works when the replicas are homogeneous, but it also allows heterogeneous replication in which replicas come from different vendors. Heterogeneous replicas reduce the impact of bugs and security compromises because they are implemented independently and are thus less likely to suffer correlated failures.
The main challenge in designing a replication scheme for transactionprocessing systems is ensuring that the different replicas execute transactions in equivalent serial orders while allowing a high degreeof concurrency. Our scheme meets this goal using a novel concurrency control protocol, commit barrier scheduling (CBS). We have implemented CBS in the context of a replicated SQL database, HRDB(Heterogeneous Replicated DB), which has been tested with unmodified production versions of several commercial and open source databases as replicas. Our experiments show an HRDB configuration that can tolerate one faulty replica has only a modest performance overhead(about 17% for the TPC-C benchmark). HRDB successfully masks several Byzantine faults observed in practice and we have used it to find a new bug in MySQL.
SecVisor
Authors: Seshadri Arvind , Luk Mark , Qu Ning , Perrig Adrian 
Published: August 2010

We propose SecVisor, a tiny hypervisor that ensures code integrity for commodity OS kernels. In particular, SecVisor ensures that only user-approved code can execute in kernel mode over the entire system lifetime. This protects the kernel against code injection attacks, such as kernel rootkits. SecVisor can achieve this propertyeven against an attacker who controls everything but the CPU, the memory controller, and system memory chips. Further, SecVisor can even defend against attackers with knowledge of zero-day kernel exploits.
Our goal is to make SecVisor amenable to formal verificationand manual audit, thereby making it possible to rule out known classes of vulnerabilities. To this end, SecVisor offers small code size and small external interface. We rely on memory virtualization to build SecVisor and implement two versions, one using software memory virtualization and the other using CPU-supported memory virtualization. The code sizes of the runtime portions of these versions are 1739 and 1112 lines, respectively. The size of the external interface for both versions of SecVisor is 2 hypercalls. It is easy to port OS kernels to SecVisor. We port the Linux kernel version 2.6.20 by adding 12 lines and deleting 81 lines, out of a total of approximately 4.3 million lines of code in the kernel.
Clowns to the left of me, jokers to the right (pearl)
Authors: McBride Conor 
Published: August 2010

This paper introduces a small but useful generalisation to the 'derivative' operation on datatypes underlying Huet's notion of 'zipper', giving a concrete representation to one-hole contexts in data which is undergoing transformation. This operator, 'dissection', turns a container-like functor into a bifunctor representing a one-hole context in which elements to the left of the hole are distinguished in type from elements to its right.
I present dissection here as a generic program, albeit for polynomial functors only. The notion is certainly applicable more widely, but here I prefer to concentrate on its diverse applications. For a start, map-like operations over the functor and fold-like operations over the recursive data structure it induces can be expressed by tail recursion alone. Further, the derivative is readily recovered from the dissection. Indeed, it is the dissection structure which delivers Huet's operations for navigating zippers.
The original motivation for dissection was to define 'division', capturing the notion of leftmost hole, canonically distinguishing values with no elements from those with at least one. Division gives rise to an isomorphism corresponding to the remainder theorem in algebra. By way of a larger example, division and dissection are exploited to give a relatively efficient generic algorithm for abstracting all occurrences of one term from another in a first-order syntax. The source code for the paper is available online and compiles with recent extensions to the Glasgow Haskell Compiler.
Circuit optimization techniques to mitigate the effects of soft errors in combinational logic
Authors: Rao Rajeev R. , Joshi Vivek , Blaauw David , Sylvester Dennis 
Published: August 2010

Soft errors in combinational logic circuits are emerging as a significant reliability problem for VLSI designs. Technology scaling trends indicate that the soft error rates (SER) of logic circuits will be dominant factor for future technology generations. SER mitigation in logic can be accomplished by optimizing either the gates inside a logic block or the flipflops present on the block boundaries. We present novel circuit optimization techniques that target these elements separately as well as in unison to reduce the SER of combinational logic circuits.
First, we describe the construction of a new class of flip-flop variants that leverage the effect of temporal masking by selectively increasing the length of the latching window thereby preventing faulty transients from being registered. In contrast to previous flip-flop designs that rely on logic duplication and complicated circuit design styles, the new variants are redesigned from the library flip-flop using efficient transistor sizing. We then propose a flip-flop selection method that uses slack information at each primary output node to determine the flip-flop configuration that produces maximum SER savings. Next, we propose a gate sizing algorithm that trades off SER reduction and area overhead. This approach first computes bounds on the maximum achievable SER reduction by resizing a gate. This bound is then used to prune the circuit graph, arriving at a smaller set of candidate gates on which we perform incremental sensitivity computations to determine the gates that are the largest contributors to circuit SER. Third, we propose a unified, co-optimization approach combining flip-flop selection with the gate sizing algorithm. The joint optimization algorithm produces larger SER reductions while incurring smaller circuit overhead than either technique taken in isolation. Experimental results on a variety of benchmarks show average SER reductions of 10.7X with gate sizing, 5.7X with flip-flop assignment, and 30.1X for the combined optimization approach, with no delay penalties and area overheads within 5-6%. The runtimes for the optimization algorithms are on the order of 1-3 minutes.
Tight bounds for clock synchronization
Authors: Lenzen Christoph , Locher Thomas , Wattenhofer Roger 
Published: August 2010

We present a novel clock synchronization algorithm and prove tight upper and lower bounds on the worst-case clock skew that may occur between any two participants in any given distributed system. More importantly, the worst-case clock skew between neighboring nodes is (asymptotically) at most a factor of two larger than the best possible bound. While previous results solely focused on the dependency of the skew bounds on the network diameter, we prove that our techniques are optimal also with respect to the maximum clock drift, the uncertainty in message delays, and the imposed bounds on the clock rates. The presented results all hold in a general model where both the clock drifts and the message delays may vary arbitrarily within pre-specified bounds.
Furthermore, our algorithm exhibits a number of other highly desirable properties. First, the algorithm ensures that the clock values remain in an affine linear envelope of real time. A better worst-case bound on the accuracy with respect to real time cannot be achieved in the absence of an external timer. Second, the algorithm minimizes the number and size of messages that need to be exchanged in a given time period. Moreover, only a small number of bits must be stored locally for each neighbor. Finally, our algorithm can easily be adapted for a variety of other prominent synchronization models.
Hyperorders and transclusion
Authors: Goulding James , Brailsford Timothy , Ashman Helen 
Published: August 2010

ZigZag is a unique hyperstructural paradigm designed by the hypertext pioneer Ted Nelson. It has piqued a lot of interest in the hypertext community in recent years because of its aim of revolutionizing electronic access to information and knowledge bases. In ZigZag information is stored in cells that are arranged into lists organized along unlimited numbers of intersecting sets of associations called dimensions. To this infrastructure a mechanism of transclusion is added, allowing the data stored in cells to span, and hence be utilized, in different contexts. Proponents of ZigZag claim that it is a flexible and universal structure for information representation, and yet the system has not been widely adopted and has been implemented even more rarely. In this paper we address the question of whether there are intrinsic theoretical reasons as to why this is the case.
While the basic features and specifications of ZigZag are well known, we delve in to the less understood area of its theoretical underpinnings to tackle this question. By modeling ZigZag within the framework of set theory we reveal a new class of hyperstructure that contains no referencable link objects whatsoever, instead grouping non-referencable binary associations into disjunct but parallel sets of common semantics (dimensions). We go on to further specialize these "dimensional models" into sets of finite partial functions, which are closed over a single domain, isolating the new class of hyperstructures we are calling hyperorders. This analysis not only sheds light on the benefits and limitations of the ZigZag hypermedia system, but also provides a framework to describe and understand a wider family of possible hyperstructure models of which it is an early example. Characteristics of Zigzag's transclusion mechanisms are also investigated, highlighting a previously unrecognized distinction, and potential irrevocable conflict, between two distinct uses of content reuse: instance and identity transclusion.
Pharmacokinetic/Pharmacodynamic Modeling Identifies SN30000 and SN29751 as Tirapazamine Analogues with Improved Tissue Penetration and Hypoxic Cell Killing in Tumors
Authors: Hicks Kevin O. , Siim Bronwyn G. , Jaiswal Jagdish K. , Pruijn Frederik B. , Fraser Annie M. , Patel Rita , Hogg Alison , Liyanage H.D. Sarath , Dorie Mary Jo , Brown J. Martin , Denny William A. , Hay Michael P. , Wilson William R. 
Published: August 2010

AbstractPurpose: Tirapazamine (TPZ) has attractive features for targeting hypoxic cells in tumors but has limited clinical activity, in part because of poor extravascular penetration. Here, we identify improved TPZ analogues by using a spatially resolved pharmacokinetic/pharmacodynamic (SR-PKPD) model that considers tissue penetration explicitly during lead optimization.Experimental design: The SR-PKPD model was used to guide the progression of 281 TPZ analogues through a hierarchical screen. For compounds exceeding hypoxic selectivity thresholds in single-cell cultures, SR-PKPD model parameters (kinetics of bioreductive metabolism, clonogenic cell killing potency, diffusion coefficients in multicellular layers, and plasma pharmacokinetics at well tolerated doses in mice) were measured to prioritize testing in xenograft models in combination with radiation.Results: SR-PKPD–guided lead optimization identified SN29751 and SN30000 as the most promising hypoxic cytotoxins from two different structural subseries. Both were reduced to the corresponding 1-oxide selectively under hypoxia by HT29 cells, with an oxygen dependence quantitatively similar to that of TPZ. SN30000, in particular, showed higher hypoxic potency and selectivity than TPZ in tumor cell cultures and faster diffusion through HT29 and SiHa multicellular layers. Both compounds also provided superior plasma PK in mice and rats at equivalent toxicity. In agreement with SR-PKPD predictions, both were more active than TPZ with single dose or fractionated radiation against multiple human tumor xenografts.Conclusions: SN30000 and SN29751 are improved TPZ analogues with potential for targeting tumor hypoxia in humans. Novel SR-PKPD modeling approaches can be used for lead optimization during anticancer drug development. Clin Cancer Res; 16(20); 4946–57. ©2010 AACR.
The Importance of Ice Vertical Resolution for Snowball Climate and Deglaciation
Authors: Abbot Dorian S. , Eisenman Ian , Pierrehumbert Raymond T. 
Published: August 2010

AbstractSea ice schemes with a few vertical levels are typically used to simulate the thermodynamic evolution of sea ice in global climate models. Here it is shown that these schemes overestimate the magnitude of the diurnal surface temperature cycle by a factor of 2–3 when they are used to simulate tropical ice in a Snowball earth event. This could strongly influence our understanding of Snowball termination, which occurs in global climate models when the midday surface temperature in the tropics reaches the melting point. A hierarchy of models is used to show that accurate simulation of surface temperature variation on a given time scale requires that a sea ice model resolve the e-folding depth to which a periodic signal on that time scale penetrates. This is used to suggest modifications to the sea ice schemes used in global climate models that would allow more accurate simulation of Snowball deglaciation.
A Simple Method to Evolve Daily Ground Temperatures from Surface Air Temperatures in Snow-Dominated Regions
Authors: Cheng Yiwei , Stieglitz Marc , Pan Feifei 
Published: August 2010

AbstractA simple model is developed to evolve daily ground temperatures from surface air temperatures (SATs) in snow-dominated areas. Ground surface temperatures (GSTs) are calculated by propagating the daily SAT through the snowpack, and attenuating the signal amplitude. Subsequent subsurface heat transfer is then modeled using the analytical solution of the one-dimensional heat conduction equation. The thermal impacts of nonconductive heat transfer processes and seasonal freeze thaw are implicitly represented by the time-dependent apparent thermal diffusivity of the subsurface. The model is tested in four snow-dominated regions: Barrow, Council, Ivotuk (all in Alaska) and Reynolds Creek Experimental Watershed (in Idaho). The model captures the seasonal evolution of the ground temperature at all sites. The model demonstrates the feasibility of simulating subsurface temperatures using only air temperature and snow depth.
Observations of Turbulence within a Natural Surf Zone
Authors: Ruessink B. G. 
Published: August 2010

Abstract
Here, the Reynolds stresses 〈u′w′〉 and 〈υ′w′〉, where u′, υ′, and w′ are the cross-shore, alongshore, and vertical turbulence velocities, respectively, and the angle brackets represent time averaging, are used to diagnose turbulence dynamics beneath natural breaking surf-zone waves. The data were collected at Truc Vert Beach, France, during a 12-day period in 1–3-m water depth with strong cross-shore and alongshore currents under high-energy wave conditions (offshore significant wave heights ranged between 2 and 8 m). The 〈u′w′〉 term is predominantly negative, increases with the ratio of wave height Hs to water depth h (∼degree of wave breaking), and decreases in magnitude toward the bed. This supports the view that the cross-shore shear stress is due to breaking-induced vortices that transport high-speed cross-shore flow downward and disintegrate close to the bed. The occasional positive sign of 〈u′w′〉 within the lower 15%–20% of the water column indicates that sometimes surface-generated turbulence is overwhelmed by bed-generated turbulence, but the conditions when this happens are not clear from the data. The term 〈υ′w′〉 is persistently of opposite sign to the alongshore mean current and decreases with height above the seabed, implying that 〈υ′w′〉 is due to bottom boundary layer processes rather than surface-generated turbulence. The bottom drag coefficient amounted to 1.6 × 10−3, similar to earlier observations. As in other high-Reynolds-number geophysical flows, time series of u′w′ and υ′w′ comprise intermittently large, short-duration (here, ∼1 s) stress events that in the data contribute considerably to the net stress in only 3%–15% of the time. The data further show that the turbulent kinetic energy is depth uniform and increases with Hs/h. The depth-averaged Froude-scaled turbulent kinetic energy beneath surf-zone bores is 0.025, a factor of 2 to 3 less than observed beneath regular laboratory waves.